The potential role of postoperative radiation therapy (PORT) for patients who have completely resected, stage III nonsmall cell lung cancer (NSCLC) with N2 disease remains controversial. By using population-based data, the authors of this report compared the survival of a concurrent cohort of elderly patients who had N2 disease treated with and without PORT.

By using the Surveillance, Epidemiology, and End Results (SEER) registry linked to Medicare records, 1307 patients were identified who had stage III NSCLC with N2 lymph node involvement diagnosed between 1992 and 2005. Propensity scoring methods and instrumental variable analysis were used to compare the survival of patients who did and did not receive PORT after controlling for selection bias.

Overall, 710 patients (54%) received PORT. Propensity score analysis indicated that PORT was not associated with improved survival in patients with N2 disease (hazard ratio [HR], 1.11; 95% confidence interval [CI], 0.97-1.27). Analyses that were limited to patients who did or did not receive chemotherapy, who received intermediate-complexity or high-complexity radiotherapy planning, or adjusted for time trends produced similar results. The instrumental variable estimator for the absolute improvement in 1-year and 3-year survival with PORT was −0.04 (95% CI, −0.15 to 0.08) and −0.08 (95% CI, −0.24 to 0.15), respectively.

The current data suggested that PORT is not associated with improved survival for elderly patients with N2 disease. These findings have important clinical implications, because SEER data indicate that a large percentage of elderly patients currently receive PORT despite the lack of definitive evidence about its effectiveness. The potential effectiveness of PORT should be evaluated further in randomized controlled trials. Cancer 2011;. © 2011 American Cancer Society.

Socioeconomic status represents an established barrier to health care access. Age, sex, and race may also play a role. The authors examined whether these affect the access to high-volume hospitals for uro-oncologic procedures in the United States.

Within the Nationwide Inpatient Sample (NIS), the authors focused on radical prostatectomy (RP), radical cystectomy, and nephrectomy (Nx) performed within the 5 most contemporary years (2003-2007). Logistic regression models were used to estimate the impact of the primary predictors on the likelihood of receiving care at a high-volume hospital.

Between 2003 and 2007, 62,165 RP, 6557 radical cystectomy, and 28,062 Nx cases were recorded within the NIS. Patient age (P = .001), year of surgery (P = .001), Charlson Comorbidity Index (P ≤ .025), median Zip Code income (highest vs lowest quartile, P = .001), and insurance status (private vs Medicare, P = .008) were independent predictors of being treated at high-volume institutions. Moreover, black race was an independent predictor of decreased utilization of high-volume institutions for radical cystectomy (P = .012), and female sex was an independent predictor of decreased utilization of high-volume institutions for Nx (P = .016).

On average, old, sick, poor, and Medicare patients were less likely to be treated at high-volume hospitals for uro-oncologic surgery. Similarly, black patients were less likely to have a radical cystectomy at a high-volume hospital, and female patients were less likely to have an Nx at a high-volume hospital. Selective referral of individuals who are less likely to receive care at such institutions may represent a health care priority intended to optimize outcomes across all population strata. Cancer 2012. © 2012 American Cancer Society.

Acute myeloid leukemia (AML) is comprised of several bone marrow-based cancers and is the most common type of leukemia in the United States. The etiology of AML is not well understood. A case-control study was conducted at The University of Texas M. D. Anderson Cancer Center to investigate associations between lifestyle characteristics and the risk of AML in Texas.

This study included 638 adult patients with de novo AML (cases) and a group of 636 matched controls. Interviewer-administered questionnaires were used to collect demographic and occupational data. The distribution of cases by World Health Organization (WHO) subtype was 71 patients (11%) with recurrent cytogenetic abnormalities (AML-RCA), 134 patients (21%) with multilineage dysplasia (AML-MD), and 389 patients (61%) with AML not otherwise categorized (AML-NOC). Multivariate logistic regression analyses were performed among all AML cases and among both sexes and each WHO subgroup.

Among men, heavy smoking (≥30 pack-years; odds ratio [OR], 1.86) and occupational solvent exposure at low levels (OR, 2.87) or moderate/high levels (OR, 4.13) statistically significantly increased the risk of AML. Among women, obesity (OR, 1.62) and solvent exposure to low levels (OR, 2.73) or moderate/high levels (OR, 3.90) increased the risk of AML. Across WHO subtypes, obesity was associated with a statistically significantly increased risk of AML-RCA (OR, 3.15), whereas solvent exposure increased the risk in all subtypes at low levels (AML-RCA: OR, 4.11; AML-MD: OR, 2.54) and moderate/high levels (AML-RCA: OR, 5.13; AML-MD: OR, 3.02). A joint effect between smoking and solvent exposure was observed, and the highest risk was observed among smokers who had solvent exposure (OR, 4.51).

The current results suggested that several factors play a role in AML predisposition with possible joint effects. Risk profiles for AML differed by sex and WHO subtype. Cancer 2012. © 2012 American Cancer Society.

The annual incidence of chronic myeloid leukemia (CML) in the United States is approximately 4800 cases. With the success of tyrosine kinase inhibitor (TKI) therapy, the all-cause annual mortality rate was reduced to 2%. Therefore, the prevalence of CML is increasing over time. Estimating the CML prevalence and plateau prevalence is important in the implementation of health care strategies and future therapeutic trials. The objective of this report was to estimate the increasing prevalence and plateau prevalence of CML in future years.

The prevalence of CML was estimated based on several parameters: the annual mortality rate on TKI therapy compared with a age-matched, normal population; the incidence of CML; the anticipated population growth in the United States; and aging of the population.

On the basis of these calculations, the mortality ratio of patients with CML compared with an age-matched normal population was approximately 1.53. The estimated prevalence of CML is approximately 70,000 in 2010, 112,000 in 2020, 144,000 in 2030, 167,000 in 2040, and 181,000 in 2050, when it will reach a near plateau prevalence.

The current results indicated that the prevalence of CML will continue to increase to reach a near plateau prevalence 35 times the annual incidence. These estimates should be considered in health care policies and in the design of future studies in CML. Cancer 2012. © 2012 American Cancer Society.

The objective of this study was to evaluate racial cancer disparities in Georgia by calculating and comparing mortality-to-incidence ratios (MIRs) by health district and in relation to geographic factors.

Data sources included cancer incidence (Georgia Comprehensive Cancer Registry), cancer mortality (Georgia Vital Records), and health factor (County Health Rankings) data. Age-adjusted incidence and mortality rates were calculated by cancer site (all sites combined, lung, colorectal, prostate, breast, oral, and cervical) for 2003-2007. MIRs and 95% confidence intervals were calculated overall and by district for each cancer site, race, and sex. MIRs were mapped by district and compared with geographic health factors.

In total, 186,419 incident cases and 71,533 deaths were identified. Blacks had higher MIRs than whites for every cancer site evaluated, and especially large differentials were observed for prostate, cervical, and oral cancer in men. Large geographic disparities were detected, with larger MIRs, chiefly among blacks, in Georgia compared with national data. The highest MIRs were detected in west and east central Georgia, and the lowest MIRs were detected in and around Atlanta. Districts with better health behavior, clinical care, and social/economic factors had lower MIRs, especially among whites.

More fatal cancers, particularly prostate, cervical, and oral cancer in men were detected among blacks, especially in central Georgia, where health behavior and social/economic factors were worse. MIRs are an efficient indicator of survival and provide insight into racial cancer disparities. Additional examination of geographic determinants of cancer fatality in Georgia as indicated by MIRs is warranted. Cancer 2012. © 2012 American Cancer Society

Disparities based on insurance status in the American health care system are well established. However, to the authors' knowledge, this is the first study to evaluate variables that may explain differences based on payer type in the outcomes after surgery for spinal metastases.

Data from the Nationwide Inpatient Sample (2005-2008) were retrospectively extracted. Patients ages 18 to 64 years who underwent surgery for spinal metastases were included. Multivariate logistic regression was performed to calculate the adjusted odds of in-hospital death and the development of a complication for Medicaid recipients and for those without insurance compared with privately insured patients. All analyses were adjusted for differences in patient age, gender, primary tumor histology, socioeconomic status, hospital bed size, and hospital teaching status.

A total of 2157 hospital admissions were evaluated. The adjusted odds of in-hospital death were significantly higher for Medicaid recipients (crude rate: 6.5%; odds ratio [OR], 1.79; 95% confidence interval [95% CI], 1.11-2.88 [P = .02]) and uninsured patients (crude rate: 7.7%; OR, 2.15; 95% CI, 1.04-4.46 [P = .04]) compared with privately insured patients (crude rate: 3.8%). Complication rates were also significantly higher for Medicaid recipients (OR, 1.34; 95% CI, 1.04-1.72 [P = .02]). However, after also adjusting for acuity of presentation, the odds of in-hospital death were not significantly different for Medicaid (OR, 1.38; 95% CI, 0.86-2.21 [P = .18]) or uninsured patients (OR, 1.86; 95% CI, 0.90-3.83 [P = .09]); in addition, complication rates did not appear to differ significantly.

This nationwide study suggests that disparities based on insurance status for patients undergoing surgery for spinal metastases may be attributable to a higher acuity of presentation. Cancer 2012. © 2012 American Cancer Society

There is a strong need to determine the best technique for O⁶-methylguanine-DNA-methyltranferase (MGMT) analysis, because MGMT status is currently used in clinical trials and occasionally in routine clinical practice for glioblastoma patients.

The authors compared analytical performances and predictive values of 5 techniques in a series of 100 glioblastoma patients who received standard of care treatment (Stupp protocol).

MGMT promoter was considered methylated in 33%, 33%, 42%, and 60% of patients by methylation-sensitive high-resolution melting, MethyLight, pyrosequencing (with an optimal risk cutoff at 8% for the average percentage of the 5 CpGs tested), and methylation-specific polymerase chain reaction (MS-PCR), respectively. Fifty-nine percent of the samples had <23% (the optimal risk cutoff) of MGMT-positive tumor cells. The best predictive values for overall survival (OS), after adjustment for age and performance status, were obtained by pyrosequencing (hazard ratio [HR], 0.32; P < .0001), MS-PCR (HR, 0.37; P < .0001), and immunohistochemistry (HR, 0.43; P = .0005) as compared with methylation-sensitive high-resolution melting (HR, 0.52 P = .02) and MethyLight (HR, 0.6; P = .05). For progression-free survival (PFS), the best predictive values were obtained with pyrosequencing (HR, 0.35; P < .0001), methylation-sensitive high-resolution melting (HR, 0.46; P = .002), and MS-PCR (HR, 0.49; P = .002). Combining pyrosequencing and immunohistochemistry slightly improved predictive power for OS, but not for PFS. Poor reproducibility and interobserver variability were, however, observed for immunohistochemistry.

Good prediction of survival in addition to high reproducibility and sensitivity made pyrosequencing the best among the 5 techniques tested in this study. Cancer 2012. © 2012 American Cancer Society

Ethical concerns about phase 1 trials persist. Important conceptual advances have been made in understanding concepts used to describe misunderstanding. However, a systematic, empirical evaluation of the frequency of misunderstanding incorporating recent developments is lacking.

The authors queried 95 participants in phase 1 trials to provide a more sophisticated estimate of the proportion who had therapeutic misconception (TM), defined as misunderstanding the research purpose or how research differs from individualized care, and therapeutic misestimation (TMis), defined as incorrectly estimating the chance of a research trial benefit as >20% or underestimating risk as 0%.

Sixty-five of 95 respondents (68.4%) had TM, which was associated in a multivariate analysis with lower education and family income (P = .008 and P = .001, respectively), but TM was not associated with the vulnerability of having hardly any treatment options. Eighty-nine of 95 respondents (94%) had TMis, although only 18% reported this was a factual estimate. Although the risks of investigational agents and those exacerbated by research, such as uncertain outcomes, were mentioned (39% and 41% of respondents, respectively), risks novel to research, such as research biopsies, were rarely mentioned (3% of respondents). Although most of these respondents believed that their chance of benefit was greater and that their risk was lower than the population chance (optimists) (54.6%), a substantial minority of respondents (37.6%) were pessimists.

TM continues to be prevalent. Estimates of personal benefit were not usually meant to report facts, it remains unknown whether respondents in the current study had TMis. Although they are not more vulnerable, phase 1 participants need improved understanding of key TM concepts, with attention to risks that are not present in standard of care. Cancer 2012. © 2012 American Cancer Society

Adenoid cystic carcinoma (ACC) of the head and neck (ACCHN) is a rare tumor of minor salivary, parotid, and submandibular glands. The biologic behavior of the disease is poorly understood, and nonsurgical treatment strategies have yet to be standardized. The long-term prognosis continues to be guarded, with an estimated 10-year survival of <60%. Population-based studies examining ACC are scarce. The authors aimed to analyze incidence rates and survival outcomes for patients diagnosed with ACCHN using national population-based data.

Data were obtained from the US National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Newly diagnosed ACCHN cases reported to SEER from 1973 through 2007 were categorized according to their sex, race, age, year of diagnosis, marital status, treatment interventions, primary tumor site, and disease stage. Incidence of ACCHN and postdiagnosis survival were examined over time and compared across different demographic and disease-related categories.

The authors identified 3026 patients with ACCHN. The mean age at diagnosis among those cases was 57.4 years (range, 11-99 years). Analyses of incidence data demonstrated a decline in ACCHN rates between 1973 and 2007, noted across all sexes and races with no detectable inflexion points. The overall 5-year, 10-year, and 15-year survival outcomes for ACCHN patients were 90.3%, 79.9%, and 69.2%, respectively. Females, patients with localized disease, and younger patients were found to have significantly better survival across all time periods (all comparison-specific log-rank P values <0.001). Multivariate analyses revealed better prognosis among women compared with men (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.65-0.82), among married compared with unmarried individuals (HR, 0.81; 95% CI, 0.71-0.91), with certain sites of origin and stage of disease (HR, 2.788; 95% CI, 2.36-3.29), and in those who had surgery of the primary tumor site (HR, 0.45; 95% CI, 0.37-0.54).

The overall incidence of ACC is declining. The noted differences in survival based on sex, marital status, site of origin, and treatment intervention require further investigation. Cancer 2012. © 2012 American Cancer Society

In clinical trials, combined 5-fluorouracil (5FU) plus oxaliplatin improves the survival of patients who have resected, stage III colon cancer with manageable toxicity. However, the tolerability of this in the general population of patients with colon cancer is uncertain.

Adverse outcomes were compared in patients with stage III colon cancer who received either 5FU or 5FU/oxaliplatin within 120 days of undergoing resection versus a control group of patients with stage II colon cancer who did not receive chemotherapy in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database and in data from the New York State Cancer Registry linked to Medicare and Medicaid. Hospitalizations, emergency room (ER) visits, and outpatient adverse events (AEs) were measured in claims from 30 days to 9 months after patients underwent resection. Multiple logistic regression was used to calculate adjusted odds ratios of events by treatment. Propensity score matching was used to minimize selection bias.

Adverse outcomes were more frequent for chemotherapy recipients. AE rates were higher in patients who received 5FU/oxaliplatin (81%) compared with patients who received 5FU alone (72%), in the SEER-Medicare data. The effect of oxaliplatin on AEs was greater in older patients: The odds ratio was 2.10 (95% confidence interval, 1.53-2.87) for patients aged ≥75 years versus 1.75 (95% confidence interval, 1.39-2.21) for patients aged <75 years. ER use was high in Medicaid patients (83% of those who received chemotherapy), but neither ER use nor hospitalization was increased by oxaliplatin. The 60-day mortality rate was 1% to 3% for patients who received 5FU alone and 1% to 2% for patients who received combined 5FU/oxaliplatin.

The incremental harms of adjuvant chemotherapy with 5FU/oxaliplatin versus 5FU alone were modest in patients with stage III colon cancer who were insured by Medicare and Medicaid. The additional harms in patients aged ≥75 years largely were restricted to outpatient events and did not extend to an increased rate of hospitalization or early death. Cancer 2012. © 2012 American Cancer Society

E7974, a synthetic analog of hemiasterlin, interacts with the tubulin molecule and overcomes resistance to other antitubulin drugs (taxanes and vinca alkaloids).

In a phase 1 study, E7974 was given intravenously over a 2- to 5-minute infusion on day 1 of every 21-day cycle. Adult patients with advanced refractory solid tumors who had adequate organ function and Eastern Cooperative Oncology Group performance status 0 to 2 were eligible for this study. A modified Fibonacci schema was used. The maximal tolerated dose (MTD) was the dose where <2 of 6 patients developed a dose-limiting toxicity (DLT).

Twenty-eight patients (19 men and 9 women; median age, 64 years) treated at different cohort dose levels (0.18 mg/m², 0.27 mg/m², 0.36 mg/m², 0.45 mg/m², and 0.56 mg/m²) received a total of 66 courses of E7974. The MTD was established at 0.45 mg/m², where 1 of 6 patients experienced DLT (grade 4 febrile neutropenia). Of the 17 refractory colon cancer patients with a median of 3 prior treatments, stable disease was seen in 7 patients (41%). There were no tumor responses. Median progression-free survival was 1.2 months, and median overall survival was 6.7 months. In pharmacokinetic analysis, E7974 was characterized by a fast and moderately large distribution (37.95-147.93 L), slow clearance (2.23-7.15 L/h), and moderate to slow elimination (time to half-life, 10.4-30.5 hours).

This study shows that E7974 once every 21-day cycle shows antitumor activity in patients with refractory solid tumors. The recommended phase 2 dose is 0.45 mg/m². Cancer 2012. © 2012 American Cancer Society

Prior studies raise concern about gender bias in cancer research, including insufficient inclusion of women or men, or studying women and men differently. The 1993 National Institutes of Health Revitalization Act aimed to eliminate gender bias in medicine. To examine changes in medical and psychological literature, this study reviews gender representation in biomedical treatment studies and psychosocial survivorship studies published in a single year.

Research published in Cancer in 2007, and all empirical psychological studies about cancer published that year, provided a 15-year update to findings reported by Meyerowitz and Hart. The gender distribution and context of included articles were coded and compared with findings from 1983 and 1992.

Across biomedical studies, 34.3% of subjects were women (vs 47% of new cancers and 48% of cancer deaths). Among men, 41.3% had sex-specific cancers (vs 12.5% [1983] and 12.3% [1992]). Among women, 46.1% had sex-specific cancers (vs 69.1% [1983] and 64.6% [1992]). Fewer women (36.8%) were represented in sex-nonspecific cancer studies (vs 41.4% [1983] and 42.5% [1992]); however, fewer studies had a significant (>20%) gender disparity. Across psychosocial studies, representation of men increased to 47.9% (vs 30.4% [1983] and 29.9% [1992]). The proportion of men in studies of feelings/relationships increased to 47% (vs 22.9% [1992]); the proportion of women in studies assessing physical/functional ability increased to 58.3% (vs 45.4%).

Women remain under-represented in sex-nonspecific biomedical research, whereas men's representation in sex-specific research increased substantially. Psychosocial research trends suggest movement from research questions supporting traditional stereotypes that women feel and men act. Cancer 2012. © 2012 American Cancer Society

Treatment of high-risk localized prostate cancer remains inadequate. The authors performed a phase 2 multicenter trial of neoadjuvant docetaxel plus bevacizumab before radical prostatectomy.

Eligibility included any of the following: prostate-specific antigen (PSA) >20 ng/mL or PSA velocity >2 ng/mL/y, cT3 disease, any biopsy Gleason score 8 to 10, and Gleason score 7 with T3 disease by endorectal magnetic resonance imaging (MRI) at 1.5 T. Also, those with ≥50% biopsy cores involved and either Gleason score 7, PSA >10, or cT2 disease were eligible. Patients were treated with docetaxel 70 mg/m² every 3 weeks for 6 cycles and bevacizumab 15 mg/m² every 3 weeks for 5 cycles. The primary endpoint was partial response by endorectal MRI.

Forty-one patients were treated. Median age was 55 years (range, 40-66 years). Baseline characteristics included: median PSA, 10.1 ng/mL; cT2, 49%, cT3, 32%; and Gleason score 8 to 10, 73%. Thirty-eight of 41 (93%) patients completed all 6 cycles. Grade ≥3 adverse events were rare, although 3 of 41 (7%) experienced febrile neutropenia. Twelve patients (29%; 95% confidence interval [CI], 16%-45%) achieved a >50% reduction in tumor volume, and 9 patients (22%; 95% CI, 11%-38%) achieved a >50% post-treatment decline in PSA. Thirty-seven of the 41 patients underwent radical prostatectomy; there were no complete pathologic responses.

Neoadjuvant docetaxel and bevacizumab is safe, and results in reductions in both tumor volume and serum PSA, in men with high-risk localized prostate cancer. The role of neoadjuvant chemotherapy in prostate cancer, and perioperative antiangiogenic therapy in general, requires further elucidation through ongoing and planned trials. Cancer 2012;. © 2012 American Cancer Society.

In patients with nonsmall cell lung carcinoma (NSCLC) who have with pathologic N1 (pN1) lymph node status, the prognostic significance of segmental lymph node (level 13) metastasis and/or subsegmental lymph node (level 14) metastasis is unknown.

Lymph node metastasis patterns were analyzed in 230 patients with NSCLC who had pN1 status. Clinical outcomes were examined for 230 patients with pN1 status and 700 patients with pN0 status. The pN1 group was stratified into 4 subgroups according to the highest level of lymph node involvement.

The 5-year disease-free survival (5DFS) rates for pN1 and pN0 patients were 50.1% and 90.5%, respectively. The highest level of lymph node involvement was a significant prognostic indicator; the 5DFS rates for patients with pN1 status who had level 13/14, lobar (level 12), interlobar (level 11), and hilar (level 10) lymph node metastasis were 69.4%, 46.4%, 46.7%, and 37%, respectively. Patient outcomes were significantly worse for those with pN1 status who had only level 13/14 lymph node metastasis than for patients with pN0 status (P = .0034), and outcomes were significantly worse for patients with pN1 status who had level 11/12 lymph node metastasis than for patients who had only level 13/14 lymph node metastasis (P = .021). The median number of level 13/14 lymph nodes examined was 3 (range, 0-22 level 13/14 lymph nodes), and metastases to these lymph nodes were detected in 61% of patients who had pN1 status. A single lymph node pN1 disease, single-level pN1 status, and squamous cell carcinoma histopathology also were indicators of a better patient outcome.

The current results indicated that the highest level of lymph node involvement may be used to stratify the outcome of patients who have NSCLC with pN1 status. Patients with pN1 status who had only level 13/14 lymph node metastasis had an intermediate 5DFS rate between that of patients with pN0 status and other patients with pN1 status. Routine examination of level 13/14 lymph nodes is important for accurate pathologic staging and for the predicting clinical outcome of patients with NSCLC. Cancer 2012;. © 2012 American Cancer Society.

Standard therapy for older patients with acute myeloid leukemia (AML) has a poor outcome. The authors have designed a combination of clofarabine plus low-dose cytarabine followed by a prolonged consolidation alternating with decitabine.

Sixty patients with a median age of 70 years (range, 60-81 years) with newly diagnosed AML were included. They received clofarabine 20 mg/m² intravenously daily for 5 days plus cytarabine 20 mg subcutaneously twice daily for 10 days. Responding patients continued for up to 17 courses of consolidation therapy including decitabine.

Forty of 59 evaluable patients responded (66%). Complete remission rate was 58%. Median relapse-free survival (RFS) was 14.1 (95% confidence interval [CI], 6.9 to not estimable), and median overall survival (OS) was 12.7 months (95% CI, 8.8 to not estimable). Median OS of responding patients (complete response [CR]/CR with platelet count <100 × 109/L) was 24.2 months (95% CI, 17 to not estimable). Compared with a historical group of patients who received clofarabine plus low-dose cytarabine with a shorter consolidation, RFS was not statistically different. Induction mortality was low (7% at 8 weeks) and toxicities manageable.

Clofarabine plus low-dose cytarabine alternating with decitabine in consolidation is active in older patients with newly diagnosed AML. The benefits of a prolonged consolidation remain unproven. Cancer 2012;. © 2012 American Cancer Society.

Cisplatin reduces plasma ghrelin levels through the 5-hydroxytryptamine (5-HT) receptor. This may cause cisplatin-induced gastrointestinal disorders and hinders the continuation of chemotherapy. The authors of this report conducted a prospective, randomized phase 2 trial to evaluate the effects of exogenous ghrelin during cisplatin-based chemotherapy.

Forty-two patients with esophageal cancer who were receiving cisplatin-based neoadjuvant chemotherapy were assigned to either a ghrelin group (n = 21) or a placebo group (n = 21). They received either intravenous infusions of synthetic human ghrelin (3 μg/kg) or saline twice daily for 1 week with cisplatin administration. The primary endpoint was changes in oral calorie intake, and the secondary endpoints were chemotherapy-related adverse events; appetite visual analog scale (VAS) scores; changes in gastrointestinal hormones and nutritional status, including rapid turnover proteins, and quality of life (QoL) estimated with the European Organization for Research and Treatment of Cancer QoL core questionnaire (QLQ-C30).

Two patients were excluded from the final analysis: One patient suspended ghrelin administration because of excessive diaphoresis, and another patient in the placebo group failed to monitor the self-questionnaire. Food intake and appetite VAS scores were significantly higher in the ghrelin group than in the placebo group (18.2 ± 5.2 kcal/kg/day vs 12.7 ± 3.4 kcal/kg/day [P = .001] and 6.2 ± 0.9 vs 4.1 ± 0.9 [P < .0001], respectively). Patients in the ghrelin group had fewer adverse events during chemotherapy related to anorexia and nausea than patients in the control group. Significant deterioration was noted after chemotherapy in the placebo group in QoL scores, appetite, nausea and vomiting, and global health status.

Short-term administration of exogenous ghrelin at the start of cisplatin-based chemotherapy stimulated food intake and minimized adverse events. Cancer 2012;. © 2012 American Cancer Society.

The presence of single-nucleotide polymorphisms (SNPs) within the 3′-untranslated regions of genes could affect the binding between a microRNA (miRNA) and its target, with consequences on gene expression regulation. Considering the important role of miRNAs in carcinogenesis, it is hypothesized here that these SNPs could also affect the individual risk of colorectal cancer (CRC).

To test this hypothesis, a list was developed of 140 somatically mutated genes deduced from previous works on the mutome of the CRC. A further selection was conducted of SNPs within target sites for miRNAs that are expressed only in the colorectum (the colorectal microRNAome) and having adequate population frequencies. This yielded 12 SNPs that were genotyped in a case-control association study on 717 colorectal cases and 1171 controls from the Czech Republic.

Statistically significant associations were found between the risk of CRC and the variant alleles of KIAA0182 (rs709805) (odds ratio = 1.57; 95% confidence interval = 1.06-2.78, for the variant homozygotes) and NUP210 genes (rs354476) (odds ratio = 1.36; 95% confidence interval = 1.02-1.82, for the variant homozygotes).

The results support the study hypothesis and highlight the importance of SNPs within miRNA-dependent regulatory regions. Further studies on the role exerted by NUP210 and KIAA0182 in colorectal carcinogenesis are warranted. Cancer 2012;. © 2012 American Cancer Society.

The treatment of diffuse tenosynovial giant cell tumor (TGCT) requires extensive surgical resection of the hypertrophic synovium and multiple soft tissue masses yet still may result in high rates of local failure. The authors of this report examined their experience in treating patients with advanced/multiply recurrent TGCT with a combination of surgery and external-beam radiotherapy.

Fifty patients who were treated for TGCT with radiotherapy and surgery from 1972 to 2006 were identified. Patient demographics, radiotherapy treatment parameters, surgical treatment, and oncologic and functional outcomes were evaluated. All patients had pathologic review at presentation and required at least 1 year follow-up.

Forty-nine patients had diffuse TGCT with both intra-articular and extra-articular disease (1 had malignant TGCT). Twenty-eight patients (56%) were referred after at least 1 local recurrence. Thirty patients (60%) underwent at least 2 operations before radiotherapy. The mean dose of radiation delivered was 39.8 gray. At a mean follow-up of 94 months (range, 19-330 months), 47 patients (94%) had not developed a recurrence or had stable disease/signal characteristics on serial cross-sectional imaging (for those patients who had gross residual disease at the time of radiotherapy). Two patients required subsequent total hip arthroplasty because of progressive osteoarthritis, and there were 4 cases of avascular necrosis (only 1 post-treatment). Forty-one patients had good/excellent function.

For patients with extensive or multiple local relapses or when surgery alone would result in a large burden of residual disease or major functional loss, the addition of moderate-dose adjuvant radiotherapy provided excellent local control while maintaining good function with low treatment-related morbidity. Cancer 2011;. © 2011 American Cancer Society.

Serum and plasma levels of vascular endothelial growth factor (VEGF) correlate with prognosis in patients with metastatic breast cancer (MBC). VEGF binds to 2 receptors on endothelial cells, VEGFR-1 and VEGFR-2. RPI.4610 (Angiozyme0) is an antiangiogenic ribozyme targeting the VEGFR-1 mRNA. Preclinical and phase 1 studies suggested that RPI.4610 is a well-tolerated agent with clinical activity in solid tumors. The authors' trial evaluated the efficacy of RPI.4610 in the treatment of patients with progressive MBC.

This phase 2, multicenter, single-arm study was designed to assess the objective response rate of RPI.4610 in patients with MBC who had experienced disease progression with at least 1 course of chemotherapy for MBC. Patients received daily subcutaneous injections of RPI.4610 100 mg/m² for 12 weeks.

Most patients (93%) had received at least 2 lines of chemotherapy previously; 69% of patients had received at least 3 lines of chemotherapy. Median follow-up was 2.76 months (range, 0.89-36.6 months). No partial responses nor complete responses were found. Median progression-free survival was 1.41 months (95% confidence interval [CI], 1.35-1.45). The median overall survival from start of treatment was 11.89 months (95% CI, 4.11-23.66). Treatment-related adverse events (AEs) were primarily grade 1 to 2 in intensity. Most common AEs were: injection site reactions, abdominal pain, anorexia, chromaturia, constipation, dyspnea, fatigue, headache, pain at the injection site, nausea, vomiting, and fever.

Although RPI.4610 demonstrated a well-tolerated safety profile, its lack of clinical efficacy precludes this drug from further development. Cancer 2012;. © 2012 American Cancer Society.

The discovery of distinct subsets of nonsmall cell lung cancer (NSCLC) characterized by activation of driver oncogenes has greatly affected personalized therapy. It is hypothesized that the dominant oncogene in NSCLC would be associated with distinct patterns of metastatic spread in NSCLC at the time of diagnosis.

A total of 209 consecutive patients with stage IV nonsquamous NSCLC with an EGFR (epidermal growth factor receptor) mutation (N = 39), KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation (N = 49), ALK (anaplastic lymphoma receptor tyrosine kinase) gene rearrangement (N = 41), or wild-type for all 3 (triple negative, N = 80) were included. The percentage of patients with metastatic disease at a given site was compared between each molecular cohort (EGFR, KRAS, or ALK) and the triple negative cohort.

ALK gene rearrangement was significantly associated with pericardial disease (odds ratio [OR] = 4.61; 95% confidence interval [CI] = 1.30, 16.37; P = .02) and pleural disease (OR = 4.80; 95% CI = 2.10, 10.97; P < .001). Patients with ALK gene rearrangements (OR = 5.50; 95% CI = 1.76, 17.18; P = .003) and patients with EGFR mutations (OR = 5.17; 95% CI = 1.63, 16.43; P = .006) were predisposed to liver metastasis compared to the triple negative cohort. No molecular cohort had a predisposition to pulmonary nodules, or adrenal, bone, or brain metastasis compared to the triple negative cohort. The mean number of metastatic disease sites in patients within the ALK rearranged cohort was significantly greater than that of the triple negative cohort (mean = 3.6 sites vs 2.5 sites, P < .0001).

The results support the hypothesis that the dominant molecular oncogenes in NSCLC are associated with different biological behaviors manifesting as distinct patterns of metastatic spread at the time of diagnosis. Cancer 2012;. © 2012 American Cancer Society.

Fluorescence in situ hybridization (FISH), using break-apart red (3′) and green (5′) ALK (anaplastic lymphoma kinase) probes, consistently shows rearrangements in <100% of tumor cells in ALK-positive (ALK+) nonsmall cell lung cancer (NSCLC). Increased copy numbers of fused and rearranged signals also occur. Here, correlations are explored between the percentage of ALK+ cells and signal copy number and their association with response to ALK inhibition.

Ninety ALK+ NSCLC cases were evaluated. The percentage of positive cells, pattern of positivity (split, single red, or both), and copy number of fused, isolated red and green signals were recorded. Thirty patients had received crizotinib.

Increased isolated red signal copy number (contributing to both single red and split patterns of positivity) correlated with a higher percentage of ALK+ cells (r = 0.743, P < .0001). Mean fused copy number was negatively associated with isolated red signal copy number (r = −0.409, P < .0001). Neither percentage of positive cells (r = 0.192, P = .3), nor copy number of isolated red signal (r = 0.274, P = .195) correlated with maximal tumor shrinkage with crizotinib.

The strong association between increased copy number of key ALK signals and percentage of positive cells suggests that the <100% rate of cellular positivity in ALK+ tumors is due to technical factors, not biological factors. In ALK+ tumors, neither the percentage of positive cells nor signal copy number appear to be informative variables for predicting benefit from ALK inhibition. The inverse relationship between fused and isolated red copy number suggests ALK+ may be a distinct “near-diploid” subtype of NSCLC that develops before significant chromosomal aneusomy occurs. Cancer 2012;. © 2012 American Cancer Society.

Continued smoking after a cancer diagnosis may adversely affect treatment effectiveness, subsequent cancer risk, and survival. The prevalence of continued smoking after cancer diagnosis is understudied.

In the multi-regional Cancer Care Outcomes Research and Surveillance cohort (lung cancer [N = 2456], colorectal cancer [N = 3063]), the authors examined smoking rates at diagnosis and 5 months after diagnosis and also study factors associated with continued smoking.

Overall, 90.2% of patients with lung cancer and 54.8% of patients with colorectal cancer reported ever smoking. At diagnosis, 38.7% of patients with lung cancer and 13.7% of patients with colorectal cancer were smoking; whereas, 5 months after diagnosis, 14.2% of patients with lung cancer and 9.0% of patients with colorectal cancer were smoking. Factors that were associated independently with continued smoking among patients with nonmetastatic lung cancer were coverage by Medicare, other public/unspecified insurance, not receiving chemotherapy, not undergoing surgery, prior cardiovascular disease, lower body mass index, lower emotional support, and higher daily ever-smoking rates (all P < .05). Factors that were associated independently with continued smoking among patients with nonmetastatic colorectal cancer were male sex, high school education, being uninsured, not undergoing surgery, and higher daily ever-smoking rates (all P < .05).

After diagnosis, a substantial minority of patients with lung and colorectal cancers continued smoking. Patients with lung cancer had higher rates of smoking at diagnosis and after diagnosis; whereas patients with colorectal cancer were less likely to quit smoking after diagnosis. Factors that were associated with continued smoking differed between lung and colorectal cancer patients. Future smoking-cessation efforts should examine differences by cancer type, particularly when comparing cancers for which smoking is a well established risk factor versus cancers for which it is not. Cancer 2012. © 2012 American Cancer Society.

In this phase 2 component of a multi-institutional, phase 2/3, randomized trial, the authors assessed the feasibility and preliminary efficacy of acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) in reducing radiation-induced xerostomia.

Patients with cancer of the head and neck who were 3 to 24 months from completing radiotherapy with or without chemotherapy (RT ± C) and who were experiencing xerostomia symptoms with basal whole saliva production ≥0.1 mL per minute and were without recurrence were eligible. Patients received twice weekly ALTENS sessions (24 sessions over 12 weeks) using a proprietary electrical stimulation unit. The primary study objective was to assess the feasibility of ALTENS treatment. Patients were considered compliant if 19 of 24 ALTENS sessions were delivered, and the targeted compliance rate was 85%. Secondary objectives measured treatment-related toxicities and the effect of ALTENS on overall radiation-induced xerostomia burden using the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS).

Of 48 accrued patients, 47 were evaluable. The median age was 60 years, 84% of patients were men, 70% completed RT ± C for >12 months, and 21% had previously received pilocarpine. Thirty-four patients completed all 24 ALTENS sessions, 9 patients completed 20 to 23 sessions, and 1 patient completed 19 sessions, representing a 94% total compliance rate. Six-month XeQOLS scores were available for 35 patients and indicated that 30 patients (86%) achieved a positive treatment response with a mean ± standard deviation reduction of 35.9% ± 36.1%. Five patients developed grade 1 or 2 gastrointestinal toxicity, and 1 had a grade 1 pain event.

The current results indicated that ALTENS treatment for radiation-induced xerostomia can be delivered uniformly in a cooperative, multicenter setting and produces possible beneficial treatment response. Given these results, the phase 3 component of this study was initiated. Cancer 2011. © 2011 American Cancer Society.

Insular thyroid cancer (ITC) is an uncommon, poorly differentiated thyroid malignancy. To date, there have been no population-level studies of the characteristics and outcomes of patients with ITC.

The authors used the Surveillance, Epidemiology, and End Results (SEER) database from 1999 to 2007 to compare the characteristics and prognosis of patients who had ITC with those of patients who had well differentiated thyroid cancer (WDTC) and anaplastic thyroid cancer (ATC). Data analyses were performed using chi-square tests, analyses of variance, log-rank tests, and multivariate regression.

There were 114 patients with ITC, 497 patients with ATC, and 34,021 patients with WDTC. The mean age of patients with ITC was 62.1 years versus 48.1 years for patients with WDTC and 69.5 years for patients with ATC (P < .001). The mean ITC tumor size was 5.9 cm versus 2.0 cm for WDTC and 6.4 cm for ATC (P < .001). Distant metastasis occurred in 31% of patients with ITC versus 4.5% of patients with WDTC and 59.1% of patients with ATC (P < .001). Insular histology was associated independently with compromised survival in the overall study sample (hazard ratio [HR], 2.1; P = .001). The 5-year disease-specific survival rate was 72.6%, 97.2%, and 9.1% for patients with ITC, WDTC, and ATC, respectively (P < .001). After adjustment, radioiodine therapy (HR, 0.15; 95% confidence interval, 0.04-0.5) and distant metastasis (HR, 15.3; 95% confidence interval, 3.7-62.2) were associated independently with ITC survival. The mortality rate was 7.1%, 12%, and 54.3% for patients with localized, regional, and distant stage ITC, respectively (P < .001). For patients who had ITC with distant metastasis, thyroidectomy and radioiodine therapy independently improved survival.

ITC is rare and aggressive. The current results indicated that its treatment should include total thyroidectomy and high-dose radioiodine for all patients and neck dissections for patients with lymph node disease. Early diagnosis and close surveillance are essential in the management of patients with ITC. Cancer 2011. © 2011 American Cancer Society.

Metastatic propensity of soft tissue sarcoma (STS) is heterogeneous and may be determined by gene expression patterns that do not correlate well with morphology. The authors have reported gene expression patterns that distinguish 2 broad classes of clear cell renal carcinoma (ccRCC-gene set), and other patterns that can distinguish heterogeneity of serous ovarian carcinoma (OVCA-gene set) and aggressive fibromatosis (AF-gene set); however, clinical follow-up data were not available for these samples.

In the current study, gene expression patterns in 73 samples of high-grade STS were examined using spotted cDNA microarray slides that contained ∼16,000 unique UniGene clusters. Approximately 50% of the genes present in the ccRCC-, OVCA-, and AF-gene sets were also represented in the data from this chip set, and these were combined to form a composite gene set of 278 probes.

Hierarchical clustering using this composite gene set suggested the existence of subsets of the STS samples. Analysis revealed differences in the time to development of metastatic disease between the clusters defined by the first branch point of the clustering dendrogram (P = .005), and also among the 4 different clusters defined by the second branch points (P = .001).

This approach suggests the existence of >2 subsets of high-grade pleomorphic STS, each with distinct clinical behavior. A composite gene set such as that described here may be useful to stratify STS in clinical trials, and may be of practical utility in patient management. Cancer 2012. © 2012 American Cancer Society.

There is limited information about the risk factors for ipsilateral breast tumor recurrence (IBTR) after patients undergo breast-conserving surgery plus radiotherapy (breast-conserving treatment [BCT]) subsequent to neoadjuvant chemotherapy (NAC). The objective of the current study was to analyze these risk factors.

The authors collected data from 375 patients who underwent BCT and received NAC and analyzed the risk of IBTR associated with undergoing BCT after NAC. The usefulness of the M. D. Anderson Prognostic Index (MDAPI) for IBTR also was validated using the current data set.

The median follow-up was 47.8 months, and the 4-year IBTR-free survival rate was 95.6%. Multivariate analysis demonstrated that estrogen receptor (ER) status and multifocality of the residual tumor were associated significantly with IBTR-free survival. In addition, patients who had ER-positive and human epidermal growth factor 2 (HER2)-negative tumors did not develop IBTR during the observation period. Although prognostic stratification according to MDAPI was relatively good for the prediction of IBTR in the study patients, the IBTR rate in the high-risk group was not very high and was lower than that in the intermediate-risk group. Multivariate analyses demonstrated that IBTR was an independent predictive factor for overall survival.

ER status and multifocality of the residual tumor after NAC were independent predictors of IBTR after BCT. The MDAPI was barely adaptable to the study patients in terms of predicting IBTR. Patients with ER-positive and HER2-negative tumors had a favorable prognosis, whereas patients who developed IBTR after NAC had significantly worse overall survival. The authors propose a new IBTR prognostic index using the 2 factors that were identified as predictive of IBTR: ER status and multifocality of the residual tumor. Cancer 2012. © 2012 American Cancer Society.

High-dose methotrexate (HDMTX)-induced acute kidney injury is a rare but life-threatening complication. The methotrexate rescue agent glucarpidase rapidly hydrolyzes methotrexate to inactive metabolites. The authors retrospectively reviewed glucarpidase use in pediatric cancer patients at their institution and evaluated whether subsequent resumption of HDMTX was tolerated.

Clinical data and outcomes of all patients who received glucarpidase after HDMTX administration were reviewed.

Of 1141 patients who received 4909 courses of HDMTX, 20 patients (1.8% of patients, 0.4% of courses) received 22 doses of glucarpidase. The median glucarpidase dose was 51.6 U/kg (range, 13-65.6 U/kg). At the time of administration, the median plasma methotrexate concentration was 29.1 μM (range, 1.3-590.6 μM). Thirteen of the 20 patients received a total of 39 courses of HDMTX therapy after glucarpidase. The median time to complete methotrexate excretion was 355 hours (range, 244-763 hours) for the HDMTX course during which glucarpidase was administered, 90 hours (range, 66-268 hours) for the next HDMTX course, and 72 hours (range, 42-116 hours) for subsequent courses. The median peak serum creatinine level during these HDMTX courses was 2.2 mg/dL (range, 0.8-9.6 mg/dL), 0.8 mg/dL (range, 0.4-1.6 mg/dL), and 0.6 mg/dL (range, 0.4-0.9 mg/dL), respectively. One patient experienced nephrotoxicity upon rechallenge with HDMTX. Renal function eventually returned to baseline in all patients, and no patient died as a result of methotrexate toxicity.

The current results indicated that it is possible to safely resume HDMTX therapy after glucarpidase treatment for HDMTX-induced acute kidney injury. Cancer 2011. © 2011 American Cancer Society.

Health-related quality of life (HRQOL), body mass index (BMI), and physical activity (PA) levels have all been associated with prognosis following breast cancer and may explain partially the higher mortality for breast cancer in certain racial/ethnic subgroups. In this study, associations between PA, BMI, and HRQOL by race were examined in a sample of breast cancer survivors.

Measures of PA, BMI, and HRQOL as well as demographic and medical characteristics of women (N = 3013, 13% nonwhite) who participated in the Women's Healthy Eating and Living Study were assessed at baseline. Analysis of covariance was used to examine the relationship between PA and obesity with HRQOL outcomes. Statistical tests were 2-sided.

African American women were less likely to meet guidelines for PA and more likely to be obese than women from other ethnic groups (P < .05). In adjusted models, women who met guidelines for PA reported significantly higher physical health composite (point differences ranged from 10.5 to 21.2 points, all P < .05) and vitality (point differences ranged from 9.9 to 16.5 points, all P < .05) scores than those who did not, regardless of race/ethnicity. Associations between obesity and HRQOL were mixed with fewer associations for Asian American and African American women and stronger associations for whites.

Breast cancer survivors from racially and ethnically diverse populations have lower levels of PA and higher rates of obesity that are generally associated with poorer HRQOL. Culturally sensitive PA and weight loss interventions may improve these lifestyle characteristics and result in improved HRQOL. Cancer 2012. © 2012 American Cancer Society.

Several promising molecular-targeted drugs are used for advanced renal cancers. However, complete remission is rarely achieved, because none of the drugs targets a key molecule that is specific to the cancer, or is associated with “oncogene addiction” (dependence on one or a few oncogenes for cell survival) of renal cancer. Recently, an anaplastic lymphoma kinase (ALK) fusion, vinculin-ALK, has been reported in pediatric renal cell carcinoma (RCC) cases who have a history of sickle cell trait. In this context, ALK inhibitor therapy would constitute a therapeutic advance, as has previously been demonstrated with lung cancer, inflammatory myofibroblastic tumors, and anaplastic large cell lymphomas.

Anti-ALK immunohistochemistry was used to screen 355 tumor tissues, using the intercalated antibody-enhanced polymer (iAEP) method. The cohort consisted of 255 clear cell RCCs, 32 papillary RCCs, 34 chromophobe RCCs, 6 collecting duct carcinomas, 10 unclassified RCCs, 6 sarcomatoid RCCs, and 12 other tumors.

Two patients (36- and 53-year-old females) were positive for ALK as determined by iAEP immunohistochemistry. Using 5′- rapid amplification of complementary DNA ends, we detected TPM3-ALK and EML4-ALK in these tumors. The results of this study were confirmed by fluorescence in situ hybridization assays. The 2 ALK-positive RCCs were unclassified (mixed features of papillary, mucinous cribriform, and solid patterns with rhabdoid cells) and papillary subtype. They comprised 2.3% of non–clear cell RCCs (2 of 88) and 3.7% of non–clear cell and nonchromophobe RCCs (2 of 54).

The results of this study indicate that ALK fusions also exist in adult RCC cases without uncommon backgrounds. These findings confirm the potential of ALK inhibitor therapy for selected cases of RCC. Cancer 2012. © 2012 American Cancer Society.

The objective of this study was to examine clinical outcomes and patterns of failure in patients with early stage breast cancer who developed an ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) using accelerated partial breast irradiation (APBI).

In total, 1440 patients (1449 tumors) with early stage breast cancer who underwent BCT were treated with the MammoSite device to deliver APBI (34 Gray [Gy] in 3.4-Gy fractions). One thousand two hundred fifty-five patients (87%) had invasive breast cancer (IBC) (median tumor size, 10 mm), and 194 patients (13%) had ductal carcinoma in situ (DCIS) (median tumor size, 8 mm). The median follow-up was 60 months.

Fifty patients (3.5%) developed an IBTR for a 5-year actuarial rate of 3.61% (3.65% for IBC and 3.36% for DCIS). It was determined that 36 recurrences (72%) represented new primary cancers, and 14 recurrences (28%) represented recurrences of the index lesion. Of the 32 recurrences with known histology, 78% were IBC, and 22% were DCIS. After IBTR, 28 of 38 patients (74%) underwent salvage mastectomy, and 9 of 38 patients (26%) had a second attempt at BCT. Adjuvant therapies included tamoxifen in 8 patients (16%) and systemic chemotherapy in 6 patients (12%). The 3-year rates of disease-free survival, cause-specific survival, and overall survival after IBTR were 58.7%, 92.1%, and 80.5%, respectively.

With 5 years of follow-up, APBI produced clinical outcomes and patterns of failure comparable to those achieved with whole breast irradiation. Patients who developed an IBTR after APBI had excellent 3-year survival outcomes after salvage treatments. Cancer 2012. © 2012 American Cancer Society.

It is believed that gonadal and extragonadal germ cell tumors (GCTs) arise from primordial germ cells and may have similar etiopathogenesis. Unlike testicular GCTs, there has been limited comprehensive population-based analysis of ovarian and extragonadal GCTs.

All malignant GCTs and all central nervous system (CNS) GCTs with benign and uncertain behavior that were registered in England in the age group 0 to 84 years from 1979 to 2003 were included in the current study. Incidence rates were calculated and adjusted to the world standard population.

There were 33,364 GCTs (92.5% testes, 3.9% ovary, 3.2% extragonadal) in individuals aged 0 to 84 years. The CNS was the most common extragonadal site. An initial peak in incidence at ages 0 to 4 years of nongerminomas was observed at all sites except ovary. Second incidence peaks between ages 10 to 39 years that were more marked among males also were observed at all sites. The ages at these incidence peaks varied by site and were 10 to 14 years (CNS), 15 to 19 years (ovary), 25 to 29 years (other extragonadal sites), and 30 to 34 years (testes). A statistically significant increase in incidence over time was observed in germinomas (testes, CNS) and nongerminomas (testes, ovary).

The age-incidence patterns observed suggested a common initiation of GCTs in embryonic/fetal life with variable rates of tumor progression as a result of subsequent events that may be site specific. The authors concluded that future genetic studies should consider GCTs from all sites to enable a better understanding of their etiology. Cancer 2012. © 2012 American Cancer Society.

High-dose chemotherapy combined with autologous stem-cell transplantation (ASCT) is the standard therapy for refractory/relapsed aggressive lymphoma. In the era of rituximab-containing frontline regimens, it is becoming more challenging to salvage patients in this setting, and novel approaches are required. This is a randomized study evaluating the safety and efficacy of standard-dose ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy (Z-BEAM) and ASCT in refractory/relapsed aggressive lymphoma.

Forty-three patients with CD20⁺-aggressive lymphoma were randomized to a treatment arm (Z-BEAM, n = 22) or control arm (BEAM alone, n = 21). Ibritumomab tiuxetan was given at 0.4 mCi/kg on day −14 before ASCT.

Patient characteristics, engraftment kinetics, and toxicity profile were similar between the 2 groups. Two-year progression-free survival (PFS) for all patients was 48% (95% confidence interval, 32%-64%): 59% and 37% after Z-BEAM and BEAM alone, respectively (P = .2). Multivariate analysis identified advanced age (hazard ratio [HR], 8.3; P = .001), high-risk disease (relapse within 12 months of diagnosis and/or secondary International Prognostic Index >2; HR, 2.8; P = .04), positive positron emission tomography-computed tomography pretransplant (HR, 2.4; P = .07), and BEAM alone (HR, 2.8; P = .03) as poor prognostic factors. Intermediate-risk patients with 1 or 2 risk factors had better PFS with Z-BEAM compared with BEAM: 69% and 29%, respectively (P = .07). Two-year overall survival was 91% and 62% after Z-BEAM and BEAM, respectively (P = .05). Similar prognostic factors determined survival. The HR for BEAM alone in the multivariate analysis was 8.1 (P = .01).

Standard-dose ibritumomab tiuxetan combined with BEAM high-dose chemotherapy is safe and possibly more effective than BEAM alone as a conditioning regimen for ASCT in the era of rituximab-containing chemotherapy regimens. Cancer 2012. © 2012 American Cancer Society.

Although most patients with myelodysplastic syndrome (MDS) exhibit bone marrow hypercellularity, a subset of them present with a hypocellular bone marrow. Specific factors associated with poor prognosis have not been investigated in patients with hypocellular MDS.

The authors studied a cohort of 253 patients with hypocellular MDS diagnosed at The University of Texas MD Anderson Cancer Center between 1993 and 2007 and a cohort of 1725 patients with hyper-/normocellular MDS diagnosed during the same time period.

Patients with hypocellular MDS presented more frequently with thrombocytopenia (P < .019), neutropenia (P < .001), low serum β-2 microglobulin (P < .001), increased transfusion dependency (P < .001), and intermediate-2/high-risk disease (57% vs 42%, P = .02) compared with patients with hyper-/normocellular MDS. However, no difference in overall survival was observed between the 2 groups (P = .28). Multivariate analysis identified poor performance status (Eastern Cooperative Oncology Group ≥2), low hemoglobin (<10 g/dL), unfavorable cytogenetics (−7/7q or complex), increased bone marrow blasts (≥5%), and high serum lactate dehydrogenase (>600 IU/L) as adverse independent factors for survival.

A new prognostic model based on these factors was built that segregated patients into 3 distinct risk categories independent of International Prognostic Scoring System (IPSS) score. This model is independent from the IPSS, further refines IPSS-based prognostication, and may be used to develop of risk-adapted therapeutic approaches for patients with hypocellular MDS. Cancer 2012. © 2012 American Cancer Society.

For limited-stage diffuse large B-cell lymphoma (DLBCL), treatment decisions are often influenced by toxicity profiles. One strategy that minimizes chemotherapy-induced toxicities is abbreviated chemotherapy plus consolidation involved-field radiotherapy (IFRT). Involved-node radiotherapy (INRT) is a new concept to DLBCL, aimed to reduce radiotherapy-induced toxicities. We retrospectively review the long-term outcomes of limited-stage DLBCL treated with abbreviated systemic therapy and radiotherapy focusing on field size: IFRT versus INRT.

The British Columbia Cancer Agency Lymphoid Cancer Database was used to identify patients diagnosed with limited-stage DLBCL (stage I/II, without B-symptoms; bulk < 10 cm) from 1981 to 2007. Patients were prescribed 3 cycles of chemotherapy plus IFRT (1981-1996) or INRT≤5 cm (1996-2007), defined as INRT to the prechemotherapy involved nodes with margins ≤ 5 cm.

A total of 288 patients were identified: 56% were aged >60 years, 34% had stage II disease, 55% had extranodal disease, 19% had elevated lactate dehydrogenase levels, and 15% received rituximab. The two radiotherapy groups were IFRT (138 patients; 48%) and INRT≤5cm (150 patients; 52%); median follow-up was 117 and 89 months, respectively. Distant relapse was the most common site of failure in both groups. After INRT≤5 cm, marginal recurrence was infrequent (2%). Time to progression (P = .823), progression-free survival (P = .575), and overall survival (P = .417) were not significantly different between the radiotherapy cohorts. Radiotherapy field size was not a significant prognostic factor on multivariate analyses.

This research is the first known body of work to apply the concept of INRT to limited-stage DLBCL. Reducing the field size from IFRT to INRT≤5 cm maintains a low marginal recurrence risk with no impact on overall outcome. Cancer 2011. © 2011 American Cancer Society.

HER-2/neu overexpression plays a critical role in breast cancer development, and its expression in ductal carcinoma in situ (DCIS) is associated with development of invasive breast cancer. A vaccine targeting HER-2/neu expression in DCIS may initiate immunity against invasive cancer.

A HER-2/neu dendritic cell vaccine was administered to 27 patients with HER-2/neu–overexpressing DCIS. The HER-2/neu vaccine was administered before surgical resection, and pre- and postvaccination analysis was conducted to assess clinical results.

At surgery, 5 of 27 (18.5%) vaccinated subjects had no evidence of remaining disease, whereas among 22 subjects with residual DCIS, HER-2/neu expression was eradicated in 11 (50%). When comparing estrogen receptor (ER)^neg with ER^pos DCIS lesions, vaccination was more effective in hormone-independent DCIS. After vaccination, no residual DCIS was found in 40% of ER^neg subjects compared with 5.9% in ER^pos subjects. Sustained HER-2/neu expression was found in 10% of ER^neg subjects compared with 47.1% in ER^pos subjects (P = .04). Postvaccination phenotypes were significantly different between ER^pos and ER^neg subjects (P = .01), with 7 of 16 (43.8%) initially presenting with ER^posHER-2/neu^pos luminal B phenotype finishing with the ER^posHER-2/neu^neg luminal A phenotype, and 3 of 6 (50%) with the ER^negHER-2/neu^pos phenotype changing to the ER^negHER-2/neu^neg phenotype.

Results suggest that vaccination against HER-2/neu is safe and well tolerated and induces decline and/or eradication of HER-2/neu expression. These findings warrant further exploration of HER-2/neu vaccination in estrogen-independent breast cancer and highlight the need to target additional tumor-associated antigens and pathways. Cancer 2011. © 2011 American Cancer Society.

This study sought to evaluate patient-reported health-related quality of life following proton therapy for prostate cancer in men ≤60 years old.

Between August 2006 and January 2010, 262 hormone-naive men ≤60 years old were treated with definitive proton therapy for prostate cancer. Before treatment and every 6 months after treatment, patients filled out the Expanded Prostate Index Composite (EPIC) and the International Index of Erectile Function (IIEF) questionnaires. Potency was defined as successful sexual intercourse in the prior month or an EPIC sexual summary (SS) score ≥60.

Median follow-up was 24 months; 90% of men completed follow-up EPIC forms within the last year. For EPIC urinary, bowel, and hormone subscales, the average decline from baseline to 2 years was ≤5 points, except for bowel function (5.2 points). SS scores declined 12.6 points after 2 years. Potency rates declined by 11% from baseline at 2 years, but 94% of men were potent with a baseline IIEF > 21, body mass index < 30, and no history of diabetes. At 2 years after treatment, only 1.8% of men required a pad for urge incontinence. On multivariate analysis, factors associated with a significant decline in SS score were mean penile bulb dose ≥40 cobalt Gy equivalents (P = .012) and radiation dose ≥80 cobalt Gy equivalents (P = .017); only diabetes was significantly associated with impotence (P = .015).

Young men undergoing proton therapy for treatment of prostate cancer have excellent outcomes with respect to erectile dysfunction, urinary incontinence, and other health-related quality of life parameters during the first 2 years after treatment. Longer follow-up is needed to confirm these findings. Cancer 2012. © 2012 American Cancer Society.

Receipt of chemotherapy at the end of life (EOL) is considered an indicator of poor quality of care for medical oncology. The objective of this study was to characterize the use of radiotherapy (RT) in patients with nonsmall cell lung cancer (NSCLC) during the same period.

Treatment characteristics of patients with incurable NSCLC who received RT at the EOL, defined as within 14 days of death, were analyzed from the National Comprehensive Cancer Network NSCLC Outcomes Database.

Among 1098 patients who died, 10% had received EOL RT. Patients who did and did not receive EOL RT were similar in terms of sex, race, comorbid disease, and Eastern Cooperative Oncology Group performance status. On multivariable logistic regression analysis, independent predictors of receiving EOL RT included stage IV disease (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.09-3.83) or multiorgan involvement (OR, 1.75; 95% CI, 1.08-2.84) at diagnosis, age <65 years at diagnosis (OR, 1.85; 95% CI, 1.21-2.83), and treating institution (OR, 1.24-5.94; P = .02). Nearly 50% of EOL RT recipients did not complete it, most commonly because of death or patient preference.

In general, EOL RT was received infrequently, was delivered more commonly to younger patients with more advanced disease, and often was not completed as planned. There also was considerable variation in its use among National Comprehensive Cancer Network institutions. Next steps include expanding this research to other cancers and settings and investigating the clinical benefit of such treatment. Cancer 2012. © 2012 American Cancer Society.

There are conflicting data regarding age as a prognostic factor in osteosarcoma. The authors conducted a study evaluating the impact of age on prognosis in children and young adults with osteosarcoma enrolled on North American cooperative group trials.

Patients with high-grade osteosarcoma of any site enrolled on North American cooperative group trials CCG-7943, POG-9754, INT-0133, and AOST0121 were included in this study. Primary tumor site, age, sex, ethnicity, histologic response, and presence of metastatic disease at diagnosis were evaluated for their impact on overall survival (OS) and event-free survival (EFS).

A total of 1054 patients were eligible and had complete data available for the study. Age was not significantly associated with any other presenting covariate analyzed except sex. Age 18 or older was associated with a statistically significant poorer EFS (P = .019) and OS (P = .043). The 10-year EFS and OS in patients <10, 10 to 17, and ≥18 years old were 55%, 55%, 37% and 68%, 60%, 41%, respectively. The poorer EFS in patients ≥18 years old was because of an increased rate of relapse. Presence of metastatic disease at diagnosis, poor histologic response, and pelvic tumor site were also associated with a poorer prognosis. In multivariate analysis, age continued to be associated with poorer EFS (P = .019) and OS (P = .049).

In osteosarcoma, age 18 to 30 years is associated with a statistically significant poorer outcome because of an increased rate of relapse. Poorer outcome in adolescent and young adult patients is not explained by tumor location, histologic response, or metastatic disease at presentation. Cancer 2012;. © 2012 American Cancer Society.

The early detection of oral squamous cell carcinoma (OSCC) is important, and a screening test with high sensitivity and specificity is urgently needed. Therefore, in this study, the authors investigated the methylation status of tumor-related genes with the objective of establishing a noninvasive method for the detection of OSCC.

Oral rinse samples were obtained from 34 patients with OSCC and from 24 healthy individuals (controls). The methylation status of 13 genes was determined by using methylation-specific polymerase chain reaction analysis and was quantified using a microchip electrophoresis system. Promoter methylation in each participant was screened by receiver operating characteristic analysis, and the utility of each gene's methylation status, alone and in combination with other genes, was evaluated as a tool for oral cancer detection.

Eight of the 13 genes had significantly higher levels of DNA methylation in samples from patients with OSCC than in controls. The genes E-cadherin (ECAD), transmembrane protein with epidermal growth factor-like and 2 follistatin-like domains 2 (TMEFF2), retinoic acid receptor beta (RARβ), and O-6 methylguanine DNA methyltransferase (MGMT) had high sensitivity (>75%) and specificity for the detection of oral cancer. OSCC was detected with 100% sensitivity and 87.5% specificity using a combination of ECAD, TMEFF2, RARβ, and MGMT and with 97.1% sensitivity and 91.7% specificity using a combination of ECAD, TMEFF2, and MGMT.

The aberrant methylation of a combination of marker genes present in oral rinse samples was used to detect OSCC with >90% sensitivity and specificity. The detection of methylated marker genes from oral rinse samples has great potential for the noninvasive detection of OSCC. Cancer 2012. © 2012 American Cancer Society.

The objective of this study was to examine patterns of care and survival in a population-based sample of patients with head and neck cancer (HNC) who were treated in the community or in hospitals that had residency training programs.

Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program were used to sample 1317 patients aged ≥20 years with invasive squamous HNC who were diagnosed during 2004 and who had vital status available through 2008.

Treatment and survival were influenced by tumor site and disease stage. Patients who had stage I/II cancer of the oral cavity generally underwent surgery; patients with stage III oral cavity disease underwent surgery and received radiation; and patients with stage IV oral cavity disease underwent surgery and received chemoradiation. Patients with early stage cancer of the oropharynx either underwent surgery or received radiation and chemotherapy, and patients with late/unstaged oropharyngeal disease primarily received radiation and chemotherapy. Patients with early stage cancer of the larynx mainly received radiation alone, and patients with late stage laryngeal disease generally received chemoradiation. Cisplatin-based regimens were used most frequently. Overall, taxanes were used in 32% of regimens, and cetuximab was used in <3% of regimens. Patients aged ≥50 years, those with a Charlson comorbidity score ≥1, those with stage IV disease, and those with cancer located in the oral cavity or larynx had poorer survival. Although facilities with residency training programs treated more black patients and more patients with late stage disease, when adjusted for other factors, survival rates were similar to those reported in facilities with no such programs.

Therapy generally followed accepted standards for 2004. Findings in particular tumor sites and stages may reflect the variability that still exists for the treatment of HNC. The use of taxanes and cetuximab is expected to increase based on new evidence of benefit. Reducing treatment-related toxicities and long-term functional deficits will be critical and especially important with the increase in human papillomavirus-related cancers. In addition, further attempts to improve survival for older patients are needed. Cancer 2012. © 2012 American Cancer Society.

The authors tested whether an educational video on the goals of care in advanced cancer (life-prolonging care, basic care, or comfort care) helped patients understand these goals and had an impact on their preferences for resuscitation.

A survey of 80 patients with advanced cancer was conducted before and after they viewed an educational video. The outcomes of interest included changes in goals of care preference and knowledge and consistency of preferences with code status.

Before viewing the video, 10 patients (13%) preferred life-prolonging care, 24 patients (30%) preferred basic care, 29 patients (36%) preferred comfort care, and 17 patients (21%) were unsure. Preferences did not change after the video, when 9 patients (11%) chose life-prolonging care, 28 patients (35%) chose basic care, 29 patients (36%) chose comfort care, and, 14 patients (18%) were unsure (P = .28). Compared with baseline, after the video presentation, more patients did not want cardiopulmonary resuscitation (CPR) (71% vs 62%; P = .03) or ventilation (80% vs 67%; P = .008). Knowledge about goals of care and likelihood of resuscitation increased after the video (P < .001). Of the patients who did not want CPR or ventilation after the video augmentation, only 4 patients (5%) had a documented do-not-resuscitate order in their medical record (kappa statistic, −0.01; 95% confidence interval, −0.06 to 0.04). Acceptability of the video was high.

Patients with advanced cancer did not change care preferences after viewing the video, but fewer wanted CPR or ventilation. Documented code status was inconsistent with patient preferences. Patients were more knowledgeable after the video, reported that the video was acceptable, and said they would recommend it to others. The current results indicated that this type of video may enable patients to visualize “goals of care,” enriching patient understanding of worsening health states and better informing decision making. Cancer 2012. © 2012 American Cancer Society.

In the United States, black males have an annual death rate from prostate cancer that is 2.4 times that of white males. The reasons for this are poorly understood.

Using the Surveillance, Epidemiology, and End Results–Medicare database, 77,038 black and white males aged >65 years were identified with a first primary diagnosis of prostate cancer between 1995 and 2005, as well as 49,769 controls. The racial gap in mortality was decomposed to differential incidence and stage-specific prostate cancer mortality. The importance of various clinical and socioeconomic factors to each of these components was then examined.

The estimated mortality gap for prostate cancer–specific mortality was 1320 more cases per 100,000 males among black than white men. This gap was due to higher prostate cancer incidence among black males (76%) and higher stage-specific mortality once diagnosed (24%). Differences in prostate-specific antigen testing, comorbidities, and income explained 29% of the difference in metastatic cancer incidence but none of the racial gap for local/regional incidence. Conditional on diagnosis, tumor characteristics explained 50% of the racial gap, comorbidities an additional 4%, choice of treatment and physician 17%, and socioeconomic factors 15%. Overall, approximately 25% of the racial gap in mortality and 86% of the gap in mortality conditional on diagnosis could be explained.

More frequent prostate-specific antigen testing for black and low-income males could potentially reduce the prostate cancer mortality gap through earlier diagnosis of tumors that otherwise may become metastatic. More aggressive treatment of prostate cancer, especially in poor communities, might also reduce the gap. Cancer 2012; © 2012 American Cancer Society.

In patients with multiple primary melanomas (MPM), mean tumor thickness tends to decrease from the first melanoma to the second melanoma, and prognosis may be improved compared with the prognosis for patients who have a single primary melanoma (SPM). In this study, the authors compared the clinicopathologic features of patients with MPM and SPM to better characterize the differences between these 2 groups and to determine whether or not there is an inherent difference in tumor aggression.

In total, 788 patients with melanoma who were enrolled prospectively in the Interdisciplinary Melanoma Cooperative Group database from 2002 to 2008 were studied. Patients with SPM and with MPM were compared with regard to clinical and primary melanoma characteristics.

Of 788 patients with melanoma, 61 patients (7.7%) had 2 or more primary melanomas. The incidence of developing a second primary melanoma 1 year and 5 years after initial melanoma diagnosis was 4.1% and 8.7%, respectively, and most of the risk accumulated within the first year. The incidence of MPM was greater in patients aged ≥60 years than in those aged ≤60 years. The absence or presence of mitosis and other tumor characteristics did not differ significantly between patients with SPM and patients with MPM (P = .61).

No difference was observed in the presence or absence of mitoses, a marker of tumor proliferation, in SPM and MPM. Because it has been demonstrated that the presence of mitosis is a powerful prognostic marker, the current findings suggested that the tumors behave similarly in patients with SPM and patients with MPM. The authors concluded that differences in tumor thickness and prognosis between SPM and MPM more likely are caused by factors other than tumor biology, such as increased surveillance. Cancer 2012;. © 2012 American Cancer Society.

The AJCC staging system and post-operative nomograms use patient and tumor characteristics to provide prognostic estimates after resection of retroperitoneal sarcoma (RPS). While these variables help to predict survival at the time of diagnosis and resection, the applicability of these prognostic factors to survivors of RPS remains unknown. We hypothesized that the variables evaluated in the current staging system and post-operative nomograms would have limited ability to predict conditional survival in patients surgically treated for RPS.

A retrospective study was conducted using National Cancer Institute-sponsored tumor registries. We identified 1,199 patients who underwent surgical resection for non-metastatic RPS from 1988 to 2007. Conditional survival was defined as time-specific estimates conditioned on living a certain number of years post-diagnosis. Cox proportional hazards regression was used to assess the impact of various factors on sarcoma-specific survival (SSS) at baseline and up to 5 years after diagnosis.

Older age, male gender, histologic subtype, and high tumor grade predicted worse SSS at the time of diagnosis. After 1 year of survival, older age, male gender, and histologic subtype were no longer significant predictors of conditional survival. Only high grade tumors remained a significant predictor of worse prognosis after 5 years of survival (HR 1.95).

This population-based study demonstrates that the factors which are predictive of survival at baseline lose significance after one year of survival. Conditional survival estimates allow clinicians to provide survivors with more meaningful prognostic estimates that may impact surveillance schedules and streamline adjuvant therapy decisions and design of future clinical trials. Cancer 2012; © 2012 American Cancer Society.

BRCA1/2 testing is not recommended for children, as risk reduction measures and screening are not generally recommended before 25 years old (YO). Little is known about the prevalence and predictors of parent communication to offspring and how offspring respond to this communication.

Semi-structured interviews were conducted with parents who had BRCA1/2 testing and at least 1 child <25 YO. Logistic regressions were utilized to evaluate associations with communication. Framework analysis was utilized to analyze open-ended responses.

A total of 253 parents completed interviews (61% response rate), reporting on 505 offspring. Twenty-nine percent of parents were BRCA1/2 mutation carriers. Three hundred thirty-four (66%) offspring learned of their parent's test result. Older offspring age (P ≤ .01), offspring gender (female, P = .05), parents' negative test result (P = .03), and parents' education (high school only, P = .02) were associated with communication to offspring. The most frequently reported initial offspring responses were neutral (41%) or relief (28%). Thirteen percent of offspring were reported to experience concern or distress (11%) in response to parental communication of their test results. Distress was more frequently perceived among offspring learning of their parent's BRCA1/2 positive or variant of uncertain significance result.

Many parents communicate their BRCA1/2 test results to young offspring. Parents' perceptions of offspring responses appear to vary by offspring age and parent test result. A better understanding of how young offspring respond to information about hereditary risk for adult cancer could provide opportunities to optimize adaptive psychosocial responses to risk information and performance of health behaviors, in adolescence and throughout an at-risk life span. Cancer 2012;. © 2012 American Cancer Society.

Primary tumors of the spinal cord, spinal meninges, and cauda equina are relatively rare, and a paucity of population-based data exist on tumors in these sites. This study intends to augment the current literature by examining incidence of these tumors on a national level.

Data from central cancer registries in the National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results (SEER) programs for 2004-2007 (covering 99.2% of US population) and 1999-2007 (covering 89.4% of US population) were analyzed. Analyses for diagnosis years 2004-2007 included cases of malignant and nonmalignant primary spinal cord, spinal meninges, and cauda equina tumors. Descriptive statistics including estimated age-adjusted incidence rates standardized to the 2000 US standard population were conducted for both malignant and nonmalignant primary spinal tumors from cases diagnosed during 2004-2007 as well as trend analyses on malignant cases of primary spinal tumors (n = 5103) for cases diagnosed during 1999-2007 using SEER*Stat 6.6.2 software.

There were 2576 cases of malignant primary spinal tumors and 9136 cases of nonmalignant primary spinal tumors in 2004-2007. The incidence of malignant and nonmalignant primary spinal tumors combined differed by age, sex, race, and ethnicity. Results of trend analyses indicated that malignant primary spinal tumors have been stable throughout the 1999-2007 period.

This large population-based study adds new insights into the descriptive epidemiology of primary spinal cord, spinal meninges, and cauda equina tumors by providing in-depth analyses of the incidence of these tumors on a national level. Cancer 2011;. © 2011 American Cancer Society.

Bortezomib has demonstrated efficacy in patients with relapsed B-cell non-Hodgkin lymphoma (NHL) both alone and in combination with other agents; however, limited data exist regarding its toxicity in combination with common frontline therapies for indolent NHL. A phase 1 study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (R-CHOP) was conducted in patients with untreated follicular lymphoma (FL) and other indolent NHLs.

Nineteen patients, including 10 patients with FL, were enrolled. The median patient age was 59 years (range, 29-71 years). Seven patients had a FL International Prognostic Index score ≥3. R-CHOP with the vincristine dose capped at 1.5 mg was administered on a 21-day cycle for 6 to 8 cycles, and 1 of 3 dose levels of bortezomib (1.0 mg/m² [n = 1], 1.3 mg/m² [n = 6], or 1.6 mg/m² [n = 12]) was administered on days 1 and 8 of each cycle using a Bayesian algorithm for dose escalation.

The maximum tolerated dose (MTD) of bortezomib with modified R-CHOP was reached at 1.6 mg/m². Dose-limiting toxicity was observed in 5 patients (1 patient at a bortezomib dose of 1.0 mg/m², 1 patient at a bortezomib dose of 1.3 mg/m², and 3 patients at a bortezomib dose of 1.6 mg/m²). Neuropathy occurred in 16 patients (84%), including 2 patients (11%) who experienced grade 3 sensory neuropathy. Grade 4 hematologic toxicity occurred in 4 patients. Of 19 evaluable patients, 100% responded, and the complete response rate was 68%. At a median follow-up of 32 months, the 3-year progression-free survival rate was 89.5%.

Bortezomib combined with modified R-CHOP produced high response rates without substantial increases in toxicity. A phase 2 study of R-CHOP and bortezomib given at this established MTD is currently ongoing. Cancer 2011;. © 2011 American Cancer Society.

Meta-analysis data demonstrate a 5% absolute survival benefit for neoadjuvant chemotherapy (NAC) using cisplatin-based combination regimens in the radical treatment of muscle-invasive bladder cancer (MIBC). However, there are no randomized, controlled trial data on the optimum regimen. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) is a dose-intense regimen that has the potential to minimize delays to definitive, potentially curative therapy. A retrospective analysis is presented of the efficacy and toxicity of AMVAC as NAC in patients with MIBC and its impact on the patient pathway.

Eighty consecutive patients with MIBC were treated with AMVAC as NAC by 2 UK multidisciplinary uro-oncology teams. Three or 4 cycles of AMVAC (methotrexate 30 mg/m², vinblastine 3 mg/m², doxorubicin 30 mg/m², and cisplatin 70 mg/m²) were given at 2-week intervals, with granulocyte colony-stimulating factor support, prior to either radical surgery or radical radiotherapy.

All planned cycles of chemotherapy were completed, without dose reduction or delay in 84% of patients. All 80 patients subsequently received their planned definitive therapy. Grade 3/4 toxicities were seen in 26% of the 42% of patients for whom toxicity data are available, including 12% grade 3/4 neutropenia. Pathological complete response to AMVAC was seen in 43% of 60 surgical patients. Objective radiological local response was seen in 83% of 57 evaluable patients. Two-year disease-free and overall survival were 65% and 77%, respectively.

AMVAC is safe and appears to be a well-tolerated and effective NAC regimen for MIBC. It minimizes delays to definitive treatment and produces excellent pathological and radiological response rates. It is an appropriate comparator for future randomized trials. Cancer 2011;. © 2011 American Cancer Society.

No previous prospective US study has examined whether the incidence of colorectal cancer (CRC) is disproportionately high in low socioeconomic status (SES) populations of both men and women. This study examined the relationship between both individual and area-level SES and CRC incidence, overall and by tumor location.

Data were obtained from the ongoing prospective National Institutes of Health-AARP Diet and Health Study of persons (50-71 years old) who resided in 6 US states and 2 metropolitan areas at baseline in 1995-1996. Incident CRCs were ascertained from tumor registries through December 2006. SES was measured by self-reported education and census-tract socioeconomic deprivation. Baseline and follow-up questionnaires collected detailed information on individual-level CRC risk factors including family history and health behaviors.

Among 506,488 participants analyzed, 7676 were diagnosed with primary invasive colorectal adenocarcinomas: 46.6% in the right colon, 26.7% in the left colon, and 25.9% in the rectum. The overall incidence of CRC was significantly higher among people who had low educational level or lived in low-SES neighborhoods, relative to respective highest-SES groups, even after accounting for other risk factors. These associations were stronger in the rectum than in left or right colon. In the right colon, there were no significant SES differences by either SES measure after accounting for covariates.

SES, assessed by either individual-level education or neighborhood measures, was associated with risk of CRC even after accounting for other risk factors. The relationship between SES and CRC was strongest in the rectum and weakest in the right colon. Cancer 2011;. © 2011 American Cancer Society.

The objective of this study was to evaluate the accuracy of the pathologic inclusion criteria from all contemporary adjuvant trials in predicting disease progression (DP) for renal cell carcinoma (RCC).

A retrospective review was conducted on 1363 patients treated surgically for M0 RCC at the Mayo Clinic (Rochester, MN), from 1990 to 2001. Clinicopathologic features were reviewed to determine eligibility for the following trials: ARISER, ASSURE, EVEREST, PROTECT, SORCE, and S-TRAC. DP was defined as local recurrence or distant metastasis after surgery. The ability of each trial's inclusion criteria to accurately predict DP was evaluated by the c (concordance) index.

From the Mayo Clinic cohort, we determined that 41%, 45%, 45%, 33%, 47%, and 23% of the patients would have been eligible for the ARISER, ASSURE, EVEREST, PROTECT, SORCE, and S-TRAC clinical trials, respectively. Overall, 23% of all patients experienced DP (n = 317). Among eligible patients, 53%, 44%, 44%, 57%, 43%, and 59% developed DP during follow-up and 10%, 6%, 6%, 13%, 6%, and 18% went onto DP while not being eligible for the ARISER, ASSURE, EVEREST, PROTECT, SORCE, and S-TRAC trials, respectively. The c index of each trial to accurately predict DP from the pathologic inclusion criteria of ARISER, ASSURE, EVEREST, PROTECT, SORCE, and S-TRAC were 0.751, 0.751, 0.751, 0.742, 0.745, and 0.691, respectively.

Although the pathologic inclusion criteria of contemporary adjuvant trials have notable differences, all 6 adjuvant trials demonstrated high predictive accuracy of DP. Overall, 43% to 59% of patients included for the adjuvant trials would develop DP, whereas 6% to 18% of patients excluded from the trials would develop DP during follow-up. Cancer 2011;. © 2011 American Cancer Society.

Capecitabine, an oral 5-fluorouracil (5-FU) prodrug, is widely used in the treatment of breast, colorectal, and gastric cancers. To guide the selection of patients with potentially the greatest benefit of experiencing antitumor efficacy, or, alternatively, of developing toxicities, identifying genomic predictors of capecitabine sensitivity could permit its more informed use.

The objective of this study was to perform capecitabine sensitivity genome-wide association studies (GWAS) using 503 well genotyped human cell lines from individuals representing multiple different world populations. A meta-analysis that included all ethnic populations then enabled the identification of novel germline determinants (single nucleotide polymorphisms [SNPs]) of capecitabine susceptibility.

First, an intrapopulation GWAS of Caucasian individuals identified reference SNP 4702484 (rs4702484) (within adenylate cyclase 2 [ADCY2]) at a level reaching genome-wide significance (P = 5.2 × 10⁻⁸). This SNP is located upstream of the 5 methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene, and it is known that the enzyme for MTRR is involved in the methionine-folate biosynthesis and metabolism pathway, which is the primary target of 5-FU-related compounds, although the authors were unable to identify a direct relation between rs4702484 and MTRR expression in a tested subset of cells. In the meta-analysis, 4 SNPs comprised the top hits, which, again, included rs4702484 and 3 additional SNPs (rs8101143, rs576523, and rs361433) that approached genome-wide significance (P values from 1.9 × 10⁻⁷ to 8.8 × 10⁻⁷). The meta-analysis also identified 1 missense variant (rs11722476; serine to asparagine) within switch/sucrose nonfermentable-related, matrix-associated, actin-dependent regulator of chromatin (SMARCAD1), a novel gene for association with capecitabine/5-FU susceptibility.

Toward the goal of individualizing cancer chemotherapy, the current study identified novel SNPs and genes associated with capecitabine sensitivity that are potentially informative and testable in any patient regardless of ethnicity. Cancer 2011;. © 2011 American Cancer Society.

To assess the potential mechanisms that may underlie increased local failure in triple negative (TN) breast cancers, an analysis was performed of the risk of residual carcinoma after lumpectomy with correlation to pathologic factors, including molecular phenotype.

A review of pathologic specimens was performed for women with invasive breast cancer treated with lumpectomy followed by reexcision. Data were collected on age; tumor size, grade, and nodal stage; estrogen receptor, progesterone receptor, and human endothelial growth factor receptor 2 (Her2); extensive intraductal component; lymphovascular invasion; margins; and reexcision findings. Univariate and multivariate logistic regression analyses were performed to evaluate for associations between pathologic features of the lumpectomy specimen and reexcision findings. Molecular phenotypes were defined by conventionally used immunohistochemical pattern.

Data were collected on 369 patients with breast cancer. The median age was 57 years, median tumor size was 1.5 cm, 36% had positive margins, 32% had positive lymph nodes, 73.5% had the luminal A subtype, 9.5% had the luminal B subtype, 4.5% were Her2-enriched, and 12.5% were TN. Overall, 32% of patients had invasive cancer in their reexcision specimens, and 51% of those with the TN subtype had residual invasive disease on reexcision compared with 30% to 31% for other subtypes. On univariate analysis, age, tumor size, margin status, lymphovascular invasion, nodal status, and TN subtype were associated with elevated risk of residual invasive cancer. On multivariate analysis using a forward stepwise model, TN subtype maintained significance, with an odds ratio of 3.28 (P = .002).

TN subtype has a statistically significant association with an increased risk of residual tumor. This suggests the putative increase in the risk of local failure in TN patients may be related to increased residual tumor burden. Cancer 2011;. © 2011 American Cancer Society.

Tumor neovascularization (TNV) is a common pathologic basis for malignant growth and metastasis. However, the mechanism of TNV pathogenesis is not fully understood. Ras homolog gene family, member A (RhoA), a Rho guanosine triphosphatase (GTPase) family member, may be involved in a hypoxia-induced vascular endothelial growth factor (VEGF) pathway that regulates TNV angiogenesis through an unclear mechanism.

The regulation of RhoA on p53, the p53 binding protein homolog murine double minute 2 (MDM2), and VEGF was analyzed in hypoxic MCF-7 cells using Western blot analysis, real-time polymerase chain reaction (PCR) analysis, coimmunoprecipitation, and immunofluorescence staining assays. Changes in proliferation, invasion, migration, stress fiber formation, and tube formation were detected in an MCF-7 human umbilical vein endothelial cell (HUVEC) coculture system. Correlations of RhoA expression with MDM2, wild-type p53 (wt-p53), and VEGF expression in breast cancer tissues and relations between RhoA and breast cancer clinical features were analyzed by immunohistochemistry.

Activated RhoA down-regulated p53 protein, which increased VEGF expression in hypoxic MCF-7 cells; whereas p53 messenger RNA levels were not altered. In addition, the ubiquitin-mediated degradation of p53 was enhanced by active RhoA. RhoA and MDM2 colocalized in the cytoplasm of hypoxic MCF-7 cells and interacted with each other physically. Furthermore, nutlin-3, a specific MDM2 inhibitor, was capable of reducing activated RhoA-induced p53 protein stability and attenuating VEGF accumulation. In an MCF-7-HUVEC coculture system, nutlin-3 effectively inhibited HUVEC proliferation, invasion, migration, stress fiber formation, and tube formation mediated by activated RhoA under hypoxic conditions. Data from 129 clinical breast cancer specimens with wt-p53 revealed that high RhoA expression was correlated with high MDM2 expression, low wt-p53 expression, and high VEGF expression.

The current data suggested that activated RhoA promotes VEGF expression and hypoxia-induced angiogenesis through the up-regulation of MDM2 to decrease p53 stability. Cancer 2011;. © 2011 American Cancer Society.

The objective of this study was to evaluate the safety, feasibility, side-effect profile, and proof of concept for focal salvage therapy using high-intensity focused ultrasound (HIFU).

A registry-based analysis was conducted between 2004 and 2009 of 430 patients who underwent HIFU. Thirty-nine patients received focal salvage therapy for localized recurrence after external beam radiotherapy. Multiparametric magnetic resonance imaging studies combined with transperineal template prostate mapping biopsies or transrectal biopsies were used to localize disease. Validated questionnaires were used to assess functional outcomes. Biochemical failure was defined by using both Phoenix criteria (prostate-specific antigen [PSA] nadir plus 2 ng/mL) and Stuttgart criteria (PSA nadir plus 1.2 ng/mL).

The mean pre-HIFU PSA level was 4.6 ng/mL. The median follow-up was 17 months (interquartile range, 10-29 months). International Index of Erectile Function-5 scores decreased from a median ± standard deviation (SD) of 18 ± 16 to 13 ± 21 at 6 months, demonstrating worsening function. Scores on the University of California Los Angeles-Expanded Prostate Cancer Index Composite Urinary domain indicate that pad-free, leak-free continence status was 64%, and the pad-free rate was 87.2% at last follow-up. One rectourethral fistula occurred and spontaneously resolved with urinary and bowel diversion. The actuarial progression-free survival rate (including PSA nonresponders) was 69% at 1 year and 49% at 2 years according to Phoenix criteria. Excluding PSA nonresponders, these rates were 74% and 58%, respectively (Phoenix criteria).

The results from this study indicated that focal salvage therapy is a potential strategy for localized recurrence after radiotherapy that may reduce the harms resulting from whole-gland salvage therapies. Cancer 2011;. © 2011 American Cancer Society.

It has been established that disparities by ethnicity in the rates of breast cancer diagnoses and disease-specific survival (DSS) exist in the United States. However, few studies have assessed differences specifically between Asians and other ethnic groups or among Asian subgroups.

The authors used the Surveillance, Epidemiology, and End Results database to identify patients who were diagnosed with invasive breast cancer between 1988 and 2008. Clinicopathologic features, treatment, and DSS rates were compared among broad ethnic groups and among Asian subgroups.

In total, there were 658,691 patients in the study, including 511,701 non-Hispanic white (NHW) women (77.7%), 57,890 black women (8.8%), 45,461 Hispanic white (HW) women (6.9%), and 43,639 Asian women (6.6%). The Asian cohort was divided into the following subgroups: Filipino, Chinese, Japanese, Indian/Pakistani, Korean, Vietnamese, Hawaiian/Pacific Islander, and other. Patients in all the Asian subgroups, except Japanese, were younger at diagnosis than NHW patients. After adjustment for disease stage, Japanese patients diagnosed with stage I through III disease had better DSS rates than patients in the NHW group or in the other Asian subgroups. Hawaiian/Pacific Islander patients with stage III or IV disease had worse DSS rates than NHW patients and patients in the other Asian subgroups. All other Asian subgroups had DSS rates similar to the DSS rate in the NHW group.

The current results indicated that disparities exist for Asian women with breast cancer who reside in the United States compared with NHW groups and among Asian subgroups. Differences in presenting clinicopathologic features may affect DSS rates, suggesting that further investigation of these disparities is warranted to increase early detection and treatment for specific subgroups. Cancer 2011;. © 2011 American Cancer Society.

Aurora-A/STK15 is a serine/threonine kinase critical for regulated chromosome segregation and cytokinesis. We investigated the association between 2 nonsynonymous single nucleotide polymorphisms in the coding region of STK15, T91A (Phe31Ile) and G169A (Val57Ile), and clinical outcome of esophageal cancer treated with preoperative chemoradiation.

Genotypes at Phe31Ile and Val57Ile were assessed from peripheral blood lymphocytes of 190 esophageal cancer patients and were correlated to response to treatment, recurrence rate, risk of death, disease-free survival (DFS) and median survival time (MTS).

All patients had resectable esophageal or gastroesophageal junction cancer and received preoperative chemoradiation followed by esophagectomy. The heterozygous variant Phe31/Ile variant was significantly associated with tumor recurrence (odds ratio [OR] = 4.39; 95% confidence interval [CI], 2.12-8.94; P < .001), shorter DFS (P = .0001), and shorter MTS (P = .012). For patients receiving cisplatin-based therapy, only the variant Phe31/Ile had an adverse effect on response (OR = 2.8; 95% CI, 1.01-5.17; P = .048) and MTS (P = .026). The variant 91A-169G haplotype carried a significant risk for lack of complete response (OR = 2.54; 95% CI, 1.15-5.54) and higher rate of recurrence (OR = 2.73; 95%CI, 1.00-7.29). The presence of at least 1 variant allele at each locus further increased the risk of recurrence (adjusted OR = 6.21; 95% CI, 2.28-17.11; P = <.001), and was associated significantly shorter DFS (P = .003).

Our study shows that functional SNPs in the STK15 gene are associated with higher rate of recurrence, higher likelihood of chemoratiotherapy-resistance, shorter DFS, and shorter MTS. Confirmation of our data and understanding the mechanisms through which STK15 functional SNPs mediate resistance to chemoradiotherapy are warranted. Cancer 2011. © 2011 American Cancer Society.

Since 1975, there has been a dramatic increase in the survival rates of pediatric and older cancer patients, but adolescent and young adult (AYA) patients ages 15 to 40 years have not had a similar improvement. Data indicate a direct correlation between increased cure rates and clinical trial enrollment.

The authors previously published data indicating inferior clinical trial enrollment when AYA patients were treated at an adult oncology center versus a pediatric oncology center. To address this deficit, a joint pediatric and adult AYA Oncology Program was established in July 2006 with the primary objective of improving outcomes by increasing therapeutic clinical trial enrollment in this population. Patients who were referred to that program from July 2006 through June 2010 were examined retrospectively to establish whether clinical trial enrollment increased compared with historic controls.

Fifty-seven patients were referred to the program from 2006 to 2010 (range, 12-16 new patients per year). Eight patients were referred for consultation only and were not treated at the University of Pittsburgh Cancer Institute or Children's Hospital of Pittsburgh. Five of 22 patients (23%) who received treatment at the pediatric cancer center were enrolled onto a clinical trial, whereas 9 of 27 patients (33%) patients who received treatment at the adult cancer center were enrolled. There was superior trial participation compared with the previous 3 years for those shared AYA patients who were treated at the adult center (P < .001).

Data from this study demonstrated that establishing a unified AYA oncology program can lead to improved clinical trial enrollment for patients who are treated at medical oncology centers. Cancer 2011. © 2011 American Cancer Society.

Enzastaurin and bevacizumab have demonstrated synergistic antitumor effects and, in phase 1 studies, the combination was well tolerated. This phase 2 study assessed enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab as maintenance therapy for metastatic colorectal cancer (MCRC).

Patients with locally advanced or MCRC and stable or responding disease after completing 6 cycles of first-line chemotherapy randomly received a loading dose of enzastaurin 1125 mg, followed by 500 mg/d subsequent doses or placebo. Both arms received 5-fluorouracil/leucovorin (leucovorin 400 mg/m² intravenously [IV], 5-fluorouracil 400-mg/m² bolus, 5-fluorouracil 2400 mg/m² IV) plus bevacizumab 5 mg/kg IV, every 2 weeks. The primary endpoint was progression-free survival (PFS), from randomization. Overall survival (OS) and PFS were also assessed from start of first-line therapy. Enrollment was stopped, and the final analysis was conducted after 73 PFS events.

Fifty-eight patients were randomized to enzastaurin and 59 to placebo. For the enzastaurin and placebo arms, respectively, the median cycles received were 9 and 10, and the median PFS was 5.8 and 8.1 months (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.84-2.16; P = .896). Median OS was not calculable because of high censoring (77.6% enzastaurin; 91.5% placebo). The median PFS from start of first-line therapy was 8.9 months for enzastaurin and 11.3 months for placebo (HR, 1.39; 95% CI, 0.86-2.23; P = .913). More enzastaurin patients developed thrombosis or embolism compared with placebo (15.8% and 1.7%; P = .008). One possibly enzastaurin-related death occurred because of arrhythmia.

Enzastaurin combined with bevacizumab-based therapy is tolerable, but does not improve PFS during maintenance therapy in patients with MCRC compared with bevacizumab-based therapy alone. Cancer 2011. © 2011 American Cancer Society.

Atypical teratoid rhabdoid tumor (ATRT) is a rare central nervous system malignancy with a poor prognosis that affects mostly young children. Although radiotherapy (RT) historically has been delayed in patients aged <3 years, emerging evidence suggests a role for RT to achieve long-term survivorship. Clinical features and age-dependent trends of RT use were evaluated for patients with ATRT.

The National Cancer Institute's Surveillance, Epidemiology, and End Results database was used to identify 144 patients with ATRT from 1973 to 2008. The primary endpoint was median overall survival (OS). Clinical and treatment variables were assessed for an association with OS using Cox proportional hazards models. Landmark analysis was used to correct for immortal time bias of adjuvant RT.

The median age at diagnosis was 1 year (range, 0-67 years). Gross total resection of the primary tumor was achieved in 39% of patients, and 33% of patients received RT. From 1992 to 2008, RT use increased 2.4-fold in patients aged ≤3 years. The median OS for was 10 months. In multivariate analyses, metastatic disease (hazard ratio, 2.83; 95% confidence interval, 1.53-5.23; P = .001) and RT (hazard ratio, 0.10; 95% confidence interval, 0.01-0.73; P = .02) were identified as independent predictors of survival. Landmark analysis confirmed a robust association between RT use and survival, which was attenuated in patients ages 4 to 17 years compared with younger patients.

The current results indicated that RT may offer a significant survival benefit for patients with ATRT and that patients aged ≤3 years may derive more benefit from initial RT compared with older children. The authors concluded that prospective clinical trials are needed to examine the role of RT in the initial management of ATRT in patients aged <3 years. Cancer 2011. © 2011 American Cancer Society.

The Community Clinical Oncology Program (CCOP) plays an essential role in the efforts of the National Cancer Institute (NCI) to increase enrollment in clinical trials. Currently, there is little practical guidance in the literature to assist provider organizations in analyzing the return on investment (ROI), or business case, for establishing and operating a provider-based research network (PBRN) such as the CCOP. In this article, the authors present a conceptual model of the business case for PBRN participation, a spreadsheet-based tool and advice for evaluating the business case for provider participation in a CCOP organization.

A comparative, case-study approach was used to identify key components of the business case for hospitals attempting to support a CCOP research infrastructure. Semistructured interviews were conducted with providers and administrators. Key themes were identified and used to develop the financial analysis tool.

Key components of the business case included CCOP start-up costs, direct revenue from the NCI CCOP grant, direct expenses required to maintain the CCOP research infrastructure, and incidental benefits, most notably downstream revenues from CCOP patients. The authors recognized the value of incidental benefits as an important contributor to the business case for CCOP participation; however, currently, this component is not calculated.

The current results indicated that providing a method for documenting the business case for CCOP or other PBRN involvement will contribute to the long-term sustainability and expansion of these programs by improving providers' understanding of the financial implications of participation. Cancer 2011. © 2011 American Cancer Society.

A study was undertaken to compare survival and 5-year mortality by Medicaid status in adults diagnosed with 8 select cancers.

Linking records from the Ohio Cancer Incidence Surveillance System (OCISS) with Ohio Medicaid enrollment data, the authors identified Medicaid and non-Medicaid patients aged 15 to 54 years and diagnosed with the following incident cancers in the years 1996-2002: cancer of the testis; Hodgkin and non-Hodgkin lymphoma; early stage melanoma, colon, lung, and bladder cancer; and pediatric malignancies (n = 12,703). Medicaid beneficiaries were placed in the pre-diagnosis group if they were enrolled in Medicaid at least 3 months before cancer diagnosis, and in the peri/post-diagnosis group if they enrolled in Medicaid upon or after being diagnosed with cancer. The authors also linked the OCISS with death certificates and data from the US Census. By using Cox and logistic regression analysis, they examined the association between Medicaid status and survival and 5-year mortality, respectively, after adjusting for patient covariates.

Nearly 11% of the study population were Medicaid beneficiaries. Of those, 45% were classified in the peri/post-diagnosis group. Consistent with higher mortality, findings from the Cox regression model indicated that compared with non-Medicaid, patients in the Medicaid pre-diagnosis and peri/post-diagnosis groups experienced unfavorable survival outcomes (adjusted hazard ratio [AHR], 1.52; 95% confidence interval [CI], 1.27-1.82 and AHR, 2.01; 95% CI, 1.70-2.38, respectively).

Medicaid status was associated with unfavorable survival, even after adjusting for confounders. The findings reflect the vulnerability of Medicaid beneficiaries and possible inadequacies in the process of care. Cancer 2011. © 2011 American Cancer Society.

Extranodal involvement is considered a poor prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL); however, the prognostic impact of specific sites of involvement has not been fully elucidated.

The authors retrospectively analyzed 1221 patients treated uniformly with standard R-CHOP therapy between 2003 and 2006. Patients with distinct forms of DLBCL such as intravascular lymphoma, primary effusion lymphoma, pyothorax-associated lymphoma, primary central nervous system lymphoma, and intraocular lymphoma were also excluded. The authors evaluated 26 extranodal sites of involvement with respect to prognostic impact. The median age was 64 years (range, 15-91 years).

Univariate analysis revealed that patients with involvement of specific extranodal sites had significantly worse overall survival (OS) than did patients without such involvement; these sites included nasal cavity, paranasal sinus, lung, pleura, small intestine, peritoneum, liver, pancreas, stomach, spleen, adrenal gland, testis, bone, bone marrow, peripheral blood, skin, and subcutaneous tissue. Patients with Waldeyer ring involvement had significantly better OS. Multivariate analysis revealed that patients with the involvement of the pleura (P < .001), small intestine (P = .015), peritoneum (P = .002), adrenal gland (P < .001), testis (P = .005), bone marrow (P < .001), and peripheral blood (P = .002) had significantly worse OS, whereas those with Waldeyer ring involvement had significantly better OS (P = .038). Subgroup analysis with the nodal and/or Waldeyer patient group also showed prognostic impact of Waldeyer ring by multivariate analysis (relative risk, 0.3; P = .04).

Extranodal involvement affects the prognosis of patients undergoing R-CHOP therapy for DLBCL. Cancer 2011. © 2011 American Cancer Society.

Diffuse large B-cell lymphomas (DLBCLs) are a biologically heterogeneous group in which various gene alterations have been reported. The aim of this study was to investigate the frequency and prognostic impact of BCL2, BCL6, and MYC rearrangements in cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP)-treated DLBCL cases.

Tissue microarrays were constructed from 239 cases of DLBCL, and the expressions of CD10, BCL6, MUM1/IRF4, and BCL2 were evaluated by immunohistochemistry. MYC, BCL2, and BCL6 rearrangements were investigated by interphase fluorescence in situ hybridization on tissue microarrays. Survival analysis was constructed from 145 R-CHOP–treated patients.

MYC, BCL2, and BCL6 rearrangements were detected in 14 (6%), 36 (15%), and 69 (29%) of 239 DLBCL patients. Double or triple rearrangements were detected in 7 (3%) of 239 DLBCL cases. Of these, 4 had BCL2 and MYC, 2 had BCL6 and MYC, and 1 had BCL2, BCL6, and MYC rearrangements. The prognosis of these cases was extremely poor, with a median survival of 9 months. MYC rearrangement was associated with significantly worse overall survival (P = .01), especially for the cases with GC phenotype (P = .009). BCL6 rearrangement also predicted significantly shorter overall survival (P = .04), especially for the non-GC phenotype (P = .03). BCL2 rearrangement had no prognostic impact on outcome. International Prognostic Index (P = .004) and MYC rearrangement (P = .009) were independent poor prognostic factors.

Analysis of MYC gene rearrangement along with BCL2 and BCL6 is critical in identifying high-risk patients with poor prognosis. Cancer 2011. © 2011 American Cancer Society.

The identification of potential tumor markers can improve therapeutic planning and patient management. The objective of this study was to highlight the role of DNA methyltransferase 3b (DNMT3b) in esophageal squamous cell carcinoma (SCC).

One hundred seventy-three esophageal SCC samples were analyzed using immunohistochemical staining to correlate the expression of DNMT3b with clinical outcome. Furthermore, a human esophageal SCC cell line, CE81T, was selected for cellular and animal experiments to investigate changes in tumor behavior and treatment response after the manipulation of DNMT3b expression.

The incidence of nuclear DNMT3b immunoreactivity in esophageal cancer specimens was significantly higher than in nonmalignant epithelium, and this incidence was linked positively to developing distant metastasis (56% in localized disease vs 80% in distant metastasis; P = .002). Furthermore, increased expression of DNMT3b was linked significantly to lower treatment response rates (P = .002) and reduced survival rates (P = .000). Inhibition of DNMT3b expression resulted in slower cellular proliferation, increased cell death, a less invasive capacity, and less epithelial-mesenchymal-transition changes. Moreover, DNMT3b silencing vectors sensitized esophageal cancer cells to irradiation and cisplatin treatment. The current results also indicated that constitutional activation of signal transducer and activator of transcription 3 (STAT3) signaling associated with inhibited expression of suppressor of cytokine signaling 3 (SOCS3) may be the mechanism underlying more aggressive tumor growth in DNMT3b-positive esophageal cancer.

DNMT3b was linked significantly to a poor prognosis for patients with esophageal cancer. Moreover, the current results indicated that targeting this enzyme may be a promising strategy for treating esophageal cancer, as evidenced by inhibited aggressive tumor behavior and treatment resistance. Cancer 2011. © 2011 American Cancer Society.

The effects of a therapeutic group by teleconference for African American women with breast cancer have not been documented, although the benefits of therapeutic groups for European women are well established. African American women with breast cancer may experience social disconnection, a sense of being cut off from partners, family, and friends because of side effects of treatment and fatalistic beliefs about cancer. A therapeutic group by teleconference may counteract these problems and improve social connection.

A randomized trial design stratified by treatment type was used. Data were collected at baseline, at the end of the intervention, and 16 weeks from baseline. Repeated-measures, fixed-factor analyses of covariance were used for each outcome. The between-subject factors were group and replicate set, and the within-subject factor was time. Physical well being and educational level differed significantly between the 2 groups at baseline and were used as covariates.

The mixed-model analysis of the outcome variables revealed significant changes over time for knowledge (P ≤ .001), with higher scores on knowledge observed for the control group. Group-by-time interactions were observed for fatalism (P = .0276), fear (P = .0163), and social connection (P = .0174) as measured by the Social Well Being subscale from the Functional Assessment of Cancer Treatment-Breast Cancer Version. No group-by-time interaction was observed for social connection as measured by the Social Support Questionnaire. Social connection measured with the Social Well Being subscale improved significantly in the intervention group, whereas fatalism and fear significantly decreased.

In this study, the authors documented the benefits of a therapeutic group by teleconference, a novel way to provide support for African American women with breast cancer. Further research should include a behavioral outcome, such as treatment adherence. Cancer 2012;. © 2011 American Cancer Society.

Patients with large, high-grade, extremity soft tissue sarcomas (STS) are at significant risk for distant recurrence and death. A regimen of preoperative chemotherapy consisting of mesna, Adriamycin (doxorubicin), ifosfamide, and dacarbazine (MAID), interdigitated with radiotherapy (RT) and followed by resection and postoperative chemotherapy with or without RT, has demonstrated high rates of local and distant control. We report the long-term follow-up data on 48 patients treated with this regimen compared to an historical matched-control patient population.

Adult patients with high-grade extremity STS ≥ 8 cm were treated with 3 cycles of preoperative chemotherapy combined with 44 Gy of RT followed by surgery. Three cycles of postoperative MAID were planned. For patients with positive surgical margins, 16 Gy of RT was delivered postoperatively.

Patients received the MAID/RT regimen from 1989 through 1999. After a median follow-up of 9.3 years in surviving patients in the MAID group and 13.2 years in surviving patients in the control group, the 7-year disease-specific and overall survival rates were 81% and 50% (P = .004) and 79% and 45% (P = .003) for the MAID and control patients, respectively. Five of 11 patients in the MAID group and 7 of 25 control patients died of sarcoma ≥5 years after treatment. One patient in the MAID group developed a fatal myelodysplasia at 53 months.

For patients with high-risk, extremity STS, the significant survival benefits conferred by an intense regimen of neoadjuvant chemoradiotherapy and surgery are sustained even with long-term follow-up. Cancer 2012;. © 2011 American Cancer Society.

Mucoepidermoid carcinoma (MEC) is the most common malignancy of the major salivary glands. Prior reports noted histological grade and tumor stage as consistently important prognostic factors. This study reviewed the experience of patients with MEC at the University of Texas MD Anderson Cancer Center to determine the impact of clinical and pathologic findings on disease outcomes.

A retrospective clinical review was performed of patients with salivary gland MEC treated at a tertiary cancer center from 1990 to 2007.

A total of 125 patients were included. The 5-year overall survival and disease-free survival of all patients were 79.3% and 76.5%, respectively. Patients with low- and intermediate-grade disease had significantly better overall survival and disease-free survival than patients with high-grade disease, but no difference in survival rates was found between low- and intermediate-grade disease. Pathologic results of positive lymph nodes, extracapsular lymph node spread, and perineural invasion were all found to be poor prognostic indicators. On multivariate analysis, advanced disease stage and perineural invasion were found to be the most significant prognostic factors.

Patients with either low- or intermediate-grade tumors uniformly have favorable local control and survival. High histological grade, advanced stage, perineural invasion, positive surgical margins, and submandibular location all portend for poor outcomes in MEC. Further advances in therapy are needed to improve outcomes for high-grade and advanced-stage disease. Cancer 2012;. © 2011 American Cancer Society.