Utilizing a population-based nested case-control study design, we enrolled 365 patients diagnosed with an estrogen receptor–positive (ER+) first primary invasive breast cancer and a second primary contralateral invasive breast cancer, and 726 matched controls diagnosed with only an ER+ first primary invasive breast cancer. Obesity, alcohol use, and smoking data were ascertained from medical record reviews and participant interviews. Using conditional logistic regression we evaluated associations between these three exposures and second primary contralateral breast cancer risk.

Obesity, consumption of ≥ 7 alcoholic beverages per week, and current smoking were all positively related to risk of contralateral breast cancer (odds ratio [OR], 1.4; 95% CI, 1.0 to 2.1; OR, 1.9; 95% CI, 1.1 to 3.2; and OR, 2.2; 95% CI, 1.2 to 4.0, respectively). Compared with women who consumed fewer than seven alcoholic beverages per week and were never or former smokers, women who consumed ≥ 7 drinks per week and were current smokers had a 7.2-fold (95% CI, 1.9 to 26.5) elevated risk of contralateral breast cancer.

Our population-based study adds to the limited available literature and suggests that obesity, smoking, and alcohol consumption influence contralateral breast cancer risk, affording breast cancer survivors three means of potentially reducing this risk.

Patients with either low- or intermediate-grade DCIS measuring 2.5 cm or smaller, or high-grade DCIS measuring 1 cm or smaller who had microscopic margin widths of 3 mm or wider and no residual calcifications on postoperative mammograms were eligible for a prospective trial conducted from 1997 to 2002 by the Eastern Cooperative Oncology Group and North Central Cancer Treatment Group. Patients entered in 2000 and later could take tamoxifen if they wished. Median age at last surgery for the entire population was 60 years (range, 28 to 88 years), and median tumor sizes in the two strata were 6 mm and 5 mm, respectively.

With a median follow-up of 6.2 years, the 5-year rate of ipsilateral breast events in the 565 eligible patients in the low/intermediate grade stratum was 6.1% (95% CI, 4.1% to 8.2%). With a median follow-up of 6.7 years, this incidence for the 105 eligible patients in the high-grade stratum was 15.3% (95% CI, 8.2% to 22.5%).

Rigorously evaluated and selected patients with low- to intermediate-grade DCIS with margins 3 mm or wider had an acceptably low rate of ipsilateral breast events at 5 years after excision without irradiation. Patients with high-grade lesions had a much higher rate, suggesting that excision alone is inadequate treatment. Further follow-up is necessary to document long-term results.

A total of 3,252 patients with breast cancer from Los Angeles and Detroit Surveillance, Epidemiology, and End Results registries were surveyed near the time of diagnosis (n = 2,260, response rate 72.2%). The primary outcomes were receipt of reconstruction, access to information about reconstruction, and decisional satisfaction. The primary independent variable was race/ethnicity (white, African American [AA], highly acculturated Latina [Latina-high], and less acculturated Latina [Latina-low]). Control variables included other sociodemographic and clinical factors. ² and multivariate logistic regression were used for the analyses.

Receipt of reconstruction varied significantly by patient race/ethnicity—40.9% of whites, 33.5% of AAs, 41.2% of Latina-high, and only 13.5% of Latina-low (P < .001)—and persisted when we controlled for demographic and clinical factors. Minority women were significantly less likely than whites to see a plastic surgeon before initial surgery and were more likely to desire more information about reconstruction (17.0% of whites v 27.0% of AAs, 30.0% of Latina-high, and 55.9% of Latina-low; P < .001). Decisional satisfaction was lowest among minority women without reconstruction (P < .001).

Minority women, particularly less acculturated Latinas, had low receipt of breast reconstruction, which may be related to limited information about the procedure and less access to plastic surgeons. Greater desire for information and lower satisfaction with surgical decisions among these patients motivate greater attention to treatment support for these patients.

Patients with clinical stage I to IIA uterine cancer were randomly assigned to laparoscopy (n = 1,696) or open laparotomy (n = 920), including hysterectomy, salpingo-oophorectomy, pelvic cytology, and pelvic and para-aortic lymphadenectomy. The main study end points were 6-week morbidity and mortality, hospital length of stay, conversion from laparoscopy to laparotomy, recurrence-free survival, site of recurrence, and patient-reported quality-of-life outcomes.

Laparoscopy was initiated in 1,682 patients and completed without conversion in 1,248 patients (74.2%). Conversion from laparoscopy to laparotomy was secondary to poor visibility in 246 patients (14.6%), metastatic cancer in 69 patients (4.1%), bleeding in 49 patients (2.9%), and other cause in 70 patients (4.2%). Laparoscopy had fewer moderate to severe postoperative adverse events than laparotomy (14% v 21%, respectively; P < .0001) but similar rates of intraoperative complications, despite having a significantly longer operative time (median, 204 v 130 minutes, respectively; P < .001). Hospitalization of more than 2 days was significantly lower in laparoscopy versus laparotomy patients (52% v 94%, respectively; P < .0001). Pelvic and para-aortic nodes were not removed in 8% of laparoscopy patients and 4% of laparotomy patients (P < .0001). No difference in overall detection of advanced stage (stage IIIA, IIIC, or IVB) was seen (17% of laparoscopy patients v 17% of laparotomy patients; P = .841).

Laparoscopic surgical staging for uterine cancer is feasible and safe in terms of short-term outcomes and results in fewer complications and shorter hospital stay. Follow-up of these patients will determine whether surgical technique impacts pattern of recurrence or disease-free survival.

The first 802 eligible patients (laparoscopy, n = 535; laparotomy, n = 267) participated in the QoL study in a Gynecologic Oncology Group (GOG) randomized trial of laparoscopy versus laparotomy (GOG 2222). Patients completed QoL assessments at baseline; at 1, 3, and 6 weeks; and at 6 months postsurgery.

In an intent-to-treat analysis, laparoscopy patients reported significantly higher Functional Assessment of Cancer Therapy–General (FACT-G) scores (P = .001), better physical functioning (P = .006), better body image (BI; P < .001), less pain (P < .001) and its interference with QoL (P < .001), and an earlier resumption of normal activities (P = .003) and return to work (P = .04) over the 6-week postsurgery period, as compared with laparotomy patients. However, the differences in BI and return to work between groups were modest, and the adjusted FACT-G scores did not meet the minimally important difference (MID) between the two surgical arms over 6 weeks. By 6 months, except for better BI in laparoscopy patients (P < .001), the difference in QoL between the two surgical techniques was not statistically significant.

Although the FACT-G did not show a MID between the two surgical groups, and only modest differences in return to work and BI were found between the two groups, statistically significantly better QoL across many parameters in the laparoscopy arm at 6 weeks provides modest support for the QoL advantage of using laparoscopy to stage patients with early endometrial cancer.

Patients enrolled onto a phase I study of sequential infusion of iodine-131 (¹³¹I) MIBG (NANT-2000-01) were eligible for inclusion if they had concomitant FDG-PET and MIBG scans. ¹³¹I-MIBG therapy was administered on days 0 and 14. For each patient, we compared all lesions identified on concomitant FDG-PET and MIBG scans and gave scans a semiquantitative score.

The overall concordance of positive lesions on concomitant MIBG and FDG-PET scans was 39.6% when examining the 139 unique anatomic lesions. MIBG imaging was significantly more sensitive than FDG-PET overall and for the detection of bone lesions (P < .001). There was a trend for increased sensitivity of FDG-PET for detection of soft tissue lesions. Both modalities showed similar improvement in number of lesions identified from day 0 to day 56 scan and in semiquantitative scores that correlated with overall response. FDG-PET scans became completely negative more often than MIBG scans after treatment.

MIBG scan is significantly more sensitive for individual lesion detection in relapsed neuroblastoma than FDG-PET, though FDG-PET can sometimes play a complementary role, particularly in soft tissue lesions. Complete response by FDG-PET metabolic evaluation did not always correlate with complete response by MIBG uptake.

Of the 183 patients prospectively investigated for renal function, 77 treated for rhabdomyosarcoma, 39 for other soft tissue sarcoma, 39 for Ewing's sarcoma, and 28 for osteosarcoma were investigated at least 5 years after treatment. No patients had received cisplatin and/or carboplatin. Glomerular and tubular functions were graded according to the Skinner system.

The median dose of ifosfamide was 54 g/m² (range, 18 to 117 g/m²). After a median follow-up of 10 years, 89.5% of patients had normal tubular function, and 78.5% had normal glomerular function rate (GFR). Serum bicarbonate and calcium were normal in all patients. Hypomagnesemia was observed in 1.2% and hypophosphatemia in 1%. The tubular threshold for phosphate was reduced in 24% of the patients (grade 1 in 15%, grade 2 in 8%, and grade 3 in 0.5%). Glycosuria was detected in 37% of the patients but was more than 0.5 g/24 hours in only 5%. Proteinuria was observed in 12%. Ifosfamide dose and interval from therapy to investigations were predictors of tubulopathy in univariate and multivariate analysis. In a multivariate analysis, an older age at diagnosis and the length of interval since treatment had independent impacts on the risk of abnormal GFR.

Renal toxicity is moderate with a moderate dose of ifosfamide. However, since it can be permanent and can get worse with time, repeated long-term evaluations are important, and this risk should be balanced against efficacy.

Data analyzed included age, sex, smoking status, underlying disease, medical and dental history, bisphosphonates (BP) type, and doses administered. Relative risks, crude and adjusted odds ratios (aORs), and cumulative hazard ratios for ONJ development were calculated.

We included 1,621 patients who received 29,006 intravenous doses of BP, given monthly. Crude ONJ incidence was 8.5%, 3.1%, and 4.9% in patients with multiple myeloma, breast cancer, and prostate cancer, respectively. Patients with breast cancer demonstrated a reduced risk for ONJ development, which turned out to be nonsignificant after adjustment for other variables. Multivariate analysis demonstrated that use of dentures (aOR = 2.02; 95% CI, 1.03 to 3.96), history of dental extraction (aOR = 32.97; 95% CI, 18.02 to 60.31), having ever received zoledronate (aOR = 28.09; 95% CI, 5.74 to 137.43), and each zoledronate dose (aOR = 2.02; 95% CI, 1.15 to 3.56) were associated with increased risk for ONJ development. Smoking, periodontitis, and root canal treatment did not increase risk for ONJ in patients receiving BP.

The conclusions of this study validated dental extractions and use of dentures as risk factors for ONJ development. Ibandronate and pamidronate at the dosages and frequency used in this study seem to exhibit a safer drug profile concerning ONJ complication; however, randomized controlled trials are needed to validate these results. Before initiation of a bisphosphonate, patients should have a comprehensive dental examination. Patients with a challenging dental situation should have dental care attended to before initiation of these drugs.

Predominantly female patients (98%) diagnosed with breast cancer (96%) who were chemotherapy-naïve and scheduled to receive an anthracycline and cyclophosphamide (AC) –based regimen were enrolled onto this multinational, randomized, double-blind, parallel-group, placebo-controlled clinical trial. All patients received dexamethasone 8 mg intravenously (IV) on day 1 and oral ondansetron 8 mg twice daily on days 1 to 3. Patients were randomly assigned to a control arm (placebo), a single oral dose casopitant arm (150 mg orally [PO] on day 1), a 3-day oral casopitant arm (150 mg PO on day 1 plus 50 mg PO on days 2 to 3), or a 3-day IV/oral casopitant arm (90 mg IV on day 1 plus 50 mg PO on days 2 to 3). The primary end point was the proportion of patients achieving complete response (no vomiting/retching or rescue medications) in the first 120 hours after the initiation of MEC.

A significantly greater proportion of patients in the single-dose oral casopitant arm, 3-day oral casopitant arm, and 3-day IV/oral casopitant arm achieved complete response (73%, 73%, and 74%, respectively) versus control (59%; P < .0001). The study did not demonstrate a reduced proportion of patients with nausea or significant nausea in those receiving casopitant. Adverse events were balanced among study arms.

All casopitant regimens studied were more effective than the control regimen. Casopitant was generally well tolerated.

A total of 264 physician offices were randomly assigned to usual care or to a series of visits from trained physician educators. CRC screening rates were measured at baseline and 12 months. The intervention costs were measured and the incremental cost-effectiveness ratio (ICER) was derived. Sensitivity analyses were based on varying cost and effectiveness estimates.

Academic detailing was associated with a 7% increase in CRC screening with colonoscopy. The total intervention cost was $147,865, and the ICER was $21,124 per percentage point increase in CRC screening rate. Sensitivity analyses that varied the costs of the intervention and the average medical practice size were associated with ICERs ranging from $13,631 to $36,109 per percentage point increase in CRC screening rates.

A comprehensive, multicomponent academic detailing intervention conducted in small practices in metropolitan New York was clinically effective in improving CRC screening rates, but was not cost effective.

Population-based, retrospective cohort study of 2,330 patients with centrally confirmed lymphoma from Nebraska and surrounding states and treated by university-based or community-based oncologists from 1982 to 2006.

Among urban residents, 321 (14%) were treated by university-based providers (UUB) and 816 (35%) were treated by community-based providers (UCB). Among rural residents, 332 (14%) were treated by university-based providers (RUB), and 861 (37%) were treated by community-based providers (RCB). The relative risk (RR) of death among UUB, UCB, and RUB were not statistically different. However, RCB had a higher risk of death (RR, 1.37; 95% CI, 1.14 to 1.65; P = .01; and RR, 1.26; 95% CI, 1.06 to 1.49; P = .01) when compared with UUB and RUB, respectively. This association was true in both low- and intermediate-risk patients. Among high-risk patients, UCB, RUB, and RCB were all at higher risk of death when compared with UUB.

Survival outcomes of patients with lymphoma may be associated with place of residence and treatment provider. High-risk patients from rural areas may benefit from better coordination of care.

We developed a decision-analytic model to evaluate lipid screening in a hypothetical cohort of 30-year-old survivors of HL who survived 5 years after mediastinal irradiation. We compared the following strategies: no screening, and screening at 1-, 3-, 5-, or 7-year intervals. Screen-positive patients were treated with statins. Markov models were used to calculate life expectancy, quality-adjusted life expectancy, and lifetime costs. Baseline probabilities, transition probabilities, and utilities were derived from published studies and US population data. Costs were estimated from Medicare fee schedules and the medical literature. Sensitivity analyses were performed.

Using an incremental cost-effectiveness ratio (ICER) threshold of $100,000 per quality-adjusted life-year (QALY) saved, lipid screening at every interval was cost effective relative to a strategy of no screening. When comparing screening intervals, a 3-year interval was cost effective relative to a 5-year interval, but annual screening, relative to screening every 3 years, had an ICER of more than $100,000/QALY saved. Factors with the most influence on the results included risk of cardiac events/death after HL, efficacy of statins in reducing cardiac events/death, and costs of statins.

Lipid screening in survivors of HL, with statin therapy for screen-positive patients, improves survival and is cost effective. A screening interval of 3 years seems reasonable in the long-term follow-up of survivors of HL.

Patients had stage IIB, III, or IV disease or had stages I to IIA disease with bulky disease or other adverse features. Radiotherapy was administered in both arms to sites of previous bulk (> 5 cm) and to splenic deposits, although this was omitted in the latter part of the trial for patients achieving complete remission (CR) in the ABVD arm. A total of 520 patients were randomly assigned and were assessed for the primary outcome measure of progression-free survival (PFS). Five hundred patients received protocol treatment, and radiotherapy was administered to 73% in the Stanford V arm and to 53% in the ABVD arm.

The overall response rates after completion of all treatment were 91% for Stanford V and 92% for ABVD. During a median follow-up of 4.3 years, there was no evidence of a difference in projected 5-year PFS and overall survival (OS) rates (76% and 90%, respectively, for ABVD; 74% and 92%, respectively, for Stanford V). More pulmonary toxicity was reported for ABVD, whereas other toxicities were more frequent with Stanford V.

In a large, randomized trial, the efficacies of Stanford V and ABVD were comparable when given in combination with appropriate radiotherapy.

We randomly assigned 2,157 patients (age range, 15 to 60 years) to receive intensive induction-consolidation chemotherapy containing either daunorubicin, idarubicin, or mitoxantrone. After achieving complete remission (CR), patients were assigned to undergo either allogeneic or autologous stem-cell transplantation (SCT), depending on the availability of a sibling donor.

The overall CR rate (69%) was similar in the three groups. Autologous SCT was performed in 37% of cases in the daunorubicin arm versus only 29% and 31% in mitoxantrone and idarubicin, respectively (P < .001). However, the disease-free survival (DFS) and survival from CR were significantly shorter in the daunorubicin arm: the 5-year DFS was 29% versus 37% and 37% in mitoxantrone and idarubicin, respectively. The proportion of patients who underwent allogeneic SCT (22%) was equivalent in the three treatment groups, and the outcome was similar as well: the 5-year overall survival rates were 34%, 34%, and 31%, respectively.

In adult patients with AML who do not receive an allogeneic SCT, the use of mitoxantrone or idarubicin instead of daunorubicin enhances the long-term efficacy of chemotherapy.

Patients with relapsed/refractory indolent NHL were eligible, with no limit on the number of previous therapies. Oral lenalidomide 25 mg was self-administered once daily on days 1 to 21 of every 28-day cycle for up to 52 weeks as tolerated, or until disease progression. The primary end point was objective response rate (ORR), with secondary end points of duration of response (DR), progression-free survival (PFS), and safety.

Forty-three enrolled patients were assessable for response and safety. Patients received a median of three prior systemic therapies (range, 1 to 17) and half were refractory to last therapy. ORR was 23% (10 of 43), including a 7% complete response (CR) or unconfirmed CR rate. Twenty-seven percent (six of 22) of patients with follicular lymphoma grade 1 or 2, and 22% (four of 18) with small lymphocytic lymphoma responded to therapy. Median DR was not reached, but was longer than 16.5 months with seven of 10 responses ongoing at 15 to 28 months. Median PFS for the whole group was 4.4 months (95% CI, 2.5 to 10.4 months). Adverse events were predictable and manageable; the most common grade 3 or 4 adverse events were neutropenia (30% and 16%, respectively) and thrombocytopenia (14% and 5%, respectively).

Oral lenalidomide monotherapy produces durable responses with manageable adverse events in patients with relapsed/refractory indolent NHL, warranting further investigation of treatment for indolent NHL.

The initial cohort was limited to patients with cutaneous T-cell lymphoma (CTCL), or subtypes mycosis fungoides or Sézary syndrome, who had received no more than two prior cytotoxic regimens. There were no limits on other types of therapy. Subsequently, the protocol was expanded to enroll patients who had received more than two prior cytotoxic regimens.

Twenty-seven patients were enrolled onto the first cohort, and a total of 71 patients are included in this analysis. These patients had undergone a median of four prior treatments, and 62 patients (87%) had advanced-stage disease (stage IIB, n = 15; stage III, n= 6; or stage IV, n = 41). Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Pharmacokinetics were evaluated with the first administration of romidepsin. Complete responses were observed in four patients, and partial responses were observed in 20 patients for an overall response rate of 34% (95% CI, 23% to 46%). The median duration of response was 13.7 months.

The histone deacetylase inhibitor romidepsin has single-agent clinical activity with significant and durable responses in patients with CTCL.

Seventy-nine patients (40 with PV and 39 with ET) have been treated. Median time from diagnosis to PEG-IFN--2a was 54 months in patients with PV and 33 months in patients with ET. Eighty-one percent of patients had received prior therapy. The first three patients received PEG-IFN--2a at 450 µg weekly. As a result of poor tolerance, this dose was decreased in a stepwise manner to a current starting dose of 90 µg weekly. Seventy-seven patients are evaluable and have been observed for a median of 21 months.

The overall hematologic response rate was 80% in PV and 81% in ET (complete in 70% and 76% of patients, respectively). The JAK2^V617F mutation was detected in 18 patients with ET and 38 patients with PV; sequential measurements by a pyrosequencing assay were available in 16 patients with ET and 35 patients with PV. The molecular response rate was 38% in ET and 54% in PV, being complete (undetectable JAK2^V617F) in 6% and 14%, respectively. The JAK2^V617F mutant allele burden continued to decrease with no clear evidence for a plateau. The tolerability of PEG-IFN--2a at 90 µg weekly was excellent.

PEG-IFN--2a resulted in remarkable clinical activity, high rates of molecular response, and acceptable toxicity in patients with advanced ET or PV. The ability of PEG-IFN--2a to induce complete molecular responses suggests selective targeting of the malignant clone.

We treated 24 patients with a variety of T-cell leukemias and lymphomas with a combination of alemtuzumab 30 mg intravenously (IV) three times weekly for up to 3 months and pentostatin 4 mg/m² IV weekly for 4 weeks followed by alternate weekly administration for up to 6 months. Prophylactic antibiotics including antiviral, antifungal, and antibacterial agents were administered during the treatment and for 2 months after its completion.

The median age of patients was 57 years (range, 21 to 79 years). Eight patients were previously untreated, and 16 had a median of two prior therapies (range, one to six regimens). Thirteen patients responded to treatment (11 complete responses [CRs] and two partial responses), for an overall response rate of 54%. The median response duration was 19.5 months. Monoclonal T-cell receptor chain gene rearrangements were detected by polymerase chain reaction in bone marrow of 20 of 22 evaluable patients and became negative in five of seven evaluable patients in CR. Opportunistic infections caused by pathogens associated with severe T-cell dysfunction were common.

The combination of alemtuzumab and pentostatin is feasible and effective in T-cell neoplasms. Although infections, including cytomegalovirus reactivation, are a concern, they may be minimized with adequate prophylactic antibiotic therapy.

Nine hundred fifty patients were randomly assigned (2:1) to receive oral satraplatin (n = 635) 80 mg/m² on days 1 to 5 of a 35-day cycle and prednisone 5 mg twice daily or placebo (n = 315) and prednisone 5 mg twice daily. Primary end points were progression-free survival and overall survival (OS). The secondary end point was time to pain progression (TPP).

A 33% reduction (hazard ratio [HR] = 0.67; 95% CI, 0.57 to 0.77; P < .001) was observed in the risk of progression or death with satraplatin versus placebo. This effect was maintained irrespective of prior docetaxel treatment. No difference in OS was seen between the satraplatin and placebo arms (HR = 0.98; 95% CI, 0.84 to 1.15; P = .80). Compared with placebo, satraplatin significantly reduced TPP (HR = 0.64; 95% CI, 0.51 to 0.79; P < .001). Satraplatin was generally well tolerated, although myelosuppression and GI disorders occurred more frequently with satraplatin.

Oral satraplatin delayed progression of disease and pain in patients with metastatic CRPC experiencing progression after initial chemotherapy but did not provide a significant OS benefit. Satraplatin was generally well tolerated. These results suggest activity for satraplatin in patients with CRPC who experience progression after initial chemotherapy.

A pilot retrospective study of 271 patients with melanoma suggested that vitamin D may protect against recurrence of melanoma. We tested these findings in a survival analysis in a cohort of 872 patients recruited to the Leeds Melanoma Cohort (median follow-up, 4.7 years).

In the retrospective study, self-reports of taking vitamin D supplements were nonsignificantly correlated with a reduced risk of melanoma relapse (odds ratio = 0.6; 95% CI, 0.4 to 1.1; P = .09). Nonrelapsers had higher mean 25-hydroxyvitamin D₃ levels than relapsers (49 v 46 nmol/L; P = .3; not statistically significant). In the cohort (prospective) study, higher 25-hydroxyvitamin D₃ levels were associated with lower Breslow thickness at diagnosis (P = .002) and were independently protective of relapse and death: the hazard ratio for relapse-free survival (RFS) was 0.79 (95% CI, 0.64 to 0.96; P = .01) for a 20 nmol/L increase in serum level. There was evidence of interaction between the vitamin D receptor (VDR) BsmI genotype and serum 25-hydroxyvitamin D₃ levels on RFS.

Results from the retrospective study were consistent with a role for vitamin D in melanoma outcome. The cohort study tests this hypothesis, providing evidence that higher 25-hydroxyvitamin D₃ levels, at diagnosis, are associated with both thinner tumors and better survival from melanoma, independent of Breslow thickness. Patients with melanoma, and those at high risk of melanoma, should seek to ensure vitamin D sufficiency. Additional studies are needed to establish optimal serum levels for patients with melanoma.

Quality indicators were identified from available literature, consensus guidelines, and melanoma experts. Thirteen experts ranked potential measures for validity on the basis of the RAND/University of California, Los Angeles Appropriateness Methodology. Adherence with individual valid indicators and a composite measure of all indicators were assessed at 1,249 Commission on Cancer hospitals by using the National Cancer Data Base (NCDB; 2004 through 2005).

Of 55 proposed quality indicators, 26 measures (47%) were rated as valid. These indicators assessed structure (n = 1), process (n = 24), and outcome (n = 1). Of the 26 measures, 10 are readily assessable by using cancer registry data. Adherence with valid indicators ranged from 11.8% to 96.5% at the patient level and 3.7% to 83.0% at the hospital level. (Adherence required that ≥ 90% of patients at a hospital receive concordant care.) Most hospitals were adherent with 50% or fewer of the individual indicators (median composite score, five; interquartile range, four to seven). Adherence was higher for diagnosis and staging measures and was lower for treatment indicators.

There is considerable variation in the quality of melanoma care in the United States. By using these formally developed quality indicators, hospitals can assess their adherence with current melanoma care guidelines through feedback mechanisms from the NCDB and can better direct quality improvement efforts.

We randomly assigned patients with metastatic melanoma, measurable disease, and one or fewer prior chemotherapy regimens to elesclomol 213 mg/m² plus paclitaxel 80 mg/m² (E + P) or to paclitaxel 80 mg/m² alone at a 2:1 ratio; regimens were given as a 1-hour intravenous infusion weekly, during 3 of every 4 weeks until disease progression per Response Evaluation Criteria in Solid Tumors or death occurred. Patients who experienced progression were unblended, and patients on paclitaxel alone were permitted to cross over to E + P. The primary efficacy end point was progression-free survival (PFS); secondary end points were response rate (RR), toxicity, and overall survival (OS; analyzed post hoc).

At 21 US sites, 53 patients were randomly assigned to E + P, and 28 patients were randomly assigned to paclitaxel. The addition of elesclomol to paclitaxel yielded a doubling of median PFS (112 v 56 days) and a 41.7% risk reduction for disease progression/death (hazard ratio, 0.583; P = .035). Respective RRs for the E + P and paclitaxel groups were 15% and 3%; median OS was 11.9 v 7.8 months. Of patients on paclitaxel alone, 19 (68%) of 28 crossed over to E + P after they experienced progression. Weekly E + P was well tolerated.

E + P resulted in a statistically significant doubling of median PFS, with an acceptable toxicity profile and encouraging OS. A multinational, phase III trial (SYMMETRY) of E + P compared with paclitaxel alone in metastatic melanoma has closed.

In this review, we explore the biology of the HDAC enzymes, summarize the pharmacologic properties of HDAC inhibitors, and examine results of selected clinical trials. We consider the potential of these inhibitors in combination therapy with targeted drugs and with cytotoxic chemotherapy.

HDAC inhibitors promote growth arrest, differentiation, and apoptosis of tumor cells, with minimal effects on normal tissue. In addition to decompaction of the histone/DNA complex, HDAC inhibition also affects acetylation status and function of nonhistone proteins. HDAC inhibitors have demonstrated antitumor activity in clinical trials, and one drug of this class, vorinostat, is US Food and Drug Administration approved for the treatment of cutaneous T-cell lymphoma. Other inhibitors in advanced stages of clinical development, including depsipeptide and MGCD0103, differ from vorinostat in structure and isoenzyme specificity, and have shown activity against lymphoma, leukemia, and solid tumors. Promising preclinical activity in combination with cytotoxics, inhibitors of heat shock protein 90, and inhibitors of proteasome function have led to combination therapy trials.

HDAC inhibitors are an important emerging therapy with single-agent activity against multiple cancers, and have significant potential in combination use.

Two search strings that included both cancer and supportive as terms (with random article type, or review or meta-analysis) explored databases from 1966 to 2008. Citations, abstracts, and papers were reviewed for inclusion criteria, and relevant data were extracted by two independent researchers. Data were validated for accuracy. Ethical and methodologic validity were evaluated by using the criteria derived from the Helsinki Requirements of the WMA; CONSORT statements for the evaluation of reports of randomized, controlled trials; and the universal requirements for ethical clinical research.

Forty-three published papers were identified that described 32 studies, 20 of which incorporated the design of treatment plus supportive care (SC) versus SC alone, and 12 of which incorporated the design of treatment versus SC. Most of the studies had poor compliance to critical Helsinki requirements, to methodologic precautions derived from the CONSORT statement for studies involving a nonpharmacologic arm, and to four of seven universal requirements for ethical clinical research.

Lack of rigor in BSC studies has contributed to a generation of research with widespread ethical and methodologic shortcomings. Ad hoc SC and lack of standardization of SC delivery may be sources of systematic bias or error in BSC trials. Rectifying these shortcomings in future studies demands greater vigilance toward these issues by researchers, institutional review boards, editors, and peer reviewers. Given the prevalence of overlooked problems that are later identified, currently open BSC studies should be reevaluated by institutional review boards and researchers to check for ethical and methodologic validity, and identified shortcomings should be addressed.

Patients with clinical T3 or T4 or node-positive rectal cancer were randomly assigned to preoperative or postoperative chemoradiotherapy. Chemotherapy consisted of fluorouracil and leucovorin with 45 Gy in 25 fractions with a 5.40-Gy boost within the original margins of treatment. In the preoperative group, surgery was performed within 8 weeks after completion of radiotherapy. In the postoperative group, chemotherapy began after recovery from surgery but no later than 4 weeks after surgery. The primary end points were disease-free survival (DFS) and overall survival (OS).

From August 1993 to June 1999, 267 patients were randomly assigned to NSABP R-03. The intended sample size was 900 patients. Excluding 11 ineligible and two eligible patients without follow-up data, the analysis used data on 123 patients randomly assigned to preoperative and 131 to postoperative chemoradiotherapy. Surviving patients were observed for a median of 8.4 years. The 5-year DFS for preoperative patients was 64.7% v 53.4% for postoperative patients (P = .011). The 5-year OS for preoperative patients was 74.5% v 65.6% for postoperative patients (P = .065). A complete pathologic response was achieved in 15% of preoperative patients. No preoperative patient with a complete pathologic response has had a recurrence.

Preoperative chemoradiotherapy, compared with postoperative chemoradiotherapy, significantly improved DFS and showed a trend toward improved OS.

We identified 269 consecutive patients who had CRC resected at our institution. Tumors were rereviewed for PNI by a pathologist blinded to the patients' outcomes. Overall and disease-free survivals were determined using the Kaplan-Meier method, with differences determined by multivariate analysis using the Cox multiple hazards model. Results were compared using the log-rank test.

PNI was identified in less than 0.5% of the initial pathology reports. On rereview, 22% of tumors in our series were found to be PNI positive. The 5-year disease-free survival rate was four-fold greater for patients with PNI-negative tumors versus those with PNI-positive tumors (65% v 16%, respectively; P < .0001). The 5-year overall survival rate was 72% for PNI-negative tumors versus 25% for PNI-positive tumors. On multivariate analysis, PNI was an independent prognostic factor for both cancer-specific overall and disease-free survival. In a subset analysis comparing patients with node-negative disease with patients with stage III disease, the 5-year disease-free survival rate was 56% for stage III patients versus 29% for patients with node-negative, PNI-positive tumors (P = .0002). Similar results were seen for overall survival.

PNI is grossly underreported in CRC and could serve as an independent prognostic factor of outcomes in these patients. PNI should be considered when stratifying CRC patients for adjuvant treatment.

Between 1992 and 2005, 1,726 invasive breast cancers were identified among 53,310 postmenopausal women from the French E3N cohort (mean duration of follow-up, 8.1 years). Hazard ratios (HRs) and CIs were estimated using Cox models, with MHT never users as the reference.

Among recent users of EP-MHT, the risk of breast cancer varied according to the timing of treatment initiation. This variation was confined to short durations of use (≤ 2 years): the HR was 1.54 (95% CI, 1.28 to 1.86) for short treatments initiated in the 3-year period following menopause onset and 1.00 (95% CI, 0.68 to 1.47) for short treatments initiated later (P = .04 for homogeneity). However, this pattern of risks was not observed in users of EP-MHT containing progesterone, among whom there was no significantly increased risk associated with short duration of use (HR was 0.87 [95% CI, 0.57 to 1.32] for treatments initiated ≤ 3 years after menopause, and HR was 0.90 [95% CI, 0.45 to 1.81] for treatments initiated later). Longer durations of EP-MHT use were generally associated with increases in breast cancer risk, whatever the gap time.

Our results suggest that, for some EP-MHT, the timing of treatment initiation transiently modulates the risk of breast cancer and that, when initiated close to menopause, even short durations of use are associated with an increased breast cancer risk. Estrogen + progesterone combinations might be an exception in this regard.

The National Surgical Adjuvant Breast and Bowel Project's Study of Tamoxifen and Raloxifene (STAR) study was a randomized clinical trial of tamoxifen 20 mg/d or raloxifene 60 mg/d in healthy postmenopausal women at increased risk of breast cancer. The 1,498 women who were randomly assigned in STAR were age 65 years and older, were not diagnosed with dementia, and were enrolled onto the Cognition in the Study of Tamoxifen and Raloxifene (Co-STAR) trial, beginning 18 months after STAR enrollment started. A cognitive test battery modeled after the one used in the Women's Health Initiative Study of Cognitive Aging (WHISCA) was administered. Technicians were centrally trained to administer the battery and recertified every 6 months. Analyses were conducted on all participants and on 273 women who completed the first cognitive battery before they started taking their medications.

Overall, there were no significant differences in adjusted mean cognitive scores between the two treatment groups across visits. There were significant time effects across the three visits for some of the cognitive measures. Similar results were obtained for the subset of women with true baseline measures.

Tamoxifen and raloxifene are associated with similar patterns of cognitive function in postmenopausal women at increased risk of breast cancer. Future comparisons between these findings and patterns of cognitive function in hormone therapy and placebo groups in WHISCA should provide additional insights into the effects of tamoxifen and raloxifene on cognitive function in older women.

Serial CTC levels were obtained in patients starting a new treatment regimen for progressive, radiographically measurable MBC. Peripheral blood was collected for CTC enumeration at baseline and at 3- to 4-week intervals. Clinical outcomes were based on radiographic studies performed in 9- to 12-week intervals.

Sixty-eight patients were evaluable for the CTC-imaging correlations, and 74 patients were evaluable for the PFS analysis. Median follow-up was 13.3 months. A statistically significant correlation was demonstrated between CTC levels and radiographic disease progression in patients receiving chemotherapy or endocrine therapy. This correlation applied to CTC results obtained at the time of imaging (odds ratio [OR], 6.3), 3 to 5 weeks before imaging (OR, 3.1), and 7 to 9 weeks before imaging (OR, 4.9). Results from analyses stratified by type of therapy remained statistically significant. Shorter PFS was observed for patients with five or more CTCs at 3 to 5 weeks and at 7 to 9 weeks after the start of treatment.

We provide, to our knowledge, the first evidence of a strong correlation between CTC results and radiographic disease progression in patients receiving chemotherapy or endocrine therapy for MBC. These findings support the role of CTC enumeration as an adjunct to standard methods of monitoring disease status in MBC.

We surveyed 258 women who recently underwent surgical treatment at six New York City hospitals for early-stage breast cancer about their care, knowledge, and beliefs about breast cancer and its treatment. As per national guidelines, all women should have received adjuvant treatment. Adjuvant treatment data were obtained from inpatient and outpatient charts. Factor analysis was used to create scales scored to 100 of treatment beliefs and knowledge, medical mistrust, and physician communication about treatment. Bivariate and multivariate analyses assessed differences between treated and untreated women.

Compared with treated women, untreated women were less likely to know that adjuvant therapies increase survival (on a 100-point scale; 66 v 75; P < .0001), had greater mistrust (64 v 53; P = .001), and had less self-efficacy (92 v 97; P < .05); physician communication about treatment did not affect patient knowledge of treatment benefits (r = 0.8; P = .21). Multivariate analysis found that untreated women were more likely to be 70 years or older (adjusted relative risk [aRR], 1.11; 95% CI, 1.00 to 1.13), to have comorbidities (aRR, 1.10; 95% CI, 1.04 to 1.12), and to express mistrust in the medical delivery system (aRR, 1.003; 95% CI, 1.00 to 1.007), even though they were more likely to believe adjuvant treatments were beneficial (aRR, 0.99; 95% CI, 0.98 to 0.99; model c, 0.84; P ≤ .0001).

Patient knowledge and beliefs about treatment and medical mistrust are mutable factors associated with underuse of effective adjuvant therapies. Physicians may improve cancer care by ensuring that discussions about adjuvant therapy include a clear presentation of the benefits, not just the risks of treatment, and by addressing patient trust in and concerns about the medical system.

Bone marrow samples from 830 Italian patients were collected on day 15, after 14 days of steroids, and one dose of intrathecal methotrexate, vincristine, daunorubicine, and asparaginase. Cells were analyzed by four-color FCM for detection of leukemia-associated immunophenotypes.

Three patient risk groups were identified by FCM: standard (< 0.1% blast cells; 42% of the total), intermediate (0.1 to < 10%; 47%), and high (≥ 10%; 11%). Their 5-year cumulative incidences of relapse were 7.5% (SE, 1.5), 17.5% (SE, 2.1), and 47.2% (SE, 5.9), respectively. In multivariate analysis, FCM was the most important prognostic factor among those available by day 15, with two-fold and five-fold increase in the risk of relapse compared with patients with less than 0.1%. PCR MRD, when added to the model, had significant prognostic impact; yet high levels of FCM MRD retained an independent ability to detect a significantly higher risk of relapse.

Measurement of FCM MRD in day 15 bone marrow was the most powerful early predictor of relapse, applicable to virtually all patients; it may complement PCR MRD–based stratification including later time points, thus allowing additional treatment tailoring.

We evaluated whether imatinib (340 mg/m²/d) with an intensive chemotherapy regimen improved outcome in children ages 1 to 21 years with Ph+ ALL (N = 92) and compared toxicities to Ph– ALL patients (N = 65) given the same chemotherapy without imatinib. Exposure to imatinib was increased progressively in five patient cohorts that received imatinib from 42 (cohort 1; n = 7) to 280 continuous days (cohort 5; n = 50) before maintenance therapy. Patients with human leukocyte antigen (HLA) –identical sibling donors underwent blood and marrow transplantation (BMT) with imatinib given for 6 months following BMT.

Continuous imatinib exposure improved outcome in cohort 5 patients with a 3-year event-free survival (EFS) of 80% ± 11% (95% CI, 64% to 90%), more than twice historical controls (35% ± 4%; P < .0001). Three-year EFS was similar for patients in cohort 5 treated with chemotherapy plus imatinib (88% ± 11%; 95% CI, 66% to 96%) or sibling donor BMT (57% ± 22%; 95% CI, 30.4% to 76.1%). There were no significant toxicities associated with adding imatinib to intensive chemotherapy. The higher imatinib dosing in cohort 5 appears to improve survival by having an impact on the outcome of children with a higher burden of minimal residual disease after induction.

Imatinib plus intensive chemotherapy improved 3-year EFS in children and adolescents with Ph+ ALL, with no appreciable increase in toxicity. BMT plus imatinib offered no advantage over BMT alone. Additional follow-up is required to determine the impact of this treatment on long-term EFS and determine whether chemotherapy plus imatinib can replace BMT.

Patients were randomly assigned to 39 weeks of VAC versus VAC/VTC; local therapy began after week 12. Patients with parameningeal RMS with intracranial extension (PME) were treated with VAC and immediate x-ray therapy. The primary study end point was failure-free survival (FFS). The study was designed with 80% power (5% two-sided level) to detect an increase in 5-year FFS from 64% to 75% with VAC/VTC.

A total of 617 eligible patients were entered onto the study: 264 were randomly assigned to VAC and 252 to VAC/VTC; 101 PME patients were nonrandomly treated with VAC. Treatment strata were embryonal RMS, stage 2/3, group III (33%); embryonal RMS, group IV, less than age 10 years (7%); alveolar RMS or undifferentiated sarcoma (UDS), stage 1 or group I (17%); alveolar RMS/UDS (27%); and PME (16%). At a median follow-up of 4.3 years, 4-year FFS was 73% with VAC and 68% with VAC/VTC (P = .3). There was no difference in effect of VAC versus VAC/VTC across risk groups. The frequency of second malignancies was similar between the two treatment groups.

For intermediate-risk RMS, VAC/VTC does not significantly improve FFS compared with VAC.

CCG 1961 entered patients with ALL 1 to 21 years of age with initial WBC count ≥ 50,000/µL and/or age ≥ 10 years. Randomly assigned therapies evaluated the impact of postinduction treatment intensification on outcome. We examined outcome and prognostic factors for 262 young adults with ALL.

Five-year event-free and overall survival rates for young adult patients are 71.5% (SE, 3.6%) and 77.5% (SE, 3.3%), respectively. Rapid responder patients (< 25% bone marrow blasts on day 7) randomly assigned to augmented therapy had 5-year event-free survival of 81.8% (SE, 7%), as compared with 66.8% (SE, 6.7%) for patients receiving standard therapy (P = .07). One versus two interim maintenance and delayed intensification courses had no significant impact on event-free survival. WBC count more than 50,000/µL was an adverse prognostic factor.

Young adult patients with ALL showing a rapid response to induction chemotherapy benefit from early intensive postinduction therapy but do not benefit from a second interim maintenance and delayed intensification phase. Given the excellent outcome with this chemotherapy, there seems to be no role for the routine use of allogeneic stem-cell transplantation in first remission for young adults with ALL.

Nine published and in-house real-time quantitative polymerase chain reaction WT1 assays were systematically evaluated within the European LeukemiaNet; the best-performing assay was applied to diagnostic AML samples (n = 620), follow-up samples from 129 patients treated with intensive combination chemotherapy, and 204 normal peripheral blood (PB) and bone marrow (BM) controls.

Considering relative levels of expression detected in normal PB and BM, WT1 was sufficiently overexpressed to discriminate ≥ 2-log reduction in transcripts in 46% and 13% of AML patients, according to the respective follow-up sample source. In this informative group, greater WT1 transcript reduction after induction predicted reduced relapse risk (hazard ratio, 0.54 per log reduction; 95% CI, 0.36 to 0.83; P = .004) that remained significant when adjusted for age, WBC count, and cytogenetics. Failure to reduce WT1 transcripts below the threshold limits defined in normal controls by the end of consolidation also predicted increased relapse risk (P = .004).

Application of a standardized WT1 assay provides independent prognostic information in AML, lending support to incorporation of early assessment of MRD to develop more robust risk scores, to enhance risk stratification, and to identify patients who may benefit from allogeneic transplantation.

Eighty-three patients with de novo adult Philadelphia chromosome (Ph) –positive ALL were enrolled onto institutional (n = 17) or Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Working Party delle Leucemia Acute (n = 66) clinical trials. Treatments included tyrosine kinase inhibitor (TKI) alone, conventional chemotherapy, or a combination of TKI and chemotherapy.

A 7p12 deletion of IKZF1 (Ikaros) was identified in 52 (63%) of 83 patients. The pattern of deletion varied among different patients, but the two most common deletion types were loss of exons 4 to 7 in 31 (37%) of 83 patients and loss of exons 2 to 7 in 17 (20%) of 83 patients. Disease-free survival (DFS) was shorter in patients with IKZF1 deletion versus patients with IKZF1 wild type (10 v 32 months, respectively; P = .02). Furthermore, a significantly shorter cumulative incidence of relapse was recorded in patients with IKZF1 deletion versus patients with IKZF1 wild type (10.1 v 56.1 months, respectively; P = .001). Multivariate analysis confirmed the negative prognostic impact of IKZF1 deletion on DFS (P = .04).

We conclude that IKZF1 deletions are likely to be a genomic alteration that significantly affects the prognosis of Ph-positive ALL in adults.

Poststudy CLL treatment information was collected. Patients were observed for survival for up to 5 years from the date of random assignment.

Poststudy CLL treatment was balanced between arms. Intent-to-treat analysis of 5-year survival showed no significant between-treatment difference (hazard ratio, 0.87; P = .34). Among the greater than 40% of patients with complete or partial remission, a significant 5-year survival benefit was observed with OBL-FC (hazard ratio, 0.60; P = .038). Among patients with fludarabine-sensitive disease who had previously demonstrated maximum benefit with OBL-FC, the previously observed survival benefit improved: a 50% reduction in the risk of death was observed (P = .004).

In relapsed/refractory CLL, OBL combined with FC offers patients who achieve complete or partial remission, as well as those who have fludarabine-sensitive disease, a significant survival benefit.

Patients with relapsed or refractory MCL were eligible for the study if they had adequate major organ function and performance status. Those with CNS disease, pleural effusion, circulating lymphoma cells ≥ 5,000/µL, or history of stem-cell transplant were ineligible. Patients with a platelet count ≥ 150,000/µL received a dose of 0.4 mCi/kg of ⁹⁰Y–ibritumomab tiuxetan, whereas those with a platelet count less than 150,000/µL received a dose of 0.3 mCi/kg.

Thirty-four patients with a median age of 68 years (range, 52 to 79 years) received the therapeutic dose. The patients had received a median of three prior treatment regimens (range, one to six treatment regimens), including those that contained rituximab (n = 32) and bortezomib (n = 7). Of the 32 patients with measurable disease, 10 (31%) achieved complete or partial remission. After a median follow-up of 22 months (range, 2 to 72+ months), an intent-to-treat analysis revealed a median event-free survival (EFS) duration of 6 months and an overall survival duration of 21 months. The median EFS for those who achieved partial or complete remission was 28 months, while it was 3 months for those whose disease did not respond (P < .0001); it was 9 months for patients whose tumor measured less than 5 cm in the largest diameter before treatment and 3 months for those whose tumor measured ≥ 5 cm (P = .015).

The single-agent activity of ⁹⁰Y–ibritumomab tiuxetan and its favorable safety profile warrant its further development for the treatment of MCL.

We performed 250K and 6.0 SNP-A analyses on 140 patients with primary (p) and secondary (s) AML and correlated the results with clinical outcomes and Flt-3/nucleophosmin (NPM-1) status.

SNP-A is more sensitive than MC in detecting unbalanced lesions (pAML, 65% v 39%, P = .002; and sAML, 78% v 51%, P = .003). Acquired somatic UPD, not detectable by MC, was common in our AML cohort (29% in pAML and 35% in sAML). Patients with SNP-A lesions including acquired somatic UPD exhibited worse overall survival (OS) and event-free survival (EFS) in pAML with normal MC and in pAML/sAML with abnormal MC. SNP-A improved the predictive value of Flt-3 internal tandem duplication/NPM-1 status, with inferior survival seen in patients with additional SNP-A defects. Multivariate analyses confirmed the independent predictive value of SNP-A defects for OS (hazard ratio [HR] = 2.52; 95% CI, 1.29 to 5.22; P = .006) and EFS (HR = 1.72; 95% CI, 1.12 to 3.48; P = .04).

SNP-A analysis allows enhanced detection of chromosomal abnormalities and provides important prognostic impact in AML.

The Surveillance, Epidemiology, and End Results database was reviewed to identify patients diagnosed between 1980 and 2005. To study the potential impact of the introduction of rituximab on survival, we used the year 2000 as cutoff point.

We identified 769 patients with testicular DLBCL. The median age at diagnosis was 68.0 years. The incidence of DLBCL increased over time, with the highest rate among whites (twice that of blacks). The median overall survival (OS) for the whole group was 4.6 years, whereas the disease-specific survival (DSS) rates at 3, 5, and 15 years were 71.5%, 62.4%, and 43.0%, respectively. Independent predictors of worse DSS were older age, diagnosis before 1986, advanced stage, left testicular involvement, and not having surgery and radiation. The use of radiation did not change significantly over time. When testicular and nodal DLBCL patients were analyzed together, testicular primary was an independent predictor of better OS and DSS. Unlike nodal DLBCL, DSS did not improve in the patients with testicular DLBCL diagnosed after the year 2000.

The incidence of testicular DLBCL is increasing. Compared with nodal DLBCL, testicular DLBCL patients have a better overall prognosis but are at higher risk of late disease-related deaths. The introduction of rituximab in clinical practice does not seem to improve their early outcome.

All patients scheduled to receive a curative surgery for a first diagnosis of nonmetastatic cancer were approached to participate in the study on the day of their preoperative visit. As part of a larger population-based longitudinal study, 991 cancer patients completed various self-report scales and an insomnia diagnostic interview at the perioperative phase (T1) and 2 months later (T2).

At T1, 28.5% of the patients met the diagnostic criteria for an insomnia syndrome, and 31.0% had insomnia symptoms; these rates decreased to 26.2% and 22.2%, respectively, at T2. The highest rates of insomnia were found in breast cancer patients, whereas the lowest rates were obtained in prostate cancer patients. Findings indicated an incidence rate of 18.6%, a persistence rate of 68.0%, and a remission rate of 32.0%. Female sex and the presence of an arousability trait (predisposing factors), a diagnosis of head and neck cancer, the administration of surgery, and an increase in anxiety symptoms between T1 and T2 (precipitating factors), and higher baseline levels and increases between T1 and T2 in dysfunctional beliefs about sleep, sleep monitoring, and maladaptive sleep behaviors (maintenance factors) were all associated with an increased risk for insomnia incidence.

This study confirms the high prevalence of insomnia comorbid with cancer during the 2 months after the perioperative visit and identifies several factors that might be involved in its development.

Expression profiling was performed on 74 nonseminomatous GCTs (NSGCTs) from cisplatin-treated patients (ie, training set) and on 34 similarly treated patients with NSGCTs (ie, validation set). A gene classifier was developed by using prediction analysis for microarrays (PAM) for the binary end point of 5-year overall survival (OS). A predictive score was developed for OS by using the univariate Cox model.

In the training set, PAM identified 140 genes that predicted 5-year OS (cross-validated classification rate, 60%). The PAM model correctly classified 90% of patients in the validation set. Patients predicted to have good outcome had significantly longer survival than those with poor predicted outcome (P < .001). For the OS end point, a 10-gene model had a predictive accuracy (ie, concordance index) of 0.66 in the training set and a concordance index of 0.83 in the validation set. Dichotomization of the samples on the basis of the median score resulted in significant differences in survival (P = .002). For both end points, the gene-based predictor was an independent prognostic factor in a multivariate model that included clinical risk stratification (P < .01 for both).

We have identified gene expression signatures that accurately predict outcome in patients with GCTs. These predictive genes should be useful for the prediction of patient outcome and could provide novel targets for therapeutic intervention.

Seven hundred twenty-two patients were randomly assigned to receive placebo or thalidomide capsules 100 to 200 mg daily for up to 2 years. All patients received gemcitabine and carboplatin every 3 weeks for up to four cycles. End points were overall survival (OS), progression-free survival (PFS), response rate, grade 3/4 toxicity, and quality of life (QoL).

The median OS rates were 8.9 months (placebo) and 8.5 months (thalidomide). The hazard ratio (HR) was 1.13 (95% CI, 0.97 to 1.32; P = .12). The 2-year survival rate was 16% and 12% in the placebo and thalidomide arms, respectively. The PFS results were consistent with those for OS. The risk of having a thrombotic event was increased by 74% in the thalidomide group: HR of 1.74 (95% CI, 1.20 to 2.52; P = .003). There were no differences in hematologic toxicities, but a slight excess of rash and neuropathy in the thalidomide group. QoL scores were similar but thalidomide was associated with less insomnia, and more constipation and peripheral neuropathy. In a retrospective analysis, patients with nonsquamous histology in the thalidomide group had a poorer survival: 2-year risk difference of 10% (95% CI, 4% to 16%; P < .001).

In this large trial of patients with NSCLC, thalidomide in combination with chemotherapy did not improve survival overall, but increased the risk of thrombotic events. Unexpectedly, survival was significantly worse in patients with nonsquamous histology.

This open-label multicenter trial for first- and second-line treatment of nonsquamous NSCLC enrolled patients with treated brain metastases. First-line patients received bevacizumab (15 mg/kg) every 3 weeks with platinum-based doublet therapy or erlotinib (at physician's decision), and second-line patients received bevacizumab with single-agent chemotherapy or erlotinib, until disease progression or death.

Of the 115 enrolled patients, 66 of 76 first-line patients received carboplatin-based chemotherapy; 22 of 39 second-line patients received pemetrexed, and nine of 39 received erlotinib. As of the June 23, 2008 data cut, among 106 safety-evaluable patients, median on-study duration was 6.3 months (range, 0 to 22 months), with a median of five bevacizumab cycles (range, one to 17), and no reported episodes of grade ≥ 2 CNS hemorrhage (95% CI, 0.0% to 3.3%). Of the bevacizumab-targeted adverse events reported, two were grade 5. Both were pulmonary hemorrhages, one occurring during treatment and the other occurring 6 weeks after the data cut; there was also one grade 4, nonpulmonary/non-CNS hemorrhage. Twenty-six patients (24.5%) discontinued study treatment as a result of an adverse event, and 37 (34.9%) discontinued because of disease progression.

Addition of bevacizumab to various chemotherapy agents or erlotinib in patients with NSCLC and treated brain metastases seems to be safe and is associated with a low incidence of CNS hemorrhage.

Patients with advanced solid tumors were eligible. Dose escalations were performed in three groups with two formulations: uncoated on an empty stomach (UES), uncoated with food (UFED), and film-coated (FC) without food. Initial dose escalation in the UES group was followed by parallel escalations in the UFED and FC groups.

Fifty-nine patients enrolled. CP-868,596 was escalated from 100 mg to 340 mg daily in the UES group, from 60 mg to 100 mg twice daily in the UFED group, and from 100 mg once daily to 140 mg twice daily in the FC group. MTDs were 200 mg daily in the UES group and 100 mg twice daily in the FC group; MTD was not reached at 100 mg twice daily in the UFED group. Dose-limiting toxicities included hematuria, increased -glutamyltransferase or ALT, insomnia, and nausea/vomiting. Most treatment-related AEs were of grades 1 to 2 severity; nausea, vomiting, and diarrhea were reported most frequently. Administration with food generally improved tolerability. CP-868,596 was absorbed slowly; systemic exposure parameters appeared to increase greater than proportionally with dose. Mean serum concentrations exceeded the preclinically predicted minimal efficacious concentration (ie, 16 ng/mL) at all dosages. Food and film coating apparently increased interpatient variability of the maximum observed plasma concentration and the area under the concentration-time curve. No objective responses were reported, and eight patients achieved stable disease (mean duration, 5.7 months).

CP-868,596 potentially demonstrated greater than dose-proportional pharmacokinetics. The recommended dosage of 100 mg twice daily with food was well tolerated. Additional development as a single agent in selected populations or in combination with chemotherapy in broader populations is warranted.

Eligible patients with metastatic and/or recurrent solid tumors received three inoculations on days 1, 22, and 43 at doses of total peptide that ranged from 0.5 to 3.0 mg. Immunogenicity was evaluated by enzyme-linked immunosorbent assay, flow cytometry, and HER2 signaling assays.

Twenty-four patients received three inoculations at the intended dose levels, which elicited antibodies able to recognize native HER2 receptor and inhibited both the proliferation of HER2-expressing cell lines and phosphorylation of the HER2 protein. The MTD was determined to be the highest dose level of 3.0 mg of the combination vaccine. There was a significant increase from dose level 1 (0.5 mg) to dose level 4 (3.0 mg) in HER2-specific antibodies. Four patients (one each with adrenal, colon, ovarian, and squamous cell carcinoma of unknown primary) were judged to have stable disease; two patients (one each with endometrial and ovarian cancer) had partial responses; and 11 patients had progressive disease. Patients with stable disease received 6-month boosts, and one patient received a 20-month boost.

The combination vaccines were safe and effective in eliciting antibody responses in a subset of patients (62.5%) and were associated with no serious adverse events, autoimmune disease, or cardiotoxicity. There was preliminary evidence of clinical activity in several patients.

A literature review was performed to obtain data on central nervous system metastases in patients with breast cancer.

HER2 amplification/overexpression is a prognostic and predictive factor for the development of CNS metastases. Autopsy data show that the incidence rate for CNS metastases in patients with breast cancer is approximately 30%; this may be higher (ie, 30% to 50%) in patients with HER2-positive disease. Treatment with trastuzumab is not associated with an increased incidence of CNS metastases. Data from three phase III adjuvant trials showed the incidence was similar between patients who received trastuzumab and those who did not. Furthermore, trastuzumab can significantly improve overall survival in HER2-positive patients who already have CNS metastases compared with patients who do not receive trastuzumab or those who have HER2-negative brain metastases. This survival advantage is conferred via systemic control of the disease. The current standard of care for patients with CNS metastases is whole-brain radiotherapy (WBRT), with or without surgery, or stereotactic radiosurgery. In the future, novel therapies or combinations of therapies may additionally improve survival in these patients.

The incidence of CNS metastases in trastuzumab-treated patients is similar to that in all patients with HER2-positive disease. Trastuzumab can improve survival in patients with HER2-positive disease with CNS metastases.

In the European Organisation for Research and Treatment of Cancer boost versus no boost trial, after whole breast irradiation, patients with microscopically complete excision of invasive tumor, were randomly assigned to receive or not an extra boost dose of 16 Gy. For a subset of 1,616 patients central pathology review was performed.

The 10-year cumulative risk of local breast cancer relapse as a first event was not significantly influenced if the margin was scored negative, close or positive for invasive tumor or ductal carcinoma in situ according to central pathology review (log-rank P = .45 and P = .57, respectively). In multivariate analysis, high-grade invasive ductal carcinoma was associated with an increased risk of local relapse (P = .026; hazard ratio [HR], 1.67), as was age younger than 50 years (P < .0001; HR, 2.38). The boost dose of 16 Gy significantly reduced the local relapse rate (P = .0006; HR, 0.47). For patients younger than 50 years old and in patients with high grade invasive ductal carcinoma, the boost dose reduced the local relapse from 19.4% to 11.4% (P = .0046; HR, 0.51) and from 18.9% to 8.6% (P = .01; HR, 0.42), respectively.

Young age and high-grade invasive ductal cancer were the most important risk factors for local relapse, while margin status had no significant influence. A boost dose of 16 Gy significantly reduced the negative effects of both young age and high-grade invasive cancer.

Three hundred sixteen consecutive mastectomy specimens (232 therapeutic, 84 prophylactic) with grossly unremarkable nipples were evaluated by coronal sections through the entire nipple and subareolar tissue. Extent and location of nipple involvement by carcinoma was assessed with the tissue deep to the skin as potential retroareolar en-face resection margin.

Seventy-one percent of nipples from therapeutic mastectomies showed no pathologic abnormality, 21% had ductal carcinoma in situ (DCIS), invasive carcinoma (IC), or lymphovascular invasion (LVI), and 8% lobular neoplasia (lobular carcinoma in situ). Human epidermal growth factor receptor 2 amplification, tumor size, and tumor-nipple distance were associated with nipple involvement by multivariate analysis (P = .0047, .0126, and .0176); histologic grade of both DCIS (P = .002) and IC (P = .03), LVI (P = .03), and lymph node involvement (P = .02) by univariate analysis. Nipple involvement by IC or DCIS was identified in the retroareolar margin with a sensitivity of 0.8 and a negative predictive value of 0.96. None of the 84 prophylactic mastectomies showed nipple involvement by IC or DCIS.

Nipple-sparing mastectomy may be suitable for selected cases of breast carcinoma with low probability of nipple involvement by carcinoma and prophylactic procedures. A retroareolar en-face margin may be used to test for occult involvement in patients undergoing nipple-sparing mastectomy.

Postmenopausal patients with stage I to III breast cancer who were taking adjuvant AIs were enrolled (n = 92). Patients who were not receiving hormone treatment were included as a control group (n = 28). Musculoskeletal sonography and EMG were applied to the patients and the controls along with markers of autoimmunity.

Thirty patients (32.6%) reported to have AI-related new-onset or worsening arthralgia. The most commonly affected joints were knee (70%), wrist (70%), and small joints of the hand (63%). Patients taking AIs had increased tendon thicknesses compared with those who never received AIs (P < .001). Patients with AI-related arthralgia had higher rates of effusion in hand joints/tendons than those without arthralgia (P = .033). More patients with AI-related arthralgia had EMG findings consistent with carpal tunnel syndrome (CTS) than those without arthralgia (P = .024). No significant difference was observed in erythrocyte sedimentation rates, C-reactive protein, antinuclear antibody, antidouble stranded DNA antibody, rheumatoid factor, or anticyclic citrullinated peptide levels between patients and controls or between those with and without arthralgia.

Patients with AI-related arthralgia often show tenosynovial changes suggesting tenosynovitis, exerting local problems but lacking a systemic inflammatory component. Our finding of increased CTS frequency also supports this hypothesis.

The current analyses were based on the 100-month median follow-up data in postmenopausal women in the two monotherapy arms (anastrozole, n = 3,092; tamoxifen, n = 3,094). Here, we investigate the natural history of patients who presented with CTS during adjuvant treatment for breast cancer and the relative importance of a range of known risk factors for CTS.

After 100 months of follow-up, 80 cases (2.6%) of CTS were reported in the anastrozole arm, compared with 23 cases (0.7%) in the tamoxifen arm (P < .0001). The majority of CTS cases were reported as mild to moderate intensity and occurred early. None of the women stopped treatment medication as a result of CTS. CTS was significantly increased for women who used prior hormone replacement therapy (P = .007) or received prior chemotherapy (P = .01). Those who were 60 years of age or older at entry were at lower risk of CTS compared with their counterparts (P = .002).

Although the use of anastrozole is associated with a greater incidence of CTS, it is rare, and most cases were of mild to moderate intensity and short duration. CTS has little impact on the overall risk-to-benefit ratio for the use of anastrozole in postmenopausal women with early breast cancer.

An independent, blinded review of radiologic and clinical data was performed, assessing progression and response according to Response Evaluation Criteria in Solid Tumors. In addition, ECOG's investigator assessments were reanalyzed using the same methods applied to the independent review. The primary end point was PFS as assessed by an independent review facility (IRF).

The addition of bevacizumab to paclitaxel resulted in a statistically significant improvement in PFS using both the IRF and investigator assessments. Hazard ratios for PFS (0.48, 95% CI, 0.385 to 0.607; P < .0001 for the IRF v 0.42, 95% CI, 0.34 to 0.52; P < .0001 for ECOG investigators) and the improvement in median PFS (11.3 v 5.8 months for the IRF v 11.4 v 5.8 months for ECOG investigators) were similar. Among patients with measurable disease at baseline, the IRF-assessed ORR was significantly higher in patients treated with paclitaxel and bevacizumab (48.9% v 22.2%; P < .0001).

The risk of progression was reduced by more than half and the ORR more than doubled with the addition of bevacizumab to weekly paclitaxel in both analyses, confirming a substantial and robust bevacizumab treatment effect. The consistency between the IRF and ECOG analyses validates the original data previously reported by ECOG in this open-label trial.

Patients were assigned to risk groups according to standard prognostic features; the low-risk group (n = 753 genotyped) received follow-up only, and the high-risk group (n = 401 genotyped) was randomly assigned to adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) or cyclophosphamide, doxorubicin, and fluorouracil (CAF), with or without tamoxifen. DNA from archived normal lymph node tissue was genotyped, and Cox proportional hazard models were used to calculate DFS associated with MPO genotypes.

Among women in the treatment arm, those with MPO G alleles had more than a two-fold reduction in hazard of recurrence (adjusted hazard ratio [HR] for GA genotypes, 0.51; 95% CI, 0.21 to 0.99; HR for GG genotypes, 0.41; 95% CI, 0.21 to 0.77). Effects were greatest among women who were further randomly assigned to tamoxifen (HR for GA genotypes, 0.28; 95% CI, 0.12 to 0.69; HR for GG genotypes, 0.19; 95% CI, 0.08 to 0.45). There were no significant associations between genotypes and DFS among women in the untreated arm, and relationships between genotypes and DFS did not differ by CAF or CMF.

These results, observed in two independent study populations, indicate that high-activity MPO genotypes are associated with better survival among women receiving cyclophosphamide-containing therapy, particularly when followed by tamoxifen therapy. MPO can be inhibited and/or upregulated by commonly used drugs; thus, our findings merit further investigation for optimization of therapeutics for breast cancer.

We evaluated deferred treatment for PCa in the Health Professionals Follow-up Study, a prospective study of 51,529 men. Cox proportional hazards models were used to calculate hazard ratios (HRs) for time to eventual treatment among men who deferred treatment for more than 1 year after diagnosis. HRs for time to metastasis or death as a result of PCa were compared between patients who deferred treatment and those who underwent immediate treatment within 1 year of diagnosis.

From among 3,331 cohort participants diagnosed with PCa from 1986 to 2007, 342 (10.3%) initially deferred treatment. Of these, 174 (51%) remained untreated throughout follow-up (mean 7.7 years); the remainder were treated an average of 3.9 years after diagnosis. Factors associated with progression to treatment among DT patients included younger age, higher clinical stage, higher Gleason score, and higher prostate-specific antigen at diagnosis. We observed similar rates for development of metastases (n = 20 and n = 199; 7.2 v 8.1 per 1,000 person-years; P = .68) and death as a result of PCa (n = 8 and n = 80; 2.4 v 2.6 per 1,000 person-years; P = .99) for DT and immediate treatment, respectively.

In this nationwide cohort, more than half the men who opted for DT remained without treatment for 7.7 years after diagnosis. Older men and men with lesser cancer severity at diagnosis were more likely to remain untreated. PCa mortality did not differ between DT and active treatment patients.

Patients with localized prostate cancer and Gleason sum ≥ 7, prostate-specific antigen (PSA) ≥ 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy. The primary end point was the difference in prostatic prostaglandin levels between the two groups. Secondary end points were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. Tertiary end points were drug safety and compliance.

Seventy-three patients consented, and 64 were randomly assigned and included in the intention-to-treat analysis. There were no treatment differences in any of the primary or secondary outcomes. Multivariable regression revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67 (P < .0001). Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities.

Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies.

Four hundred consecutive patients who underwent lymphoscintigraphy subsequently underwent a US examination before the SN procedure. When the US examination showed a suspicious or malignant pattern, patients underwent an FNAC. Median Breslow thickness was 1.8 mm; mean follow-up was 42 months (range, 4 to 82 months). We considered the US-guided FNAC positive if either US and/or FNAC were positive. If US was suggestive of abnormality, but FNAC was negative, the US-guided FNAC was considered negative.

US-guided FNAC identified 51 (65%) of 79 SN metastases. Specificity was 99% (317 of 321), with a positive predictive value of 93% and negative predictive value of 92%. SN-positive identification rate by US-guided FNAC increased from 40% in stage pT1a/b disease to 79% in stage pT4a/b disease. US-guided FNAC detected SN tumors more than 1.0 mm in 86% of cases, SN tumors of 0.1 to 1.0 mm in 46% of cases, and SN tumors less than 0.1 mm in 23% of cases. Estimated 5-year OS rates were 92% for patients with negative US-guided FNAC results and 51% for patients with positive results.

US-guided FNAC of SNs is highly accurate. Up to 65% of the patients with SN-positive results in our institution could have been spared an SN procedure.

One hundred thirty-five patients who received thalidomide from induction until the second ASCT were retrospectively analyzed in comparison with an equal number of pair mates treated with double ASCT not including thalidomide.

On an intention-to-treat basis, the addition of thalidomide to double ASCT effected a significant improvement in the rate (68% v 49%; P = .001) and duration (62% v 33% at 4 years; P < .001) of at least very good partial response (VGPR), time to progression (TTP; 61% v 41% at 4 years; P < .001) and progression-free survival (PFS; 51% v 31% at 4 years; P = .001). A trend was also noted for extended overall survival (OS) among thalidomide-treated patients (69% at 5 years v 53% for the control group), although the difference between the two groups was not statistically significant (P = .07). Benefits with thalidomide in increasing the rate of VGPR or better response, TTP, and PFS were confirmed in a multivariate analysis. Median OS after relapse was 24 months for patients receiving thalidomide added to double ASCT and 25 months for the control group. Overall, 17% of patients discontinued thalidomide, including 8% because of drug-related adverse events.

In comparison with double ASCT, the addition of first-line thalidomide to double ASCT improved clinical outcomes. Short-term thalidomide was generally well tolerated and had no adverse impact on postrelapse survival.

Pomalidomide was administered orally at a dose of 2 mg daily on days 1 through 28 of a 28-day cycle. Dexamethasone 40 mg daily was administered orally on days 1, 8, 15, and 22 of each cycle. Responses were recorded using the criteria of the International Myeloma Working Group.

Sixty patients were enrolled. Thirty-eight patients (63%) achieved confirmed response including complete response in three patients (5%), very good partial response in 17 patients (28%), and partial response in 18 patients (30%). Responses were seen in 40% of lenalidomide-refractory patients, 37% of thalidomide-refractory patients, and 60% of bortezomib-refractory patients. Responses were seen in 74% of patients with high-risk cytogenetic or molecular markers. Toxicity consisted primarily of myelosuppression. Grade 3 or 4 hematologic toxicity consisted of anemia (5%), thrombocytopenia (3%), and neutropenia (32%). One patient (1.6%) had a thromboembolic event. The median progression-free survival time was 11.6 months and was not significantly different in patients with high-risk disease compared with patients with standard-risk disease.

The combination of pomalidomide and low-dose dexamethasone is extremely active in the treatment of relapsed multiple myeloma, including high response rates in patients refractory to other novel agents.

Enrolled patients (N = 40) received up to six 3-week cycles of treatment with bortezomib 1.3 mg/m² intravenously (IV) on days 1, 4, 8, and 11; PLD 30 mg/m² IV on day 4; and dexamethasone 20 to 40 mg daily as specified in the study design. The primary end point was the complete/near-complete response (CR/nCR) rate after six cycles. Secondary end points included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). The impact of VDD on stem-cell mobilization and collection also was evaluated.

After six cycles, the ORR was 85.0% (CR/nCR, 37.5%; very good partial response [VGPR] or better, 57.5%). Patients who underwent stem-cell transplantation (SCT) after VDD (n = 30) experienced increased rates of VGPR or better (53.3% to 76.6% after SCT). Overall, 1-year PFS and OS rates were 92.5% and 97.5%, respectively. Those who achieved VGPR or better after treatment with VDD showed a significantly greater 1-year PFS versus those who achieved less than VGPR (100% v 82%, respectively; P = .03). Similar results were observed in patients who underwent SCT. Grades 3 or 4 hematologic toxicities occurred in ≤ 10% of patients; grade 2 painful neuropathy occurred in 7.5%; and grade 3 palmar-plantar erythrodysesthesia occurred in 2.5%.

VDD is highly effective for initial treatment of MM followed by SCT in appropriate patients, and it has a reasonable safety profile. Achievement of VGPR or better with this initial therapy predicted longer PFS, regardless of the consolidation therapy given.

Patients were randomly assigned (minimization method) to bortezomib 1.3 mg/m² twice weekly (days 1, 4, 8, and 11; 21-day cycle, five cycles; arm A) or bortezomib 1.6 mg/m² weekly (days 1, 8, 15, and 22; 35-day cycle, three cycles; arm B) plus rituximab 375 mg/m² weekly for 4 weeks (both arms). Response/progression was determined by International Workshop Response Criteria using oncologist/radiologist-adjudicated data from independent radiology review and investigator assessment.

Eighty-one patients (arm A, n = 41; arm B, n = 40) were enrolled. Dose-intensity was higher in arm A; mean total bortezomib received was similar between arms (18.5 and 17.1 mg/m²). In arm A, ORR was 49% (14% complete response [CR]/CR unconfirmed [CRu]), median TTP was 7.0 months, and median DOR was not reached. In arm B, ORR was 43% (10% CR/CRu), and median TTP/DOR were 10.0/9.3 months. The weekly combination regimen seemed better tolerated. Grade 3 or worse adverse events seemed more common in arm A (54%) versus arm B (35%), including thrombocytopenia (10% v 0%) and peripheral neuropathy (10% v 5%), but diarrhea seemed less frequent (7% v 15%). No grade 4 toxicities were reported in arm B.

Both bortezomib plus rituximab regimens seem feasible in relapsed or refractory indolent lymphomas. The more convenient weekly combination regimen is being compared with single-agent rituximab in an ongoing phase III study in relapsed FL.

We analyzed ERG, BAALC, and MN1 expression levels in a cohort of 210 patients with CN-AML who received intensive chemotherapy. Expression levels of ERG, BAALC, and MN1 were determined in bone marrow samples by using oligonucleotide microarrays.

High transcript levels of ERG, BAALC, and MN1 were predictors for inferior overall survival (OS) and a lower rate of complete remissions (CRs). There were significant positive correlations between the expression levels of all three genes. ERG expression levels predicted OS in elderly patients (ie, age 60 years or older) with CN-AML (P = .006) as well as in younger patients (P = .013). In multivariate analyses, high ERG expression was independently associated with a lower CR rate (P = .013), shorter event-free survival (P = .008), and shorter OS (P = .005). Patients who had low ERG levels and absent FLT3 internal tandem duplication (ITD) had a 5-year OS of 44%, and patients who had high ERG expression and FLT3 ITD had a 5-year OS of only 5%.

We analyzed a comprehensive set of molecular risk factors in a large, homogeneous CN-AML patient cohort. In this study, high ERG expression levels emerged as a strong negative prognostic factor and provided prognostic information in addition to established molecular markers.

We examined 81 DLBCLs from patients with AIDS in AMC010 (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] v CHOP-rituximab) and AMC034 (etoposide, doxorubicin, vincristine, prednisone, and dose-adjusted cyclophosphamide plus rituximab concurrent v sequential) clinical trials and compared the immunophenotype with survival data, Epstein-Barr virus (EBV) positivity, and CD4 counts.

The GC and non-GC subtypes of DLBCL did not differ significantly with respect to overall survival or CD4 count at cancer presentation. EBV could be found in both subtypes of DLBCL, although less frequently in the GC subtype, and did not affect survival. Expression of FOXP1, Blimp-1/PRDM1, or BCL-2 was not correlated with the outcome in patients with AIDS-related DLBCL.

These data indicate that with current treatment strategies for lymphoma and control of HIV infection, commonly used immunohistochemical markers may not be clinically relevant in HIV-infected patients with DLBCL. The only predictive immunohistochemical marker was found to be Ki-67, where a higher proliferation index was associated with better survival, suggesting a better response to therapy in patients whose tumors had higher proliferation rates.

We studied 121 incident childhood (0 to 14 years) NHL cases registered in the Nationwide Registry for Childhood Hematological Malignancies (1996 to 2006) and an equal number of matched controls, for whom sociodemographic, lifestyle, prenatal characteristics, and fasting blood serums were collected. Serum adiponectin and leptin levels were determined. Immunohistochemisty for adiponectin receptors expression was performed on commercially available adult NHL specimens (n = 30) and in a subset of childhood NHL cases (n = 6) that were available. Summary statistics, multiple conditional logistic regression analyses, and survival analysis were performed.

Higher serum adiponectin, but not leptin, levels were independently associated with childhood NHL (odds ratio, 1.82; 95% CI, 1.30 to 2.56), after adjusting for obesity and established risk factors. Higher adiponectin levels at diagnosis were positively associated with relapse and poor survival, but hormone levels did not differ among NHL subtypes. Adiponectin receptors 1 and 2 were present in 90% and 57% of adult samples and in 83% and 100% of childhood NHL samples, respectively.

Elevated serum adiponectin, but not leptin, levels are independently associated with childhood NHL and poor prognosis. Adiponectin receptors are expressed in NHL, suggesting that adiponectin may represent not only a potential clinically significant diagnostic and prognostic marker but also a molecule that may be implicated in NHL pathogenesis.

Data were reviewed on all 36 patients included prospectively in the French database for pediatric ALCL who were treated with vinblastine (6 mg/m²/wk) for resistant primary disease (one), a first relapse (15), or subsequent relapses (20). Fifteen patients had undergone hematopoietic stem-cell transplantation (HSCT) for a previous relapse.

Six patients were not evaluable for response, 25 (83%) of 30 evaluable patients achieved a complete remission (CR), and five experienced progressive disease. Among the 31 patients who achieved a CR with vinblastine or before its initiation, six patients were treated with HSCT and 25 with vinblastine alone (median duration, 14 months). Overall, nine of 25 patients treated with vinblastine alone have remained in CR (median, 7 years since the end of treatment), and 16 patients have relapsed. Vinblastine was still efficient for subsequent relapses. With a median follow-up of 9.2 years, 12 patients have died (four as a result of toxicity after HSCT and eight as a result of disease), and 24 patients are alive (15 following treatment with single-agent vinblastine for the last event). Five-year overall survival is 65% (95% CI, 48% to 79%), and 5-year event-free survival is 30% (95% CI, 17% to 47%).

Vinblastine is highly efficient in relapsed ALCL and may produce durable remissions. The optimal treatment duration still has to be assessed. These results should be borne in mind when designing future phase II studies with the targeted therapies directed against anaplastic lymphoma kinase.

OEO2 recruited 802 patients, 400 on CS and 402 on S. The nature of the first recurrence event and cause of death are detailed. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test. Survival by extent of resection is presented.

There were 655 deaths, 335 for S and 320 for CS. The survival benefit has been maintained with a hazard ratio (HR) of 0.84 (95% CI, 0.72 to 0.98; P = .03) which in absolute terms is a 5-year survival of 23.0% for CS compared with 17.1% for S. The treatment effect is consistent in both adenocarcinoma and squamous cell carcinoma. The first disease-free survival event was macroscopic residual disease from incomplete resection (R2) or no resection in 26.4% of the S group versus 14.3% of the CS P < .001. Three-year survival by type of resection was R0 42.4%, R1 was 18.0%, and R2 was 8.6%.

Long-term follow-up confirms that preoperative chemotherapy improves survival in operable esophageal cancer and should be considered as a standard of care.

Gene expression measurements and KRAS mutation analysis were performed on archival formalin-fixed paraffin-embedded primary tumors of 220 cmCRC patients. Response was measured using RECIST (Response Evaluation Criteria in Solid Tumors) criteria. The relation between ligand expression levels and outcome was evaluated using logistic regression for response and Cox regression for survival data. Receiver operating characteristics analysis was performed for response and survival data. CIs for the performance indices were obtained with a nonparametric bootstrap procedure. Findings were externally validated on a series of 67 samples treated in a similar setting.

In KRAS wild type (WT) patients, there was a significant association between log-transformed ligand expression and response for EREG (odds ratio for objective response, 1.90; 95% CI, 1.27 to 2.83; P = .0005; concordance index [c-index], 0.681) and for AREG (odds ratio for objective response, 1.862; 95% CI, 1.22 to 2.72; P = .0017; c-index, 0.673). In a Cox regression model, dichotomized ligand expression was significantly associated with progression-free survival (PFS) and overall survival (OS). EREG PFS hazard ratio (HR) was 0.41 (95% CI, 0.274 to 0.609; P < .001; time-dependent c-index [C index], 0.640), and AREG PFS HR was 0.43 (95% CI, 0.29 to 0.64; P < .001; C index, 0.627). EREG OS HR was 0.42 (95% CI, 0.28 to 0.63; P < .0001; C index, 0.639), and AREG OS HR was 0.40 (95% CI, 0.27 to 0.64; P < .0001; C index, 0.625). There was no predictive power of ligand expression in patients with KRAS mutation.

Expression of EGFR ligands in primary tumors significantly predicts outcome in KRAS WT cmCRC treated with cetuximab and irinotecan.

We evaluated 62 consecutive patients undergoing single fraction IG-IMRT at 71 sites for solid organ metastases. A neuroradiologist and three spine surgeons evaluated prospectively obtained magnetic resonance/computed tomography (CT) imaging studies for post-treatment fracture development and tumor recurrence.

Fracture progression was noted in 27 vertebrae (39%). Multivariate logistic regression analysis showed that CT appearance, lesion location, and percent vertebral body involvement independently predicted fracture progression. Lesions located between T10 and the sacrum were 4.6 times more likely to fracture than were lesions above T10 (95% CI, 1.1 to 19.7). Lytic lesions were 6.8 times more likely to fracture than were sclerotic and mixed lesions (95% CI, 1.4 to 33.3). As percent vertebral body involvement increased, odds of fracture also increased. Patients with fracture progression had significantly higher narcotic use, change in Karnofsky performance score, and a strong trend toward higher pain scores. Local tumor progression occurred in seven patients and contributed to one fracture. Obesity, posterior element involvement, bisphosphonate use, and local kyphosis did not confer increased risk.

Vertebral fracture is common after single fraction IG-IMRT for metastatic spine lesions. Lytic disease involving more than 40% of the vertebral body and location at or below T10 confer a high risk of fracture, the presence of which yields significantly poorer clinical outcomes. These results may help clinicians identify high-risk patients who would benefit from prophylactic vertebro- or kyphoplasty.

Previously untreated patients (n = 154) with stage IIIB or IV NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned to receive erlotinib (150 mg/d) or placebo on days 15 to 28 of a 4-week cycle that included gemcitabine (1,250 mg/m² days 1 and 8) and either cisplatin (75 mg/m² day 1) or carboplatin (5 x area under the serum concentration-time curve, day 1). The primary end point was nonprogression rate (NPR) at 8 weeks. Secondary end points included tumor response rate, NPR at 16 weeks, duration of response, progression-free survival (PFS), overall survival (OS), and safety.

The NPR at 8 weeks was 80.3% in the gemcitabine plus cisplatin or carboplatin (GC) -erlotinib arm (n = 76) and 76.9% in the GC-placebo arm (n = 78). At 16 weeks, the NPR was 64.5% for GC-erlotinib versus 53.8% for GC-placebo. The response rate was 35.5% for GC-erlotinib versus 24.4% for GC-placebo. PFS was significantly longer with GC-erlotinib than with GC-placebo (adjusted hazard ratio, 0.47; log-rank P = .0002; median, 29.4 v 23.4 weeks); this benefit was consistent across all clinical subgroups. There was no significant difference in OS. The addition of erlotinib to chemotherapy was well tolerated, with no increase in hematologic toxicity, and no treatment-related interstitial lung disease.

Sequential administration of erlotinib following gemcitabine/platinum chemotherapy led to a significant improvement in PFS. This treatment approach warrants further investigation in a phase III study.

HPV DNA was semiquantitatively measured in the cervical smears of 169 radiotherapy patients. HPV viral load was classified as low or high according to median HPV DNA titer and examined for its prognostic value. The multivariable Cox proportional hazards model was used to adjust for covariates. A relapse-predicting model was constructed to classify three risk groups for disease-free survival (DFS), which were used for internal validation.

Patients with lower HPV viral load showed worse DFS in univariate analysis. HPV type 18, younger patient age, stage group, nodal status, histologic grade, and histologic type were other prognostic factors for poor DFS. Among these factors, all except stage group were associated with HPV viral load. Multivariate analysis showed the strong influence of HPV viral load for poor DFS. The prognostic model developed using our outcome data performed well in predicting the risk of relapse.

Our data suggest that HPV viral load is a strong independent prognostic factor for DFS. HPV type 18 showed a significant relationship with poor radiotherapy outcome in univariate analysis, but not in multivariate analysis.

Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Danusertib was administered intravenously on days 1, 8, and 15 every 28 days in 6-hour or 3-hour infusion schedules (ie, 6-hour IVS or 3-hour IVS). Dose levels from 45 mg/m² in the 6-hour IVS, and from 250 mg/m² in the 3-hour IVS, were studied.

Fifty patients were treated. For the 6-hour IVS, the most frequently reported adverse effects were neutropenia (55%), nausea (25%), anorexia (23%), fatigue (20%), and diarrhea (18%). In the 3-hour IVS, fatigue (70%), neutropenia (60%), diarrhea (50%), and nausea (30%) were seen. Nonhematologic toxicity was mild to moderate. Neutropenia was dose limiting. The maximum-tolerated dose was 330 mg/m² for the 6-hour IVS and was not identified for the 3-hour IVS. The systemic exposure to danusertib increased linearly with dose. The infusion rate did not appear to remarkably influence the pharmacokinetics of danusertib. Biomarker analysis showed inhibition of histone H3 phosphorylation, indicative of aurora B inhibition, at doses of 190 mg/m² or greater. Stable disease was observed in 23.7% of evaluable patients, and disease stabilization occurred in 6 or more months in five patients.

Dose-limiting toxicity of danusertib is neutropenia, which was short lasting and generally uncomplicated; danusertib administration had limited nonhematologic toxicity. The recommended dose of danusertib for phase II studies is 330 mg/m² infused over 6 hours on days 1, 8, and 15 every 28 days.

This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m²) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m²/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected.

Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m² weekly plus irinotecan 16 mg/m²/d (pediatric) or 20 mg/m²/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%).

The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen.

We reviewed the collective experiences of many cooperative groups, governmental organizations, nongovernmental organizations, and academic investigators in their work to build international collaboration in cancer clinical trials across multiple disease sites.

More than a decade of work has led to effective global harmonization for many of the elements critical to cancer clinical trials. Many barriers remain, but effective international collaboration in academic cancer treatment trials should become the norm, rather than the exception.

Our ability to strengthen international collaborations will result in maximization of our resources and patients, permitting us to change practice by establishing more effective therapeutic strategies. Regulatory, logistical, and financial hurdles, however, often hamper the conduct of joint trials. We must work together as a global community to overcome these barriers so that we may continue to improve cancer treatment for patients around the world.