Jonathan L. Wright

Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane.

PURPOSE Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analog of the marine natural product halichondrin B. This open-label, single-arm, phase II study evaluated efficacy and tolerability of eribulin in heavily pretreated patients with metastatic breast cancer (MBC). METHODS MBC patients who were previously treated with an anthracycline and a taxane received eribulin mesylate (1.4 mg/m(2)) as a 2- to 5-minute intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Because of neutropenia (at day 15), an alternative regimen of eribulin on days 1 and 8 of a 21-day cycle was administered. The primary end point was overall response rate. RESULTS Of the 103 patients treated, the median number of prior chemotherapy regimens was four (range, one to 11 regimens). In the per-protocol population (n = 87), eribulin achieved an independently reviewed objective response rate (all partial responses [PRs]) of 11.5% (95% CI, 5.7 to 20.1) and a clinical benefit rate (PR plus stable disease > or = 6 months) of 17.2% (95% CI, 10.0 to 26.8). The median duration of response was 171 days (5.6 months; range, 44 to 363 days), the median progression-free survival was 79 days (2.6 months; range, 1 to 453 days), and the median overall survival was 275 days (9.0 months; range, 15 to 826 days). The most common drug-related grades 3 to 4 toxicities were as follows: neutropenia, 64%; leukopenia, 18%; fatigue, 5%; peripheral neuropathy, 5%; and febrile neutropenia, 4%. CONCLUSION Eribulin demonstrated activity with manageable tolerability (including infrequent grade 3 and no grade 4 neuropathy) in heavily pretreated patients with MBC when dosed as a short IV infusion on days 1 and 8 of a 21-day cycle.

The association between extent of lymphadenectomy and survival among patients with lymph node metastases undergoing radical cystectomy.

Long‐term survival in patients with lymph node‐positive bladder cancer who undergo cystectomy suggests a therapeutic role for lymphadenectomy. The objective of this study was to describe the association between extent of lymphadenectomy and survival in lymph node‐positive patients who underwent radical cystectomy.

Positive Surgical Margins at Radical Prostatectomy Predict Prostate Cancer Specific Mortality

PURPOSE Positive surgical margins in men undergoing radical prostatectomy for prostate cancer are associated with an increased risk of biochemical recurrence. Few data are available on the role of positive surgical margins in prostate cancer specific mortality. Using a large, population based national cancer registry we evaluated the risk of prostate cancer specific mortality associated with margin status. MATERIALS AND METHODS The SEER cancer registry data for patients diagnosed between 1998 and 2006 were used to identify men undergoing radical prostatectomy for prostate cancer. Margin status, pathological stage, Gleason grade and postoperative radiation therapy were recorded along with demographic data. Multivariate Cox regression analysis was used to estimate the risk of prostate cancer specific mortality associated with positive surgical margins. RESULTS A total of 65,633 patients comprised the cohort in which 291 (0.44%) prostate cancer specific deaths occurred during an average followup of 50 months. Positive surgical margins were reported in 21.2% of cases and were more common in pT3a than pT2 tumors (44% vs 18%, p <0.001) and higher grade tumors (28% vs 18%, p <0.001). The 7-year disease specific survival rates for those at highest risk for prostate cancer specific mortality (higher grade pT3a) were 97.6% for cases with negative surgical margins and 92.4% for those with positive surgical margins. Positive surgical margins were associated with a 2.6-fold increased unadjusted risk of prostate cancer specific mortality (HR 2.55, 95% CI 2.02-3.21). Positive surgical margins remained an independent predictor of prostate cancer specific mortality on multivariate analysis (HR 1.70, 95% CI 1.32-2.18). CONCLUSIONS These data demonstrate the independent role of positive surgical margins in prostate cancer specific mortality. These findings support the importance of optimizing surgical techniques to achieve a sound oncological surgical outcome with negative surgical margins when possible.

Differences in survival among patients with urachal and nonurachal adenocarcinomas of the bladder

Primary adenocarcinomas of the bladder and urachus are rare malignancies, and knowledge of the patient demographics, pathologic characteristics, and survival associated with these tumors is poor. The current study compares disease‐specific characteristics and survival associated with urachal and nonurachal primary bladder adenocarcinomas.

Prostate Cancer Specific Mortality and Gleason 7 Disease Differences in Prostate Cancer Outcomes Between Cases With Gleason 4 + 3 and Gleason 3 + 4 Tumors in a Population Based Cohort

PURPOSE Reports of biochemical recurrence after prostate cancer primary therapy show differences between Gleason 4 + 3 and 3 + 4 tumors. To our knowledge these findings have not been explored for prostate cancer specific mortality. In this population based cohort we determined prostate cancer outcomes at different Gleason scores, particularly the different Gleason 7 patterns. MATERIALS AND METHODS Men 40 to 64 years old who were diagnosed with prostate cancer between 1993 and 1996 in King County, Washington comprised the cohort. Recurrence/progression was determined by followup survey and medical record review. Mortality and cause of death were obtained from the Seattle-Puget Sound Surveillance, Epidemiology and End Results registry. HRs for outcomes were determined by Cox proportional hazards regression analysis. RESULTS In 753 men with prostate cancer 65 prostate cancer specific deaths occurred during a median followup of 13.2 years. The 10-year prostate cancer specific survival rate for Gleason 6 or less, 3 + 4, 4 + 3 and 8-10 disease was 98.4%, 92.1%, 76.5% and 69.9%, respectively. Compared to patients with Gleason 3 + 4 disease those with Gleason 4 + 3 tumors were at increased risk for prostate cancer specific mortality in the unadjusted and multivariate models (HR 2.80, 95% CI 1.26-6.18 and HR 2.12, 95% CI 0.87-5.17, respectively). In men undergoing curative therapy with radical prostatectomy or radiation therapy there was an increased risk of recurrence/progression (HR 2.10, 95% CI 1.08-4.08) and prostate cancer specific mortality (HR 3.17, 95% CI 1.04-9.67) in those with Gleason 4 + 3 vs 3 + 4 tumors in the multivariate models. No difference in prostate cancer specific mortality was seen between Gleason 4 + 3 and 8-10 tumors. CONCLUSIONS Gleason 7 prostate cancer shows heterogeneous behavior with Gleason 3 + 4 and 4 + 3 tumors conferring different prostate cancer specific mortality. These data provide important information for counseling patients with Gleason 7 prostate cancer on the natural history of the disease and may inform treatment decisions.

Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy

BACKGROUND An early report on the molecular subtyping of muscle-invasive bladder cancer (MIBC) by gene expression suggested that response to neoadjuvant chemotherapy (NAC) varies by subtype. OBJECTIVE To investigate the ability of molecular subtypes to predict pathological downstaging and survival after NAC. DESIGN, SETTING, AND PARTICIPANTS Whole transcriptome profiling was performed on pre-NAC transurethral resection specimens from 343 patients with MIBC. Samples were classified according to four published molecular subtyping methods. We developed a single-sample genomic subtyping classifier (GSC) to predict consensus subtypes (claudin-low, basal, luminal-infiltrated and luminal) with highest clinical impact in the context of NAC. Overall survival (OS) according to subtype was analyzed and compared with OS in 476 non-NAC cases (published datasets). INTERVENTION Gene expression analysis was used to assign subtypes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Receiver-operating characteristics were used to determine the accuracy of GSC. The effect of GSC on survival was estimated by Cox proportional hazard regression models. RESULTS AND LIMITATIONS The models generated subtype calls in expected ratios with high concordance across subtyping methods. GSC was able to predict four consensus molecular subtypes with high accuracy (73%), and clinical significance of the predicted consensus subtypes could be validated in independent NAC and non-NAC datasets. Luminal tumors had the best OS with and without NAC. Claudin-low tumors were associated with poor OS irrespective of treatment regimen. Basal tumors showed the most improvement in OS with NAC compared with surgery alone. The main limitations of our study are its retrospective design and comparison across datasets. CONCLUSIONS Molecular subtyping may have an impact on patient benefit to NAC. If validated in additional studies, our results suggest that patients with basal tumors should be prioritized for NAC. We discovered the first single-sample classifier to subtype MIBC, which may be suitable for integration into routine clinical practice. PATIENT SUMMARY Different molecular subtypes can be identified in muscle-invasive bladder cancer. Although cisplatin-based neoadjuvant chemotherapy improves patient outcomes, we identified that the benefit is highest in patients with basal tumors. Our newly discovered classifier can identify these molecular subtypes in a single patient and could be integrated into routine clinical practice after further validation.

Renal and Extrarenal Predictors of Nephrectomy from the National Trauma Data Bank

PURPOSE The kidney is injured in 1.4% to 3.0% of all trauma cases. The management of renal injuries is controversial, as reflected in regional and institutional variations in treatment preferences. Using a national trauma database we identified independent risk factors for nephrectomy. MATERIALS AND METHODS The population was selected from the National Trauma Data Bank, a voluntary data repository containing all trauma admissions to 268 participating trauma centers. Patients with renal injuries were identified by Abbreviated Injury Scale codes. Patient demographic, associated injuries and facility characteristics were recorded. Univariate and Poisson regression analysis with clustering by facility was performed. RESULTS Renal injury was present in 8,465 patients. Nephrectomy was performed in 4% of all blunt and 21% of all cases of penetrating renal injuries. Only 0.5% of blunt renal injury cases underwent repair compared with 15% of those of penetrating injuries. On multivariate analysis renal injury severity was the strongest predictor of nephrectomy. The relative risk of nephrectomy for grade V renal injuries was 146 (95% CI 74 to 289) and 33 (95% CI 13 to 89) in the blunt and penetrating models, respectively. The need for laparotomy and surgery on other intra-abdominal organs predicted nephrectomy in patients with blunt and penetrating injuries. Hospital trauma designation did not statistically impact nephrectomy rates. CONCLUSIONS The severity of renal injury based on the AAST organ injury scale for Renal Trauma is the strongest risk factor for nephrectomy. The need for surgery on other intra-abdominal injuries increases the risk of nephrectomy to a lesser extent. In cases of blunt trauma severe renal injury usually necessitates nephrectomy.

Multicenter Assessment of Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer

BACKGROUND The efficacy of neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (BCa) was established primarily with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), with complete response rates (pT0) as high as 38%. However, because of the comparable efficacy with better tolerability of gemcitabine and cisplatin (GC) in patients with metastatic disease, GC has become the most commonly used regimen in the neoadjuvant setting. OBJECTIVE We aimed to assess real-world pathologic response rates to NAC with different regimens in a large, multicenter cohort. DESIGN, SETTING, AND PARTICIPANTS Data were collected retrospectively at 19 centers on patients with clinical cT2-4aN0M0 urothelial carcinoma of the bladder who received at least three cycles of NAC, followed by radical cystectomy (RC), between 2000 and 2013. INTERVENTION NAC and RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was pathologic stage at cystectomy. Univariable and multivariable analyses were used to determine factors predictive of pT0N0 and ≤pT1N0 stages. RESULTS AND LIMITATIONS Data were collected on 935 patients who met inclusion criteria. GC was used in the majority of the patients (n=602; 64.4%), followed by MVAC (n=183; 19.6%) and other regimens (n=144; 15.4%). The rates of pT0N0 and ≤pT1N0 pathologic response were 22.7% and 40.8%, respectively. The rate of pT0N0 disease for patients receiving GC was 23.9%, compared with 24.5% for MVAC (p=0.2). There was no difference between MVAC and GC in pT0N0 on multivariable analysis (odds ratio: 0.89 [95% confidence interval, 0.61-1.34]; p=0.6). CONCLUSIONS Response rates to NAC were lower than those reported in prospective randomized trials, and we did not discern a difference between MVAC and GC. Without any evidence from randomized prospective trials, the best NAC regimen for invasive BCa remains to be determined. PATIENT SUMMARY There was no apparent difference in the response rates to the two most common presurgical chemotherapy regimens for patients with bladder cancer.

Comparative effectiveness of robot-assisted versus open radical prostatectomy cancer control

BACKGROUND Robot-assisted radical prostatectomy (RARP) remains controversial, and no improvement in cancer control outcomes has been demonstrated over open radical prostatectomy (ORP). OBJECTIVE To examine population-based, comparative effectiveness of RARP versus ORP pertaining surgical margin status and use of additional cancer therapy. DESIGN, SETTING, AND PARTICIPANTS This was a retrospective observational study of 5556 RARP and 7878 ORP cases from 2004 to 2009 from Surveillance Epidemiology and End Results-Medicare linked data. INTERVENTION RARP versus ORP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Propensity-based analyses were performed to minimize treatment selection biases. Generalized linear regression models were computed for comparison of RP surgical margin status and use of additional cancer therapy (radiation therapy [RT] or androgen deprivation therapy [ADT]) by surgical approach. RESULTS AND LIMITATIONS In the propensity-adjusted analysis, RARP was associated with fewer positive surgical margins (13.6% vs 18.3%; odds ratio [OR]: 0.70; 95% confidence interval [CI], 0.66-0.75), largely because of fewer RARP positive margins for intermediate-risk (15.0% vs 21.0%; OR: 0.66; 95% CI, 0.59-0.75) and high-risk (15.1% vs 20.6%; OR: 0.70; 95% CI, 0.63-0.77) disease. In addition, RARP was associated with less use of additional cancer therapy within 6 mo (4.5% vs 6.2%; OR: 0.75; 95% CI, 0.69-0.81), 12 mo (OR: 0.73; 95% CI, 0.62-0.86), and 24 mo (OR: 0.67; 95% CI, 0.57-0.78) of surgery. Limitations include the retrospective nature of the study and the absence of prostate-specific antigen levels to determine biochemical recurrence. CONCLUSIONS RARP is associated with improved surgical margin status relative to ORP for intermediate- and high-risk disease and less use of postprostatectomy ADT and RT. This has important implications for quality of life, health care delivery, and costs. PATIENT SUMMARY Robot-assisted radical prostatectomy (RP) versus open RP is associated with fewer positive margins and better early cancer control because of less use of additional androgen deprivation and radiation therapy within 2 yr of surgery.

Admission for nephrolithiasis in pregnancy and risk of adverse birth outcomes.

OBJECTIVE: Nephrolithiasis occurring during pregnancy may be associated with an elevated risk of preterm delivery and other adverse birth outcomes. The goal of this study was to describe the association between these outcomes and admission for nephrolithiasis during pregnancy. METHODS: We performed a retrospective cohort study using birth certificate records linked to Washington State hospital discharge data from 1987–2003 to compare pregnant women admitted for nephrolithiasis and randomly selected pregnant women without nephrolithiasis. The main outcomes of interest were preterm delivery, premature rupture of membranes at term or before 37 weeks of gestation, low birth weight, and infant death. RESULTS: A total of 2,239 women were admitted for nephrolithiasis, yielding a cumulative incidence of 1.7 admissions per 1,000 deliveries. Women admitted for nephrolithiasis during pregnancy had nearly double the risk of preterm delivery compared with women without stones (adjusted odds ratio 1.8, 95% confidence interval 1.5–2.1). However, they were not at higher risk for the other outcomes investigated. A total of 471 (25.9%) women had one or more procedures for kidney stones during prenatal hospitalization. Undergoing a procedure and the trimester of admission did not affect the risk of preterm delivery. CONCLUSION: Although the incidence of nephrolithiasis requiring hospital admission during pregnancy is relatively low, these women have an increased risk of preterm delivery. This has potential implications for counseling of pregnant women with kidney stones requiring hospital admission. Additionally, it may prompt definitive treatment of small, asymptomatic stones in women during reproductive years. LEVEL OF EVIDENCE: II