Citations

Object The aim of this study was to determine the prospective hemorrhage rate in a group of retrospectively identified patients in whom symptoms had an unclear relationship to an intracerebral cavernous malformation (ICM) or the malformation itself was an incidental finding. Methods Patients with incidentally discovered ICMs diagnosed between 1989 and 1999 were identified from a previously published cohort. Those with ICMs having an unclear relationship with existing symptoms were also eligible for analysis. Updated clinical and radiographic data pertaining to symptomatic intracerebral hemorrhage related to the ICM or new seizures were obtained through medical chart review and mail survey. In select patients, phone calls were made and death certificates were obtained when possible. The prospective hemorrhage rate was calculated as the number of prospective hemorrhages divided by the number of patient-years of follow-up. Results There were 1311 patient-years of follow-up among the 107 patients (49.5% male; mean age at diagnosis 52 years) eligible for this study. Forty-four patients died in the follow-up period, and the cause of death could be determined in 34 (77%). Two patients had a prospective hemorrhage, which was definitively related to the ICM in only one. Thus, the definitive prospective bleed rate was 0.08% per patient-year. No new seizures developed in any of the patients during the follow-up period. Conclusions The risk of prospective hemorrhage in patients presenting asymptomatically with ICM is very low. This information can be useful in managing such patients and may be most applicable to those with a single ICM.

The purpose of the RAZOR (randomized open vs robotic cystectomy) study is to compare open radical cystectomy ( ORC ) vs robot‐assisted RC ( RARC ), pelvic lymph node dissection ( PLND ) and urinary diversion for oncological outcomes, complications and health‐related quality of life ( HRQL ) measures with a primary endpoint of 2‐year progression‐free survival ( PFS ). RAZOR is a multi‐institutional, randomized, non‐inferior, phase III trial that will enrol at least 320 patients with T 1– T 4, N 0– N 1, M 0 bladder cancer with ≈160 patients in both the RARC and ORC arms at 15 participating institutions. Data will be collected prospectively at each institution for cancer outcomes, complications of surgery and HRQL measures, and then submitted to trial data management services Cancer Research and Biostatistics ( CRAB ) for final analyses. To date, 306 patients have been randomized and accrual to the RAZOR trial is expected to conclude in 2014. In this study, we report the RAZOR trial experimental design, objectives, data safety, and monitoring, and accrual update. The RAZOR trial is a landmark study in urological oncology, randomizing T 1– T 4, N 0– N 1, M 0 patients with bladder cancer to ORC vs RARC , PLND and urinary diversion. RAZOR is a multi‐institutional, non‐inferiority trial evaluating cancer outcomes, surgical complications and HRQL measures of ORC vs RARC with a primary endpoint of 2‐year PFS . Full data from the RAZOR trial are not expected until 2016–2017.

BACKGROUND Recombinant interleukin‐2 (rIL‐2) induces cellular cytotoxicity against leukemia blasts. Patients with acute myeloid leukemia (AML) in first complete remission (CR) may harbor minimal residual disease that is susceptible to rIL‐2–activated effector cells. METHODS In the Cancer and Leukemia Group B (CALGB) 19808 study, patients with AML in first CR were randomly assigned after all planned chemotherapy to receive a 90‐day course of subcutaneously administered rIL‐2 or no further therapy. The primary objective was to compare disease‐free survival (DFS) between the 2 treatment arms. A total of 534 patients achieved a CR, 214 of whom were randomized. Six courses of low‐dose daily rIL‐2 were given for the expansion of cytotoxic effector cells, each followed by 3‐day high‐dose boluses given to trigger cytotoxicity against minimal residual disease. RESULTS On the protocol‐specified intention‐to‐treat analysis, the hazards ratio for DFS was 0.75 (95% confidence interval, 0.52‐1.09; P = .13); the 5‐year DFS rate was 42% in the observation arm and 53% in the rIL‐2 treatment arm. The hazards ratio for overall survival (OS) was 0.88 (95% confidence interval, 0.54‐1.23; P = .34); the 5‐year OS rate was 58% for the observation arm and 63% for the rIL‐2 treatment arm. Twenty‐five of the 107 patients randomized to treatment with rIL‐2 either refused or were unable to initiate therapy and 30 patients did not complete their assigned therapy. However, significant toxicities were not commonly observed. The trial design did not anticipate the difficulties patients would encounter with protocol compliance. CONCLUSIONS The efficacy of immunotherapy with rIL‐2 administered after intensive postremission treatment was not assessed as planned because of unexpected refusals by patients and/or their physicians to comply with protocol‐directed therapy. Neither DFS nor OS was found to be significantly improved. Cancer 2014;120:1010–1017 . © 2013 American Cancer Society .

Abstract Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10−8. Results from the second analytic approach were consistent with those from the first (P > 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.

Purpose Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O 6 -methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM. Patients and Methods This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status. Results A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue. Conclusion This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.

Key Points In combination with cyclophosphamide, intravenous busulfan is associated with better leukemia-free and overall survival in AML than TBI.

The responses of glucagon, growth hormone, and insulin secretion to the oral administration of glucose and to the intravenous infusion of saline, arginine, and insulin were measured in seven patients who had stable diabetes, eight who had unstable diabetes, and seven healthy volunteers. Hyperglycemia suppressed secretion of glucagon in normal subjects but not in diabetics. The oral glucose and arginine infusion tests demonstrated partial preservation of insulin-secretory ability in stable diabetics and its virtual absence in unstable diabetics. Glucagon responses to arginine infusion were similar in all three groups. In response to hypoglycemia induced by insulin infusion, the concentrations of plasma glucagon increased in normal subjects and, to a lesser extent, in stable diabetics but increased in only two of the unstable diabetics. The impairment in glucagon response during hypoglycemia in diabetics correlated positively with the degree of diabetic instability and insulin deficiency during glucose and arginine testing. The severity of the insulin deficiency also correlated with the degree of diabetic instability. These findings support the hypothesis that inherent abnormalities of insulin and glucagon secretion may account for many of the clinical characteristics of unstable and stable diabetic patients.