Citations

BackgroundWe report results of a phase I trial designed to estimate the maximum tolerated dose (MTD), describe dose‐limiting toxicities (DLT), and characterize the pharmacokinetic profile of MK‐2206, an AKT inhibitor, in children with refractory or recurrent malignancies.ProcedureMK‐2206 was administered either every other day (Schedule 1), or once a week (Schedule 2) in a 28‐day cycle. Dose escalations in increments of ∼30% were independently made in each part using the rolling‐six design. Serial pharmacokinetic (PK) studies were obtained. Biological studies include analysis of PI3K/PTEN/AKT‐cell signaling pathway in pre and post‐therapy in PBMC and in tumors at diagnosis or recurrence.ResultsFifty patients (26 males, median age 12.6 years [range, 3.1–21.9]) with malignant glioma (16), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2), or other tumors (22) were enrolled; 40 were fully evaluable for toxicity (Schedule 1, n = 23; Schedule 2, n = 17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m2; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/m2; and grade 3 rash in 3/6 patients at dose level 4 (58 mg/m2). Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m2; grade 3 rash in 1/6 patients at 120 mg/m2; and grade 3 rash in 2/6 patients at 155 mg/m2.ConclusionsThe recommended pediatric phase 2 dose of MK‐2206 is 45 mg/m2/dose every other day or 120 mg/m2/dose weekly. PK appeared linear over the dose range studied. Pediatr Blood Cancer 2014;61:1246–1251. © 2014 Wiley Periodicals, Inc.

AbstractBackground & AimsBecause of the lack of objective tests to diagnose drug‐induced liver injury (DILI), causality assessment is a matter of debate. Expert opinion is often used in research and industry, but its test–retest reliability is unknown. To determine the test–retest reliability of the expert opinion process used by the Drug‐Induced Liver Injury Network (DILIN).MethodsThree DILIN hepatologists adjudicate suspected hepatotoxicity cases to one of five categories representing levels of likelihood of DILI. Adjudication is based on retrospective assessment of gathered case data that include prospective follow‐up information. One hundred randomly selected DILIN cases were re‐assessed using the same processes for initial assessment but by three different reviewers in 92% of cases.ResultsThe median time between assessments was 938 days (range 140–2352). Thirty‐one cases involved >1 agent. Weighted kappa statistics for overall case and individual agent category agreement were 0.60 (95% CI: 0.50–0.71) and 0.60 (0.52–0.68) respectively. Overall case adjudications were within one category of each other 93% of the time, while 5% differed by two categories and 2% differed by three categories. Fourteen per cent crossed the 50% threshold of likelihood owing to competing diagnoses or atypical timing between drug exposure and injury.ConclusionsThe DILIN expert opinion causality assessment method has moderate interobserver reliability but very good agreement within one category. A small but important proportion of cases could not be reliably diagnosed as ≥50% likely to be DILI.

BackgroundWe report the first report of an expansile crista galli (CG) mucocele treated surgically by an endoscopic endonasal approach. Only 1 other case of a CG mucocele has been previously reported in the literature. This was treated by a craniotomy approach.Case ReportWe describe the technique employed in endoscopic marsupialization. We also discuss relevant CG anatomy, pneumatization patterns, surgical approaches, and its potential to cause disease, including CG sinusitis and mucocele formation.ConclusionWe present this case to highlight that the growing experience with endoscopic techniques offer us less morbid and more functional alternatives to a variety of lesions that were once tackled by neurosurgical or external approaches. In the contemporary era, the indications for open approaches and craniotomy for frontal sinus and CG lesions is likely limited. We recommend these patients undergo careful evaluation by a surgeon experienced in advanced endoscopic techniques before being advised to undergo open or craniotomy techniques.

The high prevalence of non‐alcoholic fatty liver disease ( NAFLD ) has made the condition an important public health issue. Two clinical entities are manifestations of NAFLD , namely, non‐alcoholic fatty liver ( NAFL ) and non‐alcoholic steatohepatitis ( NASH ). The former tends to be benign and non‐progressive while the latter can progress to cirrhosis, which in rare cases gives rise to hepatocellular carcinoma. The diagnosis of NAFLD is based on: (i) a history of no or limited daily alcohol intake (<20 g for women and <30 g for men); (ii) presence of hepatic steatosis by imaging or by histology; and (iii) exclusion of other liver diseases. NAFL is defined histologically by the presence of bland, primarily macrovesicular, hepatocellular fatty change, while NASH features fatty change with inflammation and evidence of hepatocyte injury, such as ballooning degeneration. Presence of fibrosis is a sign of chronicity. Thus, the diagnosis of NAFL / NASH rests on clinicopathological criteria; it always requires both clinical and biopsy‐based information. NAFLD could be both the result and the cause of metabolic syndrome, with a vicious cycle operating between these conditions. Remaining challenges are: (i) the lack of a clear threshold alcohol intake for defining “non‐alcoholic”; (ii) a lacking consensus for the classification of fatty liver disease; and (iii) absence of a histological definition of NASH , which currently remains the gold standard for the diagnosis. Further challenges include the overlap of the criteria for NAFLD and alcoholic liver disease as many obese individuals also consume considerable volumes of alcohol.

Significance Tumor cells adapt to hypoxia by modulating energy production and utilization. Endocytosis is an energy-consuming process that is suppressed during hypoxia. Our studies show that Dynamin 2 (DNM2), a key component of endocytic machinery, is transcriptionally suppressed by HIF-1. Genetic and pharmacological inactivation of DNM2 stabilized HIF-1α and HIF-2α. Furthermore, miR-199a, which is encoded from the opposite strand of DNM2 , exerts reciprocal negative regulation upon HIF-1α and HIF-2α. Overexpression of miR-199a decreased HIF-1α and HIF-2α, cell migration, and metastasis. These findings establish a regulatory loop between endocytic pathway and hypoxic response in tumor cells.

BackgroundAllogeneic blood transfusion induces immunosuppression, and concern has been raised that it may increase propensity for cancer recurrence; however, these effects have not been confirmed. We examined the association of perioperative transfusion of allogeneic blood long‐term oncologic outcomes in patients with prostate cancer who underwent prostatectomy.Study Design and MethodsWe reviewed medical records of patients who underwent radical prostatectomy between 1991 and 2005 and received allogeneic nonleukoreduced blood. Each transfused patient was matched to two controls who did not receive blood: matching included age, surgical year, prostate‐specific antigen level, pathologic tumor stages, pathologic Gleason scores, and anesthetic type. Primary outcome was systemic tumor progression, with secondary outcomes of prostate cancer death and all‐cause mortality. Stratified proportional hazards regression analysis was used to assess differences in outcomes between the transfused and nontransfused group.ResultsA total of 379 prostatectomy patients who were transfused and 758 nontransfused controls were followed for 9.4 and 10.2 years (median), respectively. In a multivariable analysis that took into account the matched study design and adjusted for positive surgical margins and adjuvant therapies, the use of allogeneic blood was not associated with systemic tumor progression (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.39‐1.99; p = 0.76), prostate cancer–specific death (HR, 1.69; 95% CI, 0.44 to 6.48; p = 0.44), or all‐cause death (HR, 1.20; 95% CI, 0.87 to 1.67; p = 0.27).ConclusionsWhen adjusted for clinicopathologic and procedural variables transfusion of allogeneic blood was not associated with systemic tumor progression and survival outcomes.