A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors.

Background: The PI3K/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110ß could result in successful pathway inhibition while avoiding the on- and off-target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kß.Methods: We evaluated the safety, pharmacokinetics, pharmacodynamics and antitumor activity of GSK2636771 to define the recommended phase II dose (RP2D). During the dose-selection and dose-escalation stages (parts 1 and 2), patients with PTEN-deficient advanced solid tumors received escalating doses of GSK2636771 (25-500 mg once daily) using a modified 3+3 design to determine the RP2D; tumor type-specific expansion cohorts (part 3) were implemented to further assess tumor responses at the RP2D.Results: A total of 65 patients were enrolled; dose-limiting toxicities were hypophosphatemia and hypocalcemia. Adverse events included diarrhea (48%), nausea (40%), and vomiting (31%). Single- and repeat-dose exposure increased generally dose proportionally. GSK2636771 400 mg once daily was the RP2D. Phospho/total AKT ratio decreased with GSK2636771 in tumor and surrogate tissue. A castrate-resistant prostate cancer (CRPC) patient harboring PIK3CB amplification had a partial response for over a year; an additional 10 patients derived durable (≥24 weeks) clinical benefit, including two other patients with CRPC with PIK3CB alterations (≥34 weeks). GSK2636771 400 mg once daily orally induced sufficient exposure and target inhibition with a manageable safety profile.Conclusions: Genomic aberrations of PIK3CB may be associated with clinical benefit from GSK2636771. Clin Cancer Res; 23(19); 5981-92. ©2017 AACR.

Second primary cancer risk of radiation therapy after radical prostatectomy for prostate cancer: an analysis of SEER data.

OBJECTIVES: To determine the incidence of second primary cancer (SPC) and primary pelvic late SPC/radiation-induced SPC after radical prostatectomy and radiation. METHODS: A total of 228 235 prostate cancer patients in the 1973-2002 Surveillance, Epidemiology, and End Results database were studied. The age-adjusted estimates of SPCs was calculated. Competing risk multivariable Cox proportional hazards regression analysis was adjusted for age at diagnosis, race or ethnicity, and radiation and was used to evaluate the effect of treatment on SPC. RESULTS: The overall incidence of SPC was 8.4%. The most frequent pelvic SPCs were bladder (2303 cases), rectum or rectosigmoid junction (1006 cases). The most frequent nonpelvic SPCs were bronchus and lung (4131 cases), colon (2665 cases), and skin (1769 cases). The absolute risk of developing a second malignancy was 1747 cases per 100 000 in the "Radical surgery and x-ray treatment" group and 1581 in the "radical surgery" group. With regard to late primary pelvic SPC, a higher age-adjusted rate of 374 cases per 100 000 was seen in the radiated group. CONCLUSIONS: Radiation after radical surgery increased late primary pelvic SPC. No increases were seen in secondary pelvic or extrapelvic SPCs.

Phase II study of tolerance and efficacy of hyperfractionated radiation therapy and 5-fluorouracil, cisplatin, and paclitaxel (taxol) and amifostine (ethyol) in head and neck squamous cell carcinomas: A-3 protocol.

The objective of this study was to determine the toxicity and efficacy of the current phase II chemoradiation protocol. Stage III or IV locally advanced head and neck squamous cell carcinomas arising from the oral cavity, hypopharynx, oropharynx, nasopharynx, paranasal sinuses, or larynx were treated using hyperfractionated radiation (74.4 Gy at twice-daily fractions of 1.2 Gy) in combination with a 5-fluorouracil, cisplatin, paclitaxel regimen, and an amifostine infusion. Thirty-five of 36 eligible patients were evaluable. The overall survival (OVS) was 88%, 82%, and 66% at 1, 2, and 3 years respectively. Twenty-five patients (71%) had a complete response, which was maintained in 20 (57%) patients until last follow up or death. Disease-free survival (DFS) of the complete responders was 92% at 1 year and 77% at 2 years and 3 years, respectively. Percutaneous endoscopic gastrostomy dependency lasted for a median of 7 months. Grade 3 and 4 mucositis occurred in 23 and 3 patients, respectively. Comparison with a similar study (A-2) that did not include amifostine showed no significant benefit to the addition of amifostine in these patients. A locoregional control benefit should be confirmed in a prospective, randomized trial. Alternative amifostine delivery methods should be investigated.

Fluoroscopy radiation safety for spine interventional pain procedures in university teaching hospitals.

BACKGROUND: Fluoroscopic guidance is frequently utilized in performing various types of interventional techniques. The major purpose of fluoroscopy is accurate needle placement to ensure target specificity and accurate delivery of the injected drug. However, radiation exposure may be associated with risks to physician, patient, and personnel. Multiple studies have evaluated the risk of radiation exposure and techniques to reduce the risk in private practice settings. However, the literature is scant in evaluating the risk of radiation exposure in teaching hospitals in university settings. OBJECTIVE: To evaluate safety and duration of radiation exposure for fluoroscopy guided interventional pain procedures in university pain clinics. STUDY DESIGN: Retrospective, case study. METHODS: The data was reviewed from the fluoroscopy machines from March 2004 to April 2004 at two university pain clinics. Mean fluoroscopy time (FT), mean radiation dose per procedure, and utilization of pulsed fluoroscopy were analyzed. RESULTS: Data of a total of 165 cases of spine injection procedures were collected. The mean fluoroscopy time for lumbar epidural steroid injection, facet joint block, sympathetic nerve block, sacroiliac joint injection, and discography were 46.6 +/- 4.2; 81.5 +/- 12.8; 64.4 +/- 11; 50.6 +/- 41.9 and 146.8 + 25.1 seconds respectively. There were significant differences in fluoroscopy exposure times and radiation dosage for epidural steroid injection among different teaching physicians. Pulsed fluoroscopy was used in less than 10% of cases. CONCLUSION: The results of this study show that the fluoroscopy exposure time for various interventional procedures performed in the university settings are significantly higher than the radiation exposure periods in private practice settings. This study also showed significant differences among physicians in the same university setting.

FcgammaRII expression on follicular dendritic cells and immunoreceptor tyrosine-based inhibition motif signaling in B cells.

Immune complexes (IC) initiate immunoreceptor tyrosine-based inhibition motif (ITIM) signaling and inhibit B cell activation by coligating B cell receptor for antigen (BCR) and FcgammaRII. Nevertheless, IC on follicular dendritic cells (FDC) stimulate rapid germinal center (GC) B cell proliferation suggesting that interactions between IC and FDC render IC capable of B cell activation. To understand this, we studied the kinetics of FDC FcgammaRII and complement receptors 1 and 2 (CR1&2) expressions during the GC reaction and determined whether FDC FcgammaRII could bind Fc in IC and block ITIM signaling. Mice were immunized with sheep red blood cells (SRBC), and CR1&2 and FcgammaRII levels in FDC reticula were monitored. The role of FDC FcgammaRII was studied using anti-BCR-stimulated A20 cells. Levels of FDC FcgammaRII in spleens of SRBC-injected mice increased within 24 h and were dramatically increased (approximately 50-fold) on days 3 and 5. In contrast, CR1&2 levels increased less than twofold. Addition of normal FDC, but not FDC lacking FcgammaRII, reduced and reversed anti-BCR-induced SH2 domain-containing inositol phosphatase (SHIP)-1 phosphorylation in A20 cells. FDC were able to induce normal recall responses even after overnight incubation of the lymphocytes with IC to stimulate ITIM signaling. Engagement of Ig Fc with numerous FcgammaRII on FDC appears to minimize IC-induced ITIM signaling. Thus, rapid up-regulation of FDC FcgammaRII may explain why poorly immunogenic IC are rendered highly immunogenic when presented by FDC in GC.