Safety and tolerability of veliparib combined with capecitabine plus radiotherapy in patients with locally advanced rectal cancer: a phase 1b study.

BACKGROUND: Further optimisation of present standard chemoradiation is needed in patients with locally advanced rectal cancer. Veliparib, an oral poly(ADP-ribose) polymerase inhibitor, has been shown to enhance the antitumour activity of chemotherapy and radiotherapy in preclinical models. We aimed to establish the maximum tolerated dose and establish the recommended phase 2 dose of veliparib combined with neoadjuvant capecitabine and radiotherapy. METHODS: This phase 1b, open-label, multicentre, dose-escalation study was done at six hospitals (one in Australia and five in the USA). Patients were eligible if they were aged 18 years or more and were newly diagnosed with stage II to III locally advanced, resectable adenocarcinoma of the rectum with a distal tumour border of less than 12 cm from anal verge. Patients were ineligible if they had received anticancer therapy or surgery (except colostomy or ileostomy) 28 days or less before the first dose of study drug, previous pelvic radiotherapy, or previous treatment with poly (ADP-ribose) polymerase inhibitors. Enrolled patients received capecitabine (825 mg/m2 orally twice daily) with radiotherapy (50·4 Gy in 1·8 Gy fractions daily, approximately 5 days consecutively per week for about 5·5 weeks). Veliparib (20-400 mg orally twice daily) was administered daily starting on day 2 of week 1 and continuing until 2 days after radiotherapy completion. Patients underwent total mesorectal excision 5-10 weeks after radiotherapy completion. The primary objectives were to establish the maximum tolerated dose and recommended phase 2 dose of veliparib plus capecitabine and radiotherapy, with an exposure-adjusted continual reassessment methodology. Efficacy and safety analyses were done per protocol. The reported study has completed accrual and all analyses are final. This trial is registered with ClinicalTrials.gov, number NCT01589419. FINDINGS: Between June 12, 2012, and Jan 13, 2015, 32 patients received veliparib (22 in the dose-escalation group; ten in the safety expansion group); 31 were assessable for efficacy (<400 mg, n=16; 400 mg, n=15). During dose escalation, grade 2 dose-limiting toxic effects occurred in two patients; no grade 3-4 dose-limiting toxic effects were noted. Therefore, the maximum tolerated dose was not reached; the recommended phase 2 dose was selected as 400 mg twice daily. The most common treatment-emergent adverse events in all 32 patients were nausea (17 [53%]), diarrhoea (16 [50%]), and fatigue (16 [50%]). Grade 3 diarrhoea was noted in three (9%) of 32 patients; no grade 4 events were reported. Veliparib pharmacokinetics were dose proportional, with no effect on capecitabine pharmacokinetics. Tumour downstaging after surgery was noted in 22 (71%) of 31 patients; nine (29%) of 31 patients achieved a pathological complete response. INTERPRETATION: Veliparib plus capecitabine and radiotherapy had an acceptable safety profile and showed a dose-proportional pharmacokinetic profile with no effect on the pharmacokinetics of capecitabine. Preliminary antitumour activity warrants further evaluation. FUNDING: AbbVie Inc.

Liver resection for metastatic disease after y90 radioembolization: a case series with long-term follow-up.

INTRODUCTION: There are only few reports of liver resections for metastatic disease in patients previously treated with Y-90 radioembolization (RE), and long-term outcome data are sparse. We reviewed our center's experience in patients undergoing hepatectomy after hepatic RE. METHODS: A retrospective chart review of patients undergoing RE from 2004 to 2011 was performed. Demographic, clinicopathologic, operative, and long-term outcomes variables were collected. Independent pathologic review of tumor necrosis and normal liver tissue grading of fibrosis and inflammation after resection was performed. Data are expressed as medians and ranges. RESULTS: RE was delivered to 106 patients with primary and metastatic disease of the liver, of whom 9 patients (6 males, 3 females, median age 54 (47-76) years) with metastatic disease ultimately underwent resection. RE was previously administered to the right liver in five, the left liver in one, and to the whole liver in three. Two patients had a second RE performed before resection. Six of the nine patients had previously received several infusions of cytotoxic therapy. The operations occurred at a median of 115 (56-245) days after RE and included right lobectomy (n = 5), left lobectomy (n = 1), left-lateral sectionectomy (n = 1), and bilobar wedge resections (n = 2). Extrahepatic sites were resected in three patients. Median blood loss was 900 (range 250-3600) ml. Grade 3 or higher complications occurred in seven cases (78 %). Follow-up was complete all nine patients. Three patients (33 %) died within 30 days of resection. All those surviving the operative period had disease recurrence (time to recurrence: 202 [range 54-315] days), and all have since died (overall survival: 584 [range 127-1230] days). Review of resected specimens demonstrated median tumor necrosis of 70 % (range 20-90 %). In nontumor-bearing liver, fibrosis grade (0-4) and inflammation score (0-4) was 2 or less in all specimens. CONCLUSIONS: In this small cohort of highly selected and heavily pretreated patients, long-term survival in patients undergoing resection after RE appears possible, but the operations may carry substantial risks-highlighting the importance of careful patient selection for these resections. The etiology of morbidity and mortality is likely multifactorial and additional reports that include long-term outcomes will be necessary to identify more clearly the impact of RE on postoperative complications and death.

The first documented case of high-grade synovial cell sarcoma of the rectum.

A patient presented with signs and symptoms of tenesmus, urgency, and rectal bleeding that she had been experiencing over the course of several months. Full endoscopic evaluation showed a 6-cm submucosal mass approximately 10 cm from the dente line projecting as an endoluminal mass with a large broad base. An initial endoscopic resection was attempted but aborted because of significant hemorrhage, and surgical oncology was consulted. After stabilization, the patient underwent a transanal resection of the mass the following day. An endoscopic gastrointestinal anastomosis stapler resulted in a margin-negative complete resection of what was later determined to be a high-grade synovial cell sarcoma. This case report presents the first known documented case of synovial cell sarcoma of the rectum.

Two extremes of the megalourethra spectrum.

The 2 cases of megalourethra presented in this report illustrate the variability in the severity of congenital malformations associated with this condition. Surgical repair of a scaphoid-type megalourethra is discussed. Also, a digital video of megalourethra in a degloved penis is presented that uniquely illustrates the functional anatomy of this condition.

Local recurrence of prostate cancer in rectal submucosa after transrectal needle biopsy and radical prostatectomy.

A 69-year-old man with clinical Stage T1cN0M0 prostate cancer underwent radical prostatectomy, revealing negative surgical margins, focal capsular penetration, and negative lymph nodes and seminal vesicles. Five years later, his prostate-specific antigen level had increased to 0.2 ng/mL, and digital rectal examination revealed a palpable submucosal mass in the rectum that was confirmed by colonoscopy and transrectal ultrasonography. Excisional biopsy revealed prostatic adenocarcinoma similar in appearance and grade to the initial needle biopsy. This case report illustrates an extremely rare needle tract adenocarcinoma implantation after needle biopsy of the prostate.

Deacetylation of p53 after nerve growth factor treatment in PC12 cells as a post-translational modification mechanism of neurotrophin-induced tumor suppressor activation.

The tumor suppressor protein p53 is a transcription factor that regulates the response to cellular insults such as DNA damage and growth factor withdrawal. Transcriptional activity of p53 requires post-translational modification by phosphorylation and acetylation. This study used site-specific antibodies to demonstrate that nerve growth factor (NGF) treatment of PC12 cells results in p53 deacetylation at lysine (Lys) 382. Histone deacetylase (HDAC) activity, measured by a direct fluorescent assay, was increased after NGF treatment and peaked before p53 deacetylation. Inhibition of HDAC by trichostatin blocked the deacetylation of p53 and its transcriptional activity toward a reporter gene construct. Comparison of PC12 with PC12 cells containing a temperature-sensitive, dominant-negative construct showed that p53 deacetylation required functional p53. Inhibitors of MAP kinase that block p53 transactivation and inhibitors of TrkA receptor also abolished HDAC activation, indicating that deacetylation of p53 is an NGF-dependent post-translational mechanism of p53 activation. Finally, NGF or serum withdrawal did not lead to p53 deacetylation. A model is proposed in which the acetylation status of Lys 382 of p53 discriminates between cell cycle arrest and apoptosis.

Nerve growth factor withdrawal-mediated apoptosis in naive and differentiated PC12 cells through p53/caspase-3-dependent and -independent pathways.

Programmed cell death is regulated in response to a variety of stimuli, including the tumor suppressor protein p53, that can mediate cell cycle arrest through p21/Waf1 and apoptosis through the Bcl-2/Bax equilibrium and caspases. Neuronal cell apoptosis has been reported to require p53, whereas other data suggest that neuronal cell death may be independent of p53. Comparison of wild type PC12 to a temperature-sensitive PC12 cell line that depresses the normal function of p53 has permitted investigation of the importance of p53 in a variety of cell functions. This study examined the role of p53 in trophic factor withdrawal-mediated apoptosis in both naïve and differentiated PC12 cells. Our data show that as PC12 cells differentiate they are more poised to undergo apoptosis than their undifferentiated counterparts. Survival assays with XTT (sodium 3'-1-(phenylaminocarbonyl)-3,4-tetrazolium-bis(4-methoxy-6-nitro)benzene sulfonic acid) and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) demonstrated that lack of p53 is initially protective against apoptosis. The window of protection is about 20 h for naïve and 36 h for differentiated cells. Apoptosis involved caspases 3, 6, and 9. However, caspase 3 activation was absent in cells lacking p53, concomitant with the delayed apoptosis. When the expression of caspase 3 was silenced with interference RNA, wild type PC12 cells revealed a morphology and biochemistry similar to PC12[p53ts] cells, indicating that caspase 3 accounts for the observed delay in apoptosis in p53 dysfunction. These results suggest that p53 is important, but not essential, in factor withdrawal-mediated apoptosis. Parallel pathways of caspase-mediated apoptosis are activated later in the absence of functional p53.