Liposarcomas are aggressive mesenchymal cancers with poor outcomes that exhibit remarkable histologic diversity, with five recognized subtypes. Currently, the mainstay of therapy for liposarcoma is surgical excision since liposarcomas are often resistant to traditional chemotherapy. In light of the high mortality associated with liposarcoma and the lack of effective systemic therapy, we sought novel genomic alterations driving liposarcomagenesis that might serve as therapeutic targets. ZIC1, a critical transcription factor for neuronal development, is overexpressed in all five subtypes of liposarcoma compared with normal fat and in liposarcoma cell lines compared with adipose-derived stem cells (ASC). Here we show that ZIC1 contributes to the pathogenesis of liposarcoma. ZIC1 knockdown inhibits proliferation, reduces invasion, and induces apoptosis in dedifferentiated and myxoid/round cell liposarcoma cell lines, but not in either ASC or a lung cancer cell line with low ZIC1 expression. ZIC1 knockdown is associated with increased nuclear expression of p27 protein, and the down-regulation of pro-survival target genes: BCL2L13, JunD, Fam57A, and EIF3M. Our results demonstrate that ZIC1 expression is essential for liposarcomagenesis and that targeting ZIC1 or its downstream targets may lead to novel therapy for liposarcoma.

With the increased use of CT, discovering incidental pancreatic lesions has become commonplace. Lesions in the distal pancreas lend themselves well to laparoscopic resection. We reviewed our experience with laparoscopic distal pancreatectomy. During the study period, 32 distal pancreatectomies were performed. There were 20 females. Mean patient age was 58.0 years (range, 23–83 years) and mean body mass index was 29.9 kg/m2 (range, 19.9–44.7 kg/m2). Technique was laparoscopic (25) or hand-assisted (seven) with one conversion in each group. The spleen was preserved in six patients (18.8%). Mean operative time overall was 238 minutes (range, 140–515 minutes); hand-assisted was 222 minutes and laparoscopic was 254 minutes. Estimated blood loss averaged 221 mL (range, 50–1800 mL). Mean tumor size was 2.7 cm (range, 0.6–7 cm). Tumor pathology was serous cystadenoma (10), neuroendocrine tumor (six), mucinous cystic neoplasm (four), intrapapillary mucinous neoplasm (four), adenocarcinoma (three), other (four), and solid pseudopapillary neoplasm (one). Mean length of stay was 5 days (range, 3–11 days). Complications were pancreatic fistula (six), wound infection (two), pulmonary embolism (one), pancreatitis (one), myocardial infarction (one), postoperative bleed from combined laparoscopic bilateral oophorectomy (one), and pancreatic stump staple line bleed requiring reoperation (one). There were no perioperative deaths. All pancreatic fistulas resolved with conservative management.

Purpose: To determine the dose-limiting toxicities, maximum tolerated dose, and pharmacokinetics of TLK286, a novel cancer prodrug, administered weekly.Patients and Methods: Patients with advanced malignancies were treated with TLK286 administered weekly by i.v. infusion over 30 min in escalating doses 60 -960 mg/m 2 . A treatment cycle was defined as 3 weekly treatments. Patients underwent tumor assessments on day 43, and those patients receiving clinical benefit continued on treatment until disease progression or unacceptable toxicity. Safety was assessed by the WHO criteria.Results: Thirty-seven patients received 111 cycles of TLK286 at eight dose levels (median, 3 cycles; range, 1-16 cycles). In this study, TLK286 given weekly at 960 mg/m 2 was well tolerated without dose-limiting toxicities. TLK286-related toxicities included grade 1-2 nausea and vomiting, fatigue and anemia. Nine of 31 evaluable patients continued therapy beyond day 43 and received a median of 5 cycles (range of 3-16 cycles) and experienced durable stable disease or minor tumor regression. Pharmacokinetic characteristics of TLK286 are described by an optimized twocompartment model. Mild to moderate renal or hepatic organ dysfunction did not impact the elimination of TLK286.Conclusions: TLK286 administered weekly at doses up to 960 mg/m 2 were well tolerated. The safety and antitumor activity observed in a broad range of cancer types supports Phase 2 disease-specific investigations of TLK286 given weekly at 960 mg/m 2 .

The purpose of this study was to evaluate the short-term outcomes after laparoscopic and conventional parastomal hernia repairs. A retrospective review of parastomal hernia repairs was performed. Conventional repairs included primary suture repair, stoma relocation, and mesh repair. Laparoscopic repairs included the Sugarbaker and keyhole techniques. Forty-nine patients underwent repair of symptomatic parastomal hernias: 19 ileostomies, 13 colostomies, and 17 urostomies. Thirty patients underwent 39 conventional repairs. Nineteen patients underwent laparoscopic surgical repairs. Operative times were longer for laparoscopic repair (208 +/- 58 vs 162 +/- 114 minutes, P = .06). The mean length of stay was 6 days for both groups (P = .74). The mean follow-up was shorter in the laparoscopic group (20 vs 65 months, P < or = .001). There were no significant differences in the incidence of surgical site infections (11% laparoscopic vs 5% conventional, P = .60) or complication rates (63% laparoscopic vs 36% conventional, P = .67). Laparoscopic parastomal hernia repair is a feasible operation with similar short-term outcomes to conventional repairs.

Purpose: Dedifferentiated liposarcoma (DDLS), one of the most common and aggressive sarcomas, infrequently responds to chemotherapy. DDLS survival and growth depend on underexpression of C/EBPα, a tumor suppressor and transcriptional regulator controlling adipogenesis. We sought to screen and prioritize candidate drugs that increase C/EBPα expression and may therefore serve as differentiation-based therapies for DDLS. Experimental Design: We screened known bioactive compounds for the ability to restore C/EBPα expression and inhibit proliferation selectively in two DDLS cell lines but not in normal adipose-derived stem cells (ASC). Selected hits' activity was validated, and the mechanism of the most potent, SN-38, was investigated. The in vivo efficacy of irinotecan, the prodrug of SN-38, was evaluated in DDLS xenograft models. Results: Of 3,119 compounds, screen criteria were met by 19. Validation experiments confirmed the DDLS selectivity of deguelin, emetine, and SN-38 and showed that they induce apoptosis in DDLS cells. SN-38 had the lowest IC50 (approximately 10 nmol/L), and its pro-apoptotic effects were countered by knockdown of CEBPA but not of TP53. Irinotecan significantly inhibited tumor growth at well-tolerated doses, induced nuclear expression of C/EBPα, and inhibited HIF1α expression in DDLS patient-derived and cancer cell line xenograft models. In contrast, doxorubicin, the most common treatment for nonresectable DDLS, reduced tumor growth by 30% to 50% at a dose that caused weight loss. Conclusions: This high-content screen revealed potential treatments for DDLS. These include irinotecan, which induces apoptosis of DDLS cells in a C/EBPα-dependent, p53-independent manner, and should be clinically evaluated in patients with advanced DDLS.