A High-Content Screen for C/EBPα Expression Identifies Novel Therapeutic Agents in Dedifferentiated Liposarcoma.

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.

Eosinophilic enteritis confined to an ileostomy site.

Eosinophilic enteritis is a rather rare condition that can manifest anywhere from esophagus to rectum. Its description in the literature is sparse, but associations have been made with collagen vascular disease, malignancy, food allergy, parasitic or viral infections, inflammatory bowel disease, and drug sensitivity. We present the case of a 41-year-old male diagnosed with ulcerative colitis who underwent proctocolectomy with ileal pouch anal anastomosis and loop ileostomy formation utilizing Seprafilm®, who later developed eosinophilic enteritis of the loop ileostomy site. This is the first report of eosinophilic enteritis and its possible link to the use of bioabsorbable adhesion barriers.

ZIC1 overexpression is oncogenic in liposarcoma.

Liposarcomas are aggressive mesenchymal cancers with poor outcomes that exhibit remarkable histologic diversity (there are five recognized subtypes). Currently, the mainstay of therapy for liposarcoma is surgical excision because 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. 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 adipose-derived stem cells or in a lung cancer cell line with low ZIC1 expression. ZIC1 knockdown is associated with increased nuclear expression of p27 proteins and the downregulation of prosurvival target genes BCL2L13, JunD, Fam57A, and EIF3M. Our results show that ZIC1 expression is essential for liposarcomagenesis and that targeting ZIC1 or its downstream targets might lead to novel therapy for liposarcoma.

Minimally Invasive Esophagectomy: Esophagogastric Anastomosis Using the Transoral Orvil for the End-to-Side Ivor-Lewis Technique.

OBJECTIVE: : Minimally invasive esophagectomy (MIE) can be performed a variety of ways using different techniques for the anastomosis. End-to-end anastomosis (EEA) transoral circular staplers have traditionally been used in gastric bypass surgery with good success. An evaluation of the safety and utility of the EEA transoral circular stapler for esophageal anastomoses in MIE is reviewed. METHODS: : A retrospective chart review of all patients who underwent transthoracic MIE with EEA-stapled transoral anastomoses between January 2008 and May 2009 was performed. Patient demographics, indication for esophagectomy, perioperative treatments, intraoperative data, postoperative complications, hospital length of stay, and in-hospital mortality were evaluated. RESULTS: : Twenty-six consecutive patients underwent MIE with EEA circular-stapled transthoracic anastomoses. Twenty-three were male with a mean age of 64 years (32-88). Indications for esophagectomy included esophageal cancer (24), high-grade dysplasia (1), and refractory stricture (1). Fifteen patients (63%) had neoadjuvant chemotherapy and radiation. There were no conversions to open thoracotomy or laparotomy. Mean operative time was 6.0 hours. Eight patients (31%) suffered postoperative complications; including leak from the gastric conduit staple line requiring operative intervention (1), postoperative bleeding requiring multiple transfusions (1), aspiration pneumonia (1), acute respiratory distress syndrome (1), myocardial infarction (1), chylothorax (1), and anastomotic stricture (2). Median hospital length of stay was 9 days (range 6-43). There were no in-hospital mortalities. CONCLUSIONS: : In our series, the EEA circular stapler seems technically feasible and relatively safe for an intrathoracic anastomosis in MIE.

Laparoscopic and hand-assisted distal pancreatectomy.

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.

Parastomal hernia: short-term outcome after laparoscopic and conventional repairs.

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.

Phase 1 study of TLK286 (Telcyta) administered weekly in advanced malignancies.

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 two-compartment 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).

Phase I study of TLK286 (glutathione S-transferase P1-1 activated glutathione analogue) in advanced refractory solid malignancies.

PURPOSE: The purpose of this study was to determine the dose-limiting toxicities (DLTs), the maximum tolerated dose, and the pharmacokinetics of the novel glutathione analog TLK286 administered by i.v. infusion. EXPERIMENTAL DESIGN: Patients with advanced malignancies received i.v. TLK286 administered as a 30-min constant rate infusion once every 3 weeks in escalating doses from 60 to 1280 mg/m(2). Patients underwent tumor assessment on day 43 and continued on treatment until disease progression or unacceptable toxicity. RESULTS: A total of 35 patients were treated with 109 cycles of TLK286. At 1280 mg/m(2), 3 of 5 patients developed one of two observed dose limiting toxicities (DLTs). The DLTs were: mild pancreatitis (1 of 5) and bladder symptoms (2 of 5) consisting of hematuria, dysuria, and urinary frequency. All of the patients with DLTs continued on TLK286 treatment at 960 mg/m(2) (one dose below maximum tolerated dose) without recurrence of DLTs. DLTs were transient, resolved without sequelae, and noncumulative. TLK286-related toxicities included grade 1-2 nausea, vomiting, fatigue, transient microscopic hematuria, and anemia. Of 31 evaluable patients, 10 patients continued therapy (median six cycles; range, four to nine cycles). Pharmacokinetic studies of TLK286 on cycle 1 revealed a mean elimination half-life of 18 min (95% confidence interval, 16.1-19.9). Dose-proportional increases in both maximum blood concentrations and area under the blood-concentration-time curve were observed over the dose range of 60-960 mg/m(2). CONCLUSION: TLK286 was well tolerated in this study. TLK286 safety and pharmacokinetics support disease-specific evaluations of TLK286 at doses <1280 mg/m(2) administered once every three weeks in the treatment of patients with advanced malignancies.