Carson D. Liu

Safety and efficacy of postoperative continuous positive airway pressure to prevent pulmonary complications after Roux-en-Y gastric bypass.

Continuous positive airway pressure (CPAP) is used to prevent apneic arrest and/or hypoxia in patients suffering from obstructive sleep apnea. This modality has not been universally accepted for patients following upper gastrointestinal surgery because of concerns that pressurized air will inflate the stomach and proximal intestine, resulting in anastomotic disruption. This study was performed to assess the safety and efficacy of postoperative CPAP for patients undergoing a gastrojejunostomy as part of a Roux-en-Y gastric bypass (RYGB) procedure. A total of 1067 patients (837 women [78%] and 230 men [22%]) were prospectively evaluated for the risk of developing anastomotic leaks and pulmonary complications after the RYGB procedure. Of the 1067 patients undergoing gastric bypass, 420 had obstructive sleep apnea and 159 were dependent on CPAP. There were 15 major anastomotic leaks, two of which occurred in CPAP-treated patients. Contingency table analysis demonstrated that there was no correlation between CPAP utilization and the incidence of major anastomotic leakage (P = 0.6). Notably, no episodes of pneumonia were diagnosed in either group. Despite the theoretical risk of anastomotic injury from pressurized air delivered by CPAP, no anastomotic leaks occurred that were attributable to CPAP. There were no pulmonary complications in a patient population that is at risk for developing them postoperatively. CPAP is a useful modality for treating hypoventilation after RYGB without increasing the risk of developing postoperative anastomotic leaks.

Peptide YY and cancer: current findings and potential clinical applications

Peptide YY (PYY) is a naturally occurring gut hormone with mostly inhibitory actions on multiple tissue targets. PYY has been identified in several carcinoid tumors and a decreased expression of PYY may be relevant to the development and progression of colon adenocarcinoma. Treatment with PYY decreases growth in pancreatic and breast tumors, most likely through a reduction in intracellular cAMP. In cancer patients, PYY may also improve malnutrition that results from iatrogenic causes or cachexia associated with advanced disease. PYY plays a significant role in multiple aspects of cancer from regulation of cell growth to potential therapeutic applications.

Selective cyclooxygenase-2 inhibitor rofecoxib (Vioxx) induces expression of cell cycle arrest genes and slows tumor growth in human pancreatic cancer

Recent studies indicate that cyclooxygenase-2 (COX-2) is overexpressed in pancreatic adenocarcinoma and may play a critical role in this rapidly progressing form of cancer. A human pancreatic adenocarcinoma cell line, Mia PaCa-2, was incubated for 18 hours with 5µ mol/L of rofecoxib (Vioxx), a selective COX-2 inhibitor. Total RNA was isolated and gene expression analyzed by DNA microarray chips. In a separate experiment, athymic mice were orthotopically injected with 7.5 x 105 Mia PaCa-2 cells through a minilaparotomy. After 1 month, laparotomy was repeated to measure tumor size, and mice were randomized to receive reformulated rodent chow containing either 12.5 mg/kg/day of rofecoxib or no drug for 21 days. Tumor growth was assessed by comparing volume before and after treatment. In vitro, rofecoxib decreased gene expression of cyclin D1/PRAD1, a key component of cell cycle progression, while increasing expression of several cell cycle arrest genes, including p21/WAF1, p33/ING, GADD34, and GADD45 (Pµ0.05). In vivo, tumor growth was significantly reduced in treated vs. control mice (Pµ0.05). No systemic toxicity was observed in mice receiving rofecoxib. These data suggest that rofecoxib slows the growth of human pancreatic cancer through changes in gene expression that favor cell cycle arrest.

Adjuvant hormonal treatment with peptide YY or its analog decreases human pancreatic carcinoma growth

BACKGROUND Recent studies have revealed decreased pancreatic cancer cell growth upon administration of peptide YY (PYY). We examined whether adjuvant treatment with PYY or its synthetic analog, BIM-43004, would decrease human pancreatic adenocarcinoma growth. MATERIALS AND METHODS Human pancreatic ductal adenocarcinomas, MiaPaCa-2 and BxPC-3, were cultured and assessed for growth by MTT assay. Pancreatic cancer cells received 500 pmol of PYY or BIM-43004 for 24 hours prior to 5-fluorouracil (5-FU; 10 micrograms/mL) and leucovorin (40 micrograms/mL) administration. Cell membrane epidermal growth factor (EGF) receptors were analyzed by Western blotting after exposure to peptides and chemotherapy. RESULTS Cancer cell growth was reduced in all groups receiving hormonal pretreatment (23% PYY/5-FU/leucovorin versus control; 27% BIM-43004/5-FU/leucovorin versus control) as compared with groups receiving 5-FU and leucovorin only (16% versus control). The EGF receptor expression was reduced by 30% in cells treated with PYY/5-FU/leucovorin and by 45% in cells treated with BIM/5-FU/leucovorin as compared with control cells without treatment. CONCLUSION Human pancreatic cancer cell growth is further decreased when pretreated with PYY or its synthetic analog prior to chemotherapy.

Infrared laser activation of indocyanine green inhibits growth in human pancreatic cancer.

Introduction Indocyanine green (ICG) is a clinically-approved, water-soluble dye that generates reactive singlet oxygen when activated by infrared light. Infrared light offers the advantage of deeper tissue penetration making ICG photodynamic therapy (PDT) ideal for treatment of intra-abdominal cancers such as pancreatic adenocarcinoma. Aims To determine the cytotoxicity of ICG PDT in human pancreatic cancer. Methodology MIA PaCa-2, PANC-1, and BxPC-3 pancreatic cancer cells were incubated for 1 hour with 0 to 50 &mgr;g/mL ICG, serially washed to remove unbound dye, and then briefly exposed to infrared light from a diode laser at 0.45 W. MTT cell viability assays were performed at 72 hours post-treatment. Results Toxicity to ICG or infrared laser alone was not observed in any of the cell lines. Cell viability assays showed an ICG dose-dependent ablation when combined with laser exposure (+L). In all 3 cancer cell lines, significant growth inhibition was seen at 10 &mgr;g/mL ICG + L with nearly total ablation at 20 &mgr;g/mL ICG + L (P < 0.01). Conclusion ICG PDT induces consistent and dramatic pancreatic cancer cell death. Since neither ICG nor laser alone caused toxicity, combination therapy may offer effective control of tumor growth with minimal side effects in patients with unresectable primary or metastatic pancreatic cancer.

Y2 receptors decrease human pancreatic cancer growth and intracellular cyclic adenosine monophosphate levels

BACKGROUND Peptide YY (PYY), a 36 amino acid enteric hormone, is known to decrease pancreatic exocrine and endocrine function. Previous studies with BIM-43004-1, a modified PYY(22-36) Y2 receptor agonist, have revealed diminished mitochondrial activity in pretreated pancreatic cancer cells in vitro. We investigated the effects of both PYY and BIM-43004-1 on pancreatic cancer growth in vivo. METHODS The 100,000 to 150,000 human pancreatic cancer cells, Mia PaCa-2, were orthotopically transplanted into 48 male athymic mice. After 1 week animals were treated with either PYY or BIM-43004-1 at 200 pmol/kg/hr via miniosmotic pumps for 2, 3, or 4 weeks. Paired controls received saline solution. At death tumor size and mass were measured. Receptor binding studies and intracellular cyclic adenosine monophosphate (cAMP) levels were measured in vitro. RESULTS All mice had significant human cancer growth within the pancreas by histologic sections at 2, 3, and 4 weeks. Tumor mass was decreased by 60.5% in BIM-43004-1 treated mice and 27.1% in PYY treated mice. Receptor binding studies revealed binding of [125I]-BIM-43004-1 and displacement of ligand on competitive addition of nonradioactive BIM-43004-1. K dissociation constant of 4.5 nmol and 27,000 receptors per cell were quantitated by receptor binding studies. In BIM-43004-1 treated pancreatic cells a 52.5% decrease in intracellular cAMP levels was noted, whereas a 15.3% decrease was seen in PYY treated cells. CONCLUSIONS BIM-43004-1, a novel Y2 synthetic agonist, specifically binds to human pancreatic cancer cells, decreases intracellular cAMP levels, and suppresses tumor growth in vivo. Adjuvant hormonal treatment with this Y2 receptor analog may be beneficial in the treatment of patients with pancreatic adenocarcinoma.

Intraluminal peptide YY induces colonic absorption in vivo

INTRODUCTION: Peptide YY (PYY) is a 36 amino acid hormone released into the circulation and lumen of the intestine after a meal. Previous studies have shown that exogenous administration of intravenous PYY stimulates water and electrolyte absorption in both the small and large intestines. The purpose of this study was to examine the effects of intraluminal administration of PYY on colonic absorption of electrolytes and water. METHODS: Six conditioned 25-kg dogs had 20 cm of colonic Thiry-Vella fistulae surgically constructed under general anesthesia. After a two-week recovery period, the animals received intraluminal PYY at 600 pmol/kg/hour after a 90-minute steady-state basal period. The Thiry-Vella fistulae were perfused with an isotonic buffer solution containing [14C]polyethylene glycol as a volume marker. Ion and water transport were measured every 15 minutes. RESULTS: On intraluminal infusion of PYY, increased absorption of water, sodium, and chloride was observed in the colon. A twofold increase in absorption rates occurred compared with basal rates lasting more than one hour after cessation of intraluminal PYY (N = 6;P <0.05vs. basal by analysis of variance). CONCLUSION: PYYsecreting cells of the colon may contribute to the regulation of absorption after a meal. Exogenous administration of intraluminal PYY may also be a therapeutic treatment modality for malabsorption.

Cholecystokinin mediation of colonic absorption via peptide YY: Foregut-hindgut axis

Abstract. Peptide YY (PYY), a 36-amino-acid polypeptide, is found in abundance in the colon, a region where its physiologic roles are unknown. Previous studies have revealed a substantial increase in plasma PYY after cholecystokinin (CCK) administration. PYY is released from the hindgut in response to a meal and inhibits CCK release. In this study we evaluated the effects of CCK and PYY on intestinal absorption of water and electrolytes. Colonic, ileal, or jejunal Thiry-Vella fistulas (TVFs) were created in 12 dogs, and intestinal continuity was reestablished. The TVFs were perfused with an isotonic buffer solution containing [ 14 C] PEG as a volume marker. Electrolyte and water transport were measured every 15 minutes, and plasma PYY and CCK levels were measured by radioimmunoassay. Group 1 dogs received an intravenous bolus of MK329, a specific CCK receptor antagonist, at 20 nmol/kg after a standard mixed meal; group 2 colonic TVF dogs received a meal and an intravenous bolus of PYY polyclonal antibody at 1 mg/kg. Postprandially, all three regions of the bowel became significantly proabsorptive for water, sodium, and chloride. In the colon postprandial absorption was abolished by MK329 starting 60 minutes after a meal, whereas specific CCK receptor blockade blunted ileal absorption. CCK receptor blockade did not affect postprandial absorption in the jejunum. Postprandial PYY levels did not rise in MK329-treated animals. PYY antibody reduced colonic absorption during the postprandial phase. Reduction of meal-induced colonic absorption and PYY release by MK329 in awake dogs suggests an important foregut–hindgut hormonal feedback loop. Foregut-derived CCK stimulates hindgut PYY release, which in turn stimulates colonic absorption while inhibiting further CCK release.

Synthetic peptide YY analog binds to a cell membrane receptor and delivers fluorescent dye to pancreatic cancer cells

Pancreatic cancer continues to have a dismal prognosis despite multimodality treatment plans. Peptide YY (PYY) is a gut hormone that suppresses pancreatic exocrine and endocrine function. Previous experiments have shown that shortened synthetic PYY(22-36) analog decreases pancreatic cancer cell growth while also decreasing intracellular cyclic adenosine monophosphate. Our purpose was to construct an optimal synthetic PYY analog that binds to pancreatic cancer cells that may be used for imaging and therapy. Biotinylated PYY analogs with lengths ranging from PYY(l-36), PYY(9-36), PYY(14-36), PYY(22-36), and PYY(27-36) were tested with flow cytometry and receptor cross-linking studies to measure cell membrane binding. Growth inhibition studies were also performed using monotetrazolium tests to determine potency of various PYY analogs. Quantitative flow cytometry reveals the highest specific binding of PYY(14-36) to pancreatic cancer cells. Cross-linking studies reveal a receptor on the cell membrane of human pancreatic ductal adenocarcinoma cells. Growth inhibition studies reveal that PYY (14-36) has the highest potency against PANC-1 and MiaPaCa-2 cells. A novel synthetic PYY analog binds to the cell surface of pancreatic cancer cells and has the ability to deliver fluorescent dyes. The strategy of using biotinylated peptides to deliver avidin-dye complexes to cancer cells will allow imaging of pancreatic tumors and delivery of therapeutic agents.

Combined Cisplatinum and Laser Thermal Therapy for Palliation of Recurrent Head and Neck Tumors

In recent years endoscopically controlled laser-induced thermal therapy (LITT) has been increasingly accepted as a minimally invasive method for palliation of advanced or recurrent head and neck or gastrointestinal cancer. Previous studies have shown that adjuvant chemotherapy can potentiate endoscopic laser thermal ablation of obstructing tumors leading to improved palliation in advanced cancer patients. Eight patients with recurrent head and neck tumors volunteered to enroll as part of an ongoing phase II LITT clinical trial, and also elected to be treated with systemic chemotherapy (cisplatin, 80 mg/m2) followed 24 h later by palliative laser thermal ablation. Laser treatments were repeated in patients with residual disease or recurrence for a total of 27 LITT sessions. Four of the 8 patients treated with laser thermal chemotherapy remained alive after a median follow-up of 12 months. Of the 12 tumor sites treated, complete responses were located in the oral cavity (3), oropharynx (1), hypopharynx (1), maxillary sinus (1), and median survival for these patients was 9.5 months. This initial experience with cisplatinum-based laser chemotherapy indicates both safety and therapeutic potential for palliation of advanced head and neck cancer but this must be confirmed by longer follow-up in a larger cohort of patients.