Elevated LFTs Research Articles

Yield of Repeat ERCP for Persistently Elevated LFTs After a Previously Normal Cholangiogram in Liver Transplant Patients with Choledochocholedochostomy Anastomosis

Background: Biliary tract complications are common after orthotopic liver transplantation (OLT), occurring in 13–35% of pts, with biliary leaks and anastomotic strictures most often identified. ERC allows for effective and less invasive management of these complications than repeat surgical evaluation. Aim: The aim of this study was to evaluate the yield of a repeat ERCP in OLT pts with persistently elevated or rising LFTs after a previously normal ERC. Methods: Eligible OLT pts were identified by review of our ERCP database from 1999-2007.

Denileukin Diftitox (ONTAK) Plus CHOP Chemotherapy in Patients with Peripheral T-Cell Lymphomas (PTCL), the CONCEPT Trial.

PTCL are an aggressive group of lymphomas comprising a number of histopathologic subtypes for which CHOP chemotherapy has been the standard first-line regimen at many centers. Denileukin diftitox (Dd) is a recombinant DNA-derived cytotoxic protein composed of diphtheria toxin fragments A and B and the full length sequence of human interleukin-2 (IL-2). Dd targets T-cells expressing the intermediate and high-affinity IL-2 receptor. Because the mechanism of action of Dd is distinct from traditional cytotoxic chemotherapy and Dd has exhibited minimal myelosuppression, we evaluated the safety, tolerability, and efficacy of combining Dd with CHOP as first-line therapy for patients with PTCL according to the REAL classification. (Pts with mycosis fungoides or Sezary syndrome were not included.) Dd was administered at 18 mcg/kg/day on Days 1 and 2 followed by CHOP on Day 3, and G-CSF support starting Day 4, every 3 weeks for up to 6 cycles. Evaluation of response is performed after every 2 cycles of treatment.Results: Forty-one pts, 18 male/23 female, have been enrolled to date, with a median age of 52. Ten pts are not evaluable for response: 5 discontinued due to an adverse event (AE) prior to assessment of response; 3 due to lack of measurable disease at baseline; and 2 are too early to evaluate. For the 31 response-evaluable patients, the overall response rate is 90%, with 71% (22/31) CR or CRu, 19% (6/31) PR, 6% (2/31) SD, and 3% (1/31) PD. Ten of 28 responders (36%) have progressed, with a median duration of response of 13 months.PTCL subtypeNo. of PatientsNo. evaluableResponsesORRPTCL-nos20153 CR, 5 CRu, 4 PR, 2 SD, 1 PD80%Angioimmunoblastic1093 CR, 5 CRu, 1 PR100%Anaplastic large cell642 CR, 2 CRu100%Enteric T-cell211 CRu100%Hepatosplenic10n/an/aNasal/nasal type T/NK cell111 CRu100%Subcutaneous panniculitic T-cell111 PR100%Toxicities have generally been grade 1–2, were transient, and caused few dose modifications. The most common have been fatigue (62%), nausea (44%), anemia (38%), sensory neuropathy (33%), hypoalbuminemia (33%), elevated ALT (30%), dyspnea (28%), thrombocytopenia (30%), leukopenia (28%), fever (25%), elevated AST (25%), lymphopenia (25%), and hyperglycemia (25%). Forty-three percent (17/40) of patients experienced one or more grade 3–4 hematological toxicities and 40% (16/40) of patients experienced one or more grade 3–4 non-hematological toxicities. Five patients discontinued the study due to AEs, all occurring prior to Cycle 2, for: infusion-related anaphylaxis; elevated LFTs; port-related staph sepsis; pneumonia; and a death possibly resulting from tumor lysis syndrome and rhabdomyolysis.Conclusion: The combination of Dd plus CHOP has a generally manageable safety profile and to date has exhibited promising clinical activity in PTCL.

The Prevalence and Risk Factors for Abnormal Liver Enzymes in HIV-Positive Patients without Hepatitis B or C Coinfections

Abnormal liver enzymes (LFTs) are frequently seen in HIV patients. Because HCV and HBV overshadow other possible variables, little is known about the prevalence and predictive factors of abnormal LFTs in the absence of viral hepatitis. To determine the prevalence and factors associated with abnormal LFTs defined as >1.25 ULN. A retrospective analysis of HIV clinic patients was performed. Variables were determined at the time of abnormal LFTs or by history and included diabetes mellitus (DM), hypertension (HTN), dyslipidemia, HCV and HBV status, metabolic syndrome (MS), and HAART use (NRTI, NNRTI, and PI). Patients without HCV/HBV (n = 679/1,208) were younger, Caucasian, had a BMI >30 and had dyslipidemia. The prevalences of elevated LFTs in those without HCV/HBV were AST 20%, ALT 15%, and ALP 43% compared to 64%, 46%, and 63% in those with HCV (all P < 0.0001), and 98% were mild-moderate (grade 1-2). While AST was highly correlated with ALT, neither was associated with increased ALP. In those without HCV/HBV, increased AST was associated with HTN, HIV RNA, and absence of PI use; increased ALT was associated with HTN, HIV RNA, CD4 < 200, MS, and absence of PI use, while increased ALP was associated with age, BMI, CD4%, DM, and NRTI use. Mild-moderate increased liver enzymes are common in HIV patients without HCV/HBV and absence of PI use is independently associated with elevations in both AST and ALT, while features typical of hepatic steatosis (DM and BMI) are only associated with increased ALP.

Epigastric Pain with Very High LFTs and Pancreatic Enzymes – An Unusual Presentation of Papillary Stenosis

Purpose: The typical case of papillary stenosis is described as middle aged female who presents with recurrent episodes of right upper abdominal pain occurring several years after cholecystectomy with mild elevations of LFTs. Here we report an unusual case of papillary stenosis who presented with acute pancreatitis like symptoms with very high levels of LFTs and amylase and lipase followed by rapid improvement. Methods: A 53-year-old white female s/p cholecystectomy came to the emergency department because of epigastric pain, nausea and vomiting for 2 days. On physical exam, she had epigastric tenderness but no jaundice or dehydration. The liver enzymes were grossly elevated, with an aspartate aminotransferase (AST) level of 2006 IU/L, an alanine aminotransferase (AST) level of 1359 IU/L, and an alkaline phosphatase (ALP) value of 180 IU/L. Total and direct bilirubin levels were 2.2 mg/dL and 1.3 mg/dL respectively. Serum amylase and lipase were 1536 U/L and 1915 U/L respectively. A CT scan of abdomen and pelvis and abdominal sonogram were negative for pancreatitis or stones in the pancreato-biliary tree. ERCP revealed a normal papilla. Cholangiogram showed a dilated common hepatic duct of 8 mm with benign tapering to the ampulla. The cystic duct joined the common hepatic duct only few millimeters away from the ampulla. Hence the patient had a very small common bile duct. No stones were noted in the biliary tree. With the elevated LFTs, biliary pain and dilated duct, this was a case of type 1 papillary stenosis. Sphincterotomy was performed. Post ERCP follow up labs showed a marked decline in LFTs and amylase and lipase and there was marked improvement in abdominal pain. At follow up visit one week after sphincterotomy, the patient remained completely asympomatic and the LFTs and amylase and lipase were almost completely normalized (AST = 33, ALT = 154, ALP = 195, amylase = 101, lipase = 46 and total bilirubiN = 0.3). Conclusion: Papillary stenosis is not a common condition and often presents diagnostic dilemma to the clinicians. An ERCP with sphincterotomy is instrumental in diagnosing and treating papillary stenosis, and should be considered in postcholecystectomy cases with abdominal pain and elevated LFTs. Endoscopic sphinceteotomy is a recommended treatment for papillary stenosis (type 1 SOD) and is very effective and safe in experienced hands.

HIV-Associated Non-Hodgkinʼs Lymphoma of the Small Intestine

The diagnosis of small bowel tumors is often difficult due to the rarity of these lesions, and the nonspecific and variable nature of the presenting signs and symptoms. A 59 year old white male with a history of HIV\AIDS (CD4 = 73) who presented to the hospital with 1 week history of generalized weakness, poor oral intake, non productive cough and mental status changes. He denied any fever, chills, dyspnea, or GI complaints. His initial work up demonstrated WBC 16.7 (Neutrophils 25%, Bands 8%, and Lymphocytes 22%), thrombocytopenia (29000), anemia (Hgb 11.8 g/dl), and elevated LFTs (Ast 175 U/L, Alt 98 U/L, Bilirubin 1.1 mg/dl, Alkaline phosphatase 1078 U/L). He had Head CT scan which was unremarkable, abdominal U/S which revealed fatty liver with two liver cysts in the right lobe and splenomegaly, and abdominal CT scan which showed 9 cm mass like mural thickening involving the terminal ileum, moderate retroperitoneal and abdominal lymphadenopathy, splenomegaly, and small ascites. Colonoscopy was done which showed an exophytic bulky mass in the terminal ileum extending to the ileocecal valve with friable overlying mucosa. Biopsies showed Non Hodgkin's lymphoma – B cell type. The Bone marrow biopsy demonstrated bone marrow diffusely involved by non Hodgkin's lymphoma. Patient became hypoxic and more confused, the family refused any further investigations or treatments and he expired two days later. Discussion: Small bowel malignancies account for only 2–3% of all gastrointestinal (GI) neoplasms, and less than 0.4% of all cancers in the United States. Primary GI lymphoma is the most common extranodal form of lymphoma; the stomach (75%) and small bowel (9%) are most often involved. Small bowel lymphoma occurs predominantly in male adults, peaking in the seventh decade. Most tumors are focal and involve the distal small intestine. The incidence of primary intestinal lymphoma in the United States doubled between 1985 and 1991. Among the factors implicated in this increase is the increasing number of immunocompromised patients (eg, AIDS, transplantation recipients), and the increasing immigration from Third World countries.

A Rare Case of Biliary Synovial Sarcoma

A 51-year-old Hispanic male was referred to our hospital with obstructive jaundice and a possible cholangiocarcinoma. At the other hospital patient had undergone laboratory examination, CT scan and ERCP. Laboratory examination showed leucocytosis, elevated liver function tests (total bilirubin 14 mg/dl, conjugated bilirubin 10 mg/dl, and alkaline phosphatase of 800 U/per liter). Computed tomography (CT) abdomen showed dilated CBD and a mass obstructing the neck of gall bladder. During endoscopic retrograde choledochopancreatography (ERCP) lots of mucus membrane like material was expressed and sent to histopathology. No definitive pathological diagnosis could be made because of the complexity of the tissue. Patient continued to be symptomatic and had persistently elevated LFTs. After transfer, MRCP with gadolinium revealed an intraluminal mass within the common bile duct with probable extension into the gallbladder, most consistent with cholangiocarcinoma (Fig. 1). Patient underwent Whipple's procedure for this suspicious mass. Gross pathology of the resected specimen revealed two separate unconnected polypoid masses in common bile duct and gall bladder. Histopathology revealed whorls of small darkly staining cells arranged in sheets suggestive of synovial sarcoma vs. small cell carcinoma vs. peripheral neuroectodermal tumor (PNET) (Fig. 2). Various immunohistochemical stains were performed on the tumor specimen (positive for CD 99, Bcl-2 and synatophysin) favoring a poorly differentiated synovial sarcoma. Slides were reviewed with two other pathologists who concurred with the interpretation of the tumor as synovial sarcoma. To the best of our knowledge this is one of the first rare cases described in literature. Patient was lost to follow-up before initiation of chemotherapy.[figure1][figure2]FigureFigure

A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC)

5107 Background: RAD001 is an oral mammalian target of Rapamycin (mTOR) inhibitor. Three mechanisms of anti-tumor activity; shuts down tumor response to nutrients and growth factors; cell cycle arrest at late G1 and anti-angiogenesis via VEGF. Molecular alterations in the mTOR modular pathway increase sensitivity in PTEN deficient tumors such as RCC. Endpoints: time-to-progression (TTP), response rate (RR), overall survival (OS), toxicity, and to assess changes in metabolic imaging utilizing CT-PET. Methods: Eligibility included; predominant clear cell, progressive measurable MRCC, adequate organ/marrow function, zubrod performance status (ZPS) = 2, no more than 1 prior therapy, and no active CNS involvement. RAD001 is given orally at a dose of 10mg daily without an interruption (28-day cycle), with dose modifications for toxicity. Re-evaluation was assessed every 2 cycles (8 weeks). RECIST criteria is utilized. TTP and OS are determined from entry into the study. Results: 41 pts have been enrolled. 37 pts are evaluable for response/toxicity. 2 pts toxicity only. 2 pts screened failures. 31 were male/8 female, median age 60 (38–80) years. 31 pts received prior therapy. 23 pts had a ZPS of 0, 13 /1 and 3/2. Sites of disease included; lung, nodal, liver, bone, adrenal, and kidney. 9 pts had 1 metastatic site, 17 pts/2 and 13 pts/3 or more. 15 pts continue to receive RAD001. 12 pts had partial responses, 19 pts were stable for 3+ months. Median duration of therapy is 8+ (range 01–20+) months. Treatment related adverse events; mucositis, skin rash, pneumonitis, hypophosphatemia, hyperglycemia, hypertriglyceridemia, hypercholesterolemia, thrombocytopenia, anemia and elevated LFTs. PET scans have demonstrated decreased metabolic activity in responding or stable pts. Median overall survival is 11.5+ months (range 01–20+). Conclusion: RAD001 has promising anti-tumor activity in pts with MRCC demonstrated by partial response rate. Anti-tumor activity is further suggested by prolonged TTP =3 months. Anti-tumor activity, toxicity and metabolic imaging correlation will be presented. An additional 40 pts who failed prior sunitinib or sorafenib therapy are being enrolled. No significant financial relationships to disclose.

Phase II trial of paclitaxel in front-line therapy of hormone refractory metastatic prostate cancer

15628 Hormone refractory prostate cancer patients have poor prognosis with median survival of only 16 months. They are frequently elderly men with many co-morbid conditions unable to tolerate treatments with substantial toxicity. Docetaxel, the only drug shown to prolong survival causes significant toxicities, requires steroids administration, may cause poorly reversible neuropathy and requires long infusion times, all limiting its use in elderly men that are mostly affected by hormone refractory prostate cancer. Abraxane is a novel agent delivering paclitaxel without steroids, requires only 30 minutes infusion times and low toxicity potential that may be effective and more tolerable in patients with prostate cancer. The goal of our study is to evaluate the effectiveness and toxicity of Abraxane in first line chemotherapy of men with hormone refractory prostate cancer. Considering the favorable toxicity profile of Abraxane and in an effort to make our results applicable to the majority of prostate cancer patients we are including men with performance status of 2. Main eligibility criteria are: hormone refractory metastatic prostate cancer documented by PSA progression, no prior chemotherapy, PSA &gt;5 and performance status 0–2. Primary endpoint is efficacy based on PSA response. Secondary endpoints are time to PSA progression, overall survival, and toxicities. The clinical trial has been opened at Kaiser Permanente Northern California since September 2005. There are 15 patients enrolled. All have been evaluable for toxicity and the drug is very well tolerated so far by this population of patients. Out of 15 patients 12 are evaluable for response. Two patients have recently started the protocol therapy and have not met the time point for disease assessment. One patient discontinued the treatment after one infusion due to toxicity (elevated LFTs). One patient completed 11 cycles of Abraxane, while maintaining stable disease on bone scan and achieved a PR by PSA. Ten patients have come off study due to progressive disease based on clinical presentation, rising PSA or signs of radiological progression. There are currently 4 patients actively receiving therapy. Updated results will be presented at the time of ASCO 2007 meeting. No significant financial relationships to disclose.

Biliary T-Tube Remnant As the Cause of Microlithiasis and Recurrent Acute Pancreatitis, Detected By a New Per Oral Cholangioscopy System (SpyGlass)

A 62 year old female s/p cholecystectomy for cholelithiasis a year ago, with recurrent acute pancreatitis and mildly elevated LFTs with dilated biliary tree underwent ERCP that showed long cystic duct stump and dilated biliary tree without filling defects. Balloon sweep of CBD after sphinterotomy yielded only sludge. She developed another attack of acute pancreatitis after few months. MRCP showed a filling defect in the distal CBD. Repeat ERCP was done with sludge extraction. After few months, she had acute pancreatitis again and MRCP showed new distal CBD stone. An ERCP with cholangioscopy using the new per oral cholangioscopy system (SpyGlass) was done. Cholangiogram showed a filling defect in distal CBD but no filling defects in the cystic duct stump. Cholangioscopy confirmed the presence of the filling defect in distal CBD as microlithiasis, and in addition showed a tubular structure covered with sludge in the cystic duct. Balloon sweep of the cystic duct yielded a foreign body that was found to be remnant of a T-tube used during patient's cholecystectomy (picture). Presence of a foreign body in biliary tree is known to act as a nidus for sludge and microlithiasis formation. Recurrent attacks of acute pancreatitis in our patient were attributed to microlithiasis and sludge as a result of presence of T-tube remnant. Due to its hollow structure, the tube would fill with contrast and could not be visualized during ERCP. Filling with bile prevented visualization on MRCP. Being made up of radiolucent plastic material it also had evaded detection on CT scan. Direct cholangioscopy was the only diagnostic technique that enabled the detection of T-tube remnant in the cystic duct stump and subsequent removal.

A New Oral Aniticoagulant, Dabigatran Etexilate, Is Effective and Safe in Preventing Venous Thromboembolism after Total Knee Replacement Surgery (The RE-MODEL Trial).

BACKGROUND: Oral DVT prophylaxis not requiring monitoring is an advantage in orthopaedic patients. Dabigatran etexilate is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolic events (VTE) following orthopaedic surgery.METHODS: In a phase III, multicenter, non-inferiority, double-blind study, patients undergoing total knee replacement were randomized to 3 treatments. The patients received 8±2 days of oral dabigatran etexilate, 150 or 220 mg once daily starting with a half dose (i.e.75 or 110 mg) 1–4 hours after surgery, or subcutaneous enoxaparin 40 mg once daily starting 12 hours prior to surgery. The primary efficacy outcome was the composite of total VTE and all causes of mortality during the treatment period. All efficacy and safety outcome events were adjudicated by blinded independent committees.RESULTS: Efficacy could be evaluated for 1541 (75%) treated and operated patients. Total VTE and death occurred in 40.5%, 36.4% and 37.7% of patients assigned to dabigatran etexilate 150 or 220mg once daily or enoxaparin, respectively. Proximal DVT and/or PE occurred in 3.8%, 2.6% and 3.5% of patients receiving dabigatran 150 or 220mg or enoxaparin, respectively. Three deaths occurred during the treatment period, one in each of the treatment groups. Safety was evaluated for all 2076 patients receiving study treatment. The rate of major bleeding was 1.3%, 1.5% and 1.3% of patients receiving dabigatran 150 or 220mg or enoxaparin. Elevated LFTs (ALT >3xULN) occurred in 3.7%, 2.8% and 4.0% of the patients treated with 150 and 220 mg dabigatran or enoxaparin during the study. A late temporary rise in LFTs was observed in 6 patients (0.5%) who had received dabigatran.CONCLUSIONS: Non-inferiority for the primary efficacy endpoint was met for both doses of dabigatran etexilate compared to enoxaparin. There was no difference in bleeding rates between the treatment groups. Oral administration of dabigatran etexilate once daily, given early in the postoperative period, was effective and safe for the prevention of total VTE in patients undergoing total knee replacement surgery.

ERCP in the Supine and Left Lateral Position

Purpose: ERCP is an acronym for Endoscopic Retrograde Cholangiopancreatography. Traditionally, with the patient in prone position, an ERCP endoscope is passed through the mouth, esophagus and stomach into the duodenum. After the ampulla is identified, a catheter is passed through the endoscope into the pancreatic and biliary ducts, contrast material is then injected into the ducts and x-rays are taken. In skillful hands, ERCP can be very useful and life saving. Sometimes patients are very ill and require intubation before ERCP. In such patients, prone position is cumbersome, not possible or unsafe. We report three patients; two with successful ERCP in supine position, and one with successful ERCP in left lateral position. Methods: Case 1: 63 year old female morbidly obese, with significant past medical history of end stage renal disease on hemodialysis, diabetes mellitus, hypertension, presented with right upper quadrant abdominal pain, fever and jaundice. The total and direct billirubin were 20.4/17.8. AST, ALT, Alkaline Phosphatase were also elevated. Because of morbid obesity and poor respiratory status, patient could not be placed in prone position. ERCP was attempted in supine position, successful cannulation of common bile duct was achieved, billiary stricture was diagnosed and seven french 12 cm stent was placed successfully. Patient returned after 8 weeks and billiary stent was replaced again in supine position. Case 2: 63 year old male with significant history of COPD, coronary artery disease, pacemaker placement, presented with abdominal pain, fever, elevated LFTs and high white count. CAT scan revealed dilated common bile duct. Because of poor respiratory status, patient could not be placed in prone position. ERCP was attempted in left lateral position, ampulary mass with dilated common bile duct was diagnosed, a common bile duct stent was placed successfully. Case 3: 58 year old female with known history of cirrhosis, diabetes mellitus, renal stones, cholycystectomy, presented with abdominal pain, jaundice and elevated obstructive enzymes. Because of poor respiratory status, patient could not be placed in prone position. ERCP was attempted in supine position, common bile duct was cannulated successfully. Conclusions: Although the success is not guaranteed with these anecdotal case reports, one should not be dogmatic, but ought to attempt ERCP in the supine and/or left lateral position if needed.

A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC)

4530 Background: RAD001 an oral serine-threonine kinase inhibitor of mTOR, blocks progression from the GI to the S phase of the cell cycle by a mechanism of action that is unique for an anticancer drug. Mechanistically, it is thought that RAD001 may play a role in VEGF inhibition. Main endpoints were to evaluate: time to progression (TTP), response rate, toxicity and to assess changes in metabolic imaging utilizing CT-PET. Methods: Eligibility included: progressive measurable MRCC, adequate organ/marrow function, zubrod performance status (ZPS) ≤ 2, no more than 1 prior therapy, and no active CNS involvement. RAD001 is given orally at a dose of 10mg daily without an interruption (28-day cycle), with dose modifications for toxicity. Re-evaluation was assessed every 3 cycles (12 weeks). RECIST criteria is utilized to determine response rate. TTP is determined from entry into the study. Results: 25 pts have been enrolled as of this review. 19 male/6 female, range 43–80 (median 60) years. All pts had predominant clear cell elements with progressive MRCC. 17 pts received prior immunotherapy, targeted agents, or chemotherapy. 22 pts had a ZPS of 0, 2/1 and 1/2. Sites of disease included: lung, nodal, bone, adrenal, kidney and liver. 7 pts had 1 metastatic site, 10 pts/2 metastatic sites and 8 pts/3 or more metastatic sites. 22 pts continue to receive RAD001 therapy. 7 pts had partial responses, 11 pts were stable for 3+ months, (5 pts/6+ months). 4 pts too early. Median duration of therapy is 7+ months (range 1+ to 9+). Treatment related adverse events to date include: mucositis, skin rash, pneumonitis, hypophosphatemia, hyperglycemia, thrombocytopenia, anemia and elevated LFTs. Conclusion: RAD001 has promising anti-tumor activity in pts with MRCC as demonstrated by a 33% partial response rate. Anti-tumor activity was further suggested by prolonged TTP ≥ 3 months for 86% of pts. The tumor effect was also demonstrated as a second line therapy. Independent radiology review is planned. Anti-tumor activity, toxicity and metabolic imaging correlation will be presented. [Table: see text]

Phase II study of xyotax (PPX) for androgen independent prostate cancer (AIPC)

14624 Background: PPX is a polymer conjugate of paclitaxel. In preclinical studies, PPX has an improved therapeutic profile relative to paclitaxel, in addition demonstrated activity in paclitaxel-resistant tumor models. This study investigates whether single agent PPX can induce PSA responses and increase time to progression in AIPC. Methods: Eligibility included: progressive disease based on at least one of the following: a) 3 consecutive rising PSA levels or b) new or progressive measurable disease, or c) new or progressive metastatic lesions on bone scan. Castrate levels of serum testosterone (≤ 50 ug/l), anti-androgen withdrawal, no more than 1 prior chemotherapy regimen, Zubrod performance status of ≤ 2, neuropathy ≤ grade 1, and adequate organ/marrow function. PPX is administered intravenously over 10–20 minutes without routine premedications, at a dose of 150 mg/m2 every 28 days. Dose modifications are based on nature and grade of toxicity observed. Patients (pts) are restaged every 8 weeks until progression or a maximum of 12 months of therapy. Results: 12 patients (pts) (11 previously treated/1 untreated) have been enrolled to date. 7 of the previously treated pts received prior taxanes. 3 pts continue on treatment. 9 pts have completed a range of 6–28 weeks of therapy. Based on a reduction in PSA of at least 50% and maintained for at least 8 weeks, 2 previously treated pts (1 prior taxotere) responded to treatment. 3 pts demonstrated a delay in their PSA velocity. Adverse events were assessed and included: 1 pt who developed a hypersensitivity reaction, 5 pts with grade 2/3 neuropathy, 5 pts with grade 2/3 leukopenia, 2 pts with grade 3/4 neutropenia and 1 pt with grade 4 thrombocytopenia. Other common reversible grade 1/2 toxic effects have been: nausea, fatigue, elevated LFTs and anemia. 6 pts have required dose reduction. Conclusion: PPX is well tolerated and demonstrates promising activity in patients with AIPC. Efficacy assessments are measured by: absolute PSA response, PSA velocity changes, and toxicity data will be presented. [Table: see text]

First-in-human phase-I pharmacokinetic trial of NS-9, a liposomal poly(I):poly(C), in patients with liver metastases from various primary cancers

13016 Background: NS-9 is a complex of poly-inosinate [poly(I)] and poly-cytidylate [poly(C)] in a cationic liposome and is active in vitro and in vivo. Objectives: to determine the tolerability, safety, and maximal tolerated dose (MTD), and pharmacokinetics of NS-9 by 1 hr IV infusion, given daily x5 q 28 days. Methods: A phase I dose escalation study was undertaken in patients with liver metastases from solid tumors. Eligible patients were adults with ECOG PS 0–1 and no recent chemotherapy (≥ 4 wks prior). Dose cohorts studied were 0.1, 0.15, 0.2, 0.3 and 0.4mg/m2. Results: 18 patients were enrolled (13M:5F) median age 58 (range 21 to 77 yrs). Tumor types included neuroendocrine (8), and ocular melanoma (1), gastric (1), GE junction (1), esophageal (2), and colorectal (5) carcinomas. Two of three patients treated at the first dose level (0.4 mg/m2) had grade 3/4 reversible lipase elevation with or without acute pancreatitis, a dose limiting toxicity (DLT). De-escalation to doses ranging from 0.1 to 0.2 mg/m2/day was with no DLT. At 0.3 mg/m2 two of three patients treated had a DLT (neutropenia and thrombocytopenia). The MTD was determined at 0.2 mg/m2. Common toxicities included pyrexia, chills, nausea, fatigue, abdominal pain, myalgia, anorexia, sweating, neutropenia, thrombocytopenia, and elevated glucose, amylase, and LFTs. Pharmacokinetics showed rapid elimination (T1/2 ranged from 2.4 to 5.0 hours) without accumulation after multiple doses. 1 patient (esophageal Ca) had a PR in the target lesions in the liver. Conclusions: The MTD is 0.2 mg/m2/day with a hint of antitumor activity. NS-9 should be pursued in phase-II studies. No significant financial relationships to disclose.

Risk analysis in bariatric surgery: Impact of disease burden

with liver histopathology. Methods: Routine core liver biopsy was simultaneously performed on 143 (13 (9%) males and 130 (91%) females) patients at the time of Roux-en-Y gastric bypass at UC Davis. Mean BMI was 46.9 5.8 kg/m, and mean age was 43.5 8.9 years. Twenty-two patients (15.4%) of the 143 were diabetic. Routine LFTs were obtained on all patients preoperatively. Liver specimens were histologically evaluated for the presence of NASH. Results: Of the 143 patients, 56 (39.1%) were positive for NASH as confirmed by liver biopsy. Only 4 patients (2.7%) overall had elevated LFTs. All patients with elevated LFTs exhibited NASH on liver biopsy. In contrast, only 4 (7.1%) of the 56 patients, with biopsy-proven NASH, had elevated LFTs preoperatively. Seven (31.8%) of the 22 diabetic patients had NASH on liver biopsy, and only 7 (12.5%) of the 56 patients with NASH were diabetic. Conclusions: While abnormalities in LFTs may be associated with NASH, our findings indicate that NASH is more prevalent, in the morbidly obese, than can be deduced by changes in LFTs alone. Additionally, the presence of diabetes mellitus seems to be only loosely associated with NASH. PII: S1550-7289(05)00222-4

Endoscopic Snare Papillectomy a Large Single Center Series

Aims: To review the efficacy, safety, and outcome of Endoscopic Snare Papillectomy (ESP) compared to Surgical Resection (SR) for papillary adenomas (PA) at a single center. Methods: Between 1996 and 2003, a total of 64 patients were evaluated for possible ESP of which 43 (27 male, 16 females, mean age 46±12) with localized PA underwent ESP. 21 patients with large tumor size (> 3 cm) and/or high-grade dysplasia or carcinoma underwent SR. ESP was performed using a stiff polypectomy snare and electrocautery. Biliary sphincterotomy and stent placement were performed if ERCP revealed insufficient drainage. A pancreatic stent was placed in cases of delayed pancreatic drainage. All patients were admitted for 24 hours post-ESP. Complications were classified by the consensus criteria on ERCP complications. Follow-up ERCP was performed at 3-6 months and thereafter in cases of residual adenoma, symptoms, or elevated LFTs. Results: The presenting symptoms included jaundice in 20 patients(31%), anemia in 7(10.9%), non-specific abdominal pain in 11(17.3%), pancreatic symptoms in 1(1.6%). History of familial adenomatosis polyposis (FAP) was present in 10 patients (15.6%), leading to detection of PA via surveillance EGD. The mean tumor size in the ESP group was 1.7±0.44 cm and 4.1±2.5 cm in the SR group. ESP was assisted by submucosal saline injection in 36 cases (56%) and performed en bloc in 33 cases (52%). A pancreatic stent was inserted in 21/43 patients (48.8%) and a biliary stent was inserted in 4/43 patients (9.3%). The only 30-day complication in the ESP group was hemorrhage in one patient who subsequently died. There were 7 complications in the SR group. There were no cases of pancreatitis in either group. Neither age, presenting symptoms nor tumor size were associated with development of complications. In the ESP group, if patients had a history of FAP, their risk of minor bleeding was 44% vs. 15% for those without FAP (RR=3.02, 95% CI 1.01-8.99, p=0.073). SR patients had significantly longer hospital stays than ESP(mean 10.6±8.6 days vs. 1 day, p<0.0001). At follow-up, 3 ESP patients had recurrence, all benign FAP-associated PA (mean interval 5.4 months) and were treated endoscopically. Conclusion: Endoscopic resection of localized PA by experienced endoscopists is a good alternative to surgical resection. The recurrence rate post ESP is small and can be treated endoscopically. Patients with FAP must be enrolled in a long-term endoscopic surveillance program. Aims: To review the efficacy, safety, and outcome of Endoscopic Snare Papillectomy (ESP) compared to Surgical Resection (SR) for papillary adenomas (PA) at a single center. Methods: Between 1996 and 2003, a total of 64 patients were evaluated for possible ESP of which 43 (27 male, 16 females, mean age 46±12) with localized PA underwent ESP. 21 patients with large tumor size (> 3 cm) and/or high-grade dysplasia or carcinoma underwent SR. ESP was performed using a stiff polypectomy snare and electrocautery. Biliary sphincterotomy and stent placement were performed if ERCP revealed insufficient drainage. A pancreatic stent was placed in cases of delayed pancreatic drainage. All patients were admitted for 24 hours post-ESP. Complications were classified by the consensus criteria on ERCP complications. Follow-up ERCP was performed at 3-6 months and thereafter in cases of residual adenoma, symptoms, or elevated LFTs. Results: The presenting symptoms included jaundice in 20 patients(31%), anemia in 7(10.9%), non-specific abdominal pain in 11(17.3%), pancreatic symptoms in 1(1.6%). History of familial adenomatosis polyposis (FAP) was present in 10 patients (15.6%), leading to detection of PA via surveillance EGD. The mean tumor size in the ESP group was 1.7±0.44 cm and 4.1±2.5 cm in the SR group. ESP was assisted by submucosal saline injection in 36 cases (56%) and performed en bloc in 33 cases (52%). A pancreatic stent was inserted in 21/43 patients (48.8%) and a biliary stent was inserted in 4/43 patients (9.3%). The only 30-day complication in the ESP group was hemorrhage in one patient who subsequently died. There were 7 complications in the SR group. There were no cases of pancreatitis in either group. Neither age, presenting symptoms nor tumor size were associated with development of complications. In the ESP group, if patients had a history of FAP, their risk of minor bleeding was 44% vs. 15% for those without FAP (RR=3.02, 95% CI 1.01-8.99, p=0.073). SR patients had significantly longer hospital stays than ESP(mean 10.6±8.6 days vs. 1 day, p<0.0001). At follow-up, 3 ESP patients had recurrence, all benign FAP-associated PA (mean interval 5.4 months) and were treated endoscopically. Conclusion: Endoscopic resection of localized PA by experienced endoscopists is a good alternative to surgical resection. The recurrence rate post ESP is small and can be treated endoscopically. Patients with FAP must be enrolled in a long-term endoscopic surveillance program.

Successful ERCP in the Gastric Bypass Patient: Employing Surgical Access to the Excluded Stomach

Background: Roux-en-Y Gastric bypass (RNY-GBP) for obesity is associated with the development of cholelithiasis and choledocholithiasis. Endoscopic access is generally not possible. Several case reports have suggested surgical access to the excluded stomach may permit ERCP, but there is little data as to risks and success. Patients: From 3/04 – 9/04, 8 pts with RNY-GBP (open 5, laparoscopic 3), age 27 to 76, all females, underwent therapeutic ERCP. All had evidence of CBD obstruction: ampullary stenosis with elevated LFTs (n=3) or CBD stone (n=5); 7 elective and 1 emergent. Five pts had initial attempt at peroral ERCP. Six were status post-cholecystectomy. Results: In the OR, the excluded stomach was accessed by small incision open laparotomy (n=6) due to extensive adhesions from open surgery or from acute ruptured cholecystitis, or laparoscopically (n=2) using a 15 mm trocar and port. Successful passage of a gas sterilized endoscope or sheathed scope under sterile conditions was successful in traversing the pylorus and accessing the papilla. Insufflation of the intestine was adequate due to the use of purse-string suture at the gastrotomy site. Successful deep cannulation with sphincterotomy with clearance of the duct was possible in all cases, but access was deemed difficult in three and needle knife access was necessary in two. Lithotripsy, balloon or basket extraction was performed in 4 cases. Total operating time ranged from 1.2 to 5.2 hrs, but endoscopist time was 1.0 to 2.5 hrs. Challenges were noted to be orientation of the papilla, absence of usual endoscope response to insertion shaft manipulation, room layout and limited space to accommodate C-arm fluoroscopy. These were lessened when the stomach was entered in the left upper quadrant (only possible with laparoscopy). Recovery hospitalization ranged from 1 to 7 days (median 2.3 days). There were no recognized ERCP complications. One abdominal wound infection was treated with drainage and antibiotic therapy. Conclusions: In the setting of gastric bypass for obesity, surgical access to the excluded distal stomach can permit successful, although challenging, therapeutic ERCP. When possible, laparoscopic access into the left upper quadrant to access the bypassed stomach may ease the challenges of ERCP for the endoscopist. Comparative studies to other evolving technologies for access are warranted.

Phase I pharmacokinetic studies evaluating single and multiple doses of oral GW572016, a dual EGFR-ErbB2 inhibitor, in healthy subjects

GW572016 is a dual EGFR-ErbB2 inhibitor that has promise as an anticancer agent. Two phase I studies were conducted to determine the safety, tolerability and pharmacokinetics of single and multiple doses given to healthy subjects. The single dose study evaluated two groups of eight subjects in an ascending dose, 4-way cross-over, while the multiple dose study evaluated twenty-seven healthy volunteers in an ascending dose, double-blind, randomized, placebo-controlled, staggered parallel design. No serious adverse events were seen in either study. The most common adverse events for subjects receiving GW572016 were headache, diarrhea, rash, cold symptoms, gastrointestinal symptoms, and elevated LFTs, which were similar between treatment and placebo groups. Absorption of single doses of GW572016 was slightly delayed, with median t(lag) of 15 minutes (range 0-90 minutes) and achieved peak serum concentrations at a median of three hours (range 1.5-6 hours) post-dose. Serum concentrations after multiple doses of GW572016 demonstrated no significant accumulation at the 25 mg dose, and approximately 50% accumulation at the 100 mg and 175 mg doses, achieving steady state in six to seven days. A modest time-dependent increase in serum concentrations also was detected with multiple doses of GW572016. Single and multiple oral doses of GW572016 were well tolerated in healthy subjects, and resulted in dose-related systemic exposure of GW572016.

Phase II Study of Arsenic Trioxide Plus Ascorbic Acid for Relapsed and Refractory Lymphoid Malignancies: A Wisconsin Oncology Network Study.

Introduction: Arsenic trioxide (AT) has impressive single agent activity in relapsed acute promyelocytic leukemia. It also has activity in myelodysplastic syndromes and multiple myeloma. In vitro data has suggested increased cytotoxicity when combined with agents that deplete intracellular glutathione, forming the rationale for combination studies. Ascorbic acid (AA) can deplete intracellular glutathione and may potentiate the cytotoxicity of AT. Upon this basis, we initiated a phase II study of arsenic trioxide plus ascorbic acid for relapsed/refracory lymphoid malignancies. Arsenic trioxide was administered at a dose of 0.25 mg/kg IV over one hour M-F for one week and then 2X/week for 5 weeks. Each arsenic infusion was followed by an infusion of 1000 mg ascorbic acid over 15 minutes. Each 6-week cycle was followed by a two-week rest period before repeating the cycle. Treatment was continued until best response plus two cycles or progressive disease.Patient characteristics: Median age 70.5 (37–88). Gender 10M, 6F. Histologies CLL/SLL (4), Follicular (3), Mantle Cell (3), DLBCL (2), Burkitt (2), Marginal Zone (1), Hairy Cell (1). Median # Prior therapies 4 (2–13). Refractory to prior treatment 13/16. Median ECOG PS 1 (0–2). B symptoms 3/16. Elevated LDH 8/16. Elevated B2M 13/16.Results: Median number of completed cycles 1 (0–4). Eight patients did not complete cycle #1, six due to progressive disease (PD) and 2 due to toxicity. Of the 2 patients coming off for toxicity, one patient with known coronary artery disease suffered a myocardial infarction on the 4th day of treatment and expired from congestive heart failure and the other experienced repeated grade 4 hyperglycemia. Six patients completed one cycle of therapy and were removed for PD. One patient completed 3 cycles of therapy before experiencing PD. One patient with mantle cell lymphoma received 4 cycles of therapy and achieved a CRu. The overall response rate was 6% (1/16). The responding patient's treatment was stopped after 4 cycles for MD/patient preference and she experienced PD 5 months after completion of therapy. Grade 3 toxicities included thrombocytopenia (2 patients), anemia (3), neutropenia (1), stomatitis (1), anorexia (1), and elevated LFTs (1). Grade 4 toxicities included neutropenia (2) and hyperglycemia (1).Conclusions: AT plus AA in this dosing schedule had modest toxicity but limited antitumor activity. The data should be interpreted in the context of our heavily treated, essentially refractory patient population. Our trial had a two-stage design, and was closed due to lack of activity at the first stage analysis. Other doses and schedules may prove to be more efficacious.

Predicitve Value of Pretransplant Testing.

Routine evaluation prior to stem cell transplantation generally includes assessment of left ventricular ejection fraction (EF), pulmonary function, renal function, liver function, and functional status. Patients in whom compromised organ function is detected, are often deemed ineligible for myeloablative transplantation. However, the predictive value of specific pretransplant tests is not well documented, and has not been critically analyzed in patients receiving busulfan-based preparative regimens. We analyzed the prognostic value of the pretransplant evaluation performed in 1035 consecutive patients who underwent autologous (n=444) or allogeneic (n=591) transplantation with busulfan-based regimens between 2/84 and 12/03 for acute (250) or chronic leukemia (198), myelodysplasia (50), multiple myeloma (88), or Hodgkin's (139) or non-Hodgkin's lymphoma (303). Ages ranged from 4–75 (median 41). BuCy was given to 477 and BuCyVP16 to 558 individuals.Ninety three patients had EF < 50%, 61 had DLCO < 65%, 103 had elevated creatine, 130 had elevated tranaminases or bilirubin, and 116 had Karnofsky scores < 80%. For the entire group, multivariable analysis demonstrated only Karnofsky score < 80% (P < .001) and elevated LFTs (P=.04) to have significant adverse prognostic influence on survival. Karnofsky score was significant in patients undergoing autologous (P <.001) or allogenic (P <.001) transplantation. Neither EF nor DLCO were predictive of poor outcome for the overall group (P >.2), nor for the autologous or allogeneic transplant groups. However in patients undergoing transplants from unrelated donors (n=119) DLCO < 65% was a significant adverse prognostic factor (P=.004). There was no association of compromised cardiac or pulmonary function with cardiac or pulmonary failure as a primary cause of death. This study suggests that moderately compromised organ function, particularly cardiopulmonary limitations which might not be clinically apparent, are of limited value in prediction of transplant outcome. Direct clinical assessment, including functional status are of much greater value in prediction of outcome. It is hoped that this investigation will stimulate larger studies of pretransplant predictors of outcome with attention to their relevance to specific preparative regimens, sources of stem cells, and other treatment variables.