A Phase I, Dose Escalation, Single Dose Trial of Oral Attenuated Salmonella typhimurium Containing Human IL-2 in Patients With Metastatic Gastrointestinal Cancers.

Salmonella has been shown to preferentially colonize solid tumors. It is known that toxicity limits the systemic administration of immunomodulatory cytokines that have a significant anticancer effect. Therefore, we tested a unique cancer treatment strategy comprised of oral delivery of Saltikva, an attenuated strain of Salmonella typhimurium that contain the human gene for interleukin-2. In preclinical experimentation, a significant antitumor effect without toxicity was observed. A dose escalation, single dose, Phase I trial was conducted. Dose escalation (10 to 10) while monitoring for dose limiting toxicity and response was performed. Flow cytometry was conducted to determine the immunologic effect. In total 22 patients were administered Saltikva. Eight patients did not complete the trial. No toxicity or adverse events were observed. There was no survival advantage. Flow cytometry demonstrated an increase in circulating natural killer (NK) cells and NK-T cells when comparing the prestudy period. The results of this phase I dose escalation study show that oral attenuated S. typhimurium containing the human interleukin-2 gene caused no significant toxicities up to doses of 10 colony forming unit. There was no evidence of partial or complete response. All patients had progressive disease and eventually succumbed to their illness. Although no survival advantage was seen in this single dose study, the statistically significant increase in circulating NK and NK-T cell demonstrates an immunologic effect from this treatment regimen and suggest that a multiple dose study should be undertaken.

Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies.

Background Ruxolitinib, a Janus kinase 1 (JAK1)/JAK2 inhibitor, plus capecitabine improved overall survival (OS) vs capecitabine in a subgroup analysis of patients with metastatic pancreatic cancer and systemic inflammation (C-reactive protein [CRP] >13 mg/dL) in the randomized phase II RECAP study. We report results from two randomized phase III studies, JANUS 1 (NCT02117479) and JANUS 2 (NCT02119663). Patients and Methods Adults with advanced/metastatic pancreatic cancer, one prior chemotherapy regimen and CRP >10 mg/L were randomized 1:1 (stratified by modified Glasgow Prognostic Score [1 vs 2] and Eastern Cooperative Oncology Group performance status [0/1 vs 2]) to 21-day cycles of ruxolitinib 15 mg twice daily plus capecitabine 2000 mg/m2/day (Days 1-14) or placebo plus capecitabine. The primary endpoint was OS. Results Both studies were terminated following a planned interim futility/efficacy analysis of JANUS 1. Overall, 321 and 86 patients were randomized in JANUS 1 (ruxolitinib: n = 161; placebo: n = 160) and JANUS 2 (ruxolitinib: n = 43; placebo: n = 43). There was no significant difference in OS or progression-free survival (PFS) between treatments in JANUS 1 (OS: hazard ratio [HR], 0.969, 95% confidence interval [CI], 0.747-1.256; PFS: HR, 1.056; 95% CI, 0.827-1.348) or JANUS 2 (OS: HR, 1.584; 95% CI, 0.886-2.830; PFS: HR, 1.166; 95% CI, 0.687-1.978). The most common hematologic adverse event was anemia. No new safety signals with ruxolitinib or capecitabine were identified. Conclusions Ruxolitinib plus capecitabine was well tolerated in refractory pancreatic cancer patients; this combination did not improve survival.

RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long-term survival and reveals a role for ANGPTL4.

BACKGROUND: Pancreatic adenocarcinoma patients have low survival rates due to late-stage diagnosis and high rates of cancer recurrence even after surgical resection. It is important to understand the molecular characteristics associated with survival differences in pancreatic adenocarcinoma tumors that may inform patient care. RESULTS: RNA sequencing was performed for 51 patient tumor tissues extracted from patients undergoing surgical resection, and expression was associated with overall survival time from diagnosis. Our analysis uncovered 323 transcripts whose expression correlates with survival time in our pancreatic patient cohort. This genomic signature was validated in an independent RNA-seq dataset of 68 additional patients from the International Cancer Genome Consortium. We demonstrate that this transcriptional profile is largely independent of markers of cellular division and present a 19-transcript predictive model built from a subset of the 323 transcripts that can distinguish patients with differing survival times across both the training and validation patient cohorts. We present evidence that a subset of the survival-associated transcripts is associated with resistance to gemcitabine treatment in vitro, and reveal that reduced expression of one of the survival-associated transcripts, Angiopoietin-like 4, impairs growth of a gemcitabine-resistant pancreatic cancer cell line. CONCLUSIONS: Gene expression patterns in pancreatic adenocarcinoma tumors can distinguish patients with differing survival outcomes after undergoing surgical resection, and the survival difference could be associated with the intrinsic gemcitabine sensitivity of primary patient tumors. Thus, these transcriptional differences may impact patient care by distinguishing patients who would benefit from a non-gemcitabine based therapy.

Development of peripheral neuropathy and its association with survival during treatment with nab-paclitaxel plus gemcitabine for patients with metastatic adenocarcinoma of the pancreas: A subset analysis from a randomised phase III trial (MPACT).

BACKGROUND: In a phase III trial in patients with metastatic pancreatic cancer (MPC), nab-paclitaxel plus gemcitabine (nab-P/Gem) demonstrated greater efficacy but higher rates of peripheral neuropathy (PN) versus Gem. This exploratory analysis aimed to characterise the frequency, duration, and severity of PN with nab-P/Gem in the MPACT study. PATIENTS AND METHODS: Patients with previously untreated MPC received nab-P/Gem or Gem. PN was evaluated using a broad-spectrum group of Standardised Medical Dictionary for Regulatory Activities Queries (SMQ) and graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. A case report form was completed by physicians on day 1 of each cycle (also graded by NCI CTCAE version 3.0). RESULTS: In the nab-P/Gem arm, 227/421 patients (54%) experienced any-grade PN and 70 (17%) experienced grade III PN. No grade IV PN was reported. Most early-onset PN events were grade I, and treatment-related grade III PN occurred in 7% of patients who received up to three cycles of nab-P. Of those who developed grade III PN with nab-P/Gem treatment, 30 (43%) improved to grade ≤ I (median time to improvement = 29 days) and 31 (44%) resumed therapy. Development of PN was associated with efficacy; median overall survival in patients with grade III versus 0 PN was 14.9 versus 5.9 months (hazard ratio, 0.33; P < .0001). CONCLUSIONS: nab-P/Gem was associated with grade III PN in a small percentage of patients. PN development was associated with longer treatment duration and improved survival. Grade III PN was reversible to grade ≤ I in many patients (median ≈ 1 month) NCT00844649.

Appropriateness of systemic treatments in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors.

AIM: To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors (PNETs) and provide consensus treatment recommendations. METHODS: Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs, angiogenesis inhibitors, inhibitors of mammalian target of rapamycin and cytotoxic agents. At this time, there is little data to guide treatment selection and sequence. We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations. Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process. After studying the literature, a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale. Ratings were done both before and after an extended discussion of the evidence. Quantitative measurements of agreement were made and consensus statements developed from the second round ratings. RESULTS: Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology. Panelists had practiced for a mean of 15.5 years (range: 6-33). Among 202 rated scenarios, disagreement decreased from 13.2% (26 scenarios) before the face-to-face discussion of evidence to 1% (2) after. In the final ratings, 46.5% (94 scenarios) were rated inappropriate, 21.8% (44) were uncertain, and 30.7% (62) were appropriate. Consensus statements from the scenarios included: (1) it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic; (2) it is appropriate to use everolimus, sunitinib, or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors; and (3) beyond first line, these same agents can be used. In patients with uncontrolled secretory symptoms, octreotide LAR doses can be titrated up to 60 mg every 4 wk or up to 40 mg every 3 or 4 wk. CONCLUSION: Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.

Neoadjuvant interferon-based chemoradiation for borderline resectable and locally advanced pancreas cancer: a Phase II pilot study.

OBJECTIVES: Neoadjuvant chemoradiotherapy (CRT) is a viable treatment strategy for patients with pancreatic cancer. This study was conducted to evaluate the Virginia Mason Protocol (5-fluorouracil, cisplatin, interferon-α and radiation) given in the neoadjuvant setting for the treatment of locally advanced pancreatic cancer. METHODS: A Phase II pilot study evaluating interferon-based neoadjuvant CRT in patients with locally advanced pancreatic cancer was performed. RESULTS: A total of 23 patients were enrolled. The mean age of the patients was 58.6 years. Of the 23 patients, seven (30.4%) completed all treatments. In the remaining 16 (69.6%) patients, treatment was interrupted as a result of toxicity. The most commonly reported effects of toxicity were leucopoenia/cytopoenia (n = 19, 82.6%) and gastrointestinal effects (n = 19, 82.6%). Surgical resection was successful in seven (30.4%) patients. Margins were negative in six (85.7%) of these seven patients. Positive lymph nodes were identified in three (42.9%) of seven patients. Overall survival was 11.5 months. Surgery provided improved survival (22.6 months) compared with CRT alone (8.8 months). Disease-free survival in resected patients was 17.2 months. CONCLUSIONS: Interferon-based neoadjuvant CRT may allow for resection of locally advanced pancreatic cancer, but with significant toxicity. In the absence of surgical resection, survival remains dismal.

Neoadjuvant chemoradiotherapy for locally advanced pancreas cancer rarely leads to radiological evidence of tumour regression.

BACKGROUND: Neo-adjuvant chemo-radiotherapy has been proposed to improve resectability of locally-advanced pancreatic cancer (LAPC). However, the ability of neo-adjuvant therapy to induce radiological tumour regression has not been reported. METHODS: Pre- and post-treatment computed tomography (CT) scans of patients undergoing neo-adjuvant chemo-radiotherapy for LAPC were reviewed. LAPC was sub-classified into borderline resectable disease [≤ 180° involvement of the superior mesenteric artery (SMA); short-segment encasement/abutment of the common hepatic artery; or tumour-associated deformity, abutment or short-segment occlusion of the superior mesenteric vein (SMV)/ portal vein (PV) that was amenable to vascular resection and reconstruction] and locally advanced un-resectable pancreatic cancer (vascular involvement more than that described for borderline resectable pancreatic cancer). The radiological response and surgical resection rates were assessed. RESULTS: Sixteen patients received neo-adjuvant therapy for LAPC during 2005-2008. Regression of major vascular involvement, i.e. un-encasement or regression of abutment of any involved vessels was not observed in any patient. Pre- and post-treatment tumour densities were not statistically different. Fifty per cent of patients with borderline resectable disease and none of the patients with locally advanced un-resectable pancreatic cancer eventually underwent surgical resection. CONCLUSION: Neo-adjuvant treatment does not induce radiological tumour regression of LAPC with major vascular involvement. Patient selection for neo-adjuvant trial enrollment should remain focused on borderline disease which may have a potential for surgical resection.

Systemic treatment in unresectable metastatic well-differentiated carcinoid tumors: consensus results from a modified delphi process.

OBJECTIVES: This study aimed to develop expert consensus for the use of systemic treatments for unresectable metastatic well-differentiated (grade 1-2) carcinoid tumors using the RAND/UCLA modified Delphi process. METHODS: After a comprehensive literature review, 404 patient scenarios addressing the use of systemic treatments for carcinoid tumors were constructed. A multidisciplinary panel of 10 physicians assessed the scenarios as appropriate, inappropriate, or uncertain (on a 1-9 scale) or as an area of disagreement before and after an extended discussion of the evidence. RESULTS: Experts were medical and surgical oncologists, interventional radiologists, and gastroenterologists. Among rated scenarios, disagreement decreased from 14% before the meeting to 4% after. Consensus statements about midgut carcinoids included the following: (1) Somatostatin analogs are appropriate as first-line therapy for all patients; (2) In patients with uncontrolled secretory symptoms, it is appropriate to increase the dose/frequency of octreotide long-acting repeatable up to 60 mg every 4 weeks or up to 40 mg every 3 weeks as second-line therapy for refractory carcinoid syndrome. Other options may also be appropriate. Consensus was similar for non-midgut carcinoids. CONCLUSIONS: The Delphi process provided a structured methodological approach to assist clinician experts in reaching consensus on the appropriateness of specific medical therapies for the treatment of advanced carcinoid tumors.

Pathway-based pharmacogenomics of gemcitabine pharmacokinetics in patients with solid tumors.

AIM: The aim of this study was to evaluate the association of gemcitabine pathway SNPs with detailed pharmacokinetic measures obtained from solid tumor patients receiving gemcitabine-based therapy. MATERIALS & METHODS: SNPs within nine gemcitabine pathway genes, namely CDA, CMPK, DCK, DCTD, NT5C2, NT5C3, SLC28A1, SLC28A3 and SLC29A1 were analyzed for association with gemcitabine pharmacokinetics. RESULTS: Significant association of gemcitabine clearance with SNPs in NT5C2 was identified. Clearance of 2´,2´-difluorodeoxyuridine, a gemcitabine metabolite was significantly predicted by CDA, SLC29A1 and NT5C2 SNPs. This study reports an association of formation clearance of 2´,2´-difluoro-2´-deoxycytidine triphosphate, an active form of gemcitabine with SNPs within uptake transporters SLC28A1, SLC28A3 and SLC29A1. CONCLUSION: Genetic variation in gemcitabine pathway genes is associated with its pharmacokinetics and hence could influence gemcitabine response. Our study identified pharmacogenetic markers that could be further tested in larger patient cohorts and could open up opportunities to individualize therapy in solid tumor patients.

Severe electrolyte disturbances after hyperthermic intraperitoneal chemotherapy: oxaliplatin versus mitomycin C.

BACKGROUND: Oxaliplatin (OX) is increasingly used for hyperthermic intraperitoneal chemotherapy (HIPC) for patients with peritoneal metastases. Our aim was to review electrolyte disturbances and complications after HIPC with oxaliplatin (OX) versus mitomycin C (MMC). MATERIALS AND METHODS: We included patients enrolled in single-institution prospective clinical trials who underwent cytoreductive surgery and HIPC with MMC or OX. We reviewed patient demographics, pathology, perioperative course, HIPC administration, and postoperative electrolyte disturbances. Measured postoperative sodium values were corrected for systemic hyperglycemia using the formula: (measured Na(+)) × [(glucose - 100/100) × 1.6]. RESULTS: From January 2002 to April 2009 we performed 80 HIPC procedures. A total of 60 patients (75%) received MMC (dose range 12.5-50 mg/m(2)) carried in lactated ringers solution. There were 20 patients (25%) who received OX (dose range 300 × 400 mg/m(2)) carried in 5% dextrose solution. For patients receiving HIPC with OX, electrolyte disturbances were the most common complication. Compared with MMC, patients receiving OX had significant 24-h postoperative uncorrected hyponatremia (P < 0.001), corrected hyponatremia (P < 0.001), hyperglycemia (P < 0.001), and metabolic acidosis (P < 0.001). In the OX group, corrected (mean 130.5) and uncorrected (mean 127.4) sodium levels were significantly lower than preoperatively (mean 139.9, P < 0.001). The overall nonelectrolyte complication rate was 56.2%. (MMC n = 33, 55.0%; OX n = 12, 60%); the 30-day mortality rate was 0% in both groups. CONCLUSIONS: Compared with MMC, HIPC with OX was associated with significant but predictable electrolyte disturbances; however, these electrolyte disturbances were not associated with higher overall complication rates. Close monitoring with early correction is imperative to maximize perioperative care. Further studies are needed to provide mechanistic insight.

A phase I study evaluating the role of the anti-epidermal growth factor receptor (EGFR) antibody cetuximab as a radiosensitizer with chemoradiation for locally advanced pancreatic cancer.

PURPOSE: (1) To determine the safety of the epidermal growth factor receptor (EGFR) antibody cetuximab with concurrent gemcitabine and abdominal radiation in the treatment of patients with locally advanced adenocarcinoma of the pancreas. (2) To evaluate the feasibility of pancreatic cancer cell epithelial-mesenchymal transition (EMT) molecular profiling as a potential predictor of response to anti-EGFR treatment. METHODS: Patients with non-metastatic, locally advanced pancreatic cancer were treated in this dose escalation study with gemcitabine (0-300 mg/m(2)/week) given concurrently with cetuximab (400 mg/m(2) loading dose, 250 mg/m(2) weekly maintenance dose) and abdominal irradiation (50.4 Gy). Expression of E-cadherin and vimentin was assessed by immunohistochemistry in diagnostic endoscopic ultrasound fine-needle aspiration (EUS-FNA) specimens. RESULTS: Sixteen patients were enrolled in 4 treatment cohorts with escalating doses of gemcitabine. Incidence of grade 1-2 adverse events was 96%, and incidence of 3-4 adverse events was 9%. There were no treatment-related mortalities. Two patients who exhibited favorable treatment response underwent surgical exploration and were intraoperatively confirmed to have unresectable tumors. Median overall survival was 10.5 months. Pancreatic cancer cell expression of E-cadherin and vimentin was successfully determined in EUS-FNA specimens from 4 patients. CONCLUSIONS: Cetuximab can be safely administered with abdominal radiation and concurrent gemcitabine (up to 300 mg/m(2)/week) in patients with locally advanced adenocarcinoma of the pancreas. This combined therapy modality exhibited limited activity. Diagnostic EUS-FNA specimens could be analyzed for molecular markers of EMT in a minority of patients with pancreatic cancer.

Dietary supplement usage by patients with cancer undergoing chemotherapy: does prognosis or cancer symptoms predict usage?

Any interactions between chemotherapeutic drugs and dietary supplements (DS) are a concern for oncologists. This study sought to obtain pilot data about the prevalence of consumption of DS (which include vitamin/mineral supplements [VS] and herbal supplements [HS]) among patients undergoing chemotherapy and to assess the relationship between DS consumption and both cancer prognosis and secondary cancer symptoms. In this pilot study, data on demographics, DS usage, presence of secondary cancer symptoms, and cancer diagnosis and stage were collected on 100 consecutive patients with gastrointestinal cancer and 40 with breast cancer who were receiving active chemotherapy from April 2004 to July 2004. Overall prevalence of DS consumption was 52.52% +/- 8.3% (VS,48.2% +/- 8.31%; HS, 23.74% +/- 7.07%). Of HS users, 42.42% +/- 16.86% used multiple HS. Factors significantly associated with higher consumption of HS were female gender and presence of metastasis, fatigue, and cancer pain. No significant associations between consumption of DS or HS and age, cancer type, presence of pain, sleep problems, or sexual problems were seen. Approximately half of the patients undergoing chemotherapy in this pilot survey were using DS, including HS--which heralds the potential for drug-supplement interactions and warrants caution. Consumption of HS was greater among people having a higher cancer stage and symptoms such as fatigue or cancer pain; patients in these subgroups probably should be screened actively for DS use. Further studies are needed to confirm these results.

Platelet utilization and the transfusion trigger: a prospective analysis.

BACKGROUND: Prophylactic platelet (PLT) transfusion practices have become more conservative as studies support a threshold for transfusions at 10 x 10(9) per L. This change in practice may reduce our use of PLT transfusions. STUDY DESIGN AND METHODS: Data were prospectively collected to assess the impact at one academic hospital when the transition from a 20 x 10(9) to a 10 x 10(9) per L threshold prophylactic transfusion was made. RESULTS: A total of 503 patients received 7401 PLT transfusions. Seventy-four percent of the transfusions were prophylactic. During the first phase of the study, only 53 percent of transfusions were given at a pretransfusion PLT count of less than 20 x 10(9) per L and 20 percent less than 10 x 10(9) per L. In the second phase of the study when the transfusion trigger was 10 x 10(9) per L, 28 percent of transfusions were given at this level. CONCLUSION: Many prophylactic PLT transfusions were given at PLT counts higher than the recommended trigger. Although the new transfusion guidelines altered transfusion practice, only a minor change in overall PLT usage was observed. Other changes in transfusion practices, such as dose per transfusion or sampling interval, will be required before significant reduction in the costs and hazards of prophylactic PLT transfusions can be realized.

Toxicity and quality of life after cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy.

BACKGROUND: The purpose of our study was to determine the toxicity and quality of life for patients with peritoneal metastases after cytoreductive surgery (CS) plus hyperthermic intraperitoneal chemotherapy (HIPC). METHODS: From 2001 to 2005, 35 consecutive patients with peritoneal metastases enrolled in a prospective trial approved by the University of Minnesota Institutional Review Board. Their primary cancer sites included the appendix (19 patients), colon (7), mesothelioma (3), stomach (2), small bowel (2), gallbladder (1), and unknown (1). We performed CS in an effort to remove all or nearly all peritoneal tumor nodules. Using a closed technique, we administered hyperthermic mitomycin C into the peritoneal cavity for 90 min. Before treatment and then at 4-month postoperative intervals, we used the functional assessment of cancer therapy-colon subscale (FACT-C) instrument to assess the patients' quality of life. RESULTS: The median hospital stay was 9 days; 12 patients were hospitalized at least 30 days or required readmission within 30 days after treatment. The postoperative mortality rate was 0%; adverse events occurred in 18 (51%) patients. As of December 2005, 20 patients were alive; 14 had died of progressive disease and 1 of an unrelated cause. The median survival time was 21.4 months. Quality of life measurements, including trial outcome index (TOI), FACT-colon, and FACT-general, returned to baseline 4 months after treatment and were significantly improved at 8 and 12 months. CONCLUSIONS: Despite early toxicity, CS plus HIPC may prolong the overall survival rate of patients with peritoneal metastases and improve quality of life measurements.

Staged laparoscopic infusion of hyperthermic intraperitoneal chemotherapy after cytoreductive surgery.

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPC) is a promising treatment for patients with peritoneal malignancies. Traditionally, HIPC is performed concurrently with cytoreductive surgery. However, this strategy is associated with significant morbidity and mortality. In this report, we describe our initial experience with staged laparoscopic infusion of HIPC. Five patients underwent complete open cytoreductive surgery followed by staged laparoscopic HIPC several weeks later. Primary malignancies included adenocarcinoma of the ileum (one patient), adenocarcinoma of the appendix (three patients), and adenocarcinoma of the gallbladder (one patient). At a subsequent operation, we performed laparoscopic HIPC. Quality of life was measured with the Functional Assessment of Cancer Therapy-Colon Subscale (FACT-C). Mean inflow and outflow cannula temperatures were 42.1 degrees C and 40.5 degrees C, respectively. Mean peritoneal perfusion flow rates were 689.8 ml/minute. The hospital stay for all patients was 1 to 2 days. One patient developed postoperative cellulitis, one patient died of progressive tumor, and four patients are alive without tumor progression. Quality-of-life measurements had returned to baseline 4 months after treatment. Staged laparoscopic HIPC after open cytoreductive surgery is safe, feasible, and can achieve uniform temperatures and perfusion flow rates. Although the results of this pilot study are encouraging, additional studies are required to determine long-term survival and quality of life.

Chemotherapy-induced thrombosis.

Venous thromboembolism (VTE) is a frequent and potentially life-threatening complication associated with hematological and solid tumor malignancies. In patients with cancer, VTE portends a poor prognosis; in fact, only 12% of those who suffer an event will survive beyond one year. There are several different risk factors for the development of VTE in cancer patients that are well-described in the literature. One that has become increasingly recognized over the past two decades is the independent risk factor of chemotherapy. The annual incidence of VTE in patients receiving chemotherapy is estimated at 11%. This risk can climb to 20% or higher depending on the type of drug(s) being administered. In addition to chemotherapy, there are many other anti-neoplastic and supportive therapies that are also associated with an increased risk for the development of VTE. At present, several original basic science studies and clinical trials are underway in an effort to enhance our understanding of the mechanisms by which different chemotherapeutic agents can generate a prothrombotic state. The purpose of this article is to review the pertinent literature related to VTE in malignancy, and more specifically, chemotherapy and other cancer-related treatments associated with VTE.

Hepatic encephalopathy secondary to transtumoral portal-hepatic venous shunting.

Intrahepatic portal-systemic shunts causing hepatic encephalopathy are very rare. This is a case report of a patient with hepatic metastases of a pancreatic islet cell tumor that manifested with transtumoral shunts leading to hepatic encephalopathy. The diagnosis was confirmed with Doppler ultrasound and initially treated with selective transhepatic portal vein embolization followed by hepatic artery embolization, and eventually radiofrequency ablation of the largest metastases. Despite excellent short-term palliation, symptom recurrence necessitated liver resection, the results of which proved durable. A multidisciplinary treatment plan for the identification and management of potentially salvageable encephalopathy in similar patients is described.

Cholecystitis as the presenting manifestation of acute myeloid leukemia: report of a case.

We report a case of acute leukemia, which presented as cholecystitis in a previously healthy middle-aged adult. Leukemic involvement of the gastrointestinal tract is a well-known clinicopathological entity. However, leukemic infiltration of the gall bladder wall is a rare occurrence. It has only been previously described in the setting of relapsed disease and, to our knowledge, has never been reported as the primary manifestation of de novo acute leukemia. The patient in question was treated with standard induction and consolidation chemotherapy and remains in complete remission 19 months after his presentation with symptoms consistent with cholecystitis.

Local, intrahepatic, and systemic recurrence patterns after radiofrequency ablation of hepatic malignancies.

The objective of this study was to describe the recurrence patterns in patients with unresectable hepatic malignancies treated with radiofrequency ablation (RFA). As RFA is applied more widely to patients with hepatic tumors, a better understanding of the biologic behavior of these tumors and the risk of recurrence, both in the liver and systemically, is needed. A multidisciplinary team evaluated patients referred for RFA and followed them prospectively to assess local, intrahepatic, and extrahepatic disease recurrence and complication rates. Forty-five patients with 143 lesions and a minimum follow-up of 6 months (median 19.5 months) were treated. Overall, 7.7% of treated lesions had local recurrence. New intrahepatic disease was seen in 49% of patients, and 24% had evidence of new systemic tumor progression. Patients with colorectal metastatic lesions > or =4 cm at the time of the first RFA were more likely to present with local recurrence (P = 0.048). Complications occurred in 27% of patients. Although RFA has a satisfactory local failure rate and safety profile, the patient population being treated is at high risk of developing new disease. Multimodality adjuvant therapy will be necessary to realize the full potential of hepatic malignancy control with RFA.