Metastatic Gallbladder Cancer Research Articles

Metastatic Gallbladder Cancer Masquerading as Primary Colon Malignancy

We report a 69-year-old female with personal history of gallbladder cancer who was referred to our institution with a circumferential obstructing intra-luminal colonic mass that possessed pathological features common to both primary colorectal as well as gallbladder cancer, which posed a significant diagnostic and treatment challenge. This case reviews the method and rationale for arriving at the final diagnosis of gallbladder cancer metastasis and highlights the importance of modern molecular diagnostics as well as close communication between the pathologist and surgeon in its process. demonstrated findings consistent with adenocarcinoma, low- grade invasion into peri-muscular soft tissue, and was positive for lymphovascular and perineural invasion. No lymph nodes were obtained. For reasons unclear to the authors, she did not undergo repeat laparotomy for radical resection given her stage II disease (T2NxMx) and was instead followed clinically. Seven months later, she was found to have developed a 1.6cm enhancing lesion in the left hepatic lobe and was started on systemic chemotherapy with gemcitabine and capecitabine for 1.5 years without biopsy confirmation. She did well on this treatment with radiographic resolution of the liver lesion until 1 month prior to presentation, when she developed abdominal pain. A colonoscopy was performed that revealed a clearly intra-luminal, large circumferential friable mass in the sigmoid colon with luminal narrowing that did not allow passage of the scope. The lesion was biopsied and tattooed. Pathological evaluation of the lesion revealed invasive moderately differentiated, mucinous adenocarcinoma. At this point the origin of the tumor was unclear and the differential diagnosis included primary colorectal versus metastatic gallbladder. The patient was

Is gall bladder cancer a bad cancer per se?

Gall bladder cancer (GBC) has one of the poorest outcomes of all cancers. Early GBC is difficult to diagnose on even computed tomography. GB has no submucosa and the cancer infiltrates directly into the muscularis propria. GB wall is thin and important adjacent organs viz. liver, duodenum and pancreas get easily infiltrated. Tumor in the GB neck often needs extended right hepatectomy. Infiltration of duodenum/pancreas may necessitate pancreato-duodenectomy or even hepato-pancreato-duodenectomy. Mortality of surgical procedures, when performed for GBC, is higher than when performed for other cancers. Survival in GBC, even after R0 resection, is poor. There is no proven role of neo-adjuvant or adjuvant therapy for loco-regionally advanced GBC. There is no role of palliative surgery in metastatic GBC. Early GBC is diagnosed incidentally after cholecystectomy for stones and requires reoperation for completion extended cholecystectomy but unfortunately, most surgeons are not aware of this. GBC has a peculiar epidemiology and is uncommon in the West and has, therefore, not received much attention. Preventive cholecystectomy for asymptomatic stones is not recommended and there is no serum marker for screening. With all factors pitched against it, it does appear that GBC is a bad cancer per se!

Second-line FOLFOX chemotherapy in patients with metastatic gallbladder cancer and cholangiocarcinoma.

322 Background: After first-line treatment with gemcitabine-based regimen, there is not standard second-line chemotherapy for patients with metastatic gallbladder cancer (GB) and cholangiocarcinoma (CC). The aim of this study was to evaluate the activity, progression free survival (PFS), and overall survival (OS) of the FOLFOX4 regimen as second-line chemotherapy. Methods: We performed a retrospective analysis of all metastatic GB and CC that were treated with gemcitabine (Gem) based first-line chemotherapy, and second-line FOLFOX4 chemotherapy (oxaliplatin 85 mg/m2, day 1; leucovorin 200 mg/m intravenously, days 1 and 2; 5-fluorouracil 400 mg/m intravenous bolus, days 1 and 2; and 600 mg/m in 22 h intravenously, continuous infusion days 1 and 2; every 14 days) in our Institution since 2003. The response rate was evaluated every 2 to 4 months according to the RECIST criteria, and PFS/OS were calculated according to the Kaplan-Meier method. Results: Eighty patients (n=40 GB; n=40 CC) received Gem based first-line treatment (42 Gem alone; 38 Gem + platinum). There was no survival difference between Gem or Gem+platinum treatment (161 versus 254 days; p=0.09). Response rate (complete and partial response) was 16% and stable disease was 31%. Ca19-9 at presentation was predictive for OS: <100U/ml =403 days versus >100 U/ml =223 days (p=0.025). Eighteen patients (22%; n=10 GB and n=8 CC) were treated with second-line FOLFOX4. In the second-line group, stable disease was achieved in 4 patients (22%), and 11 patients progressed (66%). The median DFS and OS were 96 and 138 days respectively. The median OS for patients that received one versus both lines of chemotherapy were 161 versus 400 days (p=0.009). Conclusions: FOLFOX4 has activity in second line chemotherapy for patients with metastatic GB and CC. A prospective study is warranted to confirm this observation.

Role of Combination Chemotherapy with 5-Fluorouracil, Cisplatin and Paclitaxel for Advanced Gall Bladder Cancer

Aim: The prognosis for patients with advanced Gallbladder carcinoma is poor. Due to unresectability and relatively ineffective chemotherapy available, a need exists for effective chemotherapeutic regimen. The aim of this study was to determine the efficacy and safety profile of 5-fluorouracil, cisplatin and paclitaxel in patients with advanced Gallbladder cancer. Material and Methods: From January 2002 to July 2004, 40 patients of advanced carcinoma Gallbladder received 5-fluorouracil, cisplatin and paclitaxel. On day 1, paclitaxel was given (150 mg/m2), cisplatin was given on day 2 (50 mg/m2) and 5-fluorouracil was given from day 1 to day 3 (500 mg/m2). This cycle was repeated every three weeks and patient assessment was done. Results: Forty patients were enrolled in this study. Thirty-five were assessed for response. Five patients were lost in follow up. There were thirty females and ten males. A median of three cycles of treatment (range one to seven) was administered. Two patients achieved complete response and eleven had partial responses giving an overall response rate of 32.5% in the intention-to-treat population (95% confidence interval 11.1% to 46.5%). The median response duration was 5.3 months. The median time to progression and overall survival was 4.1 months and 11.2 months, respectively. The most common grade 3 adverse effects were neutropenia (30%), nausea (20%), vomiting (15%), diarrhea (10%), stomatitis (5%), and peripheral neuropathy (5%). Only one case had febrile neutropenia. There was no treatment related death. Conclusions: The combination of 5-fluorouracil, cisplatin and paclitaxel has promising anti-tumor activity and is well tolerated in patients with advanced and metastatic Gallbladder cancer.

Multiple primary malignancies of the liver and the colon: a complex diagnostic and decisional process with a final unanswered question

We herein present the case of a 78-year-old man with an incidental finding of a solid hepatic mass without symptoms and only a laparotomic cholecystectomy for acute cholecystitis in the past surgical history. A colonoscopy, a magnetic resonance imaging scan, a positron emission tomography scan, and a computed tomography scan completed the preoperative workup: a neoplastic lesion 4.3 × 3 cm in size was diagnosed at segments IV and V, associated with a neoplastic involvement of the splenic flexure without signs of colonic occlusion. After colonic resection, a frozen section on a granulomatous-like tissue at gastric border suggested a diagnosis of an adenocarcinoma of bilio-pancreatic type, changing the surgical strategy to include gastric resection and hepatic pedicle node dissection. The discussion turns around the idea that a final diagnosis of colon cancer with regional nodal involvement (pT3N1) and metastatic gallbladder cancer with multiple peritoneal seedings cannot be excluded.

State-of-the-art in the management of locally advanced and metastatic gallbladder cancer

Gallbladder carcinoma (GBC), classified as a biliary tract cancer (BTC) along with intrahepatic and extrahepatic cholangiocarcinomas, is a rare disease in Western countries, but a highly prevalent disease in Chile, other countries in Latin America, India and Japan. It commonly presents at an advanced stage, and has limited therapeutic options. Cisplatin/gemcitabine has emerged as the first-line standard of care for patients with advanced BTCs, but the prognosis remains poor. Development of molecularly targeted therapies in advanced BTC remains challenging. Comprehension of the molecular events in gallbladder carcinogenesis may provide a novel targeted therapeutic approach, and early stage clinical trials with targeted therapies appear promising, although the relationship between subsets of patients with positive responses to therapy and tumor genetics requires further exploration. Recent developments in targeted therapeutics, directed against several key signalling pathways in BTC, including epidermal growth factor receptor, angiogenesis, and the mitogen-activated protein kinase pathway will be discussed, in addition to the potential application of prognostic factors and markers. The future therapeutic spectrum for BTC and GBC will likely encompass novel combinations of targeted therapies with cytostatics in scientifically and molecularly directed schedules, thus permitting fewer mechanisms of escape for tumor cells.

Successful treatment of unresectable gallbladder cancer with low-dose paclitaxel as palliative chemotherapy after failure of gemcitabine and oral S-1: A case report.

A 56-year-old female with metastatic gallbladder cancer involving the liver and stenosis of the hilar bile duct was treated with gemcitabine (1,000 mg/m(2)) plus S-1 (60 mg/m(2)). After 9 cycles of therapy, CT showed evidence of stable disease; however, the serum CEA level was increased. Therefore, the chemotherapy regimen was changed to weekly low-dose paclitaxel (60 mg/m(2)). After 12 cycles of therapy, paclitaxel was reduced to 30 mg/m(2) as the patient developed neutropenia. The patient completed 32 cycles of therapy, and the tumor was reduced in size and marked improvement in bile duct stenosis was noted without any impairment in quality of life. The patient succumbed to the disease 25 months after treatment was initiated. Thus, in this case paclitaxel was more effective than gemcitabine plus S-1. Palliative chemotherapy with paclitaxel after failure of gemcitabine and 5-FU was well-tolerated; therefore, it may be an effective treatment for biliary tract cancer (BTC). A phase I study of palliative chemotherapy with weekly low-dose paclitaxel following gemcitabine (plus cisplatin) and 5-FU is currently in progress in patients with unresectable or recurrent BTC.

A phase II trial of gemcitabine and capecitabine in patients with unresectable or metastatic gallbladder cancer or cholangiocarcinoma: Southwest Oncology Group study S0202

Patients with gallbladder cancer or cholangiocarcinoma were treated with the combination of gemcitabine 1,000 mg/m(2) IV over 100 min on days 1 and 8 and capecitabine 650 mg/m(2) BID PO on days 1-14, administered every 21 days. The primary objective of this study was to assess the response rate (confirmed complete and partial responses) of gemcitabine and capecitabine used in advanced/metastatic biliary neoplasms. Secondary objectives included overall survival and toxicities. The study accrued 57 patients from September 2003 to April 2005. Three patients were ineligible, and two others received no treatment. Characteristics of analyzable patients: 35 (67%) cholangiocarcinoma, 17 (33%) gallbladder cancer; PS 0 (18 pts), 1 (26 pts), 2 (8 pts); 26 (50%) men; median age 58.8 years (29.5-85.6). Among 51 patients evaluated for toxicity, 6 experienced grade 4 toxicities. Among 52 patients, there were 7 confirmed partial responses for a confirmed response probability of 13% (95% CI: 6-26%). Six patients had an unconfirmed partial response for an overall response probability of 25% (95% CI: 14-39%). Twelve patients (23%) demonstrated stable disease. The 6-month overall survival was 55% (95% CI: 41-69%), and median survival was 7 months (95% CI: 5-8 months). The combination of gemcitabine and capecitabine is a well-tolerated regimen with activity in patients with advanced gallbladder cancer and cholangiocarcinoma.

Manejo paliativo del cáncer de vesícula biliar irresecable o metastásico: Conclusiones del Consenso Latinoamericano de Manejo del Cáncer de Vesícula Biliar

Gallbladder cancer is a rare disease in Western developed countries, but it is a highly prevalent and lethal disease in Chile and other countries in Latin America. No randomized controlled trials have been performed in gallbladder cancer to establish standard treatments. We therefore performed the first Latin American consensus meeting for the management of gallbladder cancer. In this article we present the conclusions of the panel of experts for the palliative treatment of unresectable or metastatic gallbladder cancer based on a review of the literature, the discussion of the participating experts and the opinion of the assistants. The topics reviewed included: (1) Gallbladder cancer and cholangiocarcinoma--are they the same disease?; (2) Palliative chemotherapy: indications, drugs and schedules; (3) Palliative radiotherapy; (4) Palliative Surgery; (5) Management of malignant biliary obstruction.

Complete response in gallbladder cancer to erlotinib plus gemcitabine does not require mutation of the epidermal growth factor receptor gene: a case report

BackgroundGallbladder cancer typically follows an aggressive course, with chemotherapy the standard of care for advanced disease; complete remissions are rarely encountered. The epidermal growth factor receptor (EGFR) is a promising therapeutic target but the activity of single agent oral EGFR tyrosine kinase inhibitors is low. There have been no previous reports of chemotherapy plus an EGFR-tyrosine kinase inhibitor (TKI) to treat gallbladder cancer or correlations of response with the mutation status of the tyrosine kinase domain of the EGFR gene.Case presentationA 67 year old man with metastatic gallbladder cancer involving the liver and abdominal lymph nodes was treated with gemcitabine (1000 mg/m2) on day 1 and 8 every 21 days as well as daily erlotinib (100 mg). After four cycles of therapy, the CA 19-9 normalized and a PET/CT showed a complete remission; this response was maintained by the end of 12 cycles of therapy. Gemcitabine was then discontinued and single agent erlotinib was continued as maintenance therapy. The disease remains in good control 18 months after initiation of therapy, including 6 months on maintenance erlotinib. The only grade 3 toxicity was a typical EGFR-related skin rash. Because of the remarkable response to erlotinib plus gemcitabine, we performed tumor genotyping of the EGFR gene for response predicting mutations in exons 18, 19 and 21. This disclosed the wild-type genotype with no mutations found.ConclusionThis case report demonstrates a patient with stage IV gallbladder cancer who experienced a rarely encountered complete, prolonged response after treatment with an oral EGFR-TKI plus chemotherapy. This response occurred in the absence of an EGFR gene mutation. These observations should inform the design of clinical trials using EGFR-TKIs to treat gallbladder and other biliary tract cancers; such trials should not select patients based on EGFR mutation status.

Metastatic Gallbladder Cancer Presenting as a Gingival Tumor and Deep Neck Infection

Gallbladder cancer has an extremely poor prognosis because it is often diagnosed at an advanced stage. We describe a 63-year-old woman who was treated 4 years previously for gallbladder cancer, with laparoscopic cholecystectomy and secondary hepatectomy after presenting with acute cholecystitis and gallbladder rupture. At her second presentation, she had a left lower gingival tumor and deep neck infection. Incision and drainage and tumor biopsies were performed, and pathology at both sites revealed adenocarcinoma. Positron emission tomography revealed other tumors in the left breast and left lower lung field, which were both proven to be adenocarcinoma by biopsy. The patient's presentation with a metastatic oral tumor was rare. Although the incidence is very low, physicians should consider the possibility of metastatic cancer in a patient with a history of cancer, who presents with new oral tumor or deep neck infection.

A successful treatment by hepatic arterial infusion therapy for advanced, unresectable biliary tract cancer

Biliary tract cancers (BTC) are relatively rare tumors, and the prognosis is extremely poor. There has been no standard chemotherapy for advanced BTC. However, recently, gemcitabine (GEM) have been used against BTC as the most active agent, and promising response rates and overall survival times with tolerable drug toxicities have been observed. In this article, two cases of advanced intrahepatic cholangiocarcinoma and unresectable metastatic gallbladder (GB) cancer are reported. They were treated with hepatic arterial infusion (HAI) chemotherapy using a combination of GEM and cisplatin, along with the systemic administration of GEM. As a consequence, multiple liver tumors, the GB cancer and metastatic lymph nodes regressed without severe drug toxicities, and favorable results (the overall survival times were 16 and 14 mo, respectively) were achieved. In conclusion, HAI therapy using GEM combined with cisplatin may be a useful and well-tolerated option for advanced BTC, especially in cases where multiple liver metastases are detected.

Gemcitabine, oxaliplatin and 5-FU in advanced bile duct and gallbladder carcinoma: two parallel, multicentre phase-II trials

Background:Gemcitabine, oxaliplatin and 5-fluorouracil (5-FU) are active in biliary tract cancer and have a potentially synergistic mode of action and non-overlapping toxicity. The objective of these trials was to determine response, survival and toxicity separately in patients with bile duct cancer (BDC) and gallbladder cancer (GBC) treated with gemcitabine/oxaliplatin/5-FU chemotherapy.Methods:Eligible patients with histologically proven, advanced or metastatic BDC (n=37) or GBC (n=35) were treated with gemcitabine (900 mg m−2 over 30 min), oxaliplatin (65 mg m−2) and 5-FU (1500 mg m−2 over 24 h) on days 1 and 8 of a 21-day cycle. Tumour response was the primary outcome measure.Results:Response rates were 19% (95% CI: 6–32%) and 23% (95% CI: 9–37%) for BDC and GBC, respectively. Median survivals were 10.0 months (95% CI: 8.6–12.4) and 9.9 months (95% CI: 7.5–12.2) for BDC and GBC, respectively, and 1- and 2-year survival rates were 40 and 23% in BDC and 34 and 6% in GBC (intention-to-treat analysis). Major grade III and IV adverse events were neutropenia, thrombocytopenia, elevated bilirubin and anorexia.Conclusion:Triple-drug chemotherapy achieves comparable results for response and survival to previously reported regimens, but with more toxicity.

6618 Results of a multi-center phase II study of imatinib and fluorourcail/leucovorin (FU/LV) in patients with unresectable or metastatic gallbladder or biliary tract cancer

6618 Results of a multi-center phase II study of imatinib and fluorourcail/leucovorin (FU/LV) in patients with unresectable or metastatic gallbladder or biliary tract cancer

K-ras status and response in patients with advanced or metastatic cholangiocarcinoma treated with cetuximab plus gemcitabine-oxaliplatin (GEMOX): a single center phase II study

4586 Background: As known, the mutation status of the K-ras gene affects the response to cetuximab in colorectal cancer. Less is known about K-ras status and outcome in cholangiocarcinoma. Patients with advanced cholangiocarcinoma have a poor prognosis and until now, no standard palliative chemotherapy has been defined. The purpose of this prospective single-centre phase II study was to investigate the therapeutic efficacy and K-ras status dependence of cetuximab in combination with gemcitabine and oxaliplatin in the palliative first line treatment of these patients. Methods: Patients with locally advanced or metastatic cholangiocarcinoma or gallbladder cancer were treated with cetuximab 500 mg/m2 followed by 1000mg/m2 gemcitabine (day 1) and 100mg/m2 oxaliplatin (day 2) biweekly as first line therapy. Tumour samples were obtained from 25 of 30 patients (83%). We studied the k-ras mutation status and analyzed the association between k-ras mutation and tumor response, progression-free survival (PFS) and overall survival (OS). Results: From October 2006 until July 2008 thirty patients (15 male, 15 female) with a median age of 68 were enrolled. The overall response rate of evaluable patients (30) was 63,3%, including three patient with a complete response. 5 patients (16,7%) achieved stable disease and only 6 patients (20%) progressed under chemotherapy. K-ras mutation was detected in 3 patients (12%). All three patients did not progressed under chemotherapy. Neither PFS nor OS were affected by K-ras status. The median PFS of all 30 patients was 8.3 months (95% CI 5.85–10.81) and median OS was 12.7 months (95 CI 7.96–17.37). After a mean number of 7.5 cycles any WHO grade 3 drug-related adverse events occurred in 13 patients (43%), consisting of skin toxicity in 4 patients, thrombopenia in 3, neutropenia in 1, nausea in 1, diarrhoe in 1 and PNP in 4 patients; no grade 4 side effects were noticed Conclusions: Cetuximab in combination with GEMOX induces impressive response rates which were unrelated to k-ras status. PFS and OS were remarkably improved and therefore cetuximab in combination with GEMOX deserves further evaluation in prospective randomized trials. [Table: see text]

Preliminary results of a multicenter phase II study of imatinib and fluorourcail/leucovorin (FU/LV) in patients with unresectable or metastatic gallbladder or biliary tract cancer

e15502 Background: There are no standard chemotherapeutic regimens for incurable biliary adenocarcinomas. Monotherapies with gemcitabine or FU/LV achieve occasional responses and a median overall survival of about 6 months. By blocking PDGFR a decreased intrastromal pressure may increase therapy effects of chemotherapy. The combination of imatinib and FU/LV has been shown to be safe and feasible in a previous Phase I trial. This multicenter phase II trial was designed to investigate the disease control rate (DCR) of FU/LV and imatinib. Methods: Eligibility criteria included unresectable or metastatic measurable biliary tract cancer (BTC)/gallbladder cancer (GBC), performance status < 2, adequate organ function and no clinically significant cardiovascular disease. Enrolment of 44 chemonaive patients (pts.) was planned. Pts. received LV 200 mg/m2 followed by FU 2000 mg/m2 as a 24-hour infusion on days 1 and 2 combined with 600mg imatinib on days -4 to 4 (8 days). Cycles were repeated every 2 weeks up to 12 cycles. Radiological assessments were performed every 4 cycles. Results: 41 pts (19 GBC; 22 BTC) were enrolled in this phase II study since May 2007. Median age was 62 years (range 33–77), male/female=24/17, ECOG 0/1/2=13/23/5. 35 pts. showed metastatic disease at baseline. Treatment was well tolerated. Treatment related grade 3/4 toxicities included (number of pts): diarrhea (2), edema (1), neutropenia (2), nausea (2), transient SGPT elevation (4). The DCR of 26 pts. available for response assessment at time of analysis 1 was 58% (15 pts) (1 CR, 1 PR,13 SD of at least 4 cycles). 11 pts. showed progressive disease (PD) per RECIST criteria. 3 pts. had disease stabilization after 12 cycles and continue on treatment. We present these preliminary data as they represent a large patient number in this entity and response data are promising. Conclusions: This preliminary analysis suggests that the combination of FU/LV and imatinib can be safely administrated in pts. with GBC/BTC. Early evidence of antitumor activity was seen with some pts. achieving long term stabilization of the disease. [Table: see text]

A phase II trial of the proteasome inhibitor bortezomib in patients with recurrent or metastatic adenocarcinoma of the bile duct or gallbladder (NCI #6135)

e15605 Background: There is currently no standard therapy for recurrent or metastatic cancers of the bile duct or gallbladder and available chemotherapy is of uncertain benefit. As activation of NF-κB has been described in these tumors, we initiated a phase II trial of the proteasome inhibitor bortezomib in patients with recurrent or metastatic disease. Methods: Patients with measurable metastatic or unresectable adenocarcinoma of the bile duct or gallbladder who had received up to 2 prior chemotherapy regimens were eligible. Other eligibility criteria included ECOG PS 0–2, total bilirubin ≤1.5X ULN, and ALT/AST ≤2.5 X ULN. Patients with baseline neuropathy ≥grade 2 were excluded. Bortezomib was administered at a dose of 1.3 mg/m2 as an intravenous bolus on days 1, 4, 8, and 11 of 21 day cycles with CT evaluation every 6 weeks. The primary endpoint was response rate. Null hypothesis: PR/CR≤5%. Alternative hypothesis: PR/CR ≥20%. 35 patients were required for 90% power with an early stopping rule at 20. Results: 20 patients were enrolled: 11M/9F, PS 0/1 (7/13), 6 gallbladder /14 bile duct. There was one patient with an unconfirmed partial response, 9 patients with stable disease, and 10 patients with progressive disease. Accrual was halted after 20 patients were enrolled as the early stopping rule for futility was met. Median PFS was 48 days (95% CI [32,124]) and median OS was 284 days (95% CI [155, 513]). Grade 3/4 toxicities were observed in 13 patients (65%), most commonly fatigue (4 patients), thrombocytopenia (3 patients), hyperbilirubinemia (3 patients), and hypotension (2 patients). Other SAEs at least possibly related to bortezomib included grade 3 vasculitis (1 patient) and grade 2 meningitis (1 patient). Conclusions: Bortezomib is not an active agent in the treatment of metastatic gallbladder or biliary tract cancer. No significant financial relationships to disclose.

Preliminary results of a multicenter phase II study of imatinib and fluorourcail/leucovorin (FU/LV) in patients with unresectable or metastatic gallbladder or biliary tract cancer

e15622 Background: There are no standard chemotherapeutic regimens for incurable biliary adenocarcinomas. Monotherapies with gemcitabine or FU/LV achieve occasional responses and a median overall survival of about 6 months. By blocking PDGFR a decreased intrastromal pressure may increase therapy effects of chemotherapy. The combination of imatinib and FU/LV has been shown to be safe and feasible in a previous Phase I trial. This multicenter phase II trial was designed to investigate the disease control rate (DCR) of FU/LV and imatinib. Methods: Eligibility criteria included unresectable or metastatic measurable biliary tract cancer (BTC)/gallbladder cancer (GBC), performance status < 2, adequate organ function and no clinically significant cardiovascular disease. Enrolment of 44 chemonaive patients (pts.) was planned. Pts. received LV 200 mg/m2 followed by FU 2000 mg/m2 as a 24-hour infusion on days 1 and 2 combined with 600mg imatinib on days -4 to 4 (8 days). Cycles were repeated every 2 weeks up to 12 cycles. Radiological assessments were performed every 4 cycles. Results: 41 pts (19 GBC; 22 BTC) were enrolled in this phase II study since May 2007. Median age was 62 years (range 33–77), male/female=24/17, ECOG 0/1/2=13/23/5. 35 pts. showed metastatic disease at baseline. Treatment was well tolerated. Treatment related grade 3/4 toxicities included (number of pts): diarrhea (2), edema (1), neutropenia (2), nausea (2), transient SGPT elevation (4). The DCR of 26 pts. available for response assessment at time of analysis 1 was 58% (15 pts) (1 CR, 1 PR,13 SD of at least 4 cycles). 11 pts. showed progressive disease (PD) per RECIST criteria. 3 pts. had disease stabilization after 12 cycles and continue on treatment. We present these preliminary data as they represent a large patient number in this entity and response data are promising. Conclusions: This preliminary analysis suggests that the combination of FU/LV and imatinib can be safely administrated in pts. with GBC/BTC. Early evidence of antitumor activity was seen with some pts. achieving long term stabilization of the disease. [Table: see text]

Framing family conversation after early diagnosis of iatrogenic injury and incidental findings

Surgeons are rarely formally trained in giving bad news to patients. The aim of our study was to examine and compare techniques of disclosure of iatrogenic and incidental operative findings among surgical residents. General surgery residents performed a laparoscopic cholecystectomy on the SurgicalSIM device in a mock operating room. Half (n = 8) were presented with a common bile duct injury, and half (n = 7) encountered metastatic gallbladder cancer during the operation. Both groups disclosed this information to a patient's scripted family member and completed a questionnaire. All encounters were videotaped and independently rated using a modified SPIKES protocol, a validated tool for delivering bad news. We compared disclosure of iatrogenic versus unexpected findings by year of training. Analysis was performed using the Mann-Whitney test. Regardless of the year of training, more residents were comfortable with disclosure of an incidental finding than disclosure of an iatrogenic injury (47 vs. 33%). Senior residents (PGY4-PGY5) had better ratings by SPIKES (p < 0.05), most notably for tailoring disclosure to what patient and family understand, exploring patient and family expectations, and offering to answer any questions (p < 0.05). Even though all residents felt more comfortable with disclosure of an incidental finding, the quality of the disclosure by SPIKES score was the same for iatrogenic and incidental operative findings (p = NS). In general, trainees are ill prepared for delivering bad news. Disclosure of iatrogenic injuries was more challenging compared to that of incidental findings. Senior residents do better than junior residents at delivering bad news.

Serial Analysis of Gene Expression Identifies Connective Tissue Growth Factor Expression as a Prognostic Biomarker in Gallbladder Cancer

Gallbladder cancer (GBC) is an uncommon neoplasm in the United States, but one with high mortality rates. This malignancy remains largely understudied at the molecular level such that few targeted therapies or predictive biomarkers exist. We built the first series of serial analysis of gene expression (SAGE) libraries from GBC and nonneoplastic gallbladder mucosa, composed of 21-bp long-SAGE tags. SAGE libraries were generated from three stage-matched GBC patients (representing Hispanic/Latino, Native American, and Caucasian ethnicities, respectively) and one histologically alithiasic gallbladder. Real-time quantitative PCR was done on microdissected epithelium from five matched GBC and corresponding nonneoplastic gallbladder mucosa. Immunohistochemical analysis was done on a panel of 182 archival GBC in high-throughput tissue microarray format. SAGE tags corresponding to connective tissue growth factor (CTGF) transcripts were identified as differentially overexpressed in all pairwise comparisons of GBC (P < 0.001). Real-time quantitative PCR confirmed significant overexpression of CTGF transcripts in microdissected primary GBC (P < 0.05), but not in metastatic GBC, compared with nonneoplastic gallbladder epithelium. By immunohistochemistry, 66 of 182 (36%) GBC had high CTGF antigen labeling, which was significantly associated with better survival on univariate analysis (P = 0.0069, log-rank test). An unbiased analysis of the GBC transcriptome by SAGE has identified CTGF expression as a predictive biomarker of favorable prognosis in this malignancy. The SAGE libraries from GBC and nonneoplastic gallbladder mucosa are publicly available at the Cancer Genome Anatomy Project web site and should facilitate much needed research into this lethal neoplasm.