Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma.

BACKGROUND: While surgical resection of pancreatic adenocarcinoma provides the only chance of cure, long-term survival remains poor. Immunotherapy may improve outcomes, especially as adjuvant to local therapies. Gene-mediated cytotoxic immunotherapy (GMCI) generates a systemic anti-tumor response through local delivery of an adenoviral vector expressing the HSV-tk gene (aglatimagene besadenovec, AdV-tk) followed by anti-herpetic prodrug. GMCI has demonstrated synergy with standard of care (SOC) in other tumor types. This is the first application in pancreatic cancer. METHODS: Four dose levels (3 × 10(10) to 1 × 10(12) vector particles) were evaluated as adjuvant to surgery for resectable disease (Arm A) or to 5-FU chemoradiation for locally advanced disease (Arm B). Each patient received two cycles of AdV-tk + prodrug. RESULTS: Twenty-four patients completed therapy, 12 per arm, with no dose-limiting toxicities. All Arm A patients were explored, eight were resected, one was locally advanced and three had distant metastases. CD8(+) T cell infiltration increased an average of 22-fold (range sixfold to 75-fold) compared with baseline (p = 0.0021). PD-L1 expression increased in 5/7 samples analyzed. One node-positive resected patient is alive >66 months without recurrence. Arm B RECIST response rate was 25 % with a median OS of 12 months and 1-year survival of 50 %. Patient-reported quality of life showed no evidence of deterioration. CONCLUSIONS: AdV-tk can be safely combined with pancreatic cancer SOC without added toxicity. Response and survival compare favorably to expected outcomes and immune activity increased. These results support further evaluation of GMCI with more modern chemoradiation and surgery as well as PD-1/PD-L1 inhibitors in pancreatic cancer.

Early finding of chest wall metastasis of hepatocellular carcinoma in a woman by fluorodeoxyglucose-positron emission tomography scan: a case report.

INTRODUCTION: The use of fluorodeoxyglucose-positron emission tomography to evaluate well-differentiated hepatocellular carcinomas is facing critical problems. It is reported that the activity of fluorodeoxyglucose-6-phosphatase, which converts fluorodeoxyglucose-6-phosphatase to fluorodeoxyglucose, is high in normal liver cells. However, the enzyme-converting activity of glucose-6-phosphatase of well-differentiated hepatocellular carcinomas is similar to normal liver tissue. Thus, using fluorodeoxyglucose in diagnosing primary hepatocellular carcinomas is difficult. However, using fluorodeoxyglucose to detect extrahepatic metastasis of hepatocellular carcinomas is still possible. CASE PRESENTATION: We describe the case of a 45-year-old Chinese woman who developed a recurrent lesion in the chest wall from a previous surgically resected hepatocellular carcinoma. This recurrent lesion was detected first on the basis of a positron emission tomography scan, then on the basis of a computed tomography scan and other clinical tests. CONCLUSION: This finding indicates that the positron emission tomography scan is a potentially reliable tool to screen for systemic metastatic disease in patients with hepatocellular carcinomas when other cross-sectional imaging tests such as computed tomography or magnetic resonance imaging are negative.

Transarterial radioembolization with Yttrium-90 for regional management of hepatocellular cancer: the early results of a nontransplant center.

Selective arterial radioembolization with Yttrium-90 (Y-90) microspheres has shown promise for regional management of hepatocellular cancer (HCC). Our objective was to report our early experience with this treatment modality from a nontransplant center. Treatment of patients with HCC was discussed in a multidisciplinary tumor board. Patients with unresectable disease resulting from high lesion number, ill location of the tumor, poor hepatic reserve, or medical comorbidities were offered Y-90 treatment. Liver treatment was either lobar or tumor-targeted. Response to therapy was assessed by CT scan obtained within 3 months using Response Evaluation Criteria in Solid Tumors criteria. During 2007 to 2009, 40 Y-90 radioembolizations were performed in 20 patients with age that ranged from 16 to 87 years; four patients were 80 years old or older. After the first therapy, CT assessment of the treated area showed stable disease (n=15), partial response (n=3), and progression (n=2). Of the two patients who progressed, one was retreated with a subsequent complete response. The other patient died of progressive disease. The most common side effects were mild fatigue, anorexia, and nausea. In summary, our nontransplant center experience shows that Y-90 radioembolization is a well-tolerated treatment in select patients with unresectable HCC with an associated high rate of local tumor control.

Surgical resection of primary and metastatic hepatic malignancies following portal vein embolization.

BACKGROUND: Portal vein embolization (PVE) has been used to induce hypertrophy in future liver remnants (FLRs) in preparation for major hepatic resection. We report our initial experience with PVE and identify potential predictors of unresectability following PVE. METHODS: Patients with primary and metastatic hepatic malignancies (n = 20) who underwent PVE between 2004 and 2008 were categorized by surgical resection status and clinicopathologic factors were compared. RESULTS: The cohort had the following histologies: colorectal adenocarcinoma (45%, n = 9), hepatocellular carcinoma (20%), cholangiocarcinoma (20%), and other (15%). Seven patients (35%) had previous liver-directed or regional therapy; 55% subsequently underwent successful liver resection, whereas 45% were deemed unresectable. Patients who underwent successful resection had tumor shrinkage after PVE compared to unresectable patients (% change in maximal tumor diameter, -6% vs. +45%, respectively; P = 0.027) and had a lower rate of baseline liver function test abnormality (0% vs. 56%, respectively; P = 0.004). Resected patients had an 83% 5-year overall survival. CONCLUSIONS: Baseline liver dysfunction may predict subsequent unresectable hepatic disease following PVE and tumor progression after PVE appears to increase the likelihood for finding unresectable hepatic disease. Select patients should be considered for PVE with careful surveillance during the period of FLR hypertrophy.

Treatment response to transcatheter arterial embolization and chemoembolization in primary and metastatic tumors of the liver.

INTRODUCTION: Transcatheter arterial embolization (TAE) and chemoembolization (TACE) are increasingly used to treat unresectable primary and metastatic liver tumors. The purpose of this study was to determine the objective response to TAE and TACE in unresectable hepatic malignancies and to identify clinicopathologic predictors of response. MATERIALS AND METHODS: Seventy-nine consecutive patients who underwent 119 TAE/TACE procedures between 1998 and 2006 were reviewed. The change in maximal diameter of 121 evaluable lesions in 56 patients was calculated from pre and post-procedure imaging. Response rates were determined using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. The Kaplan-Meier method was used to compare survival in responders vs. non-responders and in primary vs. metastatic histologies. RESULTS: TAE and TACE resulted in a mean decrease in lesion size of 10.3%+/-1.9% (p<0.001). TACE (vs. TAE) and carcinoid tumors were associated with a greater response (p<0.05). Lesion response was not predicted by pre-treatment size, vascularity, or histology. The RECIST partial response (PR) rate was 12.3% and all partial responders were in the TACE group. Neuroendocrine tumors, and specifically carcinoid lesions, had a significantly greater PR rate (p<0.05). Overall survival, however, was not associated with histology or radiologic response. DISCUSSION: TAE and TACE produce a significant objective treatment response by RECIST criteria. Response is greatest in neuroendocrine tumors and is independent of vascularity and lesion size. TACE appears to be superior to TAE. Although an association of response with improved survival was not demonstrated, large cohort studies are necessary to further define this relationship.

Phase II study of oxaliplatin in patients with unresectable, metastatic, or recurrent hepatocellular cancer: a California Cancer Consortium Trial.

PURPOSE: Prolonged survival for patients with unresectable hepatocellular carcinoma (HCC) is consistently reported at lower than 6 months. Oxaliplatin has recently demonstrated activity in HCC. The objective of this study was to determine the response rate, survival, time to progression, and toxicity in patients with poor prognosis HCC when treated with oxaliplatin. EXPERIMENTAL DESIGN: Patients were required to have measurable recurrent, metastatic or unresectable HCC, and to have previously been exposed to no more than 2 prior chemotherapy regimens. Karnofsky performance of 70% or above and adequate organ and hematologic function were required. All patients received treatment with oxaliplatin 100 mg/m on day 1 and 15 as a 2-hour intravenous infusion and were pretreated with antiemetics. Treatment was repeated every 28 days. RESULTS: Thirty-six patients were enrolled and evaluated, although 6 expired before the first planned evaluation. Karnofsky performance status was 70/80/90/100% in 5/9/9/13 patients, respectively. The median time to progression was 2 months; median survival was 6 months. The 6-month overall survival was 55% (95% confidence interval 41%-74%), and the 6 month event-free survival was 11% (95% confidence interval 4%-28%). CONCLUSION: Single agent, oxaliplatin, has produced one partial response of good duration in 36 patients, but failed to meet the a priori criterion for promise in this trial. Sixteen patients were observed to have stable disease with a well tolerated toxicity profile. The combination of oxaliplatin and other agents should be considered to treat HCC in those patients with good functional status.

Successful management and outcome of a postoperative aortogastric fistula in a patient with recurrent gastric cancer: report of a case.

The case of a 57-year-old patient is described, who presented with regional gastric cancer recurrence 1 year after a gastrectomy for a T3N1M0 (Stage IIIA) adenocarcinoma of the stomach. He underwent a radical resection with intraoperative radiation to the regional field. Two months postoperatively, massive upper gastrointestinal bleeding occurred. Operative management included a left thoracotomy, aortic cross-clamping, laparotomy, and suture repair of a fistula from the root of the celiac trunk to the gastric remnant, with a completion gastrectomy. The patient survived and underwent a delayed reconstruction and closure. Subsequently, several repeat bleeding episodes took place, from sources including the celiac, common hepatic, and proper hepatic arteries. Multiple angiographic coil embolization and surgical procedures became necessary, ultimately requiring an esophagostomy and cecostomy for intestinal diversion. A rectus abdominis flap coverage of the exposed large arteries was performed. Although two more bleeding episodes took place, the patient was ultimately managed successfully. He is currently free of disease 3 years after reexploration, able to take oral nutrition, with intermittent jejunostomy feeding supplements. The discussion highlights aspects relevant to this case: the importance of a complete regional resection during a gastric cancer resection, the management strategy for an acute catastrophic intra-abdominal bleeding, and possible mechanisms that could contribute to such bleeding, including intraoperative radiation and postoperative infection.