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Diego M Avella,
Guangfu Li,
Todd D Schell,
Dai Liu,
Samuel Shao-Min Zhang,
Xi Lou,
Arthur Berg,
Eric T Kimchi,
Hephzibah Rani S Tagaram,
Qing Yang, Serene Shereef,
Luis S Garcia,
Mark Kester,
Harriet C Isom,
C Bart Rountree,
Kevin F Staveley-O'Carroll
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ABSTRACT: The high rate of mortality and frequent incidence of recurrence associated with hepatocellular carcinoma (HCC) reveal the need for new therapeutic approaches. In this study we evaluated the efficacy of a novel chemoimmunotherapeutic strategy to control HCC and investigated the underlying mechanism that increased the antitumor immune response. We developed a novel orthotopic mouse model of HCC through seeding of tumorigenic hepatocytes from SV40 T antigen (Tag) transgenic MTD2 mice into the livers of syngeneic C57BL/6 mice. These MTD2-derived hepatocytes form Tag-expressing HCC tumors specifically within the liver. This approach provides a platform to test therapeutic strategies and antigen-specific immune-directed therapy in an immunocompetent murine model. Using this model we tested the efficacy of a combination of oral sunitinib, a small molecule multitargeted receptor tyrosine kinase (RTK) inhibitor, and adoptive transfer of tumor antigen-specific CD8(+) T cells to eliminate HCC. Sunitinib treatment alone promoted a transient reduction in tumor size. Sunitinib treatment combined with adoptive transfer of tumor antigen-specific CD8(+) T cells led to elimination of established tumors without recurrence. In vitro studies revealed that HCC growth was inhibited through suppression of STAT3 signaling. In addition, sunitinib treatment of tumor-bearing mice was associated with suppression of STAT3 and a block in T-cell tolerance. CONCLUSION: These findings indicate that sunitinib inhibits HCC tumor growth directly through the STAT3 pathway and prevents tumor antigen-specific CD8(+) T-cell tolerance, thus defining a synergistic chemoimmunotherapeutic approach for HCC.
Hepatology 09/2011; 55(1):141-52. · 11.66 Impact Factor
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ABSTRACT: Patients presenting with large intra-abdominal tumors often require multivisceral organ resection including partial or complete hemidiaphragm excision to achieve complete gross and microscopic tumor resection.
The ideal surgical approach to the repair of major diaphragmatic defects, particularly in a contaminated surgical field, is not well defined, but the use of prosthetic mesh in these situations is contraindicated.
We report our experience using human acellular dermal matrix for the repair of large diaphragmatic defects in these patients.
Human acellular dermal matrix is a safe and effective option in the surgical reconstruction of diaphragmatic defects in patients with large intra-abdominal tumors.
American journal of surgery 10/2009; 199(1):e12-6. · 2.36 Impact Factor
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ABSTRACT: Delayed gastric emptying (DGE) continues to be a major cause of morbidity following pancreaticoduodenectomy (PD). A change in the method of reconstruction following PD was instituted in an attempt to reduce the incidence DGE.
Patients undergoing PD from January 2002 to December 2008 were reviewed and outcomes determined. Pylorus-preserving pancreaticoduodenectomy (PPPD) with a retrocolic duodenojejunal anastomosis (n = 79) or a classic PD with a retrocolic gastrojejunostomy (n = 36) was performed prior to January 2008. Thereafter, a classic PD with an antecolic gastrojejunal anastomosis and placement of a retrogastric vascular omental patch was undertaken (n = 36).
A statistically significant decrease in DGE was noted in the antecolic group compared to the entire retrocolic group (14% vs 40%; p = 0.004) and compared to patients treated by classic PD with a retrocolic anastomosis alone (14% vs 39%; p = 0.016). On multivariate analysis, the only modifiable factor associated with reduced DGE was the antecolic technique with an omental patch, odds ratio (OR) 0.3 (confidence interval (CI) 0.1-0.8) p = 0.022. Male gender was associated with an increased risk of DGE with OR 2.3 (CI 1.1-4.8) p = 0.026.
A classic PD combined with an antecolic anastomosis and retrogastric vascular omental patch results in a significant reduction in DGE.
Journal of Gastrointestinal Surgery 07/2009; 13(9):1674-82. · 2.83 Impact Factor
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ABSTRACT: Surgical site infections cause significant postoperative morbidity and may be reduced by pressurized irrigation of high-risk laparotomy wounds before closure. This was a retrospective review (June 2007 to May 2008) from a surgical unit at a tertiary care center.
Patients undergoing laparotomy extending beyond 4 hours, when a standard wound management strategy was instituted by either simple irrigation or pressurized pulsatile lavage (<15 psi) with saline before closure, were included. The outcome measures were the surgical site infections and factors contributing to them.
The median surgical time for the patients was 8 hours, with 34 wounds managed by simple irrigation and 42 wounds managed by pulse irrigation. Both groups had similar characteristics. Overall there were 15 (20%) surgical site infections. Significantly fewer infections occurred in the pulse irrigation group (10% vs 32%; P = .019). The use of a pulse irrigation device was the only factor associated with a reduction in wound infections (P = .019).
Surgical site infections appear to be reduced with pulsatile lavage irrigation of wounds before skin closure in patients undergoing prolonged intra-abdominal surgeries.
American journal of surgery 04/2009; 198(3):381-6. · 2.36 Impact Factor
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ABSTRACT: The mortality associated with pancreaticoduodenectomy (PD) has decreased substantially in recent times, but high morbidity continues to be a significant problem. With reductions in mortality, there is increasing willingness to combine organ resections with PD when indicated. There is, however, a paucity of information regarding the morbidity and mortality of multivisceral resection (MVR) that involves pancreaticoduodenectomy (MVR-PD).
Patients undergoing PD between January 2002 and November 2007 by a single surgeon were reviewed and perioperative outcomes determined. Those treated by PD alone were compared to those undergoing MVR-PD.
There were 105 patients overall who underwent PD during the study period, with MVR-PD performed in 19 patients. Twelve (63%) patients required PD combined with right colectomy, two (11%) underwent PD combined with right nephrectomy, two (11%) required liver resection with PD, and the remaining three (16%) had various combinations of kidney, colon, adrenal and small bowel resection in addition to PD. In both groups, the main indication for surgery was pancreatic cancer; however, there were proportionally more patients in the MVR-PD group with gastrointestinal stromal tumors (two (11%) patients), sarcomas (two (11%) patients) and metastases to the periampullary region (three (16%) patients). The overall complication rate in this study was 60%. Delayed gastric emptying (39%) and pancreatic fistula (16%) were the most common complications. There was no significant difference in complications between the two groups. A non pylorus-preserving PD was more commonly performed in cases of MVR-PD (53% vs 28%; p = 0.007), operating times were longer (9.5 vs 8 h; p = 0.002), and surgical intensive care unit stay was greater (2 vs 1 days; p < 0.001). The overall median length of hospital stay (7 days) and readmission rate were similar between the groups.
MVR-PD can be performed without significant added morbidity compared to PD alone. The main indication for MVR-PD is locally advanced pancreatic cancer requiring PD combined with right hemicolectomy.
Journal of Gastrointestinal Surgery 02/2009; 13(5):915-21. · 2.83 Impact Factor
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ABSTRACT: The outcome of patients with colorectal liver metastases (CLM) undergoing surgical resection in the era of effective chemotherapy is not widely reported. In addition, factors associated with disease-specific survival (DSS) in a contemporary series of patients are not well defined. Clinical, pathologic, and outcome data for 64 patients with CLM treated by a single surgeon in a multidisciplinary setting from February 2002 to October 2007 were examined. Hepatic resection was combined with radiofrequency ablation (RFA) in 23 (36%) cases. Secondary or tertiary resection was undertaken in 12 (19%) patients. Synchronous CLM were noted in 25 (39%) cases. Neoadjuvant chemotherapy was given to 41 (64%) patients. Following hepatic resection, adjuvant chemotherapy was administered in 52 (81%) cases. There was one (2%) operative mortality. One or more complications were noted in 24 (38%) patients. Median length of hospital stay was 7 (2-7) days. Five-year DSS and overall survival were 72% and 69%, respectively. Bilobar disease (p < 0.001), local tumor extension (p = 0.02), response to neoadjuvant chemotherapy (p = 0.005), preoperative portal vein embolization (p = 0.05), number of hepatic lesions (p = 0.03), positive resection margin (p < 0.001), and node-positive primary disease (p = 0.001) were prognostically significant factors on univariate analysis. On multivariate analysis, bilobar disease (p = 0.02) and local tumor extension (p = 0.02) were the only two independent prognostic factors. We conclude that, in patients with CLM, a multidisciplinary approach encompassing an aggressive surgical policy achieves excellent 5-year survival results with acceptable operative morbidity and mortality. Bilobar disease and local extrahepatic extension of cancer appear to be independent prognostic factors for long-term survival.
Annals of Surgical Oncology 12/2008; 16(7):1860-7. · 4.17 Impact Factor
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ABSTRACT: The discovery of the c-KIT mutation and the advent of targeted drug therapy with imatinib mesylate have revolutionized the management of gastrointestinal stromal tumors (GISTs). The outcome of patients with surgically treated GISTs treated in the era of targeted drug therapy was assessed and factors associated with adverse outcomes determined.
Patients with GISTs requiring surgery at a tertiary care center from 2002 to 2007 were reviewed and prognostic factors determined.
Forty patients were surgically treated for GISTs. The median age at presentation was 59 years. The stomach (55%) was the main site of primary disease. The median tumor size was 7 cm. Eleven (28%) patients had metastatic disease at presentation. Surgery was undertaken in all patients with curative intent. Multi-organ resection was required in 10 (25%) patients. Imatinib mesylate was administered postoperatively in 68% of cases. Median follow-up was 24 months. There was a 40% recurrence rate with 63% undergoing repeat surgical resection. The peritoneum and liver were the main sites of recurrent disease. The 5-year disease-specific survival and disease-free survival (DFS) were 65% and 35%, respectively. High mitotic rate (P = 0.017) and tumor size greater than 10 cm (P = 0.009) were the only prognostically significant adverse factors of DFS on multivariate analysis, independent of imatinib mesylate treatment.
Aggressive surgical treatment and follow-up of GISTs, combined with targeted drug therapy, leads to long-term DFS survival. Tumor recurrence is independently associated with a high tumor mitotic rate and size greater than 10 cm, despite the use of adjuvant targeted drug therapy.
Journal of Gastrointestinal Surgery 07/2008; 12(11):2023-31. · 2.83 Impact Factor
