Whalen Clark

Survival After Pancreaticoduodenectomy is not Improved by Extending Resections to Achieve Negative Margins

Objective:This study was undertaken to determine the survival benefit of extending resections to obtain microscopically negative margins after positive intraoperative frozen sections. Summary Background Data:The impact of residual microscopic disease after pancreaticoduodenectomy is currently a point of controversy. It is, however, generally believed that microscopically positive margins negatively impact survival and this may be improved by ultimately achieving negative margins. Methods:Since 1995, patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma have been prospectively followed. Margin status has been codified as macro/microscopically negative (R0) or macroscopically negative/microscopically positive (R1). The impact of margin status on survival was evaluated utilizing survival curve analysis. Data are presented as median, mean ± SD where appropriate. Results:For pancreatic adenocarcinoma, 202 patients underwent pancreaticoduodenectomy. R0 resections were achieved in 158 patients, 17 of whom required extended resections to achieve complete tumor extirpation after an initially positive intraoperative frozen section (R1 → R0). R1 resections were undertaken in 44 patients. Median survival for patients undergoing R0 resections was 21 months, 26 ± 23.4 months versus 13 months, 17 ± 21.0 months for patients undergoing R1 resections (P = 0.02). Median survival for patients undergoing R1 → R0 resections was 11 months, 16 ± 17.3, (P = 0.001). Margin status had a significant correlation with “N” stage and AJCC stage but not “T” stage. Conclusion:Survival after pancreaticoduodenectomy is not improved by extending pancreatic resections to achieve negative margins after initially positive intraoperative frozen sections. Tumor-specific factors beyond the presence of disease at a surgical margin are responsible for the abbreviated survival seen in patients undergoing R1 resections.

H-graft portacaval shunts versus TIPS: ten-year follow-up of a randomized trial with comparison to predicted survivals.

Objective:To report long-term outcome of patients undergoing prosthetic 8-mm H-graft portacaval shunts (HGPCS) or TIPS and to compare actual with predicted survival data. Methods:A randomized trial comparing TIPS to HGPCS for bleeding varices began in 1993. Predicted survival was determined using MELD (Model for End-stage Liver Disease). Results:Patients undergoing TIPS (N = 66) or HGPCS (N = 66) were very similar by Childs class and MELD scores and predicted survival. After TIPS (P = 0.01) and HGPCS (P = 0.001), actual survival was superior to predicted survival. Through 24 months, actual survival after HGPCS was superior to actual survival after TIPS (P = 0.04). Compared with TIPS, survival was superior after HGPCS for patients of Childs class A and B (P = 0.07) and with MELD scores less than 13 (P = 0.04) with follow-up at 5 to 10 years. Shunt failure was less following HGPCS (P < 0.01). Conclusions:Predicted survival data for patients undergoing TIPS or HGPCS confirms an unbiased randomization. Actual survival following TIPS or HGPCS was superior to predicted survival. Shunt failure favored HGPCS, as did survival after shunting, particularly for the first few years after shunting and for patients of Childs class A or B or with MELD scores less than 13. This trial irrefutably establishes a role for surgical shunting, particularly HGPCS.

TIPS Versus Peritoneovenous Shunt in the Treatment of Medically Intractable Ascites: A Prospective Randomized Trial

Objective:We undertook a prospective randomized clinical trial comparing TIPS to peritoneovenous (PV) shunts in the treatment of medically intractable ascites to establish relative efficacy and morbidity, and thereby superiority, between these shunts. Methods:Thirty-two patients were prospectively randomized to undergo TIPS or peritoneovenous (Denver) shunts. All patients had failed medical therapy. Results:After TIPS versus peritoneovenous shunts, median (mean ± SD) duration of shunt patency was similar: 4.4 months (6 ± 6.6 months) versus 4.0 months (5 ± 4.6 months). Assisted shunt patency was longer after TIPS: 31.1 months (41 ± 25.9 months) versus 13.1 months (19 ± 17.3 months) (P < 0.01, Wilcoxon test). Ultimately, after TIPS 19% of patients had irreversible shunt occlusion versus 38% of patients after peritoneovenous shunts. Survival after TIPS was 28.7 months (41 ± 28.7 months) versus 16.1 months (28 ± 29.7 months) after peritoneovenous shunts. Control of ascites was achieved sooner after peritoneovenous shunts than after TIPS (73% vs. 46% after 1 month), but longer-term efficacy favored TIPS (eg, 85% vs. 40% at 3 years). Conclusion:TIPS and peritoneovenous shunts treat medically intractable ascites. Absence of ascites after either is uncommon. PV shunts control ascites sooner, although TIPS provides better long-term efficacy. After either shunt, numerous interventions are required to assist patency. Assisted shunt patency is better after TIPS. Treating medically refractory ascites with TIPS risks early shunt-related mortality for prospects of longer survival with ascites control. This study promotes the application of TIPS for medically intractable ascites if patients undergoing TIPS have prospects beyond short-term survival.

Post-Shunt Resource Consumption Favors Small-Diameter Prosthetic H-Graft Portacaval Shunt over TIPS for Patients with Poor Hepatic Reserve

ObjectiveTo define the role of surgical shunting for patients with poor hepatic reserve (Child’s class C) in the era of TIPS. Summary Background DataMost physicians prefer TIPS to surgical shunting for patients with poor hepatic reserve because of anticipated poor long-term survival. MethodsSixty-two patients of Child’s class C with bleeding varices not amenable to endoscopic sclerotherapy or banding were prospectively randomized to undergo TIPS or 8-mm prosthetic H-graft portacaval shunt (HGPCS) from 1993 to 1999. Resource consumption and survival after shunting were determined. ResultsTwenty-nine patients underwent TIPS and 33 underwent HGPCS. After HGPCS, survival at 3 years was favorable but not statistically superior. TIPS was more often associated with shunt stenoses/occlusions, recurrent hemorrhage, shunt revisions, and shunt failure. Long-term follow-up documented that after HGPCS, patients required fewer hospital and ICU days and fewer units of RBCs transfused. After HGPCS, cost of care was less, as was the median cost of care per day of survival. ConclusionsFor Child’s class C patients undergoing HGPCS or TIPS, long-term survival is similar, though favoring HGPCS. Similarly, measures of resource consumption and cost of care following hospital discharge favor HGPCS. HGPCS should be preferentially applied for acceptable patients without access to convenient capable post-shunt care or without definitive plans for imminent transplantation.

Complementary Strand MicroRNAs Mediate Acquisition of Metastatic Potential in Colonic Adenocarcinoma

BackgroundAltered expression of specific microRNAs (miRNA) is known to occur during colorectal carcinogenesis. However, little is known about the genome-wide alterations in miRNA expression during the neoplastic progression of primary colorectal cancers.MethodsUsing a miRNA array platform, we evaluated the expression of 668 miRNA in primary colonic adenocarcinomas. Biological functions of selected miRNA were evaluated with in vitro invasion assays.ResultsRNA was extracted for miRNA analysis from 65 primary colon cancers. We identified a seven-miRNA expression signature that differentiated stage I and stage IV primary colon cancers. We then demonstrated this signature was able to discriminate between stage II and III primary colon cancers. Six differentially expressed miRNA were downregulated in association with the development of metastases, and all 7 miRNA were complementary strand miRNA. We transfected HCT-116, a highly invasive colon cancer cell line, with corresponding downregulated miRNA and demonstrated that overexpression of three miRNA (miR200c*, miR143*, and miR424*) significantly abrogated invasive potential.ConclusionWe have identified a seven-miRNA signature that is associated with metastatic potential in the primary tumor. Forced overexpression of three downregulated miRNA resulted in attenuation of in vitro invasion, suggesting direct tumor suppressive function and further supporting the biological importance of complementary strand miRNA.

Surgery residency training programmes have greater impact on outcomes after pancreaticoduodenectomy than hospital volume or surgeon frequency

BACKGROUND Hospital volume of pancreaticoduodenectomy (PD) and surgeon frequency of PD have been shown to impact outcomes. The impact of surgery residency training programmes after PD is unknown. This study was undertaken to determine the impact of surgery training programmes on outcomes after PD, as well as their importance relative to hospital volume and surgeon frequency of PD. METHODS The State of Florida Agency for Healthcare Administration Database was queried for patients undergoing PD during 2002-2007. Measures of outcome were compared for patients undergoing PD at centres with vs. without surgery residency training programmes. RESULTS A total of 2345 PDs were identified, of which 1478 (63%) were undertaken at training centres and 867 (37%) were performed at non-training centres. Patients undergoing PD at training centres had shorter lengths of stay, lower hospital charges and lower in-hospital mortality. Relative to surgeon frequency of PD, training centres had a greater favourable impact on hospital length of stay, hospital charges and in-hospital mortality (P < 0.001 for each, ancova). Relative to hospital volume of PDs undertaken, training centres had a greater impact on hospital charges (P < 0.001, ancova). CONCLUSIONS Surgery residency training programmes have a favourable effect on outcomes following PD and their impact on outcome is greater than the impact of hospital volume or surgeon frequency of PD.

The interplay between histone deacetylases and c-Myc in the transcriptional suppression of HPP1 in colon cancer

HPP1 (hyperplastic polyposis protein 1), a tumor suppressor gene, is downregulated by promoter hypermethylation in a number of tumor types including colon cancer. c-Myc is also known to play a role in the suppression of HPP1 expression via binding to a promoter region cognate E-box site. The contribution of histone deacetylation as an additional epigenetic mechanism and its potential interplay with c-Myc in the transcriptional regulation of HPP1 are unknown. We have shown that the treatment of the HPP1-non-expressing colon cancer cell lines, HCT116 and DLD-1 with HDAC inhibitors results in re-expression of HPP1. RNAi-mediated knockdown of c-Myc as well as of HDAC2 and HDAC3 in HCT116 and of HDAC1 and HDAC3 in DLD-1 also resulted in significant re-expression of HPP1. Co-immunoprecipitation (IP), chromatin IP (ChIP), and sequential ChIP experiments demonstrated binding of c-Myc to the HPP1 promoter with recruitment of and direct interaction with HDAC3. In summary, we have demonstrated that c-Myc contributes to the epigenetic regulation of HPP1 via the dominant recruitment of HDAC3. Our findings may lead to a greater biologic understanding for the application of targeted use of HDAC inhibitors for anti-cancer therapy.

Delayed presentation of complete pancreatic ductal transection in children: management of two cases without resection

Pancreatic ductal injuries in children are rare, and ductal transections presenting in a delayed or subacute fashion are seldom reported. We describe two cases of traumatic pancreatic ductal transection secondary to physical abuse, both of which presented late to medical care. Both were managed successfully without pancreatic resection. Judicious application of non-resectional management can yield favorable outcomes in this subset of pediatric patients.

The Tumor Suppressive Effects of HPP1 Are Mediated Through JAK-STAT-Interferon Signaling Pathways.

HPP1, a novel tumor suppressive epidermal growth factor (EGF)-like ligand, mediates its effects through signal transducer and activators of transcription (STAT) activation. We previously demonstrated the importance of STAT1 activation for HPP1 function; however the contribution of STAT2 remains unclear. We sought to delineate the components of JAK-STAT-interferon (IFN) signaling specifically associated with HPP1s biological effects. Using stable HPP1-HCT116 transfectants, expression analyses were performed by polymerase chain reaction (PCR)/western blotting while expression knockdowns were achieved using siRNA. Growth parameters evaluated included proliferation, cell cycle distribution, and anchorage-independent growth. STAT dimerization, translocation, and DNA binding were examined by reporter assays, fluorescent microscopy, and chromatin immunoprecipitation (ChIP), respectively. Forced expression of HPP1 in colon cancer cell lines results in the upregulation of total and activated levels of STAT2. We have also determined that JAK1 and JAK2 are activated in response to HPP1 overexpression, and are necessary for subsequent STAT activation. Overexpression of HPP1 was associated with significant increases in STAT1:STAT1 (p=0.007) and STAT1:STAT2 (p=0.036) dimer formation, as well as subsequent nuclear translocation. By ChIP, binding of activated STAT1 and STAT2 to the interferon-signaling regulatory element promoter sites of the selected genes, protein kinase RNA-activated (PKR), IFI44, and OAS1 was demonstrated. STAT2 knockdown resulted in partial abrogation of HPP1s growth suppressive activity with increased proliferation (p<0.0001), reduced G1/G0 phase cell cycle fraction, and a restoration of growth potential in soft agar (p<0.01). Presumably as a consequence of upregulation of IFN signaling elements, HPP1 overexpression resulted in an acquisition of exogenous IFN sensitivity. Physiologic doses of IFN-α resulted in a significant reduction in proliferation (p<0.001) and increase in G1/G0 cell cycle arrest in HPP1 transfectants. STAT2 is necessary for HPP1-associated growth suppression, and mediates these effects through activation of IFN-α pathways. Given the interest in therapeutic targeting of oncogenic erbB proteins, further understanding of HPP1s role as a tumor suppressive EGF-like ligand is warranted.

The impact of sarcopenia on survival in locally advanced rectal cancer.

604 Background: The association between sarcopenia (or muscle loss) and worse oncologic outcomes has been documented in several different cancers and is thought to be a potential marker of a diminished host response to tumor. The prognostic role of sarcopenia in rectal cancer (RC) patients has yet to be elucidated. We sought to examine the impact of radiologically-defined sarcopenia on outcomes of RC patients treated by neoadjuvant chemoradiation (NCR) and radical resection. Methods: Between 1998-2010, we identified 90 patients with stage II/III RC treated by NCR and radical surgery. Sarcopenia was assessed using 3 CT-based measures derived at the L4-L5 level including mean psoas density (MPD; Hounsfield Units), total psoas area (TPA; mm2) and muscle mass index (MMI=TPA/height2; mm2/m2). Clinicopathologic data (age, gender, pretreatment and final tumor stage, treatment response and CEA level) were collected. Associations were analyzed by Wilcoxon Rank Sum while the Kaplan–Meier method, log-rank test, and ...