T.P. Kingham

Operative drainage following pancreatic resection: analysis of 1122 patients resected over 5 years at a single institution.

Background: The only prospective randomized trial evaluating the use of intraperitoneal drainage following pancreatic resection was published from our institution approximately 10 years ago. The current study sought to evaluate the evolution of practice over the last 5 years. Patients and Methods: Between June 2006 and June 2011, there were 1122 resections performed. Six surgeons were evenly grouped and compared by practice pattern: routine drainers (drains placed > 95%), selective drainers, and routine nondrainers (drains placed ∼15%). Prospectively recorded preoperative, operative, and morbidity data were assessed in uni- and multivariate models. Results: Our operative drainage rate was 49% and decreased over time (62% 2006–2008 vs 37% 2009–2011, P < 0.001). Patients without operative drains had significantly lower grade ≥3 overall morbidity (26% vs 33%; P = 0.01), shorter hospital stays (7 vs 8 days; P < 0.01), fewer readmissions (20% vs 27%; P = 0.01), and lower rates of grade ≥3 pancreatic fistula (16% vs 20%; P = 0.05). Similar reoperation (both <1%), interventional radiology procedures (15% vs 19%; P = 0.1), and mortality rates (2% vs 1%; P = 0.3) were seen in both groups. There were no differences between the routine drainers group (n = 248) and the nondrainers group (n = 478) in grade ≥3 fistula or need for interventional radiology-guided procedures. Conclusions: In this study, operative drains were used nearly half of the time and were associated with longer hospital stay, and higher grade ≥3 morbidity, fistula, and readmission rates. They did not decrease the need for reintervention or alter mortality rates. Routine prophylactic drainage after pancreatic resection could be safely abandoned.

Phase II trial of hepatic artery infusional and systemic chemotherapy for patients with unresectable hepatic metastases from colorectal cancer: Conversion to resection and long-term outcomes

PURPOSE Evaluate conversion rate of patients with unresectable colorectal-liver metastasis to complete resection with hepatic-arterial infusion plus systemic chemotherapy including bevacizumab (Bev). PATIENTS AND METHODS Forty-nine patients with unresectable colorectal liver metastases (CRLM) were included in a single-institution phase II trial. Conversion to resection was the primary outcome. Secondary outcomes included overall survival (OS), progression-free survival, and response rates. Multivariate and landmark analyses were performed to evaluate survival differences between resected and nonresected patients. RESULTS Median number of tumors was 14 and 65% were previously treated patients. A high biliary toxicity rate was found in the first 24 patients whose treatment included Bev. The remaining 25 patients were treated without Bev. Overall response rates were 76% (4 complete responses). Twenty-three patients (47%) achieved conversion to resection at a median of 6 months from treatment initiation. Median OS and progression-free survival for all patients were 38 (95% confidence interval: 28 to not reached) and 13 months (95% confidence interval: 7-16). Bev administration did not impact outcome. Conversion was the only factor associated with prolonged OS and progression-free survival in multivariate analysis. On landmark analysis, patients who had undergone resection had longer OS than those who did not undergo resection (3-year OS: 80% vs 26%). Currently, 10 of 49 (20%) patients have no evidence of disease (NED) at a median follow-up of 39 months (32-65 months). CONCLUSIONS In patients with extensive unresectable CRLM, the majority of whom were previously treated, 47% were able to undergo complete resection after combined HAI and systemic therapy. Conversion to resection is associated with prolonged survival.

Long‐term outcomes following microwave ablation for liver malignancies

Microwave ablation has emerged as a promising treatment for liver malignancies, but there are scant long‐term follow‐up data. This study evaluated long‐term outcomes, with a comparison of 915‐MHz and 2·4‐GHz ablation systems.

Tumor MHC Class I Expression Improves the Prognostic Value of T-cell Density in Resected Colorectal Liver Metastases

Using a tissue microarray of liver metastases from 158 patients with colorectal cancer, Turcotte and colleagues show that high MHC class I expression with dense intratumoral T-cell infiltration identifies patients with favorable outcomes independent of conventional prognostic factors. Tumor-infiltrating lymphocytes (TIL) in colorectal cancer liver metastases (CLM) have been associated with more favorable patient outcomes, but whether MHC class I (MHC-I) expression on cancer cells affects prognosis is uncertain. Immunohistochemistry was performed on a tissue microarray of 158 patients with CLM, who underwent partial hepatectomy with curative intent. Using the antibody HC-10, which detects HLA-B and HLA-C antigens and a minority of HLA-A antigens, MHC-I expression was correlated with β-2 microglobulin (β2m; r = 0.7; P < 0.001), but not with T-cell density (r < 0.32). The median follow-up for survivors was 9.7 years. High levels of MHC-I expression in tumors concomitant with high T-cell infiltration (CD3, CD4, or CD8) best identified patients with favorable outcomes, compared with patients with one or none of these immune features. The median overall survival (OS) of patients with MHC-IhiCD3hi tumors (n = 31) was 116 months compared with 40 months for the others (P = 0.001), and the median time to recurrence (TTR) was not reached compared with 17 months (P = 0.008). By multivariate analysis, MHChiCD3hi was associated with OS and TTR independent of the standard clinicopathologic variables. An immune score that combines MHC-I expression and TIL density may be a valuable prognostic tool in the treatment of patients with CLM. Cancer Immunol Res; 2(6); 530–7. ©2014 AACR.

Colorectal Cancer Liver Metastases and Concurrent Extrahepatic Disease Treated With Resection.

Objective: The aim of the study was to evaluate outcomes after resection of colorectal liver metastases (CRLM) and concurrent extrahepatic disease (EHD), and to define prognostic factors. Background: There is increasing evidence to support resection of liver metastases and concurrent EHD in selected patients. Long-term survival data are lacking, and prognostic factors are not well defined. Methods: Retrospective review of 219 patients was undertaken between January 1992 and December 2012, who underwent hepatectomy for CRLM and resection of synchronous EHD. Survival outcomes were estimated by the Kaplan-Meier method. Univariate and multivariate analyses of prognostic factors were performed. A scoring system for prognostication was developed. Results: The median, 3, 5, and 10-year overall survival were 34.4 months, 49%, 28%, and 10%, respectively. Disease recurred in 185 patients (90.2%) at a median of 8 months. There were 8 actual 10-year survivors. The site of EHD affected survival, with portal, retroperitoneal nodes and multiple sites associated with the worst prognoses. The size of the largest CRLM, the number of CRLM, unfavorable site of EHD, and progression of CRLM on neoadjuvant therapy were associated with overall survival on univariate and multivariate analyses. Three variables, assigned 1 point each, were used to create an EHD risk score: largest CRLM greater than 3 cm, greater than 5 CRLM, and unfavorable site of EHD. The resulting score was prognostic of overall and recurrence-free survival. Conclusions: Long-term survival is possible after resection of liver metastases and concurrent EHD, but true cure is rare. A proposed scoring system may identify patients most likely to benefit from surgery.OBJECTIVE The aim of the study was to evaluate outcomes after resection of colorectal liver metastases (CRLM) and concurrent extrahepatic disease (EHD), and to define prognostic factors. BACKGROUND There is increasing evidence to support resection of liver metastases and concurrent EHD in selected patients. Long-term survival data are lacking, and prognostic factors are not well defined. METHODS Retrospective review of 219 patients was undertaken between January 1992 and December 2012, who underwent hepatectomy for CRLM and resection of synchronous EHD. Survival outcomes were estimated by the Kaplan-Meier method. Univariate and multivariate analyses of prognostic factors were performed. A scoring system for prognostication was developed. RESULTS The median, 3, 5, and 10-year overall survival were 34.4 months, 49%, 28%, and 10%, respectively. Disease recurred in 185 patients (90.2%) at a median of 8 months. There were 8 actual 10-year survivors. The site of EHD affected survival, with portal, retroperitoneal nodes and multiple sites associated with the worst prognoses. The size of the largest CRLM, the number of CRLM, unfavorable site of EHD, and progression of CRLM on neoadjuvant therapy were associated with overall survival on univariate and multivariate analyses. Three variables, assigned 1 point each, were used to create an EHD risk score: largest CRLM greater than 3 cm, greater than 5 CRLM, and unfavorable site of EHD. The resulting score was prognostic of overall and recurrence-free survival. CONCLUSIONS Long-term survival is possible after resection of liver metastases and concurrent EHD, but true cure is rare. A proposed scoring system may identify patients most likely to benefit from surgery.

Tumor-associated Neutrophils and Malignant Progression in Intraductal Papillary Mucinous Neoplasms: An Opportunity for Identification of High-risk Disease.

Objectives: To evaluate the association of tumor-associated neutrophils (TANs) with malignant progression in intraductal papillary mucinous neoplasms (IPMNs) and to study the cyst fluid from these lesions for biomarkers of the inflammation-carcinogenesis association. Background: There is a strong link between TANs and malignant progression. Inflammatory mediators released by these cells may be a measurable surrogate marker of this progression. Methods: We evaluated 78 resected IPMNs (2004–2013). Lesions were divided into the low-risk (low- and intermediate-grade dysplasia: n = 48) and high-risk (high-grade dysplasia and invasive carcinoma: n = 30) groups. TANs were assessed and categorized (negative, low, and high). A multiplexed assay was performed to evaluate 87 different cyst fluid proteins, including cyst fluid inflammatory markers (CFIMs), as possible surrogate markers for parenchymal inflammation. Results: Significant positive correlation between grade of dysplasia and TANs was found. High levels of TANs were identified in 2%, 33%, and 89% of the lesions when stratified by grade of dysplasia into low/intermediate-grade dysplasia, high-grade dysplasia, and invasive carcinoma, respectively (P < 0.001). Higher grades of dysplasia were also found to have positive correlation with 29 of the measured proteins, of which 23 (79%) were CFIMs. Higher levels of TANs correlated with higher levels of 18 CFIMs, of which 16 (89%) were also found to be associated with higher grades of dysplasia. Conclusions: In this study, TANs were strongly associated with malignant progression in IPMNs. Measurement of CFIMs may be a surrogate marker for IPMN progression and allow for the identification of high-risk disease.

Liberal resection for (presumed) Sendai negative branch-duct intraductal papillary mucinous neoplasms--also not harmless.

W e read with interest the study by Fritz et al1 on the incidence of malignancy in “Sendai Negative” branch-duct intraductal papillary mucinous neoplasm (BD-IPMN). Their report focused on a subgroup of patients with low-risk BD-IPMN (asymptomatic, <3 cm on maximal diameter and without associated mural nodules) from a consecutive series of 268 histologically confirmed IPMN of which 123 were of the branch-duct subtype. They reported a 25% rate of malignancy (9% carcinoma in situ and 16% invasive disease) in “Sendai negative” lesions and a 30% rate in “Sendai positive” ones (P = 0.5). On this basis, they concluded that all patients with IPMN (without significant comorbidities) should be offered resection and suggest that the Sendai consensus guidelines2 be modified to this end. We find these results to be in conflict with established data and somewhat confusing, as Sendai negative lesions have been established to carry a low risk of malignancy. Multiple series have been reported from Johns Hopkins, Massachusetts General Hospital, University of Verona, and from our own institution documenting a low risk of invasive cancer in small branch-duct IPMN.3–6 Because of these data, the majority of patients with Sendai negative lesions at our institution are currently not offered resection but rather are entered into a surveillance program.7–10 The study by Fritz et al1 prompted us to look at our own data to assess our experience with “Sendai negative” IPMN. A query of our prospective database identified 283 histologically confirmed resected IPMN (38% branch-duct, 31% main-duct, 30% mixedtype, and 1% unknown). Of these, 35 patients had “Sendai negative” cysts. No invasive cancer was found, and 5 patients (14%) had highgrade dysplasia. By comparison, “Sendai positive” BD-IPMN had an overall incidence of malignancy of 35% (P = 0.04)—18% highgrade dysplasia, 17% invasive cancer.

Prospective Randomized Controlled Trial of Liberal Vs Restricted Perioperative Fluid Management in Patients Undergoing Pancreatectomy.

Objective: The aim of this study is to examine, by a prospective randomized controlled trial, the influence of liberal (LIB) vs restricted (RES) perioperative fluid administration on morbidity following pancreatectomy. Summary of Background Data: Randomized controlled trials in patients undergoing major intra-abdominal surgery have challenged the historical use of LIB fluid administration, suggesting that a more restricted regimen may be associated with fewer postoperative complications. Methods: Patients scheduled to undergo pancreatic resection were consented for randomization to a LIB (n = 164) or RES (n = 166) perioperative fluid regimen. Sample size was designed with 80% power to decrease Grade 3 complications from 35% to 21%. Results: Between July 2009 and July 2015, we randomized 330 patients undergoing pancreaticoduodenectomy (PD, n = 218), central (n = 16), or distal pancreatectomy (DP, n = 96). Patients were equally distributed for all demographic and intraoperative characteristics. Intraoperatively, LIB patients received crystalloid 12 mL/kg/h and RES patients 6 mL/kg/h. Cumulative crystalloid given (median, range, mL) days 0 to 3 was LIB: 12,252 (6600 to 21,365), RES 7808 (2700 to 16,274) P < 0.0001. Sixty-day mortality was 2 of 330 (0.6%). Median operative time for PD was 227 minutes (105 to 462) and DP 150 (44 to 323). Grade 3 complications occurred in 20% of LIB and 27% of RES patients (P = 0.6). Median length of stay was 7 and 5 days for PD and DP, respectively, in both arms. Conclusions: In a high volume institution, major perioperative complications from pancreatic resection were not significantly influenced by fluid regimens that differed approximately 1.6-fold.

The Cost of Postoperative Pancreatic Fistula Versus the Cost of Pasireotide: Results from a Prospective Randomized Trial.

Objective: The objective of this study was to determine the costs of clinically significant postoperative pancreatic fistula (POPF) and to evaluate the cost-effectiveness of routine pasireotide use. Summary of Background Data: We recently completed a prospective randomized trial that demonstrated an 11.7% absolute risk reduction of clinically significant POPF with use of perioperative pasireotide in patients undergoing pancreaticoduodenectomy or distal pancreatectomy [POPF: pasireotide (n = 152), 9% vs placebo (n = 148), 21%; P = 0.006]. Methods: An institutional modeling system was utilized to obtain total direct cost estimates from the 300 patients included in the trial. This system identified direct costs of hospitalization, physician fees, laboratory tests, invasive procedures, outpatient encounters, and readmissions. Total direct costs were calculated from the index admission to 90 days after resection. Costs were converted to Medicare proportional dollars (MP

Development and Validation of a Multi-Institutional Preoperative Nomogram for Predicting Grade of Dysplasia in Intraductal Papillary Mucinous Neoplasms (IPMNs) of the Pancreas: A Report from The Pancreatic Surgery Consortium.

). Results: Clinically significant POPF occurred in 45 of the 300 randomized patients (15%). The mean total cost for all patients was MP