Commensal fungi and their cell-wall ß-glucans direct differential responses in human intestinal epithelial cells.

Intestinal epithelial cells (IECs) are the first to encounter luminal antigens and play an active role in intestinal immune responses. We previously reported that ß-glucans, major fungal cell-wall glycans, induced chemokine secretion by IEC lines in a Dectin-1- and Syk-dependent manner. Here, we show that in contrast to ß-glucans, stimulation of IEC lines with Candida albicans and Saccharomyces cerevisiae did not induce secretion of any of the proinflammatory cytokines IL-8, CCL2, CXCL1, and GM-CSF. Commensal fungi and ß-glucans activated Syk and ERK in IEC lines. However, only ß-glucans activated p38, JNK, and the transcription factors NF-κB p65 and c-JUN, which were necessary for cytokine secretion. Furthermore, costimulation of IEC lines with ß-glucans and C. albicans yielded decreased cytokine secretion compared to stimulation with ß-glucans alone. Finally, ex vivo stimulation of human colonic mucosal explants with zymosan and C. albicans, leads to epithelial Syk and ERK phosphorylation, implying recognition of fungi and similar initial signaling pathways as in IEC lines. Lack of cytokine secretion in response to commensal fungi may reflect IECs' response to fungal glycans, other than ß-glucans, that contribute to mucosal tolerance. Skewed epithelial response to commensal fungi may impair homeostasis and contribute to intestinal inflammation.

Sarcopenia as a Predictor of Survival in Patients with Pancreatic Adenocarcinoma After Pancreatectomy.

OBJECTIVE: To determine whether sarcopenia can potentially predict worse survival after resection of pancreatic ductal adenocarcinoma. BACKGROUND: Sarcopenia is correlated with poor outcomes in hepatopancreatobiliary malignancies, but the relationship of both its qualitative and quantitative features with patient survival after pancreatectomy has not been investigated in a western population. PATIENTS AND METHODS: Preoperative cross-sectional computed tomography scans of consecutive patients who underwent pancreatectomy in 2005-2017 were evaluated for skeletal muscle index (SMI), intramuscular adipose tissue content (IMAC), and visceral-to-subcutaneous adipose tissue area ratio (VSR). Sex-specific categorical cut-offs were determined. Findings were correlated with outcome. RESULTS: The study included 111 patients, 47% of whom were female, with a median age of 67 years (range: 35-87 years), and median body mass index of 23 kg/m2 (range: 16-40 kg/m2); 77% had a Whipple procedure and 66% received adjuvant chemotherapy. Low SMI correlated with poor overall survival (OS) (P = 0.007), disease-specific survival (DSS) (P = 0.006), and recurrence-free survival (RFS) (P = 0.01). High IMAC correlated with poor OS (P = 0.04). Patients with high IMAC tended to have a shorter DSS (P = 0.09), with no correlation with RFS (P = 0.6). VSR was not associated with survival. Multivariable analysis yielded an independent association of low SMI with OS (HR = 1.7, 95%CI: 1.1-2.8, P = 0.02), DSS (HR = 1.8, 95%CI: 1.03-3.2, P = 0.04), and RFS (HR = 1.8, 95%CI: 1.1-2.8, P = 0.01), and of high IMAC with OS (HR = 1.9, 95%CI: 1.1-3.1, P = 0.01). CONCLUSION: Both qualitative and quantitative measures of skeletal muscle were independently associated with impaired survival in patients with resectable PDAC. Sarcopenia might serve as an early radiographic surrogate of aggressive tumor behavior, with potential implications for clinical decision-making and future study.

Induction FOLFIRINOX for patients with locally unresectable pancreatic ductal adenocarcinoma.

OBJECTIVES: Patients with locally advanced pancreatic adenocarcinoma (PDAC) receive induction chemotherapy with or without radiation, with the goal of R0 resection and improving survival. Herein, we evaluate the outcomes of patients who presented with Stage III PDAC and received induction FOLFIRINOX. METHODS: An institutional database was queried for consecutive patients who received induction FOLFIRINOX for locally unresectable PDAC between 2010 and 2016. Clinical and radiographic parameters were assessed pre- and posttreatment, and clinical outcomes were evaluated. RESULTS: There were 200 patients who met the inclusion criteria. The median number of cycles of FOLFIRINOX was 8, 70% (n = 140) received radiation, and 18% (n = 36) underwent resection. Median overall survival (OS) in resected patients was 36 months (95% confidence interval [CI]: 24-56), and this group had improved OS compared to patients that did not undergo resection (hazard ratio (95% CI): 0.41 (0.26-0.64), p < 0.001). Patients (n = 112) who did not progress on induction therapy but remained unresectable had a median OS of 23.9 months (95% CI: 21.1-25.4). CONCLUSION: Nearly 20% of patients with locally advanced PDAC responded sufficiently to induction FOLFIRINOX to undergo resection, which was associated with improved OS compared to patients that did not undergo resection. Patients with stable disease who remain unresectable represent a group of patients with locally advanced PDAC who may benefit from optimization of additional nonoperative treatment.

Neutrophil-to-Lymphocyte Ratio Predicts Recurrence Pattern in Patients with Resectable Colorectal Liver Metastases.

BACKGROUND: Studies have suggested that neutrophil-to-lymphocyte ratio (NLR) has value as a predictor of long-term outcomes in various cancer types. Its prognostic potential in patients with CRLM has not been thoroughly investigated. This original, retrospective study assessed the relationship between the preoperative NLR, survival outcomes, and recurrence patterns in patients after colorectal liver metastasis resection (CRLM). METHODS: The prospectively maintained database of a tertiary medical center was queried for all patients who underwent CRLM resection between 2005 and 2017. Patients were divided into two groups: NLR <3 (normal) or >3 (high). Recurrence risk was analysed using Fine and Gray correction for competing risk method and cause specific analyses. RESULTS: The cohort included 231 patients of whom 53 (23%) had a high neutrophil-to-lymphocyte ratio. At presentation, 35% had synchronous disease and 48% had a solitary metastasis; median tumor size was 2 cm. Patients with a high NLR had a significantly higher rate of simultaneous colorectal resection (P = 0.01). A high NLR was independently associated with worse OS (P = 0.02), worse DFS (P = 0.03), and higher risk of recurrence (P = 0.048), specifically recurrence with an extrahepatic pattern (P = 0.03). CONCLUSIONS: A high preoperative NLR was independently associated with poorer survival outcomes and extrahepatic recurrence pattern. The NLR appears to have prognostic importance in CRLM and may serve as a surrogate marker of aggressive systemic disease after resection. These findings warrant external validation, preferably in a prospective design.

Robotic-assisted Heller Myotomy Is a Safe Operation.

BACKGROUND: Surgical myotomy is the best therapeutic option for patients with achalasia. The minimally invasive technique is considered to be the preferred method for many surgeons. Robotic-assisted laparoscopic myotomy has several advantages over conventional laparoscopic surgery. These benefits include more accurate incisions that may result in a lower rate of intra-operative complications. OBJECTIVES: To describe our technique of performing robotic-assisted Heller myotomy and to review the initial results of this procedure. METHODS: All patients undergoing robotic-assisted Heller myotomy for achalasia between the years 2012-2018 at Rabin Medical Center were retrospectively reviewed from our institutional prospective database. RESULTS: Thirty patients underwent robotic-assisted Heller myotomy for achalasia. Mean operative time was 77 minutes (range 47-109 minutes) including docking time of the robotic system. There were no cases of conversion to laparoscopic or open surgery. There were no cases of intra-operative perforation of the mucosa. None of the patients had postoperative morbidity or mortality. Good postoperative results were achieved in 25 patients. Four patients required additional intervention (3 had endoscopic dilatations and 1 with known preoperative endstage achalasia had undergone esophagectomy). One patient was lost to follow-up. CONCLUSIONS: Robotic-assisted Heller myotomy is a safe technique with a low incidence of intra-operative esophageal perforation compared to the laparoscopic approach. We believe that robotic-assisted surgery should be the procedure of choice to treat achalasia.

Laparoscopic hand-assisted liver resection for tumours in the left lateral section.

CONTEXT: The role of the laparoscopic left lateral sectionectomy (LLLS) is debatable, and Level-1 data are lacking. AIMS: The aim of the study is to evaluate the feasibility and safety of this approach. SETTINGS AND DESIGN: This was a retrospective study. SUBJECTS AND METHODS: From 2007 to 2014, patients undergoing LLLS were identified from two institutions. STATISTICAL ANALYSIS USED: Continuous variables were compared between groups with Student's t-test or Mann-Whitney test, as appropriate by type of distribution. Categorical variables were compared with Chi-square or Fisher's exact test, depending on the number of observations. RESULTS: Thirty-eight patients were included in the study. The mean age was 63.5 + 13 years (range, 31-89), and the mean number of tumours was 1.7 + 1.5. Eleven (29%) patients underwent LLS combined with an additional liver resection (combined resections group). The mean duration of the operation and the mean estimated blood loss were significantly decreased in the LLS group compared to the combined resection group (101 + 71 min vs. 208 + 98 min and 216 + 217 ml vs. 450 + 223 ml;P < 0.05 for both, respectively). The major complications rate was 8% and no mortality occurred. CONCLUSIONS: In a subset of carefully selected cases, LLLS may provide the benefits of laparoscopy. This does not appear to compromise perioperative morbidity rates. We believe that this approach may serve as a training platform for surgical trainees.

Correction to: Hypophosphatemia as a Predictor of Organ-Specific Complications Following Gastrointestinal Surgery: Analysis of 8034 Patients.

In the original version of this article, Martin R. Weiser's last name was spelled incorrectly. It is correct as reflected here. The original article has been updated.

Hypophosphatemia as a Predictor of Organ-Specific Complications Following Gastrointestinal Surgery: Analysis of 8034 Patients.

BACKGROUND: Organ-specific complications (OSC) remain serious potential sequela of gastrointestinal surgery. Hypophosphatemia correlates with poor outcomes and may be a harbinger of OSC after gastrointestinal surgery. Our goal was to describe and evaluate the relationship between postoperative phosphate levels and OSC. METHODS: Consecutive patients who underwent pancreatic, colorectal, or gastric resections were analyzed. OSC were defined as those resulting from the failure of at least one anastomosis performed during the primary resection, manifesting as an anastomotic leak, fistula, and/or intra-abdominal abscess. Postoperative serum phosphate levels and other recognized OSC risk factors were compared among patients who did and did not develop OSC. RESULTS: A total of 8034 patients who underwent pancreatic (n = 397), colorectal (n = 5808), or gastric (n = 1829) resections were included in the study. In each resection group, the majority of patients experienced hypophosphatemia postresection with the nadir on postoperative day (POD) 2, and the subgroups that developed OSC exhibited lower phosphate levels on POD3-7. On multivariate analysis, lower phosphate level on POD3 remained significantly associated with OSC following pancreatic resection [median (interquartile range) mmol/L, 0.65 (0.53-0.76) vs. 0.71 (0.61-0.84), p = 0.045] and colorectal resection [0.71 (0.61-0.87) vs. 0.77 (0.65-0.94), p = 0.006], and lower phosphate level on POD4 remained associated with OSC following gastric resection [0.87 (0.74-1.03) vs. 0.96 (0.81-1.13), p = 0.049]. CONCLUSION: This study identified a consistent trajectory of serum phosphate levels following 3 different gastrointestinal operations and association between early postoperative phosphate levels and OSC. Persistent lower phosphate levels should raise the level of concern for evolving postoperative leak and may lead to earlier radiographic evaluation and treatment.

Incidence of Occult Intrahepatic Metastasis in Hepatocellular Carcinoma Treated With Transplantation Corresponds to Early Recurrence Rates After Partial Hepatectomy.

OBJECTIVE: This study aimed to compare the incidence of radiologically unrecognized (occult) hepatocellular carcinoma (HCC) lesions in explant hepatectomy specimens from orthotopic liver transplants (OLTs) performed for HCC with rates of HCC intrahepatic recurrence after resection. SUMMARY OF BACKGROUND DATA: Resection of HCC is associated with high rates of intrahepatic HCC recurrence. However, it is unclear whether these recurrences represent incomplete resection of unrecognized metastatic lesions from the primary tumor or subsequent de novo tumor formation due to inherent biological proclivity for HCC formation. METHODS: We collected patient, tumor, and pathology data on HCC patients treated surgically from 3696 OLTs in the Organ Procurement and Transplantation (OPTN) national database, 299 OLTs at a single transplant center, and 232 partial hepatectomies from a hepatobiliary cancer center. RESULTS: In the OPTN and high-volume transplant center cohorts, 37% and 42% of patients had occult HCC lesions on explant pathology, respectively. Among cancer center patients, the 2-year recurrence rate was 46%, and 74% of patients who recurred presented with liver only recurrence. CONCLUSION: Although the transplant and resection populations differ, occult multifocality is common in transplant explants and similar to the 46% early recurrence rate following partial hepatectomy. These data suggest that noncurative resection often results from occult intrahepatic multifocality present at the time of resection rather than a malignant predisposition of the remnant liver with de novo tumorigenesis.

The Impact of Primary Tumor Location on Long-Term Survival in Patients Undergoing Hepatic Resection for Metastatic Colon Cancer.

BACKGROUND: The impact of primary tumor location on overall survival (OS), recurrence-free survival (RFS), and long-term outcomes has not been well established in patients undergoing potentially curative resection of colorectal liver metastases (CRLM). METHODS: A single-institution database was queried for initial resections for CRLM 1992-2004. Primary tumor location determined by chart review (right = cecum to transverse; left = splenic flexure to sigmoid). Rectal cancer (distal 16 cm), multiple primaries, and unknown location were excluded. Kaplan-Meier and Cox regression methods were used. Cure was defined as actual 10-year survival with either no recurrence or resected recurrence with at least 3 years of disease-free follow-up. RESULTS: A total of 907 patients were included with a median follow-up of 11 years; 578 patients (64%) had left-sided and 329 (36%) right-sided primaries. Median OS for patients with a left-sided primary was 5.2 years (95% confidence interval [CI] 4.6-6.0) versus 3.6 years (95% CI 3.2-4.2) for right-sided (p = 0.004). On multivariable analysis, the hazard ratio for right-sided tumors was 1.22 (95% CI 1.02-1.45, p = 0.028) after adjusting for common clinicopathologic factors. Median RFS was marginally different stratified by primary location (1.3 vs. 1.7 years; p = 0.065). On multivariable analysis, location of primary was not significantly associated with RFS (p = 0.105). Observed cure rates were 22% for left-sided and 20% for right-sided tumors. CONCLUSIONS: Among patients undergoing resection of CRLM, left-sided primary tumors were associated with improved median OS. However, long-term survival and recurrence-free survival were not significantly different stratified by primary location. Patients with left-sided primary tumors displayed a prolonged clinical course suggestive of more indolent biology.

Surgical Strategy and Outcomes in Duodenal Gastrointestinal Stromal Tumor.

BACKGROUND: The surgical management of duodenal gastrointestinal stromal tumors (DGIST) is poorly characterized. Limited resection may be technically feasible and oncologically safe, but anatomic considerations may compromise the resection margins due to the proximity of critical structures, thereby necessitating more extensive resections such as pancreaticoduodenectomy. METHODS: Patients undergoing surgery for DGIST at two institutions from 1994 to 2014 were identified. Clinicopathologic and survival data were analyzed to compare outcomes in patients treated with limited or radical resection. RESULTS: Sixty patients underwent surgery for DGIST. Pancreaticoduodenectomy was performed in 38 % while the rest underwent limited resections. The most common type of limited resection was wedge resection and primary closure (49 %) followed by segmental resection with an end-to-end or side-to-side duodenojejunostomy (27 %). The pancreaticoduodenectomy group tended to have larger tumors with the majority located in D2/3 (87 %) and at the mesenteric border (91 %). The pancreaticoduodenectomy group also had significantly greater intraoperative blood loss, longer operative time, longer hospital stay, and higher 90-day morbidity and readmission rates. The 5-year relapse-free survival, recurrence-free survival, and overall survival for the pancreaticoduodenectomy versus limited resection were 81 versus 56 % (p = 0.05), 64 versus 53 % (p = 0.5), and 76 versus 72 % (p = 0.6), respectively. A surgical algorithm based on the location and size of the tumor is proposed. CONCLUSIONS: Limited resection of DGIST is safe, but may be associated with lower 5-year relapse-free survival. Pancreaticoduodenectomy is recommended for selected patients with DGIST when an R0 resection cannot be performed without removing the ampulla or part of the pancreas.

Operative morbidity and survival following hepatectomy for colorectal liver metastasis in octogenarians: a contemporary case matched series.

BACKGROUND: Clinical outcomes of octogenarians undergoing hepatectomy for colorectal liver metastases (CRLM) are poorly characterized. The current study evaluated operative morbidity, mortality and survival outcomes among a contemporary cohort of octogenarians. METHODS: Patients undergoing their first hepatectomy for CRLM were identified from institutional databases and those ≥80 years old (y) were matched 1:1 to a group of patients <80 y. Data pertaining to surgical morbidity/mortality and survival were compared using standard statistical methods. RESULTS: From 2002 to 2012, 1391 hepatectomies were performed for CRLM, 55 (4%) in patients ≥80 y. Major complications occurred twice as frequently among patients ≥80 y [10 (19%) ≥80 y versus 5 (9%) <80 y, (p = 0.270)]. No matched patient <80 y. died within 90 d of operation, whereas, 4 (7%) patients ≥80 y did, p = 0.125. Median follow-up was significantly longer for the <80 y group [44 (1-146) versus. 23 (0-102) mths, p = 0.006]. Probability of disease recurrence was not different between groups (p = 0.123) nor was the cumulative incidence of death from disease (p = 0.371). However, patients ≥80 y had significantly higher incidence of non-cancer related death (p = 0.012). CONCLUSIONS: Hepatectomy for CRLM among well-selected octogenarians is reasonable with cancer related survival outcomes similar to those observed in younger patients. However, it is associated with clinically significant morbidity/mortality and continued efforts directed at optimizing perioperative care are necessary to improve early outcomes among octogenarians.

FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis.

BACKGROUND: 35% of patients with pancreatic cancer have unresectable locally advanced disease at diagnosis. Several studies have examined systemic chemotherapy with FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) in patients with locally advanced pancreatic cancer. We aimed to assess the effectiveness of FOLFIRINOX as first-line treatment in this patient population. METHODS: We systematically searched Embase, MEDLINE (OvidSP), Web of Science, Scopus, PubMed Publisher, Cochrane, and Google Scholar from July 1, 1994, to July 2, 2015, for studies of treatment-naive patients of any age who received FOLFIRINOX as first-line treatment of locally advanced pancreatic cancer. Our primary outcome was overall survival. Secondary outcomes were progression-free survival; rates of grade 3 or 4 adverse events; and the proportion of patients who underwent radiotherapy or chemoradiotherapy, surgical resection after FOLFIRINOX, and R0 resection. We evaluated survival outcomes with the Kaplan-Meier method with patient-level data. Grade 3 or 4 adverse events, and the proportion of patients who underwent subsequent radiotherapy or chemoradiotherapy or resection, were pooled in a random-effects model. FINDINGS: We included 13 studies comprising 689 patients, of whom 355 (52%) patients had locally advanced pancreatic cancer. 11 studies, comprising 315 patients with locally advanced disease, reported survival outcomes and were eligible for patient-level meta-analysis. Median overall survival from the start of FOLFIRINOX ranged from 10·0 months (95% CI 4·0-16·0) to 32·7 months (23·1-42·3) across studies with a pooled patient-level median overall survival of 24·2 months (95% CI 21·7-26·8). Median progression-free survival ranged from 3·0 months (95% CI not calculable) to 20·4 months (6·5-34·3) across studies with a patient-level median progression-free survival of 15·0 months (95% 13·8-16·2). In ten studies comprising 490 patients, 296 grade 3 or 4 adverse events were reported (60·4 events per 100 patients). No deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent radiotherapy or chemoradiotherapy ranged from 31% to 100% across studies. In eight studies, 154 (57%) of 271 patients received radiotherapy or chemoradiotherapy after FOLFIRINOX. The pooled proportion of patients who received any radiotherapy treatment was 63·5% (95% CI 43·3-81·6, I(2) 90%). The proportion of patients who underwent surgical resection for locally advanced pancreatic cancer ranged from 0% to 43%. The proportion of patients who had R0 resection of those who underwent resection ranged from 50% to 100% across studies. In 12 studies, 91 (28%) of 325 patients underwent resection after FOLFIRINOX. The pooled proportion of patients who had resection was 25·9% (95% CI 20·2-31·9, I(2) 24%). R0 resection was reported in 60 (74%) of 81 patients. The pooled proportion of patients who had R0 resection was 78·4% (95% CI 60·2-92·2, I(2) 64%). INTERPRETATION: Patients with locally advanced pancreatic cancer treated with FOLFIRINOX had a median overall survival of 24·2 months-longer than that reported with gemcitabine (6-13 months). Future research should assess these promising results in a randomised controlled trial, and should establish which patients might benefit from radiotherapy or chemoradiotherapy or resection after FOLFIRINOX. FUNDING: None.

Hepatic Resection or Ablation for Isolated Breast Cancer Liver Metastasis: A Case-control Study With Comparison to Medically Treated Patients.

OBJECTIVE: To evaluate the efficacy of surgical treatment for patients with isolated breast cancer liver metastases (BCLM). BACKGROUND: Single-arm retrospective studies have shown promising results associated with surgery for isolated BCLM; however, this treatment remains controversial and its role is not well-defined. METHODS: A review of 2150 patients with BCLM who underwent treatment in a single institution was conducted, and 167 (8%) patients with isolated BCLM were identified. A case-control study was conducted to compare outcomes in patients with isolated BCLM who underwent surgery and/or ablation to patients who underwent conventional medical therapy. RESULTS: A total of 167 patients were included (surgery/ablation: 69; medical: 98), with a median follow-up for survivors of 73 months. Patients in the surgical cohort more frequently had estrogen receptor-positive tumors and received adjuvant chemotherapy and radiotherapy for their primary breast tumor. The hepatic tumor burden was less and the interval from breast cancer diagnosis to BCLM was significantly longer (53 vs 30 months) in the surgical cohort. Patients undergoing surgical treatment had a median recurrence-free interval of 28.5 months (95% confidence interval (CI): 19-38) with 10 patients (15%) recurrence free after 5 years. There was no significant difference in overall survival (OS) between the surgical and medical cohorts (median OS: 50 vs 45 months; 5-year OS: 38% vs 39%). CONCLUSIONS: Hepatic resection and/or ablation was not associated with a survival advantage. However, significant recurrence-free intervals can be accomplished with surgical treatment. Surgical intervention might be considered in highly selected patients with the goal of providing time off of systemic chemotherapy.

Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma.

Immune checkpoint blockade targeting the programmed death-1 (PD-1) pathway has shown efficacy in several types of cancers including mismatch-repair-deficient colorectal carcinoma. In some tumor types, programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry has shown utility as a predictive marker for response to anti-PD-1 therapies. This utility, however, remains to be determined in colorectal carcinoma. In addition, although tumor-infiltrating lymphocytes have been associated with better prognosis in colorectal carcinoma, the prognostic value of PD-1 expression in these lymphocytes and its interaction with PD-L1 expression still await investigation. To address these questions, we performed a pilot study to evaluate the patterns of PD-L1 and PD-1 immunohistochemical expression on colorectal carcinoma cells and their tumor-infiltrating lymphocytes, respectively. Using tissue microarray, we found that 5% (19/394) of colorectal carcinomas exhibited high tumor PD-L1 expression, and 19% (76/392) had elevated numbers of PD-1-positive tumor-infiltrating lymphocytes. PD-L1 levels correlated with PD-1 levels (P<0.001), and mismatch-repair-deficient tumors had significantly higher rates of high PD-L1 and PD-1 expression when compared with mismatch-repair-proficient tumors (18% vs 2% and 50% vs 13%, respectively; P<0.001 for both). Staining intensity was also stronger for both markers in mismatch-repair-deficient tumors. Furthermore, we observed that among patients with mismatch-repair-deficient colorectal carcinoma, PD-1/PD-L1 expression stratified recurrence-free survival in an inter-dependent manner: an association between high PD-1-positive tumor-infiltrating lymphocytes and improved recurrence-free survival (P=0.041) was maintained only when the tumors had low-level PD-L1 expression (P=0.006); patients whose tumors had both high PD-1-positive tumor-infiltrating lymphocytes and high PD-L1 expression had a significantly worse recurrence-free survival (P<0.001). Thus, our results not only provide a foundation for further assessment of PD-L1 immunohistochemistry as a predictive marker for anti-PD-1 therapy in colorectal carcinoma, they also shed light on the prognostic impact of tumor-infiltrating lymphocytes in different subsets of mismatch-repair-deficient colorectal carcinomas.

Observation versus Resection for Small Asymptomatic Pancreatic Neuroendocrine Tumors: A Matched Case-Control Study.

OBJECTIVE: To analyze the natural history of small asymptomatic pancreatic neuroendocrine tumors (PanNET) and to present a matched comparison between groups who underwent either initial observation or resection. Management approach for small PanNET is uncertain. METHODS: Incidentally discovered, sporadic, small (<3 cm), stage I-II PanNET were analyzed retrospectively between 1993 and 2013. Diagnosis was determined either by pathology or imaging characteristics. Intention-to-treat analysis was applied. RESULTS: A total of 464 patients were reviewed. Observation was recommended for 104 patients (observation group), and these patients were matched to 77 patients in the resection group based on tumor size at initial imaging. The observation group was significantly older (median 63 vs. 59 years, p = 0.04) and tended towards shorter follow-up (44 vs. 57 months, p = 0.06). Within the observation group, 26 of the 104 patients (25 %) underwent subsequent tumor resection after a median observation interval of 30 months (range 7-135). At the time of last follow-up of the observation group, the median tumor size had not changed (1.2 cm, p = 0.7), and no patient had developed evidence of metastases. Within the resection group, low-grade (G1) pathology was recorded in 72 (95 %) tumors and 5 (6 %) developed a recurrence, which occurred after a median of 5.1 (range 2.9-8.1) years. No patient in either group died from disease. Death from other causes occurred in 11 of 181 (6 %) patients. CONCLUSIONS: In this study, no patient who was initially observed developed metastases or died from disease after a median follow-up of 44 months. Observation for stable, small, incidentally discovered PanNET is reasonable in selected patients.

Resection margin and survival in 2368 patients undergoing hepatic resection for metastatic colorectal cancer: surgical technique or biologic surrogate?

OBJECTIVES: The impact of margin width on overall survival (OS) in the context of other prognostic factors after resection for colorectal liver metastases is unclear. We evaluated the relationship between resection margin and OS utilizing high-resolution histologic distance measurements. METHODS: A single-institution prospectively maintained database was queried for all patients who underwent an initial complete resection of colorectal liver metastases between 1992 and 2012. R1 resection was defined as tumor cells at the resection margin (0 mm). R0 resection was further divided into 3 groups: 0.1 to 0.9 mm, 1 to 9 mm, and 10 mm or greater. RESULTS: A total of 4915 liver resections were performed at Memorial Sloan Kettering Cancer Center between 1992 and 2012, from which 2368 patients were included in the current study. Half of the patients presented with synchronous disease, 43% had solitary metastasis, and the median tumor size was 3.4 cm. With a median follow-up for survivors of 55 months, the median OS of the R1, 0.1 to 0.9 mm, 1 to 9 mm, and 10 mm or more groups was 32, 40, 53, and 56 months, respectively (P < 0.001). Compared with R1 resection, all margin widths, including submillimeter margins correlated with prolonged OS (P < 0.05). The association between the margin width and OS remained significant when adjusted for all other clinicopathologic prognostic factors. CONCLUSIONS: Resection margin width is independently associated with OS. Wide margins should be attempted whenever possible. However, resection should not be precluded if narrow margins are anticipated, as submillimeter margin clearance is associated with improved survival. The prolonged OS observed with submillimeter margins is likely a microscopic surrogate for the biologic behavior of a tumor rather than the result of surgical technique.

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.

FOLFIRINOX Induction Therapy for Stage 3 Pancreatic Adenocarcinoma.

BACKGROUND: Reports show that FOLFIRINOX therapy for pancreatic ductal adenocarcinoma (PDAC) results in objective response rates two to threefold higher than those of other regimens. This study aimed to assess response and resection rates for locally unresectable (stage 3) patients initially treated with induction FOLFIRINOX. METHODS: The institutional cancer database was queried for patients treated with induction FOLFIRINOX therapy between 2010 and 2013. Patients were included in the study if they were treated at the authors' institution for stage 3 PDAC (locally unresectable) that had been adjudicated at a weekly multidisciplinary tumor board. RESULTS: The study identified 101 patients. The median age was 64 years (range 37-81 years), and the median follow-up period was 12 months (range 3-37 months). The patients received a median of six cycles (range 1-20 cycles) of induction FOLFIRINOX. No grade 4 or 5 toxicity was recorded. At the initial restaging (median of 3 months after diagnosis), 23 patients (23 %) had developed distant metastases, 15 patients (15 %) had undergone resection, and 63 patients (63 %) had proceeded to chemoradiation. In the group of 63 patients who had proceeded to chemoradiation (median of 9 months after diagnosis), an additional 16 patients (16 %) had undergone resection, and 5 patients (5 %) had developed metastases. A partial radiographic response was observed in 29 % of all the patients, which was associated with ability to perform resection (p = 0.004). The median overall survival time was 11 months for the group that progressed with FOLFIRINOX and 26 months for the group that did not progress. CONCLUSION: Nearly one third of the patients who had been initially identified as having stage 3 pancreatic carcinoma and had been treated with FOLFIRINOX responded radiographically and underwent tumor resection.