Adjuvant FOLFIRINOX in Patients with Resectable Pancreatic Cancer Is Effective but Rarely Feasible in Real Life: Is Neoadjuvant FOLFIRINOX a Better Option?

BACKGROUND: The recommended treatment for resectable pancreatic cancer (PC) is resection followed by adjuvant FOLFIRINOX. We assessed the proportion of patients that managed to complete the 12 courses of adjuvant FOLFIRINOX and compared their outcome with that of patients with borderline resectable pancreatic cancer (BRPC) who underwent resection after neoadjuvant FOLFIRINOX. METHODS: A retrospective analysis was performed on a prospectively maintained database of all PC patients who underwent resection with (2/2015-12/2021) or without (1/2018-12/2021) neoadjuvant therapy. RESULTS: A total of 100 patients underwent upfront resection, and 51 patients with BRPC received neoadjuvant treatment. Only 46 resection patients started adjuvant FOLFIRINOX, and only 23 completed 12 courses. The main reasons for not starting/completing adjuvant therapy were poor tolerance and rapid recurrence. Significantly more patients in the neoadjuvant group received at least six FOLFIRINOX courses (80.4% vs. 31%, p < 0.001). Patients who completed at least 6 courses, either pre- or postoperatively, had better overall survival (p = 0.025) than those who did not. In spite of having more advanced disease, the neoadjuvant group had comparable overall survival (p = 0.062) regardless of the number of treatment courses. CONCLUSION: Only a minority of patients (23%) undergoing upfront pancreatic resection completed the planned 12 courses of FOLFIRINOX. Patients who received neoadjuvant treatment were significantly more likely to receive at least six treatment courses. Patients receiving at least six courses had better overall survival than those who received fewer than six courses, regardless of the timing of treatment relative to surgery. Potential ways to increase chemotherapy adherence, such as administering treatment before surgery, should be considered.

Microbiota transfer following liver surgery involves microbial extracellular vesicle migration that affects liver immunity.

BACKGROUND: Short-term perioperative administration of probiotics was shown to alleviate postoperative complications and promote liver recovery among patients undergoing resection for liver malignancy. The mechanisms by which probiotic bacteria effectively influence the gut microbiome composition during the perioperative time are controversial. Here, we aim to elucidate the short-term direct biological effect of probiotic microbiota-derived vesicles on host liver cells during the perioperative period. METHODS: Probiotic-derived vesicles (pbMVs) were administered postoperatively. pbMVs were isolated and characterized from probiotics, mainly from the bacteria genus Lactobacillus, Bifidobacterium, and Lactococcus. Mice underwent bile duct ligation, sham laparotomy (SHAM), or 70% partial hepatectomy (70%PH). pbMVs were tracked in vivo, and intrahepatic cellular and molecular aspects were analyzed by flow cytometry and qRT-PCR techniques. Liver sinusoidal endothelial cells (LSECs) analysis for Vascular Cell Adhesion Molecule-1(VCAM-1) expression following pbMV stimulation of cultured liver non-parenchymal cells which had been activated by LPS. RESULTS: The administered pbMV rapidly translocated to the liver after surgery. pbMV administrations following surgeries enhanced neutrophil clearance; there was a dramatic decline in the liver neutrophil-to-lymphocyte ratio Ly6G+/CD3+ and an increase in IL6 levels. pbMVs reduced intrahepatic VCAM1 and ICAM2 expression compared with control following SHAM and decrease in IL10 levels following 70%PH. The administration of pbMV improved liver regeneration 72 hours following surgical liver resection with a significant decrease in IL17 expression. pbMVs modulated VCAM-1 on liver sinusoidal endothelial cells in liver cell culture. CONCLUSIONS: Our study findings provide mechanistic insights into the liver-gut axis following surgery and illustrate how probiotic vesicles can reduce adhesion molecule expression and affect immune cell invasion and liver immunity, resulting in improved liver recovery following hepatic surgery.

A Lymph Node Ratio Model for Prognosis of Patients with Pancreatic Neuroendocrine Tumors.

The objective of this study was to determine the prognostic value of lymph node (LN) involvement and the LN ratio (LNR) and their effect on recurrence rates and survival in patients with pancreatic neuroendocrine tumors (PNETs) undergoing surgery. This single-center retrospective study reviewed the medical records of 95 consecutive patients diagnosed with PNETs who underwent surgery at our medical center between 1997 and 2017. The retrieved information included patient demographics, pathology reports, treatments, and oncological outcomes. Results: 95 consecutive potentially suitable patients were identified. The 78 patients with PNETs who underwent surgery and for whom there was adequate data were included in the analysis. Their mean ± standard deviation age at diagnosis was 57.4 ± 13.4 years (range 20-82), and there were 50 males (64%) and 28 females (36%). 23 patients (30%) had LN metastases (N1). The 2.5- and 5-year disease-free survival (DFS) rates for the entire cohort were 79.5% and 71.8%, respectively, and their 2- and 5-year overall survival (OS) rates were 85.9% and 82.1%, respectively. The optimal value of the LNR was 0.1603, which correlated with the outcome (2-year OS p = 0.002 HR = 13.4 and 5-year DFS p = 0.016 HR = 7.2, respectively, and 5-year OS and 5-year DFS p = 0.004 HR = 9 and p = 0.001 HR = 10.6, respectively). However, the multivariate analysis failed to show that the LNR was an independent prognostic factor in PNETs. Patients with PNETs grade and stage are known key prognostic factors influencing OS and DFS. According to our results, LNR failed to be an independent prognostic factor.

Long-term outcomes of elderly patients with peritoneal metastases of colorectal origin after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

INTRODUCTION: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) were reportedly safe for the elderly. However, long-term survival data in this subgroup of patients are scarce. Our aim was to evaluate the peri-operative and long-term outcomes of CRS + HIPEC in colorectal peritoneal metastases (CRC-PM) in patients ≥70 years of age. MATERIAL AND METHODS: We retrospectively analyzed our combined institutional databases for patients who underwent CRS + HIPEC for CRC-PM. Clinical and pathological characteristics, as well as overall survival (OS) and progression-free survival (PFS) were compared between the groups. Tumor extent was measured by the peritoneal carcinomatosis index (PCI) and completeness of cytoreduction by the CCR score. Major morbidity was defined according to Clavien-Dindo classification. RESULTS: The dataset of 159 patients included 33 elderly and 126 non-elderly patients. Clinical characteristics between the groups differed only in medical comorbidities (Charlson comorbidity index 10 vs. 7, P < 0.001) and delivery of post-HIPEC adjuvant treatment (12.5% vs. 43.8%, P = 0.004). Overall PCI and CCR0 rates were similar between the groups, as were length of stay and major morbidity and mortality rates. Long-term outcomes in the elderly group were lower than those of the non-elderly (median OS: 21.8 vs. 40.5 months, P < 0.001; median PFS: 6 vs. 8 months, P = 0.02, respectively). CONCLUSIONS: CRS + HIPEC in selected elderly patients can be safe in terms of postoperative morbidity and mortality. However, despite the same surgical extents and radicality, their long-term outcomes are inferior, possibly due to under-usage of systemic chemotherapy.

Lymph Node Metastases from Visceral Peritoneal Colorectal Metastases are Associated with Systemic Recurrence.

BACKGROUND: Visceral peritoneal colorectal metastases (VPCMs) may further metastasize to lymph nodes that drain those organs. The rate of lymph node metastases (LNMs) from VPCMs and their clinical and prognostic significance are unknown. METHODS: This study retrospectively analyzed the authors' institutional databases of 160 patients with peritoneal colorectal metastases who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Patients with LNM-VPCM (n = 12) were identified by pathologic reports, and both their short- and long-term outcomes were compared with those of patients without LNM-VPCM. RESULTS: The clinical presentation and primary tumor pathologic characteristics did not differ between the two groups. The patients with LNM-VPCM had a higher tumor burden (measured by the peritoneal carcinomatosis index [PCI]) and visible remnant disease compared with those who had no LNM-VPI (10 vs 5.5 [p = 0.03] vs 33.3% vs 6.8% [p = 0.007], respectively). The postoperative outcomes also were comparable. The patients with LNM-VPCM had a shorter overall survival (OS) than those without LNM-VPCM (median OS, 22.5 months; 95% confidence interval [CI], 15.1-29.9 months vs 40.1 months; 95% CI, 38.1-42 months; p = 0.02). However, only tumor grade and PCI were predictors of OS in the multivariate analysis (hazard ratio [HR], 2.33 [p = 0.001]; 1.77 [p = 0.03], respectively). The study showed that LNM-VPCM was associated with systemic but not peritoneal recurrence compared with non-LNM-VPCM (81.8% vs 51.6% for systemic recurrence, respectively; p = 0.05). CONCLUSION: The small distinct group of patients defined by LNM-VPCM were prone to systemic recurrence. Given its correlation with systemic recurrence, LNM-VPCM may indicate the need for adjuvant treatment.

Preoperative biopsy for suspected adenocarcinoma of the pancreatic head: yield and complications.

BACKGROUND: Histologic confirmation before pancreaticoduodenectomy (PD) for suspected pancreatic cancer is often performed. We assessed the yield of preoperative biopsy in these patients considering the associated complications. METHODS: We retrospectively evaluated 216 patients that underwent PD for suspected carcinoma (CA) between 2012 and 2018. Post procedure complications and delay in surgery were assessed, as well as the postoperative diagnosis in relation to preoperative parameters. RESULTS: Preoperative biopsy was performed in 142 patients (65.7%). Pathologic findings suggestive of CA were found in 106 (74.6%), while benign histology was found in 23 (16.1%), and non-diagnostic findings in 12 (8.4%). Seventy-four patients (34.3%) were operated without a preoperative biopsy. The time from diagnosis to surgery was significantly prolonged in those that underwent biopsy compared to patients that were taken straight to surgery (40±14 versus 18±15 days, P<0.001), and 18 patients (12.6%) suffered from clinically significant post procedure complications. Patients with a preoperative biopsy suggestive of CA, and those that were operated without a preoperative histologic confirmation had comparable rates of CA as a final pathological diagnosis (95.2% and 94.5%, respectively). Nevertheless, in patients with a benign or a non-diagnostic biopsy, the rates of pathologic diagnosis of CA were 69.6% and 73.6% respectively. Elevated levels of CA19-9 and a positive preoperative biopsy were associated with a final pathology of CA. CONCLUSIONS: Preoperative histology is not uniformly required in patients with suspected pancreatic cancer. If preoperative biopsy is performed, benign histology does not rule out cancer but warrants additional evaluation prior to surgery.

Definitive Repair of Injuries to the Liver During Initial Trauma Laparotomy.

INTRODUCTION: Numerous surgical approaches and hemostatic techniques are used and have been described when operating on the traumatized liver. Despite a substantial decline in operative liver trauma, there still remains a debate on the optimal surgical approach, and goals, during the initial trauma laparotomy. Hepatic resection during the first operation, including the damage control settings, is advocated and practiced in only a select few institutions and remains highly controversial. Here, we describe our success with hepatic resection, repair, and/or hepatic vascular repair, during the trauma laparotomy with our emphasis on the collaboration between the trauma and hepatobiliary surgical teams. CASE SERIES: From 207 patients with liver injuries during the study period, 7 patients had definitive liver resection or repair during the initial trauma laparotomy. One had hepatic tissue repair, 1 had hepatic vein repair, and 5 had liver resections. All the operations involved a hepatobiliary surgeon together with the trauma team. There were no fatalities in the liver operation group, no sepsis, or need for emergent angiography because of hemorrhage. Four patients needed endoscopic retrograde cholangiopancreatography (ERCP) and stenting because of biliary leak. Three patients were discharged home and 4 to rehabilitation. DISCUSSION: Hepatic resection, and/or definitive hepatic repair, may be safe and beneficial to the patients during the initial operation even in a damage control setting when the patients' overall condition allows. We emphasize the benefit of collaboration with experienced and trained liver surgery, especially in lower volume trauma centers. ERCP is commonly needed for postoperative biliary leak and should be readily utilized.

Severe Postoperative Complications are Associated with Impaired Survival in Primary but not in Recurrent Retroperitoneal Sarcoma.

BACKGROUND: Retroperitoneal sarcoma (RPS) surgery entails multivisceral resection, which may cause postoperative complications. We assessed the effects of complications on survival to identify their predisposing factors in primary (PRPS) and recurrent (RRPS) RPS. METHODS: We retrospectively analyzed our institutional database. Severe postoperative complications (SC) were defined as Clavien-Dindo classification ≥ 3. Predisposing factors for complications were investigated, as was their effect on long-term outcomes. RESULTS: In total, 154 RPS resections (78 PRPS and 76 RRPS) performed between January 2008 and December 2018 were included. Neoadjuvant chemotherapy and multifocal tumors were more common in RRPS than PRPS (34.2% vs. 11.3%, P = 0.001 and 42.1% vs. 10.3%, P < 0.001, respectively). Although surgical extent in RRPS was limited compared with PRPS (weighted organ score 1 vs. 2, P = 0.01; transfusion requirement 23.6% vs. 35.8%, P = 0.04), SC and mortality rates were comparable. SC rates were 30.1% and 35.5% for PRPS and RRPS, respectively. NACT rate tended to be higher in PRPS patients with SC (20.8% vs. 7.4%, P = 0.09), whereas weighted organ score and transfusion requirement were increased in RRPS patients with SC (2 vs. 1, P = 0.01; 40.7% vs. 14.3%, P = 0.009, respectively). PRPS patients with SC had decreased overall survival (35 months, 95% confidence interval [CI] 12.2-57.7) compared with those without SC (90 months, 95% CI 71.4-108.5, P = 0.01). CONCLUSIONS: Postoperative complications are associated with impaired outcomes in PRPS but not in RRPS. The negative effects of complications on outcomes should be factored to perioperative management.

Protective Desmoplasia in Pancreatic Adenocarcinoma: High Vitamin D Receptor Expression and Collagen Content.

BACKGROUND/AIM: Vitamin D receptor (VDR) has been shown to suppress desmoplasia in pancreatic ductal adenocarcinoma (PDAC). Our aim was to assess the clinical effects of VDR expression and its correlation with collagen content in the desmoplasia of PDAC patients. PATIENTS AND METHODS: This is a retrospective analysis of 127 patients with peritumoral desmoplasia resected for PDAC. VDR expression and collagen content were assessed by immunohistochemistry and correlated with clinical outcome. RESULTS: Patients were classified into those with high and those with low VDR expression. High VDR expression was associated with improved overall survival (OS) in localized disease (N0) (median= 33; 95%CI=26.4-39.6 vs. 18; 15.5-20.5 months, p=0.01). Patients with high vs. low collagen content had improved OS [34, (range=22.3-45.6 months) vs. 17, (range=14.4-19.6 months), p<0.001]. The number of VDR+ cells was the same for patients with either high or low collagen content. CONCLUSION: Protective desmoplasia is associated with increased VDR expression and collagen content.

Innate inflammatory markers for predicting survival in retroperitoneal sarcoma.

INTRODUCTION: Existing prognostic tools for retroperitoneal sarcomas (RPS) utilize parameters that can be accurately determined only postoperatively. This study evaluated the application of the neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) levels for predicting prognosis in primary RPS. MATERIALS AND METHODS: We retrospectively analyzed our database of patients with primary RPS operated between 2008 and 2018. The NLR was calculated from preoperative blood tests and its association with outcomes was determined. RESULTS: The NLR values of 78 suitable patients were analyzed. Patients were classified in the NLR-high group if the NLR was ≥2.1. High-grade tumors were more common in the NLR-high group (71.6% vs 48%, P = .02). NLR-high patients had impaired overall survival (OS) and progression-free survival (PFS) compared to NLR-low patients (median OS not reached vs 74 months 95% confidence interval [CI]: 21.6-126.4, P = .03; median PFS not reached vs 48 months 95% CI: 6.5-98.6, P = .06, respectively). Multivariate analysis showed statistical significance only for PFS but not for OS (hazard ratio [HR] = 4.1, P = .03; HR = 2.3, P = .3). Patients with low CRP levels had improved OS and PFS. CONCLUSIONS: The NLR may serve as a preoperative, easily derived marker for prognosis in RPS. Serum biomarkers may prove useful in these large and spatially heterogeneous tumors.

Surgical Approach to Abdominal Tumors Involving the Inferior Vena Cava.

BACKGROUND: Abdominal tumors invading the inferior vena cava (IVC) present significant challenges to surgeons and oncologists. OBJECTIVES: To describe a surgical approach and patient outcomes. METHODS: The authors conducted a retrospective analysis of surgically resected tumors with IVC involvement by direct tumor encasement or intravascular tumor growth. Patients were classified according to level of IVC involvement, presence of intravascular tumor thrombus, and presence of hepatic parenchymal involvement. RESULTS: Study patients presented with leiomyosarcomas (n=5), renal cell carcinoma (n=7), hepatocellular carcinoma (n=1), cholangiocarcinoma (n=2), Wilms tumor (n=1), neuroblastoma (n=1), endometrial leiomyomatosis (n=1), adrenocortical carcinoma (n=1), and paraganglioma (n=1). The surgeries were conducted between 2010 and 2019. Extension of tumor thrombus above the hepatic veins required a venovenous bypass (n=3) or a full cardiac bypass (n=1). Hepatic parenchymal involvement required total hepatic vascular isolation with in situ hepatic perfusion and cooling (n=3). Circular resection of IVC was performed in five cases. Six patients had early postoperative complications, and the 90-day mortality rate was 10%. Twelve patients were alive, and six were disease-free after a mean follow-up of 1.6 years. CONCLUSIONS: Surgical resection of abdominal tumors with IVC involvement can be performed in selected patients with acceptable morbidity and mortality. Careful patient selection, and multidisciplinary involvement in preoperative planning are key for optimal outcome.

Micro-RNA Expression Patterns Predict Metastatic Spread in Solid Pseudopapillary Neoplasms of the Pancreas.

Solid pseudopapillary neoplasm (SPN) of pancreas is a rare pancreatic neoplasm with a low metastatic potential. Up to 10% of patients with localized disease at presentation will develop systemic metastases, usually in the peritoneum or the liver. Due to the rarity of SPNs and the overall excellent prognosis, reliable prognostic factors to predict malignant biological behavior remain undetermined. Therefore, we aimed to define clinical, histological, and microRNA patterns that are associated with metastatic disease. We conducted a retrospective single center study on all patients operated for SPN of pancreas between 1995 and 2018. Clinical and pathological data were collected, and expression patterns of 2,578 human microRNAs were analyzed using microRNA array (Affimetrix 4.1) in normal pancreases (NPs), localized tumors (LTs), and metastatic tumors (MTs). The diagnosis of SPN was confirmed in 35 patients who included 28 females and 3 males, with a mean age of 33.8 ± 13.9 years. The only clinical factor associated with metastases was tumor size (mean tumor size 5.20 ± 3.78 in LT vs. 8.13± 1.03 in MT, p < 0.012). Microscopic features of malignancy were not associated with metastases, nor were immunohistochemical stains, including the proliferative index KI67. Higher expressions of miR-184, miR-10a, and miR-887, and lower expressions of miR-375, miR-217, and miR-200c were observed in metastatic tissues on microarray, and validated by real-time polymerase chain reaction. Hierarchal clustering demonstrated that the microRNA expression pattern of MTs was significantly different from that of LTs. The only clinical factor associated with metastases of SPN of pancreas was tumor size. Histological features and immunohistological staining were not predictive of metastases. A panel of six microRNAs was differentially expressed in MTs, and these findings could potentially be used to predict tumor behavior. Validation of these results is needed in larger series.

Increased Rate of Complete Pathologic Response After Neoadjuvant FOLFIRINOX for BRCA Mutation Carriers with Borderline Resectable Pancreatic Cancer.

BACKGROUND: Neoadjuvant FOLFIRINOX is a standard-of-care treatment for BRPC patients. Patients with gBRCAm who have demonstrated improved response to platinum-based chemotherapy may have impaired homologous repair deficiency. This study aimed to describe the pathologic complete response rate and long-term survival for patients with germline BRCA1 or BRCA2 mutation (gBRCAm) and borderline resectable pancreatic cancer (BRPC) treated with neoadjuvant FOLFIRINOX. METHODS: A dual-center retrospective analysis was performed. Patients who had BRPC treated with neoadjuvant FOLFIRINOX followed by curative resection were identified from clinical databases. Pathologic complete response was defined as no viable tumor cells present in the specimen. Common founder Jewish germline BRCA1 or BRCA2 mutation was determined for available patients. RESULTS: The 61 BRPC patients in this study underwent resection after neoadjuvant FOLFIRINOX. Analysis of BRCA mutation was performed for 39 patients, and 9 patients were found to be BRCA2 germline mutation carriers. The pathologic complete response rate was 44.4% for the gBRCAm patients and 10% for the BRCA non-carriers (p = 0.009). The median disease-free survival was not reached for the gBRCAm patients and was 7 months for the BRCA non-carriers (p = 0.03). The median overall survival was not reached for the gBRCAm patients and was 32 months for the BRCA non-carriers (p = 0.2). After a mean follow-up period of 33.7 months, all eight patients with pathologic complete response were disease-free. CONCLUSIONS: The study showed that gBRCAm patients with BRPC have an increased chance for pathologic complete response and prolonged survival after neoadjuvant FOLFIRINOX. The results support the benefit of exposing gBRCAm patients to platinum-based chemotherapy early in the course of the disease. Neoadjuvant FOLFIRINOX should be considered for BRCA carriers who have resectable pancreatic cancer.

Resection Versus Observation of Small Asymptomatic Nonfunctioning Pancreatic Neuroendocrine Tumors.

BACKGROUND: Management of asymptomatic, nonfunctioning small pancreatic neuroendocrine tumors (PNETs) is controversial because of their overall good prognosis, and the morbidity and mortality associated with pancreatic surgery. Our aim was to compare the outcomes of resection with expectant management of patients with small asymptomatic PNETs. METHODS: Retrospective review of patients with nonfunctioning asymptomatic PNETs < 2 cm that underwent resection or expectant management at the Tel-Aviv Medical Center between 2001 and 2018. RESULTS: Forty-four patients with small asymptomatic, biopsy-proven low-grade PNETs with a KI67 proliferative index < 3% were observed for a mean of 52.48 months. Gallium67DOTATOC-PET scan was completed in 32 patients and demonstrated uptake in the pancreatic tumor in 25 (78%). No patient developed systemic metastases. Two patients underwent resection due to tumor growth, and true tumor enlargement was evidenced in final pathology in one of them. Fifty-five patients underwent immediate resection. Significant complications (Clavien-Dindo grade ≥ 3) developed in 10 patients (18%), mostly due to pancreatic leak, and led to one mortality (1.8%). Pathological evaluation revealed lymphovascular invasion in 1 patient, lymph node metastases in none, and a Ki67 index ≥ 3% in 5. No case of tumor recurrence was diagnosed after mean follow-up of 52.8 months. CONCLUSIONS: No patients with asymptomatic low-grade small PNETs treated by expectant management were diagnosed with regional or systemic metastases after a 52.8-month follow-up. Local tumor progression rate was 2.1%. Surgery has excellent long-term outcomes, but it harbors significant morbidity and mortality. Observation can be considered for selected patients with asymptomatic, small, low grade PNETs.

Prognostic significance of pancreatic fistula and postoperative complications after pancreaticoduodenectomy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The influence of postoperative complications, specifically, pancreatic fistula (PF), on long-term oncologic outcome in patients with pancreatic ductal adenocarcinoma (PDAC) is unclear. METHODS: Prospectively collected data of patients who underwent pancreaticoduodenectomy (PD) for PDAC between 2008 and 2016 were retrospectively reviewed and analyzed. Deaths within 90 days were excluded. Median follow-up time was 22 months for the entire cohort (range 2-102 months). PF was graded as biochemical leak, grade B, or grade C according to the criteria of the International Study Group on Pancreatic Fistula. Postoperative complications were graded according to the Clavien-Dindo classification (CDC). Data on clinical and pathological characteristics as well as on recurrence and survival were collected. RESULTS: Twenty-nine of the 148 identified patients (19%) developed PF, of whom 17 (11.4%) had a PF grade B or C. 29 patients developed a postoperative complication CDC grade 3 or 4. The respective 3-year disease-free survival was 15.5% and 19.2% (P = 0.725), and the 5-year overall survival was 20% and 16% (P = 0.914) in patients with and without PF. On multivariate analysis, the use of adjuvant chemotherapy, lymph node involvement, surgical margin involvement, and tumor grade were associated with patient survival. PF and postoperative complications CDC grade 3 or 4 were not associated with decreased long-term survival, disease-free survival or local recurrence rate. CONCLUSIONS: While acknowledging the limited sample size, no association was seen between PF or postoperative complications and overall or disease-free survival in patients undergoing PD for PDAC.

Omental Tissue-Mediated Tumorigenesis of Gastric Cancer Peritoneal Metastases.

The peritoneal cavity, especially the omentum, is a common site for gastric cancer metastasis, representing advanced disease stage and poor prognosis. Here, we studied the effects of omental tissue on gastric cancer tumor progression in vitro and in vivo. Utilizing in vitro models, we found that omental tissue secreted factors increased gastric cancer cellular growth (by 30-67%, P < 0.05), motility (>8-fold, P < 0.05), invasiveness (>7-fold, P < 0.05) and chemoresistance to platinum-based chemotherapeutic agents (>1.2-fold for oxaliplatin and >1.6-fold for cisplatin, P < 0.05). Using a robust proteomic approach, we identified numerous molecules secreted into the omental tissue conditioned medium (CM) which may promote gastric cancer cellular aggressiveness (i.e., IL-6, IL-8, MMP9, FN1, and CXCL-5). Next, an in vivo xenograft mouse model showed an increased human gastric adenocarcinoma tumor volume of cells co-cultured with human omental tissue secreted factors; 1.6 ± 0.55 vs. 0.3 ± 0.19 cm3 (P < 0.001), as well as increased angiogenesis. Finally, exosomes were isolated from human omental tissue CM of gastric cancer patients. These exosomes were taken up by gastric cancer cells enhancing their growth (>8-fold, P < 0.01) and invasiveness (>8-fold, P < 0.001). Proteomic analysis of the content of these exosomes identified several established cancer- related proteins (i.e., IL-6, IL-8, ICAM-1, CCl2, and OSM). Taken together, our findings imply that the omentum play an active role in gastric cancer metastasis. The data also describe specific cytokines that are involved in this cross talk, and that omental tissue- derived exosomes may contribute to these unique cellular interactions with gastric cancer cells. Further studies aimed at understanding the biology of gastric cancer intra peritoneal spread are warranted. Hopefully, such data will enable to develop future novel therapeutic strategies for the treatment of metastatic gastric cancer.

Resection vs Transplant Listing for Hepatocellular Carcinoma: An Intention-to-Treat Analysis.

BACKGROUND: Liver transplantation (LT) and liver resection (LR) are curative treatment options for patients with hepatocellular carcinoma within the Milan criteria. Severe organ shortage dictates the preference for LR. Our aim was to provide an intention-to-treat retrospective comparison of survival between patients who were placed on waiting lists for LT and those who underwent LR. METHODS: The medical records of patients with hepatocellular carcinoma within the Milan criteria treated by LR or listed for LT between 2007 and 2016 were reviewed. We performed intention-to-treat analyses of overall survival and recurrence. RESULTS: There were 54 patients on the waiting list for LT, and 30 of them underwent LR. Thirteen of the 54 patients (24%) were not transplanted because of disease-related mortality or tumor progression. The median waiting time to transplantation was 304 days. The 90-day mortality was higher in transplanted patients (9.8% vs 3.3%, P = .003). Intention-to-treat survival was similar for the LT and LR groups (5-year survival, 47.8% vs 55%, respectively, P = .185). There was a trend toward improved 5-year disease-free survival for listed patients (56.2% vs 26.3% for patients undergoing LR, P = .15). CONCLUSION: Intention-to-treat survival is similar in patients undergoing LR and those on waiting lists for LT. There is a 24% risk to drop from the transplant list. The higher perioperative mortality among patients undergoing LT is balanced by a higher tumor recurrence rate after LR.

MicroRNA profiling of pancreatic ductal adenocarcinoma (PDAC) reveals signature expression related to lymph node metastasis.

Lymph node (LN) metastasis occurs frequently in pancreatic ductal adenocarcinoma (PDAC), representing an advanced disease stage and independently predicting patient survival. Current nodal staging is inadequate preoperatively and even less so postoperatively, and molecular biomarkers are needed to improve prognostication and selection of therapy. Recent data have suggested important roles of miRNAs in PDAC tumorigenesis and progression. The aim of the present study was to identify miRNA expression signature for nodal spread in PDAC patients. Using PDAC human tissue specimens, we identified 39 miRNAs which were differently expressed in LN positive compared to LN negative PDAC samples. Of them, six miRNAs have been reported to play a role in cancer invasion and metastasis. A high versus low six- miRNA signature score was predictive of LN metastasis in the PDAC validation cohort. We demonstrated a similar expression pattern of four out of the six miRNAs in the plasma of PDAC patients. The results of our in-vitro studies revealed that miR-141 and miR-720 are involved in the process of epithelial to mesenchymal-transition in PDAC. These miRNAs significantly inhibited in vitro proliferation, migration and invasion of PDAC cells as evidence by gain- and loss- of function studies, specifically, via ZEB-1 and TWIST1 transcription factors, as well as through the activation of the MAP4K4/JNK signaling pathway.

The transcriptional profile of circulating myeloid derived suppressor cells correlates with tumor development and progression in mouse.

Myeloid derived suppressor cells (MDSCs) play key roles in cancer development. Accumulation of peripheral-blood MDSCs (PB-MDSCs) corresponds to the progression of various cancers, but provides only a crude indicator. We aimed toward identifying changes in the transcriptional profile of PB-MDSCs in response to tumor growth. CT26 colon cancer cells and B16 melanoma cells (106) were inoculated into peritoneal cavities of BALB/c mice and subcutaneously to C57-black mice, respectively. The circulating levels and global transcriptional patterns of PB CD11b+Ly6g+ MDSCs were assessed in control mice, and 4, 8, and 11 days following tumor cell inoculation. Although a significant accumulation of PB-MDSCs was demonstrated only 11 days following tumor induction, a pronounced transcriptional response was identified already on day 4 while the tumor was ~1 mm in size. Further transcriptional changes correlated with different stages of tumor growth. Key MDSC genes and canonical signaling pathways were activated along tumor progression. This phenomenon was demonstrated in both cancer models, and a consensus set of 817 genes, involved in myeloid cell recruitment and angiogenesis, was identified. The data suggest that the transcriptional signatures of PB-MDSC may serve as markers for tumor progression, as well as providing potential targets for future therapies.

CD11b+Ly6G+ myeloid-derived suppressor cells promote liver regeneration in a murine model of major hepatectomy.

Liver regeneration depends on sequential activation of pathways and cells involving the remaining organ in recovery of mass. Proliferation of parenchyma is dependent on angiogenesis. Understanding liver regeneration-associated neovascularization may be useful for development of clinical interventions. Myeloid-derived suppressor cells (MDSCs) promote tumor angiogenesis and play a role in developmental processes that necessitate rapid vascularization. We therefore hypothesized that the MDSCs could play a role in liver regeneration. Following partial hepatectomy, MDSCs were enriched within regenerating livers, and their depletion led to increased liver injury and postoperative mortality, reduced liver weights, decreased hepatic vascularization, reduced hepatocyte hypertrophy and proliferation, and aberrant liver function. Gene expression profiling of regenerating liver-derived MDSCs demonstrated a large-scale transcriptional response involving key pathways related to angiogenesis. Functionally, enhanced reactive oxygen species production and angiogenic capacities of regenerating liver-derived MDSCs were confirmed. A comparative analysis revealed that the transcriptional response of MDSCs during liver regeneration resembled that of peripheral blood MDSCs during progression of abdominal tumors, suggesting a common MDSC gene expression profile promoting angiogenesis. In summary, our study shows that MDSCs contribute to early stages of liver regeneration possibly by exerting proangiogenic functions using a unique transcriptional program.-Nachmany, I., Bogoch, Y., Sivan, A., Amar, O., Bondar, E., Zohar, N., Yakubovsky, O., Fainaru, O., Klausner, J. M., Pencovich, N. CD11b+Ly6G+ myeloid-derived suppressor cells promote liver regeneration in a murine model of major hepatectomy.