Yuman Fong

Outcomes in biliary malignancy.

The biliary malignancies that are reviewed here are gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (IHC), and perihilar cholangiocarcinoma (PHC). The focus is on outcomes after potentially curative resection of biliary malignancies. Key outcomes are postoperative mortality, median and 5‐year overall survival (OS), recurrence‐free survival, and recurrence patterns. Poor prognostic factors for recurrence and survival as well as prognostic models are also discussed. The incidence of biliary malignancies in the United States is about 5 in 100,000. Postoperative mortality for resection of GBC and IHC is similar to that of liver resections for other indications. However, 90 day postoperative mortality after liver resection for PHC is about 10%. For GBC, median OS depends strongly on the T‐stage and ranges from 8 months (pT3) to 79 months (pT1b). Median OS after resection for IHC is about 30 months, and for PHC about 38 months. The majority of patients with biliary malignancies develop a recurrence after resection. Patients with GBC recur early with a median time to recurrence of 12 months, versus about 20 months for IHC and PHC. In patients with resected IHC or PHC locoregional recurrence was the only site of recurrence in about 60% of patients, versus 15% in patients with GBC. Poor prognostic factors after resection of all biliary malignancies include the presence of lymph node metastasis, a positive surgical resection margin, and moderate or poor tumor differentiation. Several prognostic nomograms have been developed to predict long‐term outcomes of biliary cancer resection. J. Surg. Oncol. 2014 110:585–591.

Techniques for prevention of pancreatic leak after pancreatectomy

Pancreatic resections are some of the most technically challenging operations performed by surgeons, and post-operative pancreatic fistula (POPF) are not uncommon, developing in approximately 13% of pancreaticoduodenectomies and 30% of distal pancreatectomies. Multiple trials of various operative techniques in the creation of the pancreatic ductal anastomosis have been conducted throughout the years, and herein we review the literature and outcomes data regarding these techniques, although no one technique of pancreatic ductal anastomosis has been shown to be superior in decreasing rate of POPF. Similarly, we review the literature regarding techniques of pancreatic closure after distal pancreatectomy. Again, no one technique has been shown to be superior in preventing POPF; however the use of buttressing material on the pancreatic staple line in the future may be a successful means of decreasing POPF. We review adjunctive techniques to decrease POPF such as pancreatic ductal stenting, the use of various topical biologic glues, and the use of somatostatin analogue medications. We conclude that future trials will need to be conducted to find optimal techniques to decrease POPF, and meticulous attention to intra-operative details and post-operative care by surgeons is necessary to prevent POPF and optimally care for patients undergoing pancreatic resection.

The 30-year experience—A meta-analysis of randomised and high-quality non-randomised studies of hyperthermic intraperitoneal chemotherapy in the treatment of gastric cancer

IMPORTANCEnHyperthermic intraperitoneal chemotherapy (HIPEC) has been used within various multimodality strategies for the prevention and treatment of gastric cancer peritoneal carcinomatosis.nnnOBJECTIVEnTo systematically evaluate the role of HIPEC in gastric cancer and clarify its effectiveness at different stages of peritoneal disease progression.nnnDATA SOURCESnMedline and Embase databases between January 1, 1985xa0and June 1, 2016.nnnSTUDY SELECTIONnRandomised control trialsxa0and high-quality non-randomised control trialsxa0selected on a validated tool (methodological index for non-randomised studies) comparing HIPEC and standard oncological management for the treatment of advanced stage gastric cancer with and without peritoneal carcinomatosis were considered.nnnDATA EXTRACTION AND SYNTHESISnA random-effects network meta-analysis.nnnMAIN OUTCOMES AND MEASURESnThe primary outcomes were overall survival and disease recurrence. Secondary outcomes were overall complications, type of complications, and sites of recurrence.nnnRESULTSnA total of 11 RCTs and 21 non-randomised control trials (2520 patients) were included. For patients without the presence of peritoneal carcinomatosis (PC), the overall survival rates between the HIPEC and control groups at 3 or 5 years resulted in favour of the HIPEC group (risk ratio [RR]xa0=xa00.82, Pxa0=xa00.01). No difference in the 3-year overall survival (RRxa0=xa00.99, Pxa0=xa00.85) in but a prolonged median survival of 4 months in favour of the HIPEC group (WMDxa0=xa04.04, Pxa0<xa00.001) was seen in patients with PC. HIPEC was associated with significantly higher risk of complications for both patients with PC (RRxa0=xa02.15, Pxa0<xa00.01) and without (RRxa0=xa02.17, Pxa0<xa00.01). This increased risk in the HIPEC group was related to systemic drugs toxicity. Anastomotic leakage rates were found to be similar between groups.nnnCONCLUSIONSnOur study demonstrates a survival advantage of the use of HIPEC as a prophylactic strategy and suggests that patients whose disease burden is limited to positive cytology and limited nodal involvement may benefit the most from HIPEC. For patients with extensive carcinomatosis, the completeness of cytoreductive surgery is a critical prognostic factor for survival. Future RCTs should better define patient selection criteria.

Robot-assisted laparoscopic liver resection: a systematic review and pooled analysis of minor and major hepatectomies

BACKGROUNDnRobotic surgery has been introduced to overcome the limitations of conventional laparoscopy. A systematic review and meta-analysis were performed to assess the safety and feasibility for three subgroups of robot-assisted laparoscopic liver resection: (i) minor resections of easily accessible segments: 2/3, 4B, 5, 6, (ii) minor resections of difficult located segments: 1, 4A, 7, 8 and (iii) major resections: ≥ 4 segments.nnnMETHODSnA systematic search was performed in PubMed, EMBASE and Cochrane Library.nnnRESULTSnTwelve observational, mostly retrospective studies reporting on 363 patients were included. Data were pooled and analyzed. For subgroup (i) (n = 81) the weighted mean operative time was 215 ± 65 min. One conversion (1%) to laparotomy was needed. Weighted mean operative time for subgroup (ii) (n = 17) was 220 ± 60 min. No conversions were needed. For subgroup (iii) (n = 99) the weighted mean operative time was 405 ± 100 min. In this subgroup 8 robotic procedures (8%) were converted to open surgery.nnnCONCLUSIONnData show that robot-assisted laparoscopic liver resection is feasible in minor resections of all segments and major resections. Larger, prospective studies are warranted to compare the possible advantages of robot-assisted surgery with conventional laparoscopy and open surgery.

From Benchtop to Bedside: A Review of Oncolytic Virotherapy

Oncolytic viruses (OVs) demonstrate the ability to replicate selectively in cancer cells, resulting in antitumor effects by a variety of mechanisms, including direct cell lysis and indirect cell death through immune-mediate host responses. Although the mechanisms of action of OVs are still not fully understood, major advances have been made in our understanding of how OVs function and interact with the host immune system, resulting in the recent FDA approval of the first OV for cancer therapy in the USA. This review provides an overview of the history of OVs, their selectivity for cancer cells, and their multifaceted mechanism of antitumor action, as well as strategies employed to augment selectivity and efficacy of OVs. OVs in combination with standard cancer therapies are also discussed, as well as a review of ongoing human clinical trials.

Use of a mobile tower-based robot--The initial Xi robot experience in surgical oncology.

The da Vinci Xi platform provides expanded movement of the arms relative to the base, theoretically allowing increased versatility in complex multi‐field or multi‐quadrant surgery. We describe the initial Xi experience in oncologic surgery at a tertiary cancer center.

Role of MAPK in oncolytic herpes viral therapy in triple-negative breast cancer

Triple-negative breast cancers (TNBCs) have poor clinical outcomes owing to a lack of targeted therapies. Activation of the MEK/MAPK pathway in TNBC has been associated with resistance to conventional chemotherapy and biologic agents and has a significant role in poor clinical outcomes. NV1066, a replication-competent herpes virus, infected, replicated in and killed all TNBC cell lines (MDA-MB-231, HCC1806, HCC38, HCC1937, HCC1143) tested. Greater than 90% cell kill was achieved in more-sensitive lines (MDA-MB-231, HCC1806, HCC38) by day 6 at a multiplicity of infection (MOI) of 0.1. In less-sensitive lines (HCC1937, HCC1143), NV1066 still achieved >70% cell kill by day 7 (MOI 1.0). In vivo, mean volume of flank tumors 14 days after treatment with NV1066 was 57 versus 438u2009mm3 in controls (P=0.002). NV1066 significantly downregulated p-MAPK activation by 48u2009h in all cell lines in vitro and in MDA-MB-231 xenografts in vivo. NV1066 demonstrated synergistic effects with a MEK inhibitor, PD98059 in vitro. We demonstrate that oncolytic viral therapy (NV1066) effectively treats TNBC with correlation to decreased MEK/MAPK signaling. These findings merit future studies investigating the potential role of NV1066 as a sensitizing agent for conventional chemotherapeutic and biologic agents by downregulating the MAPK signaling pathway.

Calcium depletion enhances nectin-1 expression and herpes oncolytic therapy of squamous cell carcinoma

Attenuated, replication-competent, oncolytic herpes simplex virus type 1 (HSV-1) are effective at infecting and lysing many human malignancies in preclinical studies. Nectin-1 is a cell-surface receptor for HSV-1 envelope glycoprotein D (gD) that also forms a component of intercellular adherens junctions (AJs). We sought to determine if the disruption of AJs in squamous cell carcinoma (SCC) through calcium depletion could be utilized to increase nectin-1 exposure and enhance HSV therapy. NV1023 is a single copy γ134.5-deleted, lacZ-expressing, oncolytic HSV-1. Calcium depletion caused cell separation and increased nectin-1 expression for three SCC cell lines growing at confluence. NV1023 viral entry, soluble gD protein binding and NV1023 cytotoxicity were all significantly enhanced for these cell lines at low calcium conditions. The increase in NV1023 entry at low calcium conditions was abrogated by nectin-1 antibody blockade. Murine SCC flank tumors treated with ethylenediaminetetraacetic acid (EDTA) showed increased nectin-1 expression and increased susceptibility to NV1023 infection. Combined NV1023 and EDTA intratumoral injections demonstrated significantly enhanced tumor regression as compared to NV1023 alone. These findings establish, as proof-of-principle, that herpes viral receptor expression may be modulated on cancer cells to enhance oncolytic therapy. This strategy might have future application toward improving therapy with a variety of herpes vectors.

Lymphadenectomy with Optimum of 29 Lymph Nodes Retrieved Associated with Improved Survival in Advanced Gastric Cancer: A 25,000-Patient International Database Study

BACKGROUNDnGastric adenocarcinoma is an aggressive disease with frequent lymph node (LN) metastases for which lymphadenectomy results in a survival benefit. In the US, the National Comprehensive Cancer Network guidelines recommend D2 lymphadenectomy or a minimum of 15 LNs retrieved. However, retrieval of only 15 LNs is considered by most international guidelines as inadequate. We sought to evaluate the survival benefits associated with a more complete lymphadenectomy.nnnSTUDY DESIGNnAn international database was constructed by combining gastric cancer cases from the Surveillance, Epidemiology, and End Results program database (nxa0= 13,932) and the Yonsei University Gastric Cancer database (nxa0= 11,358) (total nxa0= 25,289). Kaplan-Meier survival analysis was performed along with Joinpoint analysis to obtain the optimal number of LNs to retrieve based on survival. Prognostic significance of number of nodes retrieved was then confirmed with univariate and multivariate analyses.nnnRESULTSnAnalysis for both mean and median survival yielded 29 LNs removed as the Joinpoint. This was confirmed with multivariate analysis, where 15 retrieved LNs cutoff fell out of the model and 29 retrieved LNs remained intact, with a hazard ratio of 0.799 (95% CI 0.759 to 0.842; pxa0< 0.001). Stage-stratified Kaplan-Meier analysis for a cutoff point of 29 LNs also demonstrated a statistically significant improvement in survival.nnnCONCLUSIONSnJoinpoint analysis has allowed for the creation of a model demonstrating the point at which additional dissection would not provide additional benefit. This large international dataset analysis demonstrates that the maximal survival advantage is seen by performing a lymphadenectomy with a minimum of 29 LNs retrieved.

Imaging Tunneling Membrane Tubes Elucidates Cell Communication in Tumors

Intercellular communication is a vital yet underdeveloped aspect of cancer pathobiology. This Opinion article reviews the importance and challenges of microscopic imaging of tunneling nanotubes (TNTs) in the complex tumor microenvironment. The use of advanced microscopy to characterize TNTs in vitro and ex vivo, and related extensions called tumor microtubes (TMs) reported in gliomas in vivo, has propelled this field forward. This topic is important because the identification of TNTs and TMs fills the gap in our knowledge of how cancer cells communicate at long range in vivo, inducing intratumor heterogeneity and resistance to treatment. Here we discuss the concept that TNTs/TMs fill an important niche in the ever-changing microenvironment and the role of advanced microscopic imaging to elucidate that niche.