Pathological treatment response has different prognostic implications for pancreatic cancer patients treated with neoadjuvant chemotherapy or chemoradiotherapy.

BACKGROUND: Pathological treatment effect of resected pancreatic adenocarcinoma after neoadjuvant therapy has prognostic implications. The impact for patients who received chemotherapy alone or chemoradiotherapy is not well defined. METHODS: Patients with localized pancreatic adenocarcinoma who had pancreatectomy after neoadjuvant therapy at 3 centers from 2011 to 2017 were retrospectively analyzed. The chemotherapy and chemoradiotherapy groups were evaluated separately. RESULTS: Of 525 patients, 148 received neoadjuvant chemotherapy and 377 received chemoradiotherapy. The chemoradiotherapy group had a better treatment effect (score 0: 10%, score 1: 30%, score 2: 42%, and score 3: 18%) than the chemotherapy group (score 0: 2%, score 1: 8%, score 2: 35%, and score 3: 55%) (P < .001). Median overall survival was similar between the 2 groups (25.8 vs 26.4 months). Median overall survival for score 0/1, 2, or 3 was 72.2, 38.5, and 20.0 months in the chemotherapy group and 37.9, 24.5, and 19.0 months in the chemoradiotherapy group. Score 2 in the chemotherapy group was associated with better overall survival compared to score 3 (adjusted hazard ratio: 0.49, P = .005), whereas only combined score 0/1 reached significance over score 2 for the chemoradiotherapy group (hazard ratio: 0.63, P = .006). CONCLUSION: The prognostic significance of pathological treatment effect for localized pancreatic adenocarcinoma differs for patients receiving neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy.

NAD+ depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition.

Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.

Impact of resection margin status on survival in pancreatic cancer patients after neoadjuvant treatment and pancreatoduodenectomy.

BACKGROUND: Resection margin status has been recognized as an independent prognostic factor on overall survival in pancreatic cancer patients undergoing surgical resection. However, its impact after neoadjuvant treatment remains uncertain. METHODS: We analyzed 305 patients with resectable or borderline resectable pancreatic cancer treated with neoadjuvant therapy and pancreatoduodenectomy at 3 tertiary referral centers between 2010 and 2017. Positive resection margin was defined as 1 or more cancer cells at any margin. Overall survival was measured from the date of surgery until death or last follow-up. RESULTS: One hundred and seventy-eight patients received neoadjuvant chemotherapy and 127 received neoadjuvant chemoradiotherapy. The median overall survival was 29.8 months. The 1-, 3-, and 5-year overall survival rates were 79.2%, 44.0%, and 23.5%, respectively. Negative margin was achieved in 275 (90.2%) patients. Negative margin resection patients had a significantly longer overall survival than positive resection margin patients (31.3 vs 16.3 months, P < .001). In univariate analyses, overall survival was associated with age, margin status, histologic grade, ypT, number of positive lymph nodes, perineural invasion, treatment effect, postoperative carbohydrate antigen 19-9, and adjuvant therapy. Positive margin resection, poorly differentiated carcinoma, treatment effect score of 3, postoperative carbohydrate antigen 19-9 of 37 U/mL or higher, and lack of adjuvant therapy were predictive of poor overall survival in multivariate Cox regression analysis. CONCLUSION: Margin status was an independent predictor of overall survival in patients treated with neoadjuvant therapy and pancreatoduodenectomy, supporting the use of a negative margin resection as a surrogate of adequate oncological resection in this setting. Our findings may also have significant implications for patient stratification in future randomized trials.

Histone deacetylase inhibition is synthetically lethal with arginine deprivation in pancreatic cancers with low argininosuccinate synthetase 1 expression.

Arginine (Arg) deprivation is a promising therapeutic approach for tumors with low argininosuccinate synthetase 1 (ASS1) expression. However, its efficacy as a single agent therapy needs to be improved as resistance is frequently observed. Methods: A tissue microarray was performed to assess ASS1 expression in surgical specimens of pancreatic ductal adenocarcinoma (PDAC) and its correlation with disease prognosis. An RNA-Seq analysis examined the role of ASS1 in regulating the global gene transcriptome. A high throughput screen of FDA-approved oncology drugs identified synthetic lethality between histone deacetylase (HDAC) inhibitors and Arg deprivation in PDAC cells with low ASS1 expression. We examined HDAC inhibitor panobinostat (PAN) and Arg deprivation in a panel of human PDAC cell lines, in ASS1-high and -knockdown/knockout isogenic models, in both anchorage-dependent and -independent cultures, and in multicellular complex cultures that model the PDAC tumor microenvironment. We examined the effects of combined Arg deprivation and PAN on DNA damage and the protein levels of key DNA repair enzymes. We also evaluated the efficacy of PAN and ADI-PEG20 (an Arg-degrading agent currently in Phase 2 clinical trials) in xenograft models with ASS1-low and -high PDAC tumors. Results: Low ASS1 protein level is a negative prognostic indicator in PDAC. Arg deprivation in ASS1-deficient PDAC cells upregulated asparagine synthetase (ASNS) which redirected aspartate (Asp) from being used for de novo nucleotide biosynthesis, thus causing nucleotide insufficiency and impairing cell cycle S-phase progression. Comprehensively validated, HDAC inhibitors and Arg deprivation showed synthetic lethality in ASS1-low PDAC cells. Mechanistically, combined Arg deprivation and HDAC inhibition triggered degradation of a key DNA repair enzyme C-terminal-binding protein interacting protein (CtIP), resulting in DNA damage and apoptosis. In addition, S-phase-retained ASS1-low PDAC cells (due to Arg deprivation) were also sensitized to DNA damage, thus yielding effective cell death. Compared to single agents, the combination of PAN and ADI-PEG20 showed better efficacy in suppressing ASS1-low PDAC tumor growth in mouse xenograft models. Conclusion: The combination of PAN and ADI-PEG20 is a rational translational therapeutic strategy for treating ASS1-low PDAC tumors through synergistic induction of DNA damage.

Web-Based Video Assessments of Operative Performance for Remote Telementoring.

INTRODUCTION: Performance-based feedback is critical to surgical skills acquisition. Barriers of geography and time limit trainees' access to expert mentorship. In this study, we hypothesized that telementoring using an asynchronous, web-based video interface would allow trainees to receive systematic feedback from expert mentors despite these barriers. MATERIALS AND METHODS: Between October 2014 and October 2016, 18 surgeons in Brazil, Dominican Republic, Haiti, and Paraguay underwent in-person training in Lichtenstein for hernioplasty or laparoscopic total extraperitoneal inguinal hernia repair. After initial training, surgeons submitted 6- to 12-month interval operative videos for expert review. Expert surgeons reviewed each video using the Surgus web platform with performance metrics adapted from the Operative Performance Rating Scale (OPRS). The time required to perform video review, number of freeform comments, mean OPRS scores, and variance of OPRS scores among telementors was assessed. RESULTS: A total of 18 surgeons submitted 20 operative videos, and three expert surgeons reviewed each video using the Surgus platform. The median time to perform video review was 20 minutes. Median number of freeform verbal comments was eight. Mean OPRS overall performance scores were 3.9 ± 0.9 (scale of five). Mean variance in scoring among telementors for overall performance was 0.25 (maximum 5.29), suggesting a high degree of concordance. CONCLUSIONS: Video-based assessments had a high degree of concordance among expert raters. Asynchronous performance reviews by telementors offer opportunities for longitudinal feedback that overcome geographical, material, and temporal disparities. This platform offers a means of sharing expertise in surgical training, continuing education, credentialing, and global health.

Centralized, capacity-building training of Lichtenstein hernioplasty in Brazil.

BACKGROUND: In Brazil, access to healthcare varies widely by community. Options for repair of surgically correctable conditions, such as inguinal hernias, are limited. A training program was instituted to expand access to Lichtenstein hernioplasty. METHODS: Between September, 2014 and September, 2015, 3 orders of training series took place in São Paulo, Brazil. Participating surgeons received training and assessments from expert trainers using the Operative Performance Rating Scale (OPRS). Those who completed training successfully were invited to become trainers. OPRS scores were compared between training series. Outcomes were documented up to 6 months post-training. RESULTS: The 3 orders of training series resulted in 45 surgeons trained and 213 hernias repaired. Eleven trainees subsequently became trainers. Mean post-training OPRS scores were 4.4 (scale of 5) and did not vary significantly between training series. The overall complication rate was 4.7%, with no hernia recurrences or reoperations at 6 months. CONCLUSIONS: Competency-based training generates a regional network of surgeons proficient in Lichtenstein hernioplasty. Each training session progressively expands patient access to high quality operations in underserved communities in Brazil.

Laparoscopic Stapled Sublay Repair With Self-Gripping Mesh: A Simplified Technique for Minimally Invasive Extraperitoneal Ventral Hernia Repair.

INTRODUCTION: Minimally invasive laparoscopic and robotic techniques for ventral hernia repair have evolved to achieve the benefits and minimize the limitations of both the open Rives-Stoppa sublay mesh repair and laparoscopic intraperitoneal onlay mesh (IPOM) repair. By combining the principles of a retromuscular repair with the benefits of a minimally invasive approach, these techniques attempt to decrease recurrence, increase functionality, exclude mesh from the viscera, limit infection and wound complications, and minimize pain. The difficult ergonomics, challenging dissection, and extensive suturing make traditional laparoscopic sublay repair technically challenging and has led to increased robotic utilization to overcome these limitations. We describe a laparoscopic extraperitoneal sublay mesh repair technique using an endoscopic stapler to facilitate reapproximation of the linea alba and creation of the retromuscular space, and self-gripping mesh to position and fixate the prosthetic. MATERIALS AND METHODS: Between January and June 2016, 10 patients with midline ventral and incisional hernias underwent laparoscopic extraperitoneal stapled sublay mesh repair with self-gripping mesh. Three of these cases included a laparoscopic posterior component separation with myofascial release of the transversus abdominis muscle to facilitate midline closure. Intraoperative and perioperative complications, early recurrence, pain, and narcotic usage were measured. RESULTS: There were no significant intraoperative complications or conversions to open surgery. Patients were discharged at 1.2 days on average. Early postoperative complications included a hernia site seroma in one patient, which resolved without intervention. There were no early postoperative infections or recurrences. Compared with traditional laparoscopic IPOM repair, there was less acute postoperative pain and use of analgesics. CONCLUSIONS: Laparoscopic extraperitoneal stapled sublay mesh repair is a safe and effective method for the treatment of medium- to large-sized ventral and incisional hernias. This extraperitoneal stapled approach using self-gripping mesh facilitates a minimally invasive sublay repair and abdominal wall reconstruction using traditional laparoscopic tools.

Efficacy of retroperitoneal triple neurectomy for refractory neuropathic inguinodynia.

BACKGROUND: Refractory neuropathic inguinodynia following inguinal herniorrhaphy is a common and debilitating complication. This prospective study evaluated long-term outcomes associated with laparoscopic retroperitoneal triple neurectomy. METHODS: Sixty-two consecutive patients (51 male; mean age, 47); all failing pain management; prior reoperation in 35, prior neurectomy in 26; average follow-up 681 days (range: 90 days to 3 years). Measured outcomes include numeric pain ratings, dermatomal mapping, histologic confirmation, quantitative sensory testing, complications, narcotic usage, and activity level. RESULTS: Mean numerical pain scores were significantly decreased (baseline, 8.6) at all postoperative time points (POD 1, 3.6; P < .001: POD 90, 2.3, P < .001) with durable efficacy from POD 90 to 3 years (P < .001). Quantitative sensory testing showed marked group-level increases of sensory thresholds. Narcotic dependence decreased in 57/62 and was eliminated in 44/62 and activity level improved in 58/62. CONCLUSIONS: Retroperitoneal triple neurectomy is an effective and durable treatment for refractory neuropathic inguinodynia.

Articulating and Reloadable Fixation Devices for Hernia Repair.

There have been a variety of absorbable and permanent tacks, tack deployment systems, and fasteners developed for the fixation of mesh during laparoscopic ventral hernia repair. The manufacturer recommendation for all systems is for perpendicular deployment of these tacks into the tissue. Achieving this optimal angle with previously developed deployment systems is often challenging and can lead to tack failure, mesh migration, and recurrence, or may require the placement of additional ports. Additionally, current tack deployment systems lack the ability to reload, leading to increased cost when entire systems must be opened each time a reload is necessary. This article presents products designed to addresses both of these problems. These deployment instruments incorporate an articulating shaft or a hinge mechanism allowing for improved access to different parts of the abdominal cavity and delivering perpendicular placement of tacks with fewer port sites. Devices with the option of reloadable fixation decrease costs and reduce waste.