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Overview This manuscript summarizes an excellent debate from the 2021 SSAT/Pancreas Club symposium on arterial resection in pancreas cancer. Two world-recognized experts, Professor Ugo Boggi from Pisa, IT, and Dr. Mark Truty from the Mayo Clinic in Rochester, MN, offered their views on the role of arterial resection in locally advanced pancreas ductal adenocarcinoma. Both speakers have extensive experience pushing the technical envelope with extended vascular resection in pancreatectomy. However, both highlight important concepts of resectability extending well beyond technique: namely, patient global physiology, tumor biology, and response to chemotherapy. The debate was spirited, and this subsequent review is an excellent look at the status quo. N. J. Zyromski, MD, Indianpolis, IN, November, 2021.

BackgroundThe recent development of 3D vision in laparoscopic and robotic surgical systems raises the question of whether these two procedures are equivalent. The aim of this study was to evaluate the surgical and long-term oncological outcomes of 3D laparoscopic (3D-LLR) and robotic liver resection (RLR) for hepatocellular carcinoma (HCC).MethodsThe data for operative time, morbidity, margins, and survival were reviewed for 3D-LLR and compared with RLR.ResultsFrom 2011 to 2017, 93 patients with HCC, including 58 (62%) with cirrhosis, underwent 3D-LLR [49 (53%)] or RLR [44 (47%)]. No difference was observed in operative time (269 vs. 252 min; p = 0.52), overall (27% vs. RLR: 16%; p = 0.49) and severe morbidity (4% vs. 2%; p = 0.77) or in the surgical margin width (9 vs. 11 mm; p = 0.30) between the 3D-LLR and RLR groups. The 3-year overall and recurrence-free survival rates after 3D-LLR and RLR were 82% and 24% and 91% (p = 0.16) and 48% (p = 0.18), respectively.ConclusionsThe 3D-LLR and RLR systems provide comparable surgical margins with similar short- and long-term oncological outcomes.

Objectives A laparoscopic approach improves short-term outcomes and maintains long-term outcomes compared to an open approach. In turn, the recent development of robotic surgery raises the question whether it performs as well as laparoscopic surgery. The aim of this study was to compare the short- and long-term outcomes of laparoscopic liver resection (LLR) and robotic liver resection (RLR) for malignancies. Method From 2011 to 2017, the study population included 111 patients in the LLR group and 61 in the RLR group. Short- and long-term outcomes were compared before and after propensity score matching (PSM). Results Operative mortality rate was nil. The intraoperative blood transfusion rate was higher during RLR (15% vs. 2%, p  = 0.0009). Major morbidity and hospital stay were not different between the two groups. The resection margin width (LLR 7 mm vs. RLR 10 mm, p  = 0.13) and R1 resection rates (resection margin width < 1 mm; LLR 15% vs. RLR 11%, p  = 0.49) were similar. After PSM (55 patients in each group), the blood transfusion, major morbidity, hospital stay and R1 resection were similar between the two groups. When considering the largest subset of patients with hepatocellular carcinoma including 114 patients (66%), the 3-year overall survival rate was 80% in the LLR group and 97% in the RLR group ( p  = 0.10) and remained similar after PSM ( p  = 0.27). The 3-year recurrence-free survival rate was 50% in the LLR group and 64% in the RLR group ( p  = 0.30) and remained similar after PSM ( p  = 0.26). Conclusions No differences were found in blood transfusion, incidence of positive resection margins and long-term outcomes between the two techniques. RLR does not compromise short-term and oncologic outcomes in patients with liver cancers.

The transmission of cancer from a donor organ is a rare event but has important consequences. Aim of this systematic review was to summarize all the published evidence on cancer transmission in kidney recipients. We reviewed published case reports and series describing the outcome of recipients with donor-transmitted cancer until August 2019. A total of 128 papers were included, representing 234 recipients. The most common transmitted cancers were lymphoma (n = 48, 20.5%), renal cancer (42, 17.9%), melanoma (40, 17.1%), non-small cell lung cancer (n = 13, 5.6%), neuroendocrine cancers comprising small cell lung cancer (n = 11, 4.7%) and choriocarcinoma (n = 10, 4.3%). There was a relative lack of glioblastoma and gastrointestinal cancers with only 6 and 5 cases, respectively. Melanoma and lung cancer had the worst prognosis, with 5-years overall survival of 43% and 19%, respectively; while renal cell cancer and lymphomas had a favorable prognosis with 5-years overall survival of 93 and 63%, respectively. Metastasis of cancer outside the graft was the most important adverse prognostic factor. Overall reporting was good, but information on donors’ cause of death and investigations at procurement was often lacking. Epidemiology of transmitted cancer has evolved, thanks to screening with imaging and blood tests, as choriocarcinoma transmission have almost abolished, while melanoma and lymphoma are still difficult to detect and prevent.

IntroductionThere are limited numbers of high-volume centers performing minimally invasive pancreatoduodenectomy (MIPD) routinely. Several approaches to MIPD have been described. Aim of this analysis was to show the learning curve of three different approaches to MIPD. Focus was on determining the number of cases necessary to obtain proficient level in MIPD.Patients and methodsRetrospective study wherein outcomes of 300 consecutive patients at three centers—at each center the initial 100 consecutive patients undergoing MIPD for malignant and benign tumors of the head of the pancreas and perimpullary area, performed by three experienced surgeons were collected and analyzed. ResultsOverall, 300 patients after MIPD were included: the three different cohorts (laparoscopic n = 100, hybrid n = 100, robotic n = 100). CUSUM analysis of operating time in each center demonstrated that the plateau for laparoscopic PD was n = 61, for hybrid PDes was n = 32 and for robotic PD was n = 68. Median operative time for laparoscopic, hybrid, and robotic approaches was 395 min, 404 min, 510 min, respectively. Intraoperative blood loss for laparoscopic PD, hybrid PD, and robotic PD was 250 ml, 250 ml, and 413 ml, respectively. Delayed gastric emptying occurred 12% in laparoscopic cohort, 10% in hybrid, and 53% in robotic cohort. Major complications (Clavien-Dindo III/IV) rate for laparoscopic PD, hybrid PD, and robotic PD was 32%, 37%, and 22% with 5% death in each cohorts, respectively.ConclusionThis analysis of the learning curve of three European centers found a shorter learning curve with hybrid PD as compared to laparoscopic and robotic PD. In implementation of a MIPD program, a stepwise approach might be beneficial.

BackgroundNo study has shown the oncologic non-inferiority of robotic pancreatoduodenectomy (RPD) versus open pancreatoduodenectomy (OPD) for pancreatic cancer (PC).MethodsThis is a single institution propensity score matched study comparing RPD and ODP for resectable PC, based on factors predictive of R1 resection (≤ 1 mm). Only patients operated on after completion of the learning curve in both procedures and for whom circumferential margins were assessed according to the Leeds pathology protocol were included. The primary study endpoint was the rate of R1 resection. Secondary study endpoints were as follows: number of examined lymph nodes (N), rate of perioperative transfusions, percentage of patients receiving adjuvant therapies, occurrence of local recurrence, overall survival, disease-free survival, and sample size calculation for randomized controlled trials (RCT).ResultsFactors associated with R1 resection were tumor diameter, number of positive N, N ratio, logarithm odds of positive N, and duodenal infiltration. The matching process identified 20 RPDs and 24 OPDs. All RPDs were completed robotically. R1 resection was identified in 11 RPDs (55.0%) and in 10 OPDs (41.7%) (p = 0.38). There was no difference in the rate of R1 at each margin as well as in the proportion of patients with multiple R1 margins. RPD and OPD were also equivalent with respect to all secondary study endpoints, with a trend towards lower rate of blood transfusions in RPD. Based on the figures presented herein, a non-inferiority RCT comparing RPD and OPD having the rate of R1 resection as the primary study endpoint requires 3355 pairs.ConclusionsRPD and OPD achieved the same rate of R1 resections in resectable PC. RPD was also non-inferior to OPD with respect to all secondary study endpoints. Because of the high number of patients required to run a RCT, further assessment of RPD for PC would require the implementation of an international registry.

Background Laparoscopic major hepatectomy (LMH), although safely feasible in experienced hands and in selected patients, is a formidable challenge because of the technical demands of controlling hemorrhage, sealing bile ducts, avoiding gas embolism, and maintaining oncologic surgical principles. The enhanced surgical dexterity offered by robotic assistance could improve feasibility and/or safety of minimally invasive major hepatectomy. The aim of this study was to compare perioperative outcomes of LMH and robotic-assisted major hepatectomy (RMH). Methods Pooled data from four Italian hepatobiliary centers were analyzed retrospectively. Demographic data, operative, and postoperative outcomes were collected from prospectively maintained databases and compared. Results Between January 2009 and December 2012, 25 patients underwent LMH and 25 RMH. The two groups were comparable for all baseline characteristics including type of resection and underlying pathology. Conversion to open surgery was required in one patient in each group (4 %). No difference was noted in operative time, estimated blood, and need for allogenic blood transfusions. Intermittent pedicle occlusion was required only in LMH (32 % vs. 0; p  = 0.004). Length of hospital stay, including time spent in intensive care unit, was similar between the two groups, but patients undergoing LMH showed quicker recovery of bowel activity, with shorter time to first flatus (1 vs. 3 days; p  = 0.023) and earlier tolerance to oral liquid diet (1 vs. 2 days; p  = 0.001). No difference was noted in complication rate, 90-day mortality, and readmission rate. Conclusions This retrospective multi-institution study confirms that selected patients can safely undergo minimally invasive major hepatectomy, either LMH or RMH. The fact that intermittent pedicle occlusion could be avoided in RMH suggests improved surgical ability to deal with bleeding during liver transection, but further studies are needed before any final conclusion can be drawn.

BackgroundSeveral studies have suggested a survival benefit of neoadjuvant therapy (NAT) for pancreatic ductal adenocarcinoma (PDAC) in the pancreatic head. Data concerning NAT for PDAC located in pancreatic body or tail are lacking.MethodsPost hoc analysis of an international multicenter retrospective cohort of distal pancreatectomy for PDAC in 34 centers from 11 countries (2007–2015). Patients who underwent resection after NAT were matched (1:1 ratio), using propensity scores based on baseline characteristics, to patients who underwent upfront resection. Median overall survival was compared using the stratified log-rank test.ResultsAmong 1236 patients, 136 (11.0%) received NAT, most frequently FOLFIRINOX (25.7%). In total, 94 patients receiving NAT were matched to 94 patients undergoing upfront resection. NAT was associated with less postoperative major morbidity (Clavien–Dindo ≥ 3a, 10.6% vs. 23.4%, P = 0.020) and pancreatic fistula grade B/C (9.6% vs. 21.3%, P = 0.026). NAT did not improve overall survival [27 (95% CI 14–39) versus 31 months (95% CI 19–42), P = 0.277], as compared with upfront resection. In a sensitivity analysis of 251 patients with radiographic tumor involvement of splenic vessels, NAT (n = 37, 14.7%) was associated with prolonged overall survival [36 (95% CI 18–53) versus 20 months (95% CI 15–24), P = 0.049], as compared with upfront resection.ConclusionIn this international multicenter cohort study, NAT for resected PDAC in pancreatic body or tail was associated with less morbidity and pancreatic fistula but similar overall survival in comparison with upfront resection. Prospective studies should confirm a survival benefit of NAT in patients with PDAC and splenic vessel involvement.

Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic β cells. Several studies have suggested an association between Coxsackie enterovirus seroconversion and onset of disease. However, a direct link between β cell viral infection and islet inflammation has not been established. We analyzed pancreatic tissue from six type 1 diabetic and 26 control organ donors. Immunohistochemical, electron microscopy, whole-genome ex vivo nucleotide sequencing, cell culture, and immunological studies demonstrated Coxsackie B4 enterovirus in specimens from three of the six diabetic patients. Infection was specific of β cells, which showed nondestructive islet inflammation mediated mainly by natural killer cells. Islets from enterovirus-positive samples displayed reduced insulin secretion in response to glucose and other secretagogues. In addition, virus extracted from positive islets was able to infect β cells from human islets of nondiabetic donors, causing viral inclusions and signs of pyknosis. None of the control organ donors showed signs of viral infection. These studies provide direct evidence that enterovirus can infect β cells in patients with type 1 diabetes and that infection is associated with inflammation and functional impairment.

Background There is increasing evidence of a constitutive activation of Akt in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and chemoresistance. Therefore, we evaluated the expression of phospho-Akt in PDAC tissues and cells, and investigated molecular mechanisms influencing the therapeutic potential of Akt inhibition in combination with gemcitabine. Methods Phospho-Akt expression was evaluated by immunohistochemistry in tissue microarrays (TMAs) with specimens tissue from radically-resected patients ( n  = 100). Data were analyzed by Fisher and log-rank test. In vitro studies were performed in 14 PDAC cells, including seven primary cultures, characterized for their Akt1 mRNA and phospho-Akt/Akt levels by quantitative-RT-PCR and immunocytochemistry. Growth inhibitory effects of Akt inhibitors and gemcitabine were evaluated by SRB assay, whereas modulation of Akt and phospho-Akt was investigated by Western blotting and ELISA. Cell cycle perturbation, apoptosis-induction, and anti-migratory behaviors were studied by flow cytometry, AnnexinV, membrane potential, and migration assay, while pharmacological interaction with gemcitabine was determined with combination index (CI) method. Results Immunohistochemistry of TMAs revealed a correlation between phospho-Akt expression and worse outcome, particularly in patients with the highest phospho-Akt levels, who had significantly shorter overall and progression-free-survival. Similar expression levels were detected in LPC028 primary cells, while LPC006 were characterized by low phospho-Akt. Remarkably, Akt inhibitors reduced cancer cell growth in monolayers and spheroids and synergistically enhanced the antiproliferative activity of gemcitabine in LPC028, while this combination was antagonistic in LPC006 cells. The synergistic effect was paralleled by a reduced expression of ribonucleotide reductase, potentially facilitating gemcitabine cytotoxicity. Inhibition of Akt decreased cell migration and invasion, which was additionally reduced by the combination with gemcitabine. This combination significantly increased apoptosis, associated with induction of caspase-3/6/8/9, PARP and BAD, and inhibition of Bcl-2 and NF-kB in LPC028, but not in LPC006 cells. However, targeting the key glucose transporter Glut1 resulted in similar apoptosis induction in LPC006 cells. Conclusions These data support the analysis of phospho-Akt expression as both a prognostic and a predictive biomarker, for the rational development of new combination therapies targeting the Akt pathway in PDAC. Finally, inhibition of Glut1 might overcome resistance to these therapies and warrants further studies.