Clinical Outcomes After Total Pancreatectomy: A Prospective Multicenter Pan-European Snapshot Study.

OBJECTIVE: To assess outcomes among patients undergoing total pancreatectomy (TP) including predictors for complications and in-hospital mortality. BACKGROUND: Current studies on TP mostly originate from high-volume centers and span long time periods and therefore may not reflect daily practice. METHODS: This prospective pan-European snapshot study included patients who underwent elective (primary or completion) TP in 43 centers in 16 European countries (June 2018-June 2019). Subgroup analysis included cutoff values for annual volume of pancreatoduodenectomies (<60 vs ≥60).Predictors for major complications and in-hospital mortality were assessed in multivariable logistic regression. RESULTS: In total, 277 patients underwent TP, mostly for malignant disease (73%). Major postoperative complications occurred in 70 patients (25%). Median hospital stay was 12 days (IQR 9-18) and 40 patients were readmitted (15%). In-hospital mortality was 5% and 90-day mortality 8%. In the subgroup analysis, in-hospital mortality was lower in patients operated in centers with ≥60 pancreatoduodenectomies compared <60 (4% vs 10%, P = 0.046). In multivariable analysis, annual volume <60 pancreatoduodenectomies (OR 3.78, 95% CI 1.18-12.16, P = 0.026), age (OR 1.07, 95% CI 1.01-1.14, P = 0.046), and estimated blood loss ≥2L (OR 11.89, 95% CI 2.64-53.61, P = 0.001) were associated with in-hospital mortality. ASA ≥3 (OR 2.87, 95% CI 1.56-5.26, P = 0.001) and estimated blood loss ≥2L (OR 3.52, 95% CI 1.25-9.90, P = 0.017) were associated with major complications. CONCLUSION: This pan-European prospective snapshot study found a 5% inhospital mortality after TP. The identified predictors for mortality, including low-volume centers, age, and increased blood loss, may be used to improve outcomes.

Hepatic artery flow, inspired oxygen, and hemoglobin determine liver tissue saturation measured with visible diffuse reflectance spectroscopy (vis-DRS) in an in vivo swine model.

BACKGROUND: Prompt diagnosis of vascular compromise following pediatric liver transplantation and restoration of oxygen delivery to the liver improves organ survival. vis-DRS allows for real-time measurement of liver tissue saturation. METHODS: The current study used vis-DRS to determine changes in liver saturation during clinically relevant conditions of reduced oxygen delivery. In an in vivo swine model (n = 15), we determined liver tissue saturation (St O2 ) during stepwise reduction in hepatic artery flow, different inspiratory oxygen fraction (FiO2 ), and increasing hemodilution. A custom vis-DRS probe was placed directly on the organ. RESULTS: Liver tissue saturation decreased significantly with a decrease in hepatic artery flow. A reduction in hepatic artery flow to 25% of baseline reduced the St O2 by 15.3 ± 1.4% at FiO2 0.3 (mean ± SE, p < .0013), and by 8.3 ± 1.9% at FiO2 1.0 (p = .0013). After hemodilution to 7-8 g/dl, St O2 was reduced by 31.8% ± 2.7%, p < .001 (FiO2 0.3) and 26.6 ± 2.7%, p < .001 (FiO2 : 1.0) respectively. Portal venous saturation during low hepatic artery flow was consistently higher at FiO2 1.0. The gradient between portal venous saturation and liver tissue saturation was consistently greater at lower hemoglobin levels (7.0 ± 1.6% per g/dl hemoglobin, p < .001). CONCLUSIONS: Vis-DRS showed prompt changes in liver tissue saturation with decreases in hepatic artery blood flow. At hepatic artery flows below 50% of baseline, liver saturation depended on FiO2 and hemoglobin concentration suggesting that during hepatic artery occlusion, packed red blood cell transfusion and increased FiO2 may be useful measures to reduce hypoxic damage until surgical revascularization.

Short-term outcomes after pancreatoduodenectomy in octogenarians: multicentre case-control study.

BACKGROUND: Pancreatoduodenectomy (PD) is frequently the surgical treatment indicated for a number of pathologies. Elderly patients may be denied surgery because of concerns over poor perioperative outcomes. The aim of this study was to evaluate postoperative clinical outcomes and provide evidence on current UK practice in the elderly population after PD. METHODS: This was a multicentre retrospective case-control study of octogenarians undergoing PD between January 2008 and December 2017, matched with younger controls from seven specialist centres in the UK. The primary endpoint was 90-day mortality. Secondary endpoints were index admission mortality, postoperative complications, and 30-day readmission rates. RESULTS: In total, 235 octogenarians (median age 81 (range 80-90) years) and 235 controls (age 67 (31-79) years) were included in the study. Eastern Cooperative Oncology Group performance status (median 0 (range 0-3) versus 0 (0-2); P = 0.010) and Charlson Co-morbidity Index score (7 (6-11) versus 5 (2-9); P = 0.001) were higher for octogenarians than controls. Postoperative complication and 30-day readmission rates were comparable. The 90-day mortality rate was higher among octogenarians (9 versus 3 per cent; P = 0.030). Index admission mortality rates were comparable (4 versus 2 per cent; P = 0.160), indicating that the difference in mortality was related to deaths after hospital discharge. Despite the higher 90-day mortality rate in the octogenarian population, multivariable Cox regression analysis did not identify age as an independent predictor of postoperative mortality. CONCLUSION: Despite careful patient selection and comparable index admission mortality, 90-day and, particularly, out-of-hospital mortality rates were higher in octogenarians.

Hepatopancreatoduodenectomy -a controversial treatment for bile duct and gallbladder cancer from a European perspective.

BACKGROUND: Hepatopancreatoduodenectomy (HPD) is an aggressive operation for treatment of advanced bile duct and gallbladder cancer associated with high perioperative morbidity and mortality, and uncertain oncological benefit in terms of survival. Few reports on HPD from Western centers exist. The purpose of this study was to evaluate safety and efficacy for HPD in European centers. METHOD: Members of the European-African HepatoPancreatoBiliary Association were invited to report all consecutive patients operated with HPD for bile duct or gallbladder cancer between January 2003 and January 2018. The patient and tumor characteristics, perioperative and survival outcomes were analyzed. RESULTS: In total, 66 patients from 19 European centers were included in the analysis. 90-day mortality rate was 17% and 13% for bile duct and gallbladder cancer respectively. All factors predictive of perioperative mortality were patient and disease-specific. The three-year overall survival excluding 90-day mortality was 80% for bile duct and 30% for gallbladder cancer (P = 0.013). In multivariable analysis R0-resection had a significant impact on overall survival. CONCLUSION: HPD, although being associated with substantial perioperative mortality, can offer a survival benefit in patient subgroups with bile duct cancer and gallbladder cancer. To achieve negative resection margins is paramount for an improved survival outcome.

Assessing the quality of primary care referrals to surgery of patients with diabetes in the East of England: A multi-centre cross-sectional cohort study.

AIM: Peri-operative hyperglycaemia is associated with an increased incidence of adverse outcomes. Communication between primary and secondary care is paramount to minimise these harms. National guidance in the UK recommends that the glycated haemoglobin (HbA1c) should be measured within 3 months prior to surgery and that the concentration should be less that 69 mmol/mol (8.5%). In addition, national guidance outlines the minimum dataset that should be included in any letter at the time of referral to the surgeons. Currently, it is unclear how well this process is being carried out. This study investigated the quality of information being handed over during the referral from primary care to surgical outpatients within the East of England. METHODS: Primary care referrals to nine different NHS hospital Trusts were gathered over a 1-week period. All age groups were included from 11 different surgical specialties. Referral letters were analysed using a standardised data collection tool based on the national guidelines. RESULTS: A total of 1919 referrals were received, of whom 169 (8.8%) had previously diagnosed diabetes mellitus (DM). However, of these, 38 made no mention of DM in the referral letter but were on glucose-lowering agents. Only 13 (7.7%) referrals for patients with DM contained a recent HbA1c, and 20 (11.8%) contained no documentation of glucose-lowering medication. CONCLUSION: This study has shown that the quality of referral letters to surgical specialties for patients with DM in the East of England remain inadequate. There is a clear need for improving the quality of clinical data contained within referral letters from primary care. In addition, we have shown that the rate of referral for surgery for people with diabetes is almost 50% higher than the background population with diabetes.

Management of distal cholangiocarcinoma with arterial involvement: Systematic review and case series on the role of neoadjuvant therapy.

BACKGROUND: The use of neoadjuvant therapy (NAT) in distal cholangiocarcinoma (dCCA) with regional arterial or extensive venous involvement, is not widely accepted and evidence is sparse. AIM: To synthesise evidence on NAT for dCCA and present the experience of a high-volume tertiary-centre managing dCCA with arterial involvement. METHODS: A systematic review was performed according to PRISMA guidance to identify all studies reporting outcomes of patients with dCCA who received NAT. All patients from 2017 to 2022 who were referred for NAT for dCCA at our centre were retrospectively collected from a prospectively maintained database. Baseline characteristics, NAT type, progression to surgery and oncological outcomes were collected. RESULTS: Twelve studies were included. The definition of "unresectable" locally advanced dCCA was heterogenous. Four studies reported outcomes for 9 patients who received NAT for dCCA with extensive vascular involvement. R0 resection rate ranged between 0 and 100% but without survival benefit in most cases. Remaining studies considered either NAT in resectable dCCA or inclusive with extrahepatic CCA. The presented case series includes 9 patients (median age 67, IQR 56-74 years, male:female 5:4) referred for NAT for borderline resectable or locally advanced disease. Three patients progressed to surgery and 2 were resected. One patient died at 14 months with evidence of recurrence at 6 months and the other died at 51 months following recurrence 6 months post-operatively. CONCLUSION: Evidence for benefit of NAT is limited. Consensus on criteria for uniform definition of resectability for dCCA is required. We propose using the established National-Comprehensive-Cancer-Network® criteria for pancreatic ductal adenocarcinoma.

Resection of isolated liver oligometastatic disease in pancreatic ductal adenocarcinoma: Is there a survival benefit? A systematic review.

BACKGROUND: Presence of liver metastatic disease in pancreatic ductal adenocarcinoma (PDAC), either synchronous or metachronous after pancreatic resection, is a terminal diagnosis that warrants management with palliative intent as per all international practice guidelines. However, there is an increasing interest on any potential value of surgical treatment of isolated oligometastatic disease in selected cases. AIM: To present the published evidence on surgical management of PDAC liver metastases, synchronous and metachronous, and compare the outcomes of these treatments to the current standard of care. METHODS: A systematic review was performed in line with the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines to compare the outcomes of both synchronous and metachronous liver metastases resection to standard care. RESULTS: 356 studies were identified, 31 studies underwent full-text review and of these 10 were suitable for inclusion. When synchronous resection of liver metastases was compared to standard care, most studies did not demonstrate a survival benefit with the exception of one study that utilised neoadjuvant treatment. However, resection of metachronous disease appeared to confer a survival advantage when compared to treatment with chemotherapy alone. CONCLUSION: A survival benefit may exist in resection of selected cases of metachronous liver oligometastatic PDAC disease, after disease biology has been tested with time and systemic treatment. Any survival benefit is less clear in synchronous cases; however an approach with neoadjuvant treatment and consideration of resection in some selected cases may confer some benefit. Future studies should focus on pathways for selection of cases that may benefit from an aggressive approach.

Oncological outcomes after pancreatoduodenectomy for pancreatic ductal adenocarcinoma in octogenarians: case-control study.

BACKGROUND: By the end of this decade, 70 per cent of all diagnosed pancreatic ductal adenocarcinomas will be in the elderly. Surgical resection is the only curative option. In the elderly perioperative mortality is higher, while controversy still exists as to whether aggressive treatment offers any survival benefit. This study aimed to assess the oncological benefit of pancreatoduodenectomy in octogenarians with pancreatic ductal adenocarcinoma. METHOD: Retrospective multicentre case-control study of octogenarians and younger controls who underwent pancreatoduodenectomy for pancreatic ductal adenocarcinoma between 2008 and 2017. The primary endpoint was overall survival and the secondary endpoint was disease-free survival. RESULTS: Overall, 220 patients were included. Although the Charlson co-morbidity index was higher in octogenerians, Eastern Cooperative Oncology Group performance status, ASA and pathological parameters were comparable. Adjuvant therapy was more frequently delivered in the younger group (n = 80, 73 per cent versus n = 58, 53 per cent, P = 0.006). There was no significant difference between octogenarians and controls in overall survival (20 versus 29 months, P = 0.095) or disease-free survival (19 versus 22 months, P = 0.742). On multivariable analysis, age was not an independent predictor of either oncological outcome measured. CONCLUSION: Octogenarians with pancreatic ductal adenocarcinoma of the head and uncinate process may benefit from comparable oncological outcomes to younger patients with surgical treatment. Due to the age- and disease-related frailty and co-morbidities, careful preoperative assessment and patient selection is of paramount importance.

Risk analysis for deterioration of renal function after pancreas alone transplant.

The risk of progression to renal replacement after pancreas transplant alone (PTA) is a concern in patients with pre-transplant estimated glomerular filtration rate (eGFR) < 70 mL/min/1.73 m(2). This is a retrospective, single-center risk analysis of potential factors affecting renal function after PTA. Twenty-four patients, transplanted over a three-yr period, with functioning pancreatic grafts at the study's end point were included. High tacrolimus levels (> 12 mg/dL) at six months post-transplant was the only independent risk factor identifying a substantial decline in native renal function by Cox regression analysis (HR = 14.300, CI = 1.271-160.907, p = 0.031). The presence of severe pre-transplant proteinuria (urine Pr/Cr ≥ 100 mg/mmol) marginally failed to reach significance (p = 0.056). Low eGFR levels alone (≤ 45 and ≤ 40 mL/min/1.73 m(2)) at the time of transplant did not correlate with substantial decline in renal function. Our data suggest that PTA is a justifiable therapy for patients with hypoglycemia unawareness or other life-threatening diabetic complications, even in those with borderline renal function, provided that they do not suffer from severe proteinuria and appropriate monitoring and tailoring of immunosuppression is ensured.

Incidental gallbladder cancer diagnosis confers survival advantage irrespective of tumour stage and characteristics.

BACKGROUND: Incidental gallbladder cancer (IGBC) represents 50%-60% of gallbladder cancer cases. Data are conflicting on the role of IGBC diagnosis in oncological outcomes. Some studies suggest that IGBC diagnosis does not affect outcomes, while others that overall survival (OS) is longer in these cases compared to non-incidental diagnosis (NIGBC). Furthermore, some studies reported early tumour stages and histopathologic characteristics as possible confounders, while others not. AIM: To investigate the role of IGBC diagnosis on patients' overall survival, especially after surgical treatment with curative intent. METHODS: Retrospective analysis of all patient referrals with gallbladder cancer between 2008 and 2020 in a tertiary hepatobiliary centre. Statistical comparison of patient and tumour characteristics between IGBC and NIGBC subgroups was performed. Survival analysis for the whole cohort, surgical and non-surgical subgroups was done with the Kaplan-Meier method and the use of log rank test. Risk analysis was performed with univariable and multivariable Cox regression analysis. RESULTS: The cohort included 261 patients with gallbladder cancer. 65% of cases had NIGBC and 35% had IGBC. A total of 90 patients received surgical treatment (66% of IGBC cases and 19% of NIGBC cases). NIGBC patients had more advanced T stage and required more extensive resections than IGBC ones. OS was longer in patients with IGBC in the whole cohort (29 vs 4 mo, P < 0.001), as well as in the non-surgical (14 vs 2 mo, P < 0.001) and surgical subgroups (29 vs 16.5 mo, P = 0.001). Disease free survival (DFS) after surgery was longer in patients with IGBC (21.5 mo vs 8.5 mo, P = 0.007). N stage and resection margin status were identified as independent predictors of OS and DFS. NIGBC diagnosis was identified as an independent predictor of OS. CONCLUSION: IGBC diagnosis may confer a survival advantage independently of the pathological stage and tumour characteristics. Prospective studies are required to further investigate this, including detailed pathological analysis and molecular gene expression.

Para-aortic lymph node involvement should not be a contraindication to resection of pancreatic ductal adenocarcinoma.

BACKGROUND: Para-aortic lymph nodes (PALN) are found in the aortocaval groove and they are staged as metastatic disease if involved by pancreatic ductal adenocarcinoma (PDAC). The data in the literature is conflicting with some studies having associated PALN involvement with poor prognosis, while others not sharing the same results. PALN resection is not included in the standard lymphadenectomy during pancreatic resections as per the International Study Group for Pancreatic Surgery and there is no consensus on the management of these cases. AIM: To investigate the prognostic significance of PALN metastases on the oncological outcomes after resection for PDAC. METHODS: This is a retrospective cohort study of data retrieved from a prospectively maintained database on consecutive patients undergoing pancreatectomies for PDAC where PALN was sampled between 2011 and 2020. Statistical comparison of the data between PALN+ and PALN- subgroups, survival analysis with the Kaplan-Meier method and risk analysis with univariable and multivariable time to event Cox regression analysis were performed, specifically assessing oncological outcomes such as median overall survival (OS) and disease-free survival (DFS). RESULTS: 81 cases had PALN sampling and 17 (21%) were positive. Pathological N stage was significantly different between PALN+ and PALN- patients (P = 0.005), while no difference was observed in any of the other characteristics. Preoperative imaging diagnosed PALN positivity in one case. OS and DFS were comparable between PALN+ and PALN- patients with lymph node positive disease (OS: 13.2 mo vs 18.8 mo, P = 0.161; DFS: 13 mo vs 16.4 mo, P = 0.179). No difference in OS or DFS was identified between PALN positive and negative patients when they received chemotherapy either in the neoadjuvant or in the adjuvant setting (OS: 23.4 mo vs 20.6 mo, P = 0.192; DFS: 23.9 mo vs 20.5 mo, P = 0.718). On the contrary, when patients did not receive chemotherapy, PALN disease had substantially shorter OS (5.5 mo vs 14.2 mo; P = 0.015) and DFS (4.4 mo vs 9.8 mo; P < 0.001). PALN involvement was not identified as an independent predictor for OS after multivariable analysis, while it was for DFS doubling the risk of recurrence. CONCLUSION: PALN involvement does not affect OS when patients complete the indicated treatment pathway for PDAC, surgery and chemotherapy, and should not be considered as a contraindication to resection.

Renal function in type 1 diabetics one year after successful pancreas transplantation.

The effect of pancreas transplantation on renal function remains a matter of debate. The purpose of this retrospective, single-unit study is a preliminary analysis of renal function one yr after pancreas transplant (pancreas alone [PTA] or pancreas after kidney [PAK]). Fifty-nine patients were included. Serum creatinine and estimated glomerular filtration rate (eGFR) levels were compared three, six, and 12 months post-transplantation for the whole sample and separately for PTA and PAK and high (>45 mL/min/1.73 m(2)) and low (≤45 mL/min/1.73 m(2)) pre-transplant eGFR subgroups. Overall, eGFR did not change significantly (p = 0.228) at the end of the first year post-transplant, with patients of low initial eGFR presenting a more prominent trend toward stable or improved levels. In the PAK subgroup, eGFR was significantly improved (p = 0.035). High eGFR subgroup demonstrated no significant deterioration in renal function, while patients with low initial eGFR had significantly higher levels 3 (p = 0.012) and six months (p = 0.009) post-transplant. Our study shows that renal function did not deteriorate significantly one yr after pancreas transplant (PTA or PAK), even in patients with substantial pre-existing renal dysfunction. Evaluation at a wider scale and identification of risk factors for potential deterioration are challenges for future research.

Surgical Management of Non-Metastatic Pancreatic Cancer in the United Kingdom: Results of a Nationwide Survey on Current Practice.

BACKGROUND: It is presently unclear what clinical pathways are followed for patients with non-metastatic PDAC in specialised centres for pancreatic surgery across the United Kingdom (UK). METHODS: Between August 2019 and August 2020 an electronic survey was conducted aiming at a national cohort of pancreatic surgeons in the UK. Participants replied to a list of standardised questions and clinical vignettes, and data were collected and analysed focusing on management preferences, resectability criteria, and contraindications to surgery. RESULTS: Within the study period, 65 pancreatic surgeons from 27 specialist centres in the UK (96%) completed the survey. Multidisciplinary team meetings are utilised universally for the management of patients with PDAC, however, different staging systems for resectability classification are being applied. In borderline resectable PDAC, most surgeons were keen to proceed with surgical exploration post NAT, but differences were noted in preferred chemotherapy regimens. Surgeons from standard volume institutions performed fewer vein resections annually and were more likely to deem patients with locally advanced PDAC as unresectable. Intra-institutional variability in patient management was also present and ranging between 20-80%. CONCLUSIONS: Significant variability in the surgical management of non-metastatic PDAC was identified both on inter- and intra-institutional level.

Facial rhabdomyosarcoma with an isolated pancreatic metastasis.

Rhabdomyosarcoma (RMS) is the most common soft tissue tumour in children. This is the first time a facial RMS metastatic to the pancreas is reported. The patient was a 3-year-old boy with a symptomatic solitary pancreatic metastasis of a primary facial RMS, with already one relapse in a submental lymph node. Since this was the second relapse of the disease and due to the extensive nature of the mass, the patient was considered for palliative care and a bypass procedure with a choledochojejunostomy, a gastrojejunostomy and a cholecystectomy was performed. The patient expired 6 months later.

Treatment Strategies for the Optimal Management of Locally Advanced Pancreatic Adenocarcinoma With Curative Intent: A Systematic Review.

Historically, locally advanced pancreatic adenocarcinoma (LAPDAC) was considered a palliative condition. Advances in treatment have resulted in studies reporting survival after neoadjuvant treatment and surgery similar to earlier disease stages. However, there is no consensus on optimal LAPDAC management. Our aim was a systematic review of published evidence on LAPDAC treatment strategies with curative intent. Twenty-eight studies defining LAPDAC as per established criteria and reporting outcomes after neoadjuvant treatment with a view to resection were included. Primary outcomes were resection rate and proportion of curative resections. Secondary outcomes were postoperative mortality, progression-free survival, and overall survival. Neoadjuvant treatment varied significantly, most common being the combination of folinic acid, fluorouracil, irontecan, and oxaliplatin. Median percentage of patients proceeding to surgery after completion of neoadjuvant pathway was 33.5%. Median resection rate was 25%. Median R0 resection was 80% of resected patients. These outcomes ranged 0% to 100% across studies. Ninety-day postoperative mortality ranged from 0% to 5%. Median progression-free and overall survival for resected patients were 12.9 and 30 months, respectively, versus 13.2 months overall survival for unresected patients. In conclusion, although there is wide variability in reported LAPDAC resection rates post-neoadjuvant chemotherapy, retrospective data suggest that neoadjuvant treatment followed by surgery results in improved survival.

Pancreatic exocrine insufficiency after pancreaticoduodenectomy: Current evidence and management.

Pancreaticoduodenectomy (PD) is the commonest procedure performed for pancreatic cancer. Pancreatic exocrine insufficiency (PEI) may be caused or exacerbated by surgery and remains underdiagnosed and undertreated. The aim of this review was to ascertain the incidence of PEI, its consequences and management in the setting of PD for indications other than chronic pancreatitis. A literature search of databases (MEDLINE, EMBASE, Cochrane and Scopus) was carried out with the MeSH terms "pancreatic exocrine insufficiency" and "Pancreaticoduodenectomy". Studies that analysed PEI and its complications in the setting of PD for malignant and benign disease were included. Studies reporting PEI in the setting of PD for chronic pancreatitis, conference abstracts and reviews were excluded. The incidence of PEI approached 100% following PD in some series. The pre-operative incidence varied depending on the characteristics of the patient cohort and it was higher (46%-93%) in series where pancreatic cancer was the predominant indication for surgery. Variability was also recorded with regards to the method used for the diagnosis and evaluation of pancreatic function and malabsorption. Pancreatic enzyme replacement therapy is the mainstay of the management. PEI is common and remains undertreated after PD. Future studies are required for the identification of a well-tolerated, reliable and reproducible diagnostic test in this setting.

Disruption of FAK signaling: a side mechanism in cytotoxicity.

Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase (PTK) which acts as an early modulator in the integrin signaling cascade. FAK phosphorylation and its consequent activation regulate several basic biological cellular functions. On the contrary, dysregulation of FAK signaling is implicated in the malignant transformation of cells, as well as in nonmalignant pathological conditions. With respect to cytotoxicity, accumulating data indicate that FAK participates in the mechanism of action of the known cytotoxic reactive oxygen species (ROS). Additionally, evidence was presented that different cytotoxic substances, such as arsenic (As), lead (Pb), acrylamide, methylisothiazolinone (MIT), dichlorovinylcysteine (DCVC) and halothane, acted, at least in part, by downregulating FAK tyrosine phosphorylation, while the bacterial toxins Pasteurella multocida toxin and Escherichia coli cytotoxic necrotizing factor, have been shown to exert cytotoxic effects by inducing FAK tyrosine phosphorylation. The observation that upregulation as well as downregulation of FAK activity both result in cytotoxic effects seems contradictory. Even though a common mode of action, with respect to the dysregulation of FAK signaling, for these cytotoxic substances has not yet been discovered, a cumulative approach could be established by focusing on FAK activation and signaling cascade. According to these data, interfering with FAK signaling might be of a potential use in blocking these cytotoxic effects. Further studies are needed on the possible implication of FAK in substance-induced cytotoxicity, as well as the possibility that such effects might be hindered or even blocked by restoring FAK signaling.

Locally advanced pancreas cancer: Staging and goals of therapy.

BACKGROUND: Patients with locally advanced pancreatic cancer have historically been considered inoperable. The purpose of this report was to determine resectability rates for patients with locally advanced pancreatic cancer based on our recently described definitions of type A and type B locally advanced pancreatic cancer. METHODS: An institutional prospective pancreas cancer database was queried for consecutive patients with locally advanced pancreatic cancer treated between January 2009 and June 2017. All pretreatment imaging was re-reviewed and patients were categorized as locally advanced pancreatic cancer type A or type B. Demographics, induction therapy, resection type, and outcomes were reviewed. RESULTS: We identified 108 consecutive patients; 12 were excluded from analysis due to the absence of available pretreatment imaging or they had not yet completed all intended neoadjuvant therapy. Of the remaining 96 patients (45 type A, 51 type B), disease progression occurred in 19 (20%) during induction therapy and 30 (31%) were deemed inoperable at final preoperative restaging. Therefore, 47 (49%) of 96 patients were taken to surgery and 40 (42%) underwent successful resection (28 [62%] of 45 type A and 12 [24%] of 51 type B); an RO resection was achieved in 32 (80%). Metastatic disease was found intraoperatively (6 at laparoscopy, 1 at laparotomy) in 7 (15%) of 47 patients. There were no mortalities; 6 (15%) patients experienced major postoperative complications. Resected patients had a median overall survival of 38.9 months. CONCLUSION: Locally advanced pancreatic cancer can be dichotomized into type A and B with distinctly different probabilities of completing all therapy to include surgery; thereby allowing goals of therapy to be established at the time of diagnosis. Multimodality therapy that includes surgery can be accomplished in selected patients with locally advanced pancreatic cancer and is associated with a median overall survival that approximates earlier stages of disease. (Surgery 2017;160:XXX-XXX.).