Ulf Hinz

Evaluation of the International Study Group of Pancreatic Surgery definition of delayed gastric emptying after pancreatoduodenectomy in a high-volume centre

Delayed gastric emptying (DGE) is a common complication after pancreatoduodenectomy. The International Study Group of Pancreatic Surgery (ISGPS) definition of DGE has not been evaluated and validated in a high‐volume centre.

Resection after neoadjuvant therapy for locally advanced, “unresectable” pancreatic cancer

BACKGROUNDnFor pancreatic cancer, complete macroscopic resection in combination with chemotherapy is the only potentially curative treatment. Many patients present with locally advanced cancers deemed unresectable. We sought to assess the results of exploration after neoadjuvant therapy for locally advanced possibly unresectable pancreatic cancer.nnnMETHODSnFrom a prospective database, all consecutive patients undergoing operation from October 2001 to December 2009 after neoadjuvant therapy for locally advanced pancreatic cancer were identified. Main criteria for unresectability were infiltration of the celiac axis or superior mesenteric artery. Resection rates, perioperative results, and survival were analyzed.nnnRESULTSnOf 257 patients, 199 (77.4%) had received neoadjuvant chemoradiation, and 58 (22.6%) chemotherapy only. Of 257 patients, 120 (46.7%) underwent successful resection, whereas 137 patients underwent exploration only; 47 (39.2%) multivisceral and 45 (37.5%) vascular resections (12 arterial reconstructions) were performed. There were 6 (5%) ypT0 neoplasms, 36 (30.0%) R0, 61 (50.8%) R1, and 16 (13.3%) R2 resections. The median follow-up of surviving patients (n = 22) was 22 months. Median postoperative survival was greater after resection (12.7 months) than after exploration alone (8.8 months; P < .0001). Median postoperative survival was 24.6 months after R0, 11.9 months after R1, and 8.9 months after R2 resection. The 3-year survival rate after R0 resection was 24%. To determine survival after start of neoadjuvant therapy, 3.7 months (median) have to be added.nnnCONCLUSIONnIn locally advanced, unresectable pancreatic cancer, R0/R1 resections can be achieved in up to 40% of patients who undergo operation after neoadjuvant therapy. In these cases, survival rates are similar to those observed for initially resectable pancreatic cancer.

Re-resection for isolated local recurrence of pancreatic cancer is feasible, safe, and associated with encouraging survival.

BackgroundLocal recurrence of pancreatic cancer occurs in 80xa0% of patients within 2xa0years after potentially curative resections. Around 30xa0% of patients have isolated local recurrence (ILR) without evidence of metastases. In spite of localized disease these patients usually only receive palliative chemotherapy and have a short survival.PurposeTo evaluate the outcome of surgery as part of a multimodal treatment for ILR of pancreatic cancer.MethodsAll consecutive operations performed for suspected ILR in our institution between October 2001 and October 2009 were identified from a prospective database. Perioperative outcome, survival, and prognostic parameters were assessed.ResultsOf 97 patients with histologically proven recurrence, 57 (59xa0%) had ILR. In 40 (41xa0%) patients surgical exploration revealed metastases distant to the local recurrence. Resection was performed in 41 (72xa0%) patients with ILR, while 16 (28xa0%) ILR were locally unresectable. Morbidity and mortality were 25 and 1.8xa0% after resections and 10 and 0xa0% after explorations, respectively. Median postoperative survival was 16.4xa0months in ILR versus 9.4xa0months in metastatic disease (pxa0<xa00.0001). In ILR median survival was significantly longer after resection (26.0xa0months) compared with exploration without resection (10.8xa0months, pxa0=xa00.0104). R0 resection was achieved in 18 patients and resulted in 30.5xa0months median survival. Presence of metastases, incomplete resection, and high preoperative CA 19-9 serum values were associated with lesser survival.ConclusionsResection for isolated local recurrence of pancreatic cancer is feasible, safe, and associated with favorable survival outcome. This concept warrants further evaluation in other institutions and in randomized controlled trials.

Critical appraisal of the International Study Group of Pancreatic Surgery (ISGPS) consensus definition of postoperative hemorrhage after pancreatoduodenectomy

PurposePostpancreatectomy hemorrhage (PPH) is one of the most serious complications after pancreatoduodenectomy (PD). This study analyzed and validated the International Study Group of Pancreatic Surgery (ISGPS) definition of PPH and aimed to identify risk factors for early (<24xa0h) and late PPH.MethodsPatients who underwent PD for pancreatic head tumors between 2001 and 2008 were included and complications were prospectively recorded. Factors associated with PPH were assessed by uni- and multivariate analysis.ResultsComplete datasets were available for 796 patients. Classic and pylorus-preserving PD was performed in 13.8% and 86.2% of the patients, respectively. According to the ISGPS definition, PPH occurred in 29.1% of the cases (232 of 796 patients): 4.8% grade A, 15.2% grade B, and 9.2% grade C. The definition is based largely on surrogate markers (e.g., transfusion requirement) that are affected by other critical illnesses and more than 97% of patients with mild PPH had no clinical signs of bleeding. The need for postoperative intensive care as well as the incidence of pancreatic fistula, relaparotomy, and mortality rates significantly increased from grades A to C. Thirty-seven patients (4.6%) required interventional (endoscopy or angiography) and/or relaparotomy for PPH. Relaparotomy for PPH was performed in 3.1% of all patients.Independent risk factors for early PPH were preoperative anemia (hemoglobin, <11xa0mg/dl) and multivisceral resection while advanced age, chronic renal insufficiency, increased blood loss, and long operation time were associated with late PPH.ConclusionsThe ISGPS definition of PPH is feasible and applicable but produces a high rate of false positive mild PPH cases. The different grades still significantly correlate with relevant outcome variables, thus the definition discriminates postoperative courses, but a minor modification of the definition of mild PPH is suggested. The new results further demonstrate the need to optimize preoperative anemia and chronic renal insufficiency.

Outcome of surgery for pancreatic neuroendocrine neoplasms

The incidence of pancreatic neuroendocrine neoplasms (pNEN) is increasing. This study aimed to evaluate predictors of overall survival and the indication for surgery.

Immunomonitoring of nuclear factor of activated T cells–regulated gene expression: The first clinical trial in liver allograft recipients

Long‐term calcineurin inhibitor (CNI) treatment can cause serious side effects in liver allograft recipients. An optimal risk‐to‐benefit ratio for CNI blood levels has not been established. Pharmacodynamic drug monitoring through the measurement of the CNI biological activity, that is, the expression of nuclear factor of activated T cells (NFAT)–regulated genes, seems to be a promising approach. The residual gene expression (RGE) of NFAT‐regulated genes 2 and 1.5 hours after cyclosporine A (CsA) and tacrolimus (FK‐506) intake was measured in 100 liver allograft recipients with 1 or more years of follow‐up post‐transplantation. The mean RGE in all patients was 62% ± 33%. A significant negative correlation between the CsA (P < 0.0001, r = −0.8026) and FK‐506 peak levels (P < 0.0001, r = −0.6982) and the RGE of all NFAT‐regulated genes was observed. Clinical reliability was proven too. In conclusion, the data presented in this pilot study reveal the applicability of the pharmacodynamic monitoring of CNI efficacy in liver allograft recipients. To confirm the advantage of individualized pharmacodynamic drug monitoring over pharmacokinetic drug monitoring with respect to clinical outcomes, controlled, prospective studies are needed. Liver Transpl, 2011.

Pilot study evaluating broccoli sprouts in advanced pancreatic cancer (POUDER trial) - study protocol for a randomized controlled trial

BackgroundPancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies with marked resistance to chemo- and radiotherapy. PDA-cancer stem cells (CSCs) are not targeted by current therapies and may be a reason for poor prognosis. Studies indicate that diets rich in cabbage, broccoli, and cauliflower offer cancer preventative and therapeutic benefits. Recent experimental studies have confirmed these findings and demonstrated that isothiocyanate, sulforaphane, and the polyphenol, quercetin, effectively reduced tumor growth and enhanced the sensitivity of the cancer cells to current chemotherapeutics. The aim of the present study is to test the feasibility of a randomized controlled trial on the application of freeze-dried broccoli sprouts in patients with advanced PDA.Methods and study designThe study is designed as a prospective randomized, double-blinded pilot trial with a treatment and a placebo-controlled arm in a single center setting. A total number of forty patients (18xa0years or older) in two parallel groups with advanced, surgically non-resectable PDA under palliative chemotherapy are planned for recruitment. Patients in the treatment group will receive fifteen capsules of the study substance per day (90xa0mg of active sulforaphane) during the chemotherapy treatment course. Patients in the placebo group will receive the same capsule size and portion distribution with inactive substances (mainly methylcellulose). The follow-up duration is one year. Feasibility of the study substance, adverse effects, and patient compliance, as well as levels of serum tumor markers (CEA, CA 19-9), quality of life, and patient overall survival rates will be assessed at defined points of time.DiscussionThe POUDER trial is expected to transfer promising experimental and epidemiological data into a clinical pilot study to assess the effectiveness of broccoli sprout extracts in the treatment of advanced PDA. The study objectives will provide data on the clinical feasibility and acceptability of a supportive treatment option accompanying palliative chemotherapy. Based on these results, future clinical studies to create further evidence in this field are possible.Trial registrationThe POUDER trial has been registered at ClinicalTrials.gov with an ID NCT01879878 and WHO with an ID U1111-1144-2013 on June 13th 2013.

Pharmacodynamic monitoring of nuclear factor of activated T cell-regulated gene expression in liver allograft recipients on immunosuppressive therapy with calcineurin inhibitors in the course of time and correlation with acute rejection episodes--a prospective study.

BACKGROUNDnDue to considerable pharmacokinetic (PK) variability, immunosuppression with calcineurin inhibitors (CNIs) remains challenging. The objective of this study was to assess a pharmacodynamic (PD) approach of monitoring nuclear factor of activated T cell (NFAT)-regulated gene expression in the course of time and in correlation with rejection episodes.nnnMATERIAL/METHODSn22 de novo liver allograft recipients were observed for a period of up to 12 months and the residual gene expression (RGE) of NFAT-regulated genes was monitored prospectively and correlated to acute rejection episodes.nnnRESULTSnThere was a significant increase in RGEs between the time points 4-7 months and 1 month (25±7 µg/l vs. 9±5 µg/l, p≤0.0001) and 8-12 months and 1 month (50±8 µg/l vs. 10±7 µg/l, p=0.002) in the cyclosporine A (CsA) group, whereas in the tacrolimus (Tac) group a significant increase in RGEs appeared at the time point 8-12 months first. Acute rejection episodes occurred in 4 patients within 1 month after transplantation. These patients demonstrated a higher RGE of all NFAT-regulated genes compared to the other patients (CsA-treated patients: 39±0% vs. 11±5%, p=0.0001, Tac-treated patients: 48±12% vs. 18±10%, p=0.0082).nnnCONCLUSIONSnRGE of all NFAT-regulated genes show a relation between acute rejection episodes in the early post transplant period. Thus, this PD method has the potential to aid therapeutic drug monitoring.

Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm characterized by a marked fibro-inflammatory microenvironment, the presence of which can promote both cancer induction and growth. Therefore, selective manipulation of local cytokines is an attractive, although unrealized, therapeutic approach. T cells possess a unique mechanism of p38 mitogen-activated protein kinase (MAPK) activation downstream of T cell receptor (TCR) engagement through the phosphorylation of Tyr323 (pY323). This alternative p38 activation pathway is required for pro-inflammatory cytokine production. Here we show in human PDAC that a high percentage of infiltrating pY323+ T cells was associated with large numbers of tumor necrosis factor (TNF)-α− and interleukin (IL)-17–producing CD4+ tumor-infiltrating lymphocytes (TILs) and aggressive disease. The growth of mouse pancreatic tumors was inhibited by genetic ablation of the alternative p38 pathway, and transfer of wild-type CD4+ T cells, but not those lacking the alternative pathway, enhanced tumor growth in T cell–deficient mice. Notably, a plasma membrane–permeable peptide derived from GADD45-α, the naturally occurring inhibitor of p38 pY323+ (ref. 7), reduced CD4+ TIL production of TNF-α, IL-17A, IL-10 and secondary cytokines, halted growth of implanted tumors and inhibited progression of spontaneous KRAS-driven adenocarcinoma in mice. Thus, TCR-mediated activation of CD4+ TILs results in alternative p38 activation and production of protumorigenic factors and can be targeted for therapeutic benefit.

Is Hepatic Resection for Non-colorectal, Non-neuroendocrine Liver Metastases Justified?

BackgroundDiscussions about the benefit of liver resection (LRx) for non-colorectal, non-neuroendocrine metastases are controversial. This study aimed to analyze the outcome of LRx for these patients and validate a previously published prognostic risk model.MethodsThe study analyzed 150 patients who underwent LRx for non-colorectal non-neuroendocrine (NCNN) metastases. Patients’ demographics, tumor characteristics, treatment options, and postoperative outcome were investigated. The Kaplan–Meier method and Cox regression models were used to assess survival and prognostic variables.ResultsAfter a median follow-up period of 61xa0months, 39xa0% of the patients were alive. The 30-day mortality rate was 0.7xa0%. The overall, disease-free, and intrahepatic recurrence-free survival rates were respectively 42, 29, and 51xa0% at 5xa0years and 28, 23, and 47xa0% at 10xa0years. The negative prognostic factors identified in the multivariate analysis were melanoma (pxa0=xa00.04), squamous tumors (pxa0=xa00.01), and a primary tumor liver metastasis, with an interval shorter than 2xa0years (pxa0=xa00.02), whereas the predictive prognostic factors identified were breast cancer (pxa0=xa00.04), stromal tumors (pxa0=xa00.03), and major LRx (pxa0=xa00.04). The prognostic risk score stratified patients into low risk (0–3 points: nxa0=xa050; 5-year overall survival [OS] 58xa0%), medium risk (4–6 points: nxa0=xa091; 5-year OS 35xa0%), and high risk (≥7 points: nxa0=xa09; 5-year OS, 33xa0%) groups (pxa0=xa00.01).ConclusionLiver resection for patients with NCNN metastases is a safe treatment option. More than 25xa0% of patients can achieve a long-term survival of 10xa0years when the histology of the primary tumor and the surrogates for the individual biologic tumor behavior are taken into account. Exclusion of patients with NCNN liver metastases from surgical therapy is no longer justified.