Microbiome Dysbiosis with Enterococcus Presence in the Upper Gastrointestinal Tract is A Risk Factor for Mortality in Patients Undergoing Surgery for Pancreatic Cancer.

BACKGROUND: Recent retrospective studies suggest a role for distinct microbiota in the perioperative morbidity and mortality of pancreatic head resections. OBJECTIVE: We aimed to prospectively investigate the microbial colonization of critical operative sites of pancreatic head resections to identify microbial stratification factors for surgical and long-term oncologic outcomes. METHODS: Prospective biomarker study applying 16S rRNA sequencing and microbial culturing to samples collected from various sites of the GI tract and surgical sites of patients during pancreatic head resections at a German single high-volume pancreatic center. RESULTS: A total of 101 patients were included (38 non-cancer, 63 cancer patients [50 PDAC patients]) in the study. In a first data analysis series, 16S rRNA sequencing data were utilized from 96 patients to assess associations of microbiome profiles with clinical parameters and outcomes. In general, microbiome composition varied according to sampling site, cancer, age or preoperative ERCP intervention, notably for the bile microbiome. In the PDAC subcohort, compositional variance of the bile or periampullary microbiome was significantly associated with postoperative complications such as ICU admission; on a taxonomic level we observed Enterococcus spp. to be significantly more abundant in patients developing deep or organ-space surgical site infections (SSI). Elevated Enterococcus relative abundances in the upper GI tract, in turn, were associated with 6-months mortality rates. In a second step, we focused on microbiological cultures collected from bile aspirates during surgery and investigated associations with perioperative complications and long-term survival. Notably, Enterococcus spp. were among the most prevalent pathobiont isolates observed in cancer patient bile specimens that were associated with severe SSIs, and thereby elevated mortality rates up to 24 months. Clinically relevant postoperative pancreatic fistulas or severe SSI were found as other major variables determining short-term mortality in this cancer patient cohort. In the context of adverse microbiological factors, a preoperative ERCP was also observed to segregate long-term survival, and it appeared to interact with the presence of Enterococcus spp. as highest mortality rates were observed in PDAC patients with both preoperative ERCP and presence of E. faecalis in bile aspirates. CONCLUSIONS: The presence of Enterococcus spp. in bile ducts of PDAC patients undergoing pancreatic surgery represents a significant risk factor for perioperative infections and, thereby, elevated postoperative and long-term mortality. This finding supports previous data on the use of the antibiotic drug piperacillin-tazobactam as appropriate perioperative antibiotic prophylaxis for preventing adverse outcomes after pancreatoduodenectomy.

Management of Sinistral Portal Hypertension after Pancreaticoduodenectomy.

BACKGROUND: Sinistral, or left-sided, portal hypertension (SPH) is a rare cause of upper gastrointestinal (GI) hemorrhage resulting from obstruction of the splenic vein. Venous drainage from the spleen via collaterals can result in venous hemorrhage into both the retroperitoneal and intra-abdominal spaces due to increased venous blood pressure in peripancreatic and gastroduodenal vasculature. SPH can occur secondary to pancreatitis with thrombosis of the splenic vein. Another possible cause is the surgical ligation of the splenic vein as part of pancreaticoduodenectomy (PD). Although splenectomy has been traditionally considered as the treatment of choice to relieve venous hypertension, individual concepts for each patient have to be developed. Considering the venous collateral drainage pathways, a comprehensive approach involving surgical, endoscopic, and interventional radiology interventions may be necessary to address the underlying cause of variceal bleeding. Among these approaches, splenic artery embolization (SAE) has demonstrated efficacy in mitigating the adverse effects associated with elevated venous outflow pressure. SUMMARY: This review summarizes key imaging findings in SPH patients after PD and highlights the potential of minimally invasive embolization for curative treatment of variceal hemorrhage. KEY MESSAGES: (i) SPH is a potential consequence after major pancreas surgery. (ii) Collateral flow can lead to life-threatening abdominal bleeding. (iii) Depending on the origin and localization of the bleeding, a dedicated management is required, frequently involving interventional radiology techniques.

Identification of an EMT-related Gene Signature Predicting Recurrence in Stage II/III Colorectal Cancer: A Retrospective Study in 1780 Patients.

OBJECTIVE: To identify a prognostic significant gene signature for predicting colorectal cancer (CRC) recurrence. BACKGROUND: Traditional prognostic risk assessment in stage II/III CRC patients remains controversial. Epithelial-mesenchymal transition is thought to be closely related to the malignant progression of tumors. Thus, it is promising to establish a prognostic model based on epithelial-mesenchymal transition-related gene (ERG) signature. MATERIALS AND METHODS: We retrospectively analyzed transcriptome profiles and clinical information of 1780 stage II/III CRC patients from 15 public datasets. Coefficient variant analysis was used to select reference genes for normalizing gene expression levels. Univariate, LASSO, and multivariate Cox regression analyses were combined to develop the ERG signature predicting disease-free survival (DFS). The patients were divided into high-risk and low-risk based on the ERG signature recurrence risk score. The survival analysis was performed in different CRC cohorts. RESULTS: The proposed ERG signature contained 7 cancer-related ERGs and 3 reference genes. The ERG signature recurrence risk score was prognostically relevant in all cohorts ( P <0.05) and proved as an independent prognostic factor in the training cohort. In the pooled cohort, high-risk CRC patients exhibited worse DFS ( P <0.0001) and overall survival ( P =0.0058) than low-risk patients. The predictive performance of the ERG signature was superior to Oncotype DX colon cancer. An integrated decision tree and nomogram were developed to improve prognosis evaluation. CONCLUSIONS: The identified ERG signature is a promising and powerful biomarker predicting recurrence in CRC patients. Moreover, the presented ERG signature might help to stratify patients according to their tumor biology and contribute to personalized treatment.

Outcomes and risks in palliative pancreatic surgery: an analysis of the German StuDoQ|Pancreas registry.

BACKGROUND: Non-resectability is common in patients with pancreatic ductal adenocarcinoma (PDAC) due to local invasion or distant metastases. Then, biliary or gastroenteric bypasses or both are often established despite associated morbidity and mortality. The current study explores outcomes after palliative bypass surgery in patients with non-resectable PDAC. METHODS: From the prospectively maintained German StuDoQ|Pancreas registry, all patients with histopathologically confirmed PDAC who underwent non-resective pancreatic surgery between 2013 and 2018 were retrospectively identified, and the influence of the surgical procedure on morbidity and mortality was analyzed. RESULTS: Of 389 included patients, 127 (32.6%) underwent explorative surgery only, and a biliary, gastroenteric or double bypass was established in 92 (23.7%), 65 (16.7%) and 105 (27.0%). After exploration only, patients had a significantly shorter stay in the intensive care unit (mean 0.5 days [SD 1.7] vs. 1.9 [3.6], 2.0 [2.8] or 2.1 [2.8]; P < 0.0001) and in the hospital (median 7 days [IQR 4-11] vs. 12 [10-18], 12 [8-19] or 12 [9-17]; P < 0.0001), and complications occurred less frequently (22/127 [17.3%] vs. 37/92 [40.2%], 29/65 [44.6%] or 48/105 [45.7%]; P < 0.0001). In multivariable logistic regression, biliary stents were associated with less major (Clavien-Dindo grade ≥ IIIa) complications (OR 0.49 [95% CI 0.25-0.96], P = 0.037), whereas-compared to exploration only-biliary, gastroenteric, and double bypass were associated with more major complications (OR 3.58 [1.48-8.64], P = 0.005; 3.50 [1.39-8.81], P = 0.008; 4.96 [2.15-11.43], P < 0.001). CONCLUSIONS: In patients with non-resectable PDAC, biliary, gastroenteric or double bypass surgery is associated with relevant morbidity and mortality. Although surgical palliation is indicated if interventional alternatives are inapplicable, or life expectancy is high, less invasive options should be considered.

[Personalised Surgical Therapy for Neuroendocrine Neoplasia of the Pancreas]. / Personalisierte Resektionsverfahren bei neuroendokrinen Neoplasien des Pankreas.

Neuroendocrine neoplasia of the pancreas (pNEN) has an increasing incidence and is therefore becoming increasingly clinically relevant. In addition to hormonally inactive pNEN, there are hormone-producing tumours and both inactive and active pNEN can be either sporadic or hereditary. Treatment is not only based on tumour-associated factors, but also on the individual patient's own circumstances. Treatment must be based on individual, tailor-made concepts that consider the respective factors and circumstances.

Defining the role of neoadjuvant systemic therapy in high-risk retroperitoneal sarcoma: A multi-institutional study from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group.

BACKGROUND: In patients with retroperitoneal sarcoma (RPS), the incidence of recurrence after surgery remains high. Novel treatment approaches are needed. This retrospective study evaluated patients with primary, high-risk RPS who received neoadjuvant systemic therapy followed by surgery to 1) determine the frequency and potential predictors of radiologic tumor responses and 2) assess clinical outcomes. METHODS: Clinicopathologic data were collected for eligible patients treated at 13 sarcoma referral centers from 2008 to 2018. Univariable and multivariable logistic models were performed to assess the association between clinical predictors and response. Overall survival (OS) and crude cumulative incidences of local recurrence and distant metastasis were compared. RESULTS: Data on 158 patients were analyzed. A median of 3 cycles of neoadjuvant systemic therapy (interquartile range, 2-4 cycles) were given. The regimens were mostly anthracycline based; however, there was significant heterogeneity. No patients demonstrated a complete response, 37 (23%) demonstrated a partial response (PR), 88 (56%) demonstrated stable disease, and 33 (21%) demonstrated progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Only a higher number of cycles given was positively associated with PR (P = .005). All patients underwent complete resection, regardless of the tumor response. Overall, patients whose tumors demonstrated PD before surgery showed markedly worse OS (P = .005). An indication of a better clinical outcome was seen in specific regimens given for grade 3 dedifferentiated liposarcoma and leiomyosarcoma. CONCLUSIONS: In patients with high-risk RPS, the response to neoadjuvant systemic therapy is fair overall. Disease progression on therapy may be used to predict survival after surgery. Subtype-specific regimens should be further validated.

Expression of CIB1 correlates with colorectal liver metastases but not with peritoneal carcinomatosis.

BACKGROUND: Molecular differences in colorectal cancer (CRC) are associated with the metastatic route. Patient survival is mainly driven by metastatic spread thus it is imperative to understand its key drivers to develop biomarkers for risk stratification, follow-up protocols and personalized therapy. Thus, this study aimed to identify genes associated with the metastatic route in CRC. MATERIAL AND METHODS: CRC patients resected at our clinic from 2005 to 2014 and with a minimum 5-year follow-up were included in this analysis and grouped into CRC with hepatic (HEP), peritoneal (PER) or without distant metastases (M0), and HEP/PER. Firstly, tumor RNA of 6 patients each was isolated by microdissection from formalin-fixed paraffin-embedded specimens and analyzed by a NanoString analysis. Subsequently, these results were validated with immunohistochemistry and correlated to clinicopathological parameters in a larger collective of CRC patients (HEP n = 51, PER n = 44, M0 n = 47, HEP/PER n = 28). RESULTS: Compared to M0, HEP tumors showed 20 differentially expressed genes associated with epithelial-mesenchymal transition (EMT) and angiogenesis. Compared to M0, PER tumors had 18 differentially expressed genes. The finding of different gene signatures was supported by the multidimensional principal component clustering analysis. Tumor perforation did not influence the metastatic route. CIB1 was homogenously and significantly overexpressed in HEP compared to M0 (p < 0.001), but not in PER. Furthermore, immunohistochemical validation demonstrated that the mean CIB1 expression in HEP was 80% higher than in M0 (p < 0.001). CONCLUSION: Gene expression analysis revealed that CIB1 is significantly overexpressed in CRC leading to liver metastases compared to M0 and PER. Thus, the present results suggest that CIB1 may play a crucial role for hematogenous spread to the liver but not for peritoneal carcinomatosis. Consequently, CIB1 seems to be a promising prognostic marker and a potential tool for future targeted therapies as well as early diagnostics and follow-up.

Chances, challenges and outcomes of patients with complex bilobar colorectal liver metastases approached by a combined multimodal therapy with liver resection and local ablative therapy.

BACKGROUND AND OBJECTIVES: In treatment of colorectal liver metastases (CRC-LM), liver surgery combined with systemic therapies and local ablation (LAT) allows improved survival. This study aims at the outcomes of patients with complex bilobar CRC-LM who were intended to undergo multimodal therapy with liver resection and LAT. METHODS: Forty-three CRC-LM patients with recommendation for multimodal treament were extracted from 5878 tumor board decisions between 2014 and 2017. Outcome variables included patient survival, as well as completion of hepatic clearance. Prognostic factors were identified by correlation and a Cox proportional hazards model. RESULTS: Out of 43 patients only 23 achieved complete clearance of CRC-LM. One- and 3-year overall survival of patients with cleared liver disease was 100% and 91.7%, respectively, as compared to 83.8% and 12.1%. Incomplete hepatic clearance was the strongest independent risk factor for overall survival (hazards ratio [HR], 5.86; p = .009). Risk factors for incomplete clearance were higher age (r = .34; p = .026), comorbidities (r = .40; p = .008), major complications (r = .34; p = .024), and prolonged intensive care unit stay (r = .41; p = .017). CONCLUSION: Completion of hepatic clearance is crucial to achieve long-term survival in patients with complex bilobar CRC-LM. Careful patient selection and treatment planning should avoid treatment failure before completing the intended therapy plan when multimodal treatments are planned.

Attenuated early inflammatory response in solid organ recipients with COVID-19.

Immunosuppression leaves transplanted patients at particular risk for severe acute respiratory syndrome 2 (SARS-CoV-2) infection. The specific features of coronavirus disease 2019 (COVID-19) in immunosuppressed patients are largely unknown and therapeutic experience is lacking. Seven transplanted patients (two liver, three kidneys, one double lung, one heart) admitted to the Ludwig-Maximilians-University Munich because of COVID-19 and tested positive for SARS-CoV-2 were included. The clinical course and the clinical findings were extracted from the medical record. The two liver transplant patients and the heart transplant patient had an uncomplicated course and were discharged after 14, 18, and 12 days, respectively. Two kidney transplant recipients were intubated within 48 hours. One kidney and the lung transplant recipients were required to intubate after 10 and 15 days, respectively. Immunosuppression was adapted in five patients, but continued in all patients. Compared to non-transplanted patients at the ICU (n = 19) the inflammatory response was attenuated in transplanted patients, which was proven by decreased IL-6 blood values. This analysis might provide evidence that continuous immunosuppression is safe and probably beneficial since there was no hyperinflammation evident. Although transplanted patients might be more susceptible to an infection with SARS-CoV-2, their clinical course seems to be similar to immunocompetent patients.

Improved survival after resection of colorectal liver metastases in patients with unresectable lung metastases.

BACKGROUND: Modern systemic therapies considerably improve tumour control and thus open the possibility of new surgical approaches in metastatic colorectal cancer. In this retrospective clinical cohort with a comparison group, we investigated whether liver resection in a combined liver-lung-metastasised stage is justified if pulmonary disease is not resected. METHODS: From 283 patients treated in our institution between 2000 and 2014 for combined colorectal liver- and lung metastases, 35 patients had their pulmonary metastases left in situ while they were eligible for both treatment options: resection versus non-resection of liver metastases. Effectively, 15 of these patients received whereas 20 did not receive a liver resection. In these patients, we compared overall survival and determined risk factors that are associated with poor survival, applying a Cox-Proportional Hazards model. RESULTS: Patients whose liver metastases were resected showed significantly longer median survival compared to patients who did not undergo hepatic surgery (median 2.6 vs 1.5 years, P = 0.0182). The Cox-Proportional Hazards model revealed hepatic metastasectomy to be the strongest determinant of patient survival (HR 5.27; CI: (1.89, 14.65)). CONCLUSION: Our results suggest that surgical removal of liver metastases may be beneficial in selected patients even if concomitant lung metastases cannot be resected.

Treatment with somatostatin analogs induces differentially expressed let-7c-5p and mir-3137 in small intestine neuroendocrine tumors.

BACKGROUND: Distant metastases frequently occur in gastroenteropancreatic neuroendocrine tumors. If hepatic surgery is not feasible, patients are treated with somatostatin analogs. However, the underlying mechanisms of action of this treatment remain to be defined. The aim of the present study was to analyze the micro-RNA expression profile inter-individually before and after the treatment with somatostatin analogs. MATERIAL AND METHODS: Tumor specimens of all included patients (n = 8) before and after the onset of a therapy with somatostatin analogs were analyzed and a micro-RNA expression profile (754 micro-RNAs) of each probe was generated. This analysis in an intra-individual setting was selected to avoid bias from inter-individual differences. The micro-RNA expression profiles were validated by qPCR. Patients with any other systemic treatment were excluded from the present study. RESULTS: Eight patients were included in the present study of which all had neuroendocrine tumors of the small intestine with diffuse hepatic metastases. Grouped analyses revealed that 15 micro-RNAs were differentially expressed (3 up- and 12 downregulated) after the exposure to somatostatin analogs. Additionally, let-7c-5p and mir-3137 are concordantly regulated in the inter-individually analysis. CONCLUSIONS: This is the first study analyzing the individual micro-RNA expression profile before and after a therapy with somatostatin analogs. Data from this study reveal that somatostatin analogs may in part exert their beneficial effects through an alteration in the micro-RNA expression profile.

Association between donor age and risk of graft failure after liver transplantation: an analysis of the Eurotransplant database.

Grafts from elderly donors are increasingly used for liver transplantation. As of yet there is no published systematic data to guide the use of specific age cutoffs the effect of elderly donors on patient outcomes must be clarified. This study analyzed the Eurotransplant database (01/01/2000-31/07/2014; N = 26 294) out of whom 8341 liver transplantations were filtered to identify for this analysis. 2162 of the grafts came from donors >60 including 203 from octogenarians ≥80 years. Primary outcome was the risk of graft failure according to donor age using a confounder adjusted Cox-Regression model with frailty terms (or random effects). The proportion of elderly grafts increased during the study period [i.e., octogenarians 0.1% (n = 1) in 2000 to 3.4% (n = 45) in 2013]. Kaplan-Meier and Cox-analyses revealed a reduced survival and a higher risk for graft failure with increasing donor age. Although the age effect was allowed to vary non-linearly, a linear association hazard ratio (HR = 1.1 for a 10 year increase in donor age) was evident. The linearity of the association suggests that there is no particular age at which the effect increases more rapidly, providing no evidence for a cutoff age. In clinical practice, the combination of high donor age with HU-transplantations, hepatitis C, high MELD-scores and long cold ischemic time should be avoided.

External Beam Radiation Therapy for Resectable Soft Tissue Sarcoma: A Systematic Review and Meta-Analysis.

PURPOSE: The aim of this study was to evaluate the role of preoperative and postoperative external beam radiation therapy (EBRT) in the treatment of resectable soft tissue sarcomas (STSs) of different tumor locations. METHODS: A systematic literature search was performed to identify studies investigating the effects of EBRT (versus no EBRT) on local recurrence (LR) and overall survival (OS) or comparing different EBRT sequences. Random effects meta-analyses were calculated and presented as cumulative odds ratios (ORs). RESULTS: Sixteen studies (n = 3958 patients) comparing EBRT versus no EBRT, including one randomized controlled trial (RCT) in extremity sarcoma, were analyzed. EBRT appeared to reduce LR in both retroperitoneal tumors (OR 0.47, p < 0.0001) and other locations (OR 0.49, p = 0.001). OS was improved by EBRT in retroperitoneal STSs (OR 0.37, p < 0.0001) but not in other tumor locations. Eleven studies (n = 2140), including one RCT, compared preoperative and postoperative radiotherapy. LR was less frequent following preoperative EBRT in retroperitoneal STSs (OR 0.03, p = 0.02), as well as in other tumor locations (OR 0.67, p = 0.01), while wound complications in extremity sarcoma were more frequent following preoperative EBRT (OR 2.92, p < 0.0001). Several studies included in this meta-analysis bear a high risk of bias and no RCT has been published for retroperitoneal STS. CONCLUSIONS: This meta-analysis supports the use of EBRT for local tumor control in patients with resectable STSs. Based on a small number of non-randomized studies, a positive effect on OS may exist in the subgroup of retroperitoneal STSs.

The added value of 68Ga-DOTA-TATE-PET to contrast-enhanced CT for primary site detection in CUP of neuroendocrine origin.

OBJECTIVES: To quantify the additional value of 68Ga-DOTA-TATE PET/CT in comparison with contrast-enhanced CT alone for primary tumour detection in neuroendocrine cancer of unknown primary (CUP-NET). METHODS: In total, 38 consecutive patients (27 men, 11 women; mean age 62 years) with histologically proven CUP-NET who underwent a contrast-enhanced 68Ga-DOTA-TATE PET/CT scan for primary tumour detection and staging between 2010 and 2014 were included in this IRB-approved retrospective study. Two blinded readers independently analysed the contrast-enhanced CT and 68Ga-DOTA-TATE PET datasets separately and noted from which modality they suspected a primary tumour. Consensus was reached if the results were divergent. Postoperative histopathology (24 patients) and follow-up 68Ga-DOTA-TATE PET/CT imaging (14 patients) served as the reference standards and statistical measures of diagnostic accuracy were calculated accordingly. RESULTS: The majority of confirmed primary tumours were located in the abdomen (ileum in 19 patients, pancreas in 12, lung in 2, small pelvis in 1). High interobserver agreement was noted regarding the suspected primary tumour site (Cohen's k 0.90, p < 0.001). 68Ga-DOTA-TATE PET demonstrated a significantly higher sensitivity (94 % vs. 63 %, p = 0.005) and a significantly higher accuracy (87 % vs. 68 %, p = 0.003) than contrast-enhanced CT. CONCLUSIONS: Ga-DOTA-TATE PET/CT compared with contrast-enhanced CT alone provides an improvement in sensitivity of 50 % and an improvement in accuracy of 30 % in primary tumour detection in CUP-NET. KEY POINTS: • 68Ga-DOTA-TATE PET augments the sensitivity of contrast-enhanced CT by 50 % • 68Ga-DOTA-TATE PET augments the accuracy of contrast-enhanced CT by 30 % • Somatostatin receptor-targeted hybrid imaging optimizes primary tumour detection in CUP-NET.

Synchronous colorectal liver metastases: focus on the elderly : An Effectiveness Study from Routine Care.

PURPOSE: The goal of this study was to analyze the use and the effectiveness of both surgery and different chemotherapies in patients with synchronous colorectal liver metastases (CLMs) ≥70 years compared to younger patients. METHODS: Survival was analyzed in 456 patients (24.3% ≥70 years) treated for CLM in a single center using Kaplan-Meier estimation of overall survival (OS), calculation of relative survival as estimate for disease-specific survival, and a Cox regression model. RESULTS: Complete surgical resections were achieved more often in patients aged <70 years (39.2 vs. 28.1%, P = 0.056), and young patients more frequently received irinotecan or platin-based chemotherapies (70.3 vs. 41.6%, P < 0.001). Three-year OS and relative survival of patients ≥70 years were significantly lower compared to younger patients (OS 34.3 vs. 43.5%, P = 0.0114). In a Cox regression model, complete surgical removal of liver metastases was the most effective treatment (HR 0.313, P < 0.001) followed by chemotherapy (irinotecan/platin-based: HR 0.371, 5-FU only: HR 0.673, P < 0.001). Having >5 liver metastases, the presence of extrahepatic metastases, high grading, and a nodal positive primary but not age ≥70 years were associated with an increased risk of death. CONCLUSIONS: Our data support radical resection and highly effective chemotherapy in selected elderly patients with CLM.

Temporary Intraoperative Porto-Caval Shunts in Piggy-Back Liver Transplantation Reduce Intraoperative Blood Loss and Improve Postoperative Transaminases and Renal Function: A Meta-Analysis.

BACKGROUND: The value of temporary intraoperative porto-caval shunts (TPCS) in cava-sparing liver transplantation is discussed controversially. Aim of this meta-analysis was to analyze the impact of temporary intraoperative porto-caval shunts on liver injury, primary non-function, time of surgery, transfusion of blood products and length of hospital stay in cava-sparing liver transplantation. METHODS: A systematic search of MEDLINE/PubMed, EMBASE and PsycINFO retrieved a total of 909 articles, of which six articles were included. The combined effect size and 95 % confidence interval were calculated for each outcome by applying the inverse variance weighting method. Tests for heterogeneity (I 2) were also utilized. RESULTS: Usage of a TPCS was associated with significantly decreased AST values, significantly fewer transfusions of packed red blood cells and improved postoperative renal function. There were no statistically significant differences in primary graft non-function, length of hospital stay or duration of surgery. CONCLUSION: This meta-analysis found that temporary intraoperative porto-caval shunts in cava-sparing liver transplantation reduce blood loss as well as hepatic injury and enhance postoperative renal function without prolonging operative time. Randomized controlled trials investigating the use of temporary intraoperative porto-caval shunts are needed to confirm these findings.

Impact of (68)Ga-DOTATATE PET/CT on the surgical management of primary neuroendocrine tumors of the pancreas or ileum.

BACKGROUND: Resection is the only curative treatment in patients suffering from neuroendocrine tumors (NETs) of the ileum or the pancreas. Accurate preoperative imaging is critical for surgical planning, as even findings of small and distant metastases may profoundly influence surgical management. METHODS: (68)Ga-DOTATATE PET/CT was performed preoperatively in 44 patients suffering from NET of the ileum (n = 26) or the pancreas (n = 18) before surgery at our University Hospital. Data were analyzed retrospectively by an interdisciplinary team of nuclear medicine and visceral surgery specialists. Intended surgical management was documented before and after availability of PET/CT findings. The team judged whether the imaging findings provided additional information relevant to surgical planning. RESULTS: Imaging results altered surgical management in 9 of 44 (20 %) patients, more specifically in 3 of 26 (12 %) patients with NET of the ileum and in 6 of 18 (33 %) patients with NET of the pancreas. PET/CT findings led to a more invasive surgical approach in 6 cases (3 each of ileum and pancreas) and to a less invasive strategy in 3 patients with NET of the pancreas. Although PET/CT results did not alter management in 35 of 44 patients, somatostatin receptor imaging still provided additional information for surgery planning in more than 95 % of the cases. CONCLUSIONS: Additional information provided by (68)Ga-DOTATATE PET/CT in the preoperative workup significantly influences surgical management in one-fifth of our NET patients and, notably, one-third of those suffering from NET of the pancreas.

Treatment of advanced gastrointestinal tumors with genetically modified autologous mesenchymal stromal cells (TREAT-ME1): study protocol of a phase I/II clinical trial.

BACKGROUND: Adenocarcinoma originating from the digestive system is a major contributor to cancer-related deaths worldwide. Tumor recurrence, advanced local growth and metastasis are key factors that frequently prevent these tumors from curative surgical treatment. Preclinical research has demonstrated that the dependency of these tumors on supporting mesenchymal stroma results in susceptibility to cell-based therapies targeting this stroma. METHODS/DESIGN: TREAT-ME1 is a prospective, uncontrolled, single-arm phase I/II study assessing the safety and efficacy of genetically modified autologous mesenchymal stromal cells (MSC) as delivery vehicles for a cell-based gene therapy for advanced, recurrent or metastatic gastrointestinal or hepatopancreatobiliary adenocarcinoma. Autologous bone marrow will be drawn from each eligible patient after consent for bone marrow donation has been obtained (under a separate EC-approved protocol). In the following ~10 weeks the investigational medicinal product (IMP) is developed for each patient. To this end, the patient's MSCs are stably transfected with a gamma-retroviral, replication-incompetent and self-inactivating (SIN) vector system containing a therapeutic promoter - gene construct that allows for tumor-specific expression of the therapeutic gene. After release of the IMP the patients are enrolled after given informed consent for participation in the TREAT-ME 1 trial. In the phase I part of the study, the safety of the IMP is tested in six patients by three treatment cycles consisting of re-transfusion of MSCs at different concentrations followed by administration of the prodrug Ganciclovir. In the phase II part of the study, sixteen patients will be enrolled receiving IMP treatment. A subgroup of patients that qualifies for surgery will be treated preoperatively with the IMP to verify homing of the MSCs to tumors as to be confirmed in the surgical specimen. DISCUSSION: The TREAT-ME1 clinical study involves a highly innovative therapeutic strategy combining cell and gene therapy and is conducted at a high level of pharmaceutical quality ensuring patient safety. This patient-tailored approach represents the first clinical study worldwide utilizing genetically engineered MSCs in humans. TRIAL REGISTRATION: EU Clinical Trials Register/European Union Drug Regulating Authorities Clinical Trials Database number: 2012-003741-15.

Effectiveness of regional hyperthermia with chemotherapy for high-risk retroperitoneal and abdominal soft-tissue sarcoma after complete surgical resection: a subgroup analysis of a randomized phase-III multicenter study.

OBJECTIVE: To determine whether regional hyperthermia (RHT) in addition to chemotherapy improves local tumor control after macroscopically complete resection of abdominal or retroperitoneal high-risk sarcomas. BACKGROUND: Within the prospectively randomized EORTC 62961 phase-III trial, RHT and systemic chemotherapy significantly improved local progression-free survival (LPFS) and disease-free survival (DFS) in patients with abdominal and extremity sarcomas. That trial included macroscopically complete and R2 resections. METHODS: A subgroup analysis of the EORTC trial was performed and long-term survival determined. From 341 patients, 149 (median age 52 years, 18-69) were identified with macroscopic complete resection (R0, R1) of abdominal and retroperitoneal soft-tissue sarcomas (median diameter 10 cm, G2 48.3%, G3 51.7%). Seventy-six patients were treated with EIA (etoposide, ifosfamide, doxorubicin)+RHT (≥5 cycles: 69.7%) versus 73 patients receiving EIA alone (≥5 cycles: 52.1%, P=0.027). LPFS and DFS as well as overall survival were determined. RESULTS: RHT and systemic chemotherapy significantly improved LPFS (56% vs 45% after 5 years, P=0.044) and DFS (34% vs 27% after 5 years, P=0.040). Overall survival was not significantly improved in the RHT group (57% vs 55% after 5 years, P=0.82). Perioperative morbidity and mortality were not significantly different between groups. CONCLUSIONS: In patients with macroscopically complete tumor resection, RHT in addition to chemotherapy resulted in significantly improved local tumor control and DFS without increasing surgical complications. Within a multimodal therapeutic concept for abdominal and retroperitoneal high-risk sarcomas, RHT is a treatment option beside radical surgery and should be further evaluated in future trials.

Complete pathological response to neoadjuvant pemetrexed/cisplatin in combination with regional hyperthermia in a patient with sarcomatoid peritoneal mesothelioma.

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare disease. Although most patients eligible for surgery undergo cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy, the role of perioperative systemic chemotherapy still remains undefined. Here we report the case of a 52-year-old female patient with advanced sarcomatoid DMPM. After five cycles of systemic pemetrexed and cisplatin, along with two cycles of regional hyperthermia, tumor resection with histomorphological examination showed a complete pathological response. We therefore conclude that there is a subgroup of DMPM patients that might benefit from systemic neoadjuvant chemotherapy with pemetrexed and cisplatin.