Cancer neuroscience: State of the field, emerging directions.

The nervous system governs both ontogeny and oncology. Regulating organogenesis during development, maintaining homeostasis, and promoting plasticity throughout life, the nervous system plays parallel roles in the regulation of cancers. Foundational discoveries have elucidated direct paracrine and electrochemical communication between neurons and cancer cells, as well as indirect interactions through neural effects on the immune system and stromal cells in the tumor microenvironment in a wide range of malignancies. Nervous system-cancer interactions can regulate oncogenesis, growth, invasion and metastatic spread, treatment resistance, stimulation of tumor-promoting inflammation, and impairment of anti-cancer immunity. Progress in cancer neuroscience may create an important new pillar of cancer therapy.

Microenvironmental Determinants of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) belongs to the most lethal solid tumors in humans. A histological hallmark feature of PDAC is the pronounced tumor microenvironment (TME) that dynamically evolves during tumor progression. The TME consists of different non-neoplastic cells such as cancer-associated fibroblasts, immune cells, endothelial cells, and neurons. Furthermore, abundant extracellular matrix components such as collagen and hyaluronic acid as well as matricellular proteins create a highly dynamic and hypovascular TME with multiple biochemical and physical interactions among the various cellular and acellular components that promote tumor progression and therapeutic resistance. In recent years, intensive research efforts have resulted in a significantly improved understanding of the biology and pathophysiology of the TME in PDAC, and novel stroma-targeted approaches are emerging that may help to improve the devastating prognosis of PDAC patients. However, none of anti-stromal therapies has been approved in patients so far, and there is still a large discrepancy between multiple successful preclinical results and subsequent failure in clinical trials. Furthermore, recent findings suggest that parts of the TME may also possess tumor-restraining properties rendering tailored therapies even more challenging.

Surveillance for Presumed BD-IPMN of the Pancreas: Stability, Size, and Age Identify Targets for Discontinuation.

BACKGROUND & AIMS: Currently, most patients with branch duct intraductal papillary mucinous neoplasms (BD-IPMN) are offered indefinite surveillance, resulting in health care costs with questionable benefits regarding cancer prevention. This study sought to identify patients in whom the risk of cancer is equivalent to an age-matched population, thereby justifying discontinuation of surveillance. METHODS: International multicenter study involving presumed BD-IPMN without worrisome features (WFs) or high-risk stigmata (HRS) at diagnosis who underwent surveillance. Clusters of individuals at risk for cancer development were defined according to cyst size and stability for at least 5 years, and age-matched controls were used for comparison using standardized incidence ratios (SIRs) for pancreatic cancer. RESULTS: Of 3844 patients with presumed BD-IPMN, 775 (20.2%) developed WFs and 68 (1.8%) HRS after a median surveillance of 53 (interquartile range 53) months. Some 164 patients (4.3%) underwent surgery. Of the overall cohort, 1617 patients (42%) remained stable without developing WFs or HRS for at least 5 years. In patients 75 years or older, the SIR was 1.12 (95% CI, 0.23-3.39), and in patients 65 years or older with stable lesions smaller than 15 mm in diameter after 5 years, the SIR was 0.95 (95% CI, 0.11-3.42). The all-cause mortality for patients who did not develop WFs or HRS for at least 5 years was 4.9% (n = 79), and the disease-specific mortality was 0.3% (n = 5). CONCLUSIONS: The risk of developing pancreatic malignancy in presumed BD-IPMN without WFs or HRS after 5 years of surveillance is comparable to that of the general population depending on cyst size and patient age. Surveillance discontinuation could be justified after 5 years of stability in patients older than 75 years with cysts <30 mm, and in patients 65 years or older who have cysts ≤15 mm.

Konservative versus chirurgische Therapie beim idiopathischen und sekundären Megakolon oder Megarektum im Erwachsenenalter - eine retrospektive multizentrische Kontrollstudie.

BACKGROUND: Idiopathic and secondary megacolon (MC) and megarectum (MR) in adults is associated with persistent bowel dilatation and reduced intestinal motility. Little is known about the optimal treatment of this rare disease. Therefore, we retrospectively analysed long-term data from these patients in 5 community and university hospitals, focusing on conservative versus surgical treatment. METHODS: Patient records from 7/2004 to 9/2021 were screened for colorectal diseases with severe constipation and persistent megacolon ≥ 9.0 cm and/or megarectum ≥ 6.5 cm. Follow up-data was collected through telephone interviews and written surveys. ClinicalTrialsgov NCT04340856. RESULTS: Sixty-seven patients with idiopathic (n=10) and secondary (n=57) MC or MR were identified with only 20 of 67 patients (29.9%) correctly diagnosed. Mean/median age was 64/69 (range 18-93) years. Thirty-two patients were treated with laxative regimens, and 35 underwent surgery (colostomy: n=12, segmental resection, or hemicolectomy: n=10, (sub)total colectomy: n= 13) after conservative treatment attempts in 32/35 (91.4%). The mean/median follow-up was 4.2/2.7 (range 0.1-17.0) years. The readmission rate for MC-associated symptoms was significantly higher after conservative treatment than after surgical therapy at 12 (0.84 vs. 0.36 per patient, p=0.036), 24 (1.00 vs. 0.52, p=0.048) and 36 (1.13 vs. 0.58, p=0.047) months, as was the number of patients with persistent laxative dependence (28/32 (87.5%) vs. 19/33 (57.6%); p = 0.007). Therapy-associated adverse events (Clavien-Dindo classification) were documented more often in surgically treated patients (11/35, 31.4%) (p=0.025). CONCLUSION: Surgical treatment may be considered earlier if idiopathic or secondary MC or MR is correctly diagnosed, and conservative treatment has been attempted.

Associations of body composition parameters with postoperative outcome and perineural tumour invasion after oncological pancreatic resection.

BACKGROUND: Pancreatic cancer is often accompanied by wasting conditions. While surgery is the primary curative approach, it poses a substantial risk of postoperative complications, hindering subsequent treatments. Therefore, identifying patients at high risk for complications and optimizing their perioperative general condition is crucial. Sarcopenia and other body composition abnormalities have shown to adversely affect surgical and oncological outcomes in various cancer patients. As most pancreatic tumours are located close to the neuronal control centre for the digestive tract, it is possible that neural infiltration in this area deranges bowel functions and contributes to malabsorption and malnutrition and ultimately worsen sarcopenia and weight loss. METHODS: A retrospective analysis of CT scans was performed for pancreatic cancer patients who underwent surgical tumour resection at a single high-volume centre from 2007 to 2023. Sarcopenia prevalence was assessed by skeletal muscle index (SMI), and visceral obesity was determined by the visceral adipose tissue area (VAT). Obesity and malnutrition were determined by the GLIM criteria. Sarcopenic obesity was defined as simultaneous sarcopenia and obesity. Postoperative complications, mortality and perineural tumour invasion, were compared among patients with body composition abnormalities. RESULTS: Of 437 patients studied, 46% were female, the median age was 69 (61;74) years. CT analysis revealed 54.9% of patients with sarcopenia, 23.7% with sarcopenic obesity and 45.9% with visceral obesity. Sarcopenia and sarcopenic obesity were more prevalent in elderly and male patients. Postoperative surgical complications occurred in 67.7% of patients, most of which were mild (41.6%). Severe complications occurred in 22.7% of cases and the mortality rate was 3.4%. Severe postoperative complications were significantly more common in patients with sarcopenia or sarcopenic obesity. Visceral obesity or malnutrition based on BMI alone, did not significantly impact complications. Perineural invasion was found in 80.1% of patients and was unrelated to malnutrition or body composition parameters. CONCLUSIONS: This is the first and largest study evaluating the associations of CT-based body mass analysis with surgical outcome and histopathological perineural tumour invasion in pancreatic cancer patients. The results suggest that elderly and male patients are at high risk for sarcopenia and should be routinely evaluated by CT before undergoing pancreatic surgery, irrespective of their BMI. Confirmation of the results in prospective studies is needed to assess if pancreatic cancer patients with radiographic sarcopenia benefit from preoperative amelioration of muscle mass and function by exercise and nutritional interventions.

DOTA-Based Plectin-1 Targeted Contrast Agent Enables Detection of Pancreatic Cancer in Human Tissue.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy with extremely poor patient survival rates. A key reason for the poor prognosis is the lack of effective diagnostic tools to detect the disease at curable, premetastatic stages. Tumor surgical resection is PDAC's first-line treatment, however distinguishing between cancerous and healthy tissue with current imaging tools remains a challenge. In this work, we report a DOTA-based fluorescent probe targeting plectin-1 for imaging PDAC with high specificity. To enable heterogeneous functionalization of the DOTA-core with multiple targeting peptide units and the fluorophore, a novel, fully clickable synthetic route that proceeds in one pot was developed. Extensive validation of the probe set the stage for PDAC detection in mice and human tissue. Altogether, these findings may pave the way for improved clinical understanding and early detection of PDAC progression as well as more accurate resection criteria.

Tailoring the Use of Central Pancreatectomy Through Prediction Models for Major Morbidity and Postoperative Diabetes: International Retrospective Multicenter Study.

OBJECTIVE: To develop a prediction model for major morbidity and endocrine dysfunction after CP which could help in tailoring the use of this procedure. SUMMARY BACKGROUND DATA: Central pancreatectomy (CP) is a parenchyma-sparing alternative to distal pancreatectomy for symptomatic benign and pre-malignant tumors in body and neck of the pancreas CP lowers the risk of new-onset diabetes and exocrine pancreatic insufficiency compared to distal pancreatectomy but it is thought to increase the risk of short-term complications including postoperative pancreatic fistula (POPF). METHODS: International multicenter retrospective cohort study including patients from 51 centers in 19 countries (2010-2021). Primary endpoint was major morbidity. Secondary endpoints included POPF grade B/C, endocrine dysfunction, and the use of pancreatic enzymes. Two risk model were designed for major morbidity and endocrine dysfunction utilizing multivariable logistic regression and internal and external validation. RESULTS: 838 patients after CP were included (301 (36%) minimally invasive) and major morbidity occurred in 248 (30%) patients, POPF B/C in 365 (44%), and 30-day mortality in 4 (1%). Endocrine dysfunction in 91 patients (11%) and use of pancreatic enzymes in 108 (12%). The risk model for major morbidity included male sex, age, BMI, and ASA score≥3. The model performed acceptable with an area under curve (AUC) of 0.72(CI:0.68-0.76). The risk model for endocrine dysfunction included higher BMI and male sex and performed well (AUC:0.83 (CI:0.77-0.89)). CONCLUSIONS: The proposed risk models help in tailoring the use of CP in patients with symptomatic benign and premalignant lesions in the body and neck of the pancreas and are readily available via www.pancreascalculator.com.

Position statement on the definition, incidence, diagnosis and outcome of acute on chronic pancreatitis.

BACKGROUND: Acute on chronic pancreatitis (ACP) is a relatively common condition, but there are significant gaps in our knowledge on the definition, incidence, diagnosis, treatment and prognosis. METHODS: A systematic review that followed PICO (Population; Intervention; Comparator; Outcome) recommendation for quantitative questions and PICo (Population, Phenomenon of Interest, Context) for qualitative research was done to answer 10 of the most relevant questions about ACP. Quality of evidence was judged by the GRADE criteria (Grades of Recommendation, Assessment, Development and Evaluation). The manuscript was sent for review to 12 international experts from various disciplines and continents using a Delphi process. RESULTS: The quality of evidence, for most statements, was low to very low, which means that the recommendations in general are only conditional. Despite that, it was possible to reach strong levels of agreement by the expert panel for all 10 questions. A new consensus definition of ACP was reached. Although common, the real incidence of ACP is not known, with alcohol as a major risk factor. Although pain dominates, other non-specific symptoms and signs can be present. Serum levels of pancreatic enzymes may be less than 3 times the upper limit of normal and cross-sectional imaging is considered more accurate for the diagnosis in many cases. It appears that it is less severe and with a lower mortality risk than acute pancreatitis. CONCLUSIONS: Although the evidence base is poor, this position statement provides a foundation from which to advance management of ACP.

Accurate prediction of histological grading of intraductal papillary mucinous neoplasia using deep learning.

BACKGROUND: Risk stratification and recommendation for surgery for intraductal papillary mucinous neoplasm (IPMN) are currently based on consensus guidelines. Risk stratification from presurgery histology is only potentially decisive owing to the low sensitivity of fine-needle aspiration. In this study, we developed and validated a deep learning-based method to distinguish between IPMN with low grade dysplasia and IPMN with high grade dysplasia/invasive carcinoma using endoscopic ultrasound (EUS) images. METHODS: For model training, we acquired a total of 3355 EUS images from 43 patients who underwent pancreatectomy from March 2015 to August 2021. All patients had histologically proven IPMN. We used transfer learning to fine-tune a convolutional neural network and to classify "low grade IPMN" from "high grade IPMN/invasive carcinoma." Our test set consisted of 1823 images from 27 patients, recruiting 11 patients retrospectively, 7 patients prospectively, and 9 patients externally. We compared our results with the prediction based on international consensus guidelines. RESULTS: Our approach could classify low grade from high grade/invasive carcinoma in the test set with an accuracy of 99.6 % (95 %CI 99.5 %-99.9 %). Our deep learning model achieved superior accuracy in prediction of the histological outcome compared with any individual guideline, which have accuracies between 51.8 % (95 %CI 31.9 %-71.3 %) and 70.4 % (95 %CI 49.8-86.2). CONCLUSION: This pilot study demonstrated that deep learning in IPMN-EUS images can predict the histological outcome with high accuracy.

Computed high-b-value high-resolution DWI improves solid lesion detection in IPMN of the pancreas.

OBJECTIVES: To examine the effect of high-b-value computed diffusion-weighted imaging (cDWI) on solid lesion detection and classification in pancreatic intraductal papillary mucinous neoplasm (IPMN), using endoscopic ultrasound (EUS) and histopathology as a standard of reference. METHODS: Eighty-two patients with known or suspected IPMN were retrospectively enrolled. Computed high-b-value images at b = 1000 s/mm2 were calculated from standard (b = 0, 50, 300, and 600 s/mm2) DWI images for conventional full field-of-view (fFOV, 3 × 3 × 4 mm3 voxel size) DWI. A subset of 39 patients received additional high-resolution reduced-field-of-view (rFOV, 2.5 × 2.5 × 3 mm3 voxel size) DWI. In this cohort, rFOV cDWI was compared against fFOV cDWI additionally. Two experienced radiologists evaluated (Likert scale 1-4) image quality (overall image quality, lesion detection and delineation, fluid suppression within the lesion). In addition, quantitative image parameters (apparent signal-to-noise ratio (aSNR), apparent contrast-to-noise ratio (aCNR), contrast ratio (CR)) were assessed. Diagnostic confidence regarding the presence/absence of diffusion-restricted solid nodules was assessed in an additional reader study. RESULTS: High-b-value cDWI at b = 1000 s/mm2 outperformed acquired DWI at b = 600 s/mm2 regarding lesion detection, fluid suppression, aCNR, CR, and lesion classification (p = < .001-.002). Comparing cDWI from fFOV and rFOV revealed higher image quality in high-resolution rFOV-DWI compared to conventional fFOV-DWI (p ≤ .001-.018). High-b-value cDWI images were rated non-inferior to directly acquired high-b-value DWI images (p = .095-.655). CONCLUSIONS: High-b-value cDWI may improve the detection and classification of solid lesions in IPMN. Combining high-resolution imaging and high-b-value cDWI may further increase diagnostic precision. CLINICAL RELEVANCE STATEMENT: This study shows the potential of computed high-resolution high-sensitivity diffusion-weighted magnetic resonance imaging for solid lesion detection in pancreatic intraductal papillary mucinous neoplasia (IPMN). The technique may enable early cancer detection in patients under surveillance. KEY POINTS: • Computed high-b-value diffusion-weighted imaging (cDWI) may improve the detection and classification of intraductal papillary mucinous neoplasms (IPMN) of the pancreas. • cDWI calculated from high-resolution imaging increases diagnostic precision compared to cDWI calculated from conventional-resolution imaging. • cDWI has the potential to strengthen the role of MRI for screening and surveillance of IPMN, particularly in view of the rising incidence of IPMNs combined with now more conservative therapeutic approaches.

Continuous irrigation after pancreatectomy: a systematic review.

PURPOSE: Prevention and management of postoperative pancreatic fistula (POPF) after pancreatic resections is still an unresolved issue. Continuous irrigation of the peripancreatic area is frequently used to treat necrotizing pancreatitis, but its use after elective pancreatic surgery is not well-known. With this systematic review, we sought to evaluate the current knowledge and expertise regarding the use of continuous irrigation in the surgical area to prevent or treat POPF after elective pancreatic resections. METHODS: A systematic search of the literature was conducted according to the PRISMA 2020 guidelines, screening the databases of Pubmed, Scopus, Web of Science, and Ovid MEDLINE. Because of the heterogeneity of the included articles, a statistical inference could not be performed and the literature was reviewed only descriptively. The study was pre-registered online (OSF Registry). RESULTS: Nine studies were included. Three studies provided data regarding the prophylactic use of continuous irrigation after distal and limited pancreatectomies. Here, patients after irrigation showed a lower rate of clinically relevant POPF, related complications, lengths of stay, and mortality. Six other papers reported the use of local lavage to treat clinically relevant POPF and subsequent fluid collections, with successful outcomes. CONCLUSION: In the current literature, only a few publications are focused on the use of continuous irrigation after pancreatic resection to prevent or manage POPF. The included studies showed promising results, and this technique may be useful in patients at high risk of POPF. Further investigations and randomized trials are needed.

Treatment characteristics and outcomes of pure Acinar cell carcinoma of the pancreas - A multicentric European study on radically resected patients.

BACKGROUND: Acinar cell carcinomas (ACC) belong to the exocrine pancreatic malignancies. Due to their rarity, there is no consensus regarding treatment strategies for resectable ACC. METHODS: This is a retrospective multicentric study of radically resected pure pancreatic ACC. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Further endpoints were oncologic outcomes related to tumor stage and therapeutic protocols. RESULTS: 59 patients (44 men) with a median age of 64 years were included. The median tumor size was 45.0 mm. 61.0% were pT3 (n = 36), nodal positivity rate was 37.3% (n = 22), and synchronous distant metastases were present in 10.1% of the patients (n = 6). 5-Years OS was 60.9% and median DFS 30 months. 24 out of 31 recurred systemically (n = 18 only systemic, n = 6 local and systemic). Regarding TNM-staging, only the N2-stage negatively influenced OS and DFS (p = 0.004, p = 0.001). Adjuvant treatment protocols (performed in 62.7%) did neither improve OS (p = 0.542) nor DFS (p = 0.159). In 9 cases, radical resection was achieved following neoadjuvant therapy. DISCUSSION: Radical surgery is currently the mainstay for resectable ACC, even for limited metastatic disease. Novel (neo)adjuvant treatment strategies are needed, since current systemic therapies do not result in a clear survival benefit in the perioperative setting.

Schwann cell-derived exosomes: Janus-faced mediators of regeneration and disease.

The phenotypic plasticity of Schwann cells (SCs) has contributed to the regenerative potential of the peripheral nervous system (PNS), but also pathological processes. This double-sided effect has led to an increasing attention to the role of extracellular vesicles (EVs) or exosomes in SCs to examine the intercellular communication between SCs and their surroundings. Here, we first describe the current knowledge of SC and EV biology, which forms the basis for the updates on advances in SC-derived exosomes research. We seek to explore in-depth the exosome-mediated molecular mechanisms involved in the regulation of SCs and their microenvironment. This review concludes with potential applications of SC-derived exosomes as delivery vehicles for therapeutics and biomarkers. The goal of this review is to emphasize the crucial role of SC-derived exosomes in the functional integration of the PNS, highlighting an emerging area in which there is much to explore and re-explore.

Bcl3 Couples Cancer Stem Cell Enrichment With Pancreatic Cancer Molecular Subtypes.

BACKGROUND & AIMS: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown. METHODS: Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical nf-κb signaling member, as differing in pancreatic CSCs. To determine the biological consequences of BCL3 silencing in vivo and in vitro, we generated bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models, and 2 independent patient cohorts. We assessed the correlation of bcl3 expression pattern with clinical parameters and subtypes. RESULTS: Bcl3 was significantly down-regulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via BCL3 genetic knockout enhanced tumor burden, metastasis, epithelial to mesenchymal transition, and reduced overall survival. Fluorescence-activated cell sorting analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays, all indicated that BCL3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes. CONCLUSIONS: We demonstrate that bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker for predicting subtype characterization in PDAC, thereby allowing for personalized therapeutic approaches.

Serum albumin at resection predicts in-hospital death, while serum lactate and aPTT on the first postoperative day anticipate anastomotic leakage after Ivor-Lewis-esophagectomy.

BACKGROUND: Anastomotic leakage (AL) is a major complication after esophagectomy, potentiating morbidity and mortality. There are several patient risk factors associated with AL, but high-fidelity postoperative predictors are still under debate. The aim was to identify novel reliable predictors for AL after esophagectomy. METHODS: A high-volume single-center database study, including 138 patients receiving Ivor-Lewis-esophagectomy between 2017 and 2019, was performed. Serum levels of albumin, aPTT, and lactate before and after surgery were extracted to assess their impact on AL and in-hospital mortality. RESULTS: High serum lactate on postoperative day 1 (POD1) could be shown to predict AL after esophagectomy [AL vs. no AL: 1.2 (0.38) vs. 1.0 (0.37); p < 0.001]. Accordingly, also differences of serum lactate level between end (POD0-2) and start of surgery (POD0-1) (p < 0.001) as well as between POD1 and POD0-1 (p < 0.001) were associated with AL. Accordingly, logistic regression identified serum lactate on POD 1 as an independent predictor of AL [HR: 4.37 (95% CI: 1.28-14.86); p = 0.018]. Further, low serum albumin on POD0 [2.6 (0.53) vs. 3.1 (0.56); p = 0.001] and high serum lactate on POD 0-1 [1.1 (0.29) vs. 0.9 (0.30); p = 0.043] were associated with in-hospital death. Strikingly, logistic-regression (HR: 0.111; p = 0.008) and cox-regression analysis (HR: 0.118; p = 0.003) showed low serum albumin as an independently predictor for in-hospital death after esophagectomy. CONCLUSIONS: This study identified high serum lactate as an independent predictor of AL and low serum albumin as a high-fidelity predictor of in-hospital death after esophagectomy. These parameters can facilitate improved postoperative treatment leading to better short-term as well as long-term outcomes.

The Effect of Celiac Neurolysis and Splanchnicectomy on Survival in Unresectable Pancreatic Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Intractable pancreatic pain is one of the most common symptoms of patients with pancreatic ductal adenocarcinoma (PDAC). Celiac neurolysis (CN) and splanchnicectomy were already described as effective methods to manage abdominal pain in unresectable PDAC, but their impact on overall survival (OS) has not yet been established. OBJECTIVE: We aimed to investigate the impact of CN and splanchnicectomy on the survival of patients with unresectable pancreatic cancer. METHODS: A systematic review of PubMed and Cochrane Library according to predefined searching terms was conducted in March 2020. Hazard ratios (HR) of OS data were calculated using the Mantel-Haenszel model for random effects or fixed effects. RESULT: Four randomized-controlled trials (RCTs) and 2 non-RCTs with a total of 2,507 patients were identified. The overall pooled HR did not reveal any relevant effect of CN and splanchnicectomy on OS (HR: 1.03; 95% CI: 0.81-1.32), which was also underlined by the sensitivity analysis of RCTs (HR: 1.0; 95% CI: 0.72-1.39) and non-RCTs (HR: 1.07; 95% CI: 0.71-1.63). However, subgroup analyses depending on tumor stage revealed that CN or splanchnicectomy was associated with a worsened OS in AJCC (American Joint Committee on Cancer) stage III patients with unresectable PDAC (HR: 1.22; 95% CI: 1.03-1.45), but nor for AJCC stage IV patients (HR: 1.27; 95% CI: 0.9-1.80). CONCLUSION: Although only few data are currently available, this systematic review with meta-analysis showed that in unresectable PDAC, CN or splanchnicectomy is associated with a worsened survival in stage III PDAC patients, with no effect on stage IV PDAC patients. These data call for caution in the usage of CN or splanchnicectomy in stage III PDAC and for further studies addressing this observation.

[Resection Strategies in BD-IPMN - Enucleation or Standard Resection?] / Resektionsstrategien beim BD-IPMN - Enukleation oder onkologische Resektion?

BACKGROUND: The malignant potential and the surgical management of branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) remain controversial. Enucleation (EN), as parenchyma-sparing resections of the pancreas, may be a valuable alternative to standard resections (SR), e.g., Whipple or distal pancreatectomy, for the treatment of BD-IPMN. However, its role is still poorly defined. The objective of this review is to compare indications and postoperative outcomes after pancreatic EN versus SR. METHODS: A review of the literature was carried out. Short- and long-term postoperative outcomes of both surgical approaches were evaluated. RESULTS: EN is associated with shorter operation time and less blood loss than SR. The overall surgical morbidity does not differ between the two approaches. Although EN is less invasive, the development of pancreatic fistula is the most important complication after EN, as several studies have reported a higher rate of pancreatic fistula than after SR. However, the differences between the two procedures are mitigated in high-volume centres. EN more frequently allows the preservation of pancreatic exocrine and endocrine function in comparison to SR and this is the most important advantage of this procedure. CONCLUSIONS: EN appears to be a safe and effective alternative to treat low-risk BD-IPMN, and allows preservation of endocrine and exocrine function. Moreover, postoperative complications and recurrence rates after EN are comparable to the much more extensive surgical procedures. However, pancreatic EN should be performed by experienced surgeons and, as non-oncological procedure, patients should be very accurately selected. This underlines the importance of treatment in high-volume institutions.

Diabetes and Weight Loss Are Associated With Malignancies in Patients With Intraductal Papillary Mucinous Neoplasms.

BACKGROUND & AIMS: The role of diabetes in intraductal papillary mucinous neoplasms (IPMNs) is not known. We investigated the prevalence of diabetes among patients with resected IPMNs and the association between diabetes, clinical and morphological features, and high-grade dysplasia or invasive cancer. METHODS: We collected clinical, pathology, laboratory, and demographic data from 134 patients who underwent pancreatic resection for IPMN from a referral center in Germany. We identified 50 patients with diabetes (37%). RESULTS: Higher proportions of patients with diabetes were male and older, but did not have increased body mass index, compared to patients without diabetes. Diabetes was significantly associated with main-duct involvement (odds ratio [OR], 2.827; 95% CI, 1.059-7.546; P = .038) and high-grade dysplasia or invasive carcinoma (OR, 2.692; 95% CI, 1.283-5.651; P = .009). Risk of high-grade dysplasia or invasive cancer was even higher in patients with new-onset or worsening diabetes (OR, 4.615; 95% CI, 1.423-14.698; P = .011). Fifty-eight percent of patients (18/31) with weight loss at diagnosis had diabetes vs 32% of patients (31/97) without weight loss (P = .009). However, when the analysis was restricted to IPMNs with low-grade dysplasia, weight loss and diabetes were no longer associated (42% [5/12] vs 21% [9/44]; P = .133). CONCLUSIONS: In patients with IPMNs, diabetes is associated with increased risk of main duct involvement and high-grade dysplasia or invasive carcinoma. Studies are needed to determine the relationship between diabetes and progression of IPMNs, which might lead to strategies for early detection and prevention of invasive cancer. Findings from this study should be considered in the guidelines for management of IPMN.

Secreted factors from mouse embryonic fibroblasts maintain repopulating function of single cultured hematopoietic stem cells.

Hematopoietic stem cell self-renewal, proliferation, and differentiation are independently regulated by intrinsic as well as extrinsic mechanisms. We previously demonstrated that murine proliferation of hematopoietic stem cells is supported in serum-free medium supplemented with two growth factors, stem cell factor and interleukin 11. The survival of hematopoietic stem cells is additionally improved by supplementing this medium with two more growth factors, neural growth factor and collagen 1 (four growth factors) or serum-free medium conditioned by the hematopoietic stem cell-supportive stromal UG26-1B6 cells1. Here, we describe a robust and versatile alternative source of conditioned medium from mouse embryonic fibroblasts. We found that this conditioned medium supports survival and phenotypical identity of hematopoietic stem cells, as well as cell cycle entry in single cell cultures of CD34- CD48- CD150+ Lineage- SCA1+ KIT+ cells supplemented with two growth factors. Strikingly, in comparison with cultures in serum-free medium with four growth factors, conditioned medium from mouse embryonic fibroblasts increases the numbers of proliferating clones and the number of Lineage- SCA1+ KIT+ cells, both with two and four growth factors. In addition, conditioned medium from mouse embryonic fibroblasts supports self-renewal in culture of cells with short- and long-term hematopoiesis-repopulating ability in vivo. These findings identify conditioned medium from mouse embryonic fibroblasts as a robust alternative serumfree source of factors to maintain self-renewal of in vivo-repopulating hematopoetic stem cells in culture.

Surgery and the kings of medical science : Invited Commentary: "Publication activity of chief and senior general/visceral surgeons in German university hospitals - a ten-year analysis", Böckmann et al.

BACKGROUND: Surgeons are frequently compared in terms of their publication activity to members of other disciplines who publish in journals with naturally higher impact factors. The time intensity of daily clinical duties in surgery is yet not comparable to that of these competitor disciplines. PURPOSE: Here, we aimed to critically comment on ways for improving the academic productivity of university surgerons. CONCLUSIONS: To ensure high-quality science in surgery, it is imperative that surgeons actively ask for and generate the time for high-quality research. This necessitates coordinated and combined efforts of leading university surgeons at the political level and effective presentation of the magnificent studies performed by young and talented university surgeons.