Clinical relevance of the 3-cm threshold in sigmoid diverticulitis with abscess: consensus or quandary?

PURPOSE: Diverticular abscess is a common manifestation of acute complicated diverticulitis. We aimed to analyze the clinical course of patients with diverticular abscess initially treated conservatively. METHODS: All patients with diverticular abscess undergoing elective or urgent/emergency surgery from October 2004 to October 2022 were identified from our institutional database. Depending on the abscess size, patients were divided into group A (≤ 3 cm) and group B (> 3 cm). Conservative treatment failure was defined as clinical deterioration, persistent or recurrent abscess, or urgent/emergency surgery. Baseline characteristics and short-term perioperative outcomes were recorded and compared between both groups. Uni- and multivariate analyses were conducted to identify determinants of conservative treatment failure and overall ostomy formation. RESULTS: A total of 105 patients were enrolled into group A (n = 73) and group B (n = 32). Uni- and multivariate analyses revealed abscess size as the only significant factor of conservative therapy failure [OR 9.904; p < 0.0001], while overall ostomy formation was significantly affected by an increased body mass index (BMI) [OR 1.366; p = 0.026]. There were no significant differences in perioperative outcome with the exception of a longer total hospital stay in patients managed with abscess drainage compared to antibiotics alone prior surgery in group B (p = 0.045). CONCLUSION: Abscess diameter > 3 cm is not just an arbitrary chosen cut-off value for drainage placement but has a prognostic impact on medical treatment failure in patients with complicated acute diverticulitis. In this subgroup, the choice between primary drainage and antibiotics does not appear to influence outcome at the cost of prolonged hospital stay after drainage insertion.

Predictive factors of 90-day mortality after curative hepatic resection for hepatocellular carcinoma: a western single-center observational study.

PURPOSE: The aim of this study was to identify predictive risk factors associated with 90-day mortality after hepatic resection (HR) in hepatocellular carcinoma (HCC). METHODS: All patients undergoing elective resection for HCC from a single- institutional and prospectively maintained database were included. Multivariate regression analysis was conducted to identify pre- and intraoperative as well as histopathological predictive factors of 90-day mortality after elective HR. RESULTS: Between August 2004 and October 2021, 196 patients were enrolled (148 male /48 female). The median age of the study cohort was 68.5 years (range19-84 years). The rate of major hepatectomy (≥ 3 segments) was 43.88%. Multivariate analysis revealed patient age ≥ 70 years [HR 2.798; (95% CI 1.263-6.198); p = 0.011], preoperative chronic renal insufficiency [HR 3.673; (95% CI 1.598-8.443); p = 0.002], Child-Pugh Score [HR 2.240; (95% CI 1.188-4.224); p = 0.013], V-Stage [HR 2.420; (95% CI 1.187-4.936); p = 0.015], and resected segments ≥ 3 [HR 4.700; (95% 1.926-11.467); p = 0.001] as the major significant determinants of the 90-day mortality. CONCLUSION: Advanced patient age, pre-existing chronic renal insufficiency, Child-Pugh Score, extended hepatic resection, and vascular tumor involvement were identified as significant predictive factors of 90-day mortality. Proper patient selection and adjustment of treatment strategies could potentially reduce short-term mortality.

Optimizing Growth of the Future Liver Remnant and Making In-Situ Liver Transsection Safe-A Standardized Approach to ISLT or ALPPS.

In-situ splitting of the liver before extended resection has gained broad attention. This two-step procedure requires several measures to make an effective and safe procedure. Although the procedure is performed in many institutions, there is no consensus on a uniform technique. The two steps can be divided into different parts and a standardized technique may render the procedure safer and the results will be easier to evaluate. In this paper, we describe a detailed approach to in-situ splitting that allows making both procedures safe, avoids liver necrosis, and is easily reproducible. In the first procedure the portal branches to segments I and IV to VIII are divided, the arterial branches and bile ducts to these segments are preserved and encircled and the parenchyma between segments II/III and IVa/b is divided. This avoids necrosis and bile leaks of segments I and IV and avoids urgent completion operations. In particular, the handling of vital structures close to the dissection line seems important to us. Complete splitting and securing the right and middle hepatic vein will make the second step of this procedure a minimal-risk procedure at a stage where the patient is still recovering from the more demanding first step.

A single center comparative retrospective study of in situ split plus portal vein ligation versus conventional two-stage hepatectomy for cholangiocellular carcinoma.

INTRODUCTION: Cholangiocellular carcinoma (CCA) has a poor prognosis and the goldstandard even in locally advanced cases remains radical surgical resection. This approach however is limited by the future liver remnant volume (FLRV) after extensive parenchymal dissection leading to post-operative liver failure and high mortality rates. The aim of this study was to compare the outcome of in situ liver transection with portal vein ligation (ISLT) procedure and conventional two-stage hepatectomy with portal vein embolization (PVE/TSH) in patients with CCA. METHODS: All patients with CCA and insufficient FLR considered for either ISLT or PVE/TSH were analyzed for outcomes including post-operative morbidity, mortality, and overall survival rates (OS). RESULTS: Sixteen patients received ISLT and eight patients underwent PVE/TSH. The completion rate of the second stage in the PVE/TSH group was 62% and 100% in the ISLT group (p = 0.027). The overall 90-day morbidity rates including severe complications (Clavien-Dindo ≥3b) were comparable (PVE/TSH 40% vs. ISLT 69%, p = 0.262). The median OS (PVE/TSH 7 months vs. ISLT 3 months) and the 90-day mortality rates (PVE/TSH 0% vs. ISLT 50%) did not significantly differ between the two groups (p > 0.05). In multivariate analysis, biliary resection and reconstruction was the only risk factor independently associated with 90-day post-operative morbidity [HR = 20.0; 95%CI (1.68-238.63); p = 0.018]. CONCLUSION: Our results demonstrate comparable outcomes in both groups in a rather prognostically unfavorable disease. The completion rate in the ISLT group was significantly higher than in the PVE/TSH cohort. This work encourages specialized hepato-biliary-pancreatic centers in applying the ISLT procedure in selected cases with CCA.

Clinicopathological and Prognostic Value of Survivin Expression in Surgically Resected Pancreatic Ductal Adenocarcinoma.

Background: Survival after surgery for pancreatic ductal adenocarcinoma (PDAC) remains poor. Thus, novel therapeutic concepts focus on the development of targeted therapies. In this context, inhibitor of apoptosis protein (IAP) survivin is regarded as a promising oncotherapeutic target. However, its expression and prognostic value in different tumour compartments of PDAC have not been studied. Methods: Immunohistochemical analysis of survivin in different PDAC tumour compartments from 236 consecutive patients was correlated with clinicopathological variables and survival. Results: In comparison to healthy pancreatic tissue high nuclear (p < 0.001) and high cytoplasmic (p < 0.01) survivin expression became evident in the tumour centre, along the invasion front and in lymph node metastases. Cytoplasmic overexpression of survivin in tumour centres was related to the presence of distant metastasis (p = 0.016) and UICC III/IV stages (p = 0.009), while high cytoplasmic expression at the invasion front grouped with venous infiltration (p = 0.022). Increased nuclear survivin along the invasion front correlated with perineural invasion (p = 0.035). High nuclear survivin in tumour centres represented an independent prognostic factor for overall survival of pancreatic tail carcinomas (HR 13.5 95%CI (1.4−129.7)) and correlated with a limited disease-free survival in PDAC (HR 1.80 95%CI (1.04−3.12)). Conclusion: Survivin is associated with advanced disease stages and poor prognosis. Therefore, survivin will help to identify patients with aggressive tumour phenotypes that could benefit from the inclusion in clinical trials incorporating survivin inhibitors in PDAC.

N, LNR or LODDS: Which Is the Most Appropriate Lymph Node Classification Scheme for Patients with Radically Resected Pancreatic Cancer?

BACKGROUND: Even though numerous novel lymph node (LN) classification schemes exist, an extensive comparison of their performance in patients with resected pancreatic ductal adenocarcinoma (PDAC) has not yet been performed. METHOD: We investigated the prognostic performance and discriminative ability of 25 different LN ratio (LNR) and 27 log odds of metastatic LN (LODDS) classifications by means of Cox regression and C-statistic in 319 patients with resected PDAC. Regression models were adjusted for age, sex, T category, grading, localization, presence of metastatic disease, positivity of resection margins, and neoadjuvant therapy. RESULTS: Both LNR or LODDS as continuous variables were associated with advanced tumor stage, distant metastasis, positive resection margins, and PDAC of the head or corpus. Two distinct LN classifications, one LODDS and one LNR, were found to be superior to the N category in the complete patient collective. However, only the LODDS classification exhibited statistically significant, gradually increasing HRs of their subcategories and at the same time significantly higher discriminative potential in the subgroups of patients with PDAC of the head or corpus and in patients with tumor free resection margins or M0 status, respectively. On this basis, we built a clinically helpful nomogram to estimate the prognosis of patients after radically resected PDAC. CONCLUSION: One LNR and one LODDS classification scheme were found to out-perform the N category in terms of both prognostic performance and discriminative ability, in distinct patient subgroups, with reference to OS in patients with resected PDAC.

Quality of Life in Patients with Pancreatic Cancer before and during the COVID-19 Pandemic.

BACKGROUND: Coronavirus disease 19 (COVID-19) substantially affects cancer patients due to adverse outcomes and disruptions in cancer care. Recent studies have indicated the additional stress and anxiety burden arising from the pandemic and impairing quality of life in this vulnerable group of patients. However, patients with cancer represent a heterogenous group. Therefore, we conducted a study on patients with pancreatic cancer, requiring demanding surgical interventions and chemotherapy regimens due to its aggressive tumor biology, to explore the pandemic's impact on quality of life within this homogenous cohort. METHODS: In a descriptive observational study, the quality of life of patients who had undergone pancreatic surgery for tumor resection at our institution between 2014 and the beginning of the pandemic in March 2020 was assessed. For HRQoL measurement, we used the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30), comparing their situation before the pandemic and since its beginning. An additional self-developed questionnaire was applied to assess the life circumstances during the pandemic. RESULTS: Our cohort included 26 patients. Scores from the survey in HRQoL revealed no significant changes over time between before and during the pandemic. A medium deterioration in HRQoL was apparent in social functioning, as well as a small deterioration in role functioning and emotional functioning. Worries concerning a potential impact of COVID-19 on personal health were expressed. Psychological limitations in QoL were mainly attributed to the pandemic, whereas physical limitations in QoL were rather associated with the underlying disease of pancreatic cancer. CONCLUSION: The COVID-19 pandemic is causing considerable social and emotional distress among pancreatic cancer patients. These patients will benefit from psychological support during the pandemic and beyond. Long-time survivors of pancreatic cancer, such as those included in our cohort, appear to have improved resilience facing the psychosocial challenges of the pandemic. For pancreatic cancer, surgical care is considered the cornerstone of treatment. Prolonged delays in healthcare cause serious damage to mental and physical health. To date, the longer-term clinical consequences are not known and can only be estimated. The potential tragic outcome for the vulnerable group of pancreatic cancer patients highlights the urgency of timely healthcare decisions to be addressed in the future.

Effectiveness of Video-Assisted Thoracoscopic Surgery with Bullectomy and Partial Pleurectomy in the Treatment of Primary Spontaneous Pneumothorax-A Retrospective Long-Term Single-Center Analysis.

Background: Video-assisted thoracoscopic surgery (VATS) with bullectomy and partial pleurectomy (VBPP) is an increasingly used and well-established surgical treatment for primary spontaneous pneumothorax (PSP). However, reports on its effectiveness and long-term outcomes are limited. The aim of this study was to assess and compare long-term recurrence rates following VBPP and chest tube (CT) treatment and to identify potential risk factors for disease recurrence in patients with PSP. Methods: A total of 116 patients treated either by VBPP or CT were included in this study. Long-term recurrence rates and associations between clinical parameters and recurrence of pneumothorax were analyzed. Results: Sixty-two patients (53.4%) underwent VBPP, whereas 54 (46.6%) patients underwent CT treatment only. During a median follow-up period of 76.5 months, VBPP patients experienced a significantly lower recurrence rate compared to CT patients (6/62 vs. 35/54; p < 0.0001). CT treatment (VBPP vs. CT; p < 0.001) and a large initial pneumothorax size (Collins < 4 vs. Collins ≥ 4; p = 0.018) were independent risk factors for pneumothorax recurrence. Conclusion: VBPP is an effective and safe surgical treatment for PSP. Therefore, patients with a large pneumothorax size might benefit from VBPP, as they are at high risk for disease recurrence.

Genetic Alterations Predict Long-Term Survival in Ductal Adenocarcinoma of the Pancreatic Head.

BACKGROUND: Survival of patients with adenocarcinoma of the pancreas (PDAC) is poor and has remained almost unchanged over the past decades. The genomic landscape of PDAC has been characterized in recent years. The aim of this study was to identify a genetic profile as a possible predictor of prolonged survival in order to tailor therapy for PDAC patients. METHODS: Panel next generation sequencing (NGS) and immunohistochemistry (IHC) were performed on paraffin-embedded tumor tissues from curatively treated PDAC patients. Tumor slides were re-evaluated with a focus on the histomorphology. Patients were subgrouped according to short and long overall (<4 years/>4 years) and disease-free (<2 years/>2 years) survival. RESULTS: Thirty-nine patients were included in the study. Clinicopathological staging variables as well as the histomorphological subgroups were homogenously distributed between short- and long-term overall and disease-free survivors. In survival analysis, patients with the KRAS G12D mutation and patients with TP53 nonsense and splice-site mutations had a significantly worse overall survival (OS) and disease-free survival (DFS). Patients with long-term OS and DFS showed no KRAS G12D, no TP53 nonsense or splice-site mutations. Rare Q61H/D57N KRAS mutations were only found in long-term survivors. The allele frequency rate of KRAS and TP53 mutations in tumor cells was significantly higher in short-term disease-free survivors and overall survivors, respectively. CONCLUSIONS: NGS of PDAC revealed significant differences in survival outcome in a patient collective with homogenously distributed clinicopathological variables. Further multi-institutional studies are warranted to identify more long-term survivors to detect genetic differences suitable for targeted therapy.

Two-port versus three-port video-assisted thoracoscopic surgery for primary spontaneous pneumothorax: feasibility, postoperative outcome and long-term recurrence rates.

BACKGROUND: Two-port VATS (2-P-VATS) and three-port VATS (3-P-VATS) are well-established techniques for surgical therapy of primary spontaneous pneumothorax (PSP). However, comparisons of both techniques in terms of postoperative outcome and recurrence are limited. METHODS: From January 2010 to March 2020, we retrospectively reviewed data of 58 PSP patients who underwent VATS in our institution. For statistical analysis, categorical and continuous variables were compared by chi-square test or Fisher's exact test and the Student´s t-test, respectively. Twenty-eight patients underwent 2-P-VATS and 30 were treated with 3-P-VATS. Operation time, length of hospital stay (LOS), total dose of analgesics per stay (opioids and non-opioids), duration of chest tube drainage, pleurectomy volume (PV), postoperative complications and recurrence rates were compared between both groups. RESULTS: Clinical and surgical characteristics including mean age, gender, Body-Mass-Index (BMI), pneumothorax size, smoking behaviour, history of contralateral pneumothorax, side of pneumothorax, pleurectomy volume and number of resected segments were similar in both groups. The mean operation time, LOS and total postoperative opioid and non-opioid dose was significantly higher in the 3-P-VATS group compared with the 2-P-VATS group. Despite not being statistically significant, duration of chest tube was longer in the 3-P-VATS group compared with the 2-P-VATS group. In terms of postoperative complications, the occurrence of hemothorax was significantly higher in the 3-P-VATS group (3-P-VATS vs. 2-P-VATS; p = 0.001). During a median follow-up period of 61.6 months, there was no significant statistical difference in recurrence rates in both groups (2/28 (16.7%) vs. 5/30 (7.1%); p = 0.274). CONCLUSION: Our data demonstrate that 2-P-VATS is safer and effective. It is associated with reduced length of hospital stay and decreased postoperative pain resulting in less analgesic use.

Does Video-Assisted Thoracoscopic Surgery with Bullectomy and Partial Pleurectomy for Primary Spontaneous Pneumothorax Impair Health-Related Quality of Life and Pulmonary Function?

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) with partial pleurectomy is an established treatment for primary spontaneous pneumothorax (PSP). However, postoperative pulmonary function and health-related quality of life (HR-QoL) after VATS-bullectomy with partial pleurectomy (VBPP) have not been elucidated. METHODS: Eligible patients were assessed for HR-QoL using the Short-Form 36 (SF-36) health survey. Pulmonary function (PF) was evaluated by spirometry. We compared the results of the VBPP cohort with the German national norms, and with a similar cohort of patients successfully treated by chest tube (CT) only. RESULTS: A total of 25 VBPP patients completed the SF-36 health survey, of whom 15 presented for PF assessment. Between the VBPP and CT groups, the mean forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and FEV1/FVC ratio were not statistically significantly different. However, in both groups, FVC, FEV1, and FEV1/FVC were above the lower limit of normal (LLN), suggesting no restrictive or obstructive patterns. Compared with the sex- and age-matched normal German population, patients who underwent VBPP displayed a similar physical component summary score and a significantly decreased mental component summary score. Interestingly, comparison of the SF-36 domains between the VBPP and CT groups showed no statistical difference. CONCLUSION: VBPP is a suitable surgical treatment for PSP, with no apparent adverse impacts on pulmonary or physical function. However, psychological distress and measures to counteract its impact should be considered.

Socioeconomic Impact of Recurrent Primary Spontaneous Pneumothorax: Should Video-Assisted Thoracoscopic Surgery Be Considered at First Episode of Primary Spontaneous Pneumothorax?

BACKGROUND: Current guidelines recommend video-assisted thoracoscopic surgery (VATS) for recurrent primary spontaneous pneumothorax (PSP) and for cases with persistent air leak after chest tube treatment. The socioeconomic impact of recurrent PSP on the healthcare system is insufficiently reported. METHODS: Ninety-six patients treated for PSP between 01/2010 and 01/2020 were included. Forty-eight patients underwent primary VATS, while the second group received chest tube (CT) treatment only. Length of hospital stay (LOS), duration of chest tube, prolonged air leak, postoperative complications, recurrences and treatment costs were analyzed. RESULTS: Prolonged air leaks were evident in 12.5% and 22.9% patients of the VATS and CT group, respectively. Ten (20.8%) patients in the CT group underwent VATS for persistent air leakage. During follow-up, the VATS group recurred at 8.3% compared to 52.1% in the CT group. The total cost of treatment per patient, including treatment cost due to recurrence, was EUR 1.501 in the VATS group and EUR 2.233 in the CT group. CONCLUSIONS: Primary treatment of PSP by CT is associated with an increased socioeconomic burden for patients and the healthcare system due to high recurrence rates. This burden may be reduced if VATS is considered at the first episode of PSP.

Pre-Operative MDCT Staging Predicts Mesopancreatic Fat Infiltration-A Novel Marker for Neoadjuvant Treatment?

The rates of microscopic incomplete resections (R1/R0CRM+) in patients receiving standard pancreaticoduodenectomy for PDAC remain very high. One reason may be the reported high rates of mesopancreatic fat infiltration. In this large cohort study, we used available histopathological specimens of the retropancreatic fat and correlated high resolution CT-scans with the microscopic tumor infiltration of this area. We found that preoperative MDCT scans are suitable to detect cancerous infiltration of this mesopancreatic tissue and this, in turn, was a significant indicator for both incomplete surgical resection (R1/R0CRM+) and worse overall survival. These findings indicate that a neoadjuvant treatment in PDAC patients with CT-morphologically positive infiltration of the mesopancreas may result in better local control and thus improved resection rates. Mesopancreatic fat stranding should thus be considered in the decision for neoadjuvant therapy. Background: Due to the persistently high rates of R1 resections, neoadjuvant treatment and mesopancreatic excision (MPE) for ductal adenocarcinoma of the pancreatic head (hPDAC) have recently become a topic of interest. While radiographic cut-off for borderline resectability has been described, the necessary extent of surgery has not been established. It has not yet been elucidated whether pre-operative multi-detector computed tomography (MDCT) staging reliably predicts local mesopancreatic (MP) fat infiltration and tumor extension. Methods: Two hundred and forty two hPDAC patients that underwent MPE were analyzed. Radiographic re-evaluation was performed on (1) mesopancreatic fat stranding (MPS) and stranding to peripancreatic vessels, as well as (2) tumor diameter and anatomy, including contact to peripancreatic vessels (SMA, GDA, CHA, PV, SMV). Routinely resected mesopancreatic and perivascular (SMA and PV/SMV) tissue was histopathologically re-analyzed and histopathology correlated with radiographic findings. A logistic regression of survival was performed. Results: MDCT-predicted tumor diameter correlated with pathological T-stage, whereas presumed tumor contact and fat stranding to SMA and PV/SMV predicted and correlated with histological cancerous infiltration. Importantly, mesopancreatic fat stranding predicted MP cancerous infiltration. Positive MP infiltration was evident in over 78%. MPS and higher CT-predicted tumor diameter correlated with higher R1 resection rates. Patients with positive MP stranding had a significantly worse overall survival (p = 0.023). Conclusions: A detailed preoperative radiographic assessment can predict mesopancreatic infiltration and tumor morphology and should influence the decision for primary surgery, as well as the extent of surgery. To increase the rate of R0CRM- resections, MPS should be considered in the decision for neoadjuvant therapy.

Para-aortic lymph nodes and ductal adenocarcinoma of the pancreas: Distant neighbors?

BACKGROUND: Para-aortic lymph nodes in the ductal adenocarcinoma of the pancreatic head are regarded as distant metastases. Chemotherapy is considered the only treatment option if para-aortic lymph nodes metastases are detected preoperatively or intraoperatively. The role of standardized para-aortic lymph node lymphadenectomy during pancreaticoduodenectomy remains controversial. The aim of this study was to evaluate complication profiles and survival. METHODS: All cases of ductal adenocarcinoma of the pancreatic head were evaluated from a prospectively maintained database (n = 289). Para-aortic lymph node lymphadenectomy was routinely performed in all patients with suspected ductal adenocarcinoma of the pancreatic head. Subgroup analysis was performed between patients with histologically positive (+) and negative (-) para-aortic lymph nodes. Patients receiving pancreaticoduodenectomy without para-aortic lymph node lymphadenectomy for other causes served as a control group. RESULTS: A total of 192 patients received para-aortic lymph node lymphadenectomy, of which 41 were positive for para-aortic lymph node metastases. In 97 patients with ductal adenocarcinoma of the pancreatic head, no para-aortic lymph node lymphadenectomy was performed owing to postoperative pancreatic ductal adenocarcinoma diagnosis. Clinicopathologic data were homogenously distributed. Hospital stay and postoperative morbidity demonstrated no significant difference between the 3 subgroups. The median overall survival of 19.63 months (95% confidence interval: 14.57-24.79 months) in para-aortic lymph node- patients was not statistically different when compared with the median overall survival of 18.22 months (95% confidence interval: 12.68-23.75 months) in para-aortic lymph node + patients (log-rank test P = .223). Preoperative computed tomography was a poor predictor for para-aortic lymph node status (sensitivity = 10.3%, specificity = 97.8%). CONCLUSION: This study represents the largest cohort receiving routine para-aortic lymph node lymphadenectomy. Extended lymphadenectomy can be performed safely and, although disease-free survival of para-aortic lymph node+ patients was significantly shorter, overall survival and postrelapse survival were on par with that of para-aortic lymph node- patients. Preoperative computed tomography indicating para-aortic lymph node metastasis should not preclude curative resection.

Neoadjuvant Treatment Lowers the Risk of Mesopancreatic Fat Infiltration and Local Recurrence in Patients with Pancreatic Cancer.

BACKGROUND: Survival following surgical treatment of ductal adenocarcinoma of the pancreas (PDAC) remains poor. The recent implementation of the circumferential resection margin (CRM) into standard histopathological evaluation lead to a significant reduction in R0 rates. Mesopancreatic fat infiltration is present in ~80% of PDAC patients at the time of primary surgery and recently, mesopancreatic excision (MPE) was correlated to complete resection. To attain an even higher rate of R0(CRM-) resections in the future, neoadjuvant therapy in patients with a progressive disease seems a promising tool. We analyzed radiographic and histopathological treatment response and mesopancreatic tumor infiltration in patients who received neoadjuvant therapy prior to MPE. The aim of our study was to evaluate the need for MPE following neoadjuvant therapy and if multi-detector computed tomographically (MDCT) evaluated treatment response correlates with mesopancreatic (MP) infiltration. METHOD: Radiographic, clinicopathological and survival parameters of 27 consecutive patients who underwent neoadjuvant therapy prior to MPE were evaluated. The mesopancreatic fat tissue was histopathologically analyzed and the 1 mm-rule (CRM) was applied. RESULTS: In the study collective, both the rate of R0 resection R0(CRM-) and the rate of mesopancreatic fat infiltration was 62.9%. Patients with MP infiltration showed a lower tumor response. Surgical resection status was dependent on MP infiltration and tumor response status. Patients with MDCT-predicted tumor response were less prone to MP infiltration. When compared to patients after upfront surgery, MP infiltration and local recurrence rate was significantly lower after neoadjuvant treatment. CONCLUSION: MPE remains warranted after neoadjuvant therapy. Mesopancreatic fat invasion was still evident in the majority of our patients following neoadjuvant treatment. MDCT-predicted tumor response did not exclude mesopancreatic fat infiltration.

HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer.

Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding Lysine-specific demethylase 6A, carries somatic mutations in PDAC. Here, we show that pancreas-specific Hnf1a null mutant transcriptomes phenocopy those of Kdm6a mutations, and both defects synergize with KrasG12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic, and biochemical studies to show that HNF1A recruits KDM6A to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates differentiated acinar cell programs, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. We also identify a subset of non-classical PDAC samples that exhibit the HNF1A/KDM6A-deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A deficiency promotes PDAC. They also connect the tumor-suppressive role of KDM6A deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition.

Stromal heterogeneity in pancreatic cancer and chronic pancreatitis.

BACKGROUND/OBJECTIVES: An abundant stromal reaction is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). The cells mainly responsible for the stromal reaction are activated pancreatic stellate cells (PSCs). Despite their crucial role, PSCs are not well characterized. PSCs share characteristics with the better-known hepatic stellate cells (HSCs). The aim of this study was a detailed analysis of PSCs in PDAC and CP. METHODS: Whole-slide specimens of CP (n = 12) and PDAC (n = 10) were studied by histochemistry and immunohistochemistry. The stroma was evaluated using Movat's pentachrome stain. PSCs were tested by immunohistochemistry for PSC markers (α-SMA, CD34, desmin, NGFR, SPARC and tenascin C) and HSC markers (α-crystallin B, CD56, NGF, NT-3, synaptophysin and TrkC). Alpha-SMA, tenascin C, SPARC and NT-3 staining were verified on tissue micro arrays (TMAs) from a well-characterized cohort of 223 PDAC patients. PSCs isolated from human PDAC and CP tissue samples as well as HSCs were evaluated by immunofluorescence. RESULTS: While the stroma of CP cases was characterized by a collagen-rich fibrosis, PDAC stroma displayed higher mucin content (p = 0.0002). PSCs showed variable expression of tested markers. In PDAC samples, staining of most markers was found around tumor complexes, while CP samples showed a greater variety of localizations. Alpha-SMA staining correlated with collagen-rich fibrosis (p = 0.012), while NT-3 staining correlated with mucin-rich stroma (p = 0.008). A peritumoral staining was confirmed for α-SMA, tenascin C, SPARC and NT-3 in the PDAC TMA cohort (n = 223). In a subgroup of patients with pancreatic head tumors and UICC 2009 IIB (n = 144), α-SMA staining intensity was a prognostic factor for overall survival at uni- and multivariate analysis (p = 0.036 and p = 0.002). CONCLUSIONS: The close similarities between PSCs and HSCs were confirmed. Heterogeneous expression patterns of the tested markers might reflect different levels of activation or differentiation, or even multiple subpopulations of PSCs. Survival analysis suggests an impact of stromal composition on survival.

Survivin and XIAP expression in distinct tumor compartments of surgically resected gastric cancer: XIAP as a prognostic marker in diffuse and mixed type adenocarcinomas.

There is considerable evidence that the inhibitor of apoptosis protein (IAP) family serves a role in tumorigenesis. The most studied IAP family members, survivin and X-linked inhibitor of apoptosis (XIAP), have been demonstrated to serve as biomarkers in distinct tumor entities. Thus, the present study aimed to investigate the expression levels of both IAPs in the tumor center, invasion front and lymph node metastases of surgically resected gastric cancer (GC) specimens. Tissue microarrays containing samples from 201 primary GCs were analyzed. IAP expression was detected using immunohistochemistry in different tumor compartments, normal mucosa and lymph node metastases. In addition, the association between the expression levels of these proteins, and clinicopathological parameters and overall survival was investigated. High levels of survivin and XIAP were evident in GC, when compared with normal mucosa, and were correlated with intestinal-type and well-differentiated GC, as well as low International Union Against Cancer stages. Increased XIAP expression was detected in lymph node metastases as compared with corresponding primary tumors. XIAP overexpression was identified to be an independent negative prognostic marker in diffuse and mixed type GC. These results suggest a potential role of survivin and XIAP in the early phase of gastric carcinogenesis. In addition, increased XIAP expression in lymph node metastases supports the observation that IAPs serve an essential role in metastatic tumor disease. Since XIAP expression was identified to be associated with poor survival in diffuse and mixed type GC, XIAP may serve as a novel therapeutic target in these types of GC.

Myelinated Axons in the Auricular Branch of the Human Vagus Nerve.

Transcutaneous stimulation of the auricular branch of the vagus nerve (ABVN) resulted in deactivation of temporal lobe structures, similar to invasive cervical vagus nerve (CVN) stimulation. Presumably, both methods stimulated myelinated afferent beta axons mediating anti-convulsive effects. How numbers of A beta axons in the human ABVN compare to those of the CVN is unknown. The ABVN, CVN, recurrent laryngeal nerve (RLN) and thoracic vagus nerve (TVN) were dissected from embalmed bodies. Numbers and calibers of myelinated axons were analyzed in semithin sections. Myelinated axons in the left and right ABVN averaged to 385 and 363, respectively. Numbers of A beta axons measuring ≥7 µm averaged to 64 and 78 on the left and right, respectively. Numbers of A beta axons in CVN were estimated by subtracting myelinated presumed motor axons in RLN from the total count of CVN. This resulted in 280 and 504 A beta axons on the left and right, respectively, concurring well with the thick myelinated axon count of the ipsilateral TVN (255 and 466, respectively). Thus, the ratio of A beta axons in the ABVN and CVN was ∼1:5 and 1:6 on the left and right side, respectively. These results indicate that transcutaneous ABVN stimulation might be a promising alternative to invasive CVN stimulation. Anat Rec, 299:1184-1191, 2016. © 2016 Wiley Periodicals, Inc.