Abstract Background Resection of the periadventitial neurolymphatic tissue around the superior mesenteric artery (SMA) is considered a crucial component of oncologically complete resection in pancreatic head and corpus carcinomas. However, a substantial proportion of patients experience severe postoperative diarrhea due to resection of the splanchnic nerves within the SMA-adjacent tissue. The aim of the present study was to histopathologically analyze the semi-circumferential periadventitial neurolymphatic tissue surrounding the SMA in pancreatic cancer patients for the presence of malignant cells, in order to evaluate its oncological significance and to determine whether its resection may confer a long-term survival benefit. Methods A total of 66 patients with resectable malignant tumours of the pancreas treated at the University Medical Centre Göttingen were prospectively enrolled in this exploratory pilot study. The dissected semi-circumferential tissue around the SMA was processed by complete embedding and serial sectioning and analyzed for the presence of malignant cells. Survival analyses were performed using the Kaplan–Meier method with log-rank testing. Results In 7.6% of all cases (n = 5), malignant cells were found in the tissue adjacent to the SMA (SMA+). In all SMA+-patients, histopathological workup showed a pancreatic ductal adenocarcinoma (PDAC). In 80% of SMA+-patients (n = 4), an R1 resection margin was confirmed. Patient outcomes (overall survival [OS] and cancer-specific survival [CSS]) were primarily determined by R-status. Conclusions Malignant SMA-adjacent tissue involvement was identified in 7.6% of resectable pancreatic head tumours and was exclusive to PDAC. R-status appears to be the dominant determinant of survival. These findings should be considered hypothesis-generating and require validation in larger prospective cohorts.

Low anterior resection (LAR) and abdominoperineal resection (APR) are the two main surgical procedures after preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. APR is associated with poorer prognosis; however existing data do not consider intensified CRT (5-Fluorouracil (5-FU)/Oxaliplatin + radiation) protocols. Clinicopathological data of patients treated with APR and LAR from the CAO/ARO/AIO-04 trial were analysed in terms of prognostic parameters and quality of life (QoL). Based on higher response rate after intensified CRT, subgroup analyses were performed. Data from n = 1173 patients were assessed. APR after preoperative CRT was associated with a significantly worse overall survival (p = 0.0056), disease-free survival (p < 0.0001) and local recurrence rate (p = 0.0047). Clinicopathological data including clinical T stage (p < 0.000001), grading (p = 0.0038), postoperative lymph node (LN) positivity (p = 0.013), and number of positive LN (p = 0.0049) significantly differed between procedures and showed higher values in APR patients. The quality of total mesorectal excision (TME) was significantly better (p < 0.0001) and complete resection rates were higher (p = 0.0022) in LAR compared to APR patients. Subgroup analyses showed worse LR rates in APR patients after standard CRT (5-FU mono and radiation) but not after intensified CRT. After 3 years, role functioning (p = 0.019) and physical functioning (p = 0.001) had a slightly poorer outcome in APR patients. The poorer prognosis of patients undergoing APR for locally advanced rectal cancer may be explained by clinicopathological characteristics. Intensified CRT may compensate for the higher risk of LR after APR in patients with worse TME quality. QoL in APR patients was comparable to LAR patients.

Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes described as classical/progenitor and basal-like/squamous PDAC. We hypothesized that integrative transcriptome and metabolome approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal-like/squamous subtype. Using our integrated approach, we identified endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI-UMD-German cohort and additional validation cohorts. Diminished ELAPOR1 expression was linked to high histological grade, advanced disease stage, the basal-like/squamous subtype, and reduced patient survival in PDAC. In vitro experiments demonstrated that ELAPOR1 transgene expression not only inhibited the migration and invasion of PDAC cells but also induced gene expression characteristics associated with the classical/progenitor subtype. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1-Methylnicotinamide, a known oncometabolite derived from S-adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptome and metabolome characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal-like/squamous tumors with increased disease aggressiveness in PDAC patients. These findings position ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Transcriptome analysis in PDAC patient cohorts revealed downregulation of adrenoceptor alpha 2A (ADRA2A) in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients.In vitroexperiments demonstrated thatADRA2Atransgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptome and metabolome analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype and decreased survival among PDAC patients. In vitro experiments demonstrated that LMO3 transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptome and metabolome characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC.

Inflammation and aberrant cellular metabolism are widely recognized as hallmarks of cancer. In pancreatic ductal adenocarcinoma (PDAC), inflammatory signaling and metabolic reprogramming are tightly interwoven, playing pivotal roles in the pathogenesis and progression of the disease. However, the regulatory functions of inflammatory mediators in metabolic reprogramming in pancreatic cancer have not been fully explored. Earlier, we demonstrated that pro-inflammatory mediator macrophage migration inhibitory factor (MIF) enhances disease progression by inhibiting its downstream transcriptional factor nuclear receptor subfamily 3 group C member 2 (NR3C2). Here, we provide evidence that MIF and NR3C2 interactively regulate metabolic reprogramming, resulting in MIF-induced cancer growth and progression in PDAC. MIF positively correlates with the HK1 (hexokinase 1), HK2 (hexokinase 2) and LDHA (lactate dehydrogenase) expression and increased pyruvate and lactate production in PDAC patients. Additionally, MIF augments glucose uptake and lactate efflux by upregulating HK1, HK2 and LDHA expression in pancreatic cancer cells in vitro and in mouse models of PDAC. Conversely, a reduction in HK1, HK2 and LDHA expression is observed in tumors with high NR3C2 expression in PDAC patients. NR3C2 suppresses HK1, HK2 and LDHA expression, thereby inhibiting glucose uptake and lactate efflux in pancreatic cancer. Mechanistically, MIF-mediated regulation of glycolytic metabolism involves the activation of the mitogen-activated protein kinase-ERK signaling pathway, whereas NR3C2 interacts with the activator protein 1 to regulate glycolysis. Our findings reveal an interactive role of the MIF/NR3C2 axis in regulating glucose metabolism supporting tumor growth and progression and may be a potential target for designing novel approaches for improving disease outcome.

Background: New-onset postoperative arrhythmia (PA) has previously been described as a pivotal risk factor for postoperative morbidity and mortality after visceral surgery. However, there is a lack of data concerning liver surgery. The incidence and impact of new-onset postoperative arrhythmia after liver surgery was, therefore, analyzed in a monocentric study. Methods: In total, n = 460 patients (221 female, 239 male) who underwent liver surgery between January 2012 and April 2020 without any prior arrhythmia in their medical history were included in this retrospective analysis. Clinical monitoring started with the induction of anesthesia and was terminated with discharge from the intensive care unit (ICU) or intermediate care unit (IMC). Follow-up included documentation of complications during the hospital stay, as well as long-term survival analysis. Results: Postoperative arrhythmia after liver surgery was observed in 25 patients, corresponding to an incidence of 5.4%. The occurrence of arrhythmia was significantly associated with intraoperative complications (p < 0.05), liver fibrosis/cirrhosis (p < 0.05), bile fistula/bile leakage/bilioma (p < 0.05), and organ failure (p < 0.01). Survival analysis showed a significantly poorer overall survival of patients who developed postoperative arrhythmia after liver surgery (p < 0.001). Conclusions: New-onset postoperative arrhythmia after liver surgery has an incidence of only 5.4% but is significantly associated with higher postoperative morbidity and poorer overall survival.

Background: Postoperative liver failure (PLF) is a severe complication after major liver resection (MLR). To increase the safety of patients, clinical bedside tests are of great importance. However, limitations of their applicability and validity impair their value. Methods: Preoperative measurements of the liver maximum capacity (LiMAx) were performed in n = 40 patients, who underwent MLR (≥3 segments). Matched postoperative LiMAx was measured in n = 21 patients. Liver function was compared between pretreated patients (n = 11 with portal vein embolisation (PVE) and n = 19 patients with preoperative chemotherapy) and therapy naïve patients. The LiMAx values were compared with liver-specific blood parameters and volumetric analysis. Results: In total, n = 40 patients were enrolled in this study. The majority of patients (n = 33; 82.5%) had high preoperative LiMAx values (>315 µg/kg/h), while only seven patients (17.5%) had medium values (140–315 µg/kg/h), and none of the patients had low values (<140 µg/kg/h). A comparison of pretreated patients (with PVE and/or chemotherapy) and therapy naïve patients showed no significant difference in the preoperative LiMAx values (p > 0.05). The preoperative LiMAx values were significantly higher than the matched postoperative values on postoperative day 1 (p < 0.0001). A comparison between the expected and measured postoperative LiMAx showed a difference (≥10%) in 7 out of 13 patients (53.8%). After an initial postoperative decrease in the LiMAx, the patients without complications (n = 12) showed a continuous increase until 14 days after surgery. In the patients with postoperative complications, a decrease in the LiMAx was associated with a prolonged recovery. Conclusions: For patients undergoing MLR within the 0.5% rule, which is the clinical gold standard, the LiMAx values do not offer any additional information. Additionally, the LiMAx may have reflected liver function, but it did not deliver additional information regarding postoperative liver recovery. The clinical use of LiMAx might be relevant in selected patients beyond the 0.5% rule.

Postoperative arrhythmias (PAs) are common events and have been widely investigated in cardiothoracic surgery. Within visceral surgery, a recent study revealed a significant occurrence of PA in esophageal resections. In contrast, PA in lower gastrointestinal surgery is rarely investigated and has been rudimentary described in the medical literature. The present work is a retrospective cohort study of 1171 patients who underwent surgery of lower gastrointestinal tract between 2012 and 2018. All included patients were treated and monitored in the intensive care unit (ICU) or intermediate care unit (IMC) after surgery. Follow-up, performed between January and May 2021, was obtained for the patients with PA investigating the possible persistence of PA and complications such as permanent arrhythmia or thromboembolic events after discharge. In total, n = 1171 patients (559 female, 612 male) without any history of prior arrhythmia were analyzed. Overall, PA occurred in n = 56 (4.8%) patients after surgery of the lower GI. The highest incidence of PA was seen in patients undergoing bowel surgery after mesenteric ischaemia (26.92%), followed by cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC; 16.67%). PA was significantly associated with higher age (72 years (IQR 63–78 years) vs. 64 years (IQR 55–73.5 years), p < 0.001) and longer length of stay in the ICU (median 15 days (IQR 5–25 days) vs. median 2 days (IQR 1–5 days), p < 0.001). PA was independently associated with organ failure (OR = 4.62, 95% CI 2.11–10.11, p < 0.001) and higher in-house mortality (OR = 3.37, 95% CI 1.23–9.28, p < 0.001). In median, PA occurred 66.5 h after surgery. In follow-up, 31% of all the patients with PA showed development of permanent arrhythmia. The incidence of PA after lower GI surgery is comparatively low. Its occurrence, however, seems to have severe implications since it is significantly associated with higher rates of organ failure and in-house mortality. Also, compared to the general population, the development of permanent arrhythmia is significantly higher in patients who developed new-onset PA.

Einleitung Neu aufgetretene postoperative Arrhythmien stellen einen wesentlichen Risikofaktor hinsichtlich Morbidität und Mortalität nach viszeralchirurgischen Eingriffen dar. Jedoch ist die Datenlage nach leberchirurgischen Eingriffen weitestgehend unklar.

The oncological impact of portal vein resection (PVR) in pancreatic cancer surgery remains contradictory. Different variables might have an impact on the outcome. The aim of the present study is the retrospective assessment of the frequency of PVR, histological confirmation of tumor infiltration, and comparison of oncological outcomes in PVR patients. We retrieved n = 90 patients from a prospectively collected data bank who underwent pancreas surgery between 2012 and 2019 at the University Medical Centre Göttingen (Germany) and showed a histologically confirmed pancreatic ductal adenocarcinoma (PDAC). While 50 patients (55.6%) underwent pancreatic resection combined with PVR, 40 patients (44.4%) received standard pancreatic surgery. Patients with distal pancreatectomy or a tumor other than PDAC were excluded. PVR was performed either as local excision or circular resection of the portal vein. Clinical/patient data and follow-ups were retrieved. The median follow-up period was 20.5 months. Regarding the oncological outcome, a statistically poorer CSS (p = 0.04) was observed in PVR patients. There was no difference (p = 0.18) in patients’ outcomes between tangential and complete PVR, while n = 21 (42% of PVR patients) showed portal vein infiltration. The correlation between performed PVR and resection status was statistically significant: 48.6% of PVR patients achieved R0 resections compared to 75% in non-PVR patients (p = 0.03). Patients who underwent PDAC surgery with PVR show a significantly poorer outcome regardless of PVR type. Tumor size and R-status remain two important variables significantly associated with outcome. Since there is a lack of standardization for the indication of PVR, it remains unknown if the need for resection of vein structures during pancreatic resection represents the biological aggressiveness of the tumor or is biased by the experience of the surgeon.

Inflammation and altered cellular metabolism are described as hallmarks of cancer. Although inflammatory signaling and metabolic reprogramming are highly integrated and play critical role in the development and progression of pancreatic ductal adenocarcinoma (PDAC). The role of inflammatory mediators in the regulation of metabolic reprogramming is not adequately studied in pancreatic cancer and remains to be explored. Here we show that macrophage migration inhibitory factor (MIF) collaborates with its downstream transcriptional factor nuclear-receptor-subfamily-3, group-C, member-2 (NR3C2) regulate metabolic reprogramming to support cancer growth and progression in PDAC. MIF enhances glucose uptake and lactate efflux through enhancing HK1 (hexokinase 1), HK2 (hexokinase 2) and LDHA (lactate dehydrogenase) expression in pancreatic cancer cell in vitro and in an orthotopic mouse model. Furthermore, a decreased HK1, HK2, LDHA expression, pyruvate and lactate production are found in patient tumors with lower MIF expression and MIF-deficiency tumors from genetically engineered KPC mouse model. Conversely, NR3C2 suppresses HK1, HK2, and LDHA expression and decreases glucose uptake and lactate efflux in pancreatic cancer. Mechanistically, MIF-mediated regulation of glycolytic metabolism involves MAPK-ERK Kinase pathway while NR3C2 interacts with AP-1 transcriptional factor in regulation of glycolysis metabolism. Taken together, our result demonstrates an interactive role of MIF and NR3C2 signaling in regulation cancer metabolism and therapeutic approaches target this axis may improve disease outcome in patients with PDAC. Citation Format: Shouhui Yang, Wei Tang, Azadeh Azizian, Philipp Ströbel, Yuuki Ohara, Helen Cawley, Nader Hanna, B. Michael Ghadimi, Nagireddy Putluri, S. Perwez Hussain. MIF and NR3C2 interactively regulate glucose metabolism in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 25.

Journal Article Whole 16S rRNA sequencing of the oral microbiome predicts postoperative pancreatic fistula: prospective observational cohort study Get access Christoph Ammer-Herrmenau, Christoph Ammer-Herrmenau Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Goettingen, GermanyClinical Research Unit KFO5002, University Medical Centre Goettingen, Goettingen, Germany Correspondence to: Christoph Ammer-Herrmenau, Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Robert-Kochstrasse 40, 37075 Goettingen, Germany (e-mail: christoph.herrmenau@med.uni-goettingen.de; @AmmerHerrmenau) Search for other works by this author on: Oxford Academic Google Scholar Catharina H M Lingens, Catharina H M Lingens Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Goettingen, Germany Search for other works by this author on: Oxford Academic Google Scholar Charlotte S Ratei, Charlotte S Ratei Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Goettingen, GermanyClinical Research Unit KFO5002, University Medical Centre Goettingen, Goettingen, Germany Search for other works by this author on: Oxford Academic Google Scholar Cathleen Heuer, Cathleen Heuer Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Goettingen, Germany Search for other works by this author on: Oxford Academic Google Scholar Kai Antweiler, Kai Antweiler Department of Medical Statistics, University Medical Centre Goettingen, Goettingen, Germany https://orcid.org/0000-0003-3849-044X Search for other works by this author on: Oxford Academic Google Scholar Jacob Hamm, Jacob Hamm Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Goettingen, Germany Search for other works by this author on: Oxford Academic Google Scholar Soeren M Buchholz, Soeren M Buchholz Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Goettingen, GermanyClinical Research Unit KFO5002, University Medical Centre Goettingen, Goettingen, Germany Search for other works by this author on: Oxford Academic Google Scholar Azadeh Azizian, Azadeh Azizian Department of General, Visceral and Pediatric Surgery, University Medical Centre Goettingen, Goettingen, Germany Search for other works by this author on: Oxford Academic Google Scholar Michael Ghadimi, Michael Ghadimi Clinical Research Unit KFO5002, University Medical Centre Goettingen, Goettingen, GermanyDepartment of General, Visceral and Pediatric Surgery, University Medical Centre Goettingen, Goettingen, Germany Search for other works by this author on: Oxford Academic Google Scholar Volker Ellenrieder, Volker Ellenrieder Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Goettingen, GermanyClinical Research Unit KFO5002, University Medical Centre Goettingen, Goettingen, Germany Search for other works by this author on: Oxford Academic Google Scholar ... Show more Albrecht Neesse Albrecht Neesse Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Centre Goettingen, Goettingen, GermanyClinical Research Unit KFO5002, University Medical Centre Goettingen, Goettingen, GermanyDepartment of Medicine, Israelitisches Krankenhaus Hamburg, Hamburg, Germany Search for other works by this author on: Oxford Academic Google Scholar British Journal of Surgery, znad129, https://doi.org/10.1093/bjs/znad129 Published: 01 June 2023 Article history Received: 12 January 2023 Revision received: 20 March 2023 Accepted: 28 April 2023 Published: 01 June 2023

Objective: This study aimed to compare the postoperative and pathological outcomes between carboplatin, paclitaxel, radiotherapy (CROSS) and 5-FU, leucovorine, oxaliplatin and docetaxel (FLOT) in esophageal adenocarcinoma (EAC) patients from an international, multicenter cohort. Summary of Background Data: Ongoing debate exists around optimum approach to locally advanced EAC, with proponents for perioperative chemotherapy, such as FLOT, or multimodal therapy, in particular the CROSS regimen. Methods: Patients undergoing CROSS (n = 350) and FLOT (n = 368), followed by curative esophagectomy for EAC were identified from the Oesophagogastric Anastomosis Audit. Results: The 90-day mortality was higher after CROSS than FLOT (5% vs 1%, P = 0.005), even on adjusted analyses [odds ratio (OR): 3.97, confidence interval (CI)(95%): 1.34-13.67]. Postoperative mortality in CROSS were related to higher pulmonary (74% vs 60%) and cardiac complications (42% vs 20%) compared to FLOT. CROSS was associated with higher pathologic complete response (pCR) rates (18% vs 10%, P = 0.004) and margin-negative resections (93% vs 76%, P < 0.001) compared with FLOT. On adjusted analyses, CROSS was associated with higher pCR rates (OR: 2.05, CI95%: 1.26-3.34) and margin-negative resections (OR: 4.55, CI95%: 2.70-7.69) compared to FLOT. Conclusions: This study provides real-world data CROSS was associated with higher 90-day mortality than FLOT, related to cardio-pulmonary complications with CROSS. These warrant a further review into causes and mechanisms in selected patients, and at minimum suggest the need for strict radiation therapy quality assurance. Research into impact of higher pCR rates and R0 resections with CROSS compared to FLOT on long-term survival is needed.

Pancreatic ductal adenocarcinoma (PDAC) exhibits distinct molecular subtypes: classical/progenitor and basal-like/squamous. Our study aimed to identify genes contributing to the development of the basal-like/ squamous subtype, known for its aggressiveness. Transcriptome analyses revealed consistent upregulation of SERPINB3 in basal-like/squamous PDAC, correlating with reduced patient survival. SERPINB3 transgene expression in PDAC cells enhanced in vitro invasion and promoted lung metastasis in a mouse PDAC xenograft model. Metabolome analyses unveiled a metabolic signature linked to both SERPINB3 and the basallike/squamous subtype, characterized by heightened carnitine/acylcarnitine and amino acid metabolism, associated with poor prognosis in patients with PDAC and elevated cellular invasiveness. Further analysis uncovered that SERPINB3 inhibited the cysteine protease calpain, a key enzyme in the MYC degradation pathway, and drove basal-like/squamous subtype and associated metabolic reprogramming through MYC activation. Our findings indicate that the SERPINB3-MYC axis induces the basal-like/squamous subtype, proposing SERPINB3 as a potential diagnostic and therapeutic target for this variant.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is largely refractory to available treatments. Identifying key pathways associated with disease aggressiveness and therapeutic resistance may characterize candidate targets to improve patient outcomes. We used a strategy of examining the tumors from a subset of PDAC patient cohorts with the worst survival to understand the underlying mechanisms of aggressive disease progression and to identify candidate molecular targets with potential therapeutic significance. Non-negative matrix factorization (NMF) clustering, using gene expression profile, revealed three patient subsets. A 142-gene signature specific to the subset with the worst patient survival, predicted prognosis and stratified patients with significantly different survival in the test and validation cohorts. Gene-network and pathway analysis of the 142-gene signature revealed dysregulation of Clusterin (CLU) in the most aggressive patient subset in our patient cohort. Hepatocyte nuclear factor 1 b (HNF1B) positively regulated CLU, and a lower expression of HNF1B and CLU was associated with poor patient survival. Mechanistic and functional analyses revealed that CLU inhibits proliferation, 3D spheroid growth, invasiveness and epithelial-to-mesenchymal transition (EMT) in pancreatic cancer cell lines. Mechanistically, CLU enhanced proteasomal degradation of EMT-regulator, ZEB1. In addition, orthotopic transplant of CLU-expressing pancreatic cancer cells reduced tumor growth in mice. Furthermore, CLU enhanced sensitivity of pancreatic cancer cells representing aggressive patient subset, to the chemotherapeutic drug gemcitabine. Taken together, HNF1B/CLU axis negatively regulates pancreatic cancer progression and may potentially be useful in designing novel strategies to attenuate disease progression in PDAC patients.

This cohort study examines the incidence of developing arrhythmia after upper gastrointestinal tract surgery as well as the risk factors for and outcomes of postoperative arrhythmia.

Purpose Preoperative (neoadjuvant) chemoradiotherapy (CRT) and total mesorectal excision is the standard treatment for rectal cancer patients (UICC stage II/III). Up to one-third of patients treated with CRT achieve a pathological complete response (pCR). These patients could be spared from surgery and its associated morbidity and mortality, and assigned to a “watch and wait” strategy. However, reliably identifying pCR based on clinical or imaging parameters remains challenging. Experimental design We generated gene-expression profiles of 175 patients with locally advanced rectal cancer enrolled in the CAO/ARO/AIO-94 and -04 trials. One hundred and sixty-one samples were used for building, training and validating a predictor of pCR using a machine learning algorithm. The performance of the classifier was validated in three independent cohorts, comprising 76 patients from (i) the CAO/ARO/AIO-94 and -04 trials ( n = 14), (ii) a publicly available dataset ( n = 38) and (iii) in 24 prospectively collected samples from the TransValid A trial. Results A 21-transcript signature yielded the best classification of pCR in 161 patients (Sensitivity: 0.31; AUC: 0.81), when not allowing misclassification of non-complete-responders (False-positive rate = 0). The classifier remained robust when applied to three independent datasets ( n = 76). Conclusion The classifier can identify >1/3 of rectal cancer patients with a pCR while never classifying patients with an incomplete response as having pCR. Importantly, we could validate this finding in three independent datasets, including a prospectively collected cohort. Therefore, this classifier could help select rectal cancer patients for a “watch and wait” strategy. Translational relevance Forgoing surgery with its associated side effects could be an option for rectal cancer patients if the prediction of a pathological complete response (pCR) after preoperative chemoradiotherapy would be possible. Based on gene-expression profiles of 161 patients a classifier was developed and validated in three independent datasets ( n = 76), identifying over 1/3 of patients with pCR, while never misclassifying a non-complete-responder. Therefore, the classifier can identify patients suited for “watch and wait”.

Abstract Introduction: Postoperative arrhythmias (PAs) are common events and have been widely investigated in cardiothoracic surgery. Within visceral surgery, a recent study revealed a significant occurrence of PA in esophageal resections. In contrast, PA in lower gastrointestinal surgery is rarely investigated and has been rudimentary described in the medical literature. Methods: In total, 1171 patients (559 female, 612 male) without any history of prior arrhythmia who underwent lower GI surgery between 2012 and 2018 were included and retrospectively analyzed. All included patients were treated and monitored in the intensive care unit (ICU) or intermediate care unit (IMC) after surgery. Follow-up was obtained for the patients with PA investigating the possible persistence of PA and complications such as permanent arrhythmia or thromboembolic events after discharge. Results: Overall, PA occurred in n=56 (4.8%) patients after surgery of the lower GI. The highest incidence of PA was seen in patients undergoing bowel surgery after mesenteric ischaemia (26.92%), followed by cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC; 16.67%). PA was significantly associated with higher age (p<0.001) and longer length of stay in the ICU (p<0.001). PA was independently associated with organ failure (p<0.001) and higher in-house mortality (p<0.001). In median, PA occurred 66.5 hours after surgery. In follow-up, 31% of the patients showed development of permanent arrhythmia. Discussion: The incidence of PA after lower GI surgery is comparatively low. Its occurrence, however, seems to have severe implications since it is significantly associated with higher rates of organ failure and in-house mortality. Also, compared to the general population, the development of permanent arrhythmia is significantly higher in patients who developed new-onset PA.

Abstract Background Postoperative liver failure (PLF) is a serious complication of extended liver surgery. The need for clinical bedside tests to predict sufficient liver function in the remnant liver tissue after surgery and to monitor liver function and its potential for regeneration is vital to increase the safety of patients in the perioperative setting. Methods The liver maximum capacity (LiMAx) test was prospectively applied both preoperatively (n = 40) and postoperatively (n = 19) for 40 patients who underwent extended liver surgery (≥3 segments). LiMAx values were correlated with liver-specific blood parameters as well as with volumetric analysis regarding their potential as predictors of the clinical outcome and for monitoring the liver functional capacity. Results The majority of patients (n = 33; 82.5%) had high preoperative LiMAx values (> 315 µg/kg/h), while only seven patients (17.5%) had medium values (140–315 µg/kg/h), and none of the patients had low values (< 140 µg/kg/h). According to the LiMAx algorithm and preoperative volumetry, expected and measured postoperative LiMAx were compared. They differed in 7 out of 13 patients (53.8%) with a cut-off ≥10%. After surgery, patients with an uneventful recovery (n = 12) showed a typical trend in the LiMAx values, with a drop after surgery followed by an increase until 14 days after surgery. This course was reflected similarly by blood-based tests (e.g., prothrombin time). In patients with postoperative complications, a decrease in LiMAx was associated with a prolonged recovery. Conclusions For patients undergoing extended liver surgery within the 0.5% rule, which is the clinical gold standard, LiMAx values do not offer any additional information. Additionally, LiMAx may reflect liver recovery but it did not deliver additional information regarding postoperative liver recovery. The clinical use of LiMAx might be relevant in selected patients beyond the 0.5% rule.