ChatGPT's Gastrointestinal Tumor Board Tango: A limping dance partner?

OBJECTIVES: This study aimed to assess the consistency and replicability of treatment recommendations provided by ChatGPT 3.5 compared to gastrointestinal tumor cases presented at multidisciplinary tumor boards (MTBs). It also aimed to distinguish between general and case-specific responses and investigated the precision of ChatGPT's recommendations in replicating exact treatment plans, particularly regarding chemotherapy regimens and follow-up protocols. MATERIAL AND METHODS: A retrospective study was carried out on 115 cases of gastrointestinal malignancies, selected from 448 patients reviewed in MTB meetings. A senior resident fed patient data into ChatGPT 3.5 to produce treatment recommendations, which were then evaluated against the tumor board's decisions by senior oncology fellows. RESULTS: Among the examined cases, ChatGPT 3.5 provided general information about the malignancy without considering individual patient characteristics in 19% of cases. However, only in 81% of cases, ChatGPT generated responses that were specific to the individual clinical scenarios. In the subset of case-specific responses, 83% of recommendations exhibited overall treatment strategy concordance between ChatGPT and MTB. However, the exact treatment concordance dropped to 65%, notably lower in recommending specific chemotherapy regimens. Cases recommended for surgery showed the highest concordance rates, while those involving chemotherapy recommendations faced challenges in precision. CONCLUSIONS: ChatGPT 3.5 demonstrates potential in aligning conceptual approaches to treatment strategies with MTB guidelines. However, it falls short in accurately duplicating specific treatment plans, especially concerning chemotherapy regimens and follow-up procedures. Ethical concerns and challenges in achieving exact replication necessitate prudence when considering ChatGPT 3.5 for direct clinical decision-making in MTBs.

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

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

Baseline Interleukin-6 as a Preoperative Biomarker for Liver Fibrosis.

Introduction: Liver (hepatic) fibrosis (LF) is characterized by impaired function and regenerative capacity of the liver and can lead to significantly increased morbidity and mortality in the context of surgical liver resection (LR). For this reason, it is crucial to identify the extent of LF preoperatively. Interleukin-6 (IL-6) is known to play a key role in the pathogenesis of LF, but its exact value as a preoperative marker is unknown. This study aimed to investigate the correlation between preoperatively determined IL-6 and the presence of LF. Methods: In this prospective study, IL-6 was determined in 134 consecutive patients undergoing LR. Patients with liver cirrhosis (LC) and patients with clinical or laboratory signs of inflammation were excluded. LF was graded by a blinded pathologist with regard to the degree of LF according to the Desmet classification (0-4). Baseline IL-6 and degree of LF were correlated. Results: A total of 134 patients were prospectively included prior to LR. For 104 patients, LF was graded and inflammatory parameters were available. Thirty-five of these patients showed LC (Desmet 4), and another 33 patients showed preoperatively elevated inflammatory markers. Two of the remaining patients were liver transplant patients. These patients were excluded from the final analysis. According to Desmet, the remaining 34 patients had LF grade 0 or 1 (none or minimal LF) in 26 cases and LF grade 2 or 3 (moderate-to-severe LF) in 8 cases. Correlation of LF with preoperatively determined IL-6 yielded significantly higher IL-6 levels in the group of patients with moderate-to-severe LF (Desmet 2 or 3) compared to the group with none or minimal LF (Desmet 0 or 1; p = 0.0495). Conclusion: In the context of LR, our results showed a correlation of preoperatively determined IL-6 with the extent of LF present. Higher serum baseline IL-6 concentrations were associated with a higher degree of LF, whereas no other blood parameter or score was that predictive for LF. Our results suggest that baseline IL-6 might serve as a valuable parameter to assess LF prior to LR. More patients need to be analyzed to further evaluate and confirm the predictive accuracy of IL-6 for LF.

Preoperative ultrasound elastography for postoperative pancreatic fistula prediction after pancreatoduodenectomy: A prospective study.

BACKGROUND: Postoperative pancreatic fistulas are the most frequent major complications after pancreatoduodenectomy. The soft pancreatic texture is a critical, independent risk factor for postoperative pancreatic fistulas after pancreatoduodenectomy. The current gold standard for postoperative pancreatic fistula risk evaluation consists of the surgeon's intraoperative palpation of the pancreatic texture and, thus, lacks objectivity. In this prospective study, we used ultrasound-based shear-wave elastography, image data analysis, and a fistula risk score calculator to correlate the stiffness of pancreatic tissue with the occurrence of clinically relevant postoperative pancreatic fistulas. METHODS: We included 100 patients with pancreatic pathologies (71% pancreatic ductal adenocarcinoma) and 100 healthy individuals who were preoperatively assessed via real-time tissue ultrasound-based shear-wave elastography on a Philips EPIQ 7 ultrasound device and had pancreatic parenchyma histologically evaluated with manually stained images. RESULTS: We found a significant difference in the mean elasticity between the soft (1.22 m/s) and the hard pancreas group (2.10 m/s; P < .0001). The mean elasticity significantly correlated with the pancreatic fibrosis rate and the appearance of a postoperative pancreatic fistula after pancreatoduodenectomy. Low elasticity (≤1.2 m/s, mean) correlated with soft and high elasticity (>2.0 m/s, mean) with hard pancreatic parenchyma, as assessed by pathologic evaluation. Multivariate analysis revealed a mean elasticity of <1.3 m/s as a significant cut-off predictor for clinically relevant postoperative pancreatic fistulas (P = .003; Youden-Index = 0.6945). CONCLUSION: Preoperative ultrasound-based shear-wave elastography is a feasible and objective clinical diagnostic modality in evaluating pancreatic tissue stiffness. A mean pancreatic elasticity of <1.3 m/s was a significant independent risk predictor of clinically relevant postoperative pancreatic fistulas after pancreatoduodenectomy.

Effect of Surgery on Postoperative Levels of the Gut Homeostasis-Regulating Enzyme Intestinal Alkaline Phosphatase.

BACKGROUND: Intestinal homeostasis is a crucial factor for complication-free short- and long-term postoperative recovery. The brush border enzyme intestinal alkaline phosphatase (IAP) is an important regulator of gut barrier function and intestinal homeostasis and prevents endotoxemia by detoxifying lipopolysaccharides (LPSs). As IAP is predominantly secreted by enterocytes in the duodenum, we hypothesized that pancreaticoduodenectomy (PD) leads to a significantly stronger decrease in IAP than other major abdominal surgery. STUDY DESIGN: Pre- and postoperative blood, stool, and intestinal samples were collected from patients undergoing PD, as well as other major surgical procedures without duodenectomy. The samples were analyzed using enzyme histochemistry, the para -nitrophenyl phosphate method for IAP, and the limulus amebocyte lysate assay for LPS. RESULTS: Overall, 88 patients were prospectively enrolled in the study. Fecal IAP activity negatively correlated with serum LPS (r = -0.3603, p = 0.0006). PD led to a significant decline in IAP compared to preoperative baseline levels (p < 0.0001). The decline in IAP correlated with the length of proximal small intestinal resection (r = 0.4271, p = 0.0034). Compared to controls, PD was associated with a much more pronounced reduction in IAP-also after adjusting for surgical trauma (operative time, blood loss; r = 0.4598, p = 0.0086). Simultaneously, PD triggered a clearly more prominent increase in serum LPS compared to controls (p = 0.0001). Increased postoperative LPS was associated with an elongated hospitalization (r = 0.7534, p = 0.0062) and more prominent in pancreatic cancer (p = 0.0009). CONCLUSIONS: Based upon the functional roles for IAP, supplementation with exogenous IAP might be a new treatment option to improve short- and long-term outcome after PD.

Tigecycline causes loss of cell viability mediated by mitochondrial OXPHOS and RAC1 in hepatocellular carcinoma cells.

BACKGROUND: Despite recent advances in locoregional, systemic, and novel checkpoint inhibitor treatment, hepatocellular carcinoma (HCC) is still associated with poor prognosis. The feasibility of potentially curative liver resection (LR) and transplantation (LT) is limited by the underlying liver disease and a shortage of organ donors. Especially after LR, high recurrence rates present a problem and circulating tumor cells are a major cause of extrahepatic recurrence. Tigecycline, a commonly used glycylcycline antibiotic, has been shown to have antitumorigenic effects and could be used as a perioperative and adjuvant therapeutic strategy to target circulating tumor cells. We aimed to investigate the effect of tigecycline on HCC cell lines and its mechanisms of action. METHODS: Huh7, HepG2, Hep3B, and immortalized hepatocytes underwent incubation with clinically relevant tigecycline concentrations, and the influence on proliferation, migration, and invasion was assessed in two- and three-dimensional in vitro assays, respectively. Bioinformatic analysis was used to identify specific targets of tigecycline. The expression of RAC1 was detected using western blot, RT-PCR and RNA sequencing. ELISA and flow cytometry were utilized to measure reactive oxygen species (ROS) generation upon tigecycline treatment and flow cytometry to detect alterations in cell cycle. Changes in mitochondrial function were detected via seahorse analysis. RNA sequencing was performed to examine involved pathways. RESULTS: Tigecycline treatment resulted in a significant reduction of mitochondrial function with concomitantly preserved mitochondrial size, which preceded the observed decrease in HCC cell viability. The sensitivity of HCC cells to tigecycline treatment was higher than that of immortalized non-cancerous THLE-2 hepatocytes. Tigecycline inhibited both migratory and invasive properties. Tigecycline application led to an increase of detected ROS and an S-phase cell cycle arrest. Bioinformatic analysis identified RAC1 as a likely target for tigecycline and the expression of this molecule was increased in HCC cells as a result of tigecycline treatment. CONCLUSION: Our study provides evidence for the antiproliferative effect of tigecycline in HCC. We show for the first time that this effect, likely to be mediated by reduced mitochondrial function, is associated with increased expression of RAC1. The reported effects of tigecycline with clinically relevant and achievable doses on HCC cells lay the groundwork for a conceivable use of this agent in cancer treatment.

WNT enhancing signals in pancreatic cancer are transmitted by LGR6.

The G-protein-coupled receptor LGR6 associates with ligands of the R-Spondin (RSPO) family to potentiate preexisting signals of the canonical WNT pathway. However, its importance in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we show that LGR6 is differentially expressed in various PDAC cell lines of mesenchymal and epithelial phenotype, respectively, siding with the latter subsets. LGR6 expression is altered based upon the cells' WNT activation status. Furthermore, extrinsic enhancement of WNT pathway signaling increased LGR6 expression suggestive of a reinforcing self-regulatory loop in highly WNT susceptible cells. Downregulation of LGR6 on the other hand, seemed to tamper those effects. Last, downregulation of LGR6 reduced cancer stemness as determined by functional in vitro assays. These findings shed new insights into regulatory mechanisms for the canonical WNT pathway in pancreatic cancer cells. It may also have potential value for treatment stratification of PDAC.

A Retrospective Analysis of Biliary Tract Cancer Patients Presented to the Molecular Tumor Board at the Comprehensive Cancer Center Munich.

BACKGROUND AND OBJECTIVE: With the rising importance of precision oncology in biliary tract cancer (BTC), the aim of this retrospective single-center analysis was to describe the clinical and molecular characteristics of patients with BTC who underwent comprehensive genomic profiling (CGP) and were discussed in the CCCMunichLMU molecular tumor board (MTB). PATIENTS AND METHODS: In this single-center observational study, we included BTC patients with intrahepatic cholangiocarcinoma (iCCA), extrahepatic CCA (eCCA), and gallbladder cancer (GB), who had been discussed in the institutional MTB from May 29, 2017, to July 25, 2022. Patients were followed up until 31 January 2023. Data were retrospectively collected by review of medical charts, and MTB recommendation. RESULTS: In total, 153 cases were registered to the MTB with a median follow-up of 15 months. Testing was successful in 81.7% of the patients. CGP detected targetable alterations in 35.3% of our BTC patients (most commonly ARID1A/ERBB2/IDH1/PIK3CA/BRAF-mutations and FGFR2-fusions). Recommendations for molecularly guided therapy were given in 46.4%. Of those, treatment implementation of targeted therapy followed in 19.4%. In patients receiving the recommended treatment, response rate was 57% and median overall survival was 19 months (vs 8 months in the untreated cohort). The progression-free survival ratio of 1.45 suggest a clinical benefit of molecularly guided treatment. CONCLUSIONS: In line with previous work, our series demonstrates feasibility and clinical utility of comprehensive genomic profiling in BTC patients. With the growing number of targeted agents with clinical activity in BTC, CGP should become standard of care in the management of this group of patients.

Tff2 defines transit-amplifying pancreatic acinar progenitors that lack regenerative potential and are protective against Kras-driven carcinogenesis.

While adult pancreatic stem cells are thought not to exist, it is now appreciated that the acinar compartment harbors progenitors, including tissue-repairing facultative progenitors (FPs). Here, we study a pancreatic acinar population marked by trefoil factor 2 (Tff2) expression. Long-term lineage tracing and single-cell RNA sequencing (scRNA-seq) analysis of Tff2-DTR-CreERT2-targeted cells defines a transit-amplifying progenitor (TAP) population that contributes to normal homeostasis. Following acute and chronic injury, Tff2+ cells, distinct from FPs, undergo depopulation but are eventually replenished. At baseline, oncogenic KrasG12D-targeted Tff2+ cells are resistant to PDAC initiation. However, KrasG12D activation in Tff2+ cells leads to survival and clonal expansion following pancreatitis and a cancer stem/progenitor cell-like state. Selective ablation of Tff2+ cells prior to KrasG12D activation in Mist1+ acinar or Dclk1+ FP cells results in enhanced tumorigenesis, which can be partially rescued by adenoviral Tff2 treatment. Together, Tff2 defines a pancreatic TAP population that protects against Kras-driven carcinogenesis.

In-vitro model to mimic T cell subset change in human PDAC organoid co-culture.

PURPOSE: Immunotherapies have largely failed as treatment options for pancreatic ductal adenocarcinoma (PDAC). In this field, clinical translational studies into personalized treatment are of fundamental importance. In our study, we model tumor-cell immune-cell interactions in a co-culture of primary human PDAC organoids and matched peripheral blood mononuclear cells (PBMCs). METHODS: Using flow cytometry, we evaluated changes in T cell subtypes upon co-culture of patient-derived PDAC organoids and matched PBMCs. RESULTS: After co-culturing PDAC organoids with PBMCs, we observed changes in CD4+, CD8+ and Treg cell populations. We observed favorable clinical outcome in patients whose PBMCs reacted to the co-culture with organoids. CONCLUSION: This experimental model allows to investigate interactions between patient derived PDAC organoids and their PBMCs. This co-culture system could serve as a preclinical platform to guide personalized therapeutic strategies in the future.

Diagnostic and Therapeutic Management of Early Colorectal Cancer.

Background: Early colorectal cancer (eCRC) is defined as cancer that does not cross the submucosal layer of the colon or rectum, including carcinoma in situ (pTis), pT1a, and pT1b. Early carcinomas differ in their prognosis depending on the risk profile. The differentiation between low and high risk is essential. The low-risk group includes R0-resected, well (G1) or moderately (G2) differentiated tumors without lymphatic vessel invasion (L0), without blood vessel invasion (V0) and a tumor size ≤3 cm. In this constellation, the estimated risk of lymph node metastasis is around 1% or below. The high-risk group includes tumors with incomplete resection (Rx), poor (G3) or undifferentiated (G4) carcinomas, and/or lymphatic and blood vessel invasion (L1) and size ≥3 cm. In a "high-risk" situation, there is a risk for lymph node metastasis of up to 23%. Summary: The incidence of eCRC is rising with a rate of 10% in all endoscopically removed lesions during colonoscopy. For a correct histological evaluation, all suspected lesions should be completely resected. In case of a pT1 lesion in the rectum, pelvic magnetic resonance imaging should be performed to evaluate for suspicious lymph nodes. The therapeutic approach for eCRC is based on histological assessment and ranges from endoscopic resection to radical oncological surgery. The advantages, disadvantages, and associated risks of the individual treatment strategy need to be carefully discussed on a tumor board and with the patient. Key Messages: Treatment options for early colorectal cancer depend on the histological assessment. Poorly differentiated carcinomas, a Kudo ≥ SM2 classified lesion, and a Haggitt level 4 always represent a "high-risk" situation. It should also be mentioned that in rectal cancer, local surgical tumor excision (full-wall excision) is also sufficient for pT1 carcinomas with a "low-risk" constellation (G1/G2; L0, size <3 cm) and an R0 resection.

Precision Oncology in Pancreatic Cancer: Experiences and Challenges of the CCCMunichLMU Molecular Tumor Board.

BACKGROUND: In pancreatic cancer, systemic treatment options in addition to chemotherapy remain scarce, and so far only a small proportion of patients benefit from targeted therapies. OBJECTIVE: The patients with pancreatic cancer discussed in the CCCMunichLMU Molecular Tumor Board were reviewed to gain a better real-world understanding of the challenges and chances of precision oncology in this hard-to-treat cancer. METHODS: Patients with pancreatic cancer who received comprehensive genomic profiling and were discussed in the interdisciplinary Molecular Tumor Board between May 2017 and July 2022 were included. These patients' medical charts, comprehensive genomic profiling results, and Molecular Tumor Board recommendations were analyzed in this retrospective cohort study. RESULTS: Molecular profiles of 165 patients with pancreatic cancer were discussed in the Molecular Tumor Board. In the 149 cases where comprehensive genomic profiling was successful, KRAS mutations were detected in 87.9%, TP53 in 53.0%, and CDKN2A in 14.1%. 33.3% of KRAS wild-type patients harbored targetable mutations, while these were only found in 19.1% of patients with the KRAS mutation; however, this difference was not statistically significant. 63.8% of patients with successful testing received a targeted treatment recommendation by the Molecular Tumor Board; however, only 3.2% of these were put into practice. Compared to a historic cohort of patients with pancreatic cancer with synchronous metastatic disease diagnosed between 2010 and 2017, the patients from the pancreatic cancer cohort with synchronous metastatic disease had a longer survival. CONCLUSIONS: This single-center experience emphasizes the challenges of targeted treatment in pancreatic cancer. Very few patients ultimately received the recommended therapies, highlighting the need for more and better targeted treatment options in pancreatic cancer, early comprehensive genomic profiling to allow sufficient time to put Molecular Tumor Board recommendations into practice, and close cooperation with clinical trial units to give patients access to otherwise not available targeted treatments.

The cathepsin-S/protease-activated receptor-(PAR)-2 axis drives chronic allograft vasculopathy and is a molecular target for therapeutic intervention.

BACKGROUND: Cathepsin S (CatS) and proteinase-activated receptor (PAR)-2 are involved in the remodelling of vascular walls and neointima formation as well as in alloantigen presentation and T-cell priming. Therefore, we hypothesized that CatS/PAR-2 inhibition/deficiency would attenuate chronic allograft vasculopathy. METHODS: Heterotopic aortic murine transplantation was performed from C57BL/6J donors to C57BL/6J recipients (syngeneic control group), Balb/c to C57BL/6J without treatment (allogenic control group), Balb/c to C57BL/6J with twice daily oral CatS inhibitor (allogenic treatment group) and Balb/c to Par2-/- C57BL/6J (allogenic knockout group). The recipients were sacrificed on day 28 and the grafts were harvested for histological analysis and RT-qPCR. RESULTS: After 28 days, mice of the allogenic control group exhibited significant neointima formation and massive CD8 T-cell infiltration into the neointima while the syngeneic control group showed negligible allograft vasculopathy. The mRNA expression level of CatS in allografts was 5-fold of those in syngeneic grafts. Neointima formation and therefore intima/media-ratio were significantly decreased in the treatment and knockout group in comparison to the allogenic control group. Mice in treatment group also displayed significantly fewer CD8 T cells in the neointima compared with allogeneic controls. Additionally, treatment with the CatS inhibitor and PAR2-deficiency decreased mRNA-levels of interleukins and cytokines. CONCLUSION: In conclusion, our data indicate that inhibiting CatS and PAR-2 deficiency led to a marked reduction of neointima formation and associated inflammation in a murine heterotopic model for allograft vasculopathy.

Lessons learned: the first consecutive 1000 patients of the CCCMunichLMU Molecular Tumor Board.

PURPOSE: In 2016, the University of Munich Molecular Tumor Board (MTB) was implemented to initiate a precision oncology program. This review of cases was conducted to assess clinical implications and functionality of the program, to identify current limitations and to inform future directions of these efforts. METHODS: Charts, molecular profiles, and tumor board decisions of the first 1000 consecutive cases (01/2016-03/2020) were reviewed. Descriptive statistics were applied to describe relevant findings. RESULTS: Of the first 1000 patients presented to the MTB; 914 patients received comprehensive genomic profiling. Median age of patients was 56 years and 58% were female. The most prevalent diagnoses were breast (16%) and colorectal cancer (10%). Different types of targeted or genome-wide sequencing assays were used; most of them offered by the local department of pathology. Testing was technically successful in 88%. In 41% of cases, a genomic alteration triggered a therapeutic recommendation. The fraction of patients receiving a tumor board recommendation differed significantly between malignancies ranging from over 50% in breast or biliary tract to less than 30% in pancreatic cancers. Based on a retrospective chart review, 17% of patients with an MTB recommendation received appropriate treatment. CONCLUSION: Based on these retrospective analyses, patients with certain malignancies (breast and biliary tract cancer) tend to be more likely to have actionable variants. The low rate of therapeutic implementation (17% of patients receiving a tumor board recommendation) underscores the importance of meticulous follow-up for these patients and ensuring broad access to innovative therapies for patients receiving molecular tumor profiling.

Prognostic value of primary tumor sidedness in patients with non-metastatic IBD related CRC - Is it the exception to the rule?

BACKGROUND: Although primary tumor sidedness (PTS) has a known prognostic role in sporadic colorectal cancer (CRC), its role in Inflammatory Bowel Disease related CRC (IBD-CRC) is largely unknown. Thus, we aimed to evaluate the prognostic role of PTS in patients with IBD-CRC. METHODS: All eligible patients with surgically treated, non-metastatic IBD-CRC were retrospectively identified from institutional databases at ten European and Asian academic centers. Long term endpoints included recurrence-free (RFS) and overall survival (OS). Multivariable Cox proportional hazard regression as well as propensity score analyses were performed to evaluate whether PTS was significantly associated with RFS and OS. RESULTS: A total of 213 patients were included in the analysis, of which 32.4% had right-sided (RS) tumors and 67.6% had left-sided (LS) tumors. PTS was not associated with OS and RFS even on univariable analysis (5-year OS for RS vs LS tumors was 68.0% vs 77.3%, respectively, p = 0.31; 5-year RFS for RS vs LS tumors was 62.8% vs 65.4%, respectively, p = 0.51). Similarly, PTS was not associated with OS and RFS on propensity score matched analysis (5-year OS for RS vs LS tumors was 82.9% vs 91.3%, p = 0.79; 5-year RFS for RS vs LS tumors was 85.1% vs 81.5%, p = 0.69). These results were maintained when OS and RFS were calculated in patients with RS vs LS tumors after excluding patients with rectal tumors (5-year OS for RS vs LS tumors was 68.0% vs 77.2%, respectively, p = 0.38; 5-year RFS for RS vs LS tumors was 62.8% vs 59.2%, respectively, p = 0.98). CONCLUSIONS: In contrast to sporadic CRC, PTS does not appear to have a prognostic role in IBD-CRC.

PBXIP1 - An indicator for poor outcome and metastatic spread in colorectal cancer.

Tumor cell heterogeneity in colorectal cancers within the same genetic background is a well-described phenomenon. In this work, we investigate the role of hematopoietic pre-B-cell leukemia transcription factor (PBX)-interacting protein (HPIP/PBXIP1) in tumor cell subpopulations with differential Wingless-related integration site (WNT) activity as well as its potential associations with epithelial-mesenchymal transition (EMT) and clinical associations in colorectal cancer. We used in situ analyses to identify immunohistochemical expression of PBXIP1 in normal and colorectal cancer tissues and biostatistical approaches to determine its function and regulatory correlations. Clinical associations were analyzed in a case control collection of metastatic and non-metastatic colon cancers and gene expression data sets of colorectal cancers with recorded clinical follow-up data. PBXIP1 was expressed in single epithelial cells from tumor-free colon crypts as well as in tumor cells with high WNT activity. Colorectal cancer cells close to the invasive edge seemed to possess higher PBXIP1 levels indicative of associations with EMT, whereas stromal cells in the tumor microenvironment appeared mostly negative. PBXIP1 expression was associated with local metastasis to lymph nodes as well as distant metastasis to secondary organs in a case-control collection consisting of 91 cases with or without distant metastasis. Furthermore, high expression of PBXIP1 in The Cancer Genome Atlas (TCGA) data set was associated with worse overall survival in colon cancer. PBXIP1 might serve as a novel histological prognostic and regulatory indicator for EMT processes in colorectal cancer that seems to correlate with cancer cell subtypes of high baseline WNT activity.

Adult enteric Dclk1-positive glial and neuronal cells reveal distinct responses to acute intestinal injury.

Intestinal ganglionic cells in the adult enteric nervous system (ENS) are continually exposed to stimuli from the surrounding microenvironment and need at times to respond to disturbed homeostasis following acute intestinal injury. The kinase DCLK1 and intestinal Dclk1-positive cells have been reported to contribute to intestinal regeneration. Although Dclk1-positive cells are present in adult enteric ganglia, their cellular identity and response to acute injury have not been investigated in detail. Here, we reveal the presence of distinct Dclk1-tdTom+/CD49b+ glial-like and Dclk1-tdTom+/CD49b- neuronal cell types in adult myenteric ganglia. These ganglionic cells demonstrate distinct patterns of tracing over time yet show a similar expansion in response to elevated serotonergic signaling. Interestingly, Dclk1-tdTom+ glial-like and neuronal cell types appear resistant to acute irradiation injury-mediated cell death. Moreover, Dclk1-tdTom+/CD49b+ glial-like cells show prominent changes in gene expression profiles induced by injury, in contrast to Dclk1-tdTom+/CD49b- neuronal cell types. Finally, subsets of Dclk1-tdTom+/CD49b+ glial-like cells demonstrate prominent overlap with Nestin and p75NTR and strong responses to elevated serotonergic signaling or acute injury. These findings, together with their role in early development and their neural crest-like gene expression signature, suggest the presence of reserve progenitor cells in the adult Dclk1 glial cell lineage.NEW & NOTEWORTHY The kinase DCLK1 identifies glial-like and neuronal cell types in adult murine enteric ganglia, which resist acute injury-mediated cell death yet differ in their cellular response to injury. Interestingly, Dclk1-labeled glial-like cells show prominent transcriptional changes in response to injury and harbor features reminiscent of previously described enteric neural precursor cells. Our data thus add to recently emerging evidence of reserve cellular plasticity in the adult enteric nervous system.

Myeloid-Derived Suppressor Cells in Solid Tumors.

Myeloid-derived suppressor cells (MDSCs) are one of the main suppressive cell population of the immune system. They play a pivotal role in the establishment of the tumor microenvironment (TME). In the context of cancers or other pathological conditions, MDSCs can differentiate, expand, and migrate in large quantities during circulation, inhibiting the cytotoxic functions of T cells and NK cells. This process is regulated by ROS, iNOS/NO, arginase-1, and multiple soluble cytokines. The definition of MDSCs and their phenotypes in humans are not as well represented as in other organisms such as mice, owing to the absence of the cognate molecule. However, a comprehensive understanding of the differences between different species and subsets will be beneficial for clarifying the immunosuppressive properties and potential clinical values of these cells during tumor progression. Recently, experimental evidence and clinical investigations have demonstrated that MDSCs have a close relationship with poor prognosis and drug resistance, which is considered to be a leading marker for practical applications and therapeutic methods. In this review, we summarize the remarkable position of MDSCs in solid tumors, explain their classifications in different models, and introduce new treatment approaches to target MDSCs to better understand the advancement of new approaches to cancer treatment.

Specific intraoperative antibiotic therapy abrogates the negative effect of biliary contamination on the Comprehensive Complication Index after pancreatic head resection.

BACKGROUND: The effect of bacterobilia on morbidity after pancreatoduodenectomy remains unclear. The aim of this study was to examine the influence of positive intraoperative bile cultures and perioperative antibiotic prophylaxis on morbidity measured using the Comprehensive Complication Index, a weighted composite of postoperative complications. METHODS: Intraoperative bile cultures of 182 patients who underwent pancreatoduodenectomy were obtained. We examined the effect of intraoperative bile cultures and perioperative antibiotic prophylaxis on the Comprehensive Complication Index and the occurrence of postoperative complications. To this aim, we performed general linear models controlling for relevant demographic and perioperative factors. RESULTS: Positive (versus negative) intraoperative bile cultures were associated with a higher mean Comprehensive Complication Index (25.34 vs 16.81, P = .025). The mean Comprehensive Complication Index differed significantly between individuals with positive intraoperative bile cultures and bacterial strains not covered by perioperative antibiotic prophylaxis (26.2) versus positive intraoperative bile cultures and bacterial strains sensitive to perioperative antibiotic prophylaxis (22.7) (P = .045). Positive (versus negative) intraoperative bile cultures were associated with 4.75 times (95% confidence interval: 1.74-13.00, P = .002) greater odds of wound infections. The odds of wound infection were 1.93 times (95% confidence interval: .47-8.04) greater in those with positive intraoperative bile cultures and adequate perioperative antibiotic prophylaxis and 6.14 times (95% confidence interval: 2.17-17.35) greater in those with positive intraoperative bile cultures and inadequate perioperative antibiotic prophylaxis (versus negative intraoperative bile cultures) (P = .001). CONCLUSION: Bacterobilia is associated with a significant increase in Comprehensive Complication Index and wound infections after pancreatoduodenectomy, which may be reduced by administration of a specific perioperative antibiotic prophylaxis. Acquisition of bile cultures sampled through the external conduit of patients with preoperative biliary drainage could help in selecting a specific perioperative antibiotic prophylaxis and patients with bile duct stents might benefit from broad spectrum perioperative antibiotic prophylaxis.

Pylorus resection versus pylorus preservation in pancreatoduodenectomy (PyloResPres): study protocol and statistical analysis plan for a German multicentre, single-blind, surgical, registry-based randomised controlled trial.

INTRODUCTION: Partial pancreatoduodenectomy (PD) is the treatment of choice for various benign and malignant tumours of the pancreatic head or the periampullary region. For reconstruction of the gastrointestinal passage, two stomach-preserving PD variants exist: pylorus preservation PD (ppPD) or pylorus resection PD (prPD) with preservation of the stomach. In pancreatic surgery, delayed gastric emptying (DGE) remains a serious complication after PD with an incidence varying between 4.5% and 45%, potentially delaying hospital discharge or further treatment, for example, adjuvant chemotherapy. Evidence is lacking to assess, which variant of PD entails fewer postoperative DGE. METHODS AND ANALYSIS: The protocol of a large-scale, multicentre, pragmatic, two-arm parallel-group, registry-based randomised controlled trial (rRCT) using a two-stage group-sequential design is presented. This patient-blind rRCT aims to demonstrate the superiority of prPD over ppPD with respect to the overall incidence of DGE within 30 days after index surgery in a German real-world setting. A total of 984 adults undergoing elective PD for any indication will be randomised in a 1:1 ratio. Patients will be recruited at about 30 hospitals being members of the StuDoQ|Pancreas registry established by the German Society of General and Visceral Surgery. The postoperative follow-up for each patient will be 30 days. The primary analysis will follow an intention-to-treat approach and applies a binary logistic random intercepts model. Secondary perioperative outcomes include overall severe morbidity (Clavien-Dindo classification), blood loss, 30-day all-cause mortality, postoperative hospital stay and operation time. Complication rates and adverse events will be closely monitored. ETHICS AND DISSEMINATION: This protocol was approved by the leading ethics committee of the Medical Faculty of the Ludwig-Maximilians-Universität, Munich (reference number 19-221). The results will be published in a peer-reviewed journal and presented at international conferences. Study findings will also be disseminated via the website (http://www.dgav.de/studoq/pylorespres/). TRIAL REGISTRATION NUMBER: DRKS-ID: DRKS00018842.