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Abstract Background Ductal pancreatic adenocarcinoma (PDAC) still has a dismal prognosis even when deemed resectable. A cancer free resection margin (R0) is associated with a more favourable prognosis than the presence of tumour cells at resection margin (R1). However, the precise definition of the R0 status is still a matter of debate in PDAC. For a more accurate determination of R0 in PDAC the concept of circumferential resection margins (CRM) has been established and has been incorporated into the German national S3 guideline on exocrine pancreatic cancer. However, an international standardized nomenclature of CRM is still missing, and the clinical value of the CRM concept is not yet fully established. Here we evaluate whether the CRM status as defined in the national German S3 guideline corresponds with overall and progression free survival in PDAC using data from the regional cancer registry of the State of Baden Württemberg in Germany. Methods Data from the cancer registry of the State of Baden-Württemberg, Germany, were used to assess the relationship between CRM-status and progression free survival (PFS) as well as 3-year overall survival (OS) using documented patients diagnosed with resectable ductal adenocarcinoma of the pancreas between 2015 and 2020. Patients were residents of the State of Baden-Württemberg and underwent surgery for PDAC. The R-status was assessed according to the national German S3 guideline with R0 wide/CRM- when CRM is > 1 mm from the tumour, R0 narrow/CRM + when CRM is ≤ 1 mm from the tumour and R1 when tumour cells are found at the resection margin. Results In total we identified 1098 cases surgically treated for pancreatic cancer and fulfilling the inclusion criteria. 340 patients had an R0 wide/CRM- resection, 410 patients an R0 narrow/CRM + resection, and 348 patients an R1 resection. The R0 wide/CRM- status was associated with a significantly increased median OS rate compared to the other two groups (51,5%, 37,4% and 26,7% for R0 wide/CRM-, R0 narrow/CRM + and R1, respectively). mPFS was also longer in the R0 wide/CRM- group. These findings were robust with regards to grading and tumour location. Conclusions CRM is prognostic for patients with resectable PDAC making the pathological assessment of the R-status according to the CRM concept worthwhile.

[english] Introduction: Soft tissue sarcomas (STS) are rare tumors. Based on histopathological criteria, three grades are distinguished from low (G1) to intermediate (G2) and high grade (G3). After complete initial surgical resection, some G1 STS recur as lesions with an upgrade of a previous G1 STS to a recurrent G2 STS. This upgrade indicates higher malignancy of the STS. Our aim was to find possible risk factors for these upgrades including age, localization of tumor and tumor type. Methods: This retrospective case-control study evaluated 333 patients. Of these 333, 54.7% were male and 45.3% female. All patients underwent R0 resections and among these, 10% subsequently upgraded. The processed data include age, gender, tumor type, tumor localization, local recurrence and upgrade. Results: Patients with upgrades have a higher mean age of 5.5 years than our reference collective. The tumor type has a significant effect on upgrades. Patients with fibrosarcomas are at a threefold risk of an upgrade compared to patients with other G1 STS.Conclusion: Our results indicate that age and tumor type play a key role in upgrades in G1 STS. Patients, age 60 and above and diagnosed with G1 fibrosarcomas, are three times as likely to upgrade compared to patients younger than 60 with other G1 STS. We discuss the significance of these risk factors and whether aside from complete tumor resection, additional therapies (e.g. irradiation) may be applied to improve therapeutic outcome.

Adenosquamous carcinoma of the skin (ASCS) or primary cutaneous adenosquamous carcinoma is a rare malignant neoplasm. It is characterized by the presence of both glandular and squamous cell components and a propensity for aggressive clinical behavior. Due to its rarity, it continues to pose diagnostic challenges. To date, only a few cases of this tumor have been reported, and even fewer have been thoroughly investigated via immunohistochemistry.

Despite multiple recent advances in systemic therapy for metastatic breast cancer, cases which display suboptimal response to guideline-driven treatment are frequently seen in the clinic. Effective options for such patients are limited, particularly in later line of therapy, and selection of optimal treatment options is essentially empirical and based largely on considerations of previous regimens received. Comprehensive cancer profiling includes detection of genetic alterations in tissue and circulating tumor DNA (ctDNA), immunohistochemistry (IHC) from re-biopsied metastatic disease, circulating tumor cells (CTCs), gene expression analysis and pharmacogenomics. The advent of this methodology and application to metastatic breast cancer, facilitates a more scientifically informed approach to identification of optimal systemic therapy approaches independent of the restrictions implied by clinical guidelines. Here we describe a case of metastatic breast cancer where consecutive comprehensive tumor profiling reveals ongoing tumor evolution, guiding the identification of novel effective therapeutic strategies.

Although approximately half of all metastatic colorectal cancers (mCRCs) harbour mutations in KRAS or NRAS, hardly any progress has been made regarding targeted treatment for this group over the last few years. Here, we investigated the efficacy of vertical inhibition of the RAS‐pathway by targeting epidermal growth factor receptor (EGFR) and mitogen‐activated protein kinase kinase (MEK) in patient‐derived xenograft (PDX) tumours with primary KRAS mutation. In total, 19 different PDX models comprising 127 tumours were tested. Responses were evaluated according to baseline tumour volume changes and graded as partial response (PR; ≤ − 30%), stable disease (SD; between −30% and +20%) or progressive disease (PD; ≥ + 20%). Vertical inhibition with trametinib and cetuximab induced SD or PR in 74% of analysed models, compared to 24% by monotherapy with trametinib. In cases of PR by vertical inhibition (47%), responses were lasting (as long as day 137), with a low incidence of secondary resistance (SR). Molecular analyses revealed that primary and SR was driven by transcriptional reprogramming activating the RAS pathway in a substantial fraction of tumours. Together, these preclinical data strongly support the translation of this combination therapy into clinical trials for CRC patients.

Abstract Intrahepatic cholangiocarcinoma harbours druggable genetic lesions including FGFR2 gene fusions. Reliable and accurate detection of these fusions is becoming a critical component of the molecular work‐up, but real‐world data on the performance of fluorescence in situ hybridisation (FISH) and targeted RNA‐based next‐generation sequencing (NGS) are very limited. Bridging this gap, we report results of the first round robin test for FGFR2 fusions in cholangiocarcinoma and contextualise test data with genomic architecture. A cohort of 10 cholangiocarcinoma (4 fusion positive and 6 fusion negative) was tested by the Institute of Pathology, University Hospital Heidelberg, Germany. Data were validated by four academic pathology departments in Germany. Fusion‐positive cases comprised FGFR2::BICC1, FGFR2::DBP, FGFR2::TRIM8, and FGFR2::ATE1 fusions. In a second step, a round robin test involving 21 academic and non‐academic centres testing with RNA‐based NGS approaches was carried out; five participants performed FISH testing in addition. Thirteen of 16 (81%) centres successfully passed the NGS only and 3 of 5 (60%) centres passed the combined NGS + FISH round robin test. Identified obstacles were bioinformatic pipelines not optimised for the detection of FGFR2 fusions and assays not capable of detecting unknown fusion partners. This study shows the benefit of targeted RNA‐NGS for the detection of FGFR2 gene fusions. Due to the marked heterogeneity of the genomic architecture of these fusions, fusion partner agnostic (i.e. open) methodological approaches that are capable of identifying yet unknown fusion partners are superior. Furthermore, we highlight pitfalls in subsequent bioinformatic analysis and limitations of FISH‐based tests.

Gastric carcinomas are among the most common cancers in Germany, with approximately 18,000 new cases per year.About 10 years ago, based on results of the Trastuzumab for gastric cancer (ToGA) trial, the addition of the monoclonal antibody trastuzumab to a platinum-fluoropyrimidine chemotherapy backbone became the standard-of-care 1st-line therapy for human epidermal growth factor receptor 2 (HER2)-positive gastric cancers. Only patients with primary HER2 gene amplification benefit from this therapy. Thus, accurate HER2 gene amplification detection is predictive and critical for therapy selection. As a gold standard the HER2 status is currently determined in tumor tissue specimens using immune histochemistry and fluorescent in situ hybridisation. However, HER2 amplification is detectable in only about 20 % of gastric carcinomas. The recent approval of an antibody-drug conjugate Trastuzumab deruxtecan (T-DXd) and the establishment of a new subgroup of HER2-low tumors due to the bystander effect associated with T-DXd increases the relevance of precise HER2 diagnostics.Aim of this analysis was to determine the HER2 amplification status from circulating DNA fragments in blood using a HER2 Copy Number Variation assay to establish a minimal invasive approach.For the present study, a digital droplet PCR-based method was validated relative to established tissue-based methods. Furthermore and most importantly, the changes of HER2 status during therapy were investigated in seven patients indicating that the changes of HER2 status and number of HER2 copies detected in blood can reflect on therapy efficiency and uncover treatment resistance.

Background Oral cladribine (OC) is approved for the treatment of highly active relapsing multiple sclerosis. Postmarketing safety assessments have reported rare, but occasionally severe cases of liver injury in temporal association with OC, with pathophysiologic mechanisms still unknown. In the only detailed case report on this topic, idiosyncratic drug-induced liver injury (iDILI) during OC treatment was well characterised for the first time, but occurred in the context of prior high-dose steroid exposure. Although high-dose steroids are known to induce iDILI in patients with multiple sclerosis with a delay of up to 12 weeks, OC was assumed to be the culprit agent for observed liver injury and the role of steroid exposure was not further investigated.Case Herein, we describe a case of a 35-year-old women treated with high-dose oral prednisolone during the first treatment cycle OC and subsequently developed iDILI. A causality assessment of the role of prednisolone and OC was performed using the updated Roussel Uclaf Causality Assessment Method which also included a negative re-exposure test for OC during the second OC treatment cycle 1 year later.Conclusion Our observations suggest that prednisolone or interactions between prednisolone and OC are more likely to foster development of iDILI rather than OC treatment itself.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) lacks effective treatment options beyond chemotherapy. Although molecular subtypes such as classical and QM (quasi-mesenchymal)/basal-like with transcriptome-based distinct signatures have been identified, deduced therapeutic strategies and targets remain elusive. Gene expression data show enrichment of glycolytic genes in the more aggressive and therapy-resistant QM subtype. However, whether the glycolytic transcripts are translated into functional glycolysis that could further be explored for metabolic targeting in QM subtype is still not known. Methods We used different patient-derived PDAC model systems (conventional and primary patient-derived cells, patient-derived xenografts (PDX), and patient samples) and performed transcriptional and functional metabolic analysis. These included RNAseq and Illumina HT12 bead array, in vitro Seahorse metabolic flux assays and metabolic drug targeting, and in vivo hyperpolarized [1-13C]pyruvate and [1-13C]lactate magnetic resonance spectroscopy (HP-MRS) in PDAC xenografts. Results We found that glycolytic metabolic dependencies are not unambiguously functionally exposed in all QM PDACs. Metabolic analysis demonstrated functional metabolic heterogeneity in patient-derived primary cells and less so in conventional cell lines independent of molecular subtype. Importantly, we observed that the glycolytic product lactate is actively imported into the PDAC cells and used in mitochondrial oxidation in both classical and QM PDAC cells, although more actively in the QM cell lines. By using HP-MRS, we were able to noninvasively identify highly glycolytic PDAC xenografts by detecting the last glycolytic enzymatic step and prominent intra-tumoral [1-13C]pyruvate and [1-13C]lactate interconversion in vivo. Conclusion Our study adds functional metabolic phenotyping to transcriptome-based analysis and proposes a functional approach to identify highly glycolytic PDACs as candidates for antimetabolic therapeutic avenues.

Abstract Background Colon cancer (CC) is a disease of elderly patients (pts.) with a median age of 73 years (yrs.). Lack of data about the effects of adjuvant chemotherapy (ACT) is caused by underrepresentation of this clinically relevant cohort in interventional trials. We analyzed real‐world data from the German CPP registry with regard to a possible benefit of ACT in elderly (70+ yrs.) versus younger pts. (50 to

Background: Reimplantations of autologous skull flaps after decompressive hemicraniectomies (DHs) are associated with high rates of postoperative bone flap resorption (BFR). We histologically assessed the cell viability of explanted bone flaps in certain periods of time after DH, in order to conclude whether precursors of BRF may be developed during their storage. Methods: Skull bone flaps explanted during a DH between 2019 and 2020 were stored in a freezer at either −23 °C or −80 °C. After their thawing process, the skulls were collected. Parameters of bone metabolism, namely PTH1 and OPG, were analyzed via immunohistochemistry. H&E stain was used to assess the degree of avital bone tissue, whereas the repeated assays were performed after 6 months. Results: A total of 17 stored skull flaps (8 at −23 °C; 9 at −80 °C) were analyzed. The duration of cryopreservation varied between 2 and 17 months. A relevant degree of bone avitality was observed in all skull flaps, which significantly increased at the repeated evaluation after 6 months (p < 0.001). Preservation at −23 °C (p = 0.006) as well as longer storage times (p < 0.001) were identified as prognostic factors for higher rates of bone avitality in a linear mixed regression model. Conclusions: Our novel finding shows a clear benefit from storage at −80° C, which should be carefully considered for the future management and storage of explanted skull flaps. Our analysis also further revealed a significant degree of bone avitality, a potential precursor of BFR, in skull flaps stored for several weeks. To this end, we should reconsider whether the reimplantation of autologous skull flaps instead of synthetic skull flaps is still justified.

BackgroundThe prognostic effect of resection margin status following pancreatoduodenectomy for pancreatic ductal adenocarcinoma (PDAC) remains controversial, even with the implementation of standardized pathological assessment. We therefore investigated the impact of resection margin (RM) status and RM distance in curative resected PDAC on overall survival (OS), disease-free survival (DFS) and recurrence.Method108 patients were retrieved from a prospectively maintained database of a certified pancreatic cancer center. Distribution and relationships between circumferential resection margin (CRM) involvement (CRM≤1mm; CRM>1mm; CRM≥2mm) and their prognostic impact on OS and DFS were assessed using Kaplan-Meier statistics and the Log-Rank test. Multivariate logistic regression was used explain the development of a recurrence 12 months after surgery.Results63 out of 108 patients had medial RM and 32 posterior RM involvement. There was no significant difference in OS and DFS between CRM≤1mm and CRM>1mm resections. Clearance at the medial margin of ≥2mm had an impact on OS and DFS, (RM≥2mm vs. RMConclusionNot all RM seem to have the same impact on OS and DFS, and a clearance of 1mm for definition of a negative RM (i.e. CRM>1mm) seems not sufficient. Future studies should include more patients to stratify for potential confounders we could not account for.Trial registrationThis study was registered with the German Clinical Trials Registry (reference number DRKS0017425).

Purpose The aim of this study was to retrospectively evaluate contrast-enhanced ultrasound (CEUS) findings in patients with peliosis hepatis (PH). Methods A retrospective analysis was conducted of CEUS features in 24 patients with histopathologically confirmed PH (11 men and 13 women; mean age, 32.4±7.1 years; range, 28 to 41 years). All lesions were histologically proven, either by core needle biopsy (n=10) or by hepatic surgery (n=14). Results The mean size was 36.8±12.4 mm (range, 10 to 80 mm). On B-mode ultrasonography (BMUS), all PH lesions were heterogeneously hypoechoic, with well-defined margins but irregular shapes. No mass effect was observed. During the arterial phase of CEUS, all lesions displayed mild heterogeneous hyperenhancement (83.3%, 20/24) or isoenhancement (16.7%, 4/24). Furthermore, 87.5% of the PH lesions showed mild washout after 1 minute in the portal venous phase (30-120 seconds) and mild washout in the late phase (>120 seconds). Conclusion The lack of a mass effect on BMUS, mild heterogeneous arterial hyperenhancement, and washout in the very late portal venous phase (after 1 minute) on CEUS are characteristic of PH. Although it is a histological diagnosis, PH should be considered in the differential diagnosis when the clinical context does not favor a malignancy or infection.

There exist relatively sparse and conflicting data on high-level microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) in cutaneous malignancies. We aimed to determine the expression profiles of MMR proteins (MSH2, MSH6, MLH1, and PMS2) in different progression stages of cutaneous squamous cell carcinoma (cSCC, 102 patients in total) by immunohistochemistry, and search for MSI-H in patients with low-level MMR or dMMR using multiplex-PCR. Low-level MMR protein expression was observed in five patients: One patient with primary cSCC < 2 mm thickness and low-level MLH1, three patients with primary cSCC > 6 mm (including one with low-level MSH2, as well as MSH6 expression, and two with low-level PMS2), and one patient with a cSCC metastasis showing low-level MSH2 as well as MSH6. Intergroup protein expression analysis revealed that MLH1 and MSH2 expression in actinic keratosis was significantly decreased when compared to Bowen’s disease, cSCC < 2 mm, cSCC > 6 mm, and cSCC metastasis. In cases with low-level MMR, we performed MSI-H tests revealing three cases with MSI-H and one with low-level MSI-L. We found low-level MMR expression in a small subset of patients with invasive or metastatic cSCC. Hence, loss of MMR expression may be associated with tumour progression in a small subgroup of patients with non-melanoma skin cancer.

Abstract Background The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms. Methods We analyzed 21 KRAS, NRAS, BRAF, and PI3K wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways. Results In vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies. Conclusions Our study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC.

Neuroendocrine breast cancer (NEBC) is a rare entity accounting for

A malignant ureteral obstruction is most often due to primary tumors of the ureter. However, it can occur secondary due to external tumor compression or metastatic infiltration. Distant metastases to the ureter are extremely rare. We present a case of a rare double distant metachronic metastasis to the right ureter as well as to the right renal pelvis in a 58-year-old female with a history of anterior resection for rectal cancer 2 years earlier. She presented with recurrent urinary tract infection and right hydronephrosis caused by an ureteral mass. The patient underwent a right nephroureterectomy via laparotomy. Two metastases of the rectal cancer in the ureteral mucosa were verified at histology. On account of the infiltration of the right ureteral orifice, a completion transurethral resection of the tumor was performed. A follow-up 3 and 6 months later showed no signs of tumor relapse and the patient was doing well. The differential diagnosis of malignant ureteral obstruction in patients with history of colorectal cancer should include the rare possibility of distant metastasis from the primary tumor.

Despite multiple recent advances in systemic therapy for metastatic breast cancer, cases which display suboptimal response to guideline-driven treatment are frequently seen in the clinic. Effective options for such patients are limited, particularly in later line of therapy, and selection of optimal treatment options is essentially empirical and based largely on considerations of previous regimens received. Comprehensive cancer profiling includes detection of genetic alterations in tissue and circulating tumor DNA (ctDNA), immunohistochemistry (IHC) from re-biopsied metastatic disease, circulating tumor cells (CTCs), gene expression analysis and pharmacogenomics. The advent of this methodology and application to metastatic breast cancer, facilitates a more scientifically informed approach to identification of optimal systemic therapy approaches independent of the restrictions implied by clinical guidelines. Here we describe a case of metastatic breast cancer where consecutive comprehensive tumor profiling reveals ongoing tumor evolution, guiding the identification of novel effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

Abstract Background Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. Methods NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. Discussion The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. Trial registration ClinicalTrials.gov: NCT02047513, 08/13/2014.

Factors for overall survival after pancreatic ductal adenocarcinoma (PDAC) seem to be nodal status, chemotherapy administration, UICC staging, and resection margin. However, there is no consensus on the definition for tumor free resection margin. Therefore, univariate OS as well as multivariate long-term survival using cancer center data was analyzed with regards to two different resection margin definitions. Ninety-five patients met inclusion criteria (pancreatic head PDAC, R0/R1, no 30 days mortality). OS was analyzed in univariate analysis with respect to R-status, CRM (circumferential resection margin; positive: ≤1mm; negative: >1mm), nodal status, and chemotherapy administration. Long-term survival >36 months was modelled using multivariate logistic regression instead of Cox regression because the distribution function of the dependent data violated the requirements for the application of this test. Significant differences in OS were found regarding the R status (Median OS and 95%CI for R0: 29.8 months, 22.3-37.4; R1: 15.9 months, 9.2-22.7; p = 0.005), nodal status (pN0 = 34.7, 10.4-59.0; pN1 = 17.1, 11.5-22.8; p = 0.003), and chemotherapy (with CTx: 26.7, 20.4-33.0; without CTx: 9.7, 5.2-14.1; p < .001). OS according to CRM status differed on a clinically relevant level by about 12 months (CRM positive: 17.2 months, 11.5-23.0; CRM negative: 29.8 months, 18.6-41.1; p = 0.126). A multivariate model containing chemotherapy, nodal status, and CRM explained long-term survival (p = 0.008; correct prediction >70%). Chemotherapy, nodal status and resection margin according to UICC R status are univariate factors for OS after PDAC. In contrast, long-term survival seems to depend on wider resection margins than those used in UICC R classification. Therefore, standardized histopathological reporting (including resection margin size) should be agreed upon.

Objective: Progressive hepatic fibrosis can be considered the final stage of chronic liver disease. Hepatic stellate cells (HSC) play a central role in liver fibrogenesis. Thyroid hormones (TH, e.g. thyroxine; T4 and triiodothyronine; T3) significantly affect development, growth, cell differentiation and metabolism through activation of TH receptor α and/or β (TRα/β). Here, we evaluated the influence of TH in hepatic fibrogenesis. Design: Human liver tissue was obtained from explanted livers following transplantation. TRα‐deficient (TRα‐KO) and wild‐type (WT) mice were fed a control or a profibrogenic methionine‐choline deficient (MCD) diet. Liver tissue was assessed by qRT‐PCR for fibrogenic gene expression. In vitro, HSC were treated with TGFβ in the presence or absence of T3. HSC with stable TRα knockdown and TRα deficient mouse embryonic fibroblasts (MEF) were used to determine receptor‐specific function. Activation of HSC and MEF was assessed using the wound healing assay, Western blotting, and qRT‐PCR. Results: TRα and TRβ expression is downregulated in the liver during hepatic fibrogenesis in humans and mice. TRα represents the dominant isoform in HSC. In vitro, T3 blunted TGFβ‐induced expression of fibrogenic genes in HSC and abrogated wound healing by modulating TGFβ signalling, which depended on TRα presence. In vivo, TRα‐KO enhanced MCD diet‐induced liver fibrogenesis. Conclusion: These observations indicate that TH action in non‐parenchymal cells is highly relevant. The interaction of TRα with TH regulates the phenotype of HSC via the TGFβ signalling pathway. Thus, the TH–TR axis may be a valuable target for future therapy of liver fibrosis. [ABSTRACT FROM AUTHOR]