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Background Complete mesocolic excision (CME) for right colonic cancer is a more complex operation than standard right hemicolectomy but evidence to support its routine use is still limited. This prospective multicentre study evaluated the effect of CME on long-term survival in colorectal cancer centres in Germany (RESECTAT trial). The primary hypothesis was that 5-year disease-free survival would be higher after CME than non-CME surgery. A secondary hypothesis was that there would be improved survival of patients with a mesenteric area greater than 15 000 mm2. Methods Centres were asked to continue their current surgical practices. The surgery was classified as CME if the superior mesenteric vein was dissected; otherwise it was assumed that no CME had been performed. All specimens were shipped to one institution for pathological analysis and documentation. Clinical data were recorded in an established registry for quality assurance. The primary endpoint was 5-year overall survival for stages I–III. Multivariable adjustment for group allocation was planned. Using a primary hypothesis of an increase in disease-free survival from 60 to 70 per cent, a sample size of 662 patients was calculated with a 50 per cent anticipated drop-out rate. Results A total of 1004 patients from 53 centres were recruited for the final analysis (496 CME, 508 no CME). Most operations (88.4 per cent) were done by an open approach. Anastomotic leak occurred in 3.4 per cent in the CME and 1.8 per cent in the non-CME group. There were slightly more lymph nodes found in CME than non-CME specimens (mean 55.6 and 50.4 respectively). Positive central mesenteric nodes were detected more in non-CME than CME specimens (5.9 versus 4.0 per cent). One-fifth of patients had died at the time of study with recorded recurrences (63, 6.3 per cent), too few to calculate disease-free survival (the original primary outcome), so overall survival (not disease-specific) results are presented. Short-term and overall survival were similar in the CME and non-CME groups. Adjusted Cox regression indicated a possible benefit for overall survival with CME in stage III disease (HR 0.52, 95 per cent c.i. 0.31 to 0.85; P = 0.010) but less so for disease-free survival (HR 0.66; P = 0.068). The secondary outcome (15 000 mm2 mesenteric size) did not influence survival at any stage (removal of more mesentery did not alter survival). Conclusion No general benefit of CME could be established. The observation of better overall survival in stage III on unplanned exploratory analysis is of uncertain significance.

Current literature on the role of contrast-enhanced ultrasound (CEUS) in the diagnosis of hepatocellular carcinoma (HCC) in non-cirrhotic patients is limited. The aim of this retrospective multicenter study was to analyze CEUS features of histologically proven HCC in patients with non-cirrhotic liver. In this multicenter study, 96 patients from eight medical institutions with histologically proven HCC lesions in non-cirrhotic liver were retrospectively reviewed regarding SonoVue-enhanced CEUS features. Two ultrasound experts assessed the CEUS enhancement pattern and came to a consensus using the World Federation of Societies for Ultrasound in Medicine and Biology guideline criteria. The mean size of HCC lesions included was 60.3 ± 37.8 mm (mean ± standard deviation). Most of the lesions were heterogeneous but predominantly hypo-echoic on B-mode ultrasound (64.5%, 62/96), with ill-defined margins and irregular shapes. During the arterial phase of CEUS, most of the HCC lesions in non-cirrhotic liver exhibited heterogeneous hyperenhancement (78.1%, 75/96) compared with the surrounding liver parenchyma. Almost 30% of HCC lesions (28.1%, 27/96) exhibited early wash-out (60 s). All lesions exhibited wash-out and hypo-enhancement in the late phase. CEUS features of HCC lesions in non-cirrhotic patients typically include hyperenhancement in the arterial phase and relatively rapid wash-out in the portal venous phase, which is different from HCC in cirrhotic livers and more similar to liver metastasis.

Liver cirrhosis is an established high-risk factor for HCC and the majority of patients diagnosed with HCC have cirrhosis. However, HCC also arises in non-cirrhotic livers in approximately 20 %of all cases. HCC in non-cirrhotic patients is often clinically silent and surveillance is usually not recommended. HCC is often diagnosed at an advanced stage in these patients. Current information about HCC in patients with non-cirrhotic liver is limited. Here we review the current knowledge on epidemiology, clinical features and imaging features of those patiens.

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 to70 yrs.) taking cause-specific deaths into account.We analyzed the effect of age and ACT on overall survival (OS) and cause-specific death of stage III pts. using Cox regression.In total, 1558 pts. were analyzed and follow-up was 24.6 months. 62.6% of the elderly received ACT whereas 91.1% of younger pts. (p 0.001). Oxaliplatin combinations were significantly less often given to older than younger pts. (38.8% vs. 88.9%; p 0.001). Mean Charlson comorbidity score was significantly lower in pts. that received ACT (0.61) than in those without ACT (1.16; p 0.001). ACT was an independent positive prognostic factor for cancer-related death in elderly pts. even in pts. 75+ yrs. No significant difference in the effect of ACT could be observed between age groups (interaction: cancer-specific death HR = 1.7948, p = 0.1079; death of other cause HR = 0.7384, p = 0.6705).ACT was an independent positive prognostic factor for OS. There may be a cohort of elderly with less co-morbidities who benefit from ACT.

Objective The aim of this study was to characterize duodenal mast cell (MC) and eosinophil (EO) numbers, their distribution within the lamina propria and possible impact on disease severity of paediatric celiac patients compared to children without celiac disease (CD). Methods We analysed duodenal samples of 215 children (109 CD, 106 controls) who underwent esophagogastroduodenoscopy from 2010 to 2018. After immunohistochemical staining, average MC and EO counts were histologically examined in ten high-power-fields. Additionally, cell-distribution within the lamina propria was analysed. Possible influence of relevant clinical parameters was evaluated. Statistics Student's-t-test, Mann-Whitney U-test, Chi-square-test, ANOVA, significance-level Results MC-density was higher in CD-patients compared to the control-group (23.7 (±12.1)/HPF versus 19.7 (±9.1)/HPF; p = .008), varying in number interindividually. Eosinophils were also increased in the duodenum of celiac patients (23.3 (±9.3)/HPF versus 12.2 (±6.3)/HPF; p= Conclusion MC- and EO-numbers were increased in the duodenum of CD-patients and MCs showed a different distribution-pattern in the lamina propria of celiac patients. These findings support the concept that both cell-types contribute to disease-pathogenesis. However, functional studies highlighting both cell-types' and their mediators' role regarding mucosal alterations during the course of the inflammatory process in celiac patients are needed. Trial registration number and url DRKS00024669; https://www.drks.de/drks_web/.

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 &lt, 2 mm thickness and low-level MLH1, three patients with primary cSCC &gt, 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 &lt, 2 mm, cSCC &gt, 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.

In Germany pancreas transplants are performed in only a few selected and specialized centres, usually combined with a kidney transplant. Knowlegde of the indications for and techniques of transplantation as well as of the histopathological assessment for rejection in pancreas and duodenal biopsies is not very widespread.To give an overview of the development and status quo in pancreas-kidney-transplantation in Germany summarizing the experience of the largest German pancreas transplant centre and to give a résumé of the results of histological diagnoses of biopsy specimens submitted between 06/2017 and 12/2020. Moreover, a detailed description and illustration of histological findings is included.A thorough literature search for aspects of the history, technique and indication for pancreas transplantation was performed and discussed in the context of the local experience and technical particularities specific for the transplant centre in Bochum. The occurrence of complications was compared with international reports. Results of pancreas and duodenal biopsies submitted to Erlangen between 06/2017 and 12/2020 for histological evaluation, which were evaluated according to the Banff classification, were summarized. For a better understanding key histological findings of pancreas rejection and differential diagnoses were illustrated and discussed.A total of 93 pancreas transplant specimens and 3 duodenal biopsies were included. 34.4% of pancreas specimens did not contain representative material for a diagnosis. In the remaining 61 biopsies 24.6% showed no rejection, 62.3% were diagnosed with acute T-cell mediated rejection (TCMR) and 8.2% with signs suspicious of antibody-mediated rejection (ABMR). Acute acinary epithelial injury was seen in 59%, pancreatitis in 8.2% and allograft fibrosis was reported in as many as 54.1%. Calcineurin-inhibitor toxicity was discussed in only 4.9%.Pancreas-kidney-transplantation and standardized histological assessment of the transplanted pancreas or rarely duodenum with reporting according to the updated Banff classification of pancreas transplants or previous reports of duodenal rejection are important mainstays in the management of patients with diabetes.HINTERGRUND: Die Pankreastransplantation wird in Deutschland nur in wenigen ausgewählten Zentren durchgeführt, üblicherweise in Kombination mit einer Niere. Die Kenntnis von Indikationen und Techniken der Transplantation selbst als auch der histopathologischen Abstoßungsdiagnostik mittels Pankreas- oder selten Duodenalbiopsie ist nicht sehr weit verbreitet.Darstellung der Entwicklung und des aktuellen Stands der Pankreas-Nieren-Transplantation in Deutschland anhand der Erfahrungen des größten deutschen Zentrums und Analyse der Ergebnisse der zwischen 06/2017 und 12/2020 durchgeführten Abstoßungsbiopsien inklusive ausführlicher Darstellung und Bebilderung der verschiedenen Abstoßungskategorien MATERIAL UND METHODE: Es wurde eine ausführliche Literaturrecherche zur Historie, Technik und Indikation der Pankreastransplantation durchgeführt und die technischen Besonderheiten und Erfahrungen am Bochumer Zentrum, insbesondere auch die Komplikationen, im internationalen Vergleich dargestellt. Desweiteren wurden alle im Zeitraum zwischen 06/2017 und 12/2020 durchgeführten Pankreas- oder Duodenalbiopsien, die zur Abstoßungsdiagnostik nach Erlangen gegangen waren und mittels der Banff-Klassifikation standardisiert bearbeitet wurden, anhand der vorliegenden Befunde ausgewertet und zusammenfassend dargestellt. Zum besseren Verständnis wurden die wichtigsten histologischen Entitäten bildhaft dargestellt und differenzialdiagnostische Aspekte diskutiert.Insgesamt wurden 93 Pankreastransplantat- und 3 Duodenalbiopsien untersucht. In 32 Pankreasbiopsien, d.h. 34,4 %, war kein diagnostisch verwertbares Material enthalten. Bei den verbliebenen 61 Pankreasbiopsien fanden sich bei 24,6 % keine Abstoßungszeichen, 62,3 % eine akute T-Zell-vermittelte Abstoßungsreaktion (TCMR) und 8,2 % Hinweise auf eine aktive Antikörper-vermittelte Abstoßung (ABMR). Ein akuter Azinuszellschaden wurde in 59 % der Biopsien gesehen, eine Pankreatitis in 8,2 % und eine Allograft-Fibrose in immerhin 54,1 %. Die Calcineurin-Inhibitor (CNI) Toxizität war mit 4,9% eher selten.Die Pankreas-Nieren-Transplantation inklusive der Biopsie des transplantierten Pankreas oder in seltenen Fällen auch des Spenderduodenums mit anschließender standardisierter Beurteilung entsprechend der aktuellen international gültigen Banff-Klassifikation der Pankreasabstoßung und der Empfehlungen zur Beurteilung von Duodenalbiopsien hat ihren festen Stellenwert in der Behandlung von Diabetikern.

Background Current guidelines discourage surgery for serous cystic neoplasms (SCN) of the pancreas, because of their benign character, slow growth, and excellent prognosis. Nevertheless, SCN continue to contribute up to 30% of resected cystic pancreatic lesions worldwide. Methods Spectrum of indications and outcomes of surgery were analysed in a retrospective series of 133 SCN at a single high-volume center in Germany between 2004 and 2019. Results Relevant symptoms justified surgery in 60% of patients with SCN, while 40% underwent surgery because of preoperative diagnostic uncertainty about suspected malignancy. There were 4 malignant SCN (3%). Ninety-day mortality was 0.75%, major morbidity - 15%, 10-year survival - 95%. Risks of malignant transformation and of postoperative mortality were similarly low. Conclusions Surgery is reasonable and safe for symptomatic patients with SCN. Preoperative diagnostic uncertainty is the main reason for futile resections of benign asymptomatic SCN. Conservative management with close initial surveillance should be the first choice for this population. Surgery for supposed SCN without symptoms is justified only in carefully selected patients with suspected malignancy.

Introduction In a retrospective analysis of two randomized phase III trials in mCRC patients treated first line with oxaliplatin, fluoropyrimidine with and without Bevacizumab (the AIO KRK 0207 and R091 trials) we evaluated the association of high microsatellite instability (MSI-H), immunoscore (IS) and PD-L1 expression in relation to overall survival (OS). Methods In total, 550 samples were analysed. Immunohistochemical analysis of the MMR proteins and additionally fragment length analysis was performed, molecular examinations via allele-discriminating PCR in combination with DNA sequencing. Furthermore PD-L1 and IS were assessed. Results MSI-H tumors were more frequent in right sided tumors (13.66% vs. 4.14%) and were correlated with mutant BRAF (p = 0.0032), but not with KRAS nor NRAS mutations (MT). 3.1% samples were found to be PD-L1 positive, there was no correlation of PDL1 expression with MSI-H status, but in a subgroup analysis of MSI-H tumors the percentage of PD-L1 positive tumors was higher than in MSS tumors (9.75% vs. 2.55%). 8.5% of samples showed a positive IS, MSI-H was associated with a high IS. The mean IS of the pooled population was 0.57 (SD 0.97), while the IS of MSI-H tumors was significantly higher (mean of 2.4; SD 1.4; p = Discussion Regarding OS in correlation with MSI-H, PD-L1 and IS status we did not find a significant difference. However, PD-L1 positive mCRC tended to exhibit a longer OS compared to PD-L1 negative cancers (28.9 vs. 22.1 months).

Purpose In mCRC, disease dynamics may play a critical role in the understanding of long-term outcome. We evaluated depth of response (DpR), time to DpR, and post-DpR survival as relevant endpoints. Methods We analyzed DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), early tumor shrinkage (≥ 20% reduction in tumor diameter at first reassessment), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR-image to tumor progression or death), and post-DpR overall survival (pOS = DpR-image to death) with special focus on BRAF status in 66 patients and primary tumor site in 86 patients treated within the VOLFI-trial, respectively. Results BRAF wild-type (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (− 57.6% vs. − 40.8%, p = 0.013) with a comparable time to DpR [4.0 (95% CI 3.1–4.4) vs. 3.9 (95% CI 2.5–5.5) months; p = 0.8852]. pPFS was 6.5 (95% CI 4.9–8.0) versus 2.6 (95% CI 1.2–4.0) months in favor of BRAF-WT patients (HR 0.24 (95% CI 0.11–0.53); p p Conclusions BRAF-MT patients derive a less profound treatment response compared to BRAF-WT patients. The difference in outcome according to BRAF status is evident after achievement of DpR with BRAF-MT patients hardly deriving any further disease control beyond DpR. Our observations hint towards an aggressive tumor evolution in BRAF-MT tumors, which may already be molecularly detectable at the time of DpR.

Fibrolamellar hepatocellular carcinoma (f-HCC) is a rare primary liver tumor. Imaging plays an important role in diagnosis. The aim of this retrospective study was to analyze contrast-enhanced ultrasound (CEUS) features of histologically proven f-HCC in comparison to benign focal nodular hyperplasia (FNH). 16 patients with histologically proven f-HCC lesions and 30 patients with FNH lesions were retrospectively reviewed regarding CEUS features to determine the malignant or benign nature of the focal liver lesions (FLL). Five radiologists assessed the CEUS enhancement pattern and came to a consensus using the EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) guideline criteria. Fibrolamellar hepatocellular carcinoma manifested as a single and huge FLL. On CEUS, f-HCC showed heterogeneous hyperenhancement in the arterial phase and hypoenhancement (16/16, 100 %) in the portal venous and late phases (PVLP) as a sign of malignancy. In contrast to the hypoenhancement of f-HCC in the PVLP, all patients with FNH showed hyperenhancement as the most distinctive feature (P 0.01). 8 f-HCC lesions showed a central scar as an unenhanced area (8/16, 50.0 %), which could also be detected in 53.3 % (16/30) of FNH lesions (P 0.05). By analyzing the hypoenhancement in the PVLP, CEUS imaging reliably diagnosed f-HCC as a malignant FLL. CEUS also showed differentiation between f-HCC and FNH lesions, showing similar non-enhanced central scars, whereas f-HCC lesions showed peripheral hyperenhancement in the arterial phase and early washout in the PVLP.ZIEL: Das fibrolamelläre hepatozelluläre Karzinom (f-HCC) ist ein seltener primärer Lebertumor. Die Bildgebung spielt bei der Diagnose eine wichtige Rolle. Ziel dieser retrospektiven Studie war es, die Merkmale im kontrastverstärkten Ultraschall (CEUS) bei histologisch nachgewiesenem f-HCC im Vergleich zur benignen fokalen nodulären Hyperplasie (FNH) zu analysieren. 16 Patienten mit histologisch nachgewiesenen f-HCC-Läsionen und 30 Patienten mit FNH-Läsionen wurden retrospektiv auf CEUS-Merkmale untersucht, um die maligne oder benigne Natur der fokalen Leberläsionen (FLL) zu bestimmen. 5 Radiologen bewerteten das CEUS-Enhancement-Muster und kamen zu einem Konsens unter Verwendung der Kriterien der EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) -Richtlinien. Das fibrolamelläre Leberzellkarzinom manifestierte sich als eine einzige und große FLL. Im CEUS zeigte das f-HCC ein heterogenes Hyperenhancement in der arteriellen Phase und ein Hypoenhancement (16/16, 100 %) in der portalvenösen und späten Phase (PVLP) als Marker für Malignität. Im Gegensatz zum Hypoenhancement des f-HCC in der PVLP zeigten alle Patienten mit FNH ein Hyperenhancement als auffälligstes Merkmal (p 0,01). 8 f-HCC-Läsionen zeigten eine zentrale Narbe als Bereich ohne Anreicherung (8/16; 50,0 %), welche auch bei 53,3 % (16/30) der FNH-Läsionen nachgewiesen werden konnte (p 0,05). Durch die Untersuchung des Hypoenhancements in der PVLP konnte die CEUS-Bildgebung f-HCC zuverlässig als maligne FLL diagnostizieren. Außerdem konnte CEUS zwischen f-HCC und FNH-Läsionen differenzieren und zeigte ähnliche zentrale Narben ohne Anreicherung, wobei f-HCC-Läsionen ein peripheres Hyperenhancement in der arteriellen Phase und ein frühes Wash-out in der PVLP zeigten.

The macroscopic and microscopic assessments of pancreatic cancer resection specimens belong to the standard repertoire of any department of pathology. In recent years standards have been developed regarding both macroscopic and microscopic assessments, which are laid down in international and national guidelines and classifications and are regularly updated. In this way the reporting of results and interdisciplinary communication are facilitated. These classifications and guidelines are influenced by current studies and the data from them provide information on which histopathological factors are particularly relevant for the prognosis and treatment. Due to the increasing use of neoadjuvant therapy the assessment of tumor regression in histopathological specimens is also gaining in importance. Finally, individual targeted treatments are also now available for pancreatic cancer, which require extended molecular pathological diagnostics.Die makroskopische und mikroskopische Begutachtung onkologischer Resektate von Pankreaskarzinomen gehört zum Standardrepertoire eines pathologischen Instituts. In den letzten Jahren wurden sowohl bezüglich der makroskopischen als auch der mikroskopischen Beurteilung Standards erarbeitet, die in internationalen und nationalen Leitlinien und Klassifikationen festgelegt sind und regelmäßig aktualisiert werden. Dadurch werden die Befunderstellung und auch die interdisziplinäre Kommunikation erleichtert. Beeinflusst werden diese Klassifikationen und Leitlinien durch aktuelle Studien, die Daten dazu liefern, welche pathohistologischen Faktoren besonders prognose- und therapierelevant sind. Durch den zunehmenden Einsatz einer neoadjuvanten Therapie gewinnt auch die Beurteilung der Tumorregression im pathohistologischen Präparat an Bedeutung. Zuletzt sind auch mittlerweile für das Pankreaskarzinom einzelne zielgerichtete Therapien verfügbar, die eine weiterführende molekularpathologische Diagnostik erfordern.

Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent chronic liver diseases with a rising incidence in industrial countries. This is accompanied by an increased prevalence for NAFLD-associated liver cirrhosis and an increased risk for developing hepatocellular carcinoma. The current gold standard in the diagnostics is a liver biopsy. The histopathological evaluation is performed through semiquantitative scoring. To optimize the standardization and quantification of the existing scoring systems, in the coming years procedures with artificial intelligence, such as deep learning models could be used. Fields of application could be the supplementation of conventional histopathological diagnostics, the identification of new predictive parameters for estimating the prognosis and the prediction of a possible response to treatment.Die nichtalkoholische Fettlebererkrankung (NAFLD) ist eine der häufigsten chronischen Lebererkrankungen mit steigender Inzidenz in den Industriestaaten. Damit einhergehend sind eine erhöhte Prävalenz für eine NAFLD-assoziierte Leberzirrhose und das gesteigerte Risiko für die Entwicklung eines hepatozellulären Karzinoms. Goldstandard in der Diagnostik ist die Leberbiopsie. Die histopathologische Evaluierung erfolgt mithilfe semiquantitativer Scores. Zur Optimierung der Standardisierung und Quantifizierung der bestehenden Scores könnten in den nächsten Jahren Verfahren, die sich künstlicher Intelligenz bedienen, wie „Deep-learning“-Modelle zum Einsatz kommen. Einsatzgebiete könnten die Ergänzung der konventionellen histopathologischen Diagnostik, die Identifizierung neuer prädiktiver Parameter zur Prognoseabschätzung und die Vorhersage eines möglichen Therapieansprechens sein.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with significant morbidity and mortality. Although the precise cause remains unknown, disturbances in the intestinal microbial community have been linked to its pathogenesis. Randomized controlled trials in UC and relapsing Clostridioides difficile infection (CDI) have established fecal microbiota (FM) transfer (FMT) as an effective therapy. In this context, preliminary results indicated that the transfer of sterile fecal microbiota filtrates (0.2 μm; FMF, FMFT) of donor stool also drives gastrointestinal microbiota changes and eliminates symptoms in CDI patients. However, along with the success of FMT, regulatory agencies issued safety alerts following reports of serious adverse events due to transmission of enteric pathogens through FMT. To reduce this risk, we established an extensive test protocol for our donors and quarantine regulations for the produced capsules, but alternative concepts are desirable.Our project is a randomized, controlled, longitudinal, prospective, three-arm, multicenter, double-blind study to determine the safety and efficacy of repeated long-term, multi-donor FM or FMF transfers compared to placebo using oral, frozen capsules in 174 randomized patients with mild to moderate active UC. The primary outcome will be clinical remission at week 12.This proposal aims to examine (a) the efficacy of encapsulated transfer of FM and FMF as a therapy for mild to moderate UC, (b) the short- and long-term safety of FMT and FMFT in patients with UC, and (c) the microbial and immunologic changes that occur after FMT and FMFT to help understand how and why it affects inflammatory bowel disease.ClinicalTrials.gov NCT03843385 . DRKS (Deutsches Register für Klinische Studien) DRKS00020471.

Introduction: Persistent systemic inflammation is considered to be predictive for future cardiovascular events. Here, in a patient with pyelonephritis of his failed renal allograft, consecutive coronary angiograms proved that coronary artery disease progressed within 3 weeks, when infection was uncontrolled. Patient concerns: A 52-year-old male type 2 diabetic with a failed renal allograft suffering from hematuria, leukocyturia, and chest pain at rest was hospitalized. Diagnoses: An acute coronary syndrome in presence of pyelonephritis was diagnosed. Besides pyelonephritis, the histological examination of the kidney transplant revealed signs of chronic rejection and the presence of a renal cell carcinoma in situ. Interventions: A percutaneous coronary intervention was performed, and an elective surgery for allograft removal was scheduled. However, within 5 weeks after discharge, two more surges of infection coincided with episodes of unstable angina. Outcomes: Once the renal allograft has been removed, systemic inflammation was contained. The patient was not re-hospitalized for acute-coronary syndrome within the next 12 months. Conclusion: Surges of systemic inflammation due to infection were paralleled by instability of coronary plaques as documented by repeat coronary angiograms.

BACKGROUND Secondary lymphedema is a leading sequela of cancer surgery and radiotherapy. The microsurgical transfer of lymph node flaps (LNFs) to affected limbs can improve the symptoms. The intra-abdominal cavity contains an abundant heterogenic source. The aim of this study is to aid selection among intra-abdominal LNFs. METHODS Eight LNFs were harvested in a microsurgical fashion at five sites in 16 cadavers: gastroepiploic, jejunal, ileal, ileocolic, and appendicular. These flaps were compared regarding size, weight, arterial diameter, and lymph node (LN) count after histologic verification. RESULTS One hundred and sixteen flaps were harvested. The exposed area correlated with the flap weight and volume (r2 = 0.86, r = 0.9). While gastroepiploic LNFs (geLNFs) showed the highest median weight of 99 ml, the jejunal LNFs (jLNFs) had the highest density with 3.8 LNs per 10 ml. The most reliable jLNF was 60 cm from the ligament of Treitz. Three or more LNs were contained in 94% of the jejunal, 88% of the ileal/ileocolic, and 63% of the omental LNs. The ileocolic LNF had the largest arterial diameter of 3 mm, yet the smallest volume. CONCLUSIONS jLNF and ileal LNF provide a reliable, high LN density for simultaneous, smaller recipient sites. geLNFs are more suitable for larger recipient sites.

In recent years, deep learning has been the key driver of breakthrough developments in computational pathology and other image based approaches that support medical diagnosis and treatment. The underlying neural networks as inherent black boxes lack transparency, and are often accompanied by approaches to explain their output. However, formally defining explainability has been a notorious unsolved riddle. Here, we introduce a hypothesis-based framework for falsifiable explanations of machine learning models. A falsifiable explanation is a hypothesis that connects an intermediate space induced by the model with the sample from which the data originate. We instantiate this framework in a computational pathology setting using label-free infrared microscopy. The intermediate space is an activation map, which is trained with an inductive bias to localize tumor. An explanation is constituted by hypothesizing that activation corresponds to tumor and associated structures, which we validate by histological staining as an independent secondary experiment.

Primary cutaneous anaplastic large cell lymphoma (pcALCL) belongs to the primary cutaneous CD30+ T cell lymphoproliferative disorders.1 Systemic involvement is relatively rare and rather confined to the regional lymph nodes.1We describe a patient with recurrent pcALCL and diffuse lung manifestation which spontaneously regressed after one SARS‐CoV‐2 vaccination. We report a 57‐year‐old male patient with a 10‐year history of biopsy‐proven (CD30+, CD3+, CD4+, ALK‐, clonal T cell receptor gamma chain rearrangement) pcALCL with frequent local relapses predominantly affecting his scalp and neck.

Intraductal papillary neoplasms of the biliary tract (IPNB) are rare tumors originating from the bile duct epithelium. Metastatic disease of IPNB is extremely rare and only reported in a small number of cases worldwide. Due to this limitation in number, the treatment of IPNB mainly relies on retrospective case series. We reported three cases of IPNB, one benign, one carcinoma with lymph node metastasis, and one case with histologically proven metachronous pulmonary metastasis. We correlated our findings with the existing data found in the literature. All patients underwent hemihepatectomy and complete tumor resection was achieved. Diagnosis of IPNB can be challenging due to varying presentation. The treatment of choice is surgical oncological resection in an early tumor stage. Long-term outcome highly depends on the underlying grade of dysplasia, multiplicity, and tumor-free margins. Aggressive tumor invasion is reported in up to 72% of cases in IPNB. Furthermore, the recurrence rate of IPNB is high with up to 22%. Further factors associated with an impaired survival are incomplete resection, lymph node involvement, and MUC1 expression. High potential for dysplasia and proof of invasive carcinoma upon diagnosis are hallmarks of IPNB. Metastatic disease in IPNB is reported only in small numbers. IPNB is an aggressive tumor entity with impaired long-term outcomes. A drawback for interpretation of current data is the fact that they rely on case series and reports and are not validated through more powerful randomized multicentric trials.

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. Open-Access-Publikationsfonds 2018

Numerous trials have examined the prognostic and predictive value of localization of the primary tumor (LPT) in metastastic colorectal cancer, there is limited information about the predictive value of LPT on different maintenance strategies.We analyzed progression-free survival (PFS)/overall survival (OS) on maintenance therapy according to LPT and mutational subgroups (BRAF/RAS) in patients from the AIO (Arbeitsgemeinschaft Internistische Onkologie) 0207 trial. Following induction, 471 patients were randomized to fluoropyrimidine (FU)/bevacizumab (Bev), Bev, or no treatment. Data on LPT were available in 414 (91%) patients.A total of 291 patients were left-sided (LPTl, 70%), and 123 were right-sided (LPTr, 30%). The median PFS was 3.9 months for LPTr and 5.3 months for LPTl (P = .11; hazard ratio [HR], 1.19; 95% confidence interval [CI], 0.96-1.48). There was no predictive impact of LPT on the maintenance strategies. The pairwise comparison of treatment arms showed a better PFS for FU/Bev versus no treatment independent from LPT (left, P .0001; HR, 2.39; 95% CI, 1.73-3.31; right, P = .011; HR, 1.78; 95% CI, 1.14-2.80). Analysis for OS (429 patients) confirmed the strong prognostic impact of LPT (left vs. right: 24.0 vs. 16.7 months; P .0001; HR, 1.65; 95% CI, 1.32-2.06), but also without major interaction between the LPT and maintenance arms. The strong negative prognostic impact of BRAF mutation was confirmed in right-/left-sided metastastic colorectal cancer, reaching significance in LPTl. In patients with RAS mutational status, the negative prognostic impact of the mutation remains, but its effect is stronger in LPTl (P .0001).The strong prognostic factor of LPT is confirmed undergoing oxaliplatin/FU/Bev induction therapy, whereas there seems to be no major predictive impact of LPT on different maintenance strategies.

Background : Guidance regarding adjuvant treatment decisions in stage II colorectal cancer (CRC) remains uncertain due to lack of predictive clinical or molecular markers. Recently, postoperative circulating tumour (ct)DNA has been demonstrated to be a strong prognostic marker in early colon cancer. Patients and Methods : CIRCULATE enrols patients with stage II microsatellite stable CRC in Germany (AIO) and Austria (ABCSG). Within the AIO, screening is supported by ColoPredict Plus 2.0, a molecular registry and screening platform for interventional trials. Patient-specific mutations are centrally analysed by next generation sequencing in the resected primary tumour. A postoperative plasma sample subsequently screened for the specific mutation(s). ctDNA positive (ctDNApos) patients are randomised (1:2) to control (follow up) or chemotherapy (capecitabine, oxaliplatin added a investigator's choice). ctDNA negative (ctDNAneg) patients are randomised (1:4) to be followed-up within CIRCULATE (control group) or outside the trial. Patients in the control group remain blinded to the ctDNA results. The primary objective is to compare disease free survival (DFS) of ctDNApos patients with chemotherapy or control. To demonstrate a treatment effect with a hazard ratio of 0.617 (3 year DFS rates 42.5 % vs. 25 %), 231 ctDNApos and estimated 2079 ctDNAneg patients are randomised. Secondary aims include to compare overall survival and DFS in the ctDNApos and ctDNAneg patient cohorts and ctDNA kinetics. Conclusion : The CIRCULATE trial may establish ctDNA for adjuvant treatment decision in stage II colon cancer – and with the secondary objectives – support a ctDNA guided follow up in colon cancer stage II and beyond. Micro Abstract Circulating tumour DNA (ctDNA) is a prognostic biomarker of recurrence in patients with early stage and resected colorectal cancer. The CIRCULATE study evaluates the predictive value of ctDNA with respect to adjuvant treatment in colon cancer stage II. In total, 231 patients with detectable ctDNA (ctDNApos) post resection are randomised 2:1 to chemotherapy or to control (follow-up). Patients without detectable ctDNA (approx. 2079 patients) are randomized 1:4 into control or off-study. The primary endpoint is the disease free survival.

Objective To identify patients at risk for biochemical recurrence (BCR) of prostate cancer (PCa) after radical prostatectomy (RP) with intra-operative whole-mount frozen section (FS) of the prostate. Material and methods We examined differences in BCR between patients with initial negative surgical margins at FS, patients with final negative surgical margins with initial positive margins at FS without residual PCa after secondary tumour resection, and patients with final negative surgical margins with initially positive margins at FS with residual PCa in the secondary tumour resection specimen. Institutional data of 883 consecutive patients undergoing RP were collected. Intra-operative whole-mount FS was routinely used to check for margin status and, if necessary, to resect more periprostatic tissue in order to achieve negative margins. Patients with lymph node-positive disease or final positive surgical margins were excluded from the analysis. Kaplan-Meier curves and multivariable Cox proportional hazards regression analyses adjusting for clinical covariates were employed to examine differences in biochemical recurrence-free survival (BRFS) according to the resection status mentioned above. Results The median follow-up was 22.4 months. The 1- and 2-year BRFS rates in patients with (81.0% and 72.9%, respectively; P = 0.001) and without residual PCa (90.3% and 82.3%, respectively; P = 0.033) after secondary tumour resection were significantly lower compared to patients with initial R0 status (93.4% and 90.9%, respectively). On multivariable Cox regression only residual PCa in the secondary tumour resection was associated with a higher risk of BCR compared to initial R0 status (hazard ratio 1.99, 95% confidence interval 1.01-3.92; P = 0.046). Conclusion Despite being classified as having a negative surgical margin, patients with residual PCa in the secondary tumour resection specimen face a high risk of BCR. These findings warrant closer post-RP surveillance of this particular subgroup. Further research of this high-risk subset of patients should focus on examining whether these patients benefit from early salvage therapy and how resection status impacts oncological outcomes in the changing landscape of PCa treatment.

Perioperative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) is a mainstay in the treatment of esophagogastric adenocarcinomas (EGA). Trastuzumab improved survival when added to chemotherapy in patients with HER-2-positive metastatic EGA. We investigated the combination of trastuzumab and FLOT as perioperative treatment in patients with locally advanced EGA. A multicenter phase II study evaluated the efficacy and toxicity of perioperative FLOT (24-hours 5-FU 2600 mg/m2 , leucovorin 200 mg/m2 , oxaliplatin 85 mg/mg2 , docetaxel 50 mg/m2 , trastuzumab 6 mg/kg then 4 mg/kg d1, repeated d15 for four cycles preoperatively and postoperatively followed by 9 cycles of trastuzumab monotherapy) in patients with HER-2 positive EGA. Patients had ≥cT2, any N, M0 EGA. The primary endpoint was the rate of centrally assessed pathological complete response (pCR). Secondary endpoints comprised disease-free (DFS) and overall survival (OS), R0 resection rate, toxicity and surgical morbidity. Fifty-six evaluable patients (median age 62 years) were included; n = 40 had tumors originating from the esophagogastric junction; T stage was (cT2/3/4/unknown): 4/42/8/2; n = 50 patients had cN+ disease. Main adverse events grades 3-4: leukopenia (17.9%), neutropenia (46.6%) and diarrhea (17.0%). All patients underwent tumor resections. R0 resection rate was 92.9%. Eight patients had anastomotic leakage. One postoperative death occurred. pCR was found in 12 patients (21.4%) and a further n = 14 patients (25.0%) had near complete response. Median DFS was 42.5 months and the 3-year OS rate was 82.1%. The primary endpoint of achieving a pCR >20% was reached. No unexpected safety issues were observed. Survival data are promising.

Acute appendicitis (AA) is amongst the most common causes of acute abdominal pain. In spite of progress based on risk stratifications, “negative” appendectomies are performed in up to 30% of patients whilst the appendix perforates in others. Preoperative classification of AA based on imaging is therefore recommended. The aim was to classify AA based on imaging (ultrasound/US, computed tomography/CT), surgical pathology, and/or histopathology in order to differentiate between complicated and uncomplicated AA. A new classification of acute appendicitis (CAA) shall be illustrated by typical US and CT images and be employed in a diagnostic and therapeutic algorithm. Medline, Embase, and the Cochrane Library were searched. Any study after 1970, which investigated clinical scores, pathology, US, CT, magnetic resonance imaging, and treatment of AA, was included. Typical images were taken from the author’s image database. Five main types of AA are defined, normal appendix (type 0), nonvisualised appendix (type X), uncomplicated AA (type 1), complicated AA without perforation (type 2), and complicated AA with perforation (type 3). The imaging modality is indicated by an additional letter, e.g., type p3b for free perforation on pathology. Standardised reporting of the appendix evaluation by US and CT is presented, as well as algorithms for AA management. Imaging features indicating imminent perforation, as well as likely recurrence, were both classified as complicated AA. Imaging is mandatory in suspected AA. The CAA clearly separates uncomplicated from complicated forms of AA allowing nonoperative management in selected patients with uncomplicated forms of AA.

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.

In this work, we are reporting that “Shock and Kill”, a therapeutic approach designed to eliminate latent HIV from cell reservoirs, is extrapolatable to cancer therapy. This is based on the observation that malignant cells express a spectrum of human endogenous retroviral elements (HERVs) which can be transcriptionally boosted by HDAC inhibitors. The endoretroviral gene HERV-V2 codes for an envelope protein, which resembles syncytins. It is significantly overexpressed upon exposure to HDAC inhibitors and can be effectively targeted by simultaneous application of TLR7/8 agonists, triggering intrinsic apoptosis. We demonstrated that this synergistic cytotoxic effect was accompanied by the functional disruption of the TLR7/8-NFκB, Akt/PKB, and Ras-MEK-ERK signalling pathways. CRISPR/Cas9 ablation of TLR7 and HERV-V1/V2 curtailed apoptosis significantly, proving the pivotal role of these elements in driving cell death. The effectiveness of this new approach was confirmed in ovarian tumour xenograft studies, revealing a promising avenue for future cancer therapies., Díaz-Carballo et al. find that HDAC inhibitors induces the expression of human endogenous retrovirus envelope genes in ovarian cancer cells, and that Toll-like receptor (TLR) 7/8 agonists act synergistically with HDAC inhibitors in triggering cancer cell apoptosis. The combination also reduces growth of ovarian tumour xenografts, providing a potential rationale for future therapies.

Polyps of the gastrointestinal tract encompass a variety of epithelial and non-epithelial tumour-like conditions. The most common polyps are epithelial lesions. In the upper gastrointestinal tract, reactive inflammatory changes and hyperplastic polyps dominate, whereas true neoplastic polyps, like adenomas, are much more common in the colorectum. In addition to neoplasias such as adenomas, non-neoplastic polyps such as hyperplastic polyps of the stomach may also be associated with an increased risk of malignancy. The risk of malignancy is determined by the histological subtype of polyp, as well as the size, presence and degree of dysplasia. The term "dysplasia" has been reintroduced for adenomas in the current 2019 World Health Organization (WHO) classification and replaces "intraepithelial neoplasia". A further change is the term "sessile serrated lesion" with and without dysplasia, which was formerly known as sessile serrated adenoma.Unter dem Begriff „Polypen des Gastrointestinaltrakts“ wird eine ganze Reihe von epithelialen und nichtepithelialen tumorartigen Veränderungen zusammengefasst. Generell werden reaktiv-entzündliche Veränderungen von neoplastischen Läsionen unterschieden. Die häufigsten Polypen sind epitheliale Läsionen. Im oberen Gastrointestinaltrakt dominieren reaktiv-entzündliche Veränderungen und hyperplastische Polypen, während echte neoplastische Polypen wie Adenome viel häufiger im Kolorektum auftreten. Neben echten Neoplasien wie Adenomen können auch nichtneoplastische Polypen wie hyperplastische Polypen des Magens mit einem erhöhten malignen Potenzial assoziiert sein. Das maligne Potenzial eines „Polypen“ wird durch den histologischen Typ bestimmt. Handelt es sich um eine Neoplasie, definiert das Ausmaß der Dysplasie und auch die Größe der Läsion das maligne Potenzial. Der Begriff der „Dysplasie“ wurde für Adenome in der aktuellen Klassifikation der Weltgesundheitsorganisation (WHO) von 2019 wiedereingeführt und ersetzt die „intraepitheliale Neoplasie“. Eine weitere Neuerung ist der Begriff „sessile serratierte Läsion“ mit und ohne Dysplasie, der dem früheren „sessilen serratierten Adenom“ entspricht.

A 47-year-old male presented with dyspnoea and pulmonary nodules. He had longstanding asthma, chronic rhinosinusitis and a history of seizures, having been treated with valproic acid for years. A transbronchial biopsy and a bronchoalveolar lavage yielded a eosinophilic bronchitis and alveolitis without any malignant cells. The patient was then treated with oral corticosteroids for a few months, and the antiepileptic medication was switched to levetiracetam. Within a few months the dyspnoea improved and both the pulmonary nodules and the eosinophilia in the full blood count resolved. Eosinophilic lung diseases warrant a thorough investigation. Most likely, our patient suffers from eosinophilic granulomatosis with polyangiitis. As well, the eosinophilic lung disease might have been caused by valproic acid. Similar cases have been described in the literature.Ein 47-jähriger Patient mit langjährig bekanntem Asthma bronchiale, chronischer Rhinosinusitis und langjähriger Epilepsie stellte sich aufgrund von progredienter Dyspnoe und Abgeschlagenheit in der pneumologischen Praxis vor. In einer thorakalen Röntgenaufnahme und einer nachfolgend durchgeführten thorakalen Computertomografie zeigten sich multiple pulmonale Rundherde.Eine Bronchoskopie mit bronchoalveolärer Lavage und transbronchialer Biopsie erbrachte den Befund einer eosinophilen Bronchitis und Alveolitis ohne Nachweis maligner Zellen. Nach Einleitung einer immunsuppressiven Therapie mit oralem Prednisolon und Umstellung der antikonvulsiven Therapie von Valproinsäure auf Levetiracetam besserten sich Dyspnoe und Belastbarkeit des Patienten binnen weniger Monate, einhergehend mit einem Regress der pulmonalen Rundherde und der peripheren Eosinophilie.Eine pulmonale Eosinophilie erfordert eine gründliche differenzialdiagnostische Aufarbeitung. Bei diesem Patienten ist am ehesten von einer eosinophilen Granulomatose mit Polyangiitis auszugehen. In der Literatur finden sich aber auch Fallberichte zu Valproinsäure-induzierten eosinophilen Lungenerkrankungen, sodass auch hier eine Assoziation denkbar ist.

Hepatic involvement is one of the most common manifestations in cancer of unknown primary (CUP) syndrome. The most frequent secondary neoplasms of the liver are carcinomas and malignant melanomas. Most common carcinoma metastases are adenocarcinomas originating from the digestive system or metastases of breast and lung carcinomas. Therefore, hepatic CUP syndrome is an exclusion diagnosis. Immunohistochemistry and molecular examinations are an important part of histopathological diagnosis. They do not only serve to identify the tissue of histologically origin or possible primary tumor, but also contribute to the selection of a personalized targeted therapy by detecting so-called druggable targets in the interdisciplinary management.

Colorectal cancer is one of the leading malignancies and still accounts for almost 25 000 deaths in Germany each year. Although there is accumulating data on the molecular basis, treatment and clinical outcome of patients within clinical trials evidence from the real-world setting is mostly lacking. We started the molecular registry trial Colopredict Plus in 2013 to collect clinical and molecular data from a real-world cohort of patients with early colon cancer stage II and III in 70 German colon cancer centers focusing on the prognostic impact of high microsatellite instability. In this interim report, we characterize a clinical cohort of 2615 patients, of whom 1787 tissue probes were analyzed. Microsatellite status was assessed using immunhistochemistry and fragment length analysis, with a concordance of 91.4 %. These established histopathological methods are sensitive and cost-effective. The median age was 72 years, significantly higher compared to clinical trial populations, with a median Charlson Comorbidity Index of 3. The stage-dependent incidence of microsatellite instability was 23.7 % and was associated with female gender, BRAF-mutation, UICC stage II and localization in the right colon. Survival calculated in disease free, relapse free and overall survival significantly differed between MSI-H and MSS, in favor of MSI-H patients. Multivariate age-adjusted analyses of relapse-free survival, disease-free survival, and overall survival highlighted microsatellite instability as a robust and positive prognostic marker for early colon cancer independent of age.Das kolorektale Karzinom ist weiterhin eine der häufigsten Tumorerkrankungen mit einer Mortalität von fast 25 000 pro Jahr in Deutschland. Obwohl wir mehr und mehr Daten zur molekularen Basis, zu neuen Behandlungsmethoden und Verläufen von Patienten im Rahmen klinischer Studien generieren, gibt es nur wenige Informationen aus der klinischen Versorgungsrealität. Wir starteten die molekulare Registerstudie Colopredict Plus im Jahre 2013, um klinische sowie molekulare Daten von einer „Real-World“-Kohorte von Patienten mit Kolonkarzinomen im UICC-Stadium II und III aus 70 deutschen Darmkrebszentren zu dokumentieren. Der Fokus liegt hier auf dem prognostischen Wert einer hochgradigen Mikrosatelliteninstabilität. In dieser Interimsanalyse charakterisieren wir das klinische Kollektiv von 2615 Patienten, von denen 1787 Tumorproben analysiert wurden. Der Mikrosatellitenstatus wurde via Immunhistochemie und Fragmentlängenanalyse mit einer Konkordanz von 91,4 % durchgeführt, was eine kosteneffektive histopathologische Nachweismethodik darstellt. Das mediane Alter lag bei 72 Jahren und damit deutlich höher als üblicherweise in klinischen Studien, der mediane Charlson Comorbidity Index lag bei 3. Die stadienabhängige Mikrosatelliteninstabilität-Inzidenz lag bei 23,7 % und war assoziiert mit dem weiblichen Geschlecht, BRAF-Mutationen, UICC-Stadium II und der Primärtumorlokalisation im rechten Kolon. Das Überleben berechnet in krankheitsfreiem, rezidivfreiem sowie Gesamtüberleben unterschied sich signifikant zugunsten der MSI-H-Patienten. Multivariate altersadjustierte Analysen des rezidivfreien und krankheitsfreien Überlebens sowie des Gesamtüberlebens bestätigten eine hochgradige Mikrosatelliteninstabilität als robusten und positiven prognostischer Marker für frühe Kolonkarzinome unabhängig vom Alter.

Intraoperative frozen sections can significantly improve the results of numerous visceral surgical operations. For this a close cooperation between surgery and pathology is a basic prerequisite. The main indications are the diagnostics of unclear intraoperative findings and the assessment of resection margins. Just as in any other procedure, there are also limiting factors to be considered in frozen section examinations.

Background We assessed the usefulness of circulating tumor DNA (ctDNA) pre- or post-treatment initiation for outcome prediction and treatment monitoring in metastatic colorectal cancer (mCRC). Methods Droplet digital PCR was used to measure absolute mutant V-Ki-ras2 Kirsten rat sarcoma viral oncogene ((mut)KRAS) ctDNA concentrations in 214 healthy controls (plasma and sera) and in 151 tissue-based mutKRAS positive patients with mCRC from the prospective multicenter phase 3 trial AIO KRK0207. Serial mutKRAS ctDNA was analyzed prior to and 2–3 weeks after first-line chemotherapy initiation with fluoropyrimidine, oxaliplatin, and bevacizumab in patients with mCRC and correlated with clinical parameters. Results mut KRAS ctDNA was detected in 74.8% (113/151) of patients at baseline and in 59.6% (90/151) at follow-up. mutKRAS ctDNA at baseline and follow-up was associated with poor overall survival (OS) (hazard ratio [HR] =1.88, 95% confidence interval [CI] 1.20–2.95; HR = 2.15, 95% CI 1.47–3.15) and progression-free survival (PFS) (HR = 2.53, 95% CI 1.44–4.46; HR = 1.90, 95% CI 1.23–2.95), respectively. mutKRAS ctDNA clearance at follow-up conferred better disease control (P = 0.0075), better OS (log-rank P = 0.0018), and PFS (log-rank P = 0.0018). Measurable positive mutKRAS ctDNA at follow-up was the strongest and most significant independent prognostic factor on OS in multivariable analysis (HR = 2.31, 95% CI 1.40–3.25). Conclusions Serial analysis of circulating mutKRAS concentrations in mCRC has prognostic value. Post treatment mutKRAS concentrations 2 weeks after treatment initiation were associated with therapeutic response in multivariable analysis and may be an early response predictor in patients receiving first-line combination chemotherapy. Clinicaltrialsgov Identifier NCT00973609.

Importance Total neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to be established. Objective To report the long-term results of the secondary end points prespecified in the Randomized Phase 2 Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy (CAO/ARO/AIO-12 trial) for Locally Advanced Rectal Cancer. Design, Setting, and Participants This secondary analysis of a randomized clinical trial included 311 patients who were recruited from the accrued CAO/ARO/AIO-12 trial population from June 15, 2015, to January 31, 2018, from 18 centers in Germany. Patients with cT3-4 and/or node-positive rectal adenocarcinoma were included in the analysis. Data were analyzed from June 15, 2015, to January 31, 2018. The follow-up analysis was conducted between January 31, 2018, and November 30, 2020. Interventions Patients were randomly assigned to group A for 3 cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy), or to group B for CRT before chemotherapy. Total mesorectal excision was scheduled on day 123 after the start of total neoadjuvant therapy in both groups. Main Outcomes and Measures The end points assessed in this secondary analysis included long-term oncologic outcomes, chronic toxicity, patient-reported outcome measures for global health status (GHS) and quality of life (QoL), and the Wexner stool incontinence score. Results Of the 311 patients enrolled, 306 were evaluable, including 156 in group A (mean [SD] age, 60 [11] years; 106 men [68%]) and 150 in group B (mean [SD] age, 62 [10] years; 100 men [67%]). After a median follow-up of 43 months (range, 35-60 months), the 3-year disease-free survival was 73% in both groups (hazard ratio, 0.95; 95% CI, 0.63-1.45,P = .82); the 3-year cumulative incidence of locoregional recurrence (6% vs 5%,P = .67) and distant metastases (18% vs 16%,P = .52) were not significantly different. Chronic toxicity grade 3 to 4 occurred in 10 of 85 patients (11.8%) in group A and 8 of 66 patients (9.9%) in group B at 3 years. The GHS/QoL score decreased after total mesorectal excision but returned to pretreatment levels 1 year after randomization with no difference between the groups. Stool incontinence deteriorated 1 year after randomization in both groups and only improved slightly at 3 years, but never reached baseline levels. Conclusions and Relevance This secondary analysis of a randomized clinical trial showed that CRT followed by chemotherapy resulted in higher pathological complete response without compromising disease-free survival, toxicity, QoL, or stool incontinence and is thus proposed as the preferred total neoadjuvant therapy sequence if organ preservation is a priority. Trial Registration ClinicalTrials.gov identifier:NCT02363374

A higher incidence of proximal interval cancers after colonoscopy has been reported in several follow-up studies. One possible explanation for this might be that proximally located adenomas have greater malignant potential. The aim of the present study was to assess the risk of malignancy in proximal versus distal adenomas in patients included in a large screening colonoscopy database; adenoma shape and the patients' age and sex distribution were also analyzed.Data for 2007-2012 from the German National Screening Colonoscopy Registry, including 594,614 adenomas identified during 2,532,298 screening colonoscopies, were analyzed retrospectively. The main outcome measure was the rate of high-grade dysplasia (HGD) in adenomas, used as a surrogate marker for the risk of malignancy. Odds ratios (ORs) for the rate of HGD found in adenomas were analyzed in relation to patient- and adenoma-related factors using multivariate analysis.HGD histology was noted in 20,873 adenomas (3.5%). Proximal adenoma locations were not associated with a higher HGD rate. The most significant risk factor for HGD was adenoma size (OR 10.36 ≥1 cm vs1 cm), followed by patient age (OR 1.26 and 1.46 for age groups 65-74 and 75-84 vs 55-64 years) and sex (OR 1.15 male vs female). In comparison with flat adenomas as a reference lesion, sessile lesions had a similar HGD rate (OR 1.02) and pedunculated adenomas had a higher rate (OR 1.23). All associations were statistically significant (P ≤ .05).In this large screening database, it was found that the rates of adenomas with HGD are similar in the proximal and distal colon. The presence of HGD as a risk marker alone does not explain higher rates of proximal interval colorectal cancer. We suggest that certain lesions (flat, serrated lesions) may be missed in the proximal colon and may acquire a more aggressive biology over time. A combination of endoscopy-related factors and biology may therefore account for higher rates of proximal versus distal interval colorectal cancer.

The major prognostic relevance of primary tumour location (LPT) in advanced colorectal cancer was shown in large retrospective studies, but quantitative estimates are highly heterogeneous, and there is still limited information about its impact within the framework of biomarker-guided treatment strategies. Therefore, we analysed LPT in relation to other clinical and molecular parameters, based on mature survival data from the recent randomised AIO KRK0207 trial.Patients uniformly received first-line induction treatment with a combination of bevacizumab, oxaliplatin and fluoropyrimidine. LPT was retrospectively determined using surgical reports, pathology reports and endoscopy reports. The prognostic analyses were performed using Kaplan-Meier estimations and log-rank tests, while hazard ratios (HRs) and multivariable results were derived from Cox models.Among 754 patients with unequivocal information on LPT, patients with left-sided tumours showed a median overall survival of 24.8 months compared with the right-sided cohort with 18.4 months (HR: 1.54, 95% confidence interval: 1.30-1.81, P 0.0001). In a multivariable model, LPT proved to be the strongest prognosticator (HR 1.60), with performance status, number of metastatic sites, baseline carcinoembryonic antigen (CEA) and platelets independently retaining prognostic significance. In the subgroup of patients with known RAS/BRAF status (n = 567, 75%), a BRAF mutation showed the greatest unfavourable impact (HR 3.16). Although BRAF is strongly correlated to LPT, the latter remained a significant prognosticator in the BRAF wild-type subgroup. In contrast, no major impact of LPT was seen on tumours carrying RAS mutations.Within the framework of a uniform treatment strategy according to the current standards, LPT proved to have an important, although not solely dominating, relevance for survival prognosis. Its impact seems to be low in tumours with a RAS mutation.ClinicalTrials.govNCT00973609.

Background Amyloid deposits are a typical finding in pancreatic islets from patients with type 2 diabetes. Whether this is linked to the pathogenesis of type 2 diabetes is currently unknown. Therefore, we compared the occurrence of islet amyloid in patients with type 2 diabetes, diabetes secondary to pancreatic disorders, and nondiabetic individuals. Patients and methods Pancreatic tissue from 15 nondiabetic patients, 22 patients with type 2 diabetes, and 11 patients with diabetes due to exocrine pancreatic disorders (chronic pancreatitis, pancreatic carcinoma) were stained for insulin, amyloid, and apoptosis. β-cell area, amyloid deposits, and β-cell apoptosis were quantified by morphometric analysis. Results The proportion of islets containing amyloid deposits was significantly higher in both type 2 diabetes and diabetes due to exocrine pancreatic disorders than in healthy subjects. Islets with both amyloid and apoptosis were observed more frequently in type 2 diabetes and significantly more so in diabetes due to exocrine pancreatic disorders. In both diabetic groups, apoptotic ß-cells were found significantly more frequently in islets with more prominent amyloid deposits. Conclusions The occurrence of amyloid deposits in both type 2 diabetes and diabetes secondary to exocrine pancreatic disorders suggests that islet amyloid formation is a common feature of diabetes mellitus of different etiologies and may be associated with a loss of pancreatic ß-cells.

Background Selective internal radiotherapy (SIRT) has emerged as an effective therapy for patients with liver malignancies. Here, we report our analysis of histopathological changes in tumors and healthy liver tissue after SIRT and liver resection. Our main intent was to determine if specific histopathological changes occur in tumor and normal liver tissues. Methods We identified 17 patients in whom SIRT was applied to achieve liver resectability. Samples were taken from the resected liver tissue. The tumor, tumor peripheries, and tumor-free tissue were examined microscopically. Results Microspheres were identified in the vascular tumor bed, tumor-free liver, and portal tract. More microspheres were detected in the tumor than in the healthy liver tissue. When the effects of SIRT were analyzed, most patients showed a partial pathological response. Specific histopathological changes could not be described. We did not find any typical signs of radiation-induced hepatitis in healthy liver tissue. Conclusions Our findings support the clinical experience of effective tumor control after SIRT together with minimal impairment of healthy liver tissue. The observed histopathological changes suggest that SIRT might play a role in preoperative downsizing of liver malignancies.

Vaping may lead to spontaneous pneumothorax, but there are few published reports on this phenomenon. We present a case of vaping-related pneumothorax and make recommendations for structured reporting of this emerging cause for pneumothorax. A normal-weight 34-year-old male presented to our emergency department with dyspnoea and back pain increasing over 24 hours. Chest X-ray showed a large right-sided pneumothorax. Three years ago, he had quit smoking cigarettes and switched to vaping. CT scan revealed bullae, and the patient received apical lung resection. Histology revealed mild alveolitis. Vaping is an emerging cause of lung injury. This report demonstrates a potential association between vaping and pneumothorax. However, structured reporting and future research are needed to establish a definitive (or causal) relationship between vaping and pneumothorax.

Malignant mesotheliomas are rare and aggressive tumours arising from mesothelial cells of the pleura and peritoneum. Infrequent sites of origin are the pericardium and tunica vaginalis testis. More than 80% of mesotheliomas are localized in the pleura. Men are more frequently affected than women. The median age is60 years. Asbestos exposure is the best known aetilogical risk factor and is reported in 54-90% of patients. In Germany, malignant mesotheliomas caused by occupational asbestos exposure are compensated as occupational disease since 1977. Several neoplastic and non-neoplastic lesions like metastasis, sarcomas, lymphomas or pleuritis with reactive mesothelial proliferation have to be distinguished from malignant mesotheliomas. Especially, the pathohistological differentiation between atypical reactive mesothelial proliferation from malignant mesothelioma is a diagnostic challenge.

Valid HER2 testing is essential for optimal therapy of patients with HER2-positive gastric cancer and the correct use of first-line chemotherapy. While testing for HER2 status in breast cancer is routinely performed, this is not the case for HER2 testing in gastric cancer and it is usually only performed on clinician request. An interdisciplinary German expert group (pathologists and clinicians) took the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions for the practical use of HER2 testing in this indication. The recommendations made in this manuscript reflect the consensus of all participants and reflect their opinions and long-term experience in this field.

An accurate blood-based RAS mutation assay to determine eligibility of metastatic colorectal cancer (mCRC) patients for anti-EGFR therapy would benefit clinical practice by better informing decisions to administer treatment independent of tissue availability. The objective of this study was to determine the level of concordance between plasma and tissue RAS mutation status in patients with mCRC to gauge whether blood-based RAS mutation testing is a viable alternative to standard-of-care RAS tumor testing. RAS testing was performed on plasma samples from newly diagnosed metastatic patients, or from recurrent mCRC patients using the highly sensitive digital PCR technology, BEAMing (beads, emulsions, amplification, and magnetics), and compared with DNA sequencing data of respective FFPE (formalin-fixed paraffin-embedded) tumor samples. Discordant tissue RAS results were re-examined by BEAMing, if possible. The prevalence of RAS mutations detected in plasma (51%) vs. tumor (53%) was similar, in accord with the known prevalence of RAS mutations observed in mCRC patient populations. The positive agreement between plasma and tumor RAS results was 90.4% (47/52), the negative agreement was 93.5% (43/46), and the overall agreement (concordance) was 91.8% (90/98). The high concordance of plasma and tissue results demonstrates that blood-based RAS mutation testing is a viable alternative to tissue-based RAS testing.

The unique analysis, the first preplanned HRQOL analysis of the phase III AIO KRK 0207 trial, demonstrates that continuation of active maintenance treatment (FP/Bev or Bev alone) after induction treatment is not associated with a remarkable detrimental effect on HRQOL compared with treatment discontinuation. Median EORTC QLQ-C30 scores and deterioration rates did not differ between maintenance arms. Background First-line maintenance strategies are a current matter of debate in the management of mCRC. Their impact on patient's health-related quality of life (HRQOL) has not yet been evaluated. The objective of this study was to assess whether differences in HRQOL during any active maintenance treatment compared with no maintenance treatment exist. Patient and methods Eight hundred and thirty-seven patients were enrolled in the AIO KRK 0207 trial. Four hundred and seventy-two underwent randomization (after 24 weeks of induction treatment) into one of the maintenance arms: FP plus Bev (arm A), Bev alone (arm B), or no active treatment (arm C). HRQOL were assessed every 6 weeks during induction and maintenance treatment independent from treatment stop, delay, or modification, and also continued after progression, using the EORTC QLQ-C30, QLQ-CR29. The mean value of the global quality of life dimension (GHS/QoL) of the EORTC QLQ-C30, calculated as the average of all available time points after randomization was considered as pre-specified main endpoint. Additionally, EORTC QLQ-C30 response scores were analyzed. Results For HRQOL analysis, 413 patients were eligible (arm A: 136; arm B: 142, arm C: 135). Compliance rate with the HRQOL questionnaires was 95% at time of randomization and remained high during maintenance (98%, 99%, 97% and 97% at week 6, 12, 18 and 24). No significant differences between treatment arms in the mean GHS/QoL scores were observed at any time point. Also, rates of GHS/QoL score deterioration were similar (20.5%; 17.2% and 20.7% of patients), whereas a score improvement occurred in 36.1%; 43.8% and 42.1% (arms A, B and C). Conclusion Continuation of an active maintenance treatment with FP/Bev after induction treatment was neither associated with a detrimental effect on GHS/QoL scores when compared with both, less active treatment with Bev alone or no active treatment. Clinical trials number NCT00973609 (ClinicalTrials.gov).

This trial investigated the addition of panitumumab to triplet chemotherapy with fluorouracil/folinic acid, oxaliplatin, and irinotecan (FOLFOXIRI) in a two-to-one randomized, controlled, open-label, phase II trial in patients with untreatedThe primary end point was objective response rate (ORR) according to RECIST (version 1.1). The experimental arm (modified FOLFOXIRI [mFOLFOXIRI] plus panitumumab) was considered active if the ORR was ≥ 75%. The experimental ORR was compared with an estimated ORR of 60% based on historical data, verified by a randomized control group (FOLFOXIRI). The power of the trial was 80%, with a potential type I error of 0.05. Secondary end points included secondary resection rate, toxicity, progression-free survival, and overall survival.A total of 63 patients were randomly assigned to the experimental arm and 33 patients to the control arm. The ORR of the mFOLFOXIRI plus panitumumab arm exceeded 75% and was higher when compared with that of FOLFOXIRI (87.3%The addition of panitumumab to mFOLFOXIRI in patients with

A 65-year-old German woman was admitted to a hospital emergency department with progressively worsening back pain. She died a few days later due to septic shock, the very rare cause of death was revealed by an autopsy.This case report emphasizes the importance of clinical autopsy especially against the background of hospital quality management.

N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare antibody-mediated autoimmune encephalitis often associated with an ovarian teratoma in adolescent females. Here we present a 17-year-old girl with only and unusual psychiatric symptoms as part of her NMDAR encephalitis in combination with a very small ovarian teratoma suspected by magnetic resonance (MR) imaging and finally histologically confirmed. We further review the literature of NMDAR encephalitis in combination with an ovarian teratoma and discuss the recommended radiological workup in children with a suspected ovarian tumor.