Mismatch repair deficiency, chemotherapy and survival for resectable gastric cancer: an observational study from the German staR cohort and a meta-analysis.

PURPOSE: In a post hoc analysis of the MAGIC trial, patients with curatively resected gastric cancer (GC) and mismatch repair (MMR) deficiency (MMRd) had better median overall survival (OS) when treated with surgery alone but worse median OS when treated with additional chemotherapy. Further data are required to corroborate these findings. METHODS: Between April 2013 and December 2018, 458 patients with curatively resected GC, including cancers of the esophagogastric junction Siewert type II and III, were identified in the German centers of the staR consortium. Tumor sections were assessed for expression of MLH1, MSH2, MSH6 and PMS2 by immunohistochemistry. The association between MMR status and survival was assessed. Similar studies published up to January 2021 were then identified in a MEDLINE search for a meta-analysis. RESULTS: MMR-status and survival data were available for 223 patients (median age 66 years, 62.8% male), 23 patients were MMRd (10.3%). After matching for baseline clinical characteristics, median OS was not reached in any subgroup. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd and MMRp had a HR of 0.67 (95% CI 0.13-3.37, P = 0.63) and 1.44 (95% CI 0.66-3.13, P = 0.36), respectively. The meta-analysis included pooled data from 385 patients. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd had an improved OS with a HR of 0.36 (95% CI 0.14-0.91, P = 0.03), whereas those with MMRp had a HR of 1.18 (95% CI 0.89-1.58, P = 0.26). CONCLUSION: Our data support a positive prognostic effect for MMRd in GC patients treated with surgery only and a differentially negative prognostic effect in patients treated with perioperative chemotherapy. MMR status determined by preoperative biopsies may be used as a predictive biomarker to select patients for perioperative chemotherapy in curatively resectable GC.

Deep learning for diagnosis and survival prediction in soft tissue sarcoma.

BACKGROUND: Clinical management of soft tissue sarcoma (STS) is particularly challenging. Here, we used digital pathology and deep learning (DL) for diagnosis and prognosis prediction of STS. PATIENTS AND METHODS: Our retrospective, multicenter study included a total of 506 histopathological slides from 291 patients with STS. The Cancer Genome Atlas cohort (240 patients) served as training and validation set. A second, multicenter cohort (51 patients) served as an additional test set. The use of the DL model (DLM) as a clinical decision support system was evaluated by nine pathologists with different levels of expertise. For prognosis prediction, 139 slides from 85 patients with leiomyosarcoma (LMS) were used. Area under the receiver operating characteristic (AUROC) and accuracy served as main outcome measures. RESULTS: The DLM achieved a mean AUROC of 0.97 (±0.01) and an accuracy of 79.9% (±6.1%) in diagnosing the five most common STS subtypes. The DLM significantly improved the accuracy of the pathologists from 46.3% (±15.5%) to 87.1% (±11.1%). Furthermore, they were significantly faster and more certain in their diagnosis. In LMS, the mean AUROC in predicting the disease-specific survival status was 0.91 (±0.1) and the accuracy was 88.9% (±9.9%). Cox regression showed the DLM's prediction to be a significant independent prognostic factor (P = 0.008, hazard ratio 5.5, 95% confidence interval 1.56-19.7) in these patients, outperforming other risk factors. CONCLUSIONS: DL can be used to accurately diagnose frequent subtypes of STS from conventional histopathological slides. It might be used for prognosis prediction in LMS, the most prevalent STS subtype in our cohort. It can also help pathologists to make faster and more accurate diagnoses. This could substantially improve the clinical management of STS patients.

[Status of the availability and use of next generation sequencing (NGS) in bladder cancer-a questionnaire within the uropathology working group]. / Status der Verfügbarkeit und Anwendung von "next generation sequencing" (NGS) beim Harnblasenkarzinom ­ eine Umfrage in der Arbeitsgemeinschaft Uropathologie.

BACKGROUND: Technical advancement and availability of high-throughput analysis has advanced molecular subtyping of most cancers. Thus, new possibilities for precision oncology have emerged. AIM: Therefore, we aimed to collect data regarding availability and use of next generation sequencing (NGS) for urothelial cancer within the uropathology working group of the German Society of Pathology. METHODS: We collected data by questionnaires and additionally asked for sequencing results of bladder cancers in the participating institutions. RESULTS: A total of 13 university-affiliated institutes of pathology took part in the survey. All university institutes offer NGS-based molecular panel diagnostics and provide panels covering between 15 and 170 genes. Altogether, only 20 bladder cancers were sequenced in routine diagnostics and for 10 cancers potential targeted treatment options were available. DISCUSSION: So far, despite availability of NGS diagnostics at university institutes of pathology, only few bladder cancer samples have been sequenced. Based on current data from the molecular subtyping of bladder cancers, we recommend a step-by-step protocol with basic immunohistochemistry analysis and subsequent subtype-dependent analyses, e.g., alterations of the fibroblast growth factor receptors (FGFR) or comprehensive gene panel analyses.

[Liquid biopsy in colorectal cancer : An overview of ctDNA analysis in tumour diagnostics]. / Liquid Biopsy im kolorektalen Karzinom : Ein Überblick zur ctDNA-Analyse in der Tumordiagnostik.

In current routine diagnostics, the gold standard to determine the genomic profile of colorectal cancers (CRCs) is using biopsy or surgically resected tissues. However, such a tissue sample cannot represent the entire tumour heterogeneity, because it only shows a local and temporal snapshot. As a complement to tumour tissue genotyping, liquid biopsies enable minimally invasive detection of all potential tumour-specific mutations and their dynamic changes for molecular profiling. Furthermore, they can be repeated in certain intervals for monitoring response to treatment, occurrence of drug resistance and detection of relapse. This review focusses on analyzing circulating cell-free tumour DNA (ctDNA), which is mostly released from apoptotic or necrotic tumour cells into the bloodstream or by active secretion of circulating tumour cells (CTCs). Nevertheless, there are some challenges in analyzing ctDNA. First, ctDNA represents only a small fraction of total circulating DNA, because there is an enormous wild-type background of cell-free DNA (cfDNA) released by healthy cells. Second, ctDNA is highly fragmented and the amount of ctDNA in the blood is very low. In this review, we discuss the potential, fields of application as well as challenges and limitations of liquid biopsy approaches. In more detail, we discuss the possibility of using liquid biopsies as a future application for molecular characterization of CRCs, particularly for monitoring CRC patients during anti-EGFR therapy to detect resistance mutations (e.g. KRAS mutations) or further therapy-relevant mutations. In addition, we investigate whether blood-based molecular profiling is a reliable addition to routine diagnostic approaches of tissue-based molecular characterization.

In Vitro Entero-Capillary Barrier Exhibits Altered Inflammatory and Exosomal Communication Pattern after Exposure to Silica Nanoparticles.

The intestinal microvasculature (iMV) plays multiple pathogenic roles during chronic inflammatory bowel disease (IBD). The iMV acts as a second line of defense and is, among other factors, crucial for the innate immunity in the gut. It is also the therapeutic location in IBD targeting aggravated leukocyte adhesion processes involving ICAM-1 and E-selectin. Specific targeting is stressed via nanoparticulate drug vehicles. Evaluating the iMV in enterocyte barrier models in vitro could shed light on inflammation and barrier-integrity processes during IBD. Therefore, we generated a barrier model by combining the enterocyte cell line Caco-2 with the microvascular endothelial cell line ISO-HAS-1 on opposite sides of a transwell filter-membrane under culture conditions which mimicked the physiological and inflamed conditions of IBD. The IBD model achieved a significant barrier-disruption, demonstrated via transepithelial-electrical resistance (TER), permeability-coefficient (Papp) and increase of sICAM sE-selectin and IL-8. In addition, the impact of a prospective model drug-vehicle (silica nanoparticles, aSNP) on ongoing inflammation was examined. A decrease of sICAM/sE-selectin was observed after aSNP-exposure to the inflamed endothelium. These findings correlated with a decreased secretion of ICAM/E-selectin bearing exosomes/microvesicles, as evaluated via ELISA. Our findings indicate that aSNP treatment of the inflamed endothelium during IBD may hamper exosomal/microvesicular systemic communication.

[Lymphadenectomy in oncological visceral surgery-Part 1 : Hepatobiliary tumors and pancreatic cancer]. / Lymphadenektomie in der onkologischen Viszeralchirurgie ­ Teil 1 : Hepatobiliäre Tumoren und Pankreaskarzinom.

Lymphadenectomy is an integral component of the oncological surgery of cancer of the gastrointestinal tract and the hepato-pancreato-biliary system. The lymph node dissection is mainly prognostic but may also offer therapeutic advantages in the treatment of most cancers. Moreover, lymphadenectomy enables an accurate TNM staging, which is essential for a further stratification of the individual treatment as well as the inclusion in clinical trials on adjuvant therapy. This article gives an overview of the anatomy of the lymphatic drainage system of visceral organs and summarizes the current role of a systematic lymphadenectomy in oncological surgery (Part 1: hepatobiliary tumors and pancreatic cancer).

[Prognostic significance of immune cell infiltrates in tumor pathology]. / Prognostische Bedeutung von Immunzellinfiltraten in der Tumorpathologie.

BACKGROUND: The quantity, distribution, activation status, cytokine profile, and spatial distribution of tumor-infiltrating immune cells have prognostic value and may be predictive of response to immunotherapies. OBJECTIVES: A survey of relevant immune cell populations including their prognostic significance in the most common types of tumors. METHODS: Nonsystematic assessment and a discussion of studies that were conducted to estimate the prognostic significance of certain immune cell subsets and the methodical approaches used. RESULTS: For many tumor entities, prognostically favorable and unfavorable immune cell populations can be differentiated. However, nonspecific cell markers that may partly summarize antithetic immune cell subsets can be employed. Differences in sampling procedures and the determination of cut-off levels further limit the comparability of the studies carried out so far. CONCLUSION: The phenotypic and functional heterogeneity of tumor-infiltrating immune cells requires the use of cell subset-specific antibodies and antibody combinations. Furthermore, harmonized assessment routines, validation studies, and meta-analyses are important prerequisites for potential diagnostic implementation.

[Digital pathology in immuno-oncology-current opportunities and challenges : Overview of the analysis of immune cell infiltrates using whole slide imaging]. / Digitale Pathologie in der Immunonkologie ­ Aktuelle Chancen und Herausforderungen : Überblick zur Analyse von Immunzellinfiltraten mittels Whole Slide Imaging.

BACKGROUND: Immuno-oncology requires objective and standardized methods for measuring immune cell infiltrates for therapy selection and clinical trials. METHODS: Current approaches in applying digital pathology in immuno-oncology and developments in computational image analysis were analyzed. RESULTS: Since 2008, digital pathology has had an ever increasing importance in immuno-oncology. It is currently the only technology allowing the systematic and cost-effective quantitative spatial immune-profiling of patients. The analysis of immunological biomarkers requires integrated staining and image analysis strategies from single- to multistain on slide stacks. Statistical limits of the hypothesis to be tested have to be taken into account. Digital image analysis opens a new technological role for pathology in immuno-oncology and thereby serves as a key technological driver. CONCLUSION: Digital pathology delivers objective and quantitative data on the tumor microenvironment. But currently, a fully automatic, high-throughput analytics capability is still missing. Deep learning is the remedy for this, as it improves image analysis with increasing data availability. This requires the creation of systematic data collections but will in the end deliver standardized and automatic immunological analyses.

Therapy susceptible germline-related BRCA 1-mutation in a case of metastasized mixed adeno-neuroendocrine carcinoma (MANEC) of the small bowel.

BACKGROUND: Adenocarcinomas or combined adeno-neuroendocrine carcinomas (MANEC) of small bowel usually have a dismal prognosis with limited systemic therapy options. This is the first description of a patient showing a germline-related BRCA1 mutated MANEC of his ileum. The tumor presented a susceptibility to a combined chemotherapy and the PARP1-inhibitor olaparib. CASE PRESENTATION: A 74-year old male patient presented with a metastasized MANEC of his ileum. Due to clinical symptoms his ileum-tumor and the single brain metastasis were removed. We verified the same pathogenic (class 5) BRCA1 mutation in different tumor locations. There was no known personal history of a previous malignant tumor. Nevertheless we identified his BRCA1 mutation as germline-related. A systemic treatment was started including Gemcitabine followed by selective internal radiotherapy (SIRT) to treat liver metastases and in the further course Capecitabine but this treatment finally failed after 9 months and all liver metastases showed progression. The treatment failure was the reason to induce an individualized therapeutic approach using combined chemotherapy of carboplatin, paclitaxel and the Poly (ADP-ribose) polymerase- (PARP)-inhibitor olaparib analogous to the treatment protocol of Oza et al. All liver metastases demonstrated with significant tumor regression after 3 months and could be removed. In his most current follow up from December 2017 (25 months after his primary diagnosis) the patient is in a very good general condition without evidence for further metastases. CONCLUSION: We present first evidence of a therapy susceptible germline-related BRCA1 mutation in small bowel adeno-neuroendocrine carcinoma (MANEC). Our findings offer a personalized treatment option. The germline background was unexpected in a 74-year old man with no previously known tumor burden. We should be aware of the familiar background in tumors of older patients as well.

Renal tubular epithelial cell-derived BAFF expression mediates kidney damage and correlates with activity of proliferative lupus nephritis in mouse and men.

B-cell activating factor of the tumour necrosis factor family (BAFF) is a cytokine, mainly produced by hematopoietic cells (e.g. monocytes/macrophages, dendritic cells), indispensable for B-cell maturation. The BLISS studies have demonstrated that blocking BAFF by the human monoclonal antibody belimumab is a valuable therapeutic approach in patients with clinically and serologically active systemic lupus erythematosus (SLE). However, the defined sources of BAFF, which contributes to SLE, are still unclear. Recent findings show that BAFF expression is not restricted to myeloid cells. Since lupus nephritis is the main cause of morbidity and mortality for SLE patients, the aim of this study was to investigate whether renal tubular epithelial cells (TEC) are an important source of BAFF and thus may contribute to the pathogenesis and progression of SLE. We found BAFF expression both in cultured murine and human TEC. These results could be verified with in situ data from the kidney. Moreover, BAFF expression in the kidneys of lupus-prone MRL- Faslpr mice correlated with disease activity, and BAFF expression on TEC in biopsies of patients with diffuse proliferative lupus nephritis showed a correlation with the histopathological activity index. In vitro functional assays revealed an autocrine loop of BAFF with its binding receptors on TEC, resulting in a strong induction of colony stimulating factor-1. Finally, we identified divergent effects of BAFF on TEC depending on the surrounding milieu ('inflammatory versus non-inflammatory'). Taken together, our findings indicate that renal-derived BAFF may play an important role in the pathophysiology of the systemic autoimmune disease SLE.

Immaturity for gestational age of microvasculature and placental barrier in term placentas with high weight.

OBJECTIVE: Villous immaturity for gestational age is a multifactorial developmental deviation associated with unexpected placental insufficiency, fetal hypoxia and term fetal death. In our previous work we have shown that immature CD15+/CD31+/CD34+ endothelial cells were an important indicator of placental villous immaturity and chronic insufficiency. The aim of this study was to perform a comparative analysis of CD15-marked immaturity in the vessel walls between normal and pathological term placentas of clinically and structurally heterogenous groups with normal, low and high weight. STUDY DESIGN: 165 clinically normal and pathological placentas of gestational age 39-42 with normal weight (25-75 percentile), low weight (<10 percentile) and high weight (>90 percentile) were structurally and immunohistochemically analyzed. Excluded were placentas with a severe form of placental insufficiency associated with intrauterine fetal death, low APGAR-score, genetic and chromosomal diseases or placental inflammations. The distribution patterns of CD15, CD31 and CD34 were assessed separately in the macrovasculature, microvasculature and placental barrier (PB) - associated capillaries. RESULTS: All placental groups with normal weight, low weight and high weight include normal, accelerated villous maturation or villous immaturity independent of their weight. However, a significant increase of immature CD15+/CD31+/CD34+ endothelial cells was detected in microvasculature and PB -associated capillaries in high weight-placentas (63.5%/52.2%), compared to those of normal weight (13.8%/8.2%) and low weight (16.1%/17.8%). The distribution of macrovascular immature CD15+/CD31+/CD34+ endothelial cells did not show such marked differences. CONCLUSION: We have identified the immaturity of microvasculature and PB -associated capillaries with a pathological persistency of immature CD15+/CD31+/CD34+ endothelial cells and a reduction of terminally differentiated CD15-/CD31+/CD34+ endothelial cells in a structurally and clinically heterogeneous group of high weight-placentas. We assume that immaturity of placental vessels are part of prenatal adaptational processes that can be recruited in different emergency situations and may provide potential targets of therapeutic correction of placental growth and chronic insufficiency. We therefore recommend the use of CD15-based immunophenotyping as a method to identify latent unfavorable conditions of fetal development in the intrauterine life and individual risk of disease in the postnatal period.

Implementation of an HIV-1 Triple-Target NAT Assay in the Routine Screening at Three German Red Cross Blood Centres.

BACKGROUND: Blood product safety was significantly improved by the introduction of NAT testing in the late 1990s, resulting in a strong decrease of transfusion-transmitted infections (TTIs). Due to the occurrence of HIV-1 NAT test failures as a consequence of mismatch mutations in the amplicon regions of mono-target NAT assays, the Paul Ehrlich Institute mandated the implementation of multi-target NAT assays for HIV-1 in 2014. Commercial suppliers mostly developed dual-target NAT assays, with only one implementing a triple-target NAT assay. METHODS: The HIV-1 triple-target NAT assay v3 (GFE Blut) was tested on mutated specimens and synthetic DNA bearing mutations that resulted in sample underquantification or false-negative test results. In addition, data from 2 years routine testing at three German Red Cross Blood centres were analysed. RESULTS: The HIV-1 triple-target PCR could compensate for all mutations tested and could compensate the loss of one amplicon without a significant loss of sensitivity. Data from 2 years routine testing showed a solid performance. CONCLUSION: The HIV-1 triple-target v3 assay (GFE Blut) can compensate mutations in target sequences better than a dual-target assay and is applicable to high-throughput screening, thus increasing blood product safety.

[Grading of prostate cancer]. / Grading von Prostatakarzinomen.

The current grading of prostate cancer is based on the classification system of the International Society of Urological Pathology (ISUP) following a consensus conference in Chicago in 2014. The foundations are based on the frequently modified grading system of Gleason. This article presents a brief description of the development to the current ISUP grading system.

[Multiparametric MRI and MRI-TRUS fusion biopsy in patients with prior negative prostate biopsy]. / Wertigkeit der multiparametrischen MRT und der MRT-TRUS-Fusionsbiopsie bei primär negativ biopsierten Patienten.

BACKGROUND: Multiparametric MRI (mpMRI) plays an increasingly important role in prostate cancer (PCa) diagnostics and is recommended in men with previously negative TRUS biopsy. The optimal biopsy method after mpMRI is under discussion. OBJECTIVE: Prospective, PIRADS- and START-conform analysis of the relevance of mpMRI and MRI-TRUS fusion biopsy in patients with prior negative TRUS biopsy and comparison of the detection rates of fusion-targeted biopsies (tB) and systematic transperineal saturation biopsies (sB). MATERIALS AND METHODS: Between 10/2012 and 09/2015, 287 patients with prior negative TRUS biopsy underwent mpMRI and software-assisted, rigid MRI-TRUS fusion biopsy. In addition to and strictly separated from sB (median cores n = 24), tB (median cores per patient n = 4, per lesion n = 3) were performed in case of suspicious MRI lesions (PIRADS ≥ 2). Both biopsy methods were compared by using McNemar's test. RESULTS: Of the 287 patients, 148 (52 %) had positive biopsies. Of these, 108/287 (38 %) had significant PCa (Gleason Score [GS] = 3 + 3 and PSA ≥ 10 ng/ml or GS ≥ 3 + 4) and again 43/287 (15 %) had a GS ≥ 4 + 3 PCa. sB failed to diagnose 8/148 PCa (5.4 %) and 6/108 significant PCa (5.5 %), whereas tB failed to diagnose 48 (32.4 %) PCa (p < 0.0001) and 22 (20.4 %) significant PCa (p = 0.0046). Of the PCa missed by tB, 11  had a GS ≥ 3 + 4 and 5 of these a GS = 4 + 3. On a per patient basis, MRI failed to detect 5 significant PCa, whereby 17 of the significant PCa were missed by fusion-targeted cores alone. CONCLUSIONS: In men with unsuspicious MRI (PIRADS < 3), there is a 11 % risk of significant PCa. In case of suspicious MRI lesions, the combination of both biopsy approaches offers maximum tumor detection.

Further reduction of disqualification rates by additional MRI-targeted biopsy with transperineal saturation biopsy compared with standard 12-core systematic biopsies for the selection of prostate cancer patients for active surveillance.

BACKGROUND: Active surveillance (AS) is commonly based on standard 10-12-core prostate biopsies, which misclassify ~50% of cases compared with radical prostatectomy. We assessed the value of multiparametric magnetic resonance imaging (mpMRI)-targeted transperineal fusion-biopsies in men under AS. METHODS: In all, 149 low-risk prostate cancer (PC) patients were included in AS between 2010 and 2015. Forty-five patients were initially diagnosed by combined 24-core systematic transperineal saturation biopsy (SB) and MRI/transurethral ultrasound (TRUS)-fusion targeted lesion biopsy (TB). A total of 104 patients first underwent 12-core TRUS-biopsy. All patients were followed-up by combined SB and TB for restratification after 1 and 2 years. All mpMRI examinations were analyzed using PIRADS. AS was performed according to PRIAS-criteria and a NIH-nomogram for AS-disqualification was investigated. AS-disqualification rates for men initially diagnosed by standard or fusion biopsy were compared using Kaplan-Meier estimates and log-rank tests. Differences in detection rates of the SB and TB components were evaluated with a paired-sample analysis. Regression analyses were performed to predict AS-disqualification. RESULTS: A total of, 48.1% of patients diagnosed by 12-core TRUS-biopsy were disqualified from AS based on the MRI/TRUS-fusion biopsy results. In the initial fusion-biopsy cohort, upgrading occurred significantly less frequently during 2-year follow-up (20%, P<0.001). TBs alone were significantly superior compared with SBs alone to detect Gleason-score-upgrading. NPV for Gleason-upgrading was 93.5% for PIRADS⩽2. PSA level, PSA density, NIH-nomogram, initial PIRADS score (P<0.001 each) and PIRADS-progression on consecutive MRI (P=0.007) were significant predictors of AS-disqualification. CONCLUSIONS: Standard TRUS-biopsies lead to significant underestimation of PC under AS. MRI/TRUS-fusion biopsies, and especially the TB component allow more reliable risk classification, leading to a significantly decreased chance of subsequent AS-disqualification. Cancer detection with mpMRI alone is not yet sensitive enough to omit SB on follow-up after initial 12-core TRUS-biopsy. After MRI/TRUS-fusion biopsy confirmed AS, it may be appropriate to biopsy only those men with suspected progression on MRI.

The embryo-placental CD15-positive "vasculogenic zones" as a source of propranolol-sensitive pediatric vascular tumors.

OBJECTIVE: Propranolol-induced involution is a unique biological feature of some pediatric vascular tumors, for instance infantile hemangioma (IH), cerebral cavernoma or chorioangioma. Currently, the cellular origin of these distinct tumors is unclear. In this study, we tested the hypothesis that propranolol-responsive vascular tumors are derived from common vessel-forming CD15 + progenitor cells which occur in early gestation. The aim of this study was to identify the tumor-relevant CD15 + progenitors at the early stages of embryo-placental development. MATERIALS AND METHODS: Human embryo-placental units of 4-8 weeks gestation and pediatric vascular tumors were tested for expression of the tumor-relevant markers CD15, CD31 and CD34. RESULTS: Placental vessel-forming progenitors were characterized by immunostaining for CD15, CD31, and CD34. In embryonic tissue, a discontinuous CD15+/CD31+/CD34 + progenitors was detected in immature vessels of the skin, neural tube, spinal and cerebral meninges. Similarly, vessels in IH and chorioangioma exhibited a co-expression of CD15, CD31, and CD34. In contrast, the majority of embryonic vessels presented a CD31+/CD34+, but CD15-negative immunophenotypic pattern. DISCUSSION: Our results suggest the existence of a CD15+ "vasculogenic zones" in the embryo-placental unit as well as in IH and chorioangioma. A site-specific correlation between normal embryo-placental and tumoral vessel-forming CD15 + progenitors was demonstrated. CONCLUSION: Hence, site- and stage-specific CD15 + progenitors of vascular wall could be considered as propronalol-sensitive targets and source of pre- and postnatal vascular tumors. We propose, that the CD15+ "vasculogenic zones" are a site-specific reserve of multi-lineage progenitors that could be recruited in pre- and postnatal emergency situations.

Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB.

Resistance towards the drug 5-fluorouracil (5-FU) is a key challenge in the adjuvant chemotherapy of colorectal cancer (CRC), and novel targeted approaches are required to improve the therapeutic outcome. Necroptosis is a recently discovered form of programmed cell death, which depends on receptor interacting protein 1 (RIP1) and particularly occurs under caspase-deficient conditions. The targeted induction of necroptosis represents a promising strategy to overcome apoptosis resistance in cancer. The aim of this study was to systematically explore the usage of pan-caspase inhibitors to sensitize resistant CRC cells for 5-FU. We found that pan-caspase inhibitors facilitated 5-FU-induced necroptosis, which was mediated by autocrine secretion of tumor necrosis factor α (TNF-α). TNF-α production was driven by nuclear factor κB (NF-κB) and required RIP1 kinase. In vivo xenograft experiments showed that the novel pan-caspase inhibitor IDN-7314 in combination with 5-FU synergistically blocked tumor growth. Ex vivo experiments with fresh human CRC tissue specimens further indicated that a subgroup of patients could benefit from combinatory treatment. Thereby, elevated levels of secreted TNF-α and expression of components of the necroptotic pathway might help to predict the sensitivity to pro-necroptotic therapies. Together, our results shed new light on the molecular regulation of necroptosis by NF-κB and RIP1. Moreover, we identify necroptotic cell death as an important effector mechanism of 5-FU-mediated anti-tumoral activity. On the basis of this study, we propose pan-caspase inhibitors as a novel approach in the adjuvant chemotherapy of CRC.

[Value of MRI/ultrasound fusion in primary biopsy for the diagnosis of prostate cancer]. / Stellenwert der MRT/TRUS-Fusionsbiopsie im Rahmen der Primärbiopsie beim Prostatakarzinom.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) plays an emerging role in prostate cancer diagnosis. We compared the cancer detection rates of targeted biopsy (tB) of suspicious lesions in mpMRI versus systematic transperineal saturation biopsy (sB) in men with primary suspicion of prostate cancer (PCa). METHODS: A total of 437 consecutive primary biopsy patients, who underwent transperineal systematic and fusion-guided biopsy between 2012 and 2014, were enrolled. mpMRI was evaluated based on PI-RADS. Analysis of biopsy specimen was performed following START criteria. RESULTS: Of the 437 men, 334 harbored 426 MR lesions. Overall, 274 PCa and 203 significant PCa (Gleason score (GS) ≥ 3 + 4, GS = 3 + 3 and PSA values ≥ 10 ng/ml) were detected. There were 52 (26 %) significant PCa exclusively found by sB, whereas only 18 (9 %) were identified by tB (p < 0.001). Of 80 high-grade PCa with GS ≥ 4 + 3, 70 were diagnosed by sB, and 60 by tB (p = 0.007). In addition, 54 % of all insignificant PCa (GS < 7, PSA < 10 ng/ml) were detected by sB alone (p < 0.001). AUC of mpMRI was 0.76-0.78. CONCLUSION: The combination of tB + sB detects PCa most accurately. Ongoing prospective (multicenter) studies are evaluating the status of the 12 core TRUS-guided random biopsy.