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BACKGROUND: Clinical trials have established the efficacy of brodalumab in treatment of psoriasis and psoriatic arthritis. Real-world evidence is needed to fully evaluate the drug.OBJECTIVE: Here we investigate drug survival and clinical effectiveness of brodalumab in patients with psoriasis and psoriatic arthritis in a real-world setting.METHODS: This was a retrospective single-centre study enrolling patients receiving brodalumab for psoriasis at the Department of Dermatology, Aarhus University Hospital, Denmark. The primary endpoints were drug survival, reasons for discontinuation, percentage of patients achieving a Psoriasis Area and Severity Index (PASI) ≤ 2 and clinical effectiveness against psoriatic arthritis.RESULTS: Eighty-three patients were included (mean age 49.2 ± 17.4 years, 59.0% male, 9.6% bio-naïve, mean baseline PASI 10.9 ± 6.9). Twenty-seven patients discontinued treatment primarily due to ineffectiveness and adverse events (AEs). Kaplan-Meier-estimated 1-year drug survival was 65.7%. An absolute Psoriasis Area and Severity Index (PASI) ≤ 2 was achieved by 68.2% of patients at end of follow-up, by 70.0% at weeks 12-17 and by 76.2% after 40-60 weeks of treatment. Neither drug survival nor PASI ≤ 2 was associated with baseline PASI ≥ 10, body mass index ≥ 30, previous treatment with > 2 biologics or other IL-17 inhibitors in particular (P > 0.05). Psoriatic arthritis remission or partial remission was achieved by 10 out of 18 patients with psoriatic arthritis; treatment failure was reported in 5 patients.CONCLUSIONS: Brodalumab was effective against psoriasis and psoriatic arthritis in a real-world setting. The drug survival was lower than reported in other real-world settings.

Robust biomarkers to predict response to immune checkpoint blockade (ICB) in metastatic urothelial carcinoma (mUC) are still in demand. Recently, early C-reactive protein (CRP) kinetics and especially the novel CRP flare-response phenomenon has been associated with immunotherapy response.We conducted a multicentre observational study comprising 154 patients with mUC treated with ICB to evaluate the predictive value of a previously described on-treatment CRP kinetics: CRP flare responders (at least doubling of baseline CRP within the first month after initiation of ICB followed by a decline below baseline within three months), CRP responders (decline in baseline CRP by ≥ 30% within three months without a prior flare) and the remaining patients as CRP non-responders. CRP kinetics groups were correlated with baseline parameters, PD-L1 status, progression-free survival (PFS) and overall survival (OS).Objective response was observed in 57.1% of CRP responders, 45.8% of CRP flare responders and 17.9% of CRP non-responders (P 0.001). CRP flare response was associated with prolonged PFS and OS (P 0.001). In multivariable Cox regression analysis, CRP flare responders showed a risk reduction of ∼70% for tumour progression and death compared to CRP non-responders. Subgroup analysis of CRP flare responders revealed that patients with a long-flare response (completed flare-response kinetics ≥6 weeks on-treatment) showed even more favourable outcomes following ICB (HR = 0.18, 95%-CI: 0.07-0.48, P 0.001).CRP (flare)response robustly predicts immunotherapy response and outcomes in mUC independent of PD-L1 status. Thus, early on-treatment CRP kinetics is a promising low-cost and easy-to-implement biomarker to optimise therapy monitoring in patients with mUC treated with ICB.

Objective Aim of the study was to compare working and non-working patients over a period of 12 months regarding socio-demographic, cancer-specific and mental health parameters. Methods This study was conducted as part of a Germany-wide longitudinal survey among 1398 patients in 13 national Comprehensive Cancer Centers. The sample used for analysis consisted of n = 430 cancer patients younger than 65 years (age M = 52.4 years, SD = 8.1; 67.0% females). Socio-demographic, cancer-specific and mental health parameters (Depression: Patient Health Questionnaire, Anxiety: Generalized Anxiety Disorder Scale, Distress: Distress Thermometer) were assessed at baseline during hospitalization and at 12 months follow-up. Results 73.7% of all patients (n = 317) have returned to work after one year. While working and non-working patients did not differ in socio-demographic parameters, there were significant differences in the presence of metastases, tumor and treatment status. Mixed analysis of variances revealed significant interactions between working status and time for depression (p = 0.009), anxiety (p = 0.003) and distress (p = 0.007). Non-working patients reported higher levels of depression, anxiety and distress than working patients over time. A logistic regression showed significant associations between lower depression (p = 0.019), lower distress (p = 0.033) and the absence of a tumor (p = 0.015) with working status. Conclusions The majority of cancer survivors returned to work. Non-working patients had higher levels of depression, anxiety and distress than working patients. After controlling for cancer-specific factors, mental health parameters were still independently associated with working status. Return to work can thus be associated with an improved mental health in cancer survivors. In order to establish causality, further research is necessary.

Development of malignancy is a pending threat for patients with inflammatory bowel disease (IBD). Aim of this study was to analyze cervical dysplasia and infection with human papilloma virus (HPV) in patients with IBD.This was a prospective, single center cohort study in Germany. Consecutive IBD patients admitted to the Department of Gastroenterology were sent to Gynecology, where a questionnaire was answered and gynecological examinations including a smear for cytology and HPV were taken. Participants of a general screening program constituted controls. Descriptive statistics, 95% confidence intervals and odds ratios were calculated.A total of 101 patients were recruited of which 99 patients participated. Analysis showed a significant (p = 0.05) difference between the prevalence of abnormal smears in patients with (22%) and without (6%) immunosuppressive therapy, while the latter had cervical abnormalities comparable with healthy controls (5%). All immunosuppressants showed similarly high risks for abnormal smear results. Only 11/99 (11%) patients had positive high-risk HPV tests, which is comparable with general population.The prevalence of abnormal cervical smears is higher in IBD patients compared to healthy individuals, but the difference is confined to patients with IBD and immunosuppressive therapy. Annual screening is advisable.

Endothelial dysfunction and altered nitric oxide (NO) metabolism are considered causal factors in heart failure with preserved ejection fraction (HFpEF). NO synthase activity depends on the availability of arginine and its derivatives. Thus, we analyzed arginine, associated metabolites, arginine-metabolizing enzymes and NO turnover in 20-week-old female healthy lean (L-ZSF1) and obese ZSF1 rats (O-ZSF1) with HFpEF. Serum, urine and lysates of liver, kidney and heart were analyzed. There were significantly lower lysine (− 28%), arginine (− 31%), homoarginine (− 72%) and nitrite (− 32%) levels in serum of O-ZSF1 rats. Ornithine (+ 60%) and citrulline (+ 20%) levels were higher. Similar results were found in the heart. Expression of arginine consuming enzymes in liver and kidney was unchanged. Instead, we observed a 5.8-fold higher arginase 1 expression, presumably of granulocyte origin, in serum and > fourfold increased cardiac macrophage invasion in O-ZSF1. We conclude that inflammatory cells in blood and heart consume arginine and probably homoarginine via arginase 1 and inducible NO synthase and release ornithine and citrulline. In combination with evidence for decreased NO turnover in O-ZSF1 rats, we assume lower arginine bioavailability to endothelial NO synthase.

Lynch syndrome (LS), Lynch-like syndrome (LLS), and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer (CRC). The aim of this prospective study was to characterize and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS, and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex, and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS, and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. This study may support the development of risk-adapted surveillance policies in LS, LLS and FCCX. This article is protected by copyright. All rights reserved.

In the general population with COVID-19, the male sex is an established risk factor for mortality, in part due to a more robust immune response to COVID-19 in women. Because patients on kidney function replacement therapy (KFRT) have an impaired immune response, especially kidney transplant recipients due to their use of immunosuppressants, we examined whether the male sex is still a risk factor for mortality among patients on KFRT with COVID-19. From the European Renal Association COVID-19 Database (ERACODA), we examined patients on KFRT with COVID-19 who presented between February 1st, 2020, and April 30th, 2021. 1204 kidney transplant recipients (male 62.0%, mean age 56.4 years) and 3206 dialysis patients (male 61.8%, mean age 67.7 years) were examined. Three-month mortality in kidney transplant recipients was 16.9% in males and 18.6% in females (p = 0.31) and in dialysis patients 27.1% in males and 21.9% in females (p = 0.001). The adjusted HR for the risk of 3-month mortality in males (vs females) was 0.89 (95% CI 65, 1.23, p = 0.49) in kidney transplant recipients and 1.33 (95% CI 1.13, 1.56, p = 0.001) in dialysis patients (pinteraction = 0.02). In a fully adjusted model, the aHR for the risk of 3-month mortality in kidney transplant recipients (vs. dialysis patients) was 1.39 (95% CI 1.02, 1.89, p = 0.04) in males and 2.04 (95% CI 1.40, 2.97, p interaction = 0.02). In patients on KFRT with COVID-19, the male sex is not a risk factor for mortality among kidney transplant recipients but remains a risk factor among dialysis patients. The use of immunosuppressants in kidney transplant recipients, among other factors, may have narrowed the difference in the immune response to COVID-19 between men and women, and therefore reduced the sex difference in COVID-19 mortality risk.

Treatment‐related complications contribute substantially to morbidity and mortality in acute myeloid leukemia (AML) patients undergoing induction chemotherapy. Although AML patients are susceptible to fluid overload (FO) (e.g., in the context of chemotherapy protocols, during sepsis treatment or to prevent tumor lysis syndrome), little attention has been paid to its role in AML patients undergoing induction chemotherapy. AML patients receiving induction chemotherapy between 2014 and 2019 were included in this study. FO was defined as ≥5% weight gain on day 7 of induction chemotherapy compared to baseline weight determined on the day of admission. We found FO in 23 (12%) of 187 AML patients undergoing induction chemotherapy. Application of >100 ml crystalloid fluids/kg body weight until day 7 of induction chemotherapy was identified as an independent risk factor for FO. AML patients with FO suffered from a significantly increased 90-day mortality rate and FO was demonstrated as an independent risk factor for 90-day mortality. Our data suggests an individualized, weight-adjusted calculation of crystalloid fluids in order to prevent FO-related morbidity and mortality in AML patients during induction chemotherapy. Prospective trials are required to determine the adequate fluid management in this patient population.

In renal transplantation, complement is involved in ischemia reperfusion injury, graft rejection and dysfunction. However, it is still unclear how induction of complement and its activation are initiated. Using allograft biopsies of a well-characterized cohort of 28 renal transplant patients with no rejection (Ctrl), delayed graft function (DGF), acute T-cell-mediated (TCMR) or antibody-mediated rejection (ABMR) we analyzed differences in complement reaction. For that mRNA was isolated from FFPE sections, quantified with a multiplex gene expression panel and correlated with transplant conditions and follow-up of patients. Additionally, inflammatory cells were quantified by multiplex immunohistochemistry. In allograft biopsies with TCMR and ABMR gene expression of C1QB was 2-4 fold elevated compared to Ctrl. In TCMR biopsies, mRNA counts of several complement-related genes including C1S, C3, CFB and complement regulators CFH, CR1 and SERPING1 were significantly increased compared to Ctrl. Interestingly, expression levels of about 75% of the analyzed complement related genes correlated with cold ischemia time (CIT) and markers of inflammation. In conclusion, this study suggest an important role of complement in transplant pathology which seems to be at least in part triggered by CIT. Multiplex mRNA analysis might be a useful method to refine diagnosis and explore new pathways involved in rejection.

Recent studies have reported an association between N-terminal atrial natriuretic peptide (NT-proANP) and the progression of atrial fibrillation (AF). However, NT-proANP levels in peripheral and cardiac circulation in AF patients and in non-AF individuals need to be defined. The aims of the current study are (1) to analyze NT-proANP levels in peripheral and cardiac circulation in AF patients and (2) to compare NT-proANP levels in individuals with and without AF. We recruited AF patients who were undergoing their first AF catheter ablation and non-AF individuals. Blood plasma samples taken from the femoral vein and the left atrium (LA) were collected before AF ablation in the AF patients and from the cubital vein in the non-AF controls. Low voltage areas (LVAs) were determined using high-density maps during catheter ablation and defined as

Objectives To estimate the times taken to receive clearance to return to sporting activity and to return to pre-injury level of sport competition following sport-related concussion, and to estimate the proportion of athletes who were participating at their pre-injury level of sport competition six months and one-year following sport-related concussion. Design Prospective cohort study. Methods Amateur, adult athletes (16–38 years old) were diagnosed with sport-related concussion at a university-affiliated hospital emergency department. Participants were assessed within one-week, upon medical clearance to return to sporting activity, two weeks following return to sporting activity, six months, and 12 months following sport-related concussion. We assessed sex-, age-, and activity-matched non-injured, control participants at matched time-points. Participants were asked during each study assessment whether they were participating in any sport, in a different sport than before their sport-related concussion, in the same sport but at a lower level of competition than before their sport-related concussion, or in the same sport at the same level of competition than before their sport-related concussion. Results Fifty concussed participants and 50 non-injured, control participants completed the study. The median times taken to receive clearance to return to sporting activity and to return to pre-injury level of sport competition following sport-related concussion were 13 days (95%CI = 12,16) and 31 days (95%CI = 28,32), respectively. One-year following sport-related concussion, 52% of participants reported that they were no longer participating in the same sport and at the same level of competition as they were before their sport-related concussion, compared with only 24% of participants in the non-injured, control group (p = 0.003). Conclusions A greater percentage of athletes in the concussion group were not participating at their perceived pre-injury level of sport competition one-year following sport-related concussion compared with a non-injured control group. Factors that explain the lower proportion of amateur athletes participating at their pre-injury level of sport competition one-year after sport-related concussion are likely multifaceted and should be considered in future investigations.

Acute kidney injury (AKI) complicates the clinical course of hospitalized patients by increasing need for intensive care treatment and mortality. There is only little data about its impact on AML patients undergoing intensive induction chemotherapy. In this study, we analyzed the incidence as well as risk factors for AKI development and its impact on the clinical course of AML patients undergoing induction chemotherapy. We retrospectively analyzed data from 401 AML patients undergoing induction chemotherapy between 2007 and 2019. AKI was defined and stratified according to KIDGO criteria by referring to a defined baseline serum creatinine measured on day 1 of induction chemotherapy. Seventy-two of 401 (18%) AML patients suffered from AKI during induction chemotherapy. AML patients with AKI had more days with fever (7 vs. 5, p = 0.028) and were more often treated on intensive care unit (45.8% vs. 10.6%, p < 0.001). AML patients with AKI had a significantly lower complete remission rate after induction chemotherapy and, with 402 days, a significantly shorter median overall survival (OS) (median OS for AML patients without AKI not reached). In this study, we demonstrate that the KIDGO classification allows mortality risk stratification for AML patients undergoing induction chemotherapy. Relatively mild AKI episodes have impact on the clinical course of these patients and can lead to chronic impairment of kidney function. Therefore, we recommend incorporating risk factors for AKI in decision-making considering nutrition, fluid management, as well as the choice of potentially nephrotoxic medication in order to decrease the incidence of AKI. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04482-3.

A detailed understanding of intestinal stem cell (ISC) self-renewal and differentiation is required to treat chronic intestinal diseases. However, the different models of ISC lineage hierarchy1–6 and segregation7–12 are subject to debate. Here, we have discovered non-canonical Wnt/planar cell polarity (PCP)-activated ISCs that are primed towards the enteroendocrine or Paneth cell lineage. Strikingly, integration of time-resolved lineage labelling with single-cell gene expression analysis revealed that both lineages are directly recruited from ISCs via unipotent transition states, challenging the existence of formerly predicted bi- or multipotent secretory progenitors7–12. Transitory cells that mature into Paneth cells are quiescent and express both stem cell and secretory lineage genes, indicating that these cells are the previously described Lgr5+ label-retaining cells7. Finally, Wnt/PCP-activated Lgr5+ ISCs are molecularly indistinguishable from Wnt/β-catenin-activated Lgr5+ ISCs, suggesting that lineage priming and cell-cycle exit is triggered at the post-transcriptional level by polarity cues and a switch from canonical to non-canonical Wnt/PCP signalling. Taken together, we redefine the mechanisms underlying ISC lineage hierarchy and identify the Wnt/PCP pathway as a new niche signal preceding lateral inhibition in ISC lineage priming and segregation. Polarity cues regulate intestinal stem cell fate. Bottcher et al. demonstrate that mouse intestinal stem cells, which express the Wnt/planar cell polarity reporter Flattop, are primed either towards the enteroendocrine or Paneth cell lineage.

BackgroundThe small number of organ donors forces transplant centres to consider potentially suboptimal kidneys for transplantation. Eurotransplant established an algorithm for rescue allocation (RA) of kidneys repeatedly declined or not allocated within 5 h after procurement. Data on the outcomes and benefits of RA are scarce to date.MethodsWe conducted a retrospective 8-year analysis of transplant outcomes of RA offers based on our in-house criteria catalogue for acceptance and decline of organs and potential recipients.ResultsRA donors and recipients were both older compared with standard allocation (SA). RA donors more frequently had a history of hypertension, diabetes or fulfilled expanded criteria donor key parameters. RA recipients had poorer human leucocyte antigen (HLA) matches and longer cold ischaemia times (CITs). However, waiting time was shorter and delayed graft function, primary non-function and biopsy-proven rejections were comparable to SA. Five-year graft and patient survival after RA were similar to SA. In multivariate models accounting for confounding factors, graft survival and mortality after RA and SA were comparable as well.ConclusionsFacing relevant comorbidities and rapid deterioration with the risk of being removed from the waiting list, kidney transplantation after RA was identified to allow for earlier transplantation with excellent outcome. Data from this survey propose not to reject categorically organs from multimorbid donors with older age and a history of hypertension or diabetes to aim for the best possible HLA matching and to carefully calculate overall expected CIT.

To prospectively investigate the recovery of athlete-reported symptoms and the condition-specific health-related quality of life (HRQoL) following sport-related concussion.Prospective matched-cohort study.We recruited amateur athletes who were diagnosed with sport-related concussion by emergency department physicians. Study participants were assessed at 3 time points following sport-related concussion. At each assessment, participants completed 5 condition-specific HRQoL patient-reported outcome measures to evaluate participants' perceptions of the effects of specific concussion-related symptoms on their HRQoL. We performed log-linear analyses to assess the proportion of concussed participants with clinically impaired condition-specific HRQoL compared with the proportion of participants in the control group with clinically impaired condition-specific HRQoL.Fifty participants with sport-related concussion and 50 control participants matched by sex, age, and activity completed the study. Upon return to sporting activity, there was a significantly greater proportion of participants in the concussion group who perceived that headache, neck pain, and dizziness had an adverse effect on their HRQoL compared with the control group. Two weeks after return to sporting activity, there was still a significantly greater proportion of participants in the concussion group who perceived that headache (Of concussed participants, 1 in 4 perceived that headache and dizziness had adverse effects on their HRQoL after returning to sporting activity following sport-related concussion compared with nonconcussed, control participants.

Loss-of-function mutations in the Sost gene lead to high bone mass phenotypes. Pharmacological inhibition of Sost/sclerostin provides a new drug strategy for treating osteoporosis. Questions remain as to how physical activity may affect bone mass under sclerostin inhibition and if that effect differs between males and females. We previously observed in female Sost knockout (KO) mice an enhanced cortical bone formation response to a moderate level of applied loading (900 με at the tibial midshaft). The purpose of the present study was to examine cortical bone adaptation to the same strain level applied to male Sost KO mice. Strain-matched in vivo compressive loading was applied to the tibiae of 10-, 26- and 52-week-old male Sost KO and littermate control (LC) mice. The effect of tibial loading on bone (re)modeling was measured by microCT, 3D time-lapse in vivo morphometry, 2D histomorphometry and gene expression analyses. As expected, Sost deficiency led to high cortical bone mass in 10- and 26-week-old male mice as a result of increased bone formation. However, the enhanced bone formation associated with Sost deficiency did not appear to diminish with skeletal maturation. An increase in bone resorption was observed with skeletal maturation in male LC and Sost KO mice. Two weeks of in vivo loading (900 με at the tibial midshaft) induced only a mild anabolic response in 10- and 26-week-old male mice, independent of Sost deficiency. A decrease in the Wnt inhibitor Dkk1 expression was observed 3 h after loading in 52-week-old Sost KO and LC mice, and an increase in Lef1 expression was observed 8 h after loading in 10-week-old Sost KO mice. The current results suggest that long-term inhibition of sclerostin in male mice does not influence the adaptive response of cortical bone to moderate levels of loading. In contrast with our previous strain-matched study in females showing enhanced bone responses with Sost ablation, these results in males indicate that the influence of Sost deficiency on the cortical bone formation response to a moderate level of loading differs between males and females. Clinical studies examining antibodies to inhibit sclerostin may need to consider that the efficacy of additional physical activity regimens may be sex dependent.

Purpose Central serous chorioretinopathy (CSC) is a disease presenting with detachment of the neurosensory retina and characteristic focal leakage on fluorescein angiography. The spontaneous remission rate is 84% within 6 months. In this study, the efficacy of selective retina therapy (SRT) was examined in patients with therapy refractory persistent acute CSC defined by symptoms for at least 6 months and persistent subretinal fluid (SRF) despite eplerenone therapy. Material and methods This is a prospective, monocentric observational study in 17 eyes (16 patients, mean age 42 years, 2 female). SRT was performed with the approved R:GEN laser (Lutronic, South Korea), a micropulsed 527-nm Nd:YLF laser device, with a train of 30 pulses of 1.7 μs at 100-Hz repetition rate at the point of focal leakage determined by fluorescein angiography (FA) at baseline (BSL). Visits on BSL, week 4 (wk4), and week 12 (wk12) included best corrected visual acuity (BCVA, logMar), central retinal thickness (CRT) on spectral domain optical coherence tomography (SD-OCT), and FA. Statistical analysis was performed by pair-by-pair comparisons of multiple observations in each case with Bonferroni correction for multiple testing. (IBM SPSS Statistics 25®). Results Mean CRT at BSL was 387.69 ± 110.4 μm. CRT significantly decreased by 106.31 μm in wk4 (95%-KI: 21.42–191.2; p = 0.01), by 133.63 μm in wk12 (95%-KI: 50.22–217.03; p = 0.001) and by 133.81 μm (95%-KI: 48.88–218.75; p = 0.001) compared to BSL. Treatment success defined as complete resolution of SRF occurred at wk4 in 7/17 eyes (35.3%) and at wk12 in 10/17 eyes (58.8%). Re-SRT was performed in 7/17 eyes (41.2%) after an average of 107.14 ± 96.59 days. Treatment success after Re-SRT was observed in 4/6 eyes (66.6%, 12 weeks after Re-SRT). Mean BCVA did not change significantly from BSL to any later timepoint after adjusting for multiple testing. Notably, eyes with treatment success showed better BCVA at all timepoints and gained more letters compared to failures. Conclusion Single or repetitive SRT may be an effective and safe treatment in 2 of 3 patients suffering from acute persistent CSC after 6 months of symptoms or more. We observed complete resolution of SRF in around 60% of eyes 12 weeks after first SRT treatment and also 12 weeks after Re-SRT treatment in eyes with persistent or recurrent SRF. Results on the long-term course after SRT are still pending.

In newly diagnosed systemic diffuse large B-cell lymphoma, next-generation sequencing of plasma-derived cell-free DNA (cfDNA) detects somatic mutations as accurate as genotyping of the tumor biopsy. A distinct diffuse large B-cell lymphoma entity confined to the central nervous system is primary central nervous system lymphoma (PCNSL), which requires intracerebral biopsy and neuropathologic analysis to establish the diagnosis. So far, a biomarker for diagnosis and follow-up of PCNSL that can be investigated in blood has not been identified. This article addresses the question whether somatic mutations of the CD79B and MYD88 driver genes of PCNSL can be detected in cfDNA at disease diagnosis. Stereotactic biopsies and cfDNA of 27 PCNSL patients were analyzed for CD79B and MYD88 mutations. As control, cfDNA derived from six healthy volunteers was used. CD79B and MYD88 hot spot mutations were identified in 16 of 27 (59%) and 23 of 27 (85%) PCNSL biopsies, respectively, but only in 0 of 27 (0%) and 1 of 27 (4%) corresponding cfDNA samples, respectively. In cfDNA of one of four patients with Waldenstrom disease, as a further control, the MYD88 L265P mutation was readily detected, despite complete clinical remission. These data suggest that in PCNSL even if they carry such mutations, alterations of CD79B and MYD88 cannot be reliably detected in blood-derived cfDNA obtained before intracerebral biopsy.

AIMS The aim of this retrospective cohort study was to assess the influence of early recurrence (ER) after pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (AF) on long-term outcomes and to identify clinical variables associated with ER. METHODS We retrospectively collected clinical and procedural data from 1285 patients with paroxysmal AF who underwent PVI from 2011 to 2016. Kaplan-Meier, receiver operating characteristic (ROC) curve, logistic and Cox regression analyses were performed to analyze the influence of ER on long-term outcomes. RESULTS ER was observed in 13% of patients. Kaplan-Meier analyses showed significantly different outcomes in 1285 patients with and without ER (49% vs 74%, log rank P

Only few studies examined the prognostic effect of tumor budding in esophageal adenocarcinomas so far. However, different quantification approaches were used, so results cannot be directly compared. Recently, the International Tumor Budding Consensus Conference (ITBCC) published consensus criteria for the evaluation of tumor budding in colorectal cancer, which we applied in our study. Hematoxylin and eosin (HE) and cytokeratin (AE1/AE3) stained whole tissue slides of 104 resected esophageal adenocarcinomas were evaluated. The mean count of tumor buds was analyzed in one high power field according to the ITBCC criteria and assigned to budding groups Bd1-3. Tumor budding was significantly associated with a worse overall survival. Regardless of the quantification approach, an increased number of tumor buds was significantly associated with reduced overall survival (OS) (HE: HR = 1.05 (95% CI 1.029-1.073), p 0.001; cytokeratin: HR = 1.073 (95% CI 1.045-1.101), p 0.001). In multivariable analysis tumor budding according to ITBCC criteria on HE stained slides was an independent prognostic factor. Tumor budding, according to ITBCC criteria, is an independent prognostic factor in resected esophageal adenocarcinoma. Prospective studies using ITBCC criteria are useful in the near future to validate our results.

Abstract Arginine, homoarginine (hArg), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) affect nitric oxide metabolism and altered concentrations are associated with cardiovascular morbidity and mortality. We analyzed these metabolites using liquid chromatography–tandem mass spectrometry in patients with atrial fibrillation (AF) (n = 241) with a focus on heart rhythm at blood withdrawal, AF progression phenotypes, and successful sinus rhythm (SR) restoration (n = 22). AF progression phenotypes were defined as paroxysmal AF with/without low voltage areas (LVA) and persistent AF with/without LVA. While arginine, ADMA, and hArg were within reference limits for healthy controls, SDMA was higher in the AF cohort (0.57 ± 0.12 vs. 0.53 μmol/L (97.5th percentile in reference cohort)). SR restoration in AF patients resulted in normalization of SDMA concentrations (0.465 ± 0.082 vs. 0.570 ± 0.134 μmol/L at baseline, p p = 0.006) and higher ADMA concentrations (0.526 ± 0.08 vs. 0.477 ± 0.08 μmol/L, p p = 0.046)) independent of heart rhythm at blood sampling. Summarizing, arginine metabolism imbalance is associated with AF in general and AF progression and may contribute to associated risk. Key messages • Heart rhythm at blood withdrawal affects ADMA and hArg level in AF patients. • SDMA is higher in AF patients. • SDMA levels normalize after sinus rhythm restoration. • hArg levels decrease in advanced AF progression phenotypes.

Commonly attributed to the prevalence of M2 macrophages, tumor-associated macrophages (TAM) are linked to poor outcome in Hodgkin lymphoma (HL). MYC is supposed to control the expression of M2-specific genes in macrophages, and deficiency in MYC-positive macrophages inhibits tumor growth in mouse models. To verify this hypothesis for HL, seventy-six samples were subjected to immunohistochemical double staining using CD68 or CD163 macrophage-specific antibodies and a reagent detecting MYC. For each cell population, labelled cells were grouped according to low, intermediate and high numbers and related to disease-free survival (DFS) and overall survival (OS). MYC+ cells accounted for 21% and 18% of CD68+ and CD163+ cells, respectively. Numbers of MYC− macrophages were significantly higher in EBV+ cases while no differences were observed for MYC+ macrophages between EBV+ and EBV− cases. Cases with highest numbers of macrophages usually showed worst DFS and OS. In most scenarios, intermediate numbers of macrophages were associated with better outcome than very low or very high numbers. Our observations are reminiscent of the “hormesis hypothesis” and suggest that a relative lack of TAM may allow HL growth while macrophages display an inhibitory effect with increasing numbers. Above a certain threshold, TAM may again support tumor growth.

Aim: The aim of this study was to evaluate the prognostic value of osteopontin (OPN) as a marker for left ventricular (LV) hypertrophy and its reversibility after surgical aortic valve replacement (SAVR). Patients & methods: Echocardiographic data and OPN plasma levels of 149 consecutive patients undergoing SAVR were obtained preoperatively and 3 months postoperatively. OPN was measured by Quantikine Human OPN immunoassay. Results: There was a significant correlation between higher OPN plasma levels and lower LV-mass regression. In patients receiving SAVR combined with coronary artery bypass grafting, high OPN plasma levels were also an indicator for eccentric hypertrophy phenotype. Conclusion: OPN may be a useful indicator for LV hypertrophy phenotype and could have a prognostic value to estimate LV-mass regression after SAVR.

Purpose To quantify the occurrence of tumor seeding in computed tomography (CT)-guided high-dose-rate brachytherapy (HDRBT) and to identify potential risk factors. Materials and Methods CT-HDRBT is a minimally invasive therapeutic option for local ablation of unresectable tumors. The procedure involves CT-guided placement of an enclosed catheter and high-dose-rate brachytherapy using iridium-192. Transcutaneous puncture of a tumor with subsequent retraction of the applicator has the potential risk of tumor seeding along the puncture tract. A total of 1,765 consecutive CT-HDRBT procedures were performed at this center between 2006 and 2017 and were retrospectively analyzed. In addition, a distinction was made between whether the puncture tract was irradiated or not. Follow-up imaging datasets were evaluated for tumor seeding along the former puncture tracts. Descriptive and exploratory statistical analyses of the data were performed. Results Tumor seeding was observed in 25 cases (25 of 1,765 cases [1.5%]). A total of 0.008 cases occurred per person-age. Patient age was identified as a potential risk factor with an odds ratio of 1.046 (95% confidence interval, 1.003–1.091; P = .04). There were no differences between whether the puncture tract was irradiated or not (P = .552). Conclusions Tumor seeding along the puncture tract can occur in CT-HDRBT but is rare.

BackgroundOver the past years, EGFR tyrosine kinase inhibitors (TKI) revolutionized treatment response. 1st-generation (reversible) EGFR TKI and later the 2nd –generation irreversible EGFR TKI Afatinib were aimed to improve treatment response. Nevertheless, diverse resistance mechanisms develop within the first year of therapy. Here, we evaluate the prevalence of acquired resistance mechanisms towards reversible and irreversible EGFR TKI.MethodsRebiopsies of patients after progression to EGFR TKI therapy (> 6 months) were targeted to histological and molecular analysis. Multiplexed targeted sequencing (NGS) was conducted to identify acquired resistance mutations (e.g. EGFR p.T790M). Further, Fluorescence in situ hybridisation (FISH) was applied to investigate the status of bypass mechanisms like, MET or HER2 amplification.ResultsOne hundred twenty-three rebiopsy samples of patients that underwent first-line EGFR TKI therapy (PFS ≥6 months) were histologically and molecularly profiled upon clinical progression. TheEGFRp.T790M mutation is the major mechanism of acquired resistance in patients treated with reversible as well as irreversible EGFR TKI. Nevertheless a statistically significant difference for the acquisition of T790M mutation has been identified: 45% of afatinib- vs 65% of reversible EGFR TKI treated patients developed a T790M mutation (p-value 0.02). Progression free survival (PFS) was comparable in patients treated with irreversibleEGFRirrespective of the sensitising primary mutation or the acquisition of p.T790M.ConclusionsTheEGFRp.T790M mutation is the most prominent mechanism of resistance to reversible and irreversible EGFR TKI therapy. Nevertheless there is a statistically significant difference of p.T790M acquisition between the two types of TKI, which might be of importance for clinical therapy decision.

Patients with thyroid cancer are often assumed to have no quality of life (QOL) impairments after treatment because of thyroid cancer’s good prognosis. However, the QOL implications of surgical complications and the necessity to take lifelong medication are seldom assessed. Patients who had surgery due to thyroid cancer at the University Medical Center Mainz between 2010 and 2015 and who had calcium or parathyroid hormone levels below the reference values immediately following surgery were eligible for this study. QOL was assessed using the EORTC QLQ-C30 and the thyroid cancer module EORTC QLQ-THY34. Multiple logistic regression was used to determine factors associated with a worse QOL compared with a general population. A total of 75 (56%) of 134 eligible patients participated in the study. Patients with persistent/prolonged calcium or vitamin D intake reported worse QOL in the domains of global health, physical functioning, role functioning, emotional functioning, and insomnia than patients without current intake. Current calcium and vitamin D intake, higher education, living with a partner, and age had an effect on the odds of having worse QOL than the age- and sex-adjusted general population. Prolonged calcium and/or vitamin D intake are negatively associated with certain domains of QOL in thyroid cancer patients who are at least 1 year post surgery. Assessment of calcium and vitamin D and diagnosis of hypoparathyroidism are therefore important for the follow-up of thyroid cancer survivors since it may affect their QOL.

Multidrug resistance due to facilitated drug efflux mediated by ATP-binding cassette (ABC) transporters is a main cause for failure of cancer therapy. Genetic polymorphisms in ABC genes affect the disposition of chemotherapeutics and constitute important biomarkers for therapeutic response and toxicity. Here we correlated germline variability in ABC transporters with disease-specific survival (DSS) in 960 breast cancer (BRCA), 314 clear cell renal cell carcinoma and 325 hepatocellular carcinoma patients. We find that variant burden in ABCC1 is a strong predictor of DSS in BRCA patients, whereas candidate polymorphisms are not associated with DSS. This association is highly drug-specific for subgroups treated with the MRP1 substrates cyclophosphamide (log-rank p = 0.0011) and doxorubicin (log-rank p = 0.0088) independent of age and tumor stage, whereas no association was found in individuals treated with tamoxifen (log-rank p = 0.13). Structural mapping of significant variants revealed multiple variants at residues involved in protein stability, cofactor stabilization or substrate binding. Our results demonstrate that BRCA patients with high variant burden in ABCC1 are less prone to respond appropriately to pharmacological therapy with MRP1 substrates, thus incentivizing the consideration of genomic germline data for precision cancer medicine.

BACKGROUND Reperfusion strategies in acute myocardial infarction (AMI) may result in ischemia reperfusion injury characterized by increased oxidative stress, inflammation, and ultimately death of myocardial tissue which may be of particular importance in infarct-related cardiogenic shock (CS). Many anti-oxidative and immune regulatory processes depend on selenium which in large proportions is bound to circulating selenoprotein P (SelP). Individual SelP patterns may therefore be associated with inflammatory response and possibly mortality in patients with CS post AMI. METHODS In the randomized Intra-Aortic Balloon Pump in cardiogenic Shock II (IABP-SHOCK II)-trial, 600 patients with CS complicating AMI were assigned to therapy with or without IABP. In a predefined biomarker substudy of 147 patients, we analyzed SelP levels 1 and 3 days following randomization. Samples were compared with healthy controls and associations with the unspecific inflammatory marker C-reactive protein (CRP) were analyzed. RESULTS Compared with controls SelP levels in patients with infarct-related CS were markedly higher (2.7-fold at day 1 and 5.7-fold at day 3 following AMI, all P

The timely diagnosis of abnormalities in the passive transfer of colostral immunoglobulins is important for the health and development of newborn foals. This study investigated three different methods for measuring immunoglobulin G concentration in neonatal foals. Comparison of a commercial SNAP assay, total protein concentration determination, and total globulin calculation by subtracting the albumin fraction from total protein as an indirect parameter was performed on a quantitative ELISA, which served as a reference method. The study included 119 samples from 148 foals between the age of 1 and 6 days. A blood concentration of 800 mg/dL was considered to indicate adequate absorption of immunoglobulins, and a concentration of less than 400 mg/dL was considered to be hypogammaglobulinemia. The sensitivity of the SNAP test was 64.5% and specificity was 94.7% for diagnosing sufficient absorption of immunoglobulin G at a value of 800 mg/dL. A value of 54 g/L was found to be most appropriate for the use of total protein and provided a sensitivity of 67.3% and specificity of 84.2%. For total globulins, the most appropriate value was 27 g/L, which yielded a sensitivity of 74.5% and specificity of 81.6%. At values under 400 mg/dL, the sensitivity of the SNAP test was 89.4% and the specificity was 83.0%. Here, the most suitable value for the total protein was 51 g/L. This provides a sensitivity of 65.2% and a specificity of 76.8%. The most suitable concentration for the use of total globulin was determined to be 24 g/L, which provided a sensitivity of 75.8% and a specificity of 78.1%. The study and its results show that the SNAP test, the TP, and the TP-A method perform similarly well compared to the ELISA in determining IgG concentration of ≥800 mg/dL. Based on the 95% confidence intervals, however, the Snap test and the TP-A method appear to perform similarly well but better than the TP approach for IgG concentrations400 mg/dL.

Human-directed selective breeding has modified the phenotype of the modern Persian cat towards an extreme brachycephalic phenotype (‘peke-face’ Persian), which originates from a spontaneous mutation that first appeared in the 1950s in traditional Persian types. It was suggested that the peke-face phenotype results from pathologic skull development and might represent a craniosynostosis of the coronal sutures. We followed this hypothesis and investigated the time dependent status of the neurocranial sutures and synchondroses in an ontogenetic series of doll-faced and peke-faced Persian cats compared to Domestic Shorthair cats (DSHs). Cranial suture closure was assessed by examining an ontogenetic series of formalin-fixed head specimens (n = 55) and dry skulls (n = 32) using micro-computed tomography. Sagittal, metopic, coronal and lambdoid sutures as well as intersphenoidal, spheno-occipital and spheno-ethmoid synchondroses were examined. Logistic regression analysis was performed to test the global effect of age on suture closure within a group of peke-face Persians, doll-face Persians and DSHs and the 50% probability of having a closed suture was calculated and compared between groups. Age was a perfect predictor for the condition of the coronal sutures in peke-face Persians. Coronal sutures were found to be closed at 0–0.3 months. In doll-face and DSHs, coronal sutures were open throughout the lifetime with the exception of a few very old cats. Results of this study confirmed a coronal craniosynostosis that likely causes the extreme brachycephalic skull morphology in the peke-face Persian.

Medical records from a single veterinary teaching hospital in Giessen, Germany were retrospectively reviewed for dogs presenting with medial or lateral humeral condylar fractures (HCF) between 2007 and 2019. Data regarding surgical technique and complications were collected from the medical records. These were supplemented through information obtained from telephone interviews with referral veterinarians and from an owner questionnaire completed ≥12 months after surgical repair, which also provided data regarding the outcome. Eighty dogs with 85 HCF were identified: 13 (15.3%) HCF were medial (bilateral in two dogs) and 72 (84.7%) were lateral (bilateral in three dogs). French Bulldogs (n = 19/80; 23.8%) were most commonly affected. Patients were predominantly skeletally immature and light-weight, with a median age at the time of presentation of 3 (min 2, max 118) months and with a median body weight of 6.4 (min 1, max 46) kg. There were 38 female (47.5%) and 42 male (52.5%) dogs. Fractures developed most frequently secondary to minor trauma (67/77; 87.0%). Dogs were presented in 35/84 (41.7%) cases more than 24 hours after fracture occurrence. Surgical treatment was performed in 80/85 (94.1%) HCF. An open reduction and internal fixation approach was chosen in all cases. A transcondylar screw (TS) combined with a supracondylar (SC) K-wire (67/80; 83.8%) was the most frequently used fixation technique. Considering all fracture fixation methods, complications (26/80; 32.5%) were classed as minor in 10 (12.5%), major in 14 (17.5%) and catastrophic in two (2.5%) of the 80 surgically treated HCF. Long-term outcome was excellent in 68.6% (24/35 HCF) and very good in 22.9% (8/35 HCF) of the cases for which follow-up information was obtained. Additionally, owner information revealed that 85.7% of dogs (30/35 HCF) were free of lameness in the long-term. This case series demonstrates that surgical repair of lateral and medial HCF with a TS and SC K-wire is a viable option to consider in skeletally immature and light-weight patients. Complications occur frequently after surgical fixation of HCF, but owners can expect a very good to excellent long-term outcome in the majority of cases.

BACKGROUND: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. DESIGN: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. CONCLUSION: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer. ispartof: ANNALS OF ONCOLOGY vol:33 issue:3 pages:276-287 ispartof: location:England status: published

A new therapeutic option to treat osteoporosis is focused on Wnt signaling and its inhibitor sclerostin, a product of the Sost gene. In this work, we study the effect of sclerostin deficiency on trabecular bone formation and resorption in male and female mice and whether it affects mechano-responsiveness. Male and female 10- and 26-week-old Sost knockout (KO) and littermate controls (LCs) were subjected to in vivo mechanical loading of the left tibia for 2 weeks. The right tibia served as internal control. The mice were imaged using in vivo micro-computed tomography at days 0, 5, 10, and 15 and tibiae were collected for histomorphometric analyses after euthanasia. Histomorphometry and micro-CT-based 3D time-lapse morphometry revealed an anabolic and anti-catabolic effect of Sost deficiency although increased trabecular bone resorption accompanied by diminished trabecular bone formation occurred with age. Loading led to diminished resorption in adult female but not in male mice. A net gain in bone volume could be achieved with mechanical loading in Sost KO adult female mice, which occurred through a further reduction in resorbed bone volume. Our data show that sclerostin deficiency has a particularly positive effect in adult female mice. Sclerostin antibodies are approved to treat postmenopausal women with high risk of osteoporotic fractures. Further studies are required to clarify whether both sexes benefit equally from sclerostin inhibition.

For local ablation of unresectable tumors, computed tomography-guided high-dose-rate brachytherapy (CT-HDRBT) is a minimally invasive therapeutic option involving CT-guided catheter placement and high-dose-rate irradiation with iridium-192. Possible complications are related to transcutaneous puncture, retraction of the applicator, and delivery of brachytherapy. To classify CT-HDRBT in comparison with other minimally invasive therapeutic options, it is essential to know the probability of complications and their risk factors. This study therefore aimed at quantifying the occurrence of complications in CT-HDRBT and identifying potential risk factors. Over a period of more than 10 years from 2006 to 2017, 1877 consecutive CT-HDRBTs were performed at our center and retrospectively analyzed. In 165 cases, CT-HDRBT was combined with transarterial (chemo-) embolization. Information on complications and potential risk factors was retrospectively retrieved from electronic documentation. Statistical analysis of the data was performed. No complications occurred in 85.6% of the interventions. The most common complications were bleeding (5.6%), infection (2.0%), and prolonged pain (1.5%). Summarized diameter (defined as sum of maximum diameters in axial orientation) of treated tumor lesions (odds ratio 1.008; p

Glioblastoma (GBM) is a non-T-cell–inflamed cancer characterized by an immunosuppressive microenvironment that impedes dendritic cell maturation and T-cell cytotoxicity. Proangiogenic cytokines such as VEGF and angiopoietin-2 (Ang-2) have high expression in glioblastoma in a cell-specific manner and not only drive tumor angiogenesis and vascular permeability but also negatively regulate T-lymphocyte and innate immune cell responses. Consequently, the alleviation of immunosuppression might be a prerequisite for successful immune checkpoint therapy in GBM. We here combined antiangiogenic and immune checkpoint therapy and demonstrated improved therapeutic efficacy in syngeneic, orthotopic GBM models. We observed that blockade of VEGF, Ang-2, and programmed cell death protein-1 (PD-1) significantly extended survival compared with vascular targeting alone. In the GBM microenvironment, triple therapy increased the numbers of CTLs, which inversely correlated with myeloid-derived suppressor cells and regulatory T cells. Transcriptome analysis of GBM microvessels indicated a global vascular normalization that was highest after triple therapy. Our results propose a rationale to overcome tumor immunosuppression and the current limitations of VEGF monotherapy by integrating the synergistic effects of VEGF/Ang-2 and PD-1 blockade to reinforce antitumor immunity through a normalized vasculature.

Electro-anatomical remodeling in atrial fibrillation (AF) is associated with disease initiation and progression. Troponin T (TropT) - a specific biomarker for myocardial damage - is associated with AF incidence. However, its association with AF progression is understudied. The aim of the current analysis was to investigate the association between TropT and AF progression phenotypes: persistent AF and left atrial low voltage areas (LVAs).Patients undergoing first AF ablation were included into analyses. LVAs were determined using high-density maps and defined as0.5 mV. Blood samples from femoral vein were collected before catheter ablation. The analysis of TropT serum concentrations was performed using a high-sensitive assay from Roche Diagnostics. Biomarkers, clinical, anthropometric and echocardiographic data were compared with healthy individuals from the epidemiological cohort.The study included 824 healthy individuals without overt cardiovascular disease (54 ± 10 years, 40% males) from epidemiological cohort and 241 AF patients (64 ± 11 years, 59% males, 59% persistent AF, 27% LVAs). Patients with AF had higher TropT levels and larger left atrium (LA), while healthy individuals had better renal function and ejection fraction (all p 0.001). In clinical cohort, there were significant differences between TropT levels according to AF progression groups: paroxysmal AF without/with LVAs (n = 86/12), persistent AF without/with LVAs (n = 90/53): means 7.3, 12.9, 8.4, 11.3 pg/ml, p 0.001, respectively. Similar findings were observed for LA and renal function (all p 0.001). On ROC analysis, TropT significantly predicted LVAs (AUC 0.675, 95%CI 0.598-0.752, p 0.001) in AF patients.TropT may be useful to differentiate AF progression phenotypes.

The assessment of kidney biopsies is mainly confined to specialized centres. However, sometimes a kidney biopsy is submitted to a general pathologist, and in addition peritumorous renal parenchyma in tumour nephrectomies can have concomitant non-neoplastic renal disease. Here we present a survey of inflammatory and immunologic changes in all renal compartments, which may in part indicate the need of prompt therapeutic intervention such as in vasculitis, glomerulonephritis and interstitial nephritis. It is important to take into account that renal involvement of vasculitis is mainly centred in glomeruli and only to a much lesser extent in arteries, and that the frequently observed interstitial inflammation very often is an epiphenomenon of another primary kidney disease and not an independent disease process. Typical renal patterns of injury are emphasised.Die Nierenbiopsiediagnostik wird ganz überwiegend in spezialisierten Zentren durchgeführt. Gelegentlich findet eine Nierenbiopsie jedoch ihren Weg in eine allgemeine Pathologie und auch das peritumorale Nierenparenchym kann zusätzliche pathologische Veränderungen aufweisen. Hier soll zunächst ein Überblick über entzündliche und immunologische Veränderungen in allen Nierenkompartimenten gegeben werden, die z. T. einer sehr schnellen Therapieeinleitung bedürfen, wie z. B. bei Vaskulitiden, Glomerulonephritiden und interstitiellen Nephritiden. Wichtig ist insbesondere, dass Vaskulitiden sich in der Niere vor allem im Glomerulus und viel seltener in den Arterien abspielen und dass oft beobachtete interstitielle entzündliche Infiltrate sehr häufig ein Begleitphänomen einer anderen Nierenschädigung und keine eigenständige Erkrankung darstellen. Das Augenmerk soll auf den für die Niere typischen grundlegenden Schädigungsmustern liegen.

Complement plays an important role in the direct defense to pathogens, but can also activate immune cells and the release of pro-inflammatory cytokines. However, in critically ill patients with COVID-19 the immune system is inadequately activated leading to severe acute respiratory syndrome (SARS) and acute kidney injury, which is associated with higher mortality. Therefore, we characterized local complement deposition as a sign of activation in both lungs and kidneys from patients with severe COVID-19. Using immunohistochemistry we investigated deposition of complement factors C1q, MASP-2, factor D (CFD), C3c, C3d and C5b-9 as well as myeloperoxidase (MPO) positive neutrophils and SARS-CoV-2 virus particles in lungs and kidneys from 38 patients who died from COVID-19. In addition, tissue damage was analyzed using semi-quantitative scores followed by correlation with complement deposition. Autopsy material from non-COVID patients who died from cardiovascular causes, cerebral hemorrhage and pulmonary embolism served as control (n=8). Lung injury in samples from COVID-19 patients was significantly more pronounced compared to controls with formation of hyaline membranes, thrombi and edema. In addition, in the kidney tubular injury was higher in these patients and correlated with lung injury (r=0.361*). In autopsy samples SARS-CoV-2 spike protein was detected in 22% of the lungs of COVID-19 patients but was lacking in kidneys. Complement activation was significantly stronger in lung samples from patients with COVID-19

New lineages of SARS-CoV-2 are of potential concern due to higher transmissibility, risk of severe outcomes, and/or escape from neutralizing antibodies. Lineage B.1.1.7 (the Alpha variant) became dominant in early 2021, but the association between transmissibility and risk factors, such as age of primary case and viral load remains poorly understood. Here, we used comprehensive administrative data from Denmark, comprising the full population (January 11 to February 7, 2021), to estimate household transmissibility. This study included 5,241 households with primary cases; 808 were infected with lineage B.1.1.7 and 4,433 with other lineages. Here, we report an attack rate of 38% in households with a primary case infected with B.1.1.7 and 27% in households with other lineages. Primary cases infected with B.1.1.7 had an increased transmissibility of 1.5–1.7 times that of primary cases infected with other lineages. The increased transmissibility of B.1.1.7 was multiplicative across age and viral load., Establishing the relative transmissibility of emerging variants of SARS-CoV-2 is key for pandemic management. Here, the authors use full-population administrative data from Denmark linked to PCR test results and estimate that the Alpha variant was ~60% higher than other strains circulating in early 2021.

Pathogenesis of chronic pancreatitis (CP) is still not entirely understood with many patients probably having more than 1 underlying etiology. Besides toxic-metabolic factors, genetics contribute to disease development. Mutations in cystic fibrosis transmembrane conductance regulator (CFTR) are shown to increase risk for CP. Activity of CFTR can easily be accessed in vivo by measurement of nasal potential difference (PD).We compared in this monocentric study 17 CP patients from the outpatient unit of our university hospital with 30 healthy controls regarding nasal PDs by using a superfusion protocol. Additionally, demographic and lifestyle data of all persons were recorded.Seventeen patients (12% female, median age 48 years) with CP and 30 healthy volunteers (47% female, 25 years) were included in the study. Patients with CP had a significant higher proportion of CFTR dysfunction (P = .04). Furthermore, demographics differed between the 2 groups with CP patients being older (P .001). There were differences in daily alcohol consumption (P = .001) and smoking habits (smokers vs nonsmokers: P = .01, pack years: P = .002).PD measurement is an easily accessible way to show CFTR dysfunction as an etiological factor of CP. Cigarette smoking might impair CFTR function and therefore be 1 preventable cause of CP evolution.

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients., Kinase inhibitors are widely used to treat cancer, however patients frequently develop resistance. Here, the authors investigate adaption mechanisms during drug persistence and show that stimulation of the innate immunity sensor RIG-I enhances cancer cell death when combined with kinase inhibition.

Purpose We investigated the association between social inequality and participation in a mammography screening program (MSP). Since the German government offers mammography screening free of charge, any effect of social inequality on participation should be due to educational status and not due to the financial burden. Methods The ‘Gutenberg Health Study’ is a cohort study in the Rhine-Main-region, Germany. A health check-up was performed, and questions about medical history, health behavior, including secondary prevention such as use of mammography, and social status are included. Two indicators of social inequality (equivalence income and educational status), an interaction term of these two, and different covariables were used to explore an association in different logistic regression models. Results A total of 4,681 women meeting the inclusion criteria were included. Only 6.2% never participated in the MSP. A higher income was associated with higher chances of ever participating in a mammography screening (odds ratios (OR): 1.67 per €1000; 95%CI:1.26–2.25, model 3, adjusted for age, education and an interaction term of income and education). Compared to women with a low educational status, the odds ratios for ever participating in the MSP was lower for the intermediate educational status group (OR = 0.64, 95%CI:0.45–0.91) and for the high educational status group (0.53, 95%CI:0.37–0.76). Results persisted also after controlling for relevant confounders. Conclusions Despite the absence of financial barriers for participation in the MSP, socioeconomic inequalities still influence participation. It would be interesting to examine whether the educational effect is due to an informed decision.

Aims Agents targeting vascular endothelial growth factor (VEGF) have increasingly been used for the treatment of advanced malignancies, and have been found to induce renal thrombotic microangiopathy (TMA) and proteinuria. However, histomorphological changes in human biopsies in this setting and the underlying mechanism are not yet fully understood. Therefore, we collected renal biopsy cases with a history of aVEGF therapy to review and compare morphological kidney changes in this context. Methods and results Renal biopsies of 15 patients who had received anti-VEGF (aVEGF) therapy evaluated between 2013 and 2017 at a single centre were morphologically characterised with light microscopy, electron microscopy, and immunohistochemistry (IgA, IgG, IgM, C1q, and C3), and compared with cases with acute TMA caused by atypical haemolytic-uraemic syndrome or hypertension. Morphological overlap with immune complex and cryoglobulinaemic membranoproliferative glomerulonephritis, diabetic glomerulopathy and pre-eclampsia-induced glomerulopathy are discussed. Segmental glomerular capillary microaneurysms and segmental hyalinosis were typical morphological features of aVEGF therapy-induced glomerular microangiopathy, whereas fibrin or platelet thrombi or fragmented erythrocytes were rarely found or were absent. aVEGF therapy-associated microangiopathy was diffusely distributed in the glomeruli, spared preglomerular vessels, and showed morphological characteristics of chronic TMA. In individual cases, aVEGF therapy-induced glomerular microangiopathy was accompanied by immune-complex glomerulonephritis. Conclusion aVEGF therapy-induced glomerular microangiopathy has a characteristic morphology and clinical presentation that helps to differentiate it from other causes of TMA. Awareness of these light microscopic findings allows identification of aVEGF therapy as a trigger of renal disease in critically ill cancer patients, and might therefore help in deciding on further therapy.