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In the absence of targeted treatment options, neoadjuvant chemotherapy (NACT) is applied widely for triple-negative breast cancer (TNBC). Response to NACT is an important parameter predictive of oncological outcomes (progression-free and overall survival). An approach to the evaluation of predictive markers enabling therapy individualization is the identification of tumor driver genetic mutations. This study was conducted to investigate the role of SEC62, harbored at 3q26 and identified as a driver of breast cancer pathogenesis, in TNBC. We analyzed SEC62 expression in The Cancer Genome Atlas database, and immunohistologically investigated SEC62 expression in pre- and post-NACT tissue samples from 64 patients with TNBC treated at the Department of Gynecology and Obstetrics/Saarland University Hospital/Homburg between January 2010 and December 2018 and compared the effect of SEC62 on tumor cell migration and proliferation in functional assays. SEC62 expression dynamics correlated positively with the response to NACT (p ≤ 0.01) and oncological outcomes (p ≤ 0.01). SEC62 expression stimulated tumor cell migration (p ≤ 0.01). The study findings indicate that SEC62 is overexpressed in TNBC and serves as a predictive marker for the response to NACT, a prognostic marker for oncological outcomes, and a migration-stimulating oncogene in TNBC.

The corona virus outbreak in Wuhan, China, at the end of 2019 has rapidly evolved into a pandemic which is still virulent in many countries. An infection with SARS-CoV-2 can lead to corona virus disease (Covid-19). This paper presents an overview of the knowledge gained so far with regard to histopathological lung lesions in fatal courses of Covid-19. The main findings were diffuse alveolar damage and micro-angiopathies. These included the development of hyaline membranes, thrombi, endothelial inflammation, haemorrhages and angiogenesis. Overall, the vessel lesions seemed to be more lethal than the diffuse alveolar damage. There was obvious hyperreactivity and hyperinflammation of the cellular immune system. An expanded T-cell memory may explain the increased risk of a severe course in the elderly.

MicroRNAs (miRNAs) expressed in endothelial cells (ECs) are powerful regulators of angiogenesis, which is essential for tumor growth and metastasis. Here, we demonstrated that miR-22 is preferentially and highly expressed in ECs, while its endothelial level is significantly downregulated in human non-small cell lung cancer (NSCLC) tissues when compared to matched nontumor lung tissues. This reduction of endothelial miR-22 is possibly induced by NSCLC cell-secreted interleukin-1β and subsequently activated transcription factor nuclear factor-κB. Endothelial miR-22 functions as a potent angiogenesis inhibitor that inhibits all of the key angiogenic activities of ECs and consequently NSCLC growth through directly targeting sirtuin 1 and fibroblast growth factor receptor 1 in ECs, leading to inactivation of AKT/mammalian target of rapamycin signaling. These findings provide insight into the molecular mechanisms of NSCLC angiogenesis and indicate that endothelial miR-22 represents a potential target for the future antiangiogenic treatment of NSCLC., Graphical abstract, The present study demonstrates that miR-22 is highly expressed in endothelial cells and inhibits their angiogenic activity via targeting sirtuin 1 and fibroblast growth factor receptor 1. Hence, endothelial miR-22 represents a potential biomarker and therapeutic target for the future antiangiogenic treatment of non-small cell lung cancer.

OBJECTIVES The aim of this study was to compare the diagnostic accuracy of apparent diffusion coefficient (ADC) ratios as a monoparametric magnetic resonance imaging (MRI) protocol for the detection of prostate cancer (PCa) with the established multiparametric (mp) MRI at 3.0 T. MATERIALS AND METHODS According to power analysis, 52 male patients were included in this monocenter study with prospective data collection and retrospective, blinded multireader image analysis. The study was approved by the local ethics committee. Patients were recruited from January to December 2020. Based on mpMRI findings, patients underwent in-bore MR biopsy or prostatectomy for histopathologic correlation of suspicious lesions. Three readers, blinded to the histopathologic results and images of mpMRI, independently evaluated ADC maps for the detection of PCa. The ADC ratio was defined as the lowest signal intensity (SI) of lesions divided by the SI of normal tissue in the zone of origin. Predictive accuracy of multiparametric and monoparametric MRI were compared using logistic regression analysis. Moreover, both protocols were compared applying goodness-of-fit analysis with the Hosmer-Lemeshow test for continuous ADC ratios and Pearson χ2 test for binary decision calls, correlation analysis with Spearman ρ and intraclass correlation coefficients, as well as noninferiority assessment with a TOST ("two one-sided test"). RESULTS Eighty-one histopathologically proven, unique PCa lesions (Gleason score [GS] ≥ 3 + 3) in 52 patients could be unequivocally correlated, with 57 clinically significant (cs) PCa lesions (GS ≥ 3 + 4). Multiparametric MRI detected 95%, and monoparametric ADC detected ratios 91% to 93% of csPCa. Noninferiority of monoparametric MRI was confirmed by TOST (P < 0.05 for all comparisons). Logistic regression analysis revealed comparable predictive diagnostic accuracy of ADC ratios (73.7%-87.8%) versus mpMRI (72.2%-84.7%). Spearman rank correlation coefficient for PCa aggressiveness revealed satisfactory correlation of ADC ratios (P < 0.013 for all correlations). The Hosmer-Lemeshow test for the logistic regression analysis for continuous ADC ratios indicated adequate predictive accuracy (P = 0.55-0.87), and the Pearson χ2 test showed satisfactory goodness of fit (P = 0.35-0.69, χ2 = 0.16-0.87). CONCLUSIONS Normalized ADC ratios based on advanced DWI are noninferior to mpMRI at 3.0 T for the detection of csPCa in a preselected patient cohort and proved a fast and accurate assessment tool, thus showing a potential prospect of easing the development of future screening methods for PCa.

Cervical cancer therapy is still a major clinical challenge, as patients substantially differ in their response to standard treatments, including chemoradiotherapy (CRT). During cervical carcinogenesis, T‐helper (Th)‐17 cells accumulate in the peripheral blood and tumor tissues of cancer patients and are associated with poor prognosis. In this prospective study, we find increased Th17 frequencies in the blood of patients after chemoradiotherapy and a post‐therapeutic ratio of Th17/CD4+ T cells > 8% was associated with early recurrence. Furthermore, Th17 cells promote resistance of cervical cancer cells toward CRT, which was dependent on the AKT signaling pathway. Consistently, patients with high Th17 frequencies in pretherapeutic biopsies exhibit lower response to primary CRT. This work reveals a key role of Th17 cells in CRT resistance and elevated Th17 frequencies in the blood after CRT correspond with early recurrence. Our results may help to explain individual treatment responses of cervical cancer patients and suggest evaluation of Th17 cells as a novel predictive biomarker for chemoradiotherapy responses and as a potential target for immunotherapy in cervical cancer., This study demonstrates that chemoradiotherapy‐treated patients with cervical cancer have increased frequencies of Th17 cells. Th17 frequency was associated with early cancer relapse. Additionally, high pretherapeutic Th17 amounts in situ were correlated to a failed response to chemoradiotherapy. Our work suggests that the evaluation of Th17 cells could serve as a novel predictive biomarker for chemoradiotherapy responses and a potential target for immunotherapy in patients with cervical cancers.

Salvage lymph node dissection is a rescue treatment for patients with nodal recurrence after radical prostatectomy. Very limited data are available on robotic salvage lymph node dissection. Our purpose was to investigate perioperative and oncological outcomes of robotic salvage lymph node dissection in a large monocentric series.Perioperative data, complications within 30 days after surgery and oncological outcomes as assessed by histology, prostate specific antigen changes, prostate specific antigen nadir after salvage lymph node dissection, and time to further therapy were analyzed. To identify predictive factors for oncological outcome, Kaplan-Meier and Cox-regression analyses were performed. For cases with a mismatch between preoperative positron emission tomography/computed tomography and the number of histologically positive lymph nodes, prostate specific membrane antigen immunohistochemistry was performed on removed lymph nodes.A total of 68 patients underwent robotic salvage lymph node dissection with a median operation time of 126 minutes, a blood loss of 50 ml, and a length of stay of 4 days. No major complications (Clavien 3) occurred. Median followup was 12.1 months. Median time to further therapy was 12.4 months, 37% of patients experienced complete biochemical response (prostate specific antigen0.2 ng/ml) and 11% reached an undetectable prostate specific antigen, which was maintained for1 year in 3 cases. Lower preoperative prostate specific antigen, longer time between radical prostatectomy and salvage lymph node dissection, preoperative prostate specific membrane antigen positron emission tomography/computed tomography and complete biochemical response after salvage lymph node dissection were significant predictors of longer therapy-free survival (all p0.005). Prostate specific membrane antigen immunohistochemistry revealed that prostate specific membrane antigen positron emission tomography/computed tomography tends to miss small lymph node metastases5 mm.Robotic salvage lymph node dissection is a feasible approach with low perioperative morbidity and delays further systemic therapy in most patients. Prostate specific membrane antigen positron emission tomography/computed tomography detection is mostly limited to tumor foci5 mm.

Zusammenfassung Hintergrund und Ziel der Arbeit Die Inzidenz der Basalzellkarzinome (BCC) hat in den letzten Jahrzehnten deutlich zugenommen. Ziel dieser retrospektiven Studie war es, das Rezidivrisiko von periokulären BCC nach histologisch kontrollierter Resektion zu eruieren. Patienten und Methodik Anhand der Klinikakten aus dem Zeitraum 2009 bis 2020 wurden konsekutiv 270 periokuläre BCC von 243 Patienten/Patientinnen hinsichtlich eines Rezidivauftretens nach chirurgischer Exzision untersucht. Erhoben wurden die Art des Tumors (primäres oder bereits rezidiviertes BCC), die BCC-Lokalisation innerhalb der Regio orbitalis (Oberlid nasal, mittig, temporal und Unterlid nasal, mittig, temporal), der histologische BCC-Subtyp (solide/nodulär [s/n], superfiziell-multizentrisch [sf-mz], infiltrativ/sklerodermiform [i/s], basosquamös [bsq] und gemischt [gem]) sowie der histologisch nachgewiesene Resektionsrand (in sano [R0], nicht sicher in sano [R?], nicht in sano [R1]). Die Rezidivraten wurden mittels Chi2-Test verglichen. Ergebnisse Die BCC ließen sich unterteilen in 231 primäre BCC (pBCC) und in 39 bereits rezidivierte BCC (rBCC). Bei den 231 pBCC erfassten wir für den oben genannten Zeitraum insgesamt 38 (16,5 %) Rezidive (2-Jahres-Rezidivrate 9,2 %). Bei den 39 rBCC beobachteten wir 18 (46,2 %) Rezidive (2-Jahres-Rezidivrate 37,8 %). Zudem konnte für die rBCC ein signifikant kürzerer rezidivfreier Verlauf (RFV) ($$\mathrm{\varnothing }$$ ∅ 52,6 ± 9,0 Monate) als bei den pBCC ($$\mathrm{\varnothing \ }$$ ∅ 108,6 ± 4,1 Monate) festgestellt werden (p p = 0,001): s/n = 15,9 %, sf-mz = 45,0 %, i/s = 27,8 %, bsq = 33,3 % und gem = 40,0 %. Nach R0-Resektion war die Rezidivrate von s/n-BCC signifikant geringer als nach R?/R1-Resektion (p = 0,008). Bei den Subtypen i/s (p = 0,433), bsq (p = 0,417) und gem (p = 0,143) wiesen die Rezidivraten nach R0- und nach R?/R1-Resektion keinen signifikanten Unterschied auf. Bei den sf-mz-BCC war keine Aussage zur statistischen Signifikanz möglich. Diskussion Unsere Rezidivrate erscheint vergleichsweise hoch. Allerdings wurden bei dieser Studie bewusst auch R1-resezierte BCC eingeschlossen, um eine Auswertung zu erhalten, die den klinischen Alltag möglichst realistisch wiedergibt. Möglicherweise könnten auch das Operationsverfahren oder die Art der histologischen Untersuchung sowie die Interpretation des Begriffs „Lokalrezidiv“ Grund für unterschiedliche Literaturangaben zu Rezidiven sein. Eine Abhängigkeit der Rezidivrate von der genauen Lokalisation innerhalb der Regio orbitalis konnte in dieser Studie nicht nachgewiesen werden, der jeweilige BCC-Subtyp scheint hingegen relevant zu sein. Wichtig ist, dass auch mehrere Jahre nach einer BCC-Exzision Rezidive diagnostiziert wurden. Daraus ergibt sich, dass eine Langzeitnachsorge dringend zu empfehlen ist.

The incidence of basal cell carcinoma (BCC) has significantly increased in the last decades. The aim of this retrospective study was to determine the risk of recurrence of periocular BCC after histologically controlled resection.Based on the clinical records from 2009-2020 a total of 270 consecutive periocular BCCs from 243 patients were investigated with respect to recurrence after surgical excision. For this study, the type of BCC (primary or recurrent BCC) and localization within the orbital region (upper eyelid nasal, middle, temporal and lower eyelid nasal, middle, temporal) and the histological BCC subtype, e.g. solid/nodular (s/n), superficial multicentric (s-m), infiltrative/sclerodermal (i/s), basosquamous (bsq) and mixed (gem), were recorded. Recurrence rates were compared using χThe 270 resected BCCs with 231 primary BCC (pBCC) and 39 already recurrent BCC (rBCC), were included in this study. Among the 231 pBCCs we recorded a total of 38 (16.5%, 2‑year recurrence rate 9.2%) recurrences for the abovementioned period. In the 39 rBCCs we observed 18 (46.2%) recurrences (2-year recurrence rate 37.8%). In addition, a significantly shorter recurrence-free interval (RFV, ∅ 52.6 ± 9.0 months) was observed for the rBCC than for the pBCC (∅108.6 ± 4.1 months, p 0.001). The recurrence rates did not differ significantly with respect to the location; however, there was a significant difference between the five defined subtypes (p = 0.001): s/n = 15.9%, s‑m = 45.0%, i/s = 27.8%, bsq = 33.3% and gem = 40.0%. After R0 resection the recurrence rate of s/n BCC was significantly lower than after R?/R1 resection (p = 0.008). The histological subtypes i/s (p = 0.433), bsq (p = 0.417), and gem (p = 0.143), showed no significant difference between the recurrence rates after R0 and R?/R1 resection. In s‑m BCC, a conclusion on the statistical significance was not possible.The recurrence rate appears to be comparatively high; however, R1 resected BCCs were intentionally included in this study to obtain an evaluation that reflects clinical practice as realistically as possible. It is possible that the surgical procedure and/or the type of histological examination as well as the broad interpretation of the term local recurrence could be the reason for the different recurrence data in the literature. Our data indicate that the recurrence rate is not affected by the exact localization within the orbital region, but by the respective BCC subtype. As recurrences may develop years after BCC excision a long-term follow-up is strictly recommended.HINTERGRUND UND ZIEL DER ARBEIT: Die Inzidenz der Basalzellkarzinome (BCC) hat in den letzten Jahrzehnten deutlich zugenommen. Ziel dieser retrospektiven Studie war es, das Rezidivrisiko von periokulären BCC nach histologisch kontrollierter Resektion zu eruieren.Anhand der Klinikakten aus dem Zeitraum 2009 bis 2020 wurden konsekutiv 270 periokuläre BCC von 243 Patienten/Patientinnen hinsichtlich eines Rezidivauftretens nach chirurgischer Exzision untersucht. Erhoben wurden die Art des Tumors (primäres oder bereits rezidiviertes BCC), die BCC-Lokalisation innerhalb der Regio orbitalis (Oberlid nasal, mittig, temporal und Unterlid nasal, mittig, temporal), der histologische BCC-Subtyp (solide/nodulär [s/n], superfiziell-multizentrisch [sf-mz], infiltrativ/sklerodermiform [i/s], basosquamös [bsq] und gemischt [gem]) sowie der histologisch nachgewiesene Resektionsrand (in sano [R0], nicht sicher in sano [R?], nicht in sano [R1]). Die Rezidivraten wurden mittels ChiDie BCC ließen sich unterteilen in 231 primäre BCC (pBCC) und in 39 bereits rezidivierte BCC (rBCC). Bei den 231 pBCC erfassten wir für den oben genannten Zeitraum insgesamt 38 (16,5 %) Rezidive (2-Jahres-Rezidivrate 9,2 %). Bei den 39 rBCC beobachteten wir 18 (46,2 %) Rezidive (2-Jahres-Rezidivrate 37,8 %). Zudem konnte für die rBCC ein signifikant kürzerer rezidivfreier Verlauf (RFV) ([Formula: see text]52,6 ± 9,0 Monate) als bei den pBCC ([Formula: see text]108,6 ± 4,1 Monate) festgestellt werden (p 0,001). Bezogen auf die Lokalisation, wiesen die Rezidivraten keinen signifikanten Unterschied auf. Als signifikant unterschiedlich stellten sich die Rezidivraten der 5 definierten Subtypen dar (p = 0,001): s/n = 15,9 %, sf-mz = 45,0 %, i/s = 27,8 %, bsq = 33,3 % und gem = 40,0 %. Nach R0-Resektion war die Rezidivrate von s/n-BCC signifikant geringer als nach R?/R1-Resektion (p = 0,008). Bei den Subtypen i/s (p = 0,433), bsq (p = 0,417) und gem (p = 0,143) wiesen die Rezidivraten nach R0- und nach R?/R1-Resektion keinen signifikanten Unterschied auf. Bei den sf-mz-BCC war keine Aussage zur statistischen Signifikanz möglich.Unsere Rezidivrate erscheint vergleichsweise hoch. Allerdings wurden bei dieser Studie bewusst auch R1-resezierte BCC eingeschlossen, um eine Auswertung zu erhalten, die den klinischen Alltag möglichst realistisch wiedergibt. Möglicherweise könnten auch das Operationsverfahren oder die Art der histologischen Untersuchung sowie die Interpretation des Begriffs „Lokalrezidiv“ Grund für unterschiedliche Literaturangaben zu Rezidiven sein. Eine Abhängigkeit der Rezidivrate von der genauen Lokalisation innerhalb der Regio orbitalis konnte in dieser Studie nicht nachgewiesen werden, der jeweilige BCC-Subtyp scheint hingegen relevant zu sein. Wichtig ist, dass auch mehrere Jahre nach einer BCC-Exzision Rezidive diagnostiziert wurden. Daraus ergibt sich, dass eine Langzeitnachsorge dringend zu empfehlen ist.

In this Letter to the Editor supportive data were presented to a recent paper published in this journal reporting the involvement of TRP channels in COVID-19 pneumonia and its role for new therapies. Since gene expression of TRP channels was found in human lung tissues the protein was not being reported so far. TRP channels are supposed to be involved in the pulmonary inflammation and its symptoms such as fever, cough and others. Here, TRPC6 was investigated in tissues of normal human lungs and of SARS-Cov-2 infected lungs in a preliminary study. Tissue was obtained post mortem from anatomical body donations during dissections and during pathological dissections (13 normal, 4 COVID-19 pneumoniae) and processed for immunohistochemistry. In normal lungs TRPC6 was found in the ciliated epithelium, in the wall of larger lung vessels and in the alveolar septa. In COVID-19 pneumonia the distribution of TRPC6 was different. Inflammatory lesions, cellular infiltrates, hyaline membranes and fibrosis were labelled intensively as well as dilated capillaries. These observations are from four patients with COVID-19 pneumonia.The observations do not elucidate the molecular mechanisms but support the view that TRPC6 channels are involved in normal physiology of normal human lungs and in COVID-19 pneumonia. TRPC6 might aggravate SARS-2 induced inflammation and could be a target for inhibiting drugs.

Case presentation A 71-year-old man was admitted to our hospital because of diffuse chest pain and a mass on routine chest radiography. He did not report cough, dyspnea, fever, night sweats, or weight loss. His medical history was remarkable for chronic lymphocytic leukemia diagnosed 13 years before presentation, and secondary myelodysplastic syndrome diagnosed 2 years before the onset of the current symptoms. As a curative approach, he had received a matched unrelated stem cell transplantation 16 months earlier, and he had been in complete remission since. He developed chronic graft-vs-host disease, presenting mainly as oral ulceration (grade 1, according to National Institute of Health consensus criteria), which had been treated with oral cyclosporine and extracorporeal photopheresis. The immunosuppression had been tapered 6 months before presentation. Routine medication included co-trimoxazole prophylaxis twice per week. He had no known allergies, and he denied recent travels and sick contacts.

Purpose: To analyse the changing trends in penetrating keratoplasty indications between January 2011 and December 2018, at the Department of Ophthalmology, Saarland University Medical Center, Hombu...

Background Chromosome 3q26 amplifications have been shown to represent a frequent alteration in various cancer entities including breast cancer. SEC62 - a 3q26 encoded gene - was identified as a potential oncogene and tumor-driver-gene for the pathogenesis of breast cancer. Although the precise physiological function of the respective protein Sec62 is not completely understood, it is hypothesized, that Sec62 induces an increased stress tolerance and enhances cell migration in SEC62 overexpressing cells resulting in a high rate of lymphatic metastasis and poorer overall prognosis in tumor tissue with a high Sec62 expression. We sought to further elucidate the function of Sec62 in breast cancer with special focus on its predictive role on the response to neoadjuvant chemotherapy. Materials and Methods All patients treated for primary breast cancer with neoadjuvant chemotherapy at the Department of Gynaecology and Obstetrics, Saarland University Hospital, Homburg, Germany between 01/2007 and 12/2018 were enrolled in this study. The study was approved by the Saarland institutional review board. Sec62 protein levels were analyzed in tumor tissue samples using immunohistochemistry (IHC). Sec62 immunoreactivity was evaluated by three independent examiners using the immunoreactive score (IRS) according to Remmele and Stegner (0-12). For the assessment of Sec62 protein expression in tumor cells, we rated Sec62 “negative” 0-3, “low” for a score of 4-8 and “high” for 9-12 as described in previous publications. IHC was performed on initial breast core biopsy (CB) tissue (pre-treatment) and on definite pathology specimen (PS) obtained during breast surgery after completion of neoadjuvant chemotherapy. Sec62 expression in both samples were compared and correlated with response to neoadjuvant chemotherapy evaluated pathologically using the semi-quantitative response to neoadjuvant chemotherapy scoring system by Sinn et al. ranging from 0 (no effect) to 4 (no tumor detectable). Additionally, Sec62 expression in tumor tissue was compared with the histologically tumor-free tissue of the same patient. Sec62 expression levels and correlation with response to neoadjuvant chemotherapy were compared using Wilcoxon signed-rank, Mann-Whitney and Pearson`s chi square test. Results 203 patients were assessed for eligibility. Nine cases were excluded, due to incomplete clinical information or insufficient slide quality, leaving 194 patients for final analysis. Median patient age was 54 (22-86) years and median response to neoadjuvant chemotherapy score of 2 (0-4). 20 patients (10 %) had luminal A, 46 (24 %) luminal B, 60 (31 %) Her2/neu positive and 68 (35 %) triple negative breast cancer. All analyzed slides showed an over-expression of Sec62 in breast cancer cells but no positive staining of physiologic breast tissue cells. Median Sec62 expression in core biopsies (CB) (8 (2-12)) was significantly higher compared to expression in final specimen (PS) (4 (0-12); p ≤ 0.01). Median difference between Sec62 expression of CB and PS was 2 (0-4). Regarding response to neoadjuvant chemotherapy patients with a low Sec62 expression in PS and a difference ≥ 6 between CB and PS showed a significant higher median response score compared to other patients (2 (0-4) vs. 1 (0-2); p ≤ 0.01; 4 (1-4) vs. 1 (0-4); p ≤ 0.01). When looking at breast cancer subtypes these effects were strongest in Her2/positive and triple negative patients and median Sec62 expression showed the highest decrease between CB and PS in these two subgroups (6 (-3-12); 2 (-6-12)). Conclusion We identified Sec62 as a potential biomarker for prediction of response to neoadjuvant chemotherapy in patients with primary breast cancer. This effect was observed to be strongest in patients with Her2/positive and triple negative breast cancer. Citation Format: Julia Caroline Radosa, Mariz Kasoha, Merle Doerk, Barbara Linxweiler, Maximilian Linxweiler, Florian Bochen, Rainer M Bohle, Matthias Wagner, Marc P Radosa, Erich-Franz Solomayer, Zoltan Ferenc Takacs. Role of Sec62 in prediction of response to neoadjuvant chemotherapy in patients with primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-28.

Virchows Archiv (2022). doi:10.1007/s00428-022-03319-2, Published by Springer, Berlin

Profound knowledge exists about the clinical, morphologic, genomic, and transcriptomic characteristics of most lymphoma entities. However, information is currently lacking on the dynamic behavior of malignant lymphomas. This pilot study aimed to gain insight into the motility of malignant lymphomas and bystander cells in 20 human lymph nodes. Generally, B cells were faster under reactive conditions compared with B cells in malignant lymphomas. In contrast, PD1-positive T cells did not show systematic differences in velocity between reactive and neoplastic conditions in general. However, lymphomas could be divided into two groups: one with fast PD1-positive T cells (e.g., Hodgkin lymphoma and mantle cell lymphoma, means 8.4 and 7.8 µm/min) and another with slower PD1-positive T cells (e.g., mediastinal grey zone lymphoma, mean 3.5 µm/min). Although the number of contacts between lymphoma cells and PD1-positive T cells was similar in different lymphoma types, important differences were observed in the duration of these contacts. Among the lymphomas with fast PD1-positive T cells, contacts were particularly short in mantle cell lymphoma (mean 54 s), whereas nodular lymphocyte-predominant Hodgkin lymphoma presented prolonged contact times (mean 6.1 min). Short contact times in mantle cell lymphoma were associated with the largest spatial displacement of PD1-positive cells (mean 12.3 µm). Although PD1-positive T cells in nodular lymphocyte-predominant Hodgkin lymphoma were fast, they remained in close contact with the lymphoma cells, in line with a dynamic immunological synapse. This pilot study shows for the first time systematic differences in the dynamic behavior of lymphoma and bystander cells between different lymphoma types.

We report a case in whom aortic wrapping had been performed for aortic dilatation. Ten years later, further progression of aortic root diameter was documented (root size of 66 mm). We performed complete replacement of the proximal aorta. Macroscopically and microscopically, there was extreme degeneration and thinning of the aorta under the graft.

To report a case of simultaneous bilateral ophthalmic artery occlusion in diagnosed giant cell arteritis (GCA).A 77-year-old male patient presented to the emergency department with simultaneous vision loss in both eyes for 3 hours. Headache at both temples and jaw claudication had been present for 3 weeks. Laboratory values demonstrated an initially increased C-reactive protein (CRP) of 202.0 mg/L and an erythrocyte sedimentation rate (ESR) of 100 mm within the first 20 minutes. Duplex sonography of the right and left temporal arteries revealed a "halo sign." A case of GCA was suspected, and intravenous high-dose methylprednisolone therapy was immediately administered. The clinical examination revealed a bilateral central retinal artery occlusion and fluorescein angiography showed a hot optic disc in the right eye and patchy choroidal hypoperfusion in both eyes. Biopsy of the left temporal artery was performed, which confirmed a florid temporal arteritis with complete thrombotic occlusion of the vascular lumen. Despite a good response to the administered therapy (CRP 17.0 mg/L 1 week after initiation), the visual prognosis was significantly limited through retinal and optic nerve involvement. By the follow-up examination 8 weeks later, the near visual acuity was 20/400 in the right and left eye at a distance of 16 inches.We hereby present a simultaneous bilateral ophthalmic artery occlusion as a rare complication of GCA. The combination of central retinal artery occlusion, arteritic anterior ischemic optic neuropathy, and choroidal hypoperfusion suggests an acute inflammatory involvement of the ophthalmic artery. In cases of the slightest suspicion of giant cell arteritis, an immediate high-dose steroid therapy initiation is of utmost importance.Wir berichten über einen Patienten mit gleichzeitig aufgetretenem Verschluss beider Aa. ophthalmicae bei diagnostizierter Riesenzellarteriitis.Ein 77-jähriger männlicher Patient stellte sich in der Notaufnahme mit gleichzeitigem Sehverlust auf beiden Augen vor, der seit 3 Stunden bestehe. Kopf- und Kauschmerzen waren seit 3 Wochen vorhanden. Die Laborwerte zeigten ein initial erhöhtes C-reaktives Protein (CRP) von 202,0 mg/l und eine Erythrozytensedimentationsrate (ESR) von 100 mm innerhalb der ersten 20 Minuten. Die Duplexsonografie der rechten und linken A. temporalis zeigte ein „Halo-Zeichen“ und bei Verdacht einer Riesenzellarteriitis wurde eine sofortige intravenöse hochdosierte Methylprednisolon-Therapie eingeleitet. Die klinische Untersuchung ergab einen beidseitigen Zentralarterienverschluss und die Fluoreszenzangiografie zeigte eine Leckage der Papille des rechten Auges sowie eine choroidale Hypoperfusion an beiden Augen. Es wurde eine Biopsie der linken Temporalarterie durchgeführt, die eine floride Arteriitis temporalis mit vollständigem thrombotischem Verschluss des Gefäßlumens bestätigte. Trotz eines guten Ansprechens auf die verabreichte Therapie (CRP 17,0 mg/l 1 Woche nach Beginn) war die Sehprognose durch Netzhaut- und Sehnervenbeteiligung deutlich eingeschränkt. Bei der Nachuntersuchung 8 Wochen später lag der Nahvisus bei 1/20 bei der Lesetafel am rechten und linken Auge.Wir stellen hier einen gleichzeitigen bilateralen Verschluss der A. ophthalmica als seltene Komplikation der Riesenzellarteriitis vor. Die Kombination aus Zentralarterienverschluss, arteriitischer anteriorer ischämischer Optikusneuropathie und choroidaler Hypoperfusion lässt auf eine akute entzündliche Beteiligung der A. ophthalmica schließen. Bei dem geringsten Verdacht auf eine Riesenzellarteriitis ist die sofortige Einleitung einer hochdosierten Steroidtherapie von größter Bedeutung.

To address the role of chronic antigenic stimulation in primary central nervous system lymphoma (PCNSL), we searched for autoantigens and identified sterile α-motif domain containing protein 14 (SAMD14) and neural tissue-specific F-actin binding protein I (neurabin-I) as autoantigenic targets of the B-cell receptors (BCRs) from 8/12 PCNSLs. In the respective cases, SAMD14 and neurabin-I were atypically hyper-N-glycosylated (SAMD14 at ASN339 and neurabin-I at ASN1277), explaining their autoimmunogenicity. SAMD14 and neurabin-I induced BCR pathway activation and proliferation of aggressive lymphoma cell lines transfected with SAMD14- and neurabin-I-reactive BCRs. Moreover, the BCR binding epitope of neurabin-I conjugated to truncated Pseudomonas exotoxin-killed lymphoma cells expressing the respective BCRs. These results support the role of chronic antigenic stimulation by posttranslationally modified central nervous system (CNS) driver autoantigens in the pathogenesis of PCNSL, serve as an explanation for their CNS tropism, and provide the basis for a novel specific treatment approach.

Chronic obstructive lung disease (COPD) and lung cancer are both caused by smoking and often occur as comorbidity. The programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) axis is an important canonic immunoregulatory pathway, and antibodies that specifically block PD-1 or PD-L1 have demonstrated efficacy as therapeutic agents for non-small cell lung cancer. The role of the PD-1/PD-L1 axis in the pathogenesis of COPD is unknown. Here, we analyzed the function of the PD-1/PD-L1 axis in preclinical COPD models and evaluated the concentrations of PD-1 and PD-L1 in human serum and bronchoalveolar lavage (BAL) fluids as biomarkers for COPD. Anti-PD-1 treatment decreased lung damage and neutrophilic inflammation in mice chronically exposed to cigarette smoke (CS) or nontypeable Haemophilus influenzae (NTHi). Ex vivo stimulated macrophages obtained from anti-PD-1-treated mice released reduced amounts of inflammatory cytokines. PD-L1 concentrations correlated positively with PD-1 concentrations in human serum and BAL fluids. Lung sections obtained from patients with COPD stained positive for PD-L1. Our data indicate that the PD-1/PD-L1 axis is involved in developing inflammation and tissue destruction in COPD. Inflammation-induced activation of the PD-1 pathway may contribute to disease progression.

Simple Summary Penile squamous cell carcinoma (PSCC) is the most common type of penile cancer (PeCa) and is associated with human papillomavirus (HPV) in about 50% of cases. It is of high clinical impact to identify patients who are at high risk of metastasis and are likely to benefit from adjuvant therapies. Today, valid prognostic biomarkers are scarce in penile cancer. In the present study, we attempted to identify miRNAs involved in tumor development and metastasis in distinct histological subtypes with or without HPV infection in PSCC patients. We confirmed that specific miRNAs could serve as potential diagnostic and prognostic markers in single PSCC subtypes and are associated with HPV infection. Abstract Although microRNAs are described as promising biomarkers in many tumor types, little is known about their role in PSCC. Thus, we attempted to identify miRNAs involved in tumor development and metastasis in distinct histological subtypes considering the impact of HPV infection. In a first step, microarray analyses were performed on RNA from formalin-fixed, paraffin-embedded tumor (22), and normal (8) tissue samples. Microarray data were validated for selected miRNAs by qRT-PCR on an enlarged cohort, including 27 tumor and 18 normal tissues. We found 876 significantly differentially expressed miRNAs (p ≤ 0.01) between HPV-positive and HPV-negative tumor samples by microarray analysis. Although no significant differences were detected between normal and tumor tissue in the whole cohort, specific expression patterns occurred in distinct histological subtypes, such as HPV-negative usual PSCC (95 differentially expressed miRNAs, p ≤ 0.05) and HPV-positive basaloid/warty subtypes (247 differentially expressed miRNAs, p ≤ 0.05). Selected miRNAs were confirmed by qRT-PCR. Furthermore, microarray data revealed 118 miRNAs (p ≤ 0.01) that were significantly differentially expressed in metastatic versus non-metastatic usual PSCC. The lower expression levels for miR-137 and miR-328-3p in metastatic usual PSCC were validated by qRT-PCR. The results of this study confirmed that specific miRNAs could serve as potential diagnostic and prognostic markers in single PSCC subtypes and are associated with HPV-dependent pathways.

BACKGROUND Seminomatous germ cell tumours (SGCT) are the most frequent malignancy in young men. Reliable prognostic biomarkers for the prediction of metastasis at diagnosis and the risk of relapse in clinical stage I (CSI) are lacking. Adjuvant therapies carry a risk of overtreatment, whereas salvage therapies have a risk of high toxicities. Thus, the identification of reliable prognostic biomarkers is highly desirable to identify patients who will benefit from early adjuvant treatment. MicroRNAs (miRNAs) regulate tumour development and progression, and their potential as biomarkers has already been proven in a variety of malignancies. OBJECTIVES The aim of our study was to define a specific miRNA expression pattern that discriminates metastatic from non-metastatic primary SGCT. MATERIALS AND METHODS Total RNA was isolated from 24 formalin-fixed paraffin-embedded (FFPE) primary SGCT tumours (10 non-metastatic, five metachronously and nine synchronously metastatic) and from 10 normal testicular tissue samples. Microarray analysis was performed for global miRNA expression profiling. The results were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Statistical analysis was performed using SPSS. RESULTS Microarray analyses revealed a specific miRNA pattern that distinguishes metastatic from non-metastatic SGCT. Sixty-three miRNAs were differentially expressed in metastatic compared to non-metastatic tumours (P

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Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma of B-cell origin with frequent expression of functional B-cell receptors (BCRs). Here we report that expression cloning followed by antigen screening identifies DNA-directed RNA polymerase beta’ (RpoC) from Moraxella catarrhalis as frequent antigen of BCRs of IgD+ LP cells. Patients show predominance of HLA-DRB1*04/07 and the IgVH genes encode extraordinarily long CDR3s. High-titer, light-chain-restricted anti-RpoC IgG1/κ-type serum-antibodies are additionally found in these patients. RpoC and MID/hag, a superantigen co-expressed by Moraxella catarrhalis that is known to activate IgD+ B cells by binding to the Fc domain of IgD, have additive activation effects on the BCR, the NF-κB pathway and the proliferation of IgD+ DEV cells expressing RpoC-specific BCRs. This suggests an additive antigenic and superantigenic stimulation of B cells with RpoC-specific IgD+ BCRs under conditions of a permissive MHC-II haplotype as a model of NLPHL lymphomagenesis, implying future treatment strategies., Nodular lymphocyte-predominant Hodgkin lymphoma with IgD+ lymphocyte-predominant (LP) cells is a rare clinical distinct lymphoma subset of B-cell origin. Here the authors show that antigens expressed by Moraxella catarrhalis are recognized by B cell receptors of IgD+ LP cells, suggesting the contribution of chronic antigen stimulation to lymphomagenesis.

To evaluate the prognostic potential of vimentin, p53, EGFR, CK5/6, CK 14, and CK 17 in patients with triple-negative breast cancer (TNBC). Tumor specimens of 60 patients with histologically confirmed TNBC were retrospectively analyzed. Formalin-fixed paraffin-embedded blocks of the tumor tissue were used to prepare tissue microarrays (TMAs). After immune-histochemical staining, protein expression of vimentin, p53, EGFR, CK5/6, CK 14, and CK 17 was determined and the immunoreactive score (IRS) was calculated. The protein expression was correlated to overall (OS) and disease-free survival (DFS). Ninety percent of patients suffered from an invasive ductal carcinoma T1 or T2, 66.7% were N0, and 70% had a G3 tumor with Ki67 of > 14%. Vimentin expression was found in 28/60 patients (46.7%), p53 expression in 30/60 patients (50%), and EGFR expression in 3/60 patients (5%). CK5/6, CK14, and CK17 expression was found in 60.0%, 63.3%, and 66.7%, respectively. Vimentin expression vs no expression was associated with significantly higher mean Ki67 values (52.5% vs. 31.1%; p = 0.0013) and significantly higher p53 expression (67.9% vs. 34.4%; p = 0.0097). No significant association between vimentin expression and OS (p = 0.7710) or DFS (p = 0.5558) was found during a mean follow-up of 92 months. None of the six proteins proved to be suitable prognostic factors for OS and DSF in patients with TNBC.

Non-alcoholic steatohepatitis (NASH) represents a risk factor for the development of hepatocellular carcinoma (HCC) and is characterized by quantitative and qualitative changes in hepatic lipids. Since elongation of fatty acids from C16 to C18 has recently been reported to promote both hepatic lipid accumulation and inflammation we aimed to investigate whether a frequently used mouse NASH model reflects this clinically relevant feature and whether C16 to C18 elongation can be observed in HCC development. Feeding mice a methionine and choline deficient diet to model NASH not only increased total hepatic fatty acids and cholesterol, but also distinctly elevated the C18/C16 ratio, which was not changed in a model of simple steatosis (ob/ob mice). Depletion of Kupffer cells abrogated both quantitative and qualitative methionine-and-choline deficient (MCD)-induced alterations in hepatic lipids. Interestingly, mimicking inflammatory events in early hepatocarcinogenesis by diethylnitrosamine-induced carcinogenesis (48 h) increased hepatic lipids and the C18/C16 ratio. Analyses of human liver samples from patients with NASH or NASH-related HCC showed an elevated expression of the elongase ELOVL6, which is responsible for the elongation of C16 fatty acids. Taken together, our findings suggest a detrimental role of an altered fatty acid pattern in the progression of NASH-related liver disease.

In the previous studies, we demonstrated that Sec62 is essential for tumor cell migration, epithelial-to-mesenchymal transition, and intracellular stress tolerance. An increase in Sec62 expression correlated with an increase in cervical dysplasia severity in liquid-based cytology specimens. Ki67 is an established proliferation marker. Thus, in this study, we examined a method of Sec62/Ki67 dual staining for the detection of high-grade dysplasia and cancer in cervical liquid-based cytology specimens. Sec62/Ki67 dual staining was performed on 100 cervical liquid-based cytology specimens. The staining results were correlated with cytological, immunocytological (p16/Ki67), colposcopic, and histological findings. All 56 (n = 56, 100%) cases of cervical intraepithelial neoplasia grade 3 and cervical cancer (CIN3+ lesions) were positive for Sec62/Ki67 staining, while low-grade lesions and normal cells were negative. Sec62/Ki67 staining was highly sensitive and specific for the detection of CIN2+ and CIN3+ lesions (94.37%; 100% and 100%; 84.09%, respectively). Sec62/Ki67 dual-staining immunocytochemistry is a promising cytological tool for interpreting high-grade squamous lesions in cytological specimens and for assessing the risk of progression to cancer.

To generate and characterize 3D spheroid suspension cultures from radical prostatectomy (RP) specimens as a versatile model system for organ-confined prostate cancer (PCa). Cancerous tissue samples from RP specimens were excised by a uropathologist. Preparation of 3D spheroids was done by mechanical disintegration and limited enzymatic digestion followed by serial filtration through 100 μm- and 40 μm-cell strainers. Thereafter, spheroids were cultured in a modified stem cell medium and characterized by a live/dead assay, whole-spheroid immunohistochemistry (IHC; CK5, CK8, AMACR, PSA, Ki67, AR, αSMA, Vimentin, E-Cadherin) and PSA-measurements in culture medium. Furthermore, their response to pharmaceutical treatment with docetaxel, bicalutamide, enzalutamide and abiraterone was tested. 173 RP cases were included. The median preoperative PSA-level was 16.12 ng/ml [range 0.99;345], the median Gleason score was 7b [6;10]. 64 cases were excluded due to low tumor content in frozen sections (43) or to insufficient spheroid formation (21). In the remaining 109 cases, spheroids formed successfully and stayed viable for up to several months. IHC analysis revealed AR-, CK8-, and AMACR-positivity in nearly all cases, while CK5-positive cells were detectable only occasionally as were α-SMA and Vimentin. E-Cadherin was positive in most cases. Furthermore, spheroids proved to be amenable to cryopreservation. While abiraterone had no effect and docetaxel only a moderate effect, spheroid viability was markedly reduced upon bicalutamide and enzalutamide treatment. Multicellular 3D spheroids can be generated from patient-derived RP tissue samples and serve as an innovative in vitro model of organ-confined PCa.

Dysregulation of the Wnt inhibitor dickkopf-1 protein (Dkk1) has been reported in a variety of cancers. In addition, it has been linked to the progression of malignant bone disease by impairing osteoblast activity. This study investigated serum- and tissue levels of Dkk1 in breast cancer patients with- or without bone metastases. Serum Dkk1 levels were measured by ELISA in 89 breast cancer patients and 86 healthy women. Tissue levels of Dkk1 and β-catenin, a major downstream component of Wnt transduction pathway, were tested with immunohistochemical staining in 143 different tissues, including adjacent non-tumoral breast tissues, primary breast tumours, lymph nodes metastases, and bone metastases. Serum levels of Dkk1 were significantly increased in breast cancer patients without metastases compared with healthy controls and even more increased in patients with bone metastases. Tissue expression of Dkk1 was positive in 70% of tested primary breast cancer tissues and demonstrated significant correlation with histological type and PR status. Less frequent expression of Dkk1 was found in lymph nodes metastases and bone metastases compared with adjacent non-tumoral breast tissues and primary breast tumours. Tissue expression of β-catenin was positive in the vast majority of all tested tissue types indicating activated Wnt/β-catenin signalling. Our results suggested that Wnt/β-catenin signalling in breast tumours and their secondary lymph nodes- and bone metastases is dysregulated and this could be related to aberrant Dkk1 expression levels. Hence, Dkk1 protein might provide insights into the continued development of novel comprehensive and therapeutic strategies for breast cancer and its bone metastases.

To investigate the interaction between Wnt/β-catenin and estrogen signaling pathways in endometrial cancer (EC). 119 women were involved in this study, including 65 women with histologically confirmed EC and 54 healthy women as a control group. Serum protein levels of Dkk1 were measured using ELISA. Protein expression levels of Dkk1, β-catenin, ER-β isoforms (β1, β2, β5), and ER-α were tested in paraffin-embedded tissues using IHC. Gene expression levels of Dkk1, CTNNB, ESR1, and ESR2 were tested in fresh tumorous and normal endometrium tissues using RT-PCR. EC patients had significantly higher serum levels of Dkk1 protein compared with healthy women. Dkk1 and β-catenin showed different expression pattern in tumor cells compared to it in normal cells at the protein level but not at the gene level. Protein expression levels of ERβ2 and ERα were significantly lower in tumor cells compared with tumor-adjacent normal cells. Increased protein expression levels of ERα were associated with favorable clinicopathological features and better overall survival rate (OS). Protein expression levels of ERα were correlated with protein expression levels of Dkk1 and cytoplasmic β-catenin. The association between ERα expression levels and OS was no more significant when tested in regard to Dkk1- and cytoplasmic β-catenin expression levels. Our data demonstrated that Wnt/β-catenin and estrogen signaling systems are dysregulated in EC showing; for the first time, a potential crosstalk between certain components of these two pathways, which in turn has affected the specificity of these molecules in disease characteristics. Understanding the signaling networks in EC is crucial in designing clinical trials to evaluate the efficacy of molecular-targeted agents and providing more successful therapies in the future.

Human papilloma virus (HPV) infections are one of the most common sexually transmitted diseases. We present the case of a 77-year-old Caucasian male with enormous genital warts of the penis, scrotum, groins and anus. Lesions were excised by electrosurgery. The histological examination revealed Condylomata gigantea as well as an invasive perianal squamous cell carcinoma. Mucosal “low-risk” HPV type 6 was detected. The patient had a history of an immunosuppressing disease. During the 4-year follow-up, multiple relapses occurred. Thus, particularly in immunosuppressed patients, early prophylactic HPV vaccination seems to be indicated for use in the prevention of HPV-associated mutilating and life-threatening disease. Vaccination should also protect from “low-risk” HPV.

The long non-coding RNA (lncRNA) H19 represents a maternally expressed and epigenetically regulated imprinted gene product and is discussed to have either tumor-promoting or tumor-suppressive actions. Recently, H19 was shown to be regulated under inflammatory conditions. Therefore, aim of this study was to determine the function of H19 in hepatocellular carcinoma (HCC), an inflammation-associated type of tumor. In four different human HCC patient cohorts H19 was distinctly downregulated in tumor tissue compared to normal or non-tumorous adjacent tissue. We therefore determined the action of H19 in three different human hepatoma cell lines (HepG2, Plc/Prf5, and Huh7). Clonogenicity and proliferation assays showed that H19 overexpression could suppress tumor cell survival and proliferation after treatment with either sorafenib or doxorubicin, suggesting chemosensitizing actions of H19. Since HCC displays a highly chemoresistant tumor entity, cell lines resistant to doxorubicin or sorafenib were established. In all six chemoresistant cell lines H19 expression was significantly downregulated. The promoter methylation of the H19 gene was significantly different in chemoresistant cell lines compared to their sensitive counterparts. Chemoresistant cells were sensitized after H19 overexpression by either increasing the cytotoxic action of doxorubicin or decreasing cell proliferation upon sorafenib treatment. An H19 knockout mouse model (H19Δ3) showed increased tumor development and tumor cell proliferation after treatment with the carcinogen diethylnitrosamine (DEN) independent of the reciprocally imprinted insulin-like growth factor 2 (IGF2). In conclusion, H19 suppresses hepatocarcinogenesis, hepatoma cell growth, and HCC chemoresistance. Thus, mimicking H19 action might be a potential target to overcome chemoresistance in future HCC therapy.

Micro (mi)RNAs are short, noncoding RNAs and deregulation of miRNAs and their targets are implicated in tumor generation and progression in many cancers. Meningiomas are mostly benign, slow growing tumors of the central nervous system with a small percentage showing a malignant phenotype. Following in silico prediction of potential targets of miR-34a-3p, SMAD4, FRAT1, and BCL2 have been confirmed as targets by dual luciferase assays with co-expression of miR-34a-3p and reporter gene constructs containing the respective 3'UTRs. Disruption of the miR-34a-3p binding sites in the 3'UTRs resulted in loss of responsiveness to miR-34a-3p overexpression. In meningioma cells, overexpression of miR-34a-3p resulted in decreased protein levels of SMAD4, FRAT1 and BCL2, while inhibition of miR-34a-3p led to increased levels of these proteins as confirmed by Western blotting. Furthermore, deregulation of miR-34a-3p altered cell proliferation and apoptosis of meningioma cells in vitro. We show that SMAD4, FRAT1 and BCL2 are direct targets of miR-34a-3p and that deregulation of miR-34a-3p alters proliferation and apoptosis of meningioma cells in vitro. As part of their respective signaling pathways, which are known to play a role in meningioma genesis and progression, deregulation of SMAD4, FRAT1 and BCL2 might contribute to the aberrant activation of these signaling pathways leading to increased proliferation and inhibition of apoptosis in meningiomas.

It has been suggested that stimulation of B-cell receptors (BCR) by specific antigens plays a pathogenic role in diffuse large B-cell lymphoma (DLBCL). Here, it was the aim to screen for specific reactivities of DLBCL-BCR in the spectrum of autoantigens and antigens of infectious origin. Arsenite resistance protein 2 (Ars2) was identified as the BCR target of three of five activated B-cell type DLBCL cell lines and two of 11 primary DLBCL cases. Compared to controls, Ars2 was hypophosphorylated exclusively in cases and cell lines with Ars2-specific BCR. In a validation cohort, hypophosphorylated Ars2 was found in eight of 31 activated B-cell type DLBCL, but in only one of 20 germinal center B-cell like type DLBCL. Incubation with Ars2 induced BCR-pathway activation and increased proliferation, while an Ars2/ETA’ toxin conjugate induced killing of cell lines with Ars2-reactive BCR. Ars2 appears to play a role in a subgroup of activated B-cell-type DLBCL. Moreover, transformed DLBCL lines with Ars2-reactive BCR still showed growth advantage after incubation with Ars2. These results provide knowledge about the pathogenic role of a specific antigen stimulating the BCR pathway in DLCBL.

The identification of biomarkers characterizing the invasive potential of bladder cancer could enhance the clinical management of individual patients and therefore improve prognosis. The aim of this study was to define a miRNA panel in tumor tissues as well as in urinary extracellular vesicles (EVs) for discriminating muscle-invasive bladder cancer (MIBC) from non-muscle-invasive bladder cancer (NMIBC). miRNA expression was analyzed in 24 formalin-fixed, paraffin-embedded (FFPE) tumor samples by microarray analysis and was further validated by qRT-PCR in 56 FFPE tumor samples as well as in 37 urinary EV samples. Microarray analysis revealed 63 miRNAs that were significantly differentially expressed (P