VEGFR-2 Expression in hepatozellulären und cholangiozellulären Leberkarzinomen und duktalen Pankreaskarzinomen und klinische Korrelation mit dynamischem Kontrastmittel-verstärktem CT am Beispiel von hepatozellulären Neubildungen

Tumorangioneogenese beeinflusst Tumorwachstum und Metastasenentwicklung, und wird von mehreren proangiogenetischen Faktoren beeinflusst. Die wichtigste Rolle spielt dabei der vaskuläre endotheliale Wachstumsfaktor (VEGF) und der korrespondierende Rezeptor-2 (VEGFR-2). 95 Fälle von hepatozellulären Karzinomen und 47 Fälle von intrahepatischen colangiozellulären Karzinomen wurden mit entsprechendem Kontrollgewebe in tissue micro arrays zusammengefasst. Ein klinisches Kollektiv von 34 Patienten mit hepatozellulären Karzinomen bei bekannter Leberzirrhose wurde anhand von Ganzschnitten untersucht, diese Tumore korrelierte man mit dynamischem Kontrastmittel-CT (Thaiss et. al). Getrennt wurden 74 Fälle von duktalen Pankreaskarzinomen, 24 Fälle chronischer Pankreatitis und 23 reguläre Pankreata in tissue micro arrays aufgearbeitet. Die Kollektive wurden immunhistochemisch für VEGFR-2 gefärbt. Der immunhistochemische Einsatz von VEGFR-2 diskriminiert zwischen hyper- und hypovaskularisierten Tumoren. Die zunehmende Arterialisierung bei der Genese von HCC ließ sich anhand signifikanter Zunahme der VEGFR-2 Expression darstellen. CCCs und PDAs waren bei Färbung mit VEGFR-2 hypovaskularisiert. Ebenso wie in der Studie von Thaiss war die hier vorliegende Untersuchung retrospektiv ausgerichtet und konnte nicht mit aktualisierten klinischen Daten verglichen werden. Das retrospektive Studiendesign im klinischen Kollektiv und die relative geringe Fallanzahl von DEC-CTs mit konsekutiver Histologie ohne unmittelbare Therapie oder initialem MRI vor Therapie schränkten die Aussagekraft der vorliegenden Studie etwas ein. Zusammenfassend fanden wir für HCC, DLN, RLN unterschiedliche VEGFR-2 Expressionsmuster, die gut mit nicht invasiven Perfusionsparametern bei Anwendung eines DCE-CT (oder VPCT) korrelierten. Beide Parameter ermöglichten somit eine Unterscheidung zwischen HCC und seinen Vorläuferläsionen, und sind auf Grund ihrer engen Korrelation für den Einsatz und als monitoring im Rahmen einer einer VEGFR-2 gerichteten Therapie geeignet. Inwieweit die Anwendung beider Parameter bei der Differentialdiagnose HCC/CCC in zirrhotischen Lebern und für die Beurteilung von cholangiozellulären Läsionen in der Leber herangezogen werden kann, bleibt abzuwarten. Bei der chronischen Pankreatitis als Vorläuferläsion des duktalen Pankreaskarzinomes war eine signifikant erhöhte Vaskularisierung zu erkennen, allerdings bezogen sich diese Ergebnisse auf flächenmäßig kleine TMAs. Diese Beobachtung muss in einer weiteren Studie mit regulären Schnittpräparaten verglichen werden, zumal duktale Pankreaskarzinome in unseren Untersuchung eindeutig hypovascularisiert waren. Bisher gibt es noch keinen Vergleich mit DCE-CT (oder VPCT) in Analogie zu den Ergebnissen beim HCC. Der immunhistochemische Einsatz von VEGFR-2 kann somit aufgrund der Hypervaskularisation zur Dignitätseinschätzung hepatozellulärer Proliferate und zu deren monitoring nach Therapie beitragen. Cholangiozelluläre Proliferate hingegen stellten sich als ebenso hypovaskularisiert wie das duktale Pankreaskarzinom dar

Tissue-preserving treatment with non-invasive physical plasma of cervical intraepithelial neoplasia—a prospective controlled clinical trial

ObjectiveCervical cancer represents the fourth leading cause of cancer among women and is associated with over 311,000 annual deaths worldwide. Timely diagnosis is crucial given the lengthy pre-cancerous phase, which is typified by cervical intraepithelial neoplastic lesions. However, current treatment methods are often tissue-destructive and can be accompanied by severe side effects. To address these concerns, our study introduces a novel, gentle approach for the tissue-preserving treatment of CIN lesions.ResultsWe present findings of a controlled, prospective, single-armed phase IIb clinical trial performed at the Department for Women’s Health, Tübingen, Germany. From September 2017 to March 2022 we assessed 570 participants for study eligibility. Of the screened patients, 63 participants met with CIN1/2 lesions met the inclusion criteria and were treated with non-invasive physical plasma (NIPP). Assessment of treatment efficacy was based on a comprehensive analysis of histological and cytological findings, along with high-risk HPV infection load at 3 and 6 months post-treatment. Comparative analyses were performed retrospectively with data obtained from 287 untreated patients in the control group. Our findings indicate that patients treated with NIPP experienced an 86.2% rate of full remission, along with a 3.4% rate of partial remission of CIN lesions, which compares favorably to the control group’s rates of 40.4% and 4.5%, respectively. Additionally, we observed a twofold reduction in high-risk HPV infections following NIPP treatment. Minor side effects were observed, such as mild pain during treatment and short-term smear bleeding or increased vaginal discharge within 24 h after treatment. Given the experimental nature of NIPP treatment and the availability of established standard treatments, our study was designed as a non-randomized study.ConclusionNIPP treatment offers a highly flexible and easy-to-apply method for treating pre-cancerous CIN1/2 lesions. This non-invasive approach is notable for its tissue-preserving nature, making it a promising alternative to current excisional and ablative treatments. CIN1/2 lesions were employed as preliminary in vivo models for the targeted treatment of CIN3 lesions.Clinical trial registrationhttps://www.clinicaltrials.gov, identifier NCT03218436

Delta-like protein 3 expression in paired chemonaive and chemorelapsed small cell lung cancer samples

Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC). DLL3 is expressed on the majority of SCLC samples. Because SCLC is rarely biopsied in the course of disease, data regarding DLL3 expression in relapses is not available. The aim of this study was to investigate the expression of DLL3 in chemorelapsed (but untreated with Rova-T) SCLC samples and compare the results with chemonaive counterparts. Two evaluation methods to assess DLL3 expression were explored. Additionally, we assessed if DLL3 expression of chemorelapsed and/or chemonaive samples has prognostic impact and if it correlates with other clinicopathological data. The study included 30 paired SCLC samples, which were stained with an anti DLL3 antibody. DLL3 expression was assessed using tumor proportion score (TPS) and H-score and was categorized as DLL3 low (TPS < 50%, H-score ≤ 150) and DLL3 high (TPS ≥ 50%, H-score > 150). Expression data were correlated with clinicopathological characteristics. Kaplan-Meier curves were used to illustrate overall survival (OS) depending on DLL3 expression in chemonaive and chemorelapsed samples, respectively, and depending on dynamics of expression during course of therapy. DLL3 was expressed in 86.6% chemonaive and 80% chemorelapsed SCLC samples without significant differences between the two groups. However, the extent of expression varied in a substantial proportion of pairs (36.6% with TPS, 43.3% with H-score), defined as a shift from low to high or high to low expression. TPS and H-score provided comparable results. There were no profound correlations with clinicopathological data. Survival analysis revealed a trend toward a more favorable OS in DLL low-expressing chemonaive SCLC (p = 0.57) and, in turn, in DLL3 high-expressing chemorelapsed SCLC (p = 0.42) as well as in SCLC demonstrating a shift from low to high expression (p = 0.56) without being statistically significant. This is the first study to investigate DLL3 expression in a large cohort of rare paired chemonaive-chemorelapsed SCLC specimens. Comparative analysis revealed that DLL3 expression was not stable during the course of therapy, suggesting therapy-based alterations. Unlike in chemonaive samples, a high DLL3 expression in chemorelapsed samples indicated a trend for a more favorable prognosis. Our results highlight the importance to investigate DLL3 in latest chemorelapsed SCLC tumor tissue

Primary angiosarcoma of the ovary with prominent fibrosis of the ovarian stroma. Case report of an 81-year old patient

Primary angiosarcoma of the ovary (AS) is a rare entity with only 31 reported cases. The majority are pure angiosarcomas, the remainder are associated either with teratomas or conventional epithelial tumors. More than 50% of ovarian AS are disseminated at the time of diagnosis, the minority is detected in stage I. The prognosis of ovarian angiosarcoma in general is poor. Most reports refer to younger individuals, aged from 7 to 46 years, and only 2 case reports could be found for patients older than 64 years. Here we present a very unusual case of angiosarcoma in a 81-year-old patient

Lymphoepithelioma-like carcinoma of the vulva, an underrecognized entity? Case report with a single inguinal micrometastasis detected by sentinel node technique

This report describes an unusual EBV-negative lymphoepithelioma-like carcinoma of the vulva in a 73-year-old patient. The lesion was localised at the right minor labium and was resected by partial vulvectomy. A synchronous sentinel lymph node biopsy revealed a single micrometastasis in the right inguinal region, which prompted local radiotherapy. Follow-up nine months later showed only slight vulvar atrophy, without signs of local recurrence or distant metastases

Antibody-mediated procoagulant platelets in SARS-CoV-2-vaccination associated immune thrombotic thrombocytopenia

The COVID-19 pandemic has resulted in significant morbidity and mortality worldwide. To prevent severe infection, mass COVID-19 vaccination campaigns with several vaccine types are currently underway. We report pathological and immunological findings in 8 patients who developed vaccine-induced immune thrombotic thrombocytopenia (VITT) after administration of SARS-CoV-2 vaccine ChAdOx1 nCoV-19. We analyzed patient material using enzyme immune assays, flow cytometry and heparin-induced platelet aggregation assay and performed autopsies on two fatal cases. Eight patients (5 female, 3 male) with a median age of 41.5 years (range, 24 to 53) were referred to us with suspected thrombotic complications 6 to 20 days after ChAdOx1 nCoV-19 vaccination. All patients had thrombocytopenia at admission. Patients had a median platelet count of 46.5 x109/L (range, 8 to 92). Three had a fatal outcome and 5 were successfully treated. Autopsies showed arterial and venous thromboses in various organs and the occlusion of glomerular capillaries by hyaline thrombi. Sera from VITT patients contain high titer antibodies against platelet factor 4 (PF4) (OD 2.59±0.64). PF4 antibodies in VITT patients induced significant increase in procoagulant markers (P-selectin and phosphatidylserine externalization) compared to healthy volunteers and healthy vaccinated volunteers. The generation of procoagulant platelets was PF4 and heparin dependent. We demonstrate the contribution of antibody-mediated platelet activation in the pathogenesis of VITT

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC