Complex treatment of residual metastatic germ cell cancer: A single center experience.

BACKGROUND: Testicular cancer is the most common solid malignancy among men aged 15-35. Radical orchiectomy and platinum-based chemotherapy (BEP) are curative in the majority of patients, including advanced, metastatic cases. According to current urooncology guidelines all non-seminoma patients harbouring post-chemotherapy residual masses of ≥ 1 cm should undergo salvage retroperitoneal lymph node dissection (RPLND). However, only 10% of residual tumors contain viable disease. OBJECTIVE: To assess patient outcomes and complications considering different treatment regimens and clinical characteristics. MATERIALS AND METHODS: In a retrospective cross-sectional study patients (n=127) who underwent postchemotherapy RPLND between 2007 and 2023 at our referral center were evaluated. The patients received systemic treatment at various oncology centers. The number of BEP cycles received were occasionally different from standard. Only patients with normal postchemotherapy serum tumor markers and primary testicular or extragonadal germ cell neoplasms were included. Treatment groups were established according to the number of BEP cycles received, and the extent of RPLND (bilateral or modified template). Treatment outcomes and complications were assessed. RESULTS: Standard 3-4 courses of BEP were received by 100 (78,7%) patients, while 11 (8,7%) patients underwent less, and 16 (12,6%) more courses than standard. On histopathologic evaluation viable germ cell tumor, teratoma, and necrosis/fibrosis was present in 26 (20,5%), 67 (52,7%) and 34 (26,8%) of specimen, respectively. In the 5-6 BEP series subgroup high rate of viable disease (37,5%) was found and significantly more nephrectomies were performed, than other chemotherapy subgroups. Extratesticular GCT, viable disease in residual mass or progression after RPLND indicated lower survival. Mild (Clavien-Dindo I-II) or no postoperative complications were reported in 93,7% of cases. CONCLUSIONS: The study suggests no significant benefit from exceeding 3-4 courses of BEP. Timely salvage RPLND should be performed in high volume centers for optimal treatment outcomes with acceptable complication rates. Adherence to the Heidenreich criteria is advisable where practical.

Ca2+ Dynamics of Gap Junction Coupled and Uncoupled Deiters' Cells in the Organ of Corti in Hearing BALB/c Mice.

ATP, as a paracrine signalling molecule, induces intracellular Ca2+ elevation via the activation of purinergic receptors on the surface of glia-like cochlear supporting cells. These cells, including the Deiters' cells (DCs), are also coupled by gap junctions that allow the propagation of intercellular Ca2+ waves via diffusion of Ca2+ mobilising second messenger IP3 between neighbouring cells. We have compared the ATP-evoked Ca2+ transients and the effect of two different gap junction (GJ) blockers (octanol and carbenoxolone, CBX) on the Ca2+ transients in DCs located in the apical and middle turns of the hemicochlea preparation of BALB/c mice (P14-19). Octanol had no effect on Ca2+ signalling, while CBX inhibited the ATP response, more prominently in the middle turn. Based on astrocyte models and using our experimental results, we successfully simulated the Ca2+ dynamics in DCs in different cochlear regions. The mathematical model reliably described the Ca2+ transients in the DCs and suggested that the tonotopical differences could originate from differences in purinoceptor and Ca2+ pump expressions and in IP3-Ca2+ release mechanisms. The cochlear turn-dependent effect of CBX might be the result of the differing connexin isoform composition of GJs along the tonotopic axis. The contribution of IP3-mediated Ca2+ signalling inhibition by CBX cannot be excluded.

The first experience in Hungary with split-course multimodal treatment in high risk bladder cancer / Az osztott dózisú trimodális kezelés elso hazai alkalmazása nagy kockázatú húgyhólyagdaganat esetében.

Összefoglaló. Az izominvazív vagy nagyon nagy kockázatú, felületes hólyagdaganatok kezelésének arany standardja a radikális húgyhólyag-eltávolítás (cystectomia). Válogatott betegek esetében hasonló hatékonyságú kezelés lehet az osztott dózisú (split-course) trimodális terápia, az endoszkópos tumorreszekció és a kemoirradiáció megszakított ciklusokkal történo alkalmazása. A split-course trimodális terápia a radikális cystectomiához hasonló eredményességu, a késobbi életminoség szempontjából pedig ígéretes kezelési lehetoség lehet megfeleloen kiválasztott betegek esetében. Hazánkban elso alkalommal végzett kezelést ismertetünk a téma szakirodalmi áttekintése mellett. A húgyhólyagtumor transurethralis reszekciója, maximális eradikációja után kemoirradiáció kezdodik, melyet 45 Gy sugárdózis elérésekor ismételt szövettani mintavétel szakít meg. Negatív szövettani eredmény esetén a megkezdett terápia a teljes dózis eléréséig folytatandó. Amennyiben a reszekció során élo tumor észlelheto, a radikális mutét elvégzése javasolt. A korábban transurethralis daganatreszekción négyszer átesett 54 éves beteg lokális immunterápia utáni recidívájának szövettana pT1, 'high grade' urothelialis carcinoma volt. A jól informált, kiváló fizikális statusú beteg kérését figyelembe véve split-course trimodális kezelést végeztünk. Negatív 'staging' vizsgálatok után maximális endoszkópos reszekció, majd kemoirradiáció következett. A 45 Gy besugárzás elérésekor elvégzett ismételt mintavétel azonnal feldolgozott szövettana negatív eredményt mutatott, így késedelem nélkül folytatódott a kemoirradiációs kezelés. Az eddigi kontrollvizsgálatok alapján a beteg komplett remisszióban van. A split-course trimodális terápia a radikális hólyageltávolítás megfelelo alternatívája jól informált, gondosan megválogatott betegek esetében. A szervmegtartó eljárás jobb életminoséget eredményezhet, ugyanakkor a beteget feltétlenül tájékoztatni kell, hogy sikertelenség esetén a radikális mutét is szükségessé válhat. A kezelés sikeres menedzselése csak a társszakmák szoros, jól tervezett együttmuködésével lehetséges. Orv Hetil. 2021; 162(50): 2017-2022. Summary. While radical cystectomy remains the gold standard to treat muscle-invasive or very high risk superficial bladder cancer, well selected patients can be offered split-course multimodal treatment as a similarly effective alternative, combining endoscopic tumor resection and split-course chemoradiotherapy. In highly selected patients, split-course trimodality therapy can lead to survival rates comparable to radical cystectomy with better quality of life outcomes. We present our experience with split-course trimodality treatment used for the very first time in Hungary. Maximal transurethral resection of bladder neoplasm is followed by chemoradiotherapy with repeated bladder biopsy after 45 Gy of irradiation. With negative biopsy results, chemoirradiation should be continued until full dose given. Salvage cystectomy is recommended if viable tumor is detected. Our patient (54), who previously underwent four transurethral bladder tumor resections and local immunotherapy, presented with pT1, high grade urothelial carcinoma recurrence. The well-informed, high performance status patient opted for split-course trimodality treatment. After negative staging scan results, the patient underwent complete endoscopic tumor eradication, followed by chemoradiotherapy. After 45 Gy of irradiation, repeated bladder biopsy was performed. The immediate histopathological examination found no viable tumor, therefore chemoradiotherapy was completed. Follow-up examinations suggest our patient in complete remission. Split-course trimodality treatment can be offered to well-informed and selected patients as a reasonable alternative to radical cystectomy. Though the bladder-sparing approach results in better quality of life, patients must know that in the case of treatment failure, radical cystectomy will likely be offered. Excellent multidisciplinary cooperation is a key to conduct this treatment alternative successfully. Orv Hetil. 2021; 162(50): 2017-2022.

miR-146a modulates TLR1/2 and 4 induced inflammation and links it with proliferation and lipid production via the indirect regulation of GNG7 in human SZ95 sebocytes.

Activation of Toll-like receptors (TLR) 1/2 and 4 are central in inducing inflammation in sebocytes by regulating the expression of protein coding mRNAs, however the microRNA (miRNA) profile in response to TLR activation and thus the possible role of miRNAs in modulating sebocyte functions has not been elucidated. In this work we identified miR-146a to have the highest induction in the TLR1/2 and 4 activated SZ95 sebocytes and found that its increased levels led to the down-regulation of IL-8 secretion, decreased the chemoattractant potential and stimulated the proliferation of sebocytes. Assessing the gene expression profile of SZ95 sebocytes treated with a miR-146a inhibitor, the induction of GNG7 was one of the highest, while when cells were treated with a miR-146a mimic, the expression of GNG7 was down-regulated. These findings correlated with our in situ hybridization results, that compared with control, miR-146a showed an increased, while GNG7 a decreased expression in sebaceous glands of acne samples. Further studies revealed, that when inhibiting the levels of GNG7 in SZ95 sebocytes, cells increased their lipid content and decreased their proliferation. Our findings suggest, that miR-146a could be a potential player in acne pathogenesis by regulating inflammation, inducing proliferation and, through the indirect down-regulation of GNG7, promoting the lipid production of sebocytes.

Epidermal Growth Factor Modulates Palmitic Acid-Induced Inflammatory and Lipid Signaling Pathways in SZ95 Sebocytes.

Epidermal growth factor (EGF) acts as a paracrine and autocrine mediator of cell proliferation and differentiation in various types of epithelial cells, such as sebocytes, which produce the lipid-rich sebum to moisturize the skin. However, sebum lipids via direct contact and by penetrating through the epidermis may have regulatory roles on epidermal and dermal cells as well. As EGF receptor (EGFR) is expressed throughout the proliferating and the lipid-producing layers of sebaceous glands (SGs) in healthy and acne-involved skin, we investigated the effect of EGF on SZ95 sebocytes and how it may alter the changes induced by palmitic acid (PA), a major sebum component with bioactive roles. We found that EGF is not only a potent stimulator of sebocyte proliferation, but also induces the secretion of interleukin (IL)6 and down-regulates the expression of genes involved in steroid and retinoid metabolism. Importantly, when applied in combination with PA, the PA-induced lipid accumulation was decreased and the cells secreted increased IL6 levels. Functional clustering of the differentially regulated genes in SZ95 sebocytes treated with EGF, PA or co-treated with EGF+PA further confirmed that EGF may be a potent inducer of hyperproliferative/inflammatory pathways (IL1 signaling), an effect being more pronounced in the presence of PA. However, while a group of inflammatory genes was up-regulated significantly in EGF+PA co-treated sebocytes, PA treatment in the absence of EGF, regulated genes only related to cell homeostasis. Meta-analysis of the gene expression profiles of whole acne tissue samples and EGF- and EGF+PA -treated SZ95 sebocytes showed that the EGF+PA co-activation of sebocytes may also have implications in disease. Altogether, our results reveal that PA-induced lipid accumulation and inflammation can be modulated by EGF in sebocytes, which also highlights the need for system biological approaches to better understand sebaceous (immuno)biology.

Factor XIII-A in Diseases: Role Beyond Blood Coagulation.

Multidisciplinary research from the last few decades has revealed that Factor XIII subunit A (FXIII-A) is not only involved in blood coagulation, but may have roles in various diseases. Here, we aim to summarize data from studies involving patients with mutations in the F13A1 gene, performed in FXIII-A knock-out mice models, clinical and histological studies assessing correlations between diseases severity and FXIII-A levels, as well as from in vitro experiments. By providing a complex overview on its possible role in wound healing, chronic inflammatory bowel diseases, athe-rosclerosis, rheumatoid arthritis, chronic inflammatory lung diseases, chronic rhinosinusitis, solid tumors, hematological malignancies, and obesity, we also demonstrate how the field evolved from using FXIII-A as a marker to accept and understand its active role in inflammatory and malignant diseases.

Adipokines in the Skin and in Dermatological Diseases.

Adipokines are the primary mediators of adipose tissue-induced and regulated systemic inflammatory diseases; however, recent findings revealed that serum levels of various adipokines correlate also with the onset and the severity of dermatological diseases. Importantly, further data confirmed that the skin serves not only as a target for adipokine signaling, but may serve as a source too. In this review, we aim to provide a complex overview on how adipokines may integrate into the (patho) physiological conditions of the skin by introducing the cell types, such as keratinocytes, fibroblasts, and sebocytes, which are known to produce adipokines as well as the signals that target them. Moreover, we discuss data from in vivo and in vitro murine and human studies as well as genetic data on how adipokines may contribute to various aspects of the homeostasis of the skin, e.g., melanogenesis, hair growth, or wound healing, just as to the pathogenesis of dermatological diseases such as psoriasis, atopic dermatitis, acne, rosacea, and melanoma.

Neutrophil-to-lymphocyte ratio in primary mediastinal germ cell tumors: A retrospective analysis of >20 years single institution experience.

OBJECTIVES: To obtain information on outcome stratified by histology, extent and primary treatment patients' data with primary malignant mediastinal germ cell tumors treated between 1998 and 2018 were retrospectively analyzed. METHODS: The primary treatment for localized malignant mediastinal germ cell tumors was neoadjuvant bleomycin + etoposid + cisplatin (BEP) ± surgery (n = 22); or surgery ± adjuvant BEP (n = 16). For disseminated disease (n = 21) first line BEP ± second line chemotherapy were administered. For nonseminomas (NS) the NLR at start of BEP was analyzed in relation to disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS). RESULTS: After neoadjuvant treatment the 5-year DFS was 100% for seminomas (S), and 63.4% for NS. The 5-year OS was 100% for S, and 76.9% for NS. The 5-year DFS and OS after surgery ± BEP for S was 72.9% and 100%, for NS was 75% and 87.5%, respectively. The 5-year PFS and OS of metastatic patients for S was 60% and 80%, while the median PFS and OS of NS were 5.7 and 11.1 months, respectively. Objective response (P = 0.006) and low NLR (P = 0.043) were independent prognostic markers of longer OS. CONCLUSIONS: We confirmed the good outcome of BEP-treated S, while NS had poorer prognosis. Previously published prognostic models for NS were validated. Based on NLR and response a new prognostic model was developed.