TRPS1 expression in breast angiosarcoma.

Angiosarcoma (AS) of the breast, a rare mesenchymal neoplasm, exhibits distinct forms based on etiological and genetic features. While cases with typical clinical presentation and morphology allow for a straightforward diagnosis, challenges arise when clinical data are scarce, diagnostic material is limited, or morphological characteristics overlap with other tumors, including undifferentiated carcinomas. The trichorhinophalangeal syndrome protein 1 (TRPS1), once regarded as highly specific for breast carcinomas, now faces doubts regarding its reliability. This study explores TRPS1 expression in breast AS. Our investigation revealed that 60% of AS cases displayed TRPS1 labeling, contrasting with the 40% lacking expression. Scoring by four independent readers established a consensus, designating 12/35 ASs as unequivocally TRPS1-positive. However, uncertainty surrounded nine further cases due to a lack of reader agreement (being substantial as reflected by a kappa value of 0.76). These findings challenge the perceived specificity of TRPS1, shedding light on its presence in a noteworthy proportion of breast ASs. Consequently, the study underscores the importance of a comprehensive approach in evaluating breast ASs and expands the range of entities within the differential diagnosis associated with TRPS1 labeling.

Diagnostic value of [99mTc]Tc-PSMA-I&S-SPECT/CT for the primary staging and restaging of prostate cancer.

Background: A large number of studies have proved that prostate-specific membrane antigen-positron emission tomography/computer tomography (PSMA-PET/CT) provides excellent accuracy in primary staging and restaging of prostate cancer. Less data exist with PSMA-single photon emission computed tomography (SPECT)/CT investigations. Objective: The aim of this study was to evaluate the performance of [99mTc]Tc-PSMA-I&S (for imaging and surgery) in prostate cancer. Design and methods: We retrospectively analysed PSMA-SPECT/CT scans of 20 healthy volunteers and 100 male patients with prostate cancer. All of them had histologically confirmed prostate cancer. In all, 28 patients were examined for primary staging and 72 for biochemical recurrence or progressive disease. Whole body SPECT/CT imaging was carried out 6 h after the intravenous administration of 666 ± 102 MBq [99mTc]Tc-PSMA-I&S. Images were evaluated visually and semi-quantitatively. Results: Patient-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy for primary prostate cancer were 86%, 100%, 100%, 83% and 92%, respectively. For detecting metastases in primary staging, these values were 88%, 100%, 100%, 85% and 93%, respectively. The radiopharmaceutical uptake of primary prostate cancer was significantly higher than in normal prostate. The patient-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the method in the visualization of local recurrence were 67%, 100%, 100%, 86% and 89%, and for detecting metastases in restaging were 91%, 92%, 98%, 75% and 91%, respectively. In restaging, detection rates were 37% under prostate-specific antigen level of 1 ng/mL, 74% between 1 and 5 ng/mL and 80% >5 ng/mL. Conclusion: [99mTc]Tc-PSMA-I&S-SPECT/CT can be easily integrated into the routine diagnostic practice, and it provides usable data in primary staging and restaging of prostate cancer. Quantitative assessment of PSMA-SPECT/CT has the potential to be used to differentiate between physiological and pathological intraprostatic tracer uptake.

Survival Benefit of Stereotactic Radiotherapy in the Complex Management of Metastatic Melanoma.

BACKGROUND/AIM: Targeted therapy and immunotherapy, with additional stereotactic radiation therapy (SRT) have revolutionized the management of metastatic malignant melanoma (mMM). We aimed to analyze the effectiveness and safety of SRT and determine its role in the complex management of mMM. PATIENTS AND METHODS: We treated 24 patients with solitary metastasis, 15 with oligometastatic disease and one with multiple metastases. The primary endpoint was to investigate the possible effect of stereotactic radiotherapy for metastatic lesions on patients' survival taking the systemic therapy into consideration. RESULTS: The median overall survival (OS) for the entire group was 30.07 months; 50% of them received immunotherapy, 32% received targeted therapy. Complete remission of the irradiated lesions was observed in six patients, partial tumor response was achieved in 13, while stable disease was detected in 10; tumor progression occurred in four cases. Compartmental recurrence (recurrence in the brain in a not previously irradiated region) developed in seven patients. OS was significantly longer in those with extracranial metastases treated with stereotactic body radiotherapy in comparison to brain SRT. We found a strong correlation between tumor response and mean OS (42.5 months after complete or partial remission versus 11.8 months in those with stable or progressive disease). No OS difference was observed according to the number of irradiated lesions or type of systemic therapy before SRT (no therapy: 43.6 months, with therapy: 25.7 months). Significant OS advantage was shown when immunotherapy was administered post-SRT (mean OS: with immunotherapy: 39.6 months, no immunotherapy: 18.5 months). CONCLUSION: In the case of oligometastatic MM, SRT can be used safely and with good efficiency in addition to targeted therapy/anti-programmed cell death protein 1 therapy. Improved survival warrants including SRT in the complex management of mMM, however, further studies are needed for SRT optimization.

[Morphological variants of the invasive urothelial cell carcinoma.] / Az invazív urothelsejtes carcinoma morfológiai variánsai.

Urothelial cell carcinoma is the most common malignant tumor of the urinary tract, which develops in the renal pelvis, ureter, and bladder, and rarely it develops in the ureter. Histologically, urothelial cell carcinoma is categorized into non-invasive and invasive forms. Non-invasive urothelial cell carcinoma has papillary growth, it is usually well differentiated, and has a favorable outcome, while invasive urothelial cell carcinoma infiltratively spreads the organs of origin, it is typically poorly differentiated, and often associated with a poor prognosis. In the case of invasive urothelial cell carcinoma, the clinical course is primarily determined by the depth of invasion, but according to recent data, morphological variants of urothelial cell carcinoma respond differently to oncological treatments, and their biological behavior is also distinct. These subtypes and variants are significantly underdiagnosed in Hungary and internationally because the criteria for histological diagnosis are not clear for many subsets. The latest 2022 WHO classification of urinary tract tumors significantly clarified the definitions of various subtypes and variants. In this paper, utilizing the current classification, we review and explain these subtypes' morphological, immunohistochemical, differential diagnostic, prognostic, and predictive characteristics intending to make them appear as much as possible in everyday diagnostic practice. Also, the work aims to present the individual urothelial cell carcinoma subtypes and variants to the Hungarian community of pathologists, oncologists, and urologists, so that the previously high level of urological oncology care can become even more personalized. Orv Hetil. 2023; 164(40): 1567-1582.

Prostate-specific membrane antigen-based imaging for stereotactic irradiation of low-volume progressive prostate cancer: a single-center experience.

Introduction: Prostate-specific membrane antigen (PSMA) is a transmembrane protein that may be expressed on the surface of prostate cancer (PC) cells. It enables a more sensitive and specific diagnosis PC, compared to conventional anatomical imaging. Aim: The integration of PSMA-based imaging in the personalized radiotherapy of PC patients and the evaluation of its impact on target volume definition if stereotactic body radiotherapy (SBRT) is planned for locally recurrent or oligometastatic disease. Patients and methods: The data from 363 examinations were analyzed retrospectively. Inclusion criteria were histologically verified PC and clinical data suggesting local recurrence or distant metastasis. Whole-body 99mTc-PSMA-I&S single-photon emission computed tomography (SPECT)/CT or 18F-JK-PSMA-7 positron emission tomography/computer tomography (PET/CT) was carried out, and the evaluation of the scans and biological tumor volume contouring was performed at the Department of Nuclear Medicine. The target volume delineation on topometric CT (TCT) scan was performed at the Department of Oncotherapy. The comparison of the two volumes was performed by image fusion and registration. Results: From 363 PSMA isotope-based examinations, 84 lesions of 64 patients were treated with SBRT. In 50 patients, 70 lesions were examined for intermodality comparison. The target volume defined by the PSMA density was significantly smaller than the tumor size defined by the TCT scan: GTVCT (gross tumor volume on the TCT), 27.58 ± 46.07 cm3; BTVPSMA (biological target volume on the PSMA-based examination), 16.14 ± 29.87 cm3. During geometrical analyses, the Dice similarity coefficient (DSC) was 0.56 ± 0.20 (0.07-0.85). Prostate-specific antigen (PSA) control was performed to evaluate the response: mean pre-radiotherapy (pre-RT) PSA was 16.98 ng/ml ( ± SD: 33.81), and post-RT PSA at 3 months after SBRT was 11.19 ng/ml ( ± SD: 32.85). Three-month post-therapy PSMA-based imaging was performed in 14 cases, in which we observed a decrease or cessation of isotope uptake. Conventional imaging control was performed in 42 cases (65.6% of all cases): 22 (52.4%) complete remissions, 14 (33.3%) partial remissions, four (9.5%) stable diseases, and two (4.8%) progressive diseases were described. Conclusion: PSMA-based imaging is a promising diagnostic method for specifying the stage and detecting the low-volume progression. Our results suggest that PSMA-based hybrid imaging can influence treatment decisions and target volume delineation for SBRT.

Correlation between fibroblast growth factor receptor mutation, programmed death ligand-1 expression and survival in urinary bladder cancer based on real-world data.

Background: Programmed cell death (PD)-1/PD-ligand 1 (PD-L1) inhibitors have made a breakthrough in the therapy of advanced urothelial bladder cancer (UBC). The impact of Fibroblast Growth Factor Receptor 3 (FGFR3) mutation on the effectiveness of PD-L1 treatment remains still unclear. Objective: Our study aimed to investigate the frequency of FGFR mutations at different tumor stages, and their relation to PD-L1 status and survival. Methods: 310 patients with urothelial bladder cancer and subsequent radical cystectomy were included in a retrospective study over a 10-year study period at the University of Szeged, Hungary. FGFR3 mutations from the most infiltrative areas of the tumor were analyzed by targeted next-generation sequencing and PD-L1 (28-8 DAKO) tests (tumor positive score -TPS and combined positives score-CPS). In T0 cases FGFR3 mutations were analyzed from the earlier resection samples. Survival and oncological treatment data were collected from the National Health Insurance Fund (NHIF). Neoadjuvant, adjuvant and palliative conventional chemotherapies were allowed; immunotherapies were not. The relationship between the covariates was tested using chi-square tests, and survival analysis was performed using the Kaplan-Meier model and Cox proportional hazards regression. Results: PD-L1 and FGFR could be tested successfully in 215 of the 310 UBC samples [pT0cyst 19 (8.8%); St.0-I 43 (20%); St.II 41 (19%); St.III-IV 112 (52%)]. Significant pairwise dependency was found between tumor stage, FGFR3 mutation status and PD-L1 expression (p < 0.01). Samples with FGFR mutation were more common in less advanced stages and were also less likely to demonstrate PD-L1 expression. The effect of all investigated factors on survival was found to correlate with tumor stage. Conclusion: FGFR alteration frequency varied between the different stages of cancer. Higher positivity rates were observed at early stages, but lower levels of PD-L1 expression were detected in patients with FGFR mutations across at all stages of the disease.

Angiomyolipoma of the kidney-Clinicopathological analysis of 52 cases.

The renal angiomyolipoma (AML) is a benign tumor characteristically composed of fat, smooth muscle tissue, and vessels. We collected AMLs from our nephrectomy database, reclassified them according to their histological appearance, recorded the demographic, clinical, and pathological parameters, and compared them with oncocytoma (RO) and renal cell carcinoma (RCC). Immunohistochemistry was ordered in 41 cases. In 2224 nephrectomies, we found 52 AMLs with a 53 mm median size. The mean age was 52.76. Forty-eight tumors were sporadic, while four were hereditary. The revision resulted in 31 classic, 13 leiomyoma-like, five lipoma-like, two epithelioid, and one AML with epithelial cysts. SMA was diffusely positive, except for the epithelioid type, while MelanA harbored stronger expression than HMB45. AML was more frequent in females and appeared ten and 7 years earlier than RO and RCC, respectively. The follow-up time was 7.42 years, and neither tumor-related death nor relapse occurred. AML is rare in nephrectomies and develops primarily in females in their 50s with an average size of 50-60 mm at the surgery. The histological appearance in order of frequency is classic, leiomyoma-like, lipoma-like, epithelioid, and cystic. The MelanA, HMB45, and SMA immunohistochemistry can support the light-microscopic findings.

[New aspects of chemotherapy and indications for maintenance immunotherapy in urothelial cancers]. / A kemoterápia szerepének megújulása és a fenntartó immunterápia indikációi uroteliális daganatokban.

Chemotherapy for the treatment of urothelial and bladder cancers has focused on renewed indications in light of clinical trials of modern therapies, which are described in our review. In stage T2-T4a N0-1 M0 cases, that are suitable for cisplatin, surgery is performed after neoadjuvant cisplatin- based chemotherapy. Less significant result is observed with adjuvant chemotherapy, especially in pT3-4 and/or N+ stage, if no neoadjuvant chemotherapy was administered. Cisplatin-based chemotherapy is the first-line treatment of cisplatin-eligible metastatic patients. First-line choice in chemo-fit cases with cisplatin ineligibility can be carboplatin- based chemotherapy. 4-6 cycles of cisplatin or carboplatin cause stable disease or regression, maintenance avelumab immunotherapy improves patient's survival. For those patients who progress during or after platinum-based chemotherapy, the effectiveness of chemotherapy in the second/multiple lines is less favourable in comparison with immunotherapy and targeted therapy. Modern antibody - cytotoxic drug conjugates have been discovered in the form of enfortumab vedotin and sacituzumab govitecan, and currently they seem to be effective in the third line after chemotherapy and immunotherapy.

[Therapeutic sequences in the treatment of advanced/metastatic prostate cancer]. / Terápiás szekvenciák az elorehaladott/ áttétes prosztatadaganatok gyógyszeres kezelésében.

The unprecedented development of prostate cancer therapy is a challenge for the proper sequential use of modern medicines. Patients' life expectancies improve when we use treatment lines, one after the other. There is no evidence- based guideline regarding the optimal sequence, but a number of data are available to help the physician selecting the best individualized therapeutic option. The basic treatment for advanced prostate cancer is still androgenic deprivation (ADT), to which we can add additional therapeutic agents. New types of hormonal (androgen receptor targeted, ARTA) agents are being used in an increasingly early line. Chemotherapy (CT) is the first choice in case of metastatic, hormone-sensitive disease especially in high volume cases that are causing symptoms or visceral crisis. CT is otherwise applied after ARTA. We have little but encouraging data about the early, sequential use of ARTAs with different mechanisms of action. In later lines, cross-resistance may develop between ARTA treatments, in which cases CT is the right decision. In this paper, we summarize the results of clinical trials that may help in therapeutic decision making, maximizing the benefits for patients.

[Opportunities that improve the effectivity of immunotherapy, bringing targeted therapies into focus]. / Az immunkezelés eredményességét javító lehetõségek, fókuszban a célzott terápiák.

Immunotherapy is getting more and more successful therapeutic option in case of many cancer types. Despite the clinical effectiveness of checkpoint inhibitor antibodies, long-lasting advantages can only be seen in a part of the patients, which makes necessary to examine immunotherapy more thoroughly. Immunity is influenced by the tumor, its microenvironment, and patient's characteristic and environmental factors. These elements control the strength and duration of antitumor response. Immunotherapeutic response may be more significant and may even last for years in case of hot tumors, while in most of the cases immunotherapy is not so effective in poorly immunogenic cold tumors. Combined therapies potentially increase efficiency. In our article T-cell activation phases of antitumor immune response, possible defects, their consequences and the potentially effective therapeutic opportunities are summarized shortly. Combined immunotherapy is a novel, promising possibility for modern oncology.

ERG expression can predict the outcome of docetaxel combinedwith androgen deprivation therapy in metastatic hormone-sensitiveprostate cancer.

BACKGROUND: Our study aimed to analyze the potential association between clinical parameters and ERG expression and the outcome of docetaxel chemotherapy among patients with metastatic hormone-sensitive prostate cancer. PATIENTS AND METHODS: Fifty-five patients with metastatic hormone-sensitive prostate cancer were treated with docetaxel in addition to androgen deprivation therapy. Patient characteristics, clinical factors, and tumor expression of ERG by immunohistochemistry were analyzed with respect to therapeutic response and survival data. RESULTS: Relapse free survival (RFS) and overal survival (OS) were 10.5 and 40.4 months, respectively, and both correlated with PSA response (RFS: 16.8 with a ≥50% decrease in PSA vs. 5.9 months in the case of <50% decrease, P < 0.001; OS: 40.4 vs. 11.6 months, respectively, P < 0.001). There was an association between OS and early progression (OS: 40.4 months with progression after 12 months vs. 17.9 months with progression within 12 months, P = 0.009). ERG expression was detected in 21 (42%) samples. ERG positivity was associated with favorable RFS (ERG pos. vs. neg.: 26.0 vs. 11.4 months, P = 0.003). CONCLUSION: ERG expression may have a potential predictive value with respect to the effectiveness and outcome of docetaxel chemotherapy combined with androgen deprivation therapy.

Prone Positioning on a Belly Board Decreases Rectal and Bowel Doses in Pelvic Intensity-Modulated Radiation Therapy (IMRT) for Prostate Cancer.

The presence of normal tissues in the irradiated volume limits dose escalation during pelvic radiotherapy (RT) for prostate cancer. Supine and prone positions on a belly board were compared by analyzing the exposure of organs at risk (OARs) using intensity modulated RT (IMRT). The prospective trial included 55 high risk, localized or locally advanced prostate cancer patients, receiving definitive image-guided RT. Computed tomography scanning for irradiation planning was carried out in both positions. Gross tumor volume, clinical and planning target volumes (PTV) and OARs were delineated, defining subprostatic and periprostatic rectal subsegments. At the height of the largest antero-posterior (AP) diameter of the prostate, rectal diameters and distance from the posterior prostate wall were measured. IMRT plans were generated. Normal tissue exposure and structure volumes were compared between supine and prone plans using paired t-test. In the volumes of the prostate, PTV, colon and small bowel, no significant differences were found. In prone position, all rectal volumes, diameters, and rectum-prostate distance were significantly higher, the irradiated colon and small bowel volume was lower in dose ranges of 20-40 Gy, and the exposure to all rectal segments was more favorable in 40-75 Gy dose ranges. No significant difference was found in the exposure of other OARs. Prone positioning on a belly board is an appropriate positioning method aiming rectum and bowel protection during pelvic IMRT of prostate cancer. The relative reduction in rectal exposure might be a consequence of the slight departure between the prostate and rectal wall.

[Edifications and modern strategies of localized prostate cancers' definitive therapy]. / Prosztatarákban szenvedo betegek definitív ellátásának tanulságai és modern stratégiái.

INTRODUCTION: Mortality of prostate carcinoma can be significantly decreased by the use of modern diagnostic and therapeutic options. Patients in early stages can be cured by radical surgery or radiotherapy. AIM: Overview and comparison of previous and present diagnostic and therapeutic methods regarding accuracy of diagnosis, improvement of efficiency and decrease of toxicities. We also aimed to explore general correlations in case of serious complications. METHOD: By the help of two prostate cancer patients we demonstrate the importance of accuracy and change of histological diagnosis, significance of proper imaging techniques, and also show parameters of conventional and modern radiotherapy and their acute and chronic complications. Differences of previous and present methods and their consequences were analyzed. RESULTS: By now, histological findings in the patients' diagnosis have changed. Both patients received conventional three-dimensional definitive radiotherapy in 2009-2011, and their prostate cancer was cured. In one case, urinary bladder also received radiotherapy because prostate carcinoma had infiltrated it. In the other case, the contemporary radiotherapy involved urinary bladder's fundus due to safety margins. Although acute grade 2 cystitis developed in both cases and recovered in several weeks, as late complication bladder shrinkage developed, which after the ineffectiveness of conventional therapies had to be cured by radical cystoprostatectomy - in order to cease bleeding and to cure incontinence. CONCLUSIONS: In case of prostate carcinomas, serious complications can be avoided by the improvement of diagnostic and therapeutic options. Synthesis of data could be more successful if they were analyzed in the light of previous experiences. Orv Hetil. 2018; 159(32): 1317-1325.

The Colorful Palette of Neuroendocrine Neoplasms in the Genitourinary Tract.

BACKGROUND: Neuroendocrine neoplasms include a heterogeneous group of malignant tumors. Primary neuroendocrine tumors in the genitourinary tract are rare, comprising approximately 1-2% of genitourinary malignancies. MATERIALS AND METHODS: An extensive search was performed for publications between 2000 and 2018 regarding neuroendocrine tumors of the genitourinary tract. Epidemiological, clinical, histopathological, prognostic and therapeutic data were evaluated. RESULTS: Neuroendocrine tumors of the kidneys are exceedingly rare, mostly well-differentiated. 0.5-1% of all primary bladder malignancies are small cell neuroendocrine carcinomas. Characteristically, prostatic adenocarcinoma with neuroendocrine differentiation occurs in androgen receptor-independent/castrate-resistant cancer. Small cell and large cell neuroendocrine carcinomas are the most aggressive tumors in each location. CONCLUSION: Due to the rarity and poor prognosis of these tumors, proper pathological diagnosis and early therapy are important. Therapeutic guidelines are not available. Surgery, radiotherapy and/or chemotherapy are possible treatment options; somatostatin analogs are used as standard therapy in case of well-differentiated neuroendocrine tumors.

Daily Setup Accuracy, Side-effects and Quality of Life During and After Prone Positioned Prostate Radiotherapy.

BACKGROUND/AIM: Exposure of organs at risk with prostate radiotherapy (RT) is lower in the prone position. This study is a prospective evaluation of setup accuracy, side-effects, and quality of life (QOL) during and after prone positioned RT. PATIENTS AND METHODS: Image-guided (IG) intensity-modulated (IM) RT was administered in prone position on belly-board to 55 high-risk prostate cancer (PC) patients. Rectum diameters were measured in two areas of the symphysis at the beginning of RT and during it. Side-effects, QOL, and prostate specific symptoms (PSS) were evaluated. RESULTS: Setup accuracy was similar to that reported in the literature. In the upper area of symphysis rectal diameters were significantly changed during treatment, but in the prostate region, no difference was detected. No change was detected in patients' QOL and PSS during treatment, but after RT, they improved. CONCLUSION: Prone positioned IG-IMRT is feasible with tolerable side-effects for high-risk PC patients. Changes in QOL and PSS are insignificant during RT, while improvement after RT suggests a rapid recovery.

Dose escalation can maximize therapeutic potential of sunitinib in patients with metastatic renal cell carcinoma.

BACKGROUND: In patients with metastatic renal cell cancer, based on limited evidence, increased sunitinib exposure is associated with better outcome. The survival and toxicity data of patients receiving individualized dose escalated sunitinib therapy as compared to standard management were analyzed in this study. METHODS: From July 2013, the data of metastatic renal cell cancer patients with slight progression but still a stable disease according to RECIST 1.1 criteria treated with an escalated dose of sunitinib (first level: 62.5 mg/day in 4/2 or 2 × 2/1 scheme, second level: 75 mg/day in 4/2 or 2 × 2/1 scheme) were collected prospectively. Regarding characteristics, outcome, and toxicity data, an explorative retrospective analysis of the register was carried out, comparing treatments after and before July 1, 2013 in the study (selected patients for escalated dose) and control (standard dose) groups, respectively. RESULTS: The study involved 103 patients receiving sunitinib therapy with a median overall and progression free survival of 25.36 ± 2.62 and 14.2 ± 3.22 months, respectively. Slight progression was detected in 48.5% of them. First and second-level dose escalation were indicated in 18.2% and 4.1% of patients, respectively. The dosing scheme was modified in 22.2%. The median progression free survival (39.7 ± 5.1 vs 14.2 ± 1.3 months (p = 0.037)) and the overall survival (57.5 ± 10.7 vs 27.9 ± 2.5 months (p = 0.044)) were significantly better in the study group (with dose escalation) than in the control group. Patients with nephrectomy and lower Memorial Sloan Kettering Cancer Center (MSKCC) scores showed more favorable outcomes. After dose escalation, the most common adverse events were worsening or development of fatigue, hypertension, stomatitis, and weight loss of over 10%. CONCLUSIONS: Escalation of sunitinib dosing in selected patients with metastatic renal cell cancer, especially in case of slight progression, based on tolerable toxicity is safe and improves outcome. Dose escalation in 12.5 mg steps may be recommended for properly educated patients.