Pathology & Oncology Research最新文献

Kaposi's sarcoma (KS) is a vascular intermediate malignant tumor classified into four clinical types: classic, AIDS-related, iatrogenic, and endemic. Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of KS. Six KSHV genotypes (A, B, C, D, E, and F) classified by K1 or two genotypes (P and M) by K15 have been reported. However, whether the KSHV genotype affects clinical presentation remains elusive. Herein, we investigated the association between viral genotypes and clinical presentations in patients with KS in Okinawa, an endemic area in Japan. Classic KS caused by KSHV genotype C was identified as the most common clinical type of KS in Okinawa. Conversely, 80% of the patients with AIDS-related KS were associated with genotype A. According to K15 genotyping, the population of genotype M was higher than that of genotype P. Although genotype M accounted for most cases of both classic and iatrogenic KS in Okinawa, genotype P constituted the majority of AIDS-related KS. Regarding the association between the K1 and K15 genotypes, single genotype A was associated with genotype P, whereas single genotype C was associated with genotype M. These K1 and K15 associations in Okinawa differed from those in Europe and Africa. In terms of the association between viral genotype and clinical types, A/P tended to be associated with AIDS-related KS and genotype C/M tended to be associated with classic KS. The findings of the current study suggest that the KSHV genotype in Okinawa differs from that in other countries, which is related to the KSHV geographic distribution and population migration. Our data also suggest that the viral genotype in Okinawa is associated with clinical presentations.

Introduction: Several novel morphological variants of inflammatory bowel disease (IBD)- associated dysplasias have been described in recent years. The objective of our study was to reevaluate some of our IBD-associated neoplasia cases and retrospectively identify the so-called non-conventional dysplasias (NCDs).

Methods: We established a database of IBD patients registered between 2011 and 2015 at the Department of Pathology, University of Szeged. Patients with neoplastic samples were extracted into a separate database. Clinical and pathological characteristics were documented for each case. Histological slides were retrospectively reviewed, and cases were reclassified.

Results: During the study period, 57 patients had neoplastic samples, and 47 patients were identified with conventional dysplasias (82.5%). A significant association was found between conventional dysplasias and dysplasia localization (P = 0.004), size (P = 0.012), endoscopic appearance (P = 0.006), grade (P = 0.011), macroscopic appearance of colorectal carcinoma (P = 0.009), and pT stage (P = 0.01). NCD was identified in 20 cases (35.1%). The most frequently observed subtype was serrated not otherwise specified (NOS) dysplasia (n = 6; 30%). Significant associations were detected between the development of NCD and several clinical-pathological features, including the occurrence (P < 0.001), localization (P = 0.001), size (P = 0.002), macroscopic appearance (P = 0.01), grade (P = 0.005), histological subtype (P = 0.003), pT (P = 0.003) and pM stage (P = 0.047) of colorectal carcinoma, as well as microsatellite status (P < 0.001).

Discussion: The identification of IBD-associated NCDs might play a crucial role in future clinical practice. Some authors suggest closer patient follow-up upon identification of these lesions and recommend random biopsy sampling in IBD patients to detect potentially occult lesions. Further studies involving larger national and international patient cohorts are warranted to gain a more comprehensive understanding of the clinical behavior of NCDs.

Background: Autosomal dominant genodermatoses with a predisposition for cancer make up a well-described disease group with unique cutaneous alterations in each. This should urge dermatologists to think of other consequences beyond the skin. Histological examination serves as the gold standard, and it is an effective tool for the first investigation, even nowadays in the "next-generation genetic" era. Multiple appearances of benign tumours histologically proved to be cutaneous leiomyomatosis suggest a rare disorder with germline heterozygous pathogen variant in the FH gene. The encoded fumarate hydratase is a Krebs cycle enzyme, and has a role in catalysing the transition from fumarate to malate.

Case presentation: Years before the easy accessibility of the complete genetic workup in Hungary, a yearly abdominal MRI check-up was suggested preventively for a middle-aged man with multiplex cutaneous leiomyomata. During the follow-up period papillary type 2 renal cell carcinoma was diagnosed in the left kidney at an early stage, and a successful operation saved his life without the need for aggressive chemotherapy or immunotherapy. Immunohistochemistry of tumour tissue proved FH-deficient renal cell cancer. We discuss in short the current knowledge of pathophysiology and accessible therapies regarding this aggressive malignant tumour type in the kidney, which is usually detected in the advanced stage with early metastasis. We also highlight an early sign, i.e., solitary cystic alteration in the kidney, which can be preliminarily observed before malignant transformation, which was also described in mouse models. Sanger sequencing and Multiplex-Ligation-Dependent Probe Amplification (MLPA) analysis of the FH gene was completed in the affected son of the original proband, and Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) was confirmed by demonstrating a large germline deletion in this family after years of observation.

Conclusion: Regular observation of individuals with hereditary leiomyomatosis may prevent a serious sequelae of untreatable renal malignancy.

Photobleaching of immunofluorescence signal is a well-known phenomenon, however, its impact on derived parameters characterizing number and shape of different cell types in tissue sections is less understood. Our aim was to determine whether the duration of illumination and the type of fluorophore (Alexa Fluor 546 (A546), and Alexa Fluor 488 Plus (A488)) can influence the acquired morphometric parameters of cells in the nervous system. Immunofluorescent staining of microglia and neurons was performed on mouse spinal cord sections. Mean color intensity in a field of view, number of detectable neuronal cell profiles, partial coverage of microglial profiles, and fractal geometrical parameters were determined. All measurements were made using epifluorescence microscopy with identical acquisition parameters. Most of the measured parameters suffered significant alternation after 30-60 s of illumination. The data-altering effect of photobleaching was most prominent in the case of mean fluorescent intensity. Thus, while immunofluorescent staining is useful for co-localizing different groups of cells, cell-specific quantitative morphological measurements require photostable staining. Possibility of the combination of these methods on the same section in order to achieve multi-channel localization without photobleaching is exemplified.

Pazopanib is a tyrosine-kinase inhibitor also used for the treatment of advanced soft tissue sarcomas. Our retrospective study analyzed real-world data of stage 4 sarcoma patients treated with pazopanib in our department in the past 10 years. Data were collected from the Medworks medical system, which is used for daily work in our center. A total of 99 patients were included: 46 men and 53 women The median age at the diagnosis was 49.8 years. The most common histological subtypes were leiomyosarcoma and synovial sarcoma. All patients received 800 mg of pazopanib per day, which was reduced to 400 mg in the event of toxicity. Treatment was continued until disease progression or unmanageable toxicity. The primary endpoint of the study was progression-free survival and the secondary endpoints were overall survival, overall response rate and disease control rate. The results in relation to demographic data, previous treatments, localizations of primary tumors and metastasis and histological subtypes were analyzed. In our center pazopanib was most frequently used in the third line. In total, 61 patients received perioperative therapy; the most common regimen used in the metastatic setting was VIP. Median PFS and OS were 3 months and 7 months, respectively. ORR was 14% and DCR was 40.45%. Dose reductions were necessary during the treatment of 56 patients. Hematological toxicity was detected in 23% of cases, with the most frequent events being grade 1 thrombocytopenia and grade 2 leukocytopenia. Non-hematological adverse events were documented in half of the patients. Pazopanib was more effective in earlier lines of treatment. Compared to the PALETTE phase 3 trial more patients received perioperative therapy, median PFS and OS were shorter (3 months vs. 4.6 months and 7 months vs. 11.9 months) and ORR was higher (14% vs. 9%) in our patient population. Dose reductions were more frequent in our center. Pazopanib is a therapeutic option for the treatment of advanced soft tissue sarcoma, also according to real-world data. Further investigations are needed to select patients who can benefit the most from pazopanib and to determine the most appropriate sequence of therapy.

The randomized controlled pivotal phase 3 study evaluated efficacy and safety of neoadjuvant complex biologic, Leukocyte Interleukin Injection (LI), administered for 3 consecutive weeks pre-surgery, in treatment naïve resectable locally advanced primary squamous cell carcinoma of oral cavity and soft palate. Randomization 3:1:3 to LI+/-CIZ (cyclophosphamide, indomethacin, and zinc)+SOC, or SOC (standard of care) alone. LI-treated patients received 400 IU (as interleukin-2 equivalent; 200 IU peritumorally, 200 IU perilymphatically) sequentially, daily 5 days/week for 3 weeks before surgery. All subjects were to receive SOC. Post-surgery, patients with low risk for recurrence were to receive radiotherapy, while those with high risk received concurrent chemoradiotherapy. Median follow-up was 56 months. There were 923 ITT (Intent-to-Treat) subjects (380 ITT low-risk and 467 ITT high-risk). Pre-surgery objective early response (45 objective early responders; 5 complete responses [CRs], 40 partial responses [PRs], confirmed by pathology at surgery. LI (+/- CIZ) had 8.5% objective early responders (45/529 ITT) and 16% objective early responders (34/212 ITT low-risk) vs. no reported SOC objective early responders (0/394 ITT). Objective early responders significantly lowered death rate to 22.2% (ITT LI-treated), 12.5% (ITT low-risk LI + CIZ + SOC), while the ITT low-risk SOC death rate was 48.7%. Thus, objective early response impacted overall survival (OS); proportional hazard ratios were 0.348 (95% CI: 0.152-0.801) for ITT low-risk LI-treated, 0.246 (95% CI: 0.077-0.787) for ITT low-risk LI + CIZ + SOC. ITT low-risk LI + CIZ + SOC demonstrated significant OS advantage vs. ITT low-risk SOC (unstratified log-rank p = 0.048; Cox hazard ratio = 0.68; 95% CI: 0.48-0.95, Wald p = 0.024 [controlling for tumor stage, tumor location, and geographic region]). Absolute OS advantage increased over time for ITT low-risk (LI + CIZ + SOC)-treated vs. ITT low-risk SOC: reaching 14.1% (62.7% vs. 48.6%) at 60 months, with 46.5 months median OS advantage (101.7 months vs. 55.2 months), respectively. Quality of life benefit for complete responders sustained for >3 years post LI treatment. Percent treatment-emergent adverse events were comparable among all treated groups. No excess safety issues were reported for LI over SOC alone post-surgery. NCT01265849, EUDRA:2010-019952-35.

Introduction: Immunotherapy has made a significant improvement in the treatment of patients with non-small cell lung cancer (NSCLC). It has a role in boosting the immune system, so it can fight cancer cells. Sometimes, this mechanism can lead to an overstimulation or misdirection of immune response, so it can act against the body itself. One of the organs most affected by this reaction is the thyroid gland, and there is no definitive explanation of the causes of this adverse event.

Material and methods: In this retrospective observational study, we enrolled 103 patients with NSCLC and high PD-L1 expression (>= 50%) who were treated in our Clinic for pulmonology, University Clinical Center of Serbia, using Pembrolizumab as the first-line therapy.

Results: Data analysis showed that 41 (39.81%) of 103 patients in our study had an adverse event of immunotherapy, and 21 of them had autoimmune thyroiditis (20.39%). Of all the patients, 19 of them were treated for chronic obstructive pulmonary disease (COPD) before the onset of Pembrolizumab. During treatment, eight of these patients developed thyroid dysfunction. Patients with COPD were at increased risk of developing autoimmune thyroiditis compared to non-COPD patients (OR 3.9 95% CI 1.135-13.260, p = 0.0227).

Conclusion: Our study showed that patients dealing with COPD have a 3.9 times greater risk of developing autoimmune thyroiditis as an adverse event during Pembrolizumab treatment compared with patients without COPD.

Comprehensive genomic profiling (CGP) is becoming an increasingly important tool in the clinical management of different tumours, but there is still very limited data available on its usefulness from a therapeutic point of view in mesenchymal tumours. Between January 2022 and September 2024, we performed CGP analysis with means of Oncomine Comprehensive Assay Plus (OCAplus) on 94 malignant mesenchymal tumours. The analysis covered more than 500 unique genes for single-gene and multigene biomarker insights, including tumour mutational burden (TMB) and homologous recombination deficiency (HRD). Genomic DNA and total RNA were extracted from formalin-fixed paraffin-embedded tissue blocks. Twenty-four out of 94 patients (25.5%) had potentially actionable alterations: 17 (18%) had specific genetic alterations suitable for targeted therapies, 4 (4.2%) had a high TMB (>10 mut/Mb), and 5 (5.3%) had a high HRD score >15). One additional patient had BRCA1 mutation, but the HRD score was low. Three patients received targeted therapy: one patient with a CDK4-amplified tumour (dedifferentiated liposarcoma) received CDK4 inhibitor therapy, two patients with angiosarcoma showing high TMB received immune checkpoint inhibitor therapy, and one patient with a uterine leiomyosarcoma and high HRD score received PARP inhibitor therapy. In addition, two patients with malignant phyllodes tumours received multi-thyrosine kinase inhibitor therapy. In three cases, there was refinement or reassignment of the diagnosis, based on the CGP findings. Our results demonstrate that CGP can provide useful additional information and can be beneficial in the clinical management of patients with mesenchymal tumours.

Sarcomas with an EWSR1::POU2AF3(COLCA2) fusion are a very recently described entity of preferentially sinonasal origin and with undifferentiated round/spindle cell morphology. We established a novel cell line (PF1095) carrying a EWSR1::POU2AF3 fusion from the malignant pleural effusion of a 25-year-old sarcoma patient. The patient was first diagnosed with poorly differentiated neuroendocrine carcinoma based on tumor cell morphology and positivity to markers such as EMA, synaptophysin, and CD56. Later, the EWSR1 translocation was identified in the tumor cells with unknown partners and the patient received chemotherapy according to the Ewing 2008 protocol in combination with surgery and proton beam radiotherapy. At the time of cell line establishment, the disease progressed to pleural sarcomatosis with pleural effusion. In the cell line, we identified POU2AF3 as a fusion partner of EWSR1 and a TP53 frameshift deletion. Next, we determined the sensitivity of PF1095 cells to the currently approved chemotherapies in comparison to two conventional Ewing sarcoma lines (EW-7 and MHH-ES1) with the two most frequent EWSR::FLI1 fusions. Finally, we tested potential new combination therapies. We performed cell viability, proliferation, and cell cycle assays. We found that the proliferation rate of PF1095 cells was much slower than the EWSR1::FLI1 fusion lines and they also had a lower sensitivity to both irinotecan and doxorubicin treatment. Expression level of SLFN11, a predictor of sensitivity to DNA damaging agents, was also lower in PF1095 cells. Combination treatment with the PARP inhibitors olaparib and irinotecan or doxorubicin synergistically reduced cell viability and induced cell death and cell cycle arrest. This unique cell model provides an opportunity to test therapeutic approaches preclinically for this novel and aggressive sarcoma entity.