High-grade Malignancy Research Articles

Abstract 2052: High-plex spatial multiomics of pediatric and adult diffuse midline glioma, H3 K27-altered

Abstract Background: Diffuse midline glioma (DMG), H3 K27-altered are highly aggressive malignancies of the central nervous system that affect both pediatric and adult populations. The immune layout and genetic changes within the tumor microenvironment associated with these high-grade malignancies are thought to play an integral role in the phenotypic differences in tumor presentation and clinical course between both populations. Comparative landscapes between pediatric and adult DMGs is not known. Methods: The NanoString GeoMxTM Digital Spatial Profiler platform was used to determine the immune marker and genetic layout in a cohort of both pediatric and adult DMG, H3 K27-altered tissue samples. Three fluorescently labeled antibodies targeting immune cells (CD45), epithelial cells (PanCK), tumor cells (H3 K27M) and a nucleic acid stain (SYTO-13) were used to identify and separate out the various components within the tumor tissues from selected regions of interest. The resultant information was then pooled into libraries that were run through the Illumina sequencing platform to assess transcriptomic and proteomic data for both cohorts of samples. Results: Our data revealed the immune and genetic expression seen within both populations across multiple regions of interest within the samples. Differences were seen specific to each population that may have clinical significance and warrant further exploration including a significant increase in genes associated with RTK pathways in the pediatric samples. Conclusion: The digital spatial analysis of pediatric and adult DMG, H3 K27-altered shows differences within the molecular landscape which may contribute to the clinical differences between both populations. These observed differences may play a role in future treatments and further research is needed to explore this. Citation Format: Sudarshawn Damodharan, Alyssa Rosenbloom, Mahua Dey. High-plex spatial multiomics of pediatric and adult diffuse midline glioma, H3 K27-altered [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2052.

Extranasal T/NK lymphoma with a fatal outcome: A case report

Extranodal T/NK lymphoma (LTNKEN) is a rare and aggressive form of non-Hodgkin lymphoma of high-grade malignancy. A distinction is made between the nasal forms, characterized by primary involvement of the nasal cavity, and the extranasal forms. Primary skin involvement is highly rare. Diagnosis is based on immunohistochemical studies. Treatment includes chemotherapy and radiotherapy. This type of lymphoma has a poor prognosis even with treatment. Herein, we report a Moroccan case of cutaneous T/NK lymphoma in a young patient with a primary cutaneous localization of fatal evolution. Key words: Lymphoma; Extranodal lymphoma; T/NK lymphoma; Non-hodgkin lymphoma

Awake craniotomy for low-grade gliomas

Aim: The aim of this study was to evaluate the efficacy of awake brain surgery for benign glial brain tumours in the Department of Neurosurgery of the Military Institute of Medicine in Warsaw. Materials and methods: Between 2020 and 2021, 9 out of 17 patients with a radiological diagnosis of a low-grade glioma located within or in the vicinity of eloquent brain areas were operated on under awake conditions. The average preoperative tumour volume was 29.6 cm3. Preoperative management included a repeat magnetic resonance imaging supplemented with functional magnetic resonance imaging and tractography, as well as neuropsychological assessment. The cortex and subcortical structures were stimulated intraoperatively at 1.5–4 mA. The intraoperative assessment covered: motor functions, speech, and, additionally in two patients, visual field width and contralateral neglect. Results: Based on magnetic resonance imaging on the first postoperative day, complete removal of the tumour was confirmed in 7 patients. In 2 patients, resection was subtotal due to the fact that part of the tumour that infiltrated eloquent structures was left. In 6 patients, transient neurological deterioration was observed in the early perioperative period, which resolved within 2 months after surgery. In 3 patients, histopathological examination revealed a tumour with a higher grade of malignancy than expected. Conclusions: Our experience confirms that surgical treatment of benign glial tumours using direct electrical stimulation in awake patients is an effective and safe method allowing effective tumour resection with a minimised risk of adverse neurological sequelae.

Deciphering the role of QPCTL in glioma progression and cancer immunotherapy.

Glioma is the most lethal and most aggressive brain cancer, and currently there is no effective treatment. Cancer immunotherapy is an advanced therapy by manipulating immune cells to attack cancer cells and it has been studied a lot in glioma treatment. Targeting the immune checkpoint CD47 or blocking the CD47-SIRPα axis can effectively eliminate glioma cancer cells but also brings side effects such as anemia. Glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyzes the pyroglutamylation of CD47 and is crucial for the binding between CD47 and SIRPα. Further study found that loss of intracellular QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity. However, the role of QPCTL in glioma and the relationship between its expression and clinical outcomes remains unclear. Deciphering the role of QPCTL in glioma will provide a promising therapy for glioma cancer immunotherapy. QPCTL expression in glioma tissues and normal adjacent tissues was primarily analyzed in The Cancer Genome Atlas (TCGA) database, and further validated in another independent cohort from the Gene Expression Omnibus (GEO) database, Chinese Glioma Genome Atlas (CGGA), and Human Protein Atlas (HPA). The relationships between QPCTL expression and clinicopathologic parameters and overall survival (OS) were assessed using multivariate methods and Kaplan-Meier survival curves. And the proteins network with which QPCTL interacted was built using the online STRING website. Meanwhile, we use Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA) databases to investigate the relationships between QPCTL expression and infiltrated immune cells and their corresponding gene marker sets. We analyzed the Differentially Expressed Genes (DEGs) including GO/KEGG and Gene Set Enrichment Analysis (GSEA) based on QPCTL-high and -low expression tumors. In contrast to normal tissue, QPCTL expression was higher in glioma tumor tissue (p < 0.05). Higher QPCTL expression was closely associated with high-grade malignancy and advanced tumor stage. Univariate and multivariate analysis indicated the overall survival of glioma patients with higher QPCTL expression is shorter than those with lower QPCTL expression (p < 0.05). Glioma with QPCTL deficiency presented the paucity of infiltrated immune cells and their matching marker sets. Moreover, QPCTL is essential for glioma cell proliferation and tumor growth and is a positive correlation with glioma cell stemness. High QPCTL expression predicts high grades of gliomas and poor prognosis with impaired infiltration of adaptive immune cells in the tumor microenvironment as well as higher cancer stemness. Moreover, targeting QPCTL will be a promising immunotherapy in glioma cancer treatment.

Sarcomatoid urothelial carcinoma of the renal pelvis treated with immunotherapy

BackgroundSarcomatoid carcinoma is a rare, high-grade malignancy with epithelial and mesenchymal components. It may be a good candidate for immunotherapy because it is associated with overexpression of programmed cell death ligand 1. Sarcomatoid urothelial carcinoma (UC) of the upper urinary tract is extremely rare. Here we report the first case of sarcomatoid UC of the renal pelvis that responded to immunotherapy.Case presentationA 79-year-old man was referred to our hospital complaining of various symptoms, including anorexia and abdominal pain. A computed tomography scan revealed a right atrial tumor, a 9 cm left renal mass with a renal vein tumor thrombus, para-aortic lymphadenopathy, and multiple small lung nodules. The patient underwent resection of the right atrial tumor. Pathological analysis of the tumor did not lead to an accurate diagnosis even after several rounds of immunohistochemistry. He underwent a needle biopsy of the left kidney and was initially diagnosed with collecting duct carcinoma, a rare subtype of renal cell carcinoma (RCC). Following the initial diagnosis, immunotherapy with nivolumab and ipilimumab commenced. Thereafter, almost all lesions, including the left renal tumor, were reduced in size. However, he underwent a left nephrectomy approximately a year after beginning immunotherapy due to repeated left renal bleeding. Histological examination of the nephrectomy specimen revealed two forms of cancer—sarcomatoid UC and conventional high-grade UC. Two months after surgery, the patient was found to have new lung metastases. He underwent chemotherapy with gemcitabine and cisplatin, followed by immunotherapy with pembrolizumab. However, both treatments were ineffective. The patient died of cancer 19 months after his first admission.ConclusionsThe presented case of sarcomatoid UC of the renal pelvis that partially responded to immunotherapy suggests that immunotherapy can be a promising treatment for sarcomatoid UC.

Therapeutic implication of chimeric antigen receptor T-cell therapy for head and neck squamous cell carcinoma.

Therapeutic implication of chimeric antigen receptor T-cell therapy for head and neck squamous cell carcinoma.

Nivolumab With or Without Ipilimumab in Pediatric Patients With High-Grade CNS Malignancies: Safety, Efficacy, Biomarker, and Pharmacokinetics: CheckMate 908.

Therapeutic options are limited in pediatric CNS malignancies. CheckMate 908 (NCT03130959) is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO+ipilimumab (IPI) in pediatric patients with high-grade CNS malignancies. Patients (N=166) in 5 cohorts received NIVO 3mg/kg every 2 weeks (Q2W) or NIVO 3mg/kg+IPI 1mg/kg every 3 weeks (4 doses) followed by NIVO 3mg/kg Q2W. Primary endpoints included overall survival (OS; newly diagnosed diffuse intrinsic pontine glioma [DIPG]) and progression-free survival (PFS; other recurrent/progressive or relapsed/resistant CNS cohorts). Secondary endpoints included other efficacy metrics and safety. Exploratory endpoints included pharmacokinetics and biomarker analyses. As of January 13, 2021, median OS (80% CI) was 11.7 (10.3-16.5) and 10.8 (9.1-15.8) months with NIVO and NIVO+IPI, respectively, in newly diagnosed DIPG. Median PFS (80% CI) with NIVO and NIVO+IPI was 1.7 (1.4-2.7) and 1.3 (1.2-1.5) months, respectively, in recurrent/progressive high-grade glioma; 1.4 (1.2-1.4) and 2.8 (1.5-4.5) months in relapsed/resistant medulloblastoma; and 1.4 (1.4-2.6) and 4.6 (1.4-5.4) months in relapsed/resistant ependymoma. In patients with other recurrent/progressive CNS tumors, median PFS (95% CI) was 1.2 (1.1-1.3) and 1.6 (1.3-3.5) months, respectively. Grade 3/4 treatment-related adverse-event rates were 14.1% (NIVO) and 27.2% (NIVO+IPI). NIVO and IPI first-dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor programmed death ligand 1 expression was not associated with survival. NIVO±IPI did not demonstrate clinical benefit relative to historical data. The overall safety profiles were manageable with no new safety signals.

68 Ga-FAPI-04 PET/CT in a Small Sarcomatoid Renal Cell Carcinoma With Widespread Metastases.

Sarcomatoid renal cell carcinoma is an uncommon high-grade malignancy with poor prognosis. We describe 68 Ga-FAPI-04 PET/CT findings in a patient with a small (1.8 cm in the maximum diameter) sarcomatoid clear cell renal cell carcinoma with widespread metastatic disease. Both the primary renal tumor and its metastases in bones, lymph nodes, adrenals, and liver showed increased 68 Ga-FAPI-04 uptake. The primary renal tumor showed hypovascularity on contrast-enhanced CT, mimicking papillary renal cell carcinoma. This case indicates FAPI PET/CT may be useful for detecting and staging of this unusual malignancy.

A Pilot Study of a Screening Program for Human Papillomavirus-Related Squamous Intraepithelial Lesion and Malignancy in Gynecologic Oncology Patients.

Human papillomavirus (HPV)-related squamous intraepithelial lesion (SIL) or malignancy is associated with a significantly increased risk of second-site SIL or malignancy. The primary objective of this study was to determine the feasibility and acceptability of concurrent anal, cervical, and vulvovaginal screening in patients with a history of HPV-related gynecologic high-grade SIL or malignancy. The secondary objective was to assess subjects' knowledge regarding HPV screening and risks. Women with high-grade cervical, vulvar, or vaginal SIL or malignancy were enrolled during a 1-year pilot period. Subjects with cervical SIL or malignancy underwent vulvar examination and anoscopy. Subjects with vulvovaginal SIL or malignancy underwent Pap test if indicated and anoscopy. Appropriate referrals were made for abnormal findings. Feasibility was assessed by compliance using study acceptance rate, screening procedure adherence, and referral adherence. Acceptability was assessed using a Likert-scaled question after completion of screening procedures. One hundred three women with a diagnosis of high-grade vulvovaginal or cervical SIL or carcinoma were approached regarding study enrollment; of these, 74 (71.8%) enrolled. The median score on the HPV knowledge assessment was 8.1 ± 1.6 (max score 10). Seventy-three (98.6%) of 74 patients rated the screening procedures as acceptable (score of 5/5). On examination, 14 (18.9%) subjects had abnormalities noted; 7 (9.5%) were referred for colorectal surgical evaluation, and 6/7 (85.7%) were compliant with their referral appointments. Screening examinations for other HPV-related SILs and malignancies, including Pap tests, vulvovaginal inspection, and anoscopy, are acceptable to patients, with abnormal findings in almost 1 in 5 women.

Androgen receptor-dependent regulation of metabolism in high grade bladder cancer cells

The observed sex disparity in bladder cancer (BlCa) argues that androgen receptor (AR) signaling has a role in these malignancies. BlCas express full-length AR (FL-AR), constitutively active AR splice variants, including AR-v19, or both, and their depletion limits BlCa viability. However, the mechanistic basis of AR-dependence is unknown. Here, we depleted FL-AR, AR-v19, or all AR forms (T-AR), and performed RNA-seq studies to uncover that different AR forms govern distinct but partially overlapping transcriptional programs. Overlapping alterations include a decrease in mTOR and an increase of hypoxia regulated transcripts accompanied by a decline in oxygen consumption rate (OCR). Queries of BlCa databases revealed a significant negative correlation between AR expression and multiple hypoxia-associated transcripts arguing that this regulatory mechanism is a feature of high-grade malignancies. Our analysis of a 1600-compound library identified niclosamide as a strong ATPase inhibitor that reduces OCR in BlCa cells, decreased cell viability and induced apoptosis in a dose and time dependent manner. These results suggest that BlCa cells hijack AR signaling to enhance metabolic activity, promoting cell proliferation and survival; hence targeting this AR downstream vulnerability presents an attractive strategy to limit BlCa.

Racial Disparities in Survival Outcomes of Patients With Serous Epithelial Ovarian Cancer: A Retrospective Cohort Analysis.

To identify racial disparities in five-year survival rates in women affected by serous epithelial ovarian carcinoma in the United States (US). This retrospective cohort study analyzed data from the 2010 to 2016 Surveillance, Epidemiology, and End Results (SEER) program database. Women with a primary malignancy of serous epithelial ovarian carcinoma, using International Classification of Diseases for Oncology (ICD-O) Topography Coding and ICD-O-3 Histology Coding, were included in this study. Race and ethnicity were combined into the following groups: Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Non-Hispanic Asian/Pacific Islander (NHAPI), Non-Hispanic Other (NHO), and Hispanics. Cancer-specific survival was measured at five years post-diagnosis. A comparison of baseline characteristics was assessed using Chi-squared tests. Unadjusted and adjusted Cox regression models were used to calculate hazard ratios (HR) and corresponding 95% confidence intervals (CI). From 2010 to 2016, there were 9,630 women with a primary diagnosis of serous ovarian carcinoma identified in the SEER database. A higher proportion of Asian/PI women (90.7%) were diagnosed with high-grade malignancy (poorly differentiated/undifferentiated) compared to NHW women (85.4%). NHB women (9.7%) were less likely to undergo surgery when compared to NHW women (6.7%). Hispanic women had the highest proportion of uninsured women (5.9%), while NHW and NHAPI had the lowest (2.2% each). A higher proportion of NHB (74.2%) and Asian/PI (71.3%) women presented with the distant disease compared to NHW women (70.2%). After adjustment for age, insurance, marital status, stage, metastases, and surgical resection, NHB women had the highest hazard of death within five years compared to NHW women (adjusted (adj) HR 1.22, 95% CI 1.09-1.36, p<0.001). Hispanic women also had lower five-year survival probabilities compared to NHW women (adj HR 1.21, 95% CI 1.12-1.30, p<0.001). Patients undergoing surgery had significantly increased survival probability compared to those who did not (p<0.001). As expected, women with Grade III and Grade IV disease both had significantly lower five-year survival probabilities compared to Grade I (p<0.001). This study reveals that there is an association between race and overall survival in patients with serous ovarian carcinoma, with NHB and Hispanic women having the highest hazards of death compared to NHW women. This adds to the existing body of literature as survival outcomes in Hispanic patients relative to NHW patients are not well documented. Because of the potential interplay between overall survival and several factors including race, future studies should aim to investigate other socioeconomic factors that may be impacting survival.

Clinicopathological analysis of a type of “low grade” poorly cohesive gastric adenocarcinoma not otherwise specified with a good prognosis

Poorly cohesive carcinoma not otherwise specified (PCGCA-NOS) is regarded in the most recent WHO classification as a high-grade malignancy; however, some cases may be associated with a relatively good prognosis. We have studied a series of 115 cases of PCGCA-NOS and were able to identify low-grade features in 14 cases based on three morphological manifestations. Immunohistochemical staining, EBER in situ hybridization, Feulgen staining and flow cytometry were employed. Among the 115 cases of PCGAC-NOS, 14 cases met the criteria of “low grade”, accounting for 12.2 %. The “low grade” cases exhibited more shallow invasion and less lymph node metastasis (both P < 0.05); showed less frequent expression of MUC5AC, E-cadherin and p53 (all P < 0.05). Moreover, “low grade” PCGAC-NOS had a lower proliferative index(P < 0.001). We also found that the DNA content was lower in the “low grade” group, and aneuploidy was not detected in the “low grade” group, which was sharply different from the control group (50 %). Last, “low grade” PCGAC-NOS had a more favorable prognosis. A small subset of PCGAC-NOS cases have a low grade nature, and the clinicopathological features, immunophenotypes, and cytogenetics of these “low grade” cases differ from those of traditional PCGAC-NOS.

Evaluation of tumour associated macrophages in different histopathological types and grades of canine mammary tumours

Canine mammary tumours (CMTs) are the second highest reported tumours in female dogs, following skin tumours. Human breast cancers (HBCs) and CMTs share common clinical and molecular features and hence, CMTs are considered as ideal models to study the different aspects of HBC. The study utilised samples from 25 CMT suspected cases presented to University Veterinary Hospitals in Thrissur district from December 2020 to October 2021. The tumour samples were analysed histopathologically and the lesions were classified. Among the 25 cases, one was identified as ductal hyperplasia, one as a benign myxoma and all the others were found to be malignant neoplasms. Malignant tumours were further categorised into different histotypes.Histological Malignancy Grading (HMG) was also done in 23 malignant CMTs and 21.74 percent were found to be of grade I, 47.83 per cent were grade II and 30.43 per cent were grade III. Majority of the malignant tumours were simple carcinomas which comprised tubulopapillary, ductal, cribriform, solid and comedocarcinomas. Highly aggressive tumours like cribriform, solid, comedo and inflammatory carcinomas belonged to higher grades, either II or III. Infiltration of tumour associated macrophages (TAMs) was studied in different histotypes and grades of CMTs. It was identified that malignant high grade CMTs had greater TAM infiltration and hence, with further validation TAMs could be effectively used in predicting prognosis and also as a therapeutic target.

Intrathyroid thymic carcinoma/carcinoma showing thymus-like elements (CASTLE): An extremely rare presentation of thyroid malignancy

Intrathyroid thymic carcinoma, also known as carcinoma showing thymus-like elements/CASTLE, is an uncommon malignancy that arises in the thyroid gland. This tumour shares both morphological and immunohistochemical characteristics with thymic carcinomas. Preoperative diagnosis can be challenging as the clinical and histological features may mimic other high-grade thyroid malignancies. Differentiating CASTLE from other thyroid lesions is important as it has a better prognosis.A 46-year-old man presented with progressive dysphagia, difficulty in breathing and cough for eight months. The ultrasound scan (USS) revealed a hypoechoic lesion in the right lobe of the thyroid. The cytology specimen obtained through non-US-guided fine needle aspiration (FNA) was reported as Thy5/Bethesda VI, consistent with papillary thyroid carcinoma and a total thyroidectomy was performed. Macroscopic examination revealed a white, non-encapsulated tumour in the right lobe of the thyroid, measuring 45x40x25 mm, with gross extrathyroidal extension. Microscopically, this lesion predominantly showed a squamous morphology with admixed lymphocytes. The tumour cells tested positive for CD5, CD117, CK5/6, CK19 and synaptophysin, and were negative for TTF1 and calcitonin, confirming its classification as CASTLE.This case brings attention to the difficulties encountered in diagnosing uncommon lesions in both cytology and histology and emphasizes the crucial contribution of immunohistochemistry in navigating through such complex scenarios.

Calcanectomy in primary high-grade sarcomas: Foot salvage without the need for any reconstruction

The calcaneum is a rare site for primary bone sarcomas. Calcanectomy is not considered for high-grade malignancies due to anticipated issues with obtaining negative margins, providing adequate soft-tissue coverage, and preserving satisfactory function. A below-knee amputation overcomes these difficulties and is very functional and, thus, the preferred local control option. The aim of this study is to evaluate the role of total calcanectomy, without any formal reconstruction, in high-grade calcaneal sarcomas. Over 14 years, three patients with high-grade calcaneal sarcomas underwent limb salvage surgery as opposed to amputation for their primary malignancy. Total calcanectomy was undertaken using a Cincinnati incision. No formal “calcaneal” reconstruction was undertaken after resection, essentially leaving the patient with an excision arthroplasty through the subtalar joint. The Achilles tendon was reattached to the posterior talus. Negative resection margins were achieved in all cases with the primary wound closure. Two patients are alive with no evidence of disease at 15 and 10 years. The third patient, at over 1 year postoperatively, has no evidence of local disease recurrence but has had metastasectomy for documented pulmonary metastases at the presentation. The average musculoskeletal tumor society score was 85.5%, and the average Toronto extremity salvage score was 88.5%. In our experience, even high-grade malignancies at this unusual site are potentially amenable to limb salvage. Our results show that perhaps ablative surgery should not be considered inevitable. Good functional outcomes can be achieved without reconstruction, thus minimizing potential “construct”-related morbidities.

Evaluation of the Implementation and Diagnostic Accuracy of the Paris Classification for Reporting Urinary Cytology in Voided Urine Specimens: A Cyto-Histological Correlation Study in a Cancer Center

Introduction: The Paris classification highlights the need to focus on accurately identifying high-grade urothelial carcinoma (HGUC). Herein, we aimed to assess the overall implementation and diagnostic performance of the Paris classification for reporting urinary cytology in a cancer center. Methods: All urinary cytology reports from July 2018 to December 2019 were collected (n = 1,240). Only voided urine samples were included (n = 1,180). Risk of high-grade malignancy (ROHM) was calculated for each Paris category. The diagnostic performance of urinary cytology was assessed, including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. Results: The distribution of categories was: 0.3% unsatisfactory, 90.5% negative for HGUC, 5.6% atypical urothelial cells (AUC), 1.6% suspicious for HGUC, 1.9% HGUC, and 0.1% other malignancies. No diagnosis of low-grade urothelial neoplasia was given. The ROHM was 21.4% for negative for HGUC, 66.7% for AUC, 91.7% for suspicious for HGUC, and 100% for HGUC. When using suspicious for HGUC as a cutoff, the diagnostic performance of urinary cytology in identifying HGUC histology was 46% sensitivity, 98% specificity, 96% PPV, 68% NPV, and 74% accuracy. Conclusion: Specificity of urinary cytology was very high (with only 1 false-positive result), which is important since this will trigger a clinical intervention. The ROHM for each category was in accordance with literature, except for AUC where ROHM was slightly higher (66.7%). This may be explained by the study population characteristics (cancer center; many patients treated with intravesical therapies; lack of clinical annotation for patients referred from outside institutions).

The role of glucose transporter type 1 (GLUT1) and carbonic anhydrase IX (CAIX) expression by prostate adenocarcinoma tissue in determining disease prognosis and effectiveness of radical treatment

Introduction. Today, due to the insufficient diagnostic accuracy of existing tools for determining clinically significant forms of prostate cancer, the search for new indicators that predict the course of the disease and the effectiveness of radical treatment is relevant. Various malignant tumors could increase glucose consumption and grow under hypoxic conditions. It seems promising to assess the expression level of glucose transporter type 1 (GLUT1) and carbonic anhydrase IX (CAIX) in prostate adenocarcinoma cells of different malignancy score.Objective. To determine CAIX and GLUT1 expression in ISUP grades 1-5 prostate adenocarcinoma cells for evaluation of the disease prognosis and radical prostatectomy effectiveness.Materials and methods. Immunohistochemical study of postoperative material after radical prostatectomy with determination of GLUT1 and CAIX expression by tumor cells was carried out. The presence or absence of biochemical recurrence within one year after surgery was determined. The correlation between the level of expression, the presence of biochemical relapse and a few other clinical parameters was determined.Results. GLUT1 expression level statistically significant correlated with ISUP 4 and 5 (r = 0.457, p &lt; 0.0001), prostate-specific antigen (PSA) level (r = 0.378, p &lt; 0.0001), pT3b disease stage (r = 0.380, p &lt; 0.0001), extracapsular extension (r = 0.355, p = 0.001), and inversely correlated with ISUP 1 (r = -0.274, p = 0.009). CAIX immunoexpression was observed in 10.0% of samples and the intensity was low (&lt; 20% of cells).Conclusion. Elevated expression of glucose transporter type 1 (GLUT1) by prostate adenocarcinoma cells among patients after radical prostatectomy is associated with high grade of malignancy (ISUP 4 and 5), pT3b disease stage, extracapsular extension of the tumor, as well as high PSA, which allows using it for the prognosis evaluation.

Biochemical factors in the blood serum of neuroendocrine tumor patients with carcinoid syndrome

Introduction. Carcinoid syndrome is the most common functional syndrome in patients with neuroendocrine tumors. More than 40 biochemical factors are responsible for the manifestation of carcinoid syndrome, among which serotonin is the most important. The study of biochemical markers of carcinoid syndrome and associated carcinoid heart disease is an important aim of laboratory examination in neuroendocrine tumors patients.Aim. Analysis of levels and diagnostic efficiency evaluation of chromogranin A (CgA), serotonin, pro-brain natriuretic peptide (proBNP) and platelet-derived growth factor (PDGF-BB) in the blood serum of neuroendocrine tumors patients with various clinical manifestations, including carcinoid syndrome and carcinoid heart disease.Materials and methods. 66 patients with neuroendocrine tumors of various localizations were examined (pancreas – 24 cases, small intestine – 21, large intestine – 6, lungs – 10, unkown primary focus – 5). 38 patients had liver metastases. In 43 patients, a clinic of carcinoid syndrome was observed, 16 had signs of carcinoid heart disease. The control group consisted of 30 practically healthy people. Serum levels of CgA, serotonin, and PDGF-BB were determined by enzyme immunoassay in microplate format: Chromogranin A NEOLISA (Eurodiagnostica, Sweden), Serotonin ELISA (IBL, German), and PDGF-BB ELISA Kit (Invitrogen, USA). The proBNP analysis was performed on a Cobas e601 automated analyzer (Roche, Switzerland).Results. In carcinoid syndrome, the medians of CgA, serotonin, and proBNP were the highest, differing statistically significantly from the control group. In patients with G3 tumors, the median PDGF-BB was statistically significantly higher than in controls, in contrast to G1 and G2. The highest diagnostic sensitivity in the general neuroendocrine tumors group was in CgA – 63.6 %, with a specificity of 100 %. In patients with carcinoid syndrome, the highest diagnostic sensitivity was characteristic of serotonin and chromogranin A (79 %), while in patients with CAD clinic, proBNP had the highest sensitivity – 93.8 %.Conclusion. The study revealed the high efficiency of СgA, with the highest sensitivity in common forms and tumors with high biological activity. Serotonin can be used in the diagnosis of carcinoid syndrome, associated with cardiofibrosis development. Pro-brain natriuretic peptide is a highly sensitive and specific marker of carcinoid heart disease. The highest levels of PDGF-BB are associated with a high grade of neuroendocrine tumors malignancy.

A novel association between Bmi-1 protein expression and the SUVmax obtained by 18F-FDG PET/CT in patients with gastric adenocarcinoma.

This study aimed to examine B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) in gastric adenocarcinoma (GAC) and its association with the maximal standard uptake value (SUVmax) of preoperative fluorine-18-fludeoosyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Clinicopathological data were retrospectively collected from 60 primary GAC patients. The Bmi-1 protein expression in GAC and adjacent noncancerous tissues was examined by immunohistochemistry and western blot analysis. Pearson's correlation analysis was conducted to assess the correlation between Bmi-1 expression and the SUVmax. The Bmi-1 protein levels were significantly greater in GAC versus noncancerous tissues, and higher Bmi-1 was significantly correlated with a lower degree of tumor differentiation, higher tumor stages, more lymph node metastasis, and depth of invasion. The SUVmax value was significantly correlated with the T stage, N stage, and clinical stage, but not with age, gender, tumor size, histological differentiation degree, or Lauren classification. Moreover, a significant positive correlation between Bmi-1 and SUVmax was observed in GAC tissues. In conclusion, our findings demonstrate a novel correlation between Bmi-1 and preoperative SUVmax in GAC patients who did not receive radiotherapy, chemotherapy, or targeted treatment before surgery, and both are positively correlated with unfavorable prognostic factors and a higher grade of malignancy.

Mechanotransduction in the pathogenesis of non-alcoholic fatty liver disease.

Mechanobiology is a domain of interdisciplinary research that aims to explore the impact of physical force, applied externally or internally, on cell and tissue function, including development, growth, and differentiation. Mechanotransduction is a term that describes how cells sense physical forces (such as compression, stretch, and shear stress), convert them into biochemical signals, and mount adaptive responses integrated by the nucleus. There is accumulating evidence that mechanical forces extensively inform the biological behaviour of liver cells in health and disease. Recent research has elucidated many cellular and molecular mechanisms involved in this process including the pleiotropic control and diverse effects of the paralogous transcription co-activators YAP/TAZ, which play a prominent role in mechanotransduction. The liver sinusoids represent a unique microenvironment in which cells are exposed to mechanical cues originating in the cytoskeleton and at interfaces with adjacent cells, the extracellular matrix, and vascular or interstitial fluids. In non-alcoholic fatty liver disease (NAFLD), hepatocellular lipid accumulation and ballooning, activation of inflammatory responses, dysfunction of liver sinusoidal endothelial cells, and transdifferentiation of hepatic stellate cells into a pro-contractile and pro-fibrotic phenotype have been associated with aberrant cycles of mechanosensing and mechanoresponses. The downstream consequences of disrupted mechanical homeostasis likely contribute to the progression of NAFLD and promote the development of portal hypertension, cirrhosis, and hepatocellular carcinoma. Identification of molecular targets involved in pathogenic mechanotransduction will allow for the development of novel strategies to prevent the progression of liver disease in NAFLD.