Common Form Of Cancer Research Articles

CCDC50, an essential driver involved in tumorigenesis, is a potential severity marker of diffuse large B cell lymphoma

Diffuse Large B Cell Lymphoma (DLBCL) is the most common form of blood cancer. Among the subtypes, the activated B-cell (ABC) subtype is typically more aggressive and associated with worse outcomes. However, the underlying mechanisms are not fully understood. In this study, we performed microarray analysis to identify potential ABC-DLBCL-associated genes. We employed Kaplan–Meier methods and cox univariate analysis to explore the prognostic value of the identified candidate gene Coiled-coil domain containing 50 (CCDC50). Additionally, we used DLBCL cell lines and mouse models to explore the functions and mechanisms of CCDC50. Finally, we isolated CCDC50-bearing exosomes from clinical patients to study the correlation between these exosomes and disease severity. Our results demonstrated that CCDC50 not only showed significantly positive correlations with ABC subtype, tumor stage and number of extranodal sites, but also suggested poor outcomes in DLBCL patients. We further found that CCDC50 promoted ABC-DLBCL proliferation in vitro and in vivo. Mechanistically, CCDC50 inhibited ubiquitination-mediated c-Myc degradation by stimulating the PI3K/AKT/GSK-3β pathway. Moreover, CCDC50 expression was positively correlated with c-Myc at protein levels in DLBCL patients. Additionally, in two clinical cohorts, the plasma CCDC50-positive exosomes differentiated DLBCL subtypes robustly (AUC > 0.80) and predicted disease severity effectively (p < 0.05). Our findings suggest that CCDC50 likely drives disease progression in ABC-DLBCL patients, and the CCDC50-bearing exosome holds great potential as a non-invasive biomarker for subtype diagnosis and prognosis prediction of DLBCL patients.

Extracellular vesicles promote activation of pro-inflammatory cancer-associated fibroblasts in oral cancer.

Introduction: Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer and has a survival rate of ∼50% over 5years. New treatment strategies are sorely needed to improve survival rates-and a better understanding of the mechanisms underlying tumorigenesis is needed to develop these strategies. The role of the tumor microenvironment (TME) has increasingly been identified as crucial in tumor progression and metastasis. One of the main constituents of the TME, cancer-associated fibroblasts (CAFs), plays a key role in influencing the biological behavior of tumors. Multiple mechanisms contribute to CAF activation, such as TGFβ signaling, but the role of extracellular vesicles (EVs) in CAF activation in OSCC is poorly understood. Assessing the impact of oral cancer-derived EVs on CAF activation will help to better illuminate OSCC pathophysiology and may drive development of novel treatments options. Methods: EVs were isolated from OSCC cell lines (Cal 27, SCC-9, SCC-25) using differential centrifugation. Nanoparticle tracking analysis was used for EV characterization, and Western blot to confirm the presence of EV protein markers. Oral fibroblasts were co-cultured with enriched EVs, TGFβ, or PBS over 72h to assess activation. Flow cytometry was used to evaluate CAF markers. RNA collected from fibroblasts was extracted and the transcriptome was sequenced. Conditioned media from the co-cultures was evaluated with cytokine array profiling. Results: OSCC-derived EVs can activate oral fibroblasts into CAFs that are different from those activated by TGFβ, suggesting different mechanisms of activation and different functional properties. Gene set enrichment analysis showed several upregulated inflammatory pathways in those CAFs exposed to OSCC-derived EVs. Marker genes for inflammatory CAF subtypes were also upregulated, but not in CAFs activated by TGFβ. Finally, cytokine array analysis on secreted proteins revealed elevated levels of several pro-inflammatory cytokines from EV-activated CAFs, for instance IL-8 and CXCL5. Discussion: Our results reveal the ability of OSCC-derived EVs to activate fibroblasts into CAFs. These CAFs seem to have unique properties, differing from TGFβ-activated CAFs. Gaining an understanding of the interplay between EVs and stromal cells such as CAFs could lead to further insights into OSCC tumorigenesis and potential novel therapeutics.

Conditional Knockout of N-WASP Enhanced the Formation of Keratinizing Squamous Cell Carcinoma Induced by KRasG12D.

Squamous cell carcinoma (SCC) is one of the most common forms of skin cancer in humans, and Neural Wiskott-Aldrich Syndrome Protein (N-WASP) plays a crucial role in epidermal homeostasis. To elucidate the role of N-WASP in skin cancer, we generated mice which expressed constitutively active KRas (KRasG12D) in keratinocytes with either homozygous (N-WASPKOG12D) or heterozygous (N-WASPHetG12D) N-WASP knockout upon Tamoxifen (TAM) injection. Both the N-WASPKOG12D and N-WASPHetG12D mice had similar body weights and no congenital malformations prior to the injection of TAM. Within 2 weeks of the injections, the N-WASPKOG12D mice exhibited significant reductions in weight coupled with visible tumors at numerous sites, unlike the N-WASPHetG12D mice, which had no visible tumors. We found that both sets of mice had oily, sticky skin and wet eyes 3 weeks after their exposure to TAM, indicating the overproduction of sebum/meibum. At 37 days post TAM injection, several notable observations were made. Tumors collected from the N-WASPKOG12D mice had small- to large-sized keratin pearls that were not observed in the N-WASPHetG12D mice. A Western blot and immunostaining analysis both highlighted significantly higher levels of expression of SCC markers, such as the cytokeratins 8, 17, 18, and 19 and TP63, in the tumors of the N-WASPKOG12D mice compared to those of the latter group. Furthermore, we noted increases in the expression levels of EGFR, P-ERK, GLUT1, P-mTOR, and P-4EBP in the N-WASPKOG12D mice, suggesting that the deletion of N-WASP in the keratinocytes enhanced KRas signaling and glucose uptake, resulting in aggressive tumor formation. Interestingly, a thickening of the epidermal layer within the esophagus and tongue was only observed in the N-WASPKOG12D mice. Immunostaining for PCNA emphasized a significantly higher number of PCNA-positive cells in the skin of the N-WASPKOG12D mice compared to their counterparts, implying that epidermal thickening and enhanced tumorigenesis are due to an increased proliferation of keratinocytes. Through our results, we have established that N-WASP plays a tumor-suppressive role in skin cancer.

Effects of Web-Based and Mobile Self-Care Support in Addition to Standard Care in Patients After Radical Prostatectomy: Randomized Controlled Trial.

Prostate cancer is a common form of cancer that is often treated with radical prostatectomy, which can leave patients with urinary incontinence and sexual dysfunction. Self-care (pelvic floor muscle exercises and physical activity) is recommended to reduce the side effects. As more and more men are living in the aftermath of treatment, effective rehabilitation support is warranted. Digital self-care support has the potential to improve patient outcomes, but it has rarely been evaluated longitudinally in randomized controlled trials. Therefore, we developed and evaluated the effects of digital self-care support (electronic Patient Activation in Treatment at Home [ePATH]) on prostate-specific symptoms. This study aimed to investigate the effects of web-based and mobile self-care support on urinary continence, sexual function, and self-care, compared with standard care, at 1, 3, 6, and 12 months after radical prostatectomy. A multicenter randomized controlled trial with 2 study arms was conducted, with the longitudinal effects of additional digital self-care support (ePATH) compared with those of standard care alone. ePATH was designed based on the self-determination theory to strengthen patients' activation in self-care through nurse-assisted individualized modules. Men planned for radical prostatectomy at 3 county hospitals in southern Sweden were included offline and randomly assigned to the intervention or control group. The effects of ePATH were evaluated for 1 year after surgery using self-assessed questionnaires. Linear mixed models and ordinal regression analyses were performed. This study included 170 men (85 in each group) from January 2018 to December 2019. The participants in the intervention and control groups did not differ in their demographic characteristics. In the intervention group, 64% (53/83) of the participants used ePATH, but the use declined over time. The linear mixed model showed no substantial differences between the groups in urinary continence (β=-5.60; P=.09; 95% CI -12.15 to -0.96) or sexual function (β=-.12; P=.97; 95% CI -7.05 to -6.81). Participants in the intervention and control groups did not differ in physical activity (odds ratio 1.16, 95% CI 0.71-1.89; P=.57) or pelvic floor muscle exercises (odds ratio 1.51, 95% CI 0.86-2.66; P=.15). ePATH did not affect postoperative side effects or self-care but reflected how this support may work in typical clinical conditions. To complement standard rehabilitation, digital self-care support must be adapted to the context and individual preferences for use and effect. ISRCTN Registry ISRCTN18055968; https://www.isrctn.com/ISRCTN18055968. RR2-10.2196/11625.

Antiandrogenic activity and bioavailability of magnolol analogs – A potential for prostate cancer therapeutics

BackgroundProstate cancer is the second most common form of cancer in men worldwide and there is a great need for novel treatment strategies, especially for castrate-resistant prostate cancers where the proliferation of the cancer cells is stimulated by androgens produced in the adrenal cortex and the cancer cells. PurposeIn this study, we have investigated the antiandrogenic properties of magnolol and ten synthetic analogs in vitro. Study design and methodsThe compounds were evaluated for cytotoxicity, antiandrogenic receptor activity, binding to the androgen receptor, effects on the production of Prostate-specific antigen (PSA), and potential to pass over a tight layer of Caco-2 cells mimicking gastrointestinal absorption. ResultsWe found that almost all investigated compounds were antiandrogenic in an androgen receptor reporter gene assay, with IC50 values ranging from 7 to 86 µM. Magnolol itself had the highest antiandrogenic potency. Five of the compounds were then evaluated for their binding to the androgen receptor and three of these compounds were found to bind to the receptor. These five compounds were also evaluated for their effect on the PSA production and four were found to decrease PSA production at non-cytotoxic concentrations. The antiandrogenic activity after passage through a layer of Caco-2 cells, mimicking gastrointestinal absorption, was also evaluated for three of the compounds. All three compounds were found to have the capacity to be transported from the apical to the basolateral side of the Caco-2 cell layer and exert antiandrogenic effects after the transport. ConclusionIn conclusion, this study shows that magnolol and analogs have antiandrogenic effects in vitro and that selected analogs can pass over a tight layer of Caco-2 cells, indicating a potential for good bioavailability after oral administration. These magnolol analogs thereby constitute an interesting group of compounds worthy of further evaluation as potential anti-prostate cancer therapeutics.

Biomechanical effect of neurologic dance training (NDT) for breast cancer survivors with chemotherapy-induced neuropathy: study protocol for a randomized controlled trial and preliminary baseline data

BackgroundBreast cancer (BC) is among the most common forms of cancer experienced by women. Up to 80% of BC survivors treated with chemotherapy experience chemotherapy-induced neuropathy (CIN), which degrades motor control, sensory function, and quality of life. CIN symptoms include numbness, tingling, and/or burning sensations in the extremities; deficits in neuromotor control; and increased fall risk. Physical activity (PA) and music-based medicine (MBM) are promising avenues to address sensorimotor symptoms. Therefore, we propose that we can combine the effects of music- and PA-based medicine through neurologic dance training (NDT) through partnered Adapted Tango (NDT-Tango). We will assess the intervention effect of NDT-Tango v. home exercise (HEX) intervention on biomechanically-measured variables. We hypothesize that 8 weeks of NDT-Tango practice will improve the dynamics of posture and gait more than 8 weeks of HEX.MethodsIn a single-center, prospective, two-arm randomized controlled clinical trial, participants are randomly assigned (1:1 ratio) to the NDT-Tango experimental or the HEX active control intervention group. Primary endpoints are change from baseline to after intervention in posture and gait. Outcomes are collected at baseline, midpoint, post, 1-month follow-up, and 6-month follow-up. Secondary and tertiary outcomes include clinical and biomechanical tests of function and questionnaires used to compliment primary outcome measures. Linear mixed models will be used to model changes in postural, biomechanical, and PROs. The primary estimand will be the contrast representing the difference in mean change in outcome measure from baseline to week 8 between treatment groups.DiscussionThe scientific premise of this study is that NDT-Tango stands to achieve more gains than PA practice alone through combining PA with MBM and social engagement. Our findings may lead to a safe non-pharmacologic intervention that improves CIN-related deficits.Trial registrationThis trial was first posted on 11/09/21 at ClinicalTrials.gov under the identifier NCT05114005.

A Clinico-Pathological Correlation of Breast Lumps in a Tertiary Care Centre

BACKGROUND&#x0D; Breast lump is one of the most prevalent ailments that women face. Mostly these lumps are benign, but breast malignancy is the most common form of cancer and is the second leading cause of malignancy deaths in women. Fibroadenoma is the most common benign breast mass and invasive ductal carcinoma is the most common malignancy. Delay in the detection causes the malignancy to progress to an advanced stage. Early detection of malignancies in initial stages is done using triple test to decrease mortality. Incidence of breast cancer can be reduced by 30% by the routine mammographic screening of healthy women. We wanted to correlate the clinical and pathological diagnosis in patients presenting with palpable breast lumps and assess the reliability of clinical examination as a pre-procedural diagnostic tool in this study.&#x0D; METHODS&#x0D; A prospective observational study was done in a total of 100 women. Detailed clinical history and examination were done and then compared to histopathological results. The final results were statistically analyzed.&#x0D; RESULTS&#x0D; The clinical examination exhibited a sensitivity of 97.96% and a specificity of 96.08% for the identification of cancer when the data were considered collectively. The clinical examination's positive predictive value was 95.84%, and its negative predictive value was 98.08%.&#x0D; CONCLUSIONS&#x0D; A significant correlation was also observed between the clinical diagnosis and final pathological diagnosis. So routine clinical examination would definitely be helpful in early diagnosis.

The feasibility of including human papillomavirus vaccine in Iran's national immunization program

AimCervical cancer is the second most common form of cancer in women. In order to prevent this disease, several vaccines like Cervarix [2vHPV], Cecolin, Cervarix quadrivalent and Gardasil [9vHPV]), have been included in the vaccination program of some countries. This study as a part of Health Technology Assessment (HTA), aimed to assess the feasibility of inclusion of Human Papilloma Virus (HPV) vaccine in the national vaccination program of Iran. Subject and methodsThis is a qualitative case study composed of semi structured interviews with a purposive sample of experts working extensively in the field of women's health. Data saturation reached at the 12th interview. The data was analyzed using the framework method. ResultsA total of 14 subthemes under 6 themes of the need for vaccines, lack of knowledge, cost factors, administration at early ages, creating a negative mindset, and empowering the society were identified. ConclusionIncluding HPV vaccine in the national vaccination program not only seems justifiable, but also its absence in the vaccination program violates some aspects of medical ethics principles. Therefore, the government must take steps to increase public awareness about human papillomavirus and include the aforementioned vaccine in the national vaccination program.

Studies on the Role of Compartmentalized Profiles of Cytokines in the Risk of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), the most common form of liver cancer, is frequently diagnosed late due to the absence of symptoms during early disease, thus heavily affecting the overall survival of these patients. Soluble immunological factors persistently produced during cirrhosis have been recognized as promoters of chronic inflammation and neoplastic transformation. The aim of this pilot study was to evaluate the predictive value of the cytokine profiles for HCC development. A Luminex xMAP approach was used for the quantification of 45 proteins in plasma and ascitic fluids of 44 cirrhotic patients without or with HCC of different etiologies. The association with patient survival was also evaluated. Univariate analyses revealed that very low levels of interleukin 5 (IL-5) (<15.86 pg/mL) in ascites and IL-15 (<12.40 pg/mL) in plasma were able to predict HCC onset with an accuracy of 81.8% and a sensitivity of 95.2%. Univariate analyses also showed that HCC, hepatitis B virus/hepatitis C virus infections, low levels of IL-5 and granulocyte-macrophage colony-stimulating factor in ascitic fluids, and high levels of eotaxin-1, hepatocyte growth factor and stromal-cell-derived factor 1α in plasma samples were factors potentially associated with a poor prognosis and decreased survival. Our results suggest a potential protective role of some immune modulators that may act in the peritoneal cavity to counteract disease progression leading to HCC development.

Landscape of somatic mutated genes and inherited susceptibility genes in gynecological cancer.

Traditionally, gynecological cancers have been classified based on histology. Since remarkable advancements in next-generation sequencing technology have enabled the exploration of somatic mutations in various cancer types, comprehensive sequencing efforts have revealed the genomic landscapes of some common forms of human cancer. The genomic features of various gynecological malignancies have been reported by several studies of large-scale genomic cohorts, including The Cancer Genome Atlas. Although recent comprehensive genomic profiling tests, which can detect hundreds of genetic mutations at a time from cancer tissues or blood samples, have been increasingly used as diagnostic clinical biomarkers and in therapeutic management decisions, germline pathogenic variants associated with hereditary cancers can also be detected using this test. Gynecological cancers are closely related to genetic factors, with approximately 5% of endometrial cancer cases and 20% of ovarian cancer cases being caused by germline pathogenic variants. Hereditary breast and ovarian cancer syndrome and Lynch syndrome are the two major cancer susceptibility syndromes among gynecological cancers. In addition, several other hereditary syndromes have been reported to be associated with gynecological cancers. In this review, we highlight the genes for somatic mutation and germline pathogenic variants commonly seen in gynecological cancers. We first describe the relationship between clinicopathological attributes and somatic mutated genes. Subsequently, we discuss the characteristics and clinical management of inherited cancer syndromes resulting from pathogenic germline variants in gynecological malignancies.

Dickkopf-1 (DKK1): A Diagnostic Marker for Hepatocellular Carcinoma (HCC) on Top of Chronic Hepatitis C Virus Related Diseases

Abstract Background Hepatocellular carcinoma (HCC) is a common form of cancer in the world and is the third leading cause of cancer-related death. More than 80% of its incidence is found in developing countries; rates are more than twice as high in men compared with women. HCC is the most common form among primary liver cancers occurring worldwide, about 70–85% of liver tumors. Aim of the Work This study was aimed to evaluate the clinical significance of serum Dickkopf-1 (DKK1) as a diagnostic and prognostic marker in hepatocellular carcinoma. Patients and Methods This was a prospective study that was conducted on 60 patients and 30 healty control subjects recruited from Al Sahel Teaching Hospital. Results Regarding the demographic data, there was no statistically significant difference found between 3 groups regarding age and sex. Tumor Size was &amp;lt; 2 cm in 10.0% of HCC patients, 2 – 3 cm in 56.7% of them &amp; &amp;gt; 5 cm in 33.3% of HCC patients. While number of tumors was Single in 33.3% of HCC patients, 2 – 3 in 30.0% &amp; Multiple masses in 36.7% of patients. PV thrombosis was reported in 30% of patients. Incidence of child score c in our study was significantly higher in HCC Group when compared with Liver Cirrhosis group. According to this study, there was Non statistically significant correlation Between DKKA1 (pg/ml) &amp; each of Age, HB, WBCs, Platelets, ALT, AST, Creat, Urea, Albumin, INR, Bilirubin and AFP in both all patients &amp; Liver Cirrhosis groups. While for HCC group, there was Non statistically significant correlation Between DKKA1(pg/ml), Age, HB, Platelets, ALT, Creat, Urea, Albumin, INR, Bilirubin and AFP, but there was statically significant Positive correlation Between DKKA1(pg/ml), WBCs and AST. Serum DKK1 was significantly higher in HCC group comparing with liver cirrhosis group and control group. According to our study, ROC curve showed that the best cut off point of DKKA1 to detect Liver Cirrhosis group was &amp;gt; 264.9 pg/ml with sensitivity of 56.67%, specificity of 86.67%, PPV of 81.0%, NPV of 66.7%. Another ROC curve showed that the best cut off point of DKKA1 to detect HCC group was found &amp;gt; 453 with sensitivity of 83.33%, specificity of 93.33%, PPV of 92.6%, NPV of 84.8%. Assessment of diagnostic performance of serum DKK1 when used in discriminating Group (HCC) from Group (Liver Cirrhosis), revealed a better diagnostic performance of DKK1) as the best ROC cut-off for DKK1 was &amp;gt; 1674.8 ng/mL, this had a diagnostic sensitivity of 50%, specificity 96.67%, positive predictive value 93.7%, negative predictive value 65.9%. Conclusion In conclusion, our study suggests that DKK-1 may be a key regulator in HCC progression, a promising potential therapeutic target for HCC. We also demonstrated that serum DDK-1 could be a useful marker for diagnosing HCC.

The identification of a novel orally available ferroptosis inducer for the treatment of clear cell renal carcinoma

Abstract Background Background: Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is typically initiated by inactivation of the von Hippel Lindau (VHL) gene resulting in constitutive activation of the hypoxia inducible factors, HIF-1α and HIF-2α. HIF-2α is a central driver of kidney cancer progression and is a well validated therapeutic target for ccRCC. Additionally, VHL loss and HIF activation promote lipid accumulation that increases the sensitivity of ccRCC cells to ferroptosis, a form of cell death characterized by iron dependent lipid peroxidation. However, classical inducers of ferroptosis, which induce ferroptosis in vitro, show limited activity in vivo due to possible redundancies in the extracellular space, suggesting a need for novel molecular targets for the induction of ferroptosis in vivo for therapeutic benefit. Methods Method: We performed a high-throughput screen to identify small molecule inhibitors of HIF-2α and performed additional validation and structure activity relationship studies to identify compounds with improved potency of HIF-2α inhibition. The molecular target of these inhibitors was determined by mass spectrometry using the Drug Affinity Responsive Target Stability (DARTS) assay, and target validation was confirmed using siRNA knockdown and NMR. In vivo anti-tumor efficacy was verified using syngeneic RENCA cells injected into Balb/C mice. Exposure to KD061 was verified using LC-MS/MS detection of KD061 in the plasma and tumors of treated mice. Results Results: We identified a novel molecule, KD061, which decreases levels of HIF-1/2α and induces ferroptosis in vivo through oral administration by targeting Iron Sulfur Cluster Assembly 2 (ISCA2). ISCA2 is a component of the late mitochondrial Iron Sulfur Cluster (L-ISC) assembly complex and ISCA2 inhibition either pharmacologically or using siRNA triggers the iron starvation response, resulting in iron/metals overload and death via ferroptosis. Cell death induced by KD061 was decreased by re-expression of VHL, suggesting synthetic lethality in the context of VHL loss. ISCA2 inhibition also decreased HIF-2α protein levels by blocking iron-responsive element (IRE)-dependent translation, and at higher concentrations, also decreased HIF-1α translation through unknown mechanisms. Treatment of tumor-bearing RENCA-Balb/C mice with KD061 significantly reduced tumor growth in vivo, decreased HIF-α levels and increased lipid peroxidation, suggesting increased ferroptosis in vivo. Treatment with KD061 was well tolerated at the therapeutic dose with no detectable effects on blood chemistry and blood counts. Conclusions Conclusions: Here, we describe the first orally available inducer of ferroptosis with anti-tumor efficacy in vivo. The targeting of ISCA2 using KD061 is a promising therapeutic strategy to inhibit HIF-1/2α and to induce ferroptosis in pVHL deficient cells. CDMRP DOD Funding: yes

Comparison of glass and digital slides for cervical cytopathology screening and interpretation.

Cervical cancer is the second most common form of cancer and a leading cause of premature death among women aged 15 to 44 worldwide. In Brazil, there is a high prevalence of infection by the human papillomavirus - HPV. Digital pathology optimizes time and space for reading cervicovaginal cytology slides. We evaluated the feasibility of using whole slide images (WSI) for the routine interpretation of cytology exams. A total of 99 cases of vaginal cytology were selected from a reference laboratory in Northeastern Brazil. Three cytotechnicians participated in the study. Cellular atypia was the one that most presented concordance values. Two observers almost perfectly agreed (k = 0.86 and k = 0.84, respectively) on the negative diagnoses. The performance of the evaluators for NILM (negative for intraepithelial lesion and malignancy) showed high reproducibility and sensitivity in the digital slides, mainly between evaluators A and C. In contrast, the microbiology group showed disagreement between the diagnoses by digital slides and the standard- gold. The concordance between the digital diagnoses and the gold standard for ASCUS was 89%. In the inflammatory category, Spearman's test showed similar results between raters A, B, and C (rs = 0.47, rs = 0.41, and rs = 0.47, respectively). This study reports the diagnostic validation using digital slides in view of the need to optimize the cytology visualization process. Our experience shows good diagnostic agreement between digital and optical microscopy in several analyzed categories, but mainly in relation to cellular atypia and inflammatory processes.

Abstract IA007: A novel strategy to trigger ferroptosis in kidney cancer

Abstract Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is typically initiated by inactivation of the von Hippel Lindau (VHL) gene resulting in constitutive activation of the hypoxia inducible factors, HIF-1α and HIF-2α. VHL loss and HIF activation promote lipid accumulation that increases the sensitivity of ccRCC cells to ferroptosis. Here, we reveal Iron Sulfur Cluster Assembly 2 (ISCA2) as a novel molecular target whose inhibition decreases HIF-1/2α levels and induces ferroptosis specifically in VHL-deficient cells. ISCA2 is a component of the late mitochondrial Iron Sulfur Cluster (L-ISC) assembly complex and ISCA2 inhibition either pharmacologically or using siRNA triggers the iron starvation response, resulting in iron/metals overload and death via ferroptosis. ISCA2 inhibition also decreases HIF-2α protein levels by blocking iron-responsive element (IRE)-dependent translation, and at higher concentrations, also decreases HIF-1α translation through unknown mechanisms. Strikingly, pharmacological inhibition of ISCA2 using a novel, orally available ISCA2 inhibitor significantly reduced ccRCC xenograft growth in vivo, decreased HIF-α levels and increased lipid peroxidation, suggesting increased ferroptosis in vivo. Thus, the targeting of ISCA2 may be a promising therapeutic strategy to inhibit HIF-1/2α and to induce ferroptosis in pVHL deficient cells. Citation Format: Mei Yee Koh. A novel strategy to trigger ferroptosis in kidney cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA007.

Abstract A012: Investigating the heterogeneity and clinical significance of tumor-associated macrophages in renal cell carcinoma milieu

Abstract Background: Tumor-associated macrophages (TAMs) exert a range of immunomodulatory functions in the tumor microenvironment (TME) and have been considered key regulators of tumor development. The interactions of TAMs with cancer and stromal cells in the TME have been shown to promote and sustain tumor progression; however, TAMs are largely phenotypically and functionally heterogeneous. Studies at a single-cell level are therefore necessary to understand biological and clinical relevance of heterogeneity of TAMs. Objective: To investigate the heterogeneity of TAM populations in renal cell carcinoma (RCC), the most common form of Kidney cancer, and to determine their connections to patient outcome. Methods and Results: We leverage single-cell RNA sequencing analysis of six primary RCC tumors and three Lung metastatic clear cell RCC (ccRCC) tumors, from which we identified eight TAM and two monocyte clusters shared across all nine patient tissue samples. Differential gene expression and pathway analyses revealed distinct subsets of upregulated genes and cellular pathways activated in each subpopulation. Survival analysis using gene signatures characteristic of each TAM population in datasets of ccRCC tumors (n=533) from TCGA revealed two subpopulations associated with poor patient outcome in ccRCC. Of these, one subpopulation, which we labelled as TAM-8, was characterized by upregulation of pro-inflammatory cytokines, chemokines, and growth factors such as CCL20, CXCL8, and IL1A/B. To our knowledge, this TAM population has not been described in RCC previously. We performed additional in silico functional analyses to further characterize the function of TAM-8 subpopulation, which indicated an active role in promoting immune cell infiltration and angiogenesis via various pro-inflammatory signaling pathways. Conclusion: This study provides new insight into the heterogeneity of TAM populations in RCC and defines CCL20/CXCL8/IL1High TAM-8 population as a potential driver of poor outcome and a candidate therapeutic target. Citation Format: Evelyn M. Zavacky, Minjun Kim, Ariel Madrigal, Zohreh Mehrjoo, Jonathon Spicer, Simon Tanguay, Fadi Brimo, Hamed Najafabadi, Yasser Riazalhosseini. Investigating the heterogeneity and clinical significance of tumor-associated macrophages in renal cell carcinoma milieu [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A012.

Clinical significance of the pathological type of tumor in common forms of ovarian cancer: A retrospective study

Background. Epithelial forms of ovarian cancer account for up to 90% of all ovarian malignancies. Epithelial forms of ovarian cancer are classified according to the WHO criteria of 2014 into several types: the most common are serous carcinomas (70%), mucinous carcinomas (3%), endometrioid tumors (10%), light cell cancer, transitional cell cancer, mixed and undifferentiated carcinomas are rare.&#x0D; Aim. To study the overall survival and progression-free survival depending on the stage of the disease, the pathological type of tumor and the degree of differentiation of tumor cells.&#x0D; Materials and methods. A retrospective analysis of the treatment of 467 patients with stage IIICIVB ovarian cancer in the Primorsky Regional Oncological Dispensary for the period from 2003 to 2021 was carried out. The obtained parameters were processed using standard statistical analysis methods using the IBM SPSS Statistics 26 program.&#x0D; Results. The overall results showed that the most favorable course of stage IIICIVB ovarian cancer has a serous type of ovarian cancer, probably due to its sensitivity to chemotherapy and aggressive surgical tactics. Patients with a mutation in the BRCA1/2 genes have a better prognosis in overall survival rates. BRCA1/2 mutations are associated with an improved response to chemotherapy with platinum-based drugs.&#x0D; Conclusion. The analysis made it possible to determine the most favorable prognostic factors for advanced stages of ovarian cancer, when comparing the groups of high-grade and low-grade IIIIV stage serous carcinoma, it was noted that the median overall survival, depending on the histological type, is better in the group of patients with low-grade IIIIV stage serous carcinoma. When comparing, depending on the timing of the operation performed, it can be noted that the median overall survival and median progression-free survival rates are better in the group of patients who received primary cytoreductive surgery.

PD-1 Inhibitors in Elderly and Immunocompromised Patients with Advanced or Metastatic Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) of the skin is the second most common form of skin cancer, with aging and prolonged exposure to ultraviolet rays being the main causes of the disease. Cemiplimab and pembrolizumab recently gained regulatory approval for the treatment of locally advanced and metastatic cSCC-conditions that are not treatable by surgical resection and/or radiotherapy. Although the results from the clinical trials have been promising, these studies have not included immunosuppressed, elderly patients. In this study, we included all immunocompromised and immunocompetent patients over the age of 75 years diagnosed with locally advanced or metastatic cSCC and treated with cemiplimab or pembrolizumab. The median duration of follow-up from cSCC diagnosis was 35.6 months, 82.9% of patients were male, and the median age was 83 years old. The median progression-free survival was 8.94 months. The incidence of treatment-related adverse events was 85.6%, the majority of which were grades 1 or 2. The disease control rate was 91.4%, the complete response rate was 17.1%, the partial response rate was 51.4%, the stable disease rate was 23%, and the progressive disease rate was 8.7%. Based on this study, cemiplimab and pembrolizumab for the treatment of locally advanced or metastatic cSCC in elderly, immunocompromised patients are efficacious, with acceptable safety profiles.

Modelling the Sorafenib-resistant Liver Cancer Microenvironment by Using 3-D Spheroids.

Liver cancer is the third leading cause of cancer-related mortality, and hepatocellular carcinoma (HCC) is the most common form of liver cancer, and it usually occurs in the setting of chronic liver disease and cirrhosis. For patients with advanced HCC, systemic treatment is the first choice - however, resistance occurs frequently. Sorafenib was the first tyrosine kinase inhibitor approved for advanced HCC, and resistance to the therapy is a serious concern. When sorafenib therapy fails in a patient, it can be challenging to decide whether they can undergo a second-line therapy, and to determine which therapy they will be able to tolerate. Thus, physiologically relevant in vitro preclinical models are crucial for screening potential therapies, and 3-D tumour spheroids permit studies of tumour pathobiology. In this study, a drug-resistant 3-D tumour spheroid model was developed, based on sorafenib-resistant hepatocellular carcinoma cells, LX2 stellate cells and THP-1 monocytes. Model tumour spheroids that were formed with the sorafenib-resistant cells demonstrated lower diffusion of doxorubicin and exhibited increased resistance to regorafenib. Moreover, in the sorafenib-resistant spheroids, there was increased presence of CD68-positive cells and a reduction in inflammatory marker secretion. The sorafenib-resistant cell line-derived spheroids also showed a higher expression of FGF-19, PDGF-AA and GDF-15, which are known to be involved in malignancies. This multi-cell type spheroid model represents a potentially useful system to test drug candidates in a microenvironment that mimics the drug-resistant tumour microenvironment in HCC.

Molecular genetic aberrations in the pathogenesis of multiple myeloma.

Multiple myeloma (MM) is the second most common form of blood cancer characterized by clonal expansion of malignant plasma cells within the bone marrow. MM is a complex, progressive, and highly heterogeneous malignancy, which occurs via a multistep transformation process involving primary and secondary oncogenic events. Recent advances in molecular techniques have further expanded our understanding of the mutational landscape, clonal composition, and dynamic evolution patterns of MM. The first part of this review describes the key oncogenic events involved in the initiation and progression of MM, together with their prognostic impact. The latter part highlights the most prominent findings concerning genomic aberrations promoted by gene expression profiling (GEP) and next-generation sequencing (NGS) in MM. This review provides a concise understanding of the molecular pathogenesis of the MM genome and the importance of adopting emerging molecular technology in future clinical management of MM.

Analysis of WSI Images by Hybrid Systems with Fusion Features for Early Diagnosis of Cervical Cancer.

Cervical cancer is one of the most common types of malignant tumors in women. In addition, it causes death in the latter stages. Squamous cell carcinoma is the most common and aggressive form of cervical cancer and must be diagnosed early before it progresses to a dangerous stage. Liquid-based cytology (LBC) swabs are best and most commonly used for cervical cancer screening and are converted from glass slides to whole-slide images (WSIs) for computer-assisted analysis. Manual diagnosis by microscopes is limited and prone to manual errors, and tracking all cells is difficult. Therefore, the development of computational techniques is important as diagnosing many samples can be done automatically, quickly, and efficiently, which is beneficial for medical laboratories and medical professionals. This study aims to develop automated WSI image analysis models for early diagnosis of a cervical squamous cell dataset. Several systems have been designed to analyze WSI images and accurately distinguish cervical cancer progression. For all proposed systems, the WSI images were optimized to show the contrast of edges of the low-contrast cells. Then, the cells to be analyzed were segmented and isolated from the rest of the image using the Active Contour Algorithm (ACA). WSI images were diagnosed by a hybrid method between deep learning (ResNet50, VGG19 and GoogLeNet), Random Forest (RF), and Support Vector Machine (SVM) algorithms based on the ACA algorithm. Another hybrid method for diagnosing WSI images by RF and SVM algorithms is based on fused features of deep-learning (DL) models (ResNet50-VGG19, VGG19-GoogLeNet, and ResNet50-GoogLeNet). It is concluded from the systems' performance that the DL models' combined features help significantly improve the performance of the RF and SVM networks. The novelty of this research is the hybrid method that combines the features extracted from deep-learning models (ResNet50-VGG19, VGG19-GoogLeNet, and ResNet50-GoogLeNet) with RF and SVM algorithms for diagnosing WSI images. The results demonstrate that the combined features from deep-learning models significantly improve the performance of RF and SVM. The RF network with fused features of ResNet50-VGG19 achieved an AUC of 98.75%, a sensitivity of 97.4%, an accuracy of 99%, a precision of 99.6%, and a specificity of 99.2%.