Common Cancer Research Articles

Mutational Profiling by Next-Generation Sequencing in Patients with Metastatic Non-Small Cell Lung Carcinoma: Our Experience

Introduction According to GLOBOCAN 2020, overall lung cancer is the second most common cancer in both sexes (11.4%) accounting for highest cancer-related mortality (18%).1 Adenocarcinoma subtype of non-small cell lung cancer (NSCLC) is the most common subtype and is divided into further molecular subtypes based on oncogenic driver mutations. Overall survival in these patients is poor with the use of conventional platinum-based double chemotherapy and various recent studies on targeted therapy studies have showed improved survival. Therefore, broad panel-based testing like next-generation sequencing (NGS) is strongly recommended to identify these targetable driver mutations. Aims and Objectives The aim of this study was to evaluate the mutational profile in patients with metastatic NSCLC (mNSCLC) by NGS method. Materials and Methods A hospital-based prospective observational study done on 88 patients under the Department of Medical Oncology, State Cancer Institute during a period of 1 year. All patients above 18 years of age diagnosed as mNSCLC having Eastern Cooperative Oncology Group performance status 0 to 2 and evaluated for mutational profiling by NGS method were included. Five gene panel tests including endothelial growth factor receptor (EGFR), echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK), BRAF, mesenchymal epithelial transition (MET), and ROS proto-oncogene 1 (ROS1) were used. Results and Observations Majority of mNSCLC cases were in the age group of 41 to 50 years (n = 30, 34.1%) with average age at presentation being 53.74 years. Male: female ratio was 1.14:1 and most patients were nonsmokers. Adenocarcinoma subtype of mNSCLC cases had the highest mutational burden (n = 55, 62.5%). EGFR (n = 32, 56.14%) was the most common mutation followed by EML4-ALK (n = 19, 33.33%). Most common EGFR mutation was in Exon 19. Other rare mutations were ROS1 (n = 4), BRAF V600E (n = 1), and MET (n = 1). Skeleton was the most common site of metastasis across all driver mutations. Conclusion EGFR and EML4-ALK were the commonest targetable mutations detected in the study. As there is very limited data from North Eastern region of India regarding mutational status in mNSCLC, this study opens up possibilities for further studies targeting multiple mutations to give us more comprehensive understanding of the mutational landscape of mNSCLC in this era of precision medicine.

Menstrual and reproductive factors associated with risk of breast cancer among Indian women: a cross sectional study from National Family Health Survey, 2019-21

BackgroundThe breast cancer is common cancer in women globally. The risk of breast cancer is strongly associated with women’s menstrual and reproductive factors that have been established in different countries. Therefore present study was aim to explore the association between menstrual and reproductive factors and the risk of breast cancer screening in Indian women.MethodsThe present study data has been used fifth round of the National Family Health Survey (NFHS-V) with 724,115 women in aged 15–49 in 2019-21. The self-reported ever screened of breast cancer for women aged 30–49 was the main outcome variable of the study. Logistic regression models were used to estimate odds ratios and 95% confidence intervals for breast cancer by menstrual and reproductive factors adjusted for potential confounders.ResultsLate menarche (OR = 2.20, 95% CI: 1.48–3.28), irregular menstrual cycle (OR = 1.29, 95% CI: 1.08–3.53)), delay age at first birth (OR = 1.93, 95% CI: 1.11–3.04) and contraceptive pill used (OR = 1.11, 95% CI: 0.74–2.10) were significantly associated to increases the uptake of screening breast cancer. While, a higher number of birth (OR = 0.52, 95% CI: 0.10–1.03), and long duration of breast-feeding practice (OR = 0.75, 95% CI: 0.63–0.91) were reduced to participate for screening breast cancer.ConclusionThe results of the study confirm the role of menstrual and reproductive factors in breast cancer in Indian women. Therefore, our findings are imperative for developing breast cancer prevention strategies and better preparedness. Creating awareness and providing knowledge on cancer could be key strategies for the reduction of breast cancer in Indian reproductive age group women.

Toxoplasma gondii suppresses proliferation and migration of breast cancer cells by regulating their transcriptome

BackgroundBreast cancer is the most common cancer in women worldwide. Toxoplasma gondii (T. gondii) has shown anticancer activity in breast cancer mouse models, and exerted beneficial effect on the survival of breast cancer patients, but the mechanism was unclear.MethodsThe effect of tachyzoites of T. gondii (RH and ME49 strains) on human breast cancer cells (MCF-7 and MDA-MB-231 cells) proliferation and migration was assessed using cell growth curve and wound healing assays. Dual RNA-seq was performed for T. gondii-infected and non-infected cells to determine the differentially expressed genes (DEGs). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein–Protein Interaction Networks analysis (PPI) were performed to explore the related signaling pathway and hub genes. Hub genes were validated using the Kaplan–Meier plotter database, and Pathogen Host Interaction (PHI-base) database. The results were verified by qRT-PCR.ResultsThe tachyzoites of T. gondii decreased the expression of Ki67 and increased the expression of E-cadherin, resulting in suppressing the proliferation and migration of infected human breast cancer cells. The inhibitory effect of T. gondii on breast cancer cells showed a significant dose–response relationship. Compared with the control group, 2321 genes were transcriptionally regulated in MCF-7 cells infected with T. gondii, while 169 genes were transcriptionally regulated in infected MDA-MB-231 cells. Among these genes, 698 genes in infected MCF-7 cells and 67 genes in infected MDA-MB-231 cells were validated by the publicly available database. GO and KEGG analyses suggested that several pathways were involved in anticancer function of T. gondii, such as ribosome, interleukin-17 signaling, coronavirus disease pathway, and breast cancer pathway. BRCA1, MYC and IL-6 were identified as the top three hub genes in infected-breast cancer cells based on the connectivity of PPI analysis. In addition, after interacting with breast cancer cells, the expression of ROP16 and ROP18 in T. gondii increased, while the expression of crt, TgIST, GRA15, GRA24 and MIC13 decreased.ConclusionsT. gondii transcriptionally regulates several signaling pathways by altering the hub genes such as BRCA1, MYC and IL-6, which can inhibit the breast tumor growth and migration, hinting at a potential therapeutic strategy.

Poorly differentiated mucinous carcinoma of the ascending colon complicated by bilateral ovarian mature cystic teratomas in a 17-year-old female patient: a case report

BackgroundColorectal cancer (CRC) is one of the most common cancers worldwide, and screening colonoscopy has led to a decreasing incidence rate. However, the incidence of CRC is increasing among young people, especially adolescents and young adults (AYAs) who are not routinely screened. Although CRC is the fourth most common cancer among AYAs, it is extremely rare. In younger patients, CRC is often diagnosed later, and the proportion of patients with advanced CRC is higher than that in older patients. We herein present a case of poorly differentiated mucinous carcinoma of the ascending colon complicated by bilateral ovarian mature cystic teratomas (MCTs) in an AYA.Case presentationA 17-year-old female patient presented with a chief complaint of abdominal pain and diarrhea that had persisted for more than 3 years. Colonoscopy revealed circumferential wall thickening of the ascending colon, and colonic biopsy revealed a mucous mass and findings of adenocarcinoma, predominantly signet ring cell carcinoma. Abdominal computed tomography (CT) and pelvic magnetic resonance imaging (MRI) showed bilateral ovarian tumors. Laparoscopic right hemicolectomy and enucleation of bilateral ovarian tumors were performed. Although the ascending colon cancer formed a large mass, there were no signs of peritoneal dissemination or direct invasion to the surrounding organs. Microscopically, the ascending colon was a poorly differentiated mucinous carcinoma with signet ring cell carcinoma and lymph node metastasis (9/42). The ovarian tumors were diagnosed as MCTs without any malignant components. The pathological diagnosis was ascending colon cancer (pT4aN2bM0, pStage IIIC) and bilateral ovarian MCTs. Microsatellite instability (MSI) testing was negative, and there were no gene mutations in either RAS or BRAF. Postoperative adjuvant chemotherapy with oxaliplatin and 5-FU was started.ConclusionsWe presented a case of locally advanced ascending colon cancer in a 17-year-old female patient. CRC rarely occurs in AYAs. However, the incidence has gradually increased in recent years. It should be considered as a differential diagnosis for young patients with long-term abdominal symptoms of unknown cause.

PIs versus NNRTIs and the Risk of Cancer among People with HIV

Background: The effect of initial antiretroviral therapy (ART) class on cancer risk in people with HIV (PWH) remains unclear. Setting: Cohort study of 36,322 PWH enrolled (1996-2014) in the North American AIDS Cohort Collaboration on Research and Design. Methods: We followed individuals from ART initiation (protease inhibitor [PI]-, non-nucleoside reverse transcriptase inhibitor [NNRTI]-, or integrase strand transfer inhibitor [INSTI]-based) until incident cancer, death, loss-to-follow-up, 12/31/2014, 85 months (intention-to-treat analyses [ITT]), or 30 months (per-protocol [PP] analyses). Cancers were grouped (non-mutually exclusive) as: any cancer, AIDS-defining cancers (ADC), non-AIDS-defining cancers (NADC), any infection-related cancer, and common individual cancer types. We estimated adjusted hazard ratios (aHR) comparing cancer risk by ART class using marginal structural models emulating ITT and PP trials. Results: We observed 17,004 PWH (954 cancers) with PI-based (median 6 years follow-up), 17,536 (770 cancers) with NNRTI-based (median 5 years follow-up) and 1,782 (29 cancers) with INSTI-based ART (median 2 years follow-up). Analyses with 85 months follow-up indicated no cancer risk differences. In truncated analyses, risk of ADCs (aHR 1.33; 95% CI 1.00, 1.77 [PP-analysis]) and NADCs (aHR 1.23; 95% CI 1.00, 1.51[ITT-analysis]) were higher comparing PIs vs. NNRTIs. Conclusions: Results with longer-term follow-up suggest being on a PI- versus NNRTI-based ART regimen does not affect cancer risk. We observed shorter-term associations that should be interpreted cautiously and warrant further study. Further research with longer duration of follow-up that can evaluate INSTIs, the current first-line recommended therapy, is needed to comprehensively characterize the association between ART class and cancer risk.

Follicular (Infundibular-Tricholemmal) Squamous Cell Carcinoma: A New WHO Entity. Clinicopathological Features in 103 Cases, Including Follow-Up and Implications for Patient Management.

Cutaneous follicular (infundibular-tricholemmal) squamous cell carcinoma (FSCC) is a new World Health Organization entity. We present the largest series of published cases, summarizing clinical data, diagnostic criteria, differential diagnosis, and implications for patient management. Cases were identified from 2004 to 2011. Inclusion criteria included discrete attachment(s) of the tumor to the overlying epidermis via follicular infundibula, tricholemmal keratinization, and cellular pleomorphism. Keratoacanthoma and lesions with adjacent bowenoid epidermal dysplasia were excluded. One hundred three cases of FSCC identified. 48.5% demonstrated completely circumscript borders (in situ for practical purposes), 12.6% uncertain for invasion (overwhelmingly pushing borders), and only 38.8% as clearly invasive. Follicular mucin in acantholytic spaces within tumor epithelium was a distinctive finding in 57.2% of cases. Clinical data indicated predominance in elderly (median 78.5 years) men (70.4%), with preferential head and neck location (81.6%). Many were clinically suspected as squamous cell carcinoma (48.5%). However, a significant minority were clinically diagnosed as basal cell carcinoma (40.8%). This may reflect that FSCC commonly presented as a papule or nodule (51.3%). By contrast, keratoacanthoma was less frequently suggested (17.2%) and still fewer lesions were suspected to be actinic keratosis/Bowen's disease (13.6%). Follow-up in 82 cases (median 26.5 months, range 3-144) identified 5 (6.1%) local recurrences. There was no instance of metastasis in the subgroup of lesions with completely circumscript borders. Three of 45 (6.7%) patients, with follow-up, considered to have tumors with invasive pushing, and/or infiltrative borders developed lymph node metastases. FSCC is identified as a common skin cancer, incorporating historical entities, such as infundibular carcinoma and tricholemmal carcinoma, with readily identifiable histologic features. Correct diagnosis has implications for patient management; a significant subgroup of lesions show completely circumscript borders that are considered in situ for practical purposes.

Exploration and validation of optimal cut-off values for tPSA and fPSA/tPSA screening of prostate cancer at different ages

Objective: To determine the total and age-specific cut-off values of total prostate specific antigen (tPSA) and the ratio of free PSA divided total PSA (fPSA/tPSA) for screening prostate cancer in China. Methods: Based on the Chinese Colorectal, Breast, Lung, Liver, and Stomach cancer Screening Trial (C-BLAST) and the Tianjin Common Cancer Case Cohort (TJ4C), males who were not diagnosed with any cancers at baseline since 2017 and received both tPSA and fPSA testes were selected. Based on Cox regression, the overall and age-specific (＜60, 60-＜70, and ≥70 years) accuracy and optimal cut-off values of tPSA and fPSA/tPSA ratio for screening prostate cancer were evaluated with time-dependent receiver operating characteristic curve (tdROC) and area under curve (AUC). Bootstrap resampling was used to internally validate the stability of the optimal cut-off value, and the PLCO study was used to externally validate the accuracy under different cut-off values. Results: A total of 5 180 participants were included in the study, and after a median follow-up of 1.48 years, a total of 332 prostate cancer patients were included. In the total population, the tdAUC of tPSA and fPSA/tPSA screening for prostate cancer were 0.852 and 0.748, respectively, with the optimal cut-off values of 5.08 ng/ml and 0.173, respectively. After age stratification, the age specific cut-off values of tPSA in the <60, 60-<70, and ≥70 age groups were 3.13, 4.82, and 11.54 ng/ml, respectively, while the age-specific cut-off values of fPSA/tPSA were 0.153, 0.135, and 0.130, respectively. Under the age-specific cut-off values, the sensitivities of tPSA screening for prostate cancer in males <60, 60-70, and ≥70 years old were 92.3%, 82.0%, and 77.6%, respectively, while the specificities were 84.7%, 81.3%, and 75.4%, respectively. The age-specific sensitivities of fPSA/tPSA for screening prostate cancer were 74.4%, 53.3%, and 55.9%, respectively, while the specificities were 83.8%, 83.7%, and 83.7%, respectively. Both bootstrap's internal validation and PLCO external validation provided similar results. The combination of tPSA and fPSA/tPSA could further improve the accuracy of screening. Conclusion: To improve the screening effects, it is recommended that age-specific cut-off values of tPSA and fPSA/tPSA should be used to screen for prostate cancer in the general risk population.

The role of tumor-associated macrophages in hepatocellular carcinoma-from bench to bedside: A review.

Hepatocellular carcinoma is one of the most common cancers worldwide. Despite progress in treatment, recurrence after radical treatment is common, and the prognosis remains poor for patients with advanced disease. Therefore, there is a need to identify prognostic and predictive factors for the response to therapy or more intensive surveillance or treatment. Because the tumor microenvironment plays a crucial role in the development of cancer and metastasis, it is a crucial need to understand processes that are involved in carcinogenesis. Within the microenvironment, several immune cells with different roles are present. One of the most important of these is tumor-associated macrophages. These cells may exert either antitumor or protumor roles. Several studies have suggested that tumor-associated macrophages can be used as prognostic markers. Furthermore, they may be involved in resistance to immunotherapy or systemic treatment. As they play an important role in cancer development, tumor-associated macrophages are also a good target for therapy. In this review, we briefly summarize recent progress on knowledge regarding the basic molecular characteristics, impact on prognosis and potential clinical implications of tumor-associated macrophages in hepatocellular carcinoma.

Classification of mammogram breast cancer using customized deep learning model

GLOBOCAN 2020 states that, after lung cancer, breast cancer is the most common cancer worldwide, affecting many women [1]. AI-based computer-assisted detection/diagnosis techniques can assist radiologists in diagnosing breast cancer earlier. Mammography is one of the most widely used and effective methods for detecting and treating breast cancer. This research proposes a customised deep-learning model for breast cancer categorization. To effectively categorise the breast cancer mammography image, two customised CNN models are proposed. Three real-time datasets such as MIAS, CBIS-DDSM, and INbreast were used to evaluate the efficacy of the proposed categorization strategy. The results show that the proposed method effectively classifies the image and obtains 98.78%, 97.84% and 96.92% accuracy for the datasets MIAS, INbreast and CBIS-DDSM.

The complete Kaposi sarcoma-associated herpesvirus genome induces early-onset, metastatic angiosarcoma in transgenic mice

Kaposi sarcoma (KS) is the most common cancer in persons living with HIV. It is caused by KS-associated herpesvirus (KSHV). There exists no animal model for KS. Pronuclear injection of the 170,000-bp viral genome induces early-onset, aggressive angiosarcoma in transgenic mice. The tumors are histopathologically indistinguishable from human KS. As in human KS, all tumor cells express the viral latency-associated nuclear antigen (LANA). The tumors transcribe most viral genes, whereas endothelial cells in other organs only transcribe the viral latent genes. The tumor cells are of endothelial lineage and exhibit the same molecular pattern of pathway activation as KS, namely phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR, interleukin-10 (IL-10), and vascular endothelial growth factor (VEGF). The KSHV-induced tumors are more aggressive than Ha-ras-induced angiosarcomas. Overall survival is increased by prophylactic ganciclovir. Thus, whole-virus KSHV-transgenic mice represent an accurate model for KS and open the door for the genetic dissection of KS pathogenesis and evaluation of therapies, including vaccines.

Comparison of Ultrasound and MRI in Detecting Breast Cancer: A Retrospective Study in Mumbai Hospitals, India

Introduction: Breast cancer is the most common cancer in women throughout the world. Early detection of breast cancer is very important to increase the chances of cure. Ultrasonography (USG) and magnetic resonance imaging (MRI) are two imaging methods commonly used to detect breast cancer. The aim of this study was to compare the accuracy of ultrasound and MRI in detecting breast cancer in female patients at Mumbai Hospital, India.&#x0D; Methods: A retrospective study was conducted on 2435 female patients who underwent ultrasound and MRI examinations at Mumbai Hospital, India between 2018 and 2023. Patient data was collected from electronic medical records and analyzed to compare the accuracy of ultrasound and MRI in detecting breast cancer.&#x0D; Results: The research results show that MRI is more accurate than ultrasound in detecting breast cancer. MRI sensitivity was 95.2%, while ultrasound sensitivity was 78.3%. The specificity of MRI was 98.7%, while the specificity of USG was 94.3%. The positive predictive value of MRI was 95.2%, while the positive predictive value of USG was 87.5%. The negative predictive value of MRI was 98.7%, while the negative predictive value of USG was 94.3%.&#x0D; Conclusion: MRI is recommended as the primary imaging method for detecting breast cancer in female patients. Ultrasound can be used as a complementary method to MRI.

In vitro data suggest a role for PMS2 Kozak sequence mutations in Lynch syndrome risk

Lynch syndrome (LS) is the most common hereditary cancer syndrome. Heterozygous loss-of-function variants in PMS2 are linked to LS. While these variants are not directly cancer causing, reduced PMS2 function results in the accumulation of somatic variants and increased cancer risk over time due to DNA mismatch repair dysfunction. It is reasonable that other types of genetic variation that impact the expression of PMS2 may also contribute to cancer risk. The Kozak sequence is a highly conserved translation initiation motif among higher eukaryotes and is defined as the nine base pairs upstream of the translation start codon through the first four bases of the translated sequence (5'-[GTT]GCATCCATGG-3'; human PMS2: NM_000535.7). While Kozak sequence variants in PMS2 have been reported in ClinVar in patients with suspected hereditary cancer, all variants upstream of the translation start site are currently classified as variants of undetermined significance (VUSs). We hypothesized that variants significantly disrupting the Kozak sequence of PMS2 would decrease PMS2 protein expression, contributing to increased cancer risk over time. Using a dual-luciferase reporter plasmid and site-directed mutagenesis, we generated the wild-type human PMS2 and the ClinVar VUSs within the PMS2 Kozak sequence. Besides the c.1A>C variant, which is already known to be pathogenic, we implicate six additional variants as American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) pathogenic supporting (PP) variants and classify ten as benign supporting (BP). In summary, we present a method developed for the classification of human PMS2 Kozak sequence variants that can contribute to the re-classification of VUSs identified in patients.

Lung Cancer Prediction and Classification Using Decision Tree and VGG16 Convolutional Neural Networks

Introduction A malignant abnormal growth that starts in the tissues of the lungs is called Lung Cancer. It ranks among the most common and lethal cancers globally. Lung Cancer is particularly dangerous because of its aggressive nature and how quickly it can extend to other areas of the body. We propose a two-step verification architecture to check the presence of Lung Cancer. The model proposed by this paper first assesses the patient based on a few questions about the patient's symptoms and medical background. Then, the algorithm determines whether the patient has a low, medium, or high risk of developing lung cancer by diagnosing the response using the “Decision Tree” classification at an accuracy of 99.67%. If the patient has a medium or high risk, we further validate the finding by examining the patient's CT scan image using the “VGG16” CNN model at an accuracy of 92.53%. Background One of the key areas of research on Lung Cancer prediction is to identify patients based on symptoms and medical history. Its subjective nature makes it challenging to apply in real-world scenarios. Another research area in this field involves forecasting the presence of cancer cells using CT scan imagery, providing high accuracy. However, it requires physician intervention and is not appropriate for early-stage prediction. Objective This research aims to forecast the severity of Lung Cancer by analyzing the patient with a few questions regarding the symptoms and past medical conditions. If the patient has a medium or a high risk, we further examine their CT scan, validate the result and also predict the type of Lung Cancer. Methodology This paper uses the “Decision Tree” algorithm and the Customised “VGG16” model of CNN for the implementation. The “Decision Tree” algorithm is used to analyze the answers given by the patient to distinguish the severity of Lung Cancer. We further use Convolution Neural Networks with a Customised “VGG16” model to examine the patient's CT scan image, validate the result and categorize the type of Lung Cancer. Results The “Decision Tree” approach for forecasting the severity of lung cancer yields an accuracy of 99.67%. The accuracy of the customized “VGG16” CNN model to indicate the type of Lung Cancer suffered by the patient is 92.53% Conclusion This research indicates that our technique provides greater accuracy than the prior approaches for this problem and has extensive use in the prognosis of Lung Cancer.

A new perspective on Endometrial Carcinoma classification and management strategies in context of molecular subtypes.

Endometrial cancer is the most common gynecological cancer and the second most prevalent female malignancy in the developed world. It is typically diagnosed in postmenopausal women, presenting with the characteristic clinical symptom of uterine abnormal bleeding. In the past, only two histological types were considered. However, it has become increasingly evident that endometrial cancer is a clinically heterogeneous disease, and this heterogeneity is closely associated with the diversity of underlying molecular alterations. The Cancer Genome Atlas classification has significantly advanced the diagnosis, risk stratification, and management of endometrial cancer by categorizing it into four molecular subgroups, each characterized by distinct mutational burdens and copy number alterations.

Cancer-associated fibroblast activation predicts progression, metastasis, and prognosis of cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and the metastatic disease is associated with poor prognosis. Cancer-associated fibroblasts (CAFs) promote progression of cancer, but their role in cSCC is largely unknown. We examined the potential of CAF markers in the assessment of metastasis risk and prognosis of primary cSCC. We utilized multiplexed fluorescence immunohistochemistry for profiling CAF landscape in metastatic and non-metastatic primary human cSCCs, in metastases, and in premalignant epidermal lesions. Quantitative high-resolution image analysis was performed with two separate panels of antibodies for CAF markers and results were correlated with clinical and histopathological parameters including disease-specific mortality. Increased stromal expression of fibroblast activation protein (FAP), α-smooth muscle actin, and secreted protein acidic and rich in cysteine (SPARC) were associated with progression to invasive cSCC. Elevation of FAP and platelet-derived growth factor receptor-β (PDGFRβ) expression was associated with metastasis risk of primary cSCCs. High expression of PDGFRβ and periostin correlated with poor prognosis. Multimarker combination defined CAF subset, PDGFRα-/PDGFRβ+/FAP+, was associated with invasion and metastasis, and independently predicted poor disease-specific survival. These results identify high PDGFRβ expression alone and multimarker combination PDGFRα-/PDGFRβ+/FAP+ by CAFs as potential biomarkers for risk of metastasis and poor prognosis.

DROSHA regulates mesenchymal gene expression in Wilms tumor.

Wilms tumor, the most common pediatric kidney cancer, resembles embryonic renal progenitors. Currently, there are no ways to therapeutically target Wilms tumor driver mutations, such as in the microRNA processing gene DROSHA. Here we used a "multi-omics" approach to define the effects of DROSHA mutation in Wilms tumor. We categorized Wilms tumor mutations into four mutational subclasses with unique transcriptional effects: microRNA processing, MYCN activation, chromatin remodeling, and kidney developmental factors. In particular, we find that DROSHA mutations are correlated with de-repressing microRNA target genes that regulate differentiation and proliferation and a self-renewing, mesenchymal state. We model these findings by inhibiting DROSHA expression in a Wilms tumor cell line, which led to upregulation of the cell cycle regulator cyclin D2 (CCND2). Furthermore, we observed that DROSHA mutations in Wilms tumor and DROSHA silencing in vitro were associated with a mesenchymal state with aberrations in redox metabolism. Accordingly, we demonstrate that Wilms tumor cells lacking microRNAs are sensitized to ferroptotic cell death through inhibition of glutathione peroxidase 4 (GPX4), the enzyme that detoxifies lipid peroxides. Implications: This study reveals genotype-transcriptome relationships in Wilms tumor and points to ferroptosis as a potentially therapeutic vulnerability in one subset of Wilms tumor.

Role of Protein Tyrosine Phosphatase Receptor Type E (PTPRE) in Chemoresistant Retinoblastoma.

Protein tyrosine phosphatase receptor type E (PTPRE) is a member of the "classical" protein tyrosine phosphatase subfamily and regulates a variety of cellular processes in a tissue-specific manner by antagonizing the function of protein tyrosine kinases. PTPRE plays a tumorigenic role in different human cancer cells, but its role in retinoblastoma (RB), the most common malignant eye cancer in children, remains to be elucidated. Etoposide-resistant RB cell lines and RB patients display significant higher PTPRE expression levels compared to chemosensitive counterparts and the healthy human retina, respectively. PTPRE promotor methylation analyses revealed that PTPRE expression in RB is not regulated via this mechanism. Lentiviral PTPRE knockdown (KD) induced a significant decrease in growth kinetics, cell viability, and anchorage-independent growth of etoposide-resistant Y79 and WERI RB cells. Caspase-dependent apoptosis rates were significantly increased and a re-sensitization for etoposide could be observed after PTPRE depletion. In vivo chicken chorioallantoic membrane (CAM) assays revealed decreased tumor formation capacity as well as reduced tumor size and weight following PTPRE KD. Expression levels of miR631 were significantly downregulated in etoposide-resistant RB cells and patients. Transient miR631 overexpression resulted in significantly decreased PTPRE levels and concomitantly decreased proliferation and increased apoptosis levels in etoposide-resistant RB cells. These impacts mirror PTPRE KD effects, indicating a regulation of PTPRE via this miR. Additionally, PTPRE KD led to altered phosphorylation of protein kinase SGK3 and-dependent on the cell line-AKT and ERK1/2, suggesting potential PTPRE downstream signaling pathways. In summary, these results indicate an oncogenic role of PTPRE in chemoresistant retinoblastoma.

Bioinformatics and system biology approaches to determine the connection of SARS-CoV-2 infection and intrahepatic cholangiocarcinoma.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), has infected millions of individuals worldwide, which poses a severe threat to human health. COVID-19 is a systemic ailment affecting various tissues and organs, including the lungs and liver. Intrahepatic cholangiocarcinoma (ICC) is one of the most common liver cancer, and cancer patients are particularly at high risk of SARS-CoV-2 infection. Nonetheless, few studies have investigated the impact of COVID-19 on ICC patients. With the methods of systems biology and bioinformatics, this study explored the link between COVID-19 and ICC, and searched for potential therapeutic drugs. This study identified a total of 70 common differentially expressed genes (DEGs) shared by both diseases, shedding light on their shared functionalities. Enrichment analysis pinpointed metabolism and immunity as the primary areas influenced by these common genes. Subsequently, through protein-protein interaction (PPI) network analysis, we identified SCD, ACSL5, ACAT2, HSD17B4, ALDOA, ACSS1, ACADSB, CYP51A1, PSAT1, and HKDC1 as hub genes. Additionally, 44 transcription factors (TFs) and 112 microRNAs (miRNAs) were forecasted to regulate the hub genes. Most importantly, several drug candidates (Periodate-oxidized adenosine, Desipramine, Quercetin, Perfluoroheptanoic acid, Tetrandrine, Pentadecafluorooctanoic acid, Benzo[a]pyrene, SARIN, Dorzolamide, 8-Bromo-cAMP) may prove effective in treating ICC and COVID-19. This study is expected to provide valuable references and potential drugs for future research and treatment of COVID-19 and ICC.

Robotic versus Laparoscopic Liver Resections for Colorectal Metastases: A Systematic Review and Meta-Analysis.

Colorectal cancer is the third most common cancer worldwide, and the liver is the most common localization of metastatic disease. The incidence of minimally invasive liver surgery is increasing, and robotic surgery (RLR) is believed to overcome some limitations of a laparoscopic approach (LRL). We performed a systematic review and meta-analysis of operative and short-term oncologic outcomes of the laparoscopic versus robotic-assisted liver resection for colorectal liver metastases. An online search of PubMed, Embase, Scopus, and the Cochrane databases was performed. Eight studies involving 3210 patients were considered eligible for the meta-analysis. In the LRL group, a higher conversion to open rate (12.4%) was observed compared to the RLR (6.7%; p = <0.001). 30-day mortality was 0.7% for the LRL group compared to 0.5% for the RLR group (p = 0.76). Mortality in longer periods among LLR and RLR amounted to 18.2% vs. 8.0% for 1-year mortality (p = 0.07), 34.1% vs. 26.7% for 2-year mortality (p = 0.13), and 52.3% vs. 48.3% for 3-year mortality (p = 0.46). The length of hospital stay was 5.6 ± 2.5 vs. 5.8 ± 2.1 days, respectively (p = 0.47). There were no significant differences between the incidence of individual complications in the LRL and RLR groups (p = 0.78). Laparoscopic or robotic approaches for colorectal liver metastases are comparable in terms of safety and effectiveness. There are significant advantages to robotic surgery, although there is still no long-term evidence concerning overall survival, and the number of patients operated on using RLR remains small.

Remnant cholesterol is an effective biomarker for predicting survival in patients with breast cancer

BackgroundBreast cancer is the most common malignancy in women worldwide. The relationship between remnant cholesterol (RC) and the prognosis of patients with breast cancer has not been clearly reported. This study investigated the prognostic value of RC in predicting mortality in patients with breast cancer.MethodsThis study prospectively analysed 709 women patients with breast cancer from the Investigation on Nutrition Status and Clinical Outcome of Common Cancers (INSCOC) project. Restricted cubic splines were used to analyse the dose-response relationship between RC and breast cancer mortality. The Kaplan–Meier method was used to evaluate the overall survival of patients with breast cancer. A Cox regression analyses was performed to assess the independent association between RC and breast cancer mortality. Inverse probability of treatment weighting (IPTW) using the propensity score was used to reduce confounding. Sensitivity analysis was performed after excluding patients with underlying diseases and survival times shorter than one year.ResultsA linear dose-response relationship was identified between RC and the risk of all-cause mortality in patients with breast cancer (p = 0.036). Kaplan–Meier survival analysis and log-rank test showed that patients with high RC levels had poorer survival than those with low RC levels (p = 0.007). Univariate and multivariate Cox regression analyses showed that RC was an independent risk factor for mortality in women patients with breast cancer. IPTW-adjusted analyses and sensitivity analyses showed that CR remained a prognostic factor.ConclusionsRC is an independent risk factor for the prognosis of patients with breast cancer, and patients with higher RC levels have poorer survival.