Staging Of Malignancies Research Articles

Surgical complications following sentinel lymph node biopsy guided by γ-probe and methylene blue in 113 tumour-bearing dogs.

Sentinel lymph node biopsy (SLNB) is an accepted veterinary surgical procedure given the impact of early detection of nodal metastases on staging of several canine malignancies. This study aims at reporting the incidence and risk factors for surgical complications of SLNB in tumour-bearing dogs. A total of 113 client-owned dogs that underwent tumour excision and SLNB guided by γ-probing and blue dye were retrospectively enrolled. Recorded variables included: signalment, location and number of extirpated lymphocenters and nodes, time for SLNB, histopathological status of excised nodes. Incidence of SLNB complications was calculated. They were classified as minor and major based on severity and required treatment, and as short-term (0-30 days) and long-term (31-90 days). Univariate analysis with generalized linear model with binomial error estimated the association between variables and incidence of SLNB complications. Significance was set at 5%. Median overall time for SLNB was 25 min. Surgeons excised one node in 38% of dogs and multiple nodes in 62% of cases, belonging to one (62%) or multiple (38%) lymphocenters. Metastases were detected in 45% of nodes. No intraoperative complications occurred. The overall incidence of postoperative complications of SLNB was 21,24%, the majority of which (91.67%) were minor. Only increasing dogs' weight was associated with an increased incidence of SLNB complications (p=.00976). Sentinel lymphadenectomy was associated with a relatively low incidence of complications, most of which were self-limiting. The low morbidity and previously reported impact on staging of SLNB justify its implementation to collect data for prognostic studies.

Toll-like receptor 4 promotes bladder cancer progression upon S100A8/A9 binding, which requires TIRAP-mediated TPL2 activation

Bladder cancer is an often widely disseminated and deadly cancer. To block the malignant outgrowth of bladder cancer, we must elucidate the molecular-level characteristics of not only bladder cancer cells but also their surrounding milieu. As part of this effort, we have long been studying extracellular S100A8/A9, which is elevated by the inflammation associated with certain cancers. Extracellularly enriched S100A8/A9 can hasten a shift to metastatic transition in multiple types of cancer cells. Intriguingly, high-level S100A8/A9 has been detected in the urine of bladder-cancer patients, and the level increases with the stage of malignancy. Nonetheless, S100A8/A9 has been investigated mainly as a potential biomarker of bladder cancers, and there have been no investigations of its role in bladder-cancer growth and metastasis. We herein report that extracellular S100A8/A9 induces upregulation of growth, migration and invasion in bladder cancer cells through its binding with cell-surface Toll-like receptor 4 (TLR4). Our molecular analysis revealed the TLR4 downstream signal that accelerates such cancer cell events. Tumor progression locus 2 (TPL2) was a key factor facilitating the aggressiveness of cancer cells. Upon binding of S100A8/A9 with TLR4, TPL2 activation was enhanced by an action with a TLR4 adaptor molecule, TIR domain-containing adaptor protein (TIRAP), which in turn led to activation of the mitogen-activated protein kinase (MAPK) cascade of TPL2. Finally, we showed that sustained inhibition of TLR4 in cancer cells effectively dampened cancer survival in vivo. Collectively, our results indicate that the S100A8/A9-TLR4-TPL2 axis influences the growth, survival, and invasive motility of bladder cancer cells.

Improving lung cancer detection using faster region‐based convolutional neural network aided with fuzzy butterfly optimization algorithm

SummaryLung cancer is the most deadly type of cancer and it is caused by genetic variations in lung tissues. Other causes of lung cancer are alcohol, smoking, and threatening gas exposures. The diagnosis of lung cancer is an intricate task and early detection of lung cancer can help to get the exact treatment in advance. The application of a computer‐aided diagnosis process helps to predict lung cancer earlier, nonetheless, it does not provide better accuracy. The overfitting nature of features and dimensionality of lung cancer can prevent it from obtaining maximum accuracy. Hence, we proposed a novel faster region convolutional neural network (RCNN) based fuzzy butterfly optimization algorithm (FBOA) to achieve better prediction accuracy and effectiveness. The proposed Faster RCNN can provide better positioning of lung cancer swiftly and effectively and the FBOA approach can be used to perform two‐stage classification. The fuzzy rules used in the FBOA can be utilized to find the severity of the lung cancer and differentiate the Benign stage and Malignant stage effectively. The experimental analyses are performed in MATLAB simulation. The preprocessing of images is performed by different tools from MATLAB and is to format the images as required. The cancer imaging archive (TCIA) dataset is utilized to analyze the performance of the proposed method and compared with various state‐of‐art works. The performance of the proposed method is evaluated by using different evaluation metrics such as precision, recall, F‐measure, and accuracy and attained 99, 98, 99, and 97% respectively. Thus, our proposed method outperforms all the other approaches.

Upregulation of Metallothionein 1 G (MT1G) Negatively Regulates Ferroptosis in Clear Cell Renal Cell Carcinoma by Reducing Glutathione Consumption.

Ferroptosis is characterized by lipid peroxidation and iron accumulation, closely associated with clear cell renal cell carcinoma (ccRCC). It is of great significance for prognostic prediction and treatment of ccRCC to find biomarkers related to ferroptosis. We conducted several bioinformatic analyses using the transcriptome data and clinical information derived from online databases. Firstly, we identified the differentially expressed target genes in ccRCC. Then, t test and COX analysis were used to determine whether it was an independent prognostic factor combined with clinical information. String and gene set enrichment analysis (GSEA) were used to predict its function. Finally, we used ccRCC cells: 769-P and KAKI-1 in vitro to verify the regulation of target genes on cell proliferation apoptosis, iron metabolism, and GSH metabolism, which were used to judge the effect of target genes on ferroptosis. The study showed that MT1G is downregulated in ccRCC tissues compared with normal renal tissues. However, the ccRCC patients with higher expression relatively had higher malignancy and advanced stages. MT1G is an independent adverse factor for the prognosis of ccRCC. The protein interaction network analysis and GSEA showed that MT1G was closely related to GSH metabolism-related proteins (GSR) and lipid oxidation-related proteins (PLA2G2A). Samples with high expression of MT1G were enriched in “glutathione metabolism,” “oxidative phosphorylation,” and “proteasome,” whose function was involved in GSH metabolism and lipid peroxidation. The term associated with the occurrence and development of tumors included “P53 signaling pathway.” Furthermore, in vitro experiments showed that MT1G partially blocked ferroptosis induced by erastin and sorafenib-induced ccRCC cell lines (769-P and CAKI-1). The mechanism may be that MT1G affects ferroptosis by regulating GSH consumption in ccRCC cells. MT1G may be a negative regulator of ferroptosis in ccRCC cells and a biomarker of poor prognosis.

Evaluation of Sex Hormone in Benign and Malignant Breast Cancer in Iraqi Women

Elevated levels of circulating estrogens and androgens are linked to higher breast cancer risk among postmenopausal women; however, little is known about hormone levels within the breast. Hormone concentrations within the breast may not be reflected in the blood and are likely important contributors to breast carcinogenesis. The present study investigated the sex hormone (Estrogen, progesterone, Prolactin and testosterone). Female patients are divided into three groups (Benign, malignant and control). Benign (B)(34 patients) is divided into sub-groups including Benign premenopausal stage (B1)(17 patients) Benign postmenopausal stage (B2) (17 patients) and Malignant (M)(34 patients), Malignant premenopausal stage (M1) (17patients) and Malignant postmenopausal stage (M2)(17patients), and control group (C) include (11) premenopausal stage (C1) and (11) postmenopausal stage (C2). The expression level of soluble sex hormone (Estrogen, progesterone, Prolactin and testosterone) in serum was determined by an ELISA. Technique. The patients attended the Center for Early Detection of Breast Tumor at an oncology teaching hospital in Medical City. The study was conducted on 15/February (2021) to 20/July (2021). The values of Estrogen hormone in premenopausal malignant M1 (34.76 ±4.26 pg/ml) decreased significantly (P≤0.05) in comparison with C1, but it was non-significant in comparison with C2 and B1. M2 (64.28 ±4.17 pg/ml) shows a non-significant increase compared with C1, but it increased significantly with C2, B2 and M1. The values of progesterone hormone B1(12.75 ±3.34ng/ml) and B2( 13.06 ±2.98 ng/ml) was non-significant(P≤0.05) in comparison with C1 (8.17 ±2.87 ng/ml) and C2(6.28 ±2.87 ng/ml).M1 (14.30 ±4.29 ng/ml) and M2 (15.76 ±4.34 ng/ml) show non-significant difference in comparison with C1,C2,B1and B2. The values of Prolactin hormone in the M1(32.07±3.56(µIU/ml)) and M2(29.42±3.16) show non-significant difference(p>0.05) with C1,C2,B1 and B2.levelsTestosterone hormone show a significant in M1(1.462 ±0.11(ng/ml)) increased (p<0.05) in comparison with C1,C2,B1,B2. M2(1.392 ±0.10(ng/ml)) increase significantly(p<0.05) in comparison with C1,C2,B1,B2 and M1. concluded from this study that the levels of estrogen increased significantly in postmenopausal malignant M2 women with breast cancer, and the levels of testosterone hormone significant increase in pre and postmenopausal breast cancer women, the levels of Prolactin and progesterone hormone showed non-significant differences in comparison with other groups. Keywords: Sex Hormone, Benign, malignant, Breast Cancer,

A Systematic Review and Meta-Analysis Evaluating Geographical Variation in Outcomes of Cancer Patients Treated in ICUs.

OBJECTIVES:The reported mortality rates of cancer patients admitted to ICUs vary widely. In addition, there are no studies that examined the outcomes of critically ill cancer patients based on the geographical regions. Therefore, we aimed to evaluate the mortality rates among critically ill cancer patients and provide a comparison based on geography.DATA SOURCES:PubMed, EMBASE, and Web of Science.STUDY SELECTION:We included observational studies evaluating adult patients with cancer treated in ICUs. We excluded non-English studies, those with greater than 30% hematopoietic stem cell transplant or postsurgical patients, and those that evaluated a specific type of critical illness, stage of malignancy, or age group.DATA EXTRACTION:Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. Studies were classified based on the continent in which they were conducted. Primary outcomes were ICU and hospital mortality. We pooled effect sizes by geographical region.DATA SYNTHESIS:Forty-six studies were included (n = 110,366). The overall quality of studies was moderate. Most of the published literature was from Europe (n = 22), followed by North America (n = 9), Asia (n = 8), South America (n = 5), and Oceania (n = 2). Pooled ICU mortality rate was 38% (95% CI, 33–43%); the lowest mortality rate was in Oceania (26%; 95% CI, 22–30%) and highest in Asia (51%; 95% CI, 44–57%). Pooled hospital mortality rate was 45% (95% CI, 41–49%), with the lowest in North America (37%; 95% CI, 31–43%) and highest in Asia (54%; 95% CI, 37–71%).CONCLUSIONS:More than half of cancer patients admitted to ICUs survived hospitalization. However, there was wide variability in the mortality rates, as well as the number of available studies among geographical regions. This variability suggests an opportunity to improve outcomes worldwide, through optimizing practice and research.

Clinicopathological Characteristics and Surgical Findings of Epithelial Ovarian Carcinoma

Introduction: Ovarian cancer was the third most common gynecological cancer globally in 2020. The objective of this study was to delineate clinicopathological characteristics and surgical findings of epithelial ovarian carcinoma in our context.
 Methods: This is a descriptive cross-sectional study conducted at Bhaktapur Cancer Hospital, from March, 2023 to May, 2023. Ethical approval was obtained from Institutional Review Board (Ref. No. 773/2079/80). Data pertaining patient characteristics, initial symptoms, pre-operative CA-125 level, risk of malignancy index, stage, histology, type and extent of surgery and residual disease were evaluated in 35 cases of epithelial ovarian carcinoma. Data were analyzed using SPSS version 16.0.
 Results: Among 35 cases of epithelial ovarian carcinoma, majority occurred in postmenopausal women (57.1%) with mean age 53 years. The most common presentation was abdominal distension (51.4%). Majority of patients had raised preoperative serum CA-125 level (94.2%) and RMI score (91.4%). Most of them presented in advanced stage III and IV (85.7%) with histology type high grade serous 2 carcinoma (82.8%). Eleven patients (31.4%) underwent primary cytoreductive surgery and 24 (68.5%) patients received neoadjuvant chemotherapy with three to six cycles of Carboplatin and Paclitaxel and underwent interval cytoreductive surgery. At surgery, majority had no residual disease (R 0 94.2%).
 Conclusions: Majority of epithelial ovarian carcinoma occurred in postmenopausal women with abdominal distension. Most of them presented in advanced stage III-IV with histology high grade serous carcinoma. They underwent interval cytoreductive surgery more than primary cytoreductive surgery. At surgery, majority had no residual disease.

ANALYSIS OF GENITAL TRACT MALIGNANCIES IN POSTMENOPAUSAL FEMALES – A HOSPITAL-BASED STUDY

Introduction: Female genital tract malignancy is common carcinoma. In the developed countries, ovarian cancer is the most common cancer and in developing countries, carcinoma cervix is the most common malignancy. Menopause does not cause cancer, but the risk of developing cancer increases as women ages. Therefore, women who have been through natural menopause are more likely to develop cancer because they are older. A woman who experiences menopause after age 55 has increased risk of ovarian, breast, and uterine cancers. The risk is greater if women also began menstruating before age 12. This is because a woman who menstruates longer than normal during her lifetime is exposed to more estrogen and has more ovulation. Hence, aims and objectives of our study are: (1) To determine the incidence of different genital malignancies in postmenopausal females and (2) to analyzes diagnosis and treatment of genital malignancies in postmenopausal females. Methods: 1. Data were collected using predesigned proforma; consent was taken from every participant, 2. After collection of data, it was tabulated. Statistical calculation and subsequent analysis was made has been presented in the form of Tables and graphs. Results: A total of 401 cases reported to the institute during a period of 1 year. Out of which, 107 patients were that of genital carcinoma. Incidence of female genital tract carcinoma was 26.68%. Approximately 73.87% (82 patients) of cases were that of cervical cancer. Conclusion: Hence, from above study, the most of the patients were diagnosed in advanced stage of malignancy. Carcinoma cervix was the most common female genital tract cancer with ovarian cancer taking the second rank. This is unfortunate as cancer cervix is preventable to a large extent as it takes a decade or more to progress from pre-invasive to invasive lesion, there are various screening modalities to diagnosed the cervix in pre-invasive age, that is, when it still curable.

Investigation of physical properties of Fe3O4/Au-Ag@MoS2 nanoparticles on heat distribution in cancerous liver tissue

Liver cancer has significantly grown in recent years, and thus its mortality rate has also increased since its symptoms appear to be in malignant stages and the treatment path at this stage is extremely challenging. New therapies based on producing heat in cancerous tissues have opened up a new way to treat cancer. This study investigated the treatment of liver cancer by the magnetic hyperthermia approach and nanoparticles (NPs) such as iron oxide () core with gold (Au), silver (Ag) alloy shell, and molybdenum disulfide () coating. The optical properties of these NPs within the tumor, including the extinction coefficient and surface plasmon peak (SPR) as a function of size, structure, different compositions, and thickness, were also examined using the effective medium theory, followed by assessing the impact of temperature distribution through the analytical modeling of an alternating current magnetic field. The results demonstrated that NPs with a compound of a 3 nm thick cover of Au-Ag alloy, and two layers of have the best coefficient of extinction and SPR in the biological window. The Au-Ag alloy improved the extinction coefficient and simultaneously prevented the accumulation of magnetic NPs. Considering that the Au-Ag alloy alone cannot function within the range of biological windows, was used, which increased the extinction efficiency at higher wavelengths. The examination of the temperature distribution in the tumor for the proposed alloy compound indicated that after a short time from irradiation initiation, the tumor temperature reaches 45 °C. Further, the temperature distribution within the tumor tissue reached its maximum value at the center of the tumor and decreased dramatically while getting away from the center. Finally, the use of magnetic hyperthermia enabled localized delivery of therapeutic doses to malignant tumors, thereby representing superior performance and efficiency over the photothermal method.

Predictors of lung entrapment in malignant pleural effusion

IntroductionMalignant pleural effusion (MPE) is a common complication in advanced stages of malignancy and is associated with poor prognosis. Non-expandable lung (NEL) often occurs and its presence influences the MPE approach. Our main objective was to assess risk factors for malignant NEL. MethodsPatients diagnosed with pathologically confirmed MPE between January 2012 and December 2018 in our institution were retrospectively analyzed. Demographic and clinical data of patients were reviewed and compared according to the presence or absence of NEL. A univariate and multivariate binary logistic regression analysis were used to determine predictors of the development of NEL. ResultsOf 365 patients included, 68 (18.6%) had NEL. After multivariate analysis, we found that loculated MPE (OR 8.63, 95%CI 4.30-17.33, p<0.001), complete hemithorax opacification (OR 2.81, 95%CI 1.17-6.76, p<0.021), lung cancer (OR 2.09, 95%CI 1.01-4.31, p=0.047) and higher effusion-serum LDH ratio (OR 1.09, 95%CI 1.00-1.17, p=0.039) were independent predictors of malignant NEL. There were no significant differences compared with expandable lung group regarding time from primary malignancy diagnosis to MPE diagnosis (3.0, IQR 0.0-75.8 vs 2.0, IQR 0.0-75.5 weeks, p=0.942) or MPE symptoms onset to MPE diagnosis (4.0, IQR 1.0-9.0 vs 3.0, IQR 1.0-9.0 weeks, p=0.497). Patients with NEL had a higher number of therapeutic pleural drainages (3.0, IQR 2.0-6.0 vs 2.0, IQR 1.0-3.0; p<0.001) and longer hospital stay (32.5, IQR 15.5-46.3 vs 21.0, IQR 11.0-36.0, p=0.007), measured in hospitalization days until the end of life, than patients with expandable lung. The rate of recurrence of pleural effusion was not significantly different between groups (p=0.291). Overall survival (OS) was 3.0 (95%CI, 2.3-3.7) months, regardless of lung expandability (p=0.923). ConclusionLoculated MPE, complete hemithorax opacification, lung cancer and a higher effusion-serum LDH ratio were found to be independent predictors for NEL. These patients underwent thoracocenteses more frequently and had longer hospitalization days, although without significant impact in the OS.

MUCINOUS CARCINOMA OF THE OVARY IN PERITONEAL FLUID

Peritoneal cytology is crucial in the diagnosis and staging of abdominal and pelvic malignancies. Diagnostic pitfalls can be avoided by having an understanding of the different methods of sampling, a familiarity with cytomorphology of the various specimen types, adequate clinical history, and an ability to prepare cell blocks and/or review other prior or concurrent specimens. Ovarian cancer is the second most frequent type of gynecological malignancy but the most lethal. While high-grade serous carcinoma is the most common histological subtype, mucinous carcinoma of the ovary (MCO) was believed to constitute around 4% of ovarian malignancies. It is critical to diagnose these rare tumors correctly to ensure proper treatment, avoid mortality, and preserve fertility for young women.

Knowledge and Attitude of Cervical Cancer Screening and Vaccination in Patients Attending Gynecology Outpatient Clinic at a Tertiary Care Hospital in Pakistan.

Shamaila ShamaunBackground Cervical cancer is the third most prevalent female cancer in Pakistan; nearly 70% present at a very advanced stage of malignancy due to lack of awareness, proper screening, and vaccination. Therefore, we aimed to assess the knowledge and attitude toward screening, vaccination, and risk factors of cervical cancer in sexually active women of Pakistan. Methods This cross-sectional study was conducted at the gynecology outpatient clinic of a public sector hospital in Karachi, Pakistan, from December 2021 to March 2022. We included sexually active women with exception of diagnosed cases of cervical cancer, pregnancy, vaginal bleeding, and psychological disorder. Collected data were regarding demographic characteristics, awareness regarding cervical cancer, screening, human papillomavirus (HPV) vaccine, and risk factors, history of cervical screening, and wiliness to opt-in for cervical screening. Results We included 226 women with a mean age of 41.25 ± 10.54 years. The mean parity level was observed to be 3.8 ± 1.95. A majority of women were housewives by profession (88.9%) and uneducated (61.9%). Only 41.2% (93) of women were aware of cervical cancer, 33.6% (76) were aware of cervical screening, and only 15.9% (36) had a history of cervical screening. Only four women (1.8%) were aware of the HPV vaccine and 31% (70) showed intention to opt-in for cervical screening. A vast majority of women (96.9%) were not aware of the risk factors of cervical cancer. Conclusion(s) We have observed poor awareness regarding cervical cancer, HPV vaccination, and cervical screening among women in our population. Lack of awareness was not restricted to a certain segment but it prevails all across the demographic in our population.

Sensing performance of Bragg fibers having a defect layer utilizing confinement loss analysis for brain cancer cells detection

The sensing performance of the Bragg fiber having a defect layer in the cladding region is optimized for brain cancer cell detection using the refractive index of brain lesions fluids. The optimization is achieved by comparing the confinement loss of low contrast and a high contrast defected Bragg fiber with similar standard Bragg fiber. Using the transfer matrix method and matching the fields at various interfaces equation of confinement loss is obtained in presence of a defect layer. It is observed that the sensing performance of low contrast waveguide is better than high contrast waveguide in the absence of the defect layer but the situation become reversed in presence of a defect layer. Wavelength interrogation shows high sensing performance with the variation of defect layer refractive index while intensity interrogation shows high sensing performance with the variation of core refractive index. Here wavelength interrogation of high contrast defected Bragg fiber is demonstrated to detect normal and abnormal brain tissues due to its feasibility. Our analysis shows that the respective maximum sensitivity, detection accuracy, and quality parameters are 12.1519 nm/RIU, 4365.7235, and 41.6161 RIU−1 in the benign stage corresponding to the wall of brain and 11.0233 nm/RIU, 4242.7191 and 38.8281 RIU−1 in the malignant stage corresponding to low-grade glioma.

Epigenetic regulation of autophagy in gastrointestinal cancers

The development of novel therapeutic approaches is necessary to manage gastrointestinal cancers (GICs). Considering the effective molecular mechanisms involved in tumor growth, the therapeutic response is pivotal in this process. Autophagy is a highly conserved catabolic process that acts as a double-edged sword in tumorigenesis and tumor inhibition in a context-dependent manner. Depending on the stage of malignancy and cellular origin of the tumor, autophagy might result in cancer cell survival or death during the GICs' progression. Moreover, autophagy can prevent the progression of GIC in the early stages but leads to chemoresistance in advanced stages. Therefore, targeting specific arms of autophagy could be a promising strategy in the prevention of chemoresistance and treatment of GIC. It has been revealed that autophagy is a cytoplasmic event that is subject to transcriptional and epigenetic regulation inside the nucleus. The effect of epigenetic regulation (including DNA methylation, histone modification, and expression of non-coding RNAs (ncRNAs) in cellular fate is still not completely understood. Recent findings have indicated that epigenetic alterations can modify several genes and modulators, eventually leading to inhibition or promotion of autophagy in different cancer stages, and mediating chemoresistance or chemosensitivity. The current review focuses on the links between autophagy and epigenetics in GICs and discusses: 1) How autophagy and epigenetics are linked in GICs, by considering different epigenetic mechanisms; 2) how epigenetics may be involved in the alteration of cancer-related phenotypes, including cell proliferation, invasion, and migration; and 3) how epidrugs modulate autophagy in GICs to overcome chemoresistance.

ANALYSIS OF SYMPTOMS IN OVARIAN CANCER AND ITS HISTOPATHOLOGICAL CORRELATION: A CROSS SECTIONAL STUDY

Ovarian cancer is the fth common cancer affecting the population and it is a silent killer, as it is diagnosed in later stages. The symptoms of ovarian cancer are nonspecic and a screening tool for ovarian cancer is not there. Diagnosis of ovarian cancer is often delayed due to their presentation with vague and nonspecic symptoms. This study tried to evaluate the symptoms in patients with ovarian cancer and correlate them with the type and stage of malignancy. Analyze the type, duration and frequency of the symptomsObjective: in patients with ovarian cancer and to correlate these symptoms with the type of malignancy and stage of the disease. All patientsMethods: admitted to the Gynaecology Department of Government Medical College, Thrissur with suspected ovarian cancer during the study period were recruited and surveyed using a baseline health questionnaire and a symptom index assessment form suggested by Goff et al was used (1). Assessment was then done to look for any correlation between the symptom duration, severity and frequency of symptoms and the type of ovarian malignancy. Fatigue followed by indigestion, increase in abdominal size, abdominal bloating, backache,Results and Discussion- feeling full quickly were the most common symptoms. A mean of 7.6 symptoms out of 23 symptoms enquired about in these women were present for a duration of 1 - 4 months. Abdominal bloating sensation was signicantly increased in patients more than 50yrs of age. A rise in CA125 value was also associated signicantly with fatigue and abdominal bloating sensation. Epithelial ovarian tumors were found to be signicantly associated with indigestion and feeling of fullness quickly. Non epithelial varieties were more often associated with menstrual irregularities and constipation. The symptom index can be used as a screening tool for ovarian cancer. Ignoring early warning symptoms will result inConclusion- late diagnosis of ovarian malignancy and thereby worsen the prognosis for such women.

Development and validation of a prognostic predictive model of pulmonary spindle cell carcinoma from the surveillance, epidemiology and end results database.

BackgroundPulmonary spindle cell carcinoma (PSCC) is a rare type of non-small cell lung cancer (NSCLC). The prognostic influent factors and therapeutic methods of PSCC are unclear, for there are only some case reports or small samples’ analysis. This study aims to find prognosis related factors of PSCC, develop and validate a nomogram to predict their survival probability.MethodsThe Surveillance, Epidemiology, and End Results (SEER) 18 Registries database (2000–2018) was searched to study PSCC. According to diagnosed time, data was divided into primary cohort (2000–2015) and validation cohort (2016–2018), both followed until December 31 2018. Chosen by Least Absolute Shrinkage and Selection Operator (LASSO) regression, age, sex, stage, surgery, chemotherapy, N, size and history of malignancy were taken out as predictive variables. The primary cohort was used to develop a nomogram to predict 1-, 3- and 5-year overall survival (OS) probability, and be validated by the validation cohort using concordance index (C-index) and calibration curves. Both cohorts were used to conduct a Cox regression to find the influential factors on OS of PSCC.ResultsThe nomogram shows a good concordance and discrimination on the prediction of OS, both internal (n=457 and C-index is 0.79) and external validation (n=100 and C-index is 0.76). The median survival time of PSCC is 4 months, with 20.1% OS possibility in 5 years. Multivariate analysis identified patients of older age [hazard ratio (HR), 1.02; 95% confidence interval (CI): 1.01–1.04], larger size of neoplasm (HR, 1.01; 95% CI: 1.01–1.01), M1 (HR, 2.96; 95% CI: 2.17–4.04), N2 (HR, 2.55; 95% CI: 1.81–3.59) or N3 (HR, 2.99; 95% CI: 1.58–5.66), regional stages (HR, 2.11; 95% CI: 1.29–3.44) and distant stages (HR, 6.17; 95% CI: 3.83–9.94) had a lower OS possibility, while surgery (HR, 0.39; 95% CI: 0.28–0.53) and history of malignancy (HR, 0.68; 95% CI: 0.48–0.98) was protective factors for PSCC. PSCC survived longer with surgery performed instead of chemotherapy or radiotherapy.ConclusionsPatients of PSCC have a poor prognosis, and using the nomogram developed by this study can predict their 1-, 3- and 5-year OS probability. Surgery is a better choice for PSCC and more studies are necessary to find potential treatment like targeted therapy, programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1).

Breast cancer cell-derived extracellular vesicles promote CD8+ T cell exhaustion via TGF-β type II receptor signaling

Cancer immunotherapies have shown clinical success in various types of tumors but the patient response rate is low, particularly in breast cancer. Here we report that malignant breast cancer cells can transfer active TGF-β type II receptor (TβRII) via tumor-derived extracellular vesicles (TEV) and thereby stimulate TGF-β signaling in recipient cells. Up-take of extracellular vesicle-TβRII (EV-TβRII) in low-grade tumor cells initiates epithelial-to-mesenchymal transition (EMT), thus reinforcing cancer stemness and increasing metastasis in intracardial xenograft and orthotopic transplantation models. EV-TβRII delivered as cargo to CD8+ T cells induces the activation of SMAD3 which we demonstrated to associate and cooperate with TCF1 transcription factor to impose CD8+ T cell exhaustion, resulting in failure of immunotherapy. The levels of TβRII+ circulating extracellular vesicles (crEV) appears to correlate with tumor burden, metastasis and patient survival, thereby serve as a non-invasive screening tool to detect malignant breast tumor stages. Thus, our findings not only identify a possible mechanism by which breast cancer cells can promote T cell exhaustion and dampen host anti-tumor immunity, but may also identify a target for immune therapy against the most devastating breast tumors.

TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability

ABSTRACT The challenge of rapid macromolecular synthesis enforces the energy-hungry cancer cell mitochondria to switch their metabolic phenotypes, accomplished by activation of oncogenic tyrosine kinases. Precisely how kinase activity is directly exploited by cancer cell mitochondria to meet high-energy demand, remains to be deciphered. Here we show that a non-receptor tyrosine kinase, TNK2/ACK1 (tyrosine kinase non receptor 2), phosphorylated ATP5F1A (ATP synthase F1 subunit alpha) at Tyr243 and Tyr246 (Tyr200 and 203 in the mature protein, respectively) that not only increased the stability of complex V, but also increased mitochondrial energy output in cancer cells. Further, phospho-ATP5F1A (p-Y-ATP5F1A) prevented its binding to its physiological inhibitor, ATP5IF1 (ATP synthase inhibitory factor subunit 1), causing sustained mitochondrial activity to promote cancer cell growth. TNK2 inhibitor, (R)-9b reversed this process and induced mitophagy-based autophagy to mitigate prostate tumor growth while sparing normal prostate cells. Further, depletion of p-Y-ATP5F1A was needed for (R)-9b-mediated mitophagic response and tumor growth. Moreover, Tnk2 transgenic mice displayed increased p-Y-ATP5F1A and loss of mitophagy and exhibited formation of prostatic intraepithelial neoplasia (PINs). Consistent with these data, a marked increase in p-Y-ATP5F1A was seen as prostate cancer progressed to the malignant stage. Overall, this study uncovered the molecular intricacy of tyrosine kinase-mediated mitochondrial energy regulation as a distinct cancer cell mitochondrial vulnerability and provided evidence that TNK2 inhibitors can act as “mitocans” to induce cancer-specific mitophagy. Abbreviations: ATP5F1A: ATP synthase F1 subunit alpha; ATP5IF1: ATP synthase inhibitory factor subunit 1; CRPC: castration-resistant prostate cancer; DNM1L: dynamin 1 like; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Mdivi-1: mitochondrial division inhibitor 1; Mut-ATP5F1A: Y243,246A mutant of ATP5F1A; OXPHOS: oxidative phosphorylation; PC: prostate cancer; PINK1: PTEN induced kinase 1; p-Y-ATP5F1A: phosphorylated tyrosine 243 and 246 on ATP5F1A; TNK2/ACK1: tyrosine kinase non receptor 2; Ub: ubiquitin; WT: wild type

Epithelial tumor compartment- and adjacent stromal compartment-specific expression of PARP1 in different anatomical sites in patients with HGSOC

High-grade serous ovarian carcinoma (HGSOC) is responsible for the majority of ovarian cancer-associated deaths. PARP (poly-(ADP-ribose) polymerase) inhibitors (PARPi) (olaparib, rucaparib and niraparib) have been approved in recent years to be used in both the frontline setting as maintenance therapy and in the recurrent setting for patients with ovarian cancer (OC). Previous studies have reported an increased expression of PARP1, a sensor for DNA damage, in OC; however, its compartment (epithelial tumor vs stroma)-, anatomical site (fallopian tube, omentum, ovary and serous tubal in situ carcinoma)- and histotype-specific expression have not been studied. Here, we showed that PARP1 protein levels are higher in epithelial tumors compared to adjacent non-malignant stroma at four different anatomical locations in HGSOC, with the most significant difference in PARP1 levels in omental metastases. Furthermore, we found that PARP1 protein levels are elevated in tumors relative to normal tissue in the fallopian tube, omentum and ovary in patients with HGSOC, again with the most significant difference in the omentum. We also showed that PARP1 expression is increased in a malignant and invasive stage in mouse ovarian surface epithelium cells, and that PARP1 mRNA levels are lower in mucinous histotype compared to serous histotype of epithelial OC. These findings indicate that a better understanding of compartment-, anatomical location- and histotype-specific changes in PARP1 levels in OC is needed since PARP inhibitors are currently being used in the treatment of patients with OC.

The role of autophagy for cancer treatment: A systematic review

Autophagy is a highly conserved catabolic process that regulates nutrient deprivation and metabolic stress through lysosomal degradation. In addition, autophagy is also identified to regulate various processes such as maintaining cellular homeostasis, conserving genomic stability, immunity, inflammation and quality control. The dysregulation of autophagy promotes the development of various diseases such as obesity, diabetes, neurodegenerative disease and cancer. However, autophagy expresses a dichotomous role in cancer. During the initial stage of malignancy, autophagy acts as a suppressor. Nevertheless, in the established tumors, autophagy is exploited as an adaptive mechanism to support the growing energy needs induced by hypoxia and oxidative stress. Therefore, the prosurvival role of autophagy is prominent in advanced tumorigenesis. Despite its role in cancer, autophagy also significantly contributes to the cancer metastasis, maintenance of cancer stemness and anoikis resistance. Further, these findings speculate the need for inhibiting the prosurvival autophagy from augmenting treatment modalities. Recently, anti-autophagic therapies emerged as alternative approach for effective cancer treatment. Thus, in this review, we briefly discussed the dynamic function of autophagy in cancer and the key factors and pathways that mediate tumor-induced autophagy. Finally, we highlighted some of the target-specific antagonists that could harness against the prosurvival autophagy and could serve as effective cancer therapeutics in the future.