Expression of cell surface zinc transporter LIV1 in triple negative breast cancer is an indicator of poor prognosis and therapy failure.

Triple negative breast cancers (TNBC) are an aggressive molecular subtype of breast carcinoma (BC) identified by the lack of receptor expression for estrogen, progesterone, & human epidermal growth factor receptor-2. Lack of tangible drug targets warrants further research in TNBC. LIV1, is a zinc (Zn) transporter known to be overexpressed in few cancer types including BCs. Recently, in the United States of America, FDA approved the use of a new drug targeting LIV1, antibody drug conjugate SGN-LIV1A for treatment of TNBC patients. Though LIV1 also has a role in modulating immune cells by its differential transport of Zn, a correlation between the tumor cell expression of LIV1 and immune cell infiltrations were scantily reported. Further adequate baseline data on LIV1 expression in other populations have not been documented. Our objective was to screen a large Indian cohort of TNBC patient samples for LIV1, categorize the immune cell infiltration using CD4/CD8 expression and correlate the findings with therapy outcomes. Further, we also investigated for LIV1 expression in matched samples of primary & secondary tumors; pre & postchemotherapy in TNBC patients. Results showed an elevated expression of LIV1 in TNBC samples as compared to adjacent normal, the mean Q scores being 183.06 ± 6.39 and 120.78 ± 7.37 (p < 0.0001), respectively. Similarly, LIV1 levels were elevated in secondary tumors than primary & in patient samples postchemotherapy as compared to naïve. In the TNBC cohort, using automated method, cell morphology parameters were computed and analysis showed LIV1 levels were elevated in grade 3 TNBC samples presenting with altered cell morphology parameters namely cell size, cell perimeter, & nucleus size. Thus indicating LIV1 expressing TNBC samples portrayed an aggressive phenotype. Finally, TNBC patients with 3+ staining intensity showed poor survival (4.44 year) as compared to patients with 2+ LIV1 expression (5.47 year), emphasizing that LIV1 expression is a poor prognostic factor in TNBC. In conclusion, the study reports elevated expression of LIV1 in a large Indian TNBC cohort; high expression is a poor prognostic factor and correlated with aggressive disease and indicating the need for LIV1 targeted therapies.

Characterizing colon cancer stages through optical polarimetry-assisted digital staining.

Tissue polarimetry has been gaining importance in extracting useful diagnostic information from the structural attributes of tissues, which vary in response to the tissue health status and hence find great potential in cancer diagnosis. However, the complexities associated with cancer make it challenging to isolate the characteristic changes as the tumor progresses using polarimetry. This study attempts to experimentally characterize the polarimetric behavior in colon cancer associated with various stages of development. Bulk and unstained sections of normal and tumor colon tissue were imaged in the reflection and transmission polarimetry configurations at low and high imaging resolutions using an in-house developed Mueller polarimeter. Through this study, we observed that the information about the major contributors of scattering in colon tissue, manifesting in depolarization and retardance, can be obtained from the bulk tissue and unstained sections. These parameters aid in characterizing the polarimetric changes as the colon tumor progresses. While the unstained colon section best indicated the depolarization contrast between normal and tumor, the contrast through the retardance parameter was more pronounced in the bulk colon tissue. The results suggest that the polarimetric "digitally stained" images obtained by Mueller polarimetry are comparable with the bulk tissue counterparts, making it useful for characterizing colon cancer tissues across different stages of development.

Inflammation-induced PELP1 expression promotes tumorigenesis by activating GM-CSF paracrine secretion in the tumor microenvironment.

The inflammatory tumor microenvironment has been implicated as a major player fueling tumor progression and an enabling characteristic of cancer, proline, glutamic acid, and leucine-rich protein 1 (PELP1) is a novel nuclear receptor coregulator that signals across diverse signaling networks, and its expression is altered in several cancers. However, investigations to find the role of PELP1 in inflammation-driven oncogenesis are limited. Molecular studies here, utilizing macrophage cell lines and animal models upon stimulation with lipopolysaccharide (LPS) or necrotic cells, showed that PELP1 is an inflammation-inducible gene. Studies on the PELP1 promoter and its mutant identified potential binding of c-Rel, an NF-κB transcription factor subunit, to PELP1 promoter upon LPS stimulation in macrophages. Recruitment of c-Rel onto the PELP1 promoter was validated by chromatin immunoprecipitation, further confirming LPS mediated PELP1 expression through c-Rel-specific transcriptional regulation. Macrophages that overexpress PELP1 induces granulocyte-macrophage colony-stimulating factor secretion, which mediates cancer progression in a paracrine manner. Results from preclinical studies with normal-inflammatory-tumor progression models demonstrated a progressive increase in the PELP1 expression, supporting this link between inflammation and cancer. In addition, animal studies demonstrated the connection of PELP1 in inflammation-directed cancer progression. Taken together, our findings provide the first report on c-Rel-specific transcriptional regulation of PELP1 in inflammation and possible granulocyte-macrophage colony-stimulating factor-mediated transformation potential of activated macrophages on epithelial cells in the inflammatory tumor microenvironment, reiterating the link between PELP1 and inflammation-induced oncogenesis. Understanding the regulatory mechanisms of PELP1 may help in designing better therapeutics to cure various inflammation-associated malignancies.

Detection and Estimation of Age of Injuries in Fresh Bodies Using Immunohistochemistry.

ABSTRACT: A cross-sectional study of the wound age estimation from the forensic skin wound samples was performed immunohistochemically with a sample size of 40 (n = 40). The samples were segregated according to the appropriate stages of wound healing with the help of hematoxylin-eosin staining. Later, they were subjected to immunohistochemistry staining with anti-AQP3 antibody. Quantification of the expression of AQP3 in the injured and uninjured formalin-fixed skin tissues was done semiquantitatively and manually under 400× magnifications. The AQP3-positive cells were correlated with the duration of injury, and the results were statistically analyzed. More AQP3 expressions were found in the proliferative phase than the inflammatory and maturation phase of wound healing. Neither the diversity in age group nor the sex differentiation showed any specific correlation with the expression of keratinocytic aquaporin cells. Likewise, parameters such as the type of injury, mode of injury, and the postmortem interval also did not show any significant relationship with the expression of the aquaporin positivity. Thus, it is revealed that skin wounds between 5 and 10 days expressed aquaporin cell numbers of more than 300. Hence AQP3 estimation helps in determining the time since injury with a more accuracy.

Zinc transporter LIV1: A promising cell surface target for triple negative breast cancer.

Breast cancer is one of the leading causes contributing to the global cancer burden. The triple negative breast cancer (TNBC) molecular subtype accounts for the most aggressive type. Despite progression in therapeutic options and prognosis in breast cancer treatment options, there remains a high rate of distant relapse. With advancements in understanding the role of zinc and zinc carriers in the prognosis and treatment of the disease, the scope of precision treatment/targeted therapy has been expanded. Zinc levels and zinc transporters play a vital role in maintaining cellular homeostasis, tumor surveillance, apoptosis, and immune function. This review focuses on the zinc transporter, LIV1, as an essential target for breast cancer prognosis and emerging treatment options. Previous studies give an insight into the role of LIV1 in fulfilling the most important hallmarks of cancer such as apoptosis, metastasis, invasion, and evading the immune system. Normal tissue expression of LIV1 is limited. Higher expression of LIV1 has been linked to Epithelial-Mesenchymal Transition, histological grade of cancer, and early node metastasis. LIV1 was found to be one of the attractive targets in the therapeutic hunt for TNBCs. TNBCs are an immunogenic breast cancer subtype. As zinc transporters are known to serve as the metabolic gatekeepers of immune cells, this review bridges tumor infiltrating lymphocytes, TNBC and LIV1. In addition, the suitability of LIV1 as an antibody-drug conjugate (Seattle genetics [SGN]-LIV1A) target in TNBC, represents a promising strategy for patients. Early clinical trial results reveal that this novel agent reduces tumor burden by inducing mitotic arrest, immunomodulation, and immunogenic cell death, warranting further investigation of SGN-LIV1A in combination with immuno-oncology agents. Priming the patient's immune response in combination with SGN-LIV1A could eventually change the landscape for the TNBC patient population.

Androgen Receptor Expression in Hypospadias.

INTRODUCTION: The exact mechanism behind the development of hypospadias is unclear. Research studies on androgen receptor (AR) expression are controversial with results stating all possible outcomes - AR elevated, similar, or reduced when compared to normal. AIMS: The aim is to study the AR expression and hormone levels in hypospadias patients and compare them with children having normal genitalia. METHODS: Group 1 (controls) involved patients who underwent circumcision for phimosis while Group 2 involved hypospadias patients who did not receive any preoperative testosterone. Preoperative hormonal assay included luteinizing hormone, follicle-stimulating hormone, and free testosterone levels in all the patients. The foreskin specimen was analyzed for AR expression using immunohistochemistry (anti-AR antibody PathnSitu, clone R441, 1/100 dilution). AR staining was expressed as H score. The H score was calculated by multiplying the intensity of staining and the percentage of stained cells showing cytoplasmic positivity at high power (×40). RESULTS: There were 27 patients in Group 1 while 16 in Group 2 (distal 10; proximal 6).There was no significant difference in the age distribution. The mean H score was significantly higher (189.5) in hypospadias patients compared to controls (97.5) and was significantly higher in proximal (220) compared to distal (159) hypospadias. There was no significant difference in hormone levels between groups. CONCLUSION: AR expression was significantly elevated in hypospadias patients. It was higher in proximal compared to distal hypospadias, probably due to end-organ overexpression. Further larger trials are likely to through light into this controversial subject.

Interleukin-6 Receptor (IL-6R) Expression in Human Gastric Carcinoma and its Clinical Significance.

The aim of the study is to analyse the expression of Interleukin-6 receptor in different human gastric tissue and to correlate with the clinicopathological features of the patients. Immunohistochemistry was done against the IL-6R antibody and the Q-score was calculated from the staining pattern. Higher Q-scores were observed in tumour cells than the adjacent normal cells which were statistically significant. We also observed a significant correlation between the expressions of IL-6R and the clinicopathological features These findings suggest that IL-6R may represent as a therapeutic target for gastric carcinoma and serve as a prognostic indicator, as well.

A Rapid Special Staining Technique for Identification of Normal Ureter by Frozen Section in Children With Ureteropelvic Junction Obstruction.

BACKGROUND: The exact etiology of ureteropelvic junction obstruction (UPJO) is unknown, and inadequate excision of the narrow segment has been proposed as a cause of failure in 5% to 7% of cases of pyeloplasty. AIMS: To study whether frozen section can be useful to detect normal ureter distal to UPJO during pyeloplasty. METHODS: Histological sections from 31 patients with UPJO were analyzed for collagen to muscle ratio (CMR) on conventional (formalin) and rapid (frozen section) Masson's trichrome staining. Pathological findings were correlated with postoperative outcomes analyzed at 1-year follow-up and expressed as excellent, moderate, or mild improvement, static and deterioration based on ultrasound grade, differential renal function, and renogram drainage pattern. RESULTS: There was a very strong positive correlation (r = .94; P = .001) between CMR by conventional and rapid frozen Masson's trichrome staining. There was a very strong negative correlation between pyeloplasty outcomes and CMR on conventional staining (r = -.94; P = .001) or rapid frozen Masson's trichrome staining (r = -.91; P = .001). Regression analysis revealed that a CMR of 1.2 or less (95% confidence interval: 1.9-0.7) was associated with a successful outcome. CONCLUSIONS: It is feasible to intraoperatively identify normal ureter distal to UPJO using CMR analysis on the novel rapid frozen section technique reported.

KIBRA attains oncogenic activity by repressing RASSF1A.

BACKGROUND: KIBRA-initially identified as a neuronal associated protein is now shown to be functionally associated with other tissue types as well. KIBRA interacts with dyenin light chain 1 and this interaction is essential for oestrogen receptor transactivation in breast cancer cells. KIBRA as a substrate of Cdk1, Aurora kinase and ERK plays an important role in regulating cell cycle, cell proliferation and migration. Despite these evidences, the exact role of KIBRA in cancer progression is not known. METHODS: We studied the expression of KIBRA in breast tissues and breast cancer cell lines by western blotting, immunohistochemisry (IHC) and RT-PCR. Stable over expression and knockdown clones were generated to study the transforming properties of KIBRA by conventional assays. Xenograft studies were performed in nude mice to study the in vivo tumourigenic efficacy of KIBRA. qPCR array was performed to understand the molecular mechanism behind oncogenic activity of KIBRA. RESULTS: Our results showed that KIBRA is upregulated in breast cancer cells and in malignant human breast tumours by both western blotting and IHC. Interestingly, we found that KIBRA expression level goes up with increase in breast cancer progression in well-established MCF10A model system. Further, results from stable overexpression clones of KIBRA in fibroblasts (Rat-1) and epithelial breast cancer cells (ZR75) and lentiviral short hairpin RNA-mediated knockdown (KD) clones of KIBRA in ZR75 showed increase in transforming properties with KIBRA overexpression and vice-versa. Results also showed that fibroblasts stably overexpressing KIBRA showed increased tumourigenic potential in nude mice. By adopting a quantitative PCR array-based approach, we identified RASSF1A, a tumour suppressor, as a transcriptional target of KIBRA. CONCLUSIONS: This is the first study to demonstrate the in vivo tumourigenic property of KIBRA in a nude mouse model and also unravel the underlying molecular mechanism of KIBRA-mediated transformation via repression of RASSF1A.British Journal of Cancer advance online publication, 29 June 2017; doi:10.1038/bjc.2017.192 www.bjcancer.com.

INSM1 expression in neuroendocrine tumors in a tertiary care hospital.

AIM: Neuroendocrine tumors are heterogenous group of neoplasms that includes benign and malignant tumors that originate from neuroendocrine or nonneuroendocrine organs. Insulinoma-associated protein 1 (INSM1) is a zinc finger transcription factor originally isolated from subtraction library of human insulinoma. The main aim was to study the INSM1 expression in a spectrum of neuroendocrine tumors and a limited spectrum of nonneuroendocrine tumors. MATERIALS AND METHODS: A total of 100 cases of which 57 neuroendocrine neoplasms and 43 nonneuroendocrine neoplasms were included in the study. Immunohistochemistry (IHC) was done and expression patterns of INSM1 were analyzed. Pituitary adenoma, medullary carcinoma of thyroid, pheochromocytoma lung, gastrointestinal, and pancreatic neuroendocrine tumors were the neuroendocrine tumors that were included in the study. Papillary carcinoma of thyroid, gastrointestinal adenocarcinoma, lung adenocarcinoma, and squamous cell carcinoma were the nonneuroendocrine tumors that were included in the study. Depending upon the tissue availability, comparison of INSM1 with synaptophysin and chromogranin was also done in few neuroendocrine tumors. RESULTS: All the 57 neuroendocrine tumors showed positive expression for INSM1 and all the nonneuroendocrine tumors were negative for INSM1. This study is statistically significant. CONCLUSION: Our study suggests that INSM1 is a diagnostic marker for neuroendocrine tumors with high degree of sensitivity and specificity. The study is significant and suggests that INSM1- IHC shows nuclear positivity in a spectrum of neuroendocrine tumors. Being a nuclear marker, interpretation is easy and more reliable than the cytoplasmic markers. INSM1 has a stronger positivity than synaptophysin and chromogranin in the present study especially for small cell carcinoma lung. Hence, INSM1 may be included in the routine panel for neuroendocrine tumors along with synaptophysin and chromogranin.

Results of Temporary Drainage of Poorly Functioning Kidneys With Ureteropelvic Junction Obstruction: Does the Histology of Persistent Poor Functioning Kidneys Indicate an Increased Risk of Hypertension?

OBJECTIVE: To review our experience with managing poorly functioning kidneys with ureteropelvic junction obstruction (PFK-UPJO) with differential renal function (DRF) <10% by a trial of temporary drainage, as the management of such kidneys is controversial. We also studied the histopathologic changes in the nephrectomy specimens of persistent PFK-UPJO, as tubulointerstitial damage may predispose to hypertension. METHODS: A retrospective review of cases undergoing treatment for unilateral UPJO over 5-year period in 2 centers was conducted. In PFK-UPJO, 4-6 weeks trial of drainage with double J stent or percutaneous nephrostomy was employed. Those kidneys that improved DRF to >10% underwent pyeloplasty, while persistent PFK underwent nephrectomy; the specimens were studied for interstitial fibrosis/tubular atrophy (IF/TA), arterial lesions, and arteriole lesions. RESULTS: Of 402 patients with unilateral UPJO that underwent surgical management, 17 (4.1%) had PFK-UPJO. After 4-6 weeks trial of drainage, 6 kidneys (35.2%) with improved DRF underwent pyeloplasty, while 11 kidneys with persistent PFK underwent nephrectomy; significant IF/TA, arterial, and arteriolar changes were noted in 9 (82%), 9 (82%), and 4 (36%) kidneys, respectively, including 7 kidneys in normotensive children. Two (11.7%) children had hypertension at presentation; 1 child remains hypertensive even after nephrectomy. CONCLUSION: In PFK-UPJO, trial of temporary drainage seems appropriate to decide plan of management; 35% of such kidneys improved function after drainage. Most persistent PFK demonstrated severe and irreversible histologic changes that may predispose to hypertension if they are preserved, and we suggest that such kidneys may be removed. Long-term follow-up of all preserved PFK-UPJO is strongly recommended.

Immunohistochemical expression of histone modification pattern in adult glioblastoma.

BACKGROUND: Despite the growing advances in molecular research and therapeutics, glioblastomas are still considered highly invasive aggressive tumors with a median survival of 15 months. Genetic alterations have been studied in detail; however, additionally, there is now growing evidence on the role of epigenetic alterations in glioblastoma. Recently, histone modification patterns have been found to have a significant part in gene expression and prognosis. However, further research in this field is warranted to establish its role for the betterment of these patients with the deadly disease. AIMS: To determine the immunohistochemical expression of histone modifications like histone-3-lysine-18 acetylation (H3K18Ac) and histone-4-lysine 20 trimethylation (H4K20triMe) in glioblastoma patients. MATERIALS AND METHODS: This is a retrospective study of 48 glioblastoma patients who underwent surgery. Immunohistochemistry (IHC) for tri-methyl-histone-H4 (Lys20) (H4K20triMe) and acetyl-histone-H3 (Lys18) (H3K18Ac) was performed in paraffin-embedded tissues manually, and the expression was noted. Data on the mitotic index and overall survival was collected and statistically analyzed. RESULTS: The mean age was 50 years with a M: F ratio of 1.6:1. Out of 48 cases, 60% (28 cases) demonstrated positivity for H3K18Ac and 98% (46 cases) for H4K20triMe. The pattern of expression was nuclear with increased expression adjacent to necrosis and at the invasive front. The overall median Q score for H3K18Ac was 1/12 and for H4K20triMe was 6/12. No significant statistical significance was observed between histone expression, Ki67%, and overall survival. CONCLUSION: Histone modification patterns are being explored in detail in an array of tumors. They also have a potential role in glioblastoma for risk stratification and instituting appropriate treatment based on the prognosis. Epigenetic changes like histone modification patterns, in addition to genetics, can pave the way for a better molecular understanding of glioblastomas and provide hope in the future to improve the survival of these patients with deadly diseases.

Immunohistochemical Evaluation of Notch1 in Ovarian Tumours and Its Prognostic Implications.

BACKGROUND: Ovarian cancer is the fifth most common malignancy among women and the second most common gynaecological malignancy. Surface epithelial ovarian tumours constitute two-thirds of all ovarian tumours. Most high-grade serous carcinoma patients gain an initial complete response but eventually succumb to relapse and death leaving the overall survival grim. Therefore, new regimens targeting the pathways involved in metastasis and chemoresistance are essential for the development of more effective therapies. Notch signalling is one of the pleiotropic signalling pathways that plays a key role in differentiation and tissue morphogenesis. It has been observed that this Notch signalling pathway is seen to be deregulated in various cancers. It is thought to have an oncogenic role in ovarian cancer. Our objective in this study is to evaluate the immunohistochemical expression pattern of Notch1 in surface epithelial ovarian tumours and its correlation with the clinicopathological profile. METHODS: This study includes a total of 100 cases of borderline and malignant surface epithelial ovarian tumours. Clinical data of the patients were obtained from the medical records section. HPE slides were examined and one representative paraffin block was selected for each patient. IHC of Notch1 was performed and analyzed. The staining pattern for Notch1 was calculated using the Q score. RESULTS: Immunohistochemistry (IHC) evaluation of Notch1 in surface epithelial ovarian tumours in this study showed an increased intensity of Notch1 staining in high-grade serous malignant tumours. The grading and staging of tumours were compared with Notch1 expression. Statistical analysis was performed using Spearman Rank order correlation analysis. There was a significant correlation (0.01 level, two-tailed) between the grading and staging of ovarian tumours and Notch1 expression. CONCLUSION: Assessing Notch1 expression in ovarian cancer by IHC is a useful tool in view of its clinical applications, development of targeted therapies and as a marker of prognosis. The intensity of the Notch1 stain appears to be directly proportional to the grade of tumour. This may offer a potential targeted therapy against the Notch signalling pathway in tumours that strongly express Notch1.

Clinico-Pathological and Radiological Spectrum of Mediastinal Masses in a Tertiary Care Center: A Cross-Sectional Study.

Introduction The phrase "mediastinal mass" refers to a mass within the mediastinum. About 50% of all mediastinal masses, including teratoma, thymoma, lymphoma, and thyroid illness, are anterior mediastinal tumors. Data on the mediastinal mass in India are relatively sparse, especially in this region, compared to those from other countries. Mediastinal masses are very infrequent lesions that might occasionally present a diagnostic and therapeutic challenge to the doctor. The current study describes the socio-demographic characteristics, symptoms, diagnosis, and location of mediastinal mass among the study participants. Methodology We carried out a retrospective, cross-sectional study in a tertiary care center in Chennai for three years. We included patients with an age above 16 years who visited the tertiary care center in Chennai during the study period. We included all patients with a mediastinal mass diagnosed by CT scan, with or without signs and symptoms of mediastinal compression. Patients under the age of 16 and those with insufficient data were both excluded from the study. As per the universal sampling technique, we included all the patients who met the eligibility criteria during the study period (three years) as study subjects. By using the hospital records, we collected all data about the patients like socio-demographic data, presenting complaints, past history, x-ray findings, and co-morbidities. Similarly, we recorded blood parameters, pleural fluid parameters, and histopathological reports from the laboratory register. Results The mean age of the study participants was 41.11 years, with a high proportion of patients belonging to the age group of 21 to 30 years. Over 70% of the study participants were male. Only about 54.5% of the study participants had symptoms because of a mediastinal mass. The most common local symptom felt by the patients was dyspnea, followed by a dry cough. Weight loss was the most common symptom for the patients. Most study participants (47.7%) had seen a doctor within one month of the onset of symptoms. About 4.5% of the patients had pleural effusion, as diagnosed by x-ray. Most of the study participants had a mass in the anterior mediastinum, followed by the posterior mediastinum. Most of the participants (15.9%) had non-caseating granulomatous inflammation suggestive of sarcoidosis.  Conclusion The most common tumor found in our study was lymphoma, which was followed by non-caseating granulomatous disease and thymoma. Anterior compartments are most commonly involved. We observed the most common presentation in the third decade of life with a male to female ratio of 2:1, with dyspnea being the most common symptom, followed by a dry cough. Our study found 4.5% of the patients had pleural effusion as a complication.

Sacrococcygeal mass in a 3-year-old unfolding as Dabska tumor-A very rare entity.

ABSTRACT: Papillary intralymphatic angioendothelioma, previously known as Dabska's tumor, is a very rare entity in children involving the skin and soft tissue. It is a low grade tumor characterized by papillary endovascular proliferations of atypical endothelial cells and anastomosing vascular channels in the dermis. We present a 3-year-old male child, with a history of swelling and mild pain in the right upper gluteal region, progressive in nature for 1 month duration. On examination, the swelling was soft to firm and mildly tender. Radiology was suggestive of Sacro-coccygeal teratoma. Grossly, it was an ill-defined grey brown lesion measuring 3.5 × 3 × 2 cm. Microscopy showed lesion arranged in papillary pattern with slit like vascular channels and intra luminal proliferations of hobnail like endothelial cells. Morphology and immunohistochemical studies revealed a diagnosis of Papillary intralymphatic angioendothelioma.

Biphasic squamoid alveolar renal cell carcinoma: A rare entity with an even rarer presentation as cutaneous metastases - A case report.

Biphasic squamoid alveolar renal cell carcinoma (BSARCC) is a newly emerging distinct and rare morphologic variant of renal cell carcinoma (RCC). Morphological, immunohistochemical, and molecular data have shown that BSARCC is closely related to papillary RCC type 1. We report a case of Biphasic squamoid alveolar renal cell carcinoma with a rare presentation as cutaneous metastases. This variant tends to show an aggressive behavior. Hence, accurate histopathological diagnosis can help in effective treatment and for close follow-up of the patients.

Immunohistochemical Analysis of PD-1 and FOXP3 in Tumor-Infiltrating Lymphocytes in Human Gliomas.

Introduction Despite the growing advances in molecular research and therapeutics, gliomas continue to be highly invasive and progressive tumors. There is still a need for the development of reliable prognostic biomarkers for effective therapeutic intervention. This study aims to investigate the extent of immunosuppression in glial tumors by analyzing the clinical significance of the expressions of PD-1 and FOXP3 in gliomas. Methods This is a retrospective study from 52 glioma patients who underwent surgery. Immunohistochemistry (IHC) for PD-1 and FOXP3 was performed on paraffin-embedded tissue sections manually and their expressions were noted. Data on IDH1 mutational status and mitotic index was collected and statistically analyzed. Results Immunohistochemical analysis showed that out of 52 cases, 71.15% (37/52) demonstrated cytoplasmic positivity for PD-1 and 73.1% (38/52) of the cases for nuclear FOXP3 expression. Statistical analysis suggested that elevated PD-1 and FOXP3 expressions were significantly correlated with tumor grade and increased mitotic index (P<0.05 for both the markers). Conclusion Concurrent use of checkpoint inhibitors along with other treatment modalities is being studied in a variety of solid tumors. Expressions of negative immune regulators like PD-1 and Foxp3 can pave way for a better understanding of the extent of immunosuppression in the glial tumor environment, which is imperative to formulate new therapeutic approaches.

Differentiation of urothelial carcinoma in histopathology images using deep learning and visualization.

Artificial Intelligence is a tool poised to transform healthcare, with use in diagnostics and therapeutics. The widespread use of digital pathology has been due to the advent of whole slide imaging. Cheaper storage for digital images, along with unprecedented progress in artificial intelligence, have paved the synergy of these two fields. This has pushed the limits of traditional diagnosis using light microscopy, from a more subjective to a more objective method of looking at cases, incorporating grading too. The grading of histopathological images of urothelial carcinoma of the urinary bladder is important with direct implications for surgical management and prognosis. In this study, the aim is to classify urothelial carcinoma into low and high grade based on the WHO 2016 classification. The hematoxylin and eosin-stained transurethral resection of bladder tumor (TURBT) samples of both low and high grade non-invasive papillary urothelial carcinoma were digitally scanned. Patches were extracted from these whole slide images to feed into a deep learning (Convolution Neural Network: CNN) model. Patches were segregated if they had tumor tissue and only included for model training if a threshold of 90% of tumor tissue per patch was seen. Various parameters of the deep learning model, known as hyperparameters, were optimized to get the best accuracy for grading or classification into low- and high-grade urothelial carcinoma. The model was robust with an overall accuracy of 90% after hyperparameter tuning. Visualization in the form of a class activation map using Grad-CAM was done. This indicates that such a model can be used as a companion diagnostic tool for grading of urothelial carcinoma. The probable causes of this accuracy are summarized along with the limitations of this study and future work possible.

Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence.

Ovarian cancers are tumors that originate from the different cells of the ovary and account for almost 4% of all the cancers in women globally. More than 30 types of tumors have been identified based on the cellular origins. Epithelial ovarian cancer (EOC) is the most common and lethal type of ovarian cancer which can be further divided into high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous carcinoma. Ovarian carcinogenesis has been long attributed to endometriosis which is a chronic inflammation of the reproductive tract leading to progressive accumulation of mutations. Due to the advent of multi-omics datasets, the consequences of somatic mutations and their role in altered tumor metabolism has been well elucidated. Several oncogenes and tumor suppressor genes have been implicated in the progression of ovarian cancer. In this review, we highlight the genetic alterations undergone by the key oncogenes and tumor suppressor genes responsible for the development of ovarian cancer. We also summarize the role of these oncogenes and tumor suppressor genes and their association with a deregulated network of fatty acid, glycolysis, tricarboxylic acid and amino acid metabolism in ovarian cancers. Identification of genomic and metabolic circuits will be useful in clinical stratification of patients with complex etiologies and in identifying drug targets for personalized therapies against cancer.

Navigating Tumour Microenvironment and Wnt Signalling Crosstalk: Implications for Advanced Cancer Therapeutics.

Cancer therapeutics face significant challenges due to drug resistance and tumour recurrence. The tumour microenvironment (TME) is a crucial contributor and essential hallmark of cancer. It encompasses various components surrounding the tumour, including intercellular elements, immune system cells, the vascular system, stem cells, and extracellular matrices, all of which play critical roles in tumour progression, epithelial-mesenchymal transition, metastasis, drug resistance, and relapse. These components interact with multiple signalling pathways, positively or negatively influencing cell growth. Abnormal regulation of the Wnt signalling pathway has been observed in tumorigenesis and contributes to tumour growth. A comprehensive understanding and characterisation of how different cells within the TME communicate through signalling pathways is vital. This review aims to explore the intricate and dynamic interactions, expressions, and alterations of TME components and the Wnt signalling pathway, offering valuable insights into the development of therapeutic applications.