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Gall bladder cancer (GBC) is common among the socioeconomically deprived populations of certain geographical regions. Aflatoxin is a genotoxic hepatocarcinogen, which is recognized to have a role in the pathogenesis of hepatocellular carcinoma. However, the role of aflatoxin in the pathogenesis of GBC is largely unknown. We determined serum AFB1‐Lys albumin adduct (AAA) levels as a marker of aflatoxin exposure in the patients with GBC and compared to those without GBC. The relationship of AAA levels to cytogenetic (TP53mutation&HER2/neu amplification) and radiological characteristics of the tumor was assessed. We included GBC cases (n = 51) and non‐GBC controls (n = 100). Mean serum AAA levels were higher in the GBC group (n = 51) than those without GBC (n = 100) (26.1 ± 12.2 vs. 13.1 ± 11.9 ng/mL; p <.001). HER2/neu expression was associated with higher AAA levels compared to those with equivocal or negative expression (43.9 ± 3 vs. 28.6 ± 10 vs. 19.3 ± 7 ng/mL; p <.001). Older age (age >50 years) (odds ratio [OR] = 3.2 [CI: 1.3–8.2]; p =.013), positive Helicobacter pylori serology (OR = 5.1 [CI: 1.4–17.8]; p =.012), presence of GS (OR = 5 [CI: 1.5–16.9]; p =.009) and detectable AAA levels (OR = 6.8 [CI: 1.3–35.7]; p =.024) were independent risk factors for the presence of the GBC among all study subjects. Among patients harboring GS, older age (age >50 years) (OR = 4.5 [CI: 1.3–14.9]; p =.015), female gender (OR = 3.8 [CI: 1.2–12.5]; p =.027), presence of multiple GS (OR = 21.9 [CI: 4.8–100.4]; p <.001) and high serum AAA levels (OR = 5.3 [CI: 1.6–17.3]; p =.006) were independent risk factors for the presence of the GBC. Elderly age >50 years (OR = 2.6 [CI: 1.3–5.2]; p =.010) and frequent peanut consumption (OR = 2.3 [CI: 1.1–4.9]; p =.030) were independent risk factors for high serum AAA levels. The current study has implications for the prevention of GBC through the reduction of dietary aflatoxin exposure. [ABSTRACT FROM AUTHOR]

Simple Summary: T cell receptor-engineered T (TCR-T) cell therapy, which engineers the cells of the immune system to enhance their ability for targeting tumor cells, holds great promise, especially for solid tumors. One major challenge in this field is the identification of the right T Cell Receptor, which constitutes the core of developing these therapies. Our study introduces a new approach for the discovery and analysis of the entire repertoire of naturally-occurring antigen-specific TCRs utilizing state-of-the-art single-cell sequencing technology. This method could greatly improve the development of personalized cancer therapies and may lead to more effective treatments for a variety of tumors. Background: Adoptive cell therapy is the most promising approach for battling cancer, with T cell receptor-engineered T (TCR-T) cell therapy emerging as the most viable option for treating solid tumors. Current techniques for preparing TCR-T cell therapy provide a limited number of candidates TCRs, missing the comprehensive view of the repertoire, which may hinder the identification of the most effective TCRs. Methods: Dendritic cells were primed with immunogenic peptides of the antigen of interest to expand antigen-specific CD8 T lymphocytes from peripheral blood. Following that, the entire repertoire of naturally occurring antigen-specific TCRs was analyzed using single-cell RNA sequencing, alongside the assessment of the dominancy, transcriptome, and binding specificity of the obtained clonotypes, utilizing the TCRscape tool and ERGO-II neural network to identify the most effective candidate for TCR-T cell therapy development. Finally, TCR-T cells with the candidate TCR were obtained, followed by assessing their functionality and selectivity. Results: The developed protocol achieved a remarkable increase in the percentage of antigen-specific T cells by more than 200-fold, with more than 100 antigen-specific TCR clonotypes identified. The resulting TCR-T cells demonstrated high cytotoxicity and selectivity for the targeted antigen, indicating their potential to preferentially target tumor cells. Conclusions: This study offers a comprehensive approach for the discovery and analysis of not only few, but the entire repertoire of naturally occurring antigen-specific TCRs for TCR-T cell therapy development. Additionally, the proposed approach can be tailored to accommodate different types of antigens and MHC variants, making it a highly versatile tool for both research and clinical applications. [ABSTRACT FROM AUTHOR]

Abstract Background Mortality from breast cancer is principally due to tumor recurrence. Recurrent breast cancers arise from the pool of residual tumor cells, termed minimal residual disease, that survive treatment and may exist in a dormant state for 20 years or more following treatment of the primary tumor. As recurrent breast cancer is typically incurable, understanding the mechanisms underlying dormant tumor cell survival is a critical priority in breast cancer research. The importance of this goal is further underscored by emerging evidence suggesting that targeting dormant residual tumor cells in early-stage breast cancer patients may be a means to prevent tumor recurrence and its associated mortality. In this regard, the role of autophagy in dormant tumor cell survival and recurrence remains unresolved, with conflicting reports of both pro-survival/recurrence-promoting and pro-death/recurrence-suppressing effects of autophagy inhibition in dormant tumor cells. Resolving this question has important clinical implications. Methods We used genetically engineered mouse models that faithfully recapitulate key features of human breast cancer progression, including minimal residual disease, tumor dormancy, and recurrence. We used genetic and pharmacological approaches to inhibit autophagy, including treatment with chloroquine, genetic knockdown of ATG5 or ATG7, or deletion of BECN and determined their effects on dormant tumor cell survival and recurrence. Results We demonstrate that the survival and recurrence of dormant mammary tumor cells following therapy is dependent upon autophagy. We find that autophagy is induced in vivo following HER2 downregulation and remains activated in dormant residual tumor cells. Using genetic and pharmacological approaches we show that inhibiting autophagy by chloroquine administration, ATG5 or ATG7 knockdown, or deletion of a single allele of the tumor suppressor Beclin 1 is sufficient to inhibit mammary tumor recurrence, and that autophagy inhibition results in the death of dormant mammary tumor cells in vivo. Conclusions Our findings demonstrate a pro-tumorigenic role for autophagy in tumor dormancy and recurrence following therapy, reveal that dormant tumor cells are uniquely reliant upon autophagy for their survival, and indicate that targeting dormant residual tumor cells by inhibiting autophagy impairs tumor recurrence. These studies identify a pharmacological target for a cellular state that is resistant to commonly used anti-neoplastic agents and suggest autophagy inhibition as an approach to reduce dormant minimal residual disease in order to prevent lethal tumor recurrence.

Cancer has higher incidence and mortality rates in men compared to women because of the sex genetics. Tumors and malignant diseases such as gallbladder, pancreas and liver cancers have poor prognosis which threaten the human lives. Conducive treatment strategies are thus required to improve men’s health. Herein, phenotypic screening of strains, bacteria and microbiomes by the mutational genomics is presented as novel therapeutic strategy. Mutant genomes can reduce toxicity, negative stress and sensitivity of the human body through genomic resetting and recombination. However, studies are lacking on microbial or genome-related therapeutics from the pharmacological perspective. This paper thus presents new strategies and directions in anticancer therapy including mutant genome-based human epidermal growth factor receptor 2 (HER2)/neu, vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR), mitogen-activated protein kinase (MAPK) rat sarcoma/rapidly accelerated fibrosarcoma/MAPK/ERK Kinase/extracellular signal-regulated kinase (RAS/RAF/MEK/ERK) pathway, phosphoinositide 3-Kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, programmed death-1/programmed death-ligand 1 (PD-1/PD-L1), high tumor mutational burden (TMB) and immune checkpoint inhibitor (ICI) therapy. They are all relevant to human physiology. Moreover, strategies for treating aggressive tumors and preventive cancer are discussed along with the clinical case studies for future therapeutic applications.

Background: Mortality from breast cancer is principally due to tumor recurrence. Recurrent breast cancers arise from the pool of residual tumor cells, termed minimal residual disease, that survive treatment and may exist in a dormant state for 20 years or more following treatment of the primary tumor. As recurrent breast cancer is typically incurable, understanding the mechanisms underlying dormant tumor cell survival is a critical priority in breast cancer research. The importance of this goal is further underscored by emerging evidence suggesting that targeting dormant residual tumor cells in early-stage breast cancer patients may be a means to prevent tumor recurrence and its associated mortality. In this regard, the role of autophagy in dormant tumor cell survival and recurrence remains unresolved, with conflicting reports of both pro-survival/recurrence-promoting and pro-death/recurrence-suppressing effects of autophagy inhibition in dormant tumor cells. Resolving this question has important clinical implications. Methods: We used genetically engineered mouse models that faithfully recapitulate key features of human breast cancer progression, including minimal residual disease, tumor dormancy, and recurrence. We used genetic and pharmacological approaches to inhibit autophagy, including treatment with chloroquine, genetic knockdown of ATG5 or ATG7, or deletion of BECN and determined their effects on dormant tumor cell survival and recurrence. Results: We demonstrate that the survival and recurrence of dormant mammary tumor cells following therapy is dependent upon autophagy. We find that autophagy is induced in vivo following HER2 downregulation and remains activated in dormant residual tumor cells. Using genetic and pharmacological approaches we show that inhibiting autophagy by chloroquine administration, ATG5 or ATG7 knockdown, or deletion of a single allele of the tumor suppressor Beclin 1 is sufficient to inhibit mammary tumor recurrence, and that autophagy inhibition results in the death of dormant mammary tumor cells in vivo. Conclusions: Our findings demonstrate a pro-tumorigenic role for autophagy in tumor dormancy and recurrence following therapy, reveal that dormant tumor cells are uniquely reliant upon autophagy for their survival, and indicate that targeting dormant residual tumor cells by inhibiting autophagy impairs tumor recurrence. These studies identify a pharmacological target for a cellular state that is resistant to commonly used anti-neoplastic agents and suggest autophagy inhibition as an approach to reduce dormant minimal residual disease in order to prevent lethal tumor recurrence. [ABSTRACT FROM AUTHOR]

Introduction Gastric cancer has become the third leading cause of cancer deaths globally. It accounts for 5.7% of cancer around the world, with a rate of mortality around 8.2%. Evaluation of human epidermal growth factor receptor 2 (HER2)/neu overexpression for targeted therapies is presently the mainstay of treatment in gastric cancer. High Ki-67 index expression in gastric cancer is an indicator of poor prognosis. Objectives To study the prevalence of HER2/neu expression and Ki-67 index in various types, sites, grade, and stage of gastric adenocarcinoma and to determine the correlation between HER2/neu expression and Ki-67 index. Materials and Methods This is a prospective study in a tertiary care hospital, Kolkata from January 2019 to June 2020. Gastrectomy and endoscopic biopsy of gastric adenocarcinoma were studied for histopathology and immunohistochemistry (HER2/neu and Ki-67 index). Statistical analysis used: SPSS (version 21.0, IBM, Chicago, Illinois, United States) for windows software. Results Among 54 cases, most of them were intestinal type, antral, moderately differentiated, stage III cases. HER2 expression and high Ki-67 index were observed in 28.0 and 40.75% cases, respectively. Statistically significant correlation was found in both HER2 expression and high Ki-67 index with location of the tumor and pathological nodal (pN) stage. A positive correlation was found between HER2/neu score and Ki-67 index (p=0.007) (correlation coefficient=0.4). Conclusion A positive correlation was found between HER2/neu positivity and high Ki-67 index, both were associated with higher pathological tumor stage and pN stage. So, advanced cases may be considered for targeted therapy using trastuzumab. [ABSTRACT FROM AUTHOR]

Background. Obesity is a growing problem in the world. Correlations have been found between increasing body mass index (BMI) and breast cancer (BC). BC has multiple predictive and prognostic factors like hormonal receptors, human epidermal growth factor 2 receptor, stage of the disease and grade. Obesity may be differentially related to the risk of different subtypes given the various potential mechanisms underlying its association with breast cancer. The study aims to analyze the association between BMI, BC histopathologic, ER, PR and HER2/neu receptors expression, tumor size axillary nodes involvement, metastasis and nuclear grade. Methods. A cross sectional study was conducted involving 256 cases with breast cancer. Oncology teaching hospital based BC cases had been interviewed and data collected regarding weight and height, estrogen and progesterone receptors status, human epidermal growth factor 2 receptor, stage of the disease, grade of tumor at time of diagnosis, and categorize the cases to pre and postmenopausal state and then subdivided according to body mass index (normal, overweight, obese) and compared between three groups. Results. Overweight / obese people showed a significant statistical effect with estrogen and progesterone receptors, positive p value = 0.026, 0.007 respectively, larger tumor size, p value =0.035, and more lymph node involvement, p-value =0.031 in post-menopausal women, while premenopausal cases did not show significant statistical effect regarding the above-mentioned variables. Body mass index difference did not show a significant statistical effect on human epidermal growth factor 2 receptor, metastasis at diagnosis, tumor grade in both pre and postmenopausal cases. Conclusion. Body mass index difference affects postmenopausal BC cases rather than premenopausal as overweight / obese cases presented with more estrogen and progesterone receptors positive, larger tumor size and more lymph node involvement.

Introduction: Bladder cancer is a global disease, ranks as the fourth most prevalent cancer. The incidence and prevalence increase with age. Grade and aggressiveness have been found to be related with different genetic expression and mutation. Aims: To evaluate any relation of grade and invasiveness of urothelial cancer with varied expression of immune histochemical marker p63 and her2/neu. Materials and methods: The present study was a hospital based prospective cross-sectional study. This Study was conducted from July 2021 to April 2023 in the Urology department of a tertiary care hospital. Total 90 patients undergoing trans urethral resection of bladder tumour (TURBT) were included in this study. Result: It was found that, patients who had decreased p63 expression had high grade in tumours (93.1%) compared to patients who were expressing normal p63 (32.8%) and this was statistically significant (p < 0.0001). Tumours with decreased p63 also appeared to be more invasive, 62.1% were found to be muscle invasive. Tumours with her2 neu expression found to be more aggressive in nature, 85.7% had high grade features and 53.6% were muscle invasive. Conclusion: Our findings suggest that immunohistochemical expression of HER2/neu positive and decreased p63 expression were associated with high grade and invasiveness in case of bladder carcinoma. [ABSTRACT FROM AUTHOR]

Salivary duct carcinoma (SDC) is a rare and highly aggressive malignant salivary gland neoplasm, accounting for only 0.2% of salivary gland tumours. It predominantly affects the parotid gland and represents a significant concern with limited prevalence (1-1.2 individuals per million). We present a case of a 65-year-old female patient with a clinical history of swelling and pain in the right lower jaw region for six months. Diagnostic investigations revealed a well-defined submandibular gland lesion. Subsequent histopathological and immunohistochemical findings confirmed the lesion to be SDC. This case report emphasises the challenges in diagnosing this aggressive malignancy, which stems from its rarity and resemblance to other neoplasms. It is worth noting that the involvement of the submandibular gland is observed in a mere 12% of SDC cases, while females account for only 25% of the reported instances. [ABSTRACT FROM AUTHOR]

Human papillomaviruses (HPVs) are a major cause of cancer. While surgical intervention remains effective for a majority of HPV-caused cancers, the urgent need for medical treatments targeting HPV-infected cells persists. The pivotal early genes E6 and E7, which are under the control of the viral genome's long control region (LCR), play a crucial role in infection and HPV-induced oncogenesis, aswell as immune evasion. In this study, proteomic analysis of endosomes uncovered the cointernalization of ErbB2 receptor tyrosine kinase, also called HER2/neu, with HPV16 particles from the plasma membrane. Although ErbB2 overexpression has been associated with cervical cancer, its influence on HPV infection stages was previously unknown. Therefore, we investigated the role of ErbB2 in HPV infection, focusing on HPV16. Through siRNA-mediated knockdown and pharmacological inhibition studies, we found that HPV16 entry is independent of ErbB2. Instead, our signal transduction and promoter assays unveiled a concentration- and activationdependent regulatory role of ErbB2 on the HPV16 LCR by supporting viral promoter activity. We also found that ErbB2's nuclear localization signal was not essential for LCR activity, but rather the cellular ErbB2 protein level and activation status that were inhibited by tucatinib and CP-724714. These ErbB2-specific tyrosine kinase inhibitors as well as ErbB2 depletion significantly influenced the downstream Akt and ERK signaling pathways and LCR activity. Experiments encompassing lowrisk HPV11 and high-risk HPV18 LCRs uncovered, beyond HPV16, the importance of ErbB2 in the general regulation of the HPV early promoter. Expanding our investigation to directly assess the impact of ErbB2 on viral gene expression, quantitative analysis of E6 and E7 transcript levels in HPV16 and HPV18 transformed cell lines unveiled a noteworthy decrease in oncogene expression following ErbB2 depletion, concomitant with the downregulation of Akt and ERK signaling pathways. In light of these findings, we propose that ErbB2 holds promise as potential target for treating HPV infections and HPV-associated malignancies by silencing viral gene expression. [ABSTRACT FROM AUTHOR]

Objective: To identify if targeted positron emission tomography (PET) imaging with radiolabeled antibodies can predict tumor growth rate and ultimate tumor size in a murine flank schwannoma model. Study Design: Animal research study. Methods: Rat schwannoma cells were cultured and implanted into 40 athymic nude mice. Once tumors reached 5 mm in diameter, 30 mice were injected with zirconium‐89 labeled antibodies (HER2/Neu, vascular endothelial growth factor receptor 2 (VEGFR2), or IgG isotype). PET/CT was performed, and standardized uptake values (SUV) were recorded. Tumors were serially measured until mice were sacrificed per IACUC protocol. Statistical analysis was performed to measure correlations between SUV values, tumor size, and growth. Results: Mean tumor sizes in mm3 on Day 0 were 144 ± 162 for anti‐HER2/Neu, 212 ± 247 for anti‐VEGFR2, and 172 ± 204 for IgG isotype groups respectively. Mean growth rates in mm3/day were 531 ± 250 for HER2, 584 ± 188 for VEGFR2, and 416 ± 163 for the IgG isotype group. For both initial tumor size and growth rates, there was no significant difference between groups. There were significant correlations between maximum tumor volume and both the SUV max in the HER2 group (p = 0.0218, R2 = 0.5020), and we observed significant correlations between growth rate, and SUV values (p = 0.0156, R2 = 0.5394). Respectively, in the anti‐VEGFR2 group, there were no significant correlations. Conclusion: In a murine schwannoma model, immunotargeted PET imaging with anti‐HER2/Neu antibodies predicted tumor growth rate and final tumor size. Laryngoscope, 134:1372–1380, 2024 [ABSTRACT FROM AUTHOR]

(1) Background: We have previously shown that the use of an artificial supramolecular two-component system based on chimeric recombinant proteins 4D5scFv-barnase and barstar-heat shock protein 70 KDa (HSP70) allows targeted delivery of HSP70 to the surface of tumor cells bearing HER2/neu antigen. In this work, we studied the possibility to using DARPin9_29-barnase as the first targeting module recognizing HER2/neu-antigen in the HSP70 delivery system. (2) Methods: The effect of the developed systems for HSP70 delivery to human carcinomas SK-BR-3 and BT474 cells hyperexpressing HER2/neu on the activation of cytotoxic effectors of the immune cells was studied in vitro. (3) Results: The results obtained by confocal microscopy and cytofluorimetric analysis confirmed the binding of HSP70 or its fragment HSP70-16 on the surface of the treated cells. In response to the delivery of HSP70 to tumor cells, we observed an increase in the cytolytic activity of different cytotoxic effector immune cells from human peripheral blood. (4) Conclusions: Targeted modification of the tumor cell surface with molecular structures recognized by cytotoxic effectors of the immune system is among new promising approaches to antitumor immunotherapy. [ABSTRACT FROM AUTHOR]

Background: This study was conducted to investigate the presence of α-SMA (alpha-Smooth Muscle Actin) positive myofibroblasts in the stroma of invasive breast carcinoma with the help of immunohistochemistry (IHC) markers and investigate the correlation between α-SMA and known clinicopathological prognostic factors of breast tumors along with estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 neu (HER2/neu). Methods: This was a hospital-based study carried out from September 2019 to September 2021 in the Department of Pathology, Maharaja Krushna Chandra Gajapati (M.K.C.G) Medical College, Berhampur, among 75 patients undergoing surgery for palpable breast lesions. The study was approved by the institutional ethics committee (IEC), and written informed consent was obtained from the participants. Results: ER and PR status were negatively correlated with tumor grade and demonstrated statistical significance. HER2/neu receptor and α-SMA expressions were correlated with tumor grade and demonstrated statistical significance. In our study, 96% (n=72) had invasive breast carcinoma, followed by 2 cases of lobular carcinoma and 1 case of mucinous breast carcinoma. In the present study, 47% (n=35) of cases were of grade 3, followed by grade 2 (40%, n=30), and grade 1 (13%, n=10). In grade 3 cases, the majority were HER2-positive with strong SMA expression. Strong SMA activity was observed with an increase in HP grade (Histopathological grading is done as per MBR, i.e., Modified Bloom Richardson grading). Conclusion: α-SMA immunostaining does not correlate with age, size of the tumor, disease stage, or lymph node metastasis. α-SMA positivity shows no significant correlation with ER and PR receptor status. There is a significant correlation between α-SMA immunostaining and tumor grade and with HER2 receptor positivity. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is a significant global health concern, affecting millions of women each year. The molecular characterization of breast cancer has become crucial for tailoring personalized treatment strategies and predicting patient outcomes. Among the key biomarkers that guide treatment decisions, the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2/neu) play pivotal roles in determining the disease behavior and response to therapy. Understanding HER-2 expressions and hormone receptors is essential for developing treatment strategies and making decisions regarding breast cancer. Aims and Objectives: The study was conducted to determine the prevalence of different subtypes based on the status of ER, PR, and Her2/neu receptors in this specific patient population and to Analyze the correlation between these molecular subtypes and clinicopathological characteristics, such as age, tumor size, grade, and lymph node status. Materials and Methods: This is a Retrospective observational study conducted on 126 cases of breast carcinoma patients in Government General hospital, Kurnool. Slides were prepared from blocks containing cancer tissue, and immunohistochemical staining was done for ER PR & Her2neu expressions. Interpretation of expressions was done using Allred scoring system for ER, PR and the College of American pathologists guidelines for Her2neu expressions. Statistical analysis was performed to determine the statistical significance by applying chi-square test. Results: The majority of the tumors were HER2/neu negative, positive for ER and PR. When it came to ER and PR positive tumors, most of them were Grade I. The current investigation established a correlation between age, tumor grade and ER and PR, but not with tumor size, lymph node status. There was a correlation between ER and PR expression, but not with HER2/neu. Conclusion: Adjuvant hormonal therapy may result in a favorable outcome for cases that test positive for ER and PR. In order to provide prognostic information and therapeutic benefits, hormone receptor assessment is strongly advised for clinical management of breast cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: Gastric cancer the fourth leading cause of cancer-related death. Overexpression of HER2 is seen in a significant number of gastric cancer cases leading to the development of targeted therapy with anti-HER2 antibodies like Transtuzumab. However, uncertainty persists regarding the association between the clinicopathological features of gastric cancer patients and HER2 overexpression. Aim: This study aims to find the association between clinicopathological features of gastric adenocarcinoma and HER2 overexpression. Materials and Methods: This descriptive observational study was conducted in the Department of Pathology of a tertiary care hospital laboratory in Mangalore from January 2018 to April 2021. In this study we analysed 75 consecutive specimens of gastric/gastroesophageal junction tumours. Histological types other than gastric adenocarcinoma were excluded from the study. Diagnosis was confirmed using hematoxylin and eosin (H&E) slides. IHC was done using mouse monoclonal antibody HER2 from Biogenex. Scoring for HER2 was done by Hoffmann scoring system. Tumours were classified according to Lauren's histological classification into Intestinal and diffuse type. Other relevant details like patient's age, gender, type of specimen, tumour location, histological type and tumour grade were collected and tabulated. Results: Out of the 75 cases of adenocarcinomas analysed in this study 48 were biopsy specimens and 27 were gastrectomy specimens. In our study the rate of overall Her2 overexpression was 25.3%. Also, Her2 overexpression was associated with Intestinal type (26.9%), GEJ Tumours, moderately differentiated carcinomas and male gender. There was no correlation of HER 2 positivity with age. (30.6%, p = 0.006). Conclusion: Since, status of HER2 expression by IHC plays pivotal role in the treatment of gastric cancer, testing for the same has increased in the recent times. Hence knowing the association of HER2 expression with clinicopathological features has a clear advantage. [ABSTRACT FROM AUTHOR]

Background & Objective: The highest mortality rate in gynecologic cancers is attributed to ovarian origin. Expression of the estrogen and progesterone receptors (ER and PR) and human epidermal growth factor receptor 2 (Her2/neu) in endometrial cancer and breast cancer was found to be associated with the response to treatment and prognosis. However, because of inconsistent results from previous studies, the data regarding ovarian cancer is still inconclusive. Materials & Methods: The current retrospective cross-sectional study was performed on 234 tissue samples of different types of ovarian tumors (benign, borderline and malignant) from the archive of the University Kebangsaan Malaysia Medical Center (UKMMC) during 10 years. Tissue microarrays (TMAs) were constructed on representative areas of formalin-fixed paraffin-embedded tissue blocks using ER, PR and HER2 immunohistochemical staining. Results: The prevalence of ER and PR overexpression was 36% and 35% in benign tumors, 8% and 24% in borderline tumors and 51% and 46% in malignant tumors, respectively. ERa overexpression was more common among serous malignant ovarian tumors (49%) (P<0.001). PR positivity was more prevalent in serous benign tumors (P=0.02). There was no significant relationship between the stage of the tumor and the status of ERa (P=0.12) and PR (P=0.19). Her2/neu overexpression was only seen in borderline neoplasms (8%) and malignant mucinous tumors (4%). No association was found between Her2/neu overexpression and the level of tumor differentiation, clinical stage, tumor size, or patient's age. Conclusion: The observed ER positivity in serous carcinoma and Her2/neu overexpression in malignant mucinous tumors, could be considered as a clue for choosing therapeutic agents. The role of anti-HER2 therapy in clear cell carcinoma is still debated and needs more investigation. [ABSTRACT FROM AUTHOR]

Background: In 21st century, Cancer has emerged as the one of the major public health problem across the globe. It exerts a significant impact on everyone involved ranging from individual affected to their families, communities and healthcare systems. According to GLOBOCON 2020, female breast cancer has surpassed the lung cancer as the most common cancer across worldwide with an estimate of 2.3 million new cases (11.7%) being diagnosed followed by lung cancer (11.4%). Objectives: The present study was conducted to study the overexpression of cyclooxygenase-2 (COX-2) in the patients of breast cancer and its association with the clinical, pathological data, including age, size, site of tumor, histological type, grade, lymph node metastasis and stage of tumor. Material and Methods: This was a Prospective Study carried out in a Tertiary Care Centre situated at western part of India. The study duration was 1 year, and the period was from November 2022 to November 2023 with the department of Pathology after obtaining clearance from the institutional ethics committee and written informed consent from the study participants. All patients diagnosed with breast carcinoma attending Tertiary Care Centre were included. Exclusion criteria included tru-cut biopsy, breast excisions without axillary evacuation, lumpectomies without axillary evacuation, cases with no residual invasive carcinoma after pre-surgical (neoadjuvant) chemotherapy or with massive necrosis or fibrosis. A p-value of <0.05 was considered statistically significant. Results: Out of 20 patients, 85% of patients were females and rest 15% males. ER positivity was seen in 85% of cases, while PR positivity was observed in 75% of cases. HER-2/neu overexpressed was seen in 20% while COX-2 overexpression on immunohistochemistry was seen in 10% patients. The association between COX-2 overexpression and ER negative was statistically significant (p = 0.016). Conclusion: It can be concluded from the present study that the inhibition of COX-2 expression may lead to retard tumour progression and thus, limiting breast carcinogenesis which may have therapeutic implications for the prevention and treatment of breast cancer in such patients with high risk. [ABSTRACT FROM AUTHOR]

Background: The use of systemic therapy in elderly patients with Her2/neu-positive breast cancers has been questioned given the potential for cardiac side effects with several of the agents frequently used. This study aimed to evaluate trends in use of systemic therapy in patients 70 years and older. Methods: The 2010-2016 SEER database was used to collect data on female patients with non-metastatic Her2/neu-positive breast cancer. Data was stratified to compare systemic therapy use in patients <70 vs ≥70. Results: A total of 62,014 patients were included in the study. Of those, 79.0% (38,760) of patients <70 years old received systemic therapy while only 45.2% (5844) of patients ≥70 received systemic therapy (P < .001). Of patients ≥70 with ER positive tumors, 42.1% received systemic therapy and those with ER negative tumors, 52.1% received systemic therapy. The mortality rate in patients ≥70 was 8.5% in those who received systemic therapy and 12.1% in those who did not (P < .001). Conclusions: There remains a significant difference in rates of systemic therapy administration in the elderly population with an associated increase in mortality due to their cancer. Continuing educational efforts could be of benefit. [ABSTRACT FROM AUTHOR]

Two bis-(imidazolium–vanillylidene)-(R,R)-diaminocyclohexane ligands (H2(VAN)2dach, H2L1,2) and their Pd(II) complexes (PdL1 and PdL2) were successfully synthesized and structurally characterized using microanalytical and spectral methods. Subsequently, to target the development of new effective and safe anti-breast cancer chemotherapeutic agents, these complexes were encapsulated by lipid nanoparticles (LNPs) to formulate (PdL1LNP and PdL2LNP), which are physicochemically and morphologically characterized. PdL1LNP and PdL2LNP significantly cause DNA fragmentation in MCF-7 cells, while trastuzumab has a 10% damaging activity. Additionally, the encapsulated Pd1,2LNPs complexes activated the apoptotic mechanisms through the upregulated P53 with p < 0.001 and p < 0.05, respectively. The apoptotic activity may be triggered through the activity mechanism of the Pd1,2LNPs in the inhibitory actions against the FGFR2/FGF2 axis on the gene level with p < 0.001 and the Her2/neu with p < 0.05 and p < 0.01. All these aspects have triggered the activity of the PdL1LNP and PdL2LNP to downregulate TGFβ1 by p < 0.01 for both complexes. In conclusion, LNP-encapsulated Pd(II) complexes can be employed as anti-cancer drugs with additional benefits in regulating the signal mechanisms of the apoptotic mechanisms among breast cancer cells with chemotherapeutic-safe actions. [ABSTRACT FROM AUTHOR]

Objective: We aimed to compare cisplatin and oxaliplatin-based therapies in patients with HER2-positive gastric cancer. Material and Method: We evaluated clinicopathological and treatment data of the patients who used cisplatin, fluoropyrimidine, trastuzumab (CFT) or oxaliplatin, capecitabine, trastuzumab (OCT) retrospectively. The clinicopathological characteristics of the two groups were assessed, as well as their survival results. Results: Twenty-three (57.5%) patients received CFT regimen, and seventeen (42.5%) patients OCT regimen. Clinicopathological features and ECOG performance status were similar in between groups. Median progression-free survival was 12 (CI 95%, 10.8-13.1) months in the CFT group and 8.6 (CI 95%, 5.9-11.3) months in the OCT group (p =0.39). Median overall survival (OS) was 21.7 (95% CI 16.9-26.4) months in the CFT group and 13.6 (CI 95%, 6.7-20.5) months in the OFT group. In univariate analysis, the change in OS between the two groups was statistically significant; however, the findings were not confirmed in multivariate analysis. Conclusion: There was a trend in the study that patients treated with CFT had better OS compared to OCT. This situation did not reach statistical significance. Treatment-related toxicities were similar between the two groups. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to quantitatively evaluate HER2/neu oncogene amplification and p53 tumor suppressor gene deletion in breast cancer with real-time polymerase chain reaction (RT-PCR). Materials and Methods: Sections obtained from the tumor tissues of 50 patients were paraffinized on slides, and DNA extraction was performed. HER2/neu amplification and p53 deletion were analyzed using RT-PCR with respect to immunohistochemistry (IHC). Results: For 25 patients with breast cancer, we compared IHC and RT-PCR results for the quantitative measurement of HER2/neu expression. We found a significant correlation between the results obtained using IHC and RT-PCR (p < 0.05). Taking the results of IHC as reference, the sensitivity and specificity of the RT-PCR method were 57% and 83%, respectively. HER2/neu amplification and p53 deletion did not have a significant correlation with tumor size, histological grade, lymph node invasion, and status of estrogen receptor and progesterone receptor (p>0.05, for all). Conclusion: RT-PCR measured gene levels reliably and accurately with high sensitivity and specificity, making it superior to IHC, which is subjective. [ABSTRACT FROM AUTHOR]

Background & Aims: This study aimed to determine the significance of immunohistochemistry (IHC) and its correlation using HER-2/NEU and cytokeratins in a histopathologic study of GI neoplasms. Materials & Methods: This retrospective- prospective study was conducted on 50 gastric biopsies along with patient details and stained with H and E method for histopathology. Immunohistochemistry with HER-2/NEU, cytokeratin-7 and cytokeratin-20 were also done. Results: 60% were males among total sample size. Adenocarcinoma prevalence was 76%, followed by mucinous adenocarcinoma in 10%, signet cell ring cell carcinoma in 6%, and mixed adeno-neuroendocrine tumor in 4%. Sarcoma and papillary adenocarcinoma contributed to 2% each. Among study population, 60% were of grade II, 32% were of grade III, and 6% were of grade I. Low-grade sarcoma was present in 2%. Well differentiated tumors were 6%, moderately differentiated tumors were 60%, and poorly differentiated tumors were 32%. Among study population, 16% were positive for Her 2 neu, 20% were positive for CK7, and CK20 was positive in 28%, respectively. Among the study population, 2.63% of adenocarcinomas, all of mixed adeno-neuroendocrine, 60% of mucinous adenocarcinomas, and 66.66% of signet ring cell carcinomas were positive for Her2neu. 18.42% of adenocarcinomas, 50% of mixed adeno-neuroendocrine and 66.66% of signet ring cell carcinomas were positive for CK7. 21.05% of adenocarcinomas, all of mucinous adenocarcinomas, and 33.33% of signet ring cell carcinomas were positive for CK20. Conclusion: 16% were positive for Her 2 neu, 20% were positive for CK7, and CK20 was positive among 28%. There was no correlation between the histopathology status and receptor positivity.

Breast cancer, a prevalent form of cancer in women, presents various categories that pose challenges in defining specific treatment approaches. Immunohistochemistry, a combination of immunology and histology, has made significant advancements in identifying specific surface receptors on cancer cells. This information serves as the basis for guiding appropriate treatment regimens and predicting prognosis for patients. A survey conducted on 75 tissue samples revealed the diversity of breast carcinoma types, with the infiltrative tubular form being the most common, accounting for 73.3% of cases. By utilizing immunoassay markers on these tissues, the expression rates of ER (estrogen receptor), PR (progesterone receptor), and Her2/neu were determined to be 29.2%, 52%, and 22.7%, respectively. Classification of breast cancer based on these markers showed that the ER/PR+HER2- group accounted for 24% of cases. The ER-/PR+HER2- group accounted for 18.7%, while the ER+/PR+HER2+, ER-/PR+HER2+, and ER-PR+Her2+ groups each represented 12% of cases. The ER-/PRHER2+HER2+ group accounted for 8%, and a subgroup where all three markers were negative accounted for 22.7% of cases. Estrogen and progesterone expression showed a moderately positive correlation (0 < r = 0.445 < 0.5; p 0.05) and exhibited a reverse correlation with r = -0.016

Background: HER2/neu is associated with increased tumor grade, and Ki-67 is related to tumor recurrence and stage progression. This study aims to evaluate the clinical profile in patients with urothelial neoplasms and correlate the expression of HER2/neu and Ki-67 in urothelial carcinomas. Methods: This is a five-year retrospective study from June 2017 to May 2022 with forty cases from the Department of Pathology. A microscopic examination was done to assess the tumor stage and histological grade. Immunohistochemistry was performed with HER2/neu and Ki-67. Results: 65% (26/40) of the cases were diagnosed as infiltrating urothelial carcinoma, 30% (12) of the cases as low-grade non-invasive urothelial carcinoma, one case as a papillary urothelial neoplasm of low malignant potential (PUNLMP), and one case as urothelial papilloma. 95.5% of infiltrating carcinomas and 84.5% of low-grade non-invasive carcinomas were Ki-67-positive. A significant correlation was observed between the expression of Her-2/neu and Ki-67 and the 2016 World Health Organization (WHO) grading system of urothelial carcinoma. Moderate-to-strong HER2/neu overexpression (2+ or 3+) was observed in only 18% of cases. Conclusion: The expression of ki-67 increased with an increase in the grade of tumor, which shows its prognostic importance. The relation between Ki-67 expression and the histologic grade of the tumor and the presence of lymphovascular invasion was significant. A significant correlation was observed between the grade of the carcinoma and the immunohistochemical expression of HER2/neu, in which 19.3% of high-grade carcinoma cases showed immunohistochemical expression of the HER2/neu marker. Further studies with a larger population group are required to establish the role of HER2/neu as a prognostic marker.

Human papillomaviruses (HPVs) are a major cause of cancer. While surgical intervention remains effective for a majority of HPV-caused cancers, the urgent need for medical treatments targeting HPV-infected cells persists. The pivotal early genes E6 and E7, which are under the control of the viral genome’s long control region (LCR), play a crucial role in infection and HPV-induced oncogenesis, as well as immune evasion. In this study, proteomic analysis of endosomes uncovered the co-internalization of ErbB2 receptor tyrosine kinase, also called HER2/neu, with HPV16 particles from the plasma membrane. Although ErbB2 overexpression has been associated with cervical cancer, its influence on HPV infection stages was previously unknown. Therefore, we investigated the role of ErbB2 in HPV infection, focusing on HPV16. Through siRNA-mediated knockdown and pharmacological inhibition studies, we found that HPV16 entry is independent of ErbB2. Instead, our signal transduction and promoter assays unveiled a concentration- and activation-dependent regulatory role of ErbB2 on the HPV16 LCR by supporting viral promoter activity. We also found that ErbB2’s nuclear localization signal was not essential for LCR activity, but rather the cellular ErbB2 protein level and activation status that were inhibited by tucatinib and CP-724714. These ErbB2-specific tyrosine kinase inhibitors as well as ErbB2 depletion significantly influenced the downstream Akt and ERK signaling pathways and LCR activity. Experiments encompassing low-risk HPV11 and high-risk HPV18 LCRs uncovered, beyond HPV16, the importance of ErbB2 in the general regulation of the HPV early promoter. Expanding our investigation to directly assess the impact of ErbB2 on viral gene expression, quantitative analysis of E6 and E7 transcript levels in HPV16 and HPV18 transformed cell lines unveiled a noteworthy decrease in oncogene expression following ErbB2 depletion, concomitant with the downregulation of Akt and ERK signaling pathways. In light of these findings, we propose that ErbB2 holds promise as potential target for treating HPV infections and HPV-associated malignancies by silencing viral gene expression.

Objective: To correlate the results of HER2/neu protein overexpression on immunohistochemistry (IHC) and gene amplification on fluorescence in situ hybridization (FISH) and to document the problems faced in performing FISH procedure. Methods: This was an observational retrospective study covering five years from January 1st, 2015 - December 31st, 2019 at Histopathology Department of Shifa International Hospital (SIH), Islamabad. All cases of breast cancer that underwent florescence in situ hybridization (FISH) were retrieved. Correlation between HER2/neu overexpression on IHC and its amplification on FISH was analyzed. Problems in application of FISH were recorded. Results: Out of 451 cases submitted for HER2/neu testing by FISH, 68 cases (15%) were rejected. Gene amplification was seen in 139 (36.29%) cases. Total cases with HER2/neu IHC score of 2+ were 330 cases and out of which gene amplification was seen in 98 cases (29.69%) whereas 93.1% (41/44) 3+ IHC cases were amplified. Poor fixation, inadequate amount of tumor with crushing artefacts and dye application to the biopsy fragments were causes of sample rejection. Conclusions: Her2/neu amplification was seen in most Her2/neu 3+ cases and approximately one-third of Her2neu 2+ cases. Proper fixation, adequate biopsy material with standardized processing is required to yield useful results on FISH. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor 2 (HER2) is an oncogene involved in tumour genesis and progression. It is expressed in 7% of patients with colorectal cancer (CRC) and is associated with drug resistance of epidermal growth factor receptor monoclonal antibodies. With the emergence of the therapeutic dilemma of CRC and the survival benefits of targeting HER2 for patients with breast cancer and gastric cancer, the significance of HER2 in CRC and the prognostic value of anti-HER2 therapy have been widely concerned, clinical researches on HER2-positive CRC have been continuously carried out. Currently, the diagnostic criteria for HER2 positive CRC have gradually been unified. HER2-targeting therapies such as monoclonal antibodies, tyrosine kinase inhibitors, antibody-drug coupling and HER2-related immunotherapy alone or in combination have shown good efficacy and brought significant survival benefits for HER2 positive CRC. This paper reviews the research progress of HER2 in CRC.

Aim. To determine informative prognostic criteria for assessing the HER2 / neu status in primary breast cancer using 99mTc-DARPinG3.Materials and methods. The study included 10 patients with breast cancer (T1-4N0-2M0) before systemic therapy, who underwent a radionuclide study using 99mTc-DARPinG3 at a dose of 3,000 μg. Five patients were characterized by HER2 / neu overexpression in primary breast cancer, whereas 5 patients were HER2-negative. For all patients, morphological and immunohistochemical studies and fluorescence in situ hybridization (FISH) of the primary tumor nodule were carried out. Single-photon emission computed tomography (SPECT) of the chest was performed for all patients 4 hours after the injection of 99mTc-DARPinG3.Results. The total activity of 99mTc-DARPinG3 was 522.4 ± 341.8 MBq. The comparative analysis showed that higher uptake of the labeled protein in HER2-positive breast cancer was significant (p = 0.0159, Mann – Whitney U test). The analysis of the ratios showed significant differences in the tumor-to-background ratios in patients with HER2-positive breast cancer (p < 0.0159, Mann – Whitney U test). Based on the logistic regression analysis, a mathematical model was developed to predict the status of HER2 / neu in primary breast cancer patients (specificity and sensitivity 100%; p = 0.0004) using 99mTc-DARPinG3 at a dose of 3,000 mcg 4 hours after the injection of the radiopharmaceutical.Conclusion. The results of the study allow to consider the tumor-to-background ratio 4 hours after the injection of 99mTc-DARPinG3 as an additional prognostic parameter for determining the HER2 / neu status in primary breast cancer.

Introduction: The purpose of this study is to determine if p53 and Her2/neu have prognostic value in recognizing more aggressive behavior and low prognostic breast cancer. p53 is involved in regulating cell proliferation-inducing apoptosis and enhancing chromosomal stability. In carcinogenesis, disturbance of these roles tends to play significant role. There is evidence that overexpression of Her2 and p53 is implicated in the development of breast cancer. Her2 (c-erbB2) encodes a membrane protein (p185) that, after interaction with its ligands, is phosphorylated by tyrosine. Overexpression of Her2 occurs by either gene amplification or by overexpression of mRNA. Materials and Methods: Fifty consecutive diagnosed cases of infiltrating duct carcinoma over a period of 2 years were reviewed from archived pathology records. Evaluation of p53 and Her2/neu staining was analyzed and staining was scored. Results: p53 and Her2/neu were both positive in 14% of cases, both were negative in 24% of cases. p53 positivity with Her2/neu negativity was seen in 52% of cases, whereas p53 negativity and Her2/neu positivity were seen in 10% of cases. Follow-up was available in 21 cases, and survival pattern of patients according to various clinicopathological parameters was done. Conclusion: A well-defined cutoff to label p53 overexpression will help in ascertaining the role of p53 as a prognostic marker. Her2/neu overexpression is associated with lymph node involvement.

Background: The number of elderly patients with breast cancer has increased in recent years, many of whom reside alone. This makes choosing their treatment difficult because of domestic considerations and declining physical and cognitive functions. Chemotherapy is often omitted owing to age, and treatment can subsequently be inadequate. Case presentation: Our patient was an 82-year-old woman presenting with the chief complaint of an enlarged left breast mass. The mass had undergone selfdestruction with hemorrhage and enlarged left axillary and supraclavicular lymph nodes. She lived alone; therefore, initial chemotherapy of trastuzumab (HER)+pertuzumab (PER)+weekly paclitaxel (wPTX) two-step dose reduction was performed in the hospital. A subcutaneous mass appeared, which disappeared after irradiation. Subsequently, tri-weekly HER+PER administration was continued. Conclusion: A multidisciplinary approach to therapy may offer elderly patients living alone with inoperable breast cancer patients the ability to continue treatment and control their disease following careful consideration of their comorbidities and decline in physical and cognitive functions. Such multidisciplinary treatment options minimize the occurrence of side effects, allowing for long-term continuation of therapy, helping to maintain quality of life and potentially prolonging overall survival. [ABSTRACT FROM AUTHOR]

Objective: Breast cancer (BC) is one of the most commonly diagnosed solid malignancies in women worldwide. Purpose: Finding new non-invasive circulating diagnostic biomarkers will facilitate the early prediction of BC and provide valuable insight into disease progression and response to therapy using a safe and more accessible approach available every inspection time. Therefore, our present study aimed to investigate expression patterns of potentially circulating biomarkers that can differentiate well between benign, malignant, and healthy subjects. Methods: To achieve our target, quantitative analyses were performed for some circulating biomarkers which have a role in the proliferation and tumor growth, as well as, glutamic acid, and human epidermal growth receptor 2 (HER2) in blood samples of BC patients in comparison to healthy controls using qRT-PCR, liquid chromatography/mass spectrometry (LC/MS/MS), and ELISA. Results: Our findings showed that the two miRNAs (miRNA-145, miRNA-382) were expressed at lower levels in BC sera than healthy control group, while miRNA-21 was expressed at higher levels in BC patients than control subjects. Area under ROC curves of BC samples revealed that AUC of miRNA-145, miRNA-382, miRNA-21, and glutamic acid was evaluated to equal 0.99, 1.00, 1.00 and 1.00, respectively. Besides, there was a significantly positive correlation between miRNA-145 and miRNA-382 (r = 0.737), and a highly significant positive correlation between miRNA-21 and glutamic acid (r = 0.385). Conclusion: Based on our results, we conclude that the detection of serum miRNA-145, -382 and -21 as a panel along with glutamic acid, and circulating HER2 concentrations could be useful as a non-invasive diagnostic profiling for early prediction of breast cancer in Egyptian patients. It can provide an insight into disease progression, discriminate between malignancy and healthy control, and overcome the use limitations (low sensitivity and specificity, repeated risky exposure, and high cost) of other detecting tools, including mammography, magnetic resonance imaging, and ultrasound. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most common malignancy and the leading cause of cancer-related deaths in females. Accordingly, the evaluation of new prognostic markers and therapeutic targets is of vital importance. Here, we aimed to detect androgen receptor (AR) status and define its association with clinicopathologic parameters in patients with invasive breast cancer. Materials and Methods: In this study, AR status was studied in 104 patients with invasive breast carcinoma by immunohistochemistry. Besides, its association with clinicopathologic factors, i.e., age, menopausal status, tumor size, lymph node involvement, tumor stage, tumor grade and estrogen receptor (ER), progesterone receptor (PR), Her2/neu, Ki-67and P53 were investigated. Results: AR was positive in 84 patients (80.8%), and its expression in ER-positive (85.7%) and PR-positive (85.6%) patients were remarkably higher than in ER-negative (46.2%) and PR-negative (50%) patients (p= 0.001 and p=0.002, respectively). AR expression was noticeably lower in Her2/neu-positive (25%) patients compared to Her2/neu-negative (87.9%) ones (p=0.000). AR expression was also higher in patients with smaller, earlier stage, and low mitotically active tumors, but the association was not statistically significant. Conclusion: The expression of AR in patients with breast cancer was found to be high and its association with ER-positive, PR-positive, and HER2/neu-negative tumors was found to be significant. In that light, this receptor may play an important role in the determination of prognosis and targeted therapy in breast cancer. [ABSTRACT FROM AUTHOR]

•Genomic tumor testing is an important tool in guiding treatment for gynecologic malignancies.•Targetable mutations may lead to new therapies in gynecologic cancer treatment.•Her2/neu mutations in serous ovarian carcinomas can be targeted with ERBB2 inhibitors.•Afatinib shows promising response rates in lung cancers carrying Her2/neu mutations.•Afatinib may be effective in serous ovarian tumors exhibiting Her2/neu or ERBB2 mutations.

•Genomic tumor testing is an important tool in guiding treatment for gynecologic malignancies.•Targetable mutations may lead to new therapies in gynecologic cancer treatment.•Her2/neu mutations in serous ovarian carcinomas can be targeted with ERBB2 inhibitors.•Afatinib shows promising response rates in lung cancers carrying Her2/neu mutations.•Afatinib may be effective in serous ovarian tumors exhibiting Her2/neu or ERBB2 mutations.

An antibody-cytokine fusion protein, composed of the murine single-chain cytokine interleukin-12 (IL-12) genetically fused to a human IgG3 specific for the human tumor-associated antigen HER2/neu maintains antigen binding, cytokine bioactivity, and IL-12 heparin-binding activity. This latter property is responsible for the binding of the cytokine to glycosaminoglycans (GAGs) on the cell surface and the extracellular matrix and has been implicated in modulating IL-12 bioactivity. Previous studies indicate that the p40 subunit of human and murine IL-12 is responsible for the heparin-binding activity of this heterodimeric cytokine. In the present study we used bioinformatic analysis and site-directed mutagenesis to develop a version of the antibody-(IL-12) fusion protein without heparin-binding activity. This was accomplished by replacing the basic arginine (R) and lysine (K) residues in the cluster of amino acids 254-260 (RKKEKMK) of the murine IL-12 p40 subunit by the neutral non-polar amino acid alanine (A), generating an AAAEAMA mutant fusion protein. ELISA and flow cytometry demonstrated that the antibody fusion protein lacks heparin-binding activity but retains antigen binding. A T-cell proliferation assay showed IL-12 bioactivity in this construct. However, the IL-12 bioactivity is decreased compared to its non-mutated counterpart, which is consistent with an ancillary role of the heparin-binding site of IL-12 in modulating its activity. Thus, we have defined a cluster of amino acid residues with a crucial role in the heparin-binding activity of murine IL-12 in the context of an antibody-cytokine fusion protein.

HER2-positive breast cancer occurs in 15–20% of breast cancer patients and is associated primarily with a poor prognosis of the disease and the need for highly specific targeted therapy. Despite the clinical importance of determining HER2/neu, traditional diagnostic methods have their disadvantages and require the study of new additional research techniques.The information presented in this review makes it possible to consider current trends in the radionuclide diagnosis of HER2-positive breast cancer using the latest class of alternative scaffold proteins and to consider various aspects of their use in clinical practice.

Background: Treatment of uterine serous carcinoma (USC) is challenging; effective treatment options for metastatic and recurrent disease are needed. Case: A 68-year-old woman with recurrent, metastatic, USC overexpressing HER2/neu experienced durable response to the antibody drug conjugate (ADC) trastuzumab-deruxtecan (T-DXd), after failing multiple standard and experimental treatments targeting HER2/neu. She experienced a significant reduction in disease burden, disappearance of metastatic back bone pain as well as normalization of CA-125 quickly after starting treatment. Her disease continued to show response to treatment over 5 months and 7 cycles of T-DXd therapy. She did not experience any dose-limiting side effects and tolerated treatment with 5.4 mg/kg T-DXd without issue. Conclusion: T-DXd may present a new treatment option for chemotherapy-resistant uterine serous carcinoma.

This study aimed at exploring the expression and clinical significance of aromatase P450, adhesion molecule CD24 and HER2/neu in endometrial cancer. The expression of aromatase P450, adhesion molecule CD24 and HER2/neu was detected by immunohistochemistry in 15 cases of endometrial hyperplasia group, 50 cases of endometrial adenocarcinoma and 3 cases of uterine papillary adenocarcinoma, with 15 cases of normal endometrium as control group. We detected no expression of aromatase P450, adhesion molecule CD24 or HER2/neu in control group. Aromatase P450 positive expression rate was 66.7% in endometrial hyperplasia group and 70.3% in endometrial carcinoma group, without significant difference (p>0.05). There was no significant difference (p>0.05) in the positive expression rate of aromatase P450 between different myometrial invasion groups of endometrial adenocarcinomas. CD24 positive expression rate was 40.0% in endometrial hyperplasia group and 79.6% in endometrial carcinoma group, with significant difference (p

Background: Breast cancer is the most common malignancy and the leading cause of cancer-related deaths in females. Accordingly, the evaluation of new prognostic markers and therapeutic targets is of vital importance. Here, we aimed to detect androgen receptor (AR) status and define its association with clinicopathologic parameters in patients with invasive breast cancer. Materials and Methods: In this study, AR status was studied in 104 patients with invasive breast carcinoma by immunohistochemistry. Besides, its association with clinicopathologic factors, i.e., age, menopausal status, tumor size, lymph node involvement, tumor stage, tumor grade and estrogen receptor (ER), progesterone receptor (PR), Her2/neu, Ki-67and P53 were investigated. Results: AR was positive in 84 patients (80.8%), and its expression in ER-positive (85.7%) and PR-positive (85.6%) patients were remarkably higher than in ER-negative (46.2%) and PR-negative (50%) patients (p= 0.001 andp=0.002, respectively). AR expression was noticeably lower in Her2/neu positive (25%) patients compared to Her2/neu negative (87.9%) ones (p=0.000). AR expression was also higher in patients with smaller, earlier stage, and low mitotically active tumors, but the association was not statistically significant. Conclusion: The expression of AR in patients with breast cancer was found to be high and its association with ER-positive, PR-positive, and HER2/neu-negative tumors was found to be significant. In that light, this receptor may play an important role in the determination of prognosis and targeted therapy in breast cancer.

Background: Prostate cancer development and progression to androgen-independent disease is correlated with increased expression of growth factors and receptors capable of establishing autocrine and/or paracrine growth-stimulatory loops. Overexpression of the Her2/neu receptor tyrosine kinase has been associated with the progression to androgen independence in prostate cancer cells. Objective: Our primary aim was to investigate the frequency of HER2/neu amplification in prostate biopsy specimens in newly diagnosed metastatic carcinoma prostate and its correlation to progression of androgen independent carcinoma. Materials and Methods: In our study, expression of HER2/neu was carried out by immunohistochemical analysis in TRUS biopsy specimen of newly diagnosed metastatic carcinoma prostate. Results: Out of 36 patients, seven (19.4%) showed her2neu overexpression on immunohistochemical staining. Five out of seven (71%) were associated with higher histological grade >7 at diagnosis (p < 0.05). Her2neu overexpression was not significantly associated with age and serum PSA at diagnosis. However progression to castration resistant stage was not dependant on Her2/neu status (p > 0.05). Conclusion: Overexpression of her2/neu was associated with high grade carcinoma prostate at diagnosis, however progression to castration resistant stage was not related with her2neu expression. [ABSTRACT FROM AUTHOR]

Compared with sun-exposed melanomas, less is known regarding the pathogenesis of sun-protected melanomas. Sun-protected melanomas share many epidemiologic factors, but their genetic heterogeneity is not well studied. We investigated the genomic profile of acral, mucosal, and vulvovaginal melanomas. We hypothesize that mucosal melanomas, recognized for their uniquely aggressive clinical behavior, have distinct genomic features. We performed whole transcriptome messenger RNA and DNA (1711 genes) sequencing, messenger RNA expression profiling, tumor mutational burden, ultraviolet signature, and copy number variants analysis on 29 volar/digital acral, 7 mucosal, and 6 vulvovaginal melanomas. There was significant genetic heterogeneity, particularly in acral melanomas, with 36% having BRAF alterations, whereas other melanomas had none (P =.0159). Nonzero ultraviolet signatures were more frequent in acral melanomas, suggesting greater ultraviolet involvement. Mucosal melanomas formed a distinct group with increased expression of cell cycle and proliferation genes. Various targetable aberrations were identified, such as AURKA and ERBB2 , in mucosal and acral melanomas, respectively. The sample size was a small. There is significant genetic heterogeneity among sun-protected melanomas. Mucosal melanomas have upregulation in cell cycle and proliferation genes, which may explain their aggressive behavior. Ultraviolet radiation plays some role in a subset of acral but not other melanomas. [ABSTRACT FROM AUTHOR]

The overexpression of the human epidermal growth factor 2 (HER2/neu) oncogene is predictive of adverse breast cancer prognosis. Silencing the HER2/neu overexpression using siRNA may be an effective treatment strategy. Major requirements for siRNA-based therapy are safe, stable, and efficient delivery systems to channel siRNA into target cells. This study assessed the efficacy of cationic lipid-based systems for the delivery of siRNA. Cationic liposomes were formulated with equimolar ratios of the respective cholesteryl cytofectins, 3β-N-(N′, N′-dimethylaminopropyl)-carbamoyl cholesterol (Chol-T) or N, N-dimethylaminopropylaminylsuccinylcholesterylformylhydrazide (MS09), with the neutral helper lipid, dioleoylphosphatidylethanolamine (DOPE), with and without a polyethylene glycol stabilizer. All cationic liposomes efficiently bound, compacted, and protected the therapeutic siRNA against nuclease degradation. Liposomes and siRNA lipoplexes were spherical, <200 nm in size, with moderate particle size distributions (PDI < 0.4). The siRNA lipoplexes exhibited minimal dose-dependent cytotoxicity and effective HER2/neu siRNA transfection in the HER2/neu overexpressing SKBR-3 cells. The non-PEGylated Chol-T-siRNA lipoplexes induced the highest HER2/neu silencing at the mRNA (10000-fold decrease) and protein levels (>111.6-fold decrease), surpassing that of commercially available Lipofectamine 3000 (4.1-fold reduction in mRNA expression). These cationic liposomes are suitable carriers of HER2/neu siRNA for gene silencing in breast cancer. [ABSTRACT FROM AUTHOR]

Introduction: Patients with HER2-positive metastatic breast cancer are at risk for developing brain metastases. Different anti-HER2 treatments can be used in the management of the disease. In this study, we aimed to evaluate the prognosis and the factors affecting the prognosis in brain metastatic patients with HER2-positive breast cancer. Methods: Clinical and pathological features of HER2-positive metastatic breast cancer patients and magnetic resonance imaging features at the onset of brain metastasis were recorded. Survival analyses were performed using Kaplan-Meier and Cox regression methods. Results: Analyses of the study were performed by including 83 patients. The median age was 49 (25–76). All patients had HER2 receptor-positive tumors. Thirty-five (42.2%) patients had a hormone-positive disease. Thirty-two (38.6%) patients had de novo metastatic disease. Brain metastasis sites were found to be bilateral – 49.4%, right brain – 21.7%, left brain – 12%, and unknown – 16.9%, respectively. The median brain metastasis largest size was 16 mm (range 5–63). The median follow-up time from the post-metastasis period was 36 months. Median overall survival (OS) was found as 34.9 months (95% CI, 24.6–45.2). In multivariate analysis for factors affecting OS, estrogen receptor status (p = 0.025), number of chemotherapy agents used with trastuzumab (p = 0.010), number of HER2-based therapy (p = 0.010), and the largest size of brain metastasis (p = 0.012) were found to be statistically significant. Conclusions: In this study, we demonstrated the prognosis in brain metastatic patients with HER2-positive breast cancer. When the factors affecting the prognosis were evaluated, we determined that the largest size of brain metastasis, estrogen receptor positivity, and the use of TDM-1 and lapatinib plus capecitabine consecutively during the treatment process affected the prognosis of the disease. [ABSTRACT FROM AUTHOR]

Carcinosarcomas are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression and limited therapeutic options. We compared the efficacy of trastuzumab deruxtecan (DS-8201a), a novel HER2/neu-targeting antibody-drug conjugate (ADC) to an ADC isotype control (MAAA-9199) against primary uterine and ovarian carcinosarcomas in vitro and in vivo. Twelve primary carcinosarcoma (CS) cell lines were evaluated for HER2/neu surface expression by immunohistochemistry (IHC) and by flow cytometry, and gene amplification by fluorescence in situ hybridization (FISH) assays. The in vitro experiments included cytotoxicity and bystander killing effect assays on three cell lines of variable HER2/neu expression. In vivo activity was studied in a mouse CS xenograft model of 3+ HER2/neu uterine CS. In vitro studies showed that DS-8201a was highly effective against uterine and ovarian CS cell lines demonstrating 3+ HER2/neu expression compared to MAAA-9199 control; there was no significant improvement in the 0 HER2/neu CS cell line. However, DS-8201a induced efficient bystander killing of 0 HER2/neu tumor cells when admixed with 3+ HER2/neu cells. In vivo studies confirmed that DS-8201a was more effective than MAAA-9199 in 3+ HER2/neu-expressing CS xenografts. DS-8201a may represent a novel and highly effective ADC against HER2/neu-expressing CS. • DS-8201a exhibited marked cytotoxicity in vitro among HER2/neu expressing cell lines. • 0 HER2/neu cells are receptive to bystander killing effect from DS-8201a when mixed with 3+ HER2/neu-expressing cells. • DS-8201a inhibits HER2/neu expressing carcinosarcoma tumor growth in patient-derived xenografts. • DS-8201a is an effective antibody drug conjugate against HER2/neu-expressing uterine and ovarian carcinosarcomas. [ABSTRACT FROM AUTHOR]

Only few studies reported in literature that has elucidated in detail the implications of molecular typing in metastatic and recurrent breast cancer. In this prospective study, we have analysed in depth the pattern of expression, discordances of molecular markers in various metastatic sites, and recurrent cases and their response to chemotherapy/targeted agents and the prognostic outcome. The primary aim of the study was to determine ER, PR, HER2/NEU, and Ki-67 from recurrent and metastatic carcinoma breast to study the expression pattern and discordance and also to study the degree of discordance in relation to the site of metastasis and pattern of metastasis (synchronous vs metachronous) and discordance pattern with the response to chemotherapy and median overall survival rates in months in available subset of patients. Prospective open-label study done at the Government Rajaji Hospital, Madurai Medical College, and Government Royapettah Hospital, Kilpauk Medical College, India, from November 2014 to August 2021. All breast carcinoma patients with recurrence or oligo metastasis (defined as one organ with less than 5 metastases in our study) with known receptor status were eligible and 110 patients were enrolled in the study. ER (ER + to ER −) discordance was seen in 19 (26.38%) cases. PR (PR + to PR -Ve) discordance was seen in 14 (19.17%) cases. HER2/NEU (HER2/NEU + Ve to -Ve) discordance was seen in 3 (16.6%) cases. Ki-67 discordance was seen in 54 (49.09%) cases. High Ki-67 as a proliferative marker has increased response to chemotherapy but earlier relapse and disease progression especially in Luminal B type. In further subset analysis, ER, PR, and HER2/NEU discordance is higher for lung metastasis (ER, PR 61.1%, p value.001, HER2/NEU 5.5%), followed by liver metastasis (ER, PR 50%, p value.0023, 1 case turning ER -ve to + ve, HER2/NEU 1 (10%)). In lung, discordance is more for metachronous metastasis. In liver, discordance is 100% for synchronous metastasis. Synchronous metastasis with discordance in ER and PR is associated with rapid disease progression. High Ki-67 subset of Luminal B–like tumors progressed rapidly than triple negative and HER2/NEU positive subset. Complete clinical response rate in contralateral axillary node metastasis group was 87.8%, followed by local only recurrence with high Ki-67 where chemotherapy had response rate of 81% and 2 years DFS of 93.12% after excision. Certain subsets like contralateral axillary nodes and supraclavicular nodes which present as oligo metastatic disease with discordance and high Ki-67 respond well to chemotherapeutics and targeted agents improving the OS in this subset of patients. Molecular markers and their expression and discordance pattern determine the therapeutic outcome and prognosis of the disease. Early identification and targeting the discordance would go a long way in improving the outcome and DFS and OS of breast cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of this study is to determine if p53 and Her2/neu have prognostic value in recognizing more aggressive behavior and low prognostic breast cancer. p53 is involved in regulating cell proliferation-inducing apoptosis and enhancing chromosomal stability. In carcinogenesis, disturbance of these roles tends to play significant role. There is evidence that overexpression of Her2 and p53 is implicated in the development of breast cancer. Her2 (c-erbB2) encodes a membrane protein (p185) that, after interaction with its ligands, is phosphorylated by tyrosine. Overexpression of Her2 occurs by either gene amplification or by overexpression of mRNA. Materials and Methods: Fifty consecutive diagnosed cases of infiltrating duct carcinoma over a period of 2 years were reviewed from archived pathology records. Evaluation of p53 and Her2/neu staining was analyzed and staining was scored. Results: p53 and Her2/neu were both positive in 14% of cases, both were negative in 24% of cases. p53 positivity with Her2/neu negativity was seen in 52% of cases, whereas p53 negativity and Her2/neu positivity were seen in 10% of cases. Follow-up was available in 21 cases, and survival pattern of patients according to various clinicopathological parameters was done. Conclusion: A well-defined cutoff to label p53 overexpression will help in ascertaining the role of p53 as a prognostic marker. Her2/neu overexpression is associated with lymph node involvement. [ABSTRACT FROM AUTHOR]

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Gastric cancer (GC) represents one of the most fatal neoplasms in gastrointestinal oncology and affected patients can only hope for cure in limited disease. In a metastatic situation however, patients have a worse prognosis finally resulting in cancer-related death. Some improvements were made by using intensified chemotherapy such as the FLOT protocol (5-FU, leucovorin, oxaliplatin and docetaxel). However, a breakthrough in the treatment of advanced GC has been achieved by pre-therapeutical tumor analysis for potentially targetable alterations. Microsatellite instability, PD-L1 expression, Epstein Barr virus, and human epidermal growth factor receptor-2 (HER2) overexpression or amplification are the most beneficial targets, if addressed, can prolong survival in a palliative situation. Whether the combination of these targeted therapeutics with chemotherapy can bring long-term survival or even a chance of cure in a metastatic situation is not clear. Here, we report the case of a 30-year-old man with GC and extensive metastases who was cured by anti-HER2 antibody Trastuzumab combined with the FLOT regime. Initial staging showed an exophytic Siewert type III tumor and extensive hepatic metastases. Histology resulted in gastric adenocarcinoma with HER2 overexpression (2+, FISH positive). Twelve courses of chemotherapy comprising Trastuzumab and FLOT were administered. After treatment, the extensive liver metastases had disappeared with no evidence of residual tumor growth on the CT scans. Monotherapy of Trastuzumab was continued until gastrectomy with D2 lymph node dissection and probing of liver tissue, which revealed no residual tumor cells. Five years after surgery, there is continued complete remission. In conclusion, Trastuzumab in combination with FLOT may have curative potential even for metastatic stages of HER-2-positive GC.