Characterization of immune checkpoints expression and lymphocyte densities of iranian breast cancer patients; the co-expression status and clinicopathological associates.

BACKGROUND: Breast malignancies are now the most common and deadliest type of neoplasms among women worldwide. Novel therapeutic approaches are needed to combat advanced stages of breast cancer. In this study, we aimed to investigate the expression and co-expression status of three immune checkpoints (PD-1, PD-L1, and LAG-3), as well as tumor-infiltrating lymphocytes (TIL) scores, and to further establish their potential correlations with clinicopathologic features. METHODS: We performed a retrospective study on 361 pathologic samples of breast cancer. Immunohistochemistry was performed to assess the status of the immune checkpoint markers, and H&E staining was used to score TILs. The correlations of the immune checkpoint markers of tumor cells and tumor-associated immune cells and TIL scores with clinicopathological characteristics were analyzed. RESULTS: Out of 361 assessed samples, LAG-3 was positive in 51%, while IC PD-L1 and TC PD-L1 were detectable in 36% and 8.9%, respectively. Moreover, both IC PD-L1 and LAG-3 stained positively in 24.4% of samples. IC PD-L1 expression was significantly higher in tumors with higher nuclear, mitotic, and overall grades and tubule formation. In addition, TC PD-L1 and LAG-3 exhibited a similar trend for higher overall grading. Tumors with positive estrogen- and progesterone-receptor (ER and PR) expression had significantly lower IC PD-L1 and TC PD-L1 staining, while LAG-3 positivity was more prevalent in HER2 positive samples. Tumors that were positive for these biomarkers had significantly higher Ki-67 scores. LAG-3 expression showed significant correlations with PD-1 and IC PD-L1 expression. Besides, the co-expression of LAG-3 and IC PD-L1 was significantly more encountered in luminal B and triple-negative subtypes, compared to the luminal A subtype. Regarding TILs, their scoring was significantly higher in ER and PR negative and HER2 positive samples. Intriguingly, samples with positive staining for LAG-3, IC PD-L1, and TC PD-L1 had significantly higher TIL scorings. CONCLUSIONS: Immune checkpoints show differentially different levels of expression in certain molecular subtypes of breast cancer. Moreover, they reveal a meaningful correlation with each other, proliferation indices, and histologic grades. Finally, a sizable proportion of breast cancers co-express PD-L1 and LAG-3, which will make them appropriate targets for future combined ICIs.

Proven Aspergillus flavus pulmonary aspergillosis in a COVID-19 patient: A case report and review of the literature.

Severe COVID-19 patients complicated with aspergillosis are increasingly reported. We present a histopathological proven case of fatal COVID-19-associated pulmonary aspergillosis (CAPA), due to Aspergillus flavus. This report and existing published literature indicate diagnostic challenges and poor outcomes of CAPA in ICU patients.

Breast Cytology and Pathology in Pregnancy and Lactation.

Breast tissue reveals some physiologic changes during pregnancy and lactation due to hormonal alterations. Whole range of breast diseases including inflammatory, benign and malignant neoplasms can be seen in pregnancy but due to concurrent physiologic changes, may lead to diagnostic challenges. This chapter reviews sampling methods and histologic features of common benign breast lesions in pregnancy and lactation periods.

Histology of Pregnancy-Associated Breast Cancer.

Breasts are one of the most common sites of neoplastic lesions in women during pregnancy and lactation. This chapter reviews carcinomas of the breast during pregnancy and lactation while focusing on histologic features, biomarker profiles and some involved molecular pathways. Also, a brief review of previous studies on this field is performed.

The role of transferrin receptor in the Helicobacter pylori pathogenesis; L-ferritin as a novel marker for intestinal metaplasia.

Helicobacter pylori growth requirements is a prerequisite to invade gastric epithelium and the process of injury to gastric cells will eventually lead to gastric cancer. The aim of this study is to investigate the effect of iron challenge on the expression of genes involved in iron homeostasis. The presence of Phosphoglucosamine mutase (glmM), cytotoxin-associated gene A (cagA) and vacuolating cytotoxin A (vacA) genes and mRNA expression of Iron Regulatory Protein 2 (IRP2), Transferrin Receptor (TFRC) and Ferritin Light Chain (FTL) genes in samples of 28 normal gastric mucosa, 33 chronic gastritis, 29 gastritis with intestinal metaplasia, 29 intestinal type adenocarcinoma patients were examined by real-time PCR. Immunohistochemistry was used to analyze cellular localization and protein levels. In the all H. pylori positive tissues, particularly in the basal regions of foveolar cells, TFRC was overexpressed (P < 0.05), and regardless of the H. pylori infection, FTL was overexpressed in all patient, exclusively in metaplastic glandular cells (P < 0.05). Furthermore, overexpression of IRP2 was associated with H. pylori positive chronic gastritis and intestinal metaplasia (P < 0.05). Our findings confirm the role of transferrin receptor in H. pylori attachment into the gastric mucosa to capture iron. Overexpression of FTL gene in metaplastic cells could be considered as a research background to investigate the role of this gene in the differentiation of gastric cells into intestinal metaplasia. In addition, this gene could be suggested as a diagnostic marker to be included among the other markers routinely performed by clinical diagnostic laboratories.

Peripheral T-Cell Lymphoma Presenting as a Primary Uterine Cervix Mass: A Report of a Rare Case.

Malignant lymphoma is a rare form of malignancy in the uterine cervix. Most of the previously reported cases were B-cell lymphomas. We present a case of primary peripheral T-cell lymphoma, not otherwise specified, in the uterine cervix in a 49-year-old woman with a history of severe vaginal bleeding. The patient was treated with a CHOP (cyclophosphamide, adriamycin, vincristine, and prednisolone) chemotherapy regimen and 28 cycles of radiotherapy. Three months later, she presented with generalized lymphadenopathy and sudden left-eye ptosis as a complication of CNS involvement and died after 20 months from the initial disease presentation.

Doxorubicin-related cardiotoxicity: review of fundamental pathways of cardiovascular system injury.

Over the years, advancements in the field of oncology have made remarkable strides in enhancing the efficacy of medical care for patients with cancer. These modernizations have resulted in prolonged survival and improved the quality of life for these patients. However, this progress has also been accompanied by escalation in mortality rates associated with anthracycline chemotherapy. Anthracyclines, which are known for their potent antitumor properties, are notorious for their substantial cardiotoxic potential. Remarkably, even after 6 decades of research, a conclusive solution to protect the cardiovascular system against doxorubicin-induced damage has not yet been established. A comprehensive understanding of the pathophysiological processes driving cardiotoxicity combined with targeted research is crucial for developing innovative cardioprotective strategies. This review seeks to explain the mechanisms responsible for structural and functional alterations in doxorubicin-induced cardiomyopathy.

Evaluation of PD-L1 antigen expression using immunohistochemistry technique in medullary thyroid carcinoma samples.

BACKGROUND: Markers related to the mechanism of tumoral cell escape from the immune system have received more attention. The PD-L1 molecule encoded by the "CD274" gene binds to T lymphocytes and can inhibit these cells. Therefore, increasing the expression of this marker on inflammatory or tumor cells can indicate tumor progression invasiveness and long-term consequences. The present study aimed to determine the expression of the PD-L1 marker in thyroid medullary tumors and to evaluate its role in predicting long-term outcomes after cancer. METHODS: This retrospective longitudinal study was performed on pathology samples of patients with medullary thyroid carcinoma referred to the Cancer Institute of Imam Khomeini Hospital from 2015 to 2020. Slides related to medullary thyroid tumors were examined. A tissue microarray was used to evaluate the immunohistochemistry of PD-L1. Patients were followed up to assess the occurrence of recurrence. Out of 207 patients evaluated in the present study, histopathological information of 144 patients was available. RESULTS: The expression rate of PD-L1 in our community was 14.6% in lymphocyte cells, 35.4% in tumor cells, and 12.5% in both cells. The presence of metastasis at the time of diagnosis was reported in 35 cases (72.9%), and the occurrence of tumor recurrence was reported in 38 cases (79.2%). There was no relationship between the expression of this marker and the sex and age of patients. In addition, PD-L1 expression was unrelated to the two main characteristics of this cancer, namely tumor size and its focality. The presentation of tumor PD (L1) (but not lymphocytic) was a prognostic marker for synchronous metastasis at cancer diagnosis but could not predict tumor recurrence. CONCLUSION: PD-L1 tumor marker expression is predictable in 14.6% of lymphocyte cells, 35.4% of tumor cells, and 12.5% in the selected Iranian population with medullary thyroid cancer. The expression of this marker is not related to the morphological characteristics of the tumor, such as tumor size or focality.

Assessment of the relationship between miR-499C/T (rs3746444) polymorphism and lung carcinoma in Iranian population; a case-control study.

Introduction: Lung carcinoma is characterized by uncontrollable division of respiratory system cells with detrimental and lethal consequences on human health. Critical roles of microRNAs (miR) are scientifically approved in biological and pathological pathways, such as the role of miR-499 (rs3746444) in lung carcinomas. Thus, in this case-control investigation, we aimed to assess the probable relationship between miR-499C/T variant and the occurrence of lung carcinoma in Iranian population for the first time. Methods: Genotype of miR-499 polymorphism was described by the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) assay in patients and healthy individuals. Following definite diagnosis of lung carcinoma, the blood samples were collected, and the DNA extraction was performed by Salting-Out method. Finally, data were analysed by SPSS (v. 20) and the significant level was considered p-value<0.05. Results: Statistically, the frequency of combined genotypes of CC+CT were 83.33% and 35% and TT+CT were 100% and 92% in case and control individuals, respectively. Also, individuals with genotypes of TC (OR: 3.08, CI95%: 3.03-3.17, p<0.0001), TC+CC (OR: 0.10, CI95%: 0.05-0.23, p<0.0001), CC (OR: 0, CI95%: 0.00-0.60, p=0.0214), and TC (OR: 0.07, CI95%: 0.030.15, p<0.0001) represented statistically significant (p<0.05) differences lung carcinoma than those with TT, TT, TT+TC, and TT+CC genotypes, respectively. The frequency of miR-499C (78.5%) and miR-499T (21.5%) alleles were also statistically significantly (p<0.05) difference associated with lung carcinoma in patients than controls. Conclusion: In this study, a possible relationship among miR-499C/T polymorphism and lung carcinoma was detected in Iranian population. Since this study was conducted for the first time, thus other supplementary assessments are needed for definite conclusion.

Huge spindle cell sarcoma of esophagus in a middle-aged man with a recent-onset dysphagia: Case report.

INTRODUCTION: Esophageal sarcoma is a rare neoplasm of the gastrointestinal tract. The majority of the esophageal neoplasms have an epithelial origin. In this report, we present a case of a middle-aged man with an enormous spindle cell sarcoma whose symptoms initiated only a few weeks before diagnosis. PRESENTATION OF CASE: A 41-year-old man with an unremarkable past medical history and physical examination presented with recent aggravation of cough and severe, progressive dysphagia to solid foods resulting in a 25-kilogram weight loss without any prior symptoms. He had no history of cigarette smoking and alcohol consumption. The CT scan showed a huge soft tissue mass with heterogeneous enhancement from the proximal esophagus to 4 cm above the gastro-esophageal junction, causing luminal bulging. Trans-hiatal esophagectomy and gastric pull-up were performed. Pathology report confirmed the diagnosis of sarcoma. Further pathological evaluation using immune-histochemical studies, confirmed the tumor as spindle cell sarcoma. The postoperative period was uneventful, and there were no signs and symptoms related to tumor recurrence one year after surgery. DISCUSSION: The most challenging aspect of diagnosing sarcomas is differentiating them from other pathologies, such as gastrointestinal stromal tumors, synovial sarcomas, sarcomatoid carcinomas, melanomas, and solitary fibrous tumors. Immunohistochemical studies play a vital role in this differentiation. Additionally, cytokeratin AE1/AE3 has been introduced as a marker of epithelial differentiation and can verify the presence of the epithelial component in tumors, such as in carcinosarcomas. CONCLUSION: Considering the potential for an unusual size, sarcoma should be considered in a differential diagnosis for huge esophageal masses.

Does MRI have added value in ultrasound-detected BIRADS-3 breast masses in candidates for assisted reproductive therapy?

Background: Ultrasound-detected breast lesions with probably benign features are a great challenge for clinicians, especially in breasts with dense composition. We aimed to investigate the finding of two radiologic modalities on these lesions. Methods: This retrospective cross-sectional study recruited patients including (1) candidates of assisted reproductive therapy (ART), (2) patients with prior high-risk lesions, and (3) the "suspected" BIRADS-3 masses referring to masses that US BIRADS-3 was not compatible with the clinical breast exam. The degree of agreement in diagnosing BIRADS-3 lesions between two modalities of magnetic resonance imaging (MRI) and ultrasonography (US), and comparison of the lesions in US and MRI were the study variables. Results: A total number of 123 lesions in 67 patients with a median age of 38 (IQR: 11, range: 17-67). In the examination by MRI, 107 (87.0 %) lesions were BIRADS-3 indicating the agreement level between these two modalities. The median size of the lesions in US was 9 mm (IQR: 5, range: 3-43) and 9 mm (IQR: 10, range: 4-46) in MRI. The measured size of the lesions between the two modalities was highly correlated (Spearman correlation coefficient: 0.889, P-value < 0.001). MRI evaluation revealed two cases of deep lesions which were missed in the US imaging. Conclusions: This study found relatively high agreement values between US and MRI in detecting BIRADS-3 breast lesions in candidates for ART or patients with prior high-risk lesions. Also, MRI could downgrade about one-tenth of the cases to a lower BIRADS level and resolved the need for closer follow-up.

Rhabdomyosarcoma mimicking lymphoma.

Background: Rhabdomyosarcoma (RMS) is a malignant soft tissue tumor that accounts for approximately one-half of soft tissue sarcomas in childhood age groups. Metastatic RMS is a rare condition that occurs in less than 25% of patients at diagnosis and can have variable clinical presentations. Case presentation: Here we report a 17-year-old boy with history of weight loss, fever and generalized bone pain admitted for severe hypercalcemia. The definite diagnosis of RMS was performed with immune-phenotyping of the metastatic lymph-node biopsy. The primary tumor site was not found. His bone scan showed diffuse bone metastasis and significant soft tissue technetium uptake due to extra-osseous calcification. Conclusion: Metastatic RMS can mimic lymphoproliferative disorders at presentation. Clinicians must be aware of this diagnosis especially in young adults.

Pleural CEA, CA-15-3, CYFRA 21-1, CA-19-9, CA-125 discriminating malignant from benign pleural effusions: Diagnostic cancer biomarkers.

INTRODUCTION: There is a need for a rapid, accurate, less-invasive approach to distinguishing malignant from benign pleural effusions. We investigated the diagnostic value of five pleural tumor markers in exudative pleural effusions. METHODS: By immunochemiluminescence assay, we measured pleural concentrations of tumor markers. We used the receiver operating characteristic curve analysis to assess their diagnostic values. RESULTS: A total of 281 patients were enrolled. All tumor markers were significantly higher in malignant pleural effusions than benign ones. The area under the curve of carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 15-3, cytokeratin fragment 19 (CYFRA) 21-1, CA-19-9, and CA-125 were 0.81, 0.78, 0.75, 0.65, and 0.65, respectively. Combined markers of CEA + CA-15-3 and CEA + CA-15-3 + CYFRA 21-1 had a sensitivity of 87% and 94%, and specificity of 75% and 58%, respectively. We designed a diagnostic algorithm by combining pleural cytology with pleural tumor marker assay. CEA + CYFRA 21-1 + CA-19-9 + CA-15-3 was the best tumor markers panel detecting 96% of cytologically negative malignant pleural effusions, with a negative predictive value of 98%. CONCLUSIONS: Although cytology is specific enough, it has less sensitivity in identifying malignant pleural fluids. As a result, the main gap is detecting malignant pleural effusions with negative cytology. CEA was the best single marker, followed by CA-15-3 and CYFRA 21-1. Through both cytology and suggested panels of tumor markers, malignant and benign pleural effusions could be truly diagnosed with an accuracy of about 98% without the need for more invasive procedures, except for the cohort with negative cytology and a positive tumor markers panel, which require more investigations.

Pathogenic role of Twist-1 protein in hydatidiform molar pregnancies and investigation of its potential diagnostic utility in complete moles.

BACKGROUND: Complete and partial moles (PM) are the most common gestational trophoblastic diseases. Due to some overlapping morphological findings, ancillary studies may be necessary. METHODS: In this cross-sectional study, 47 cases of complete mole (CM) and 40 cases of PM were randomly selected based on histopathological criteria. Only those cases that were agreed upon by two expert gynecological pathologists and confirmed by the P57 IHC study were included. The expression level of the Twist-1 marker in villi stromal cells, as well as syncytiotrophoblasts, was evaluated quantitatively (percentage of positive cells), qualitatively (staining intensity) and as a total comprehensive score. RESULTS: Expression of Twist-1 is higher and more intense in villous stromal cells of CMs (p < 0.001). Moderate to strong staining intensity in more than 50% of villous stromal cells, can differentiate CM and PM with 89.5% sensitivity and 75% specificity. In syncytiotrophoblasts of CM, Twist-1 expression was significantly lower than PM (p < 0.001). Negative or weak staining intensity in less than 10% of syncytiotrophoblasts, can distinguish CM and PM with 82.9% sensitivity and 60% specificity. CONCLUSION: A higher expression of Twist-1 in villous stromal cells of hydatidiform moles is a sensitive and specific marker for the diagnosis of CMs. An elevated expression of this marker in villous stromal cells suggests another pathogenic mechanism for more aggressiveness of CMs in addition to the characteristics of trophoblast cells. The opposite result was obtained in the expression of Twist-1 in the syncytiotrophoblasts, compatible with defects in the process of formation of these supportive cells in CMs.

Cushing syndrome secondary to a mediastinal carcinoid tumor: a case report.

Neuroendocrine tumors (NET) are a rare and diverse set of malignancies that can develop anywhere within the body. ACTH-producing mediastinal NETs often originate from the thymus in the anterior mediastinum and are very rare. Primary diagnostic modalities for NETs include CT scan, MRI, scintigraphy, and Ga-DOTA PET scan. Here we report a case of a young male without any past medical history presenting with hypercortisolism secondary to a middle mediastinal typical carcinoid tumor. The patient underwent a successful resection which reduced serum ACTH levels. To the best of our knowledge, this is the first case of Cushing syndrome caused by a middle mediastinal NET.

Giant primary low-grade fibromyxoid sarcoma arising from the left pulmonary parenchyma: A case report and literature review.

BACKGROUND: Low-grade fibromyxoid sarcoma is a rare painless neoplasm that primarily grows in young adults' proximal extremities and trunks. The lungs are infrequent sites for this type of sarcoma. CASE PRESENTATION: We reported a 26-year-old female that presented with a chief complaint of chest pain from a few months ago to Kasra hospital, Tehran, Iran, in August 2021. Chest computed tomography (CT) showed a hypodense mass with a well-defined margin measuring 9.3 cm in the left upper lobe and multiple hypodense lesions with a lobulated appearance with a total diameter of 15.5 × 13.5 cm in the left lower lobe of the lung. CONCLUSION: This is the largest case of primary pulmonary low-grade fibromyxoid sarcoma (30 × 28 × 7 cm), which seemed unresectable at first evaluation. Due to the extent of the tumor, left pneumonectomy was performed, leading to attenuation of symptoms and no recurrence at a six-month follow-up.

MCM6 versus Ki-67 in diagnosis of luminal molecular subtypes of breast cancers.

BACKGROUND: Currently, breast cancers are divided into four major molecular subtypes. The distinction between the luminal A and luminal B subtypes is mainly based on the cellular proliferation indices and is assessed by the Ki-67 scoring. Due to the limitations in the assessment and expression of Ki-67, we hypothesized that minichromosome maintenance protein 6 (MCM6) might be taken as a surrogate marker to differentiate molecular subtypes and aid in more precise grading of tumors. METHODS: We performed a retrospective, cross-sectional study on 124 samples of breast cancer and 40 samples of normal breast tissue. Relevant clinical information was retrieved from the Cancer Institute database. RESULTS: MCM6 could discriminate between various categories of histologic grades, tubule formation, mitotic indices, and nuclear pleomorphism (P = 0.002 for tubule formation and P < 0.001 for other). Moreover, the MCM6 score exhibited a significant correlation with the mitotic count (P < 0.001). However, the Ki-67 score could not discriminate subgroups of the mitotic index and nuclear pleomorphism. Compared to the luminal A subtype, luminal B exhibited a higher MCM6 score (P = 0.01). Besides, MCM6 scores were higher for certain subtypes with more aggressive behaviors, such as hormone receptor (HR)-negative disease, and human epidermal growth factor receptor 2 (HER2)-enriched and triple-negative breast cancers, as there was a significantly higher MCM6 mean score in the HR-negative in comparison to the luminal breast cancers (P < 0.001). Similarly, higher MCM6 scores were observed among samples with more advanced nuclear grades, tubule formation, and overall grades. CONCLUSION: MCM6 can differentiate luminal A and luminal B subtypes and is correlated with mitotic counts. However, this study was unable to prove the superiority of MCM6 in differentiating between molecular subtypes compared to the Ki-67 score. Nevertheless, in our study, MCM6 was superior to Ki-67 in exhibiting correlations with the mitotic grade, tubule formation, and nuclear grades. More studies are needed to standardize its assessment methods, determine more robust cut-off values, and evaluate its associations with prognostic features of breast cancer.

Characterization of persistent materials of deposited PM2.5 in the human lung.

Clearance of deposited urban air particulates (PMs) from the lung is vital for the protection of the lung tissue. Several studies have investigated the behavior of immune cells against these particulates in vitro and in vivo. However, the fate of particulates in the lung is yet unclear. Here, we report the results of our investigations on the clearance of particulates from the lung. Twelve normal lung tissue samples were taken from nonsmoking and non-occupationally exposed patients who needed lung lobectomy or segmentectomy. The remaining particulates were isolated from the alveolar area and extracellular matrix (ECM), separately, and their chemical composition was determined using the FE-SEM EDAX and GC-MS. Moreover, urban air PM2.5 was collected in two forms dry and washed. These were characterized too. Our results showed that none of the metals in the deposited particulates structure is fully water-soluble. After contact with mucosal liquid, the alveolar particulates included Fe, Al, Si, Ti, and Ni. These elements were absent in the PMs isolated from ECM. The organics of alveolar and ECM particulates were the same and included tetra-decane, hexadecane, and octa-decane. None of the organics present in the urban air PM2.5, such as PAHs, were available in isolated particulates from the lung tissue. This study shows that the full clearance of inhaled particulates does not happen in the lung. The immune system's primary function is detoxification by removing all components identifiable by immune cells. After that, the remained PMs will be relocated and deposited into the ECM.

Primary thoracic gastrinoma causing Zollinger-Ellison syndrome.

Gastrinomas are located largely in the pancreaticoduodenal region. However, gastrinomas have also been found in non-pancreaticoduodenal regions. Our study is a rare report of gastrinomas within the thoracic cavity. A 53-year-old male patient presented with acute abdomen and multiple prepyloric ulcers. Serum gastrin level was significantly elevated. Computed tomography (CT) scan of the chest, abdomen, and pelvis showed a mass in the inferior section of the right hemithorax. Octreotide scan also confirmed a neuroendocrine tumor (NET)-like mass in the right para-aortic region in the right hemithorax. In thoracotomy, a hypervascular solid tumor was detected adjacent to the aorta, also receiving a branch from the aorta. We ligated the feeding artery and resected the 3-cm tumor. The post-operative serum gastrin level was 36 pg/mL, which implied that the tumor was successfully resected. The pathology assessment reported nests of monotonous low-grade neuroendocrine cells with salt and pepper nuclei with rare mitotic features, cellular uniformity, and abundant amphophilic cytoplasm, confirming the diagnosis of gastrinoma. Based on our report, we suggest that the search for gastrinomas should include not only the abdominal sites but also uncommon areas like the thoracic cavity.