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.

Historical Cohort of Severe Congenital Neutropenia in Iran: Clinical Course, Laboratory Evaluation, Treatment, and Survival.

INTRODUCTION: Severe congenital neutropenia (SCN) is one of the primary immunodeficiency diseases developed by genetic alterations. Mutations in several genes including HAX-1 , G6PC3 , jagunal , and VPS45 account for autosomal recessive SCN. PATIENTS AND METHODS: Patients with SCN registered in the Iranian Primary Immunodeficiency Registry and referred to our clinic at the Children's Medical Center were reviewed. RESULTS: Thirty-seven eligible patients with a mean age of 28.51 ± 24.38 months at the time of diagnosis were included. Nineteen cases had consanguineous parents and 10 cases had confirmed or unconfirmed positive family history. The most prevalent infectious symptoms were oral infections followed by respiratory infections. We identified HAX-1 mutation in 4, ELANE mutation in 4 cases, G6PC3 mutation in 1, and WHIM syndrome in 1 case. Other patients remained genetically unclassified. After the median follow-up of 36 months from the time of diagnosis, the overall survival was 88.88%. The mean event-free survival was 185.84 months (95% CI: 161.02, 210.66). DISCUSSION: Autosomal recessive SCN is more common in countries with high rates of consanguinity like Iran. The genetic classification was possible only for a few patients in our study. This might suggest that there are other autosomal recessive genes causative of neutropenia that have yet to be described.

Investigation of BRCAness associated miRNA-gene axes in breast cancer: cell-free miR-182-5p as a potential expression signature of BRCAness.

The concept of the 'BRCAness' phenotype implies the properties that some sporadic breast cancers (BC) share with BRCA1/2-mutation carriers with hereditary BC. Breast tumors with BRCAness have deficiencies in homologous recombination repair (HRR), like BRCA1/2-mutation carriers, and consequently could benefit from poly-(ADP)-ribose polymerase (PARP) inhibitors and DNA-damaging chemotherapy. Triple-negative breast cancers (TNBC) show a higher frequency of BRCAness than the other BC subtypes. Therefore, looking for BRCAness-related biomarkers could improve personalized management of TNBC patients. microRNAs (miRNAs) play a pivotal role in onco-transcriptomic profiles of tumor cells besides their suitable features as molecular biomarkers. The current study aims to evaluate the expression level of some critical miRNAs-mRNA axes in HRR pathway in tumors and plasma samples from BC patients. The expression levels of three multi-target miRNAs, including miR-182-5p, miR-146a-5p, and miR-498, as well as six downstream HRR-related protein-coding genes, have been investigated in the breast tumors and paired adjacent normal tissues by Real-time PCR. In the next step, based on the results derived from the previous step, we examined the level of cell-free miR-182-5p in the blood plasma samples from the patients. Our results highlight the difference between TNBC and non-TNBC tumor subgroups regarding the dysregulation of the key miRNA/mRNA axes involved in the HRR pathway. Also, for the first time, we show that the level of cell-free miR-182-5p in plasma samples from BC patients could be a clue for screening BC patients eligible for receiving PARP inhibitors through a personalized manner. Altogether, some sporadic BC patients, especially sporadic TNBC, have epigenetically dysregulated HRR pathway that could be identified and benefit from BRCAness-specific therapeutic agents.

DNA Methylation of CD70 Promoter in Juvenile Systemic Lupus Erythematosus.

INTRODUCTION: Epigenetic alterations in pathogenesis of systemic lupus erythematosus (SLE) have gained more attention recently in adults. We assessed the methylation of CD70 promoter, a costimulatory molecule on T cells, in juvenile SLE (JSLE), and compared this to that found in controls and the literature of adult SLE patients. METHODS: DNA methylation status was evaluated on peripheral blood from JSLE patients and healthy controls. RESULTS: Twenty-five patients with JSLE and 24 healthy controls were compared. JSLE patients had lower unmethylated CpG islands compared to the control group (mean ± SD; 0.78 ± 0.42 vs 10503.80 ± 39796.95). However, the difference was not significant (P-value; 0.22). CONCLUSION: Despite hypomethylation of CD70 gene promoter in CD4+ T-cells from adult patients with SLE, no statistically significant differences observed in patients with JSLE compared with healthy controls. This may suggest a mechanism different in JSLE patients than in adults.

Recent progress in immunotherapy of breast cancer targeting the human epidermal growth factor receptor 2 (HER2).

OBJECTIVE: Breast cancer is responsible for most of the cancer-induced deaths in women around the world. The current review will discuss different approaches of targeting HER2, an epidermal growth factor overexpressed in 30% of breast cancer cases. DATA SOURCES: We conducted a search on Pubmed and Scopus databases to find studies relevant to HER2+ breast cancers and targeting HER2 as means of immunotherapy. Out of 1043 articles, 105 studies were included in this review. DATA SUMMARY: As well as the introduction of HER2 and breast cancer subtypes, we discussed various aspects of HER2-targeting immunotherapy including monoclonal antibodies, Antibody-drug conjugates (ADCs), Chimeric Antigen Receptor (CAR) T-cells and vaccines. CONCLUSIONS: Despite several ways of controlling breast cancer, the need to investigate new drugs and approaches seems to be much significant as this cancer still has a heavy burden on people's health and survival.

COVID-19 in Patients with Cancer.

With more than 5 million cases and 333,212 deaths, COVID-19 (or SARS-CoV-2) continues to spread. General symptoms of this disease are similar to that of many other viral respiratory diseases, including fever, cough, dyspnea, and fatigue, with a chance of progression to more severe complications. However, the virus does not affect all people equally, and cases with comorbidities such as malignancies, cardiovascular diseases, respiratory diseases, and kidney diseases are at higher risk of developing severe events, including requiring intensive ventilation, intensive care unit (ICU) admission, and death. Patients with cancer are more likely to be infected with COVID-19, which is possibly due to their immunological dysfunction or frequent clinic visits. Also, there is a higher chance that these patients experience severe events because of the medication they receive. In this chapter, we will review the main clinical manifestations of COVID-19 in patients with cancer. Recommendations and challenges for managing resources, organizing cancer centers, treatment of COVID-19-infected cancer patients, and performing cancer research during this pandemic will also be discussed.

Prevention of COVID-19: Preventive Strategies for General Population, Healthcare Setting, and Various Professions.

The disease 2019 (COVID-19) made a public health emergency in early 2020. Despite attempts for the development of therapeutic modalities, there is no effective treatment yet. Therefore, preventive measures in various settings could help reduce the burden of disease. In this chapter, the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19, non-pharmaceutical approaches at individual and population level, chemoprevention, immunoprevention, preventive measures in different healthcare settings and other professions, special considerations in high-risk groups, and the role of organizations to hamper the psychosocial effects will be discussed.

Prognosis of Congenital Pseudarthrosis of the Tibia: Effect of Site of Tibial Pseudarthrososis and Fibular Involvement.

BACKGROUND: Congenital pseudarthrosis of the tibia is a rare condition that has long been one of the most challenging concerns in pediatric orthopedic surgery. When the fracture occurs, a recalcitrant nonunion is expected. This is why successful treatment means maintaining a long-term union. In this study, we aimed to assess the therapeutic outcomes for the middle and distal third fractures of the tibia and to explore whether the treatment of concurrent fibular pseudoarthrosis affects the outcome. METHODS: We studied 12 patients with congenital pseudarthrosis of the tibia (Crawford type 4) from 2014 to 2019. A combination approach including intramedullary rod, Ilizarov apparatus, corticocancellous bone graft, and periosteal graft was used. In the initial surgery, we did not fix the ankle and subtalar joints. RESULTS: As a result, the union was achieved in 67% of the cases after the index surgery. All of the cases with primary nonunion were related to the concurrent fibular and distal third tibial pseudarthrosis. In addition, ignoring the treatment of fibular pseudarthrosis in the index surgery led to ankle valgus deformity both in the middle and in the distal third tibial pseudarthrosis. We finally achieved a 100% union rate in all cases, with no subsequent refracture. CONCLUSIONS: Surgery at an early age was associated with favorable results and minimized deformity. In concurrent fibular and distal third tibial pseudarthrosis, it is recommended to transfix the ankle and subtalar joints to create a cross-union with fibula so that the intense union can be confidently obtained with more cross-section to prevent ankle valgus deformity. LEVEL OF EVIDENCE: Level IV-case series.

Pro-tumorigenic functions of macrophages at the primary, invasive and metastatic tumor site.

The tumor microenvironment (TME) not only facilitates cancer progression from the early formation to distant metastasis, but also it differs itself from time to time alongside the tumor evolution. Tumor-associated macrophages (TAMs), whether as pre-existing tissue-resident macrophages or recruited monocytes, are an inseparable part of this microenvironment. As their parents are broadly classified into a dichotomic, simplistic M1 and M2 subtypes, TAMs also exert paradoxical and diverse phenotypes as they are settled in different regions of TME and receive different microenvironmental signals. Briefly, M1 macrophages induce an inflammatory precancerous niche and flame the early oncogenic mutations, whereas their M2 counterparts are reprogrammed to release various growth factors and providing an immunosuppressive state in TME as long as abetting hypoxic cancer cells to set up a new vasculature. Further, they mediate stromal micro-invasion and co-migrate with invasive cancer cells to invade the vascular wall and neural sheath, while another subtype of TAMs prepares suitable niches much earlier than metastatic cells arrive at the target tissues. Accordingly, at the neoplastic transformation, during the benign-to-malignant transition and through the metastatic cascade, macrophages are involved in shaping the primary, micro-invasive and pre-metastatic TMEs. Whether their behavioral plasticity is derived from distinct genotypes or is fueled by microenvironmental cues, it could define these cells as remarkably interesting therapeutic targets.

Importance of TNF-alpha and its alterations in the development of cancers.

TNF-alpha is involved in many physiologic and pathologic cellular pathways, including cellular proliferation, differentiation, and death, regulation of immunologic reactions to different cells and molecules, local and vascular invasion of neoplasms, and destruction of tumor vasculature. It is obvious that because of integrated functions of TNF-alpha inside different physiologic systems, it cannot be used as a single-agent therapy for neoplasms; however, long-term investigation of its different cellular pathways has led to recognition of a variety of subsequent molecules with more specific interactions, and therefore, might be suitable as prognostic and therapeutic factors for neoplasms. Here, we will review different aspects of the TNF-alpha as a cytokine involved in both physiologic functions of cells and pathologic abnormalities, most importantly, cancers.

IL-17 and colorectal cancer: From carcinogenesis to treatment.

Colorectal cancer (CRC) is one of the most common types of cancer in the world. Several factors contribute to the development of this cancer. Tumor formation in colon triggers immune responses such as immune cells proliferation, phenotype alteration, cytokine synthesis and release, which lead to IL-17 producing T cells, the differentiated CD4+ T cells i.e. T helper 17. IL-17 is a pro-inflammatory cytokine, which its level is up regulated in serum and tissues of CRC patients. Several studies have shown that IL-17 has an important role in metastasis and prognosis of CRC. The aim of this review is to summarize the role of this cytokine in tumorigenesis, angiogenesis and metastasis of CRC and discuss its value in diagnosis, prognosis and treatment of CRC.

Passive-specific immunotherapy with monoclonal antibodies for prostate cancer: A systematic review.

INTRODUCTION: Treatment of metastatic castration-resistant prostate cancer with conventional therapies is still not successful. Therefore, application of novel biological approaches such as immunotherapy, which appears to be more effective and less toxic, is necessary. Monoclonal antibodies against cancer specific antigens are a kind of immunotherapy that have been approved for specific types of cancer and are being investigated for prostate cancer as well. The aim of this review was to assess the effectiveness and safety of monoclonal antibodies for treatment of advanced prostate cancer. METHOD: According to the search strategy stated in our systematic review protocol, Scopus, Medline, TRIP, CENTRAL, ProQuest, DART and OpenGrey databases were searched. Data collection and quality assessment were done independently by two authors and any disagreements between the collected data were resolved by a third author. A meta-analysis was not feasible as there was a considerable statistical heterogeneity among the trials. Hence, this review was limited to a narrative analysis of the included studies. RESULTS: We found 9756 references by applying search strategy in 4 databases of journal articles and 3 databases of grey literature. We then discarded 3957 duplicate citations using Endnote software and 5143 articles due to obvious irrelevancy of their topics in primary screening. In secondary screening of 656 fulltexts, we excluded 538 articles, and finally included 12 trials in this systematic review, updated on 23 June 2017. The overall quality of the studies was fair. In general, results of this systematic review show promising advances in the treatment of prostate cancer patients with monoclonal antibodies against prostate-specific antigens with regard to PSA/disease response. Some of the studies reported pain relief after treatment as well. CONCLUSION: Currently, the role of immunotherapy in the treatment of advanced prostate cancer still remains debated. Although passive specific immunotherapy could be offered as a novel therapeutic option in the coming years, patients should be informed about the risks and benefits of this therapy. One of the obstacles in this review was the lack of adequate assessment of survival-related endpoints reported in the included studies. Our study provides support for further research in this field.

Basic understanding and therapeutic approaches to target toll-like receptors in cancerous microenvironment and metastasis.

Toll-like receptors (TLRs) are transmembrane components that sense danger signals, like damage- and pathogen-associated molecular pattern molecules, as receptors, and maintain homeostasis in tissues. They are mainly involved in immune system activation through a variety of mediators, which either carry out (1) elimination of pathogenic threats and redressing homeostatic imbalances or (2) contribution to the initiation and worsening of pathological conditions, including cancers. Under physiological conditions, TLRs coordinate the innate and adaptive immunity, and inhibit autoimmune disorders. In pathological conditions, such as cancer, they can present both tumor and receptor-specific roles. Although the roles of individual TLRs in various cancers have been described, the effects of targeting TLRs to treat cancer and prevent metastasis are still controversial. A growing body of literature has suggested contribution of both activators and inhibitors of TLR signaling pathway for cancer treatment, dependent on several context-specific factors. In short, TLRs can play dual roles with contradictory outcomes in neoplastic conditions. This hampers the development of TLR-based therapeutic interventions. A better understanding of the interwoven TLR pathways in cancerous microenvironment is necessary to design TLR-based therapies. In this review, we consider the molecular mechanisms of TLRs signaling and their involvement in tumor progression. Therapeutic modalities targeting TLRs for cancer treatment are discussed as well.

Extensive Deep Tissue Involvement in Nicolau Syndrome and Below-Knee Amputation: A Case Report and Literature Review.

Nicolau syndrome (NS) is a rare cutaneous drug reaction in response to injections administered via any route. Based on the available studies in the medical literature, NS presents as skin and subcutaneous fat necrosis, and typically, it does not cause severe complications such as acute limb ischemia or death. In this study, we report the case of a 6-year-old boy who received an intramuscular injection of benzathine penicillin G for the treatment of bacterial pharyngitis, and subsequently developed a severe case of NS, which eventually led to below-knee amputation of the right lower limb. Although a few approaches have been suggested for the management of NS, they might not be effective under certain circumstances. Early detection, close monitoring, and consistent interventions, such as surgical fasciotomy and debridement procedures, might be necessary in severe cases of NS.

Bilateral localized bullous pemphigoid in a young adult patient: A case report.

Bullous pemphigoid is the most common autoimmune subepidermal blistering disease, which typically presents in the elderly. Localized bullous pemphigoid is a rare variant of bullous pemphigoid, with only about 100 cases reported up to date. In this report, we describe a 32-year-old healthy male patient with bilateral hemorrhagic bullae and erosive lesions limited to the lower extremities. A biopsy for hematoxylin and eosin stain and direct immunofluorescence established the diagnosis of bullous pemphigoid. The blistering responded well to oral and topical steroids. The exact etiology of this rare variant of bullous pemphigoid remains unknown, leading to ongoing debates and numerous suggested hypotheses.

The Role of Ketogenic Diet in the Treatment of Neuroblastoma.

The ketogenic diet (KD) was initially used in 1920 for drug-resistant epileptic patients. From this point onward, ketogenic diets became a pivotal part of nutritional therapy research. To date, KD has shown therapeutic potential in many pathologies such as Alzheimer's disease, Parkinson's disease, autism, brain cancers, and multiple sclerosis. Although KD is now an adjuvant therapy for certain diseases, its effectiveness as an antitumor nutritional therapy is still an ongoing debate, especially in Neuroblastoma. Neuroblastoma is the most common extra-cranial solid tumor in children and is metastatic at initial presentation in more than half of the cases. Although Neuroblastoma can be managed by surgery, chemotherapy, immunotherapy, and radiotherapy, its 5-year survival rate in children remains below 40%. Earlier studies have proposed the ketogenic diet as a possible adjuvant therapy for patients undergoing treatment for Neuroblastoma. In this study, we seek to review the possible roles of KD in the treatment of Neuroblastoma.

The role of myeloid-derived suppressor cells in lung cancer and targeted immunotherapies.

INTRODUCTION: Lung cancer is the deadliest cancer in both sexes combined globally due to significant delays in diagnosis and poor survival. Despite advances in the treatment of lung cancer, the overall outcomes remain poor and traditional chemotherapy fails to provide long-term benefits for many patients. Therefore, new treatment strategies are needed to increase overall survival. Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells taking part in lung cancer, as has been described in other types of tumors. MDSCs immunosuppressive activity is mediated by arginases (ARG-1 and ARG-2), nitric oxide (NO), reactive oxygen species (ROS), peroxynitrite, PD-1/PD-L1 axis, and different cytokines. MDSCs can be a target for lung cancer immunotherapy by inducing their differentiation into mature myeloid cells, elimination, attenuation of their function, and inhibition of their accumulation. AREAS COVERED: In this review, the immunosuppressive function of MDSCs, their role in lung cancer, and strategies to target them, which could result in increased efficacy of immunotherapy in patients with lung cancer, are discussed. EXPERT OPINION: Identification of important mechanisms and upstream pathways involved in MDSCs functions paves the way for further preclinical and clinical lung cancer research, which could lead to the development of novel therapeutic approaches.

Tumor-infiltrating lymphocyte therapy for lung cancer and its future paradigms.

INTRODUCTION: Lung cancer is the leading cause of cancer death, with an estimated 1.8 million deaths contributing to this cancer in 2020. Despite advances in treatment options and various approaches being attempted, the survival rate remains low. AREAS COVERED: In this review, we aim to provide an overview of the efficacy of tumor-infiltrating lymphocyte (TIL) therapy for lung cancer based on existing clinical trials. We also discuss the current challenges and future landscape of this treatment modality. EXPERT OPINION: Lung cancer can be a suitable candidate for TIL therapy due to its high mutational burden. Specifically, it has shown promising results for non-small cell lung cancer resistant to immune checkpoint inhibitors. Still, there are many restrictions associated with the ex vivo expansion and delivery of TILs, limiting their availability. For this reason, applying TIL for the treatment of lung cancer has not been extensively investigated yet and only a few clinical trials have shown favorable results of TIL therapy in patients with lung cancer. Thus, facilitating this costly, labor-intensive and time-consuming process is of utmost importance to increase the number of performed studies and to detect eligible patients who could benefit most from this treatment modality.

Cancer Immunoprevention: Current Status and Future Directions.

Cancer is one of the most serious diseases affecting health and the second leading cause of death worldwide. Despite the development of various therapeutic modalities to deal with cancer, limited improvement in overall survival of patients has been yielded. Since there is no certain cure for cancer, detection of premalignant lesions, and prevention of their progression are vital to the decline of high morbidity and mortality of cancer. Among approaches to cancer prevention, immunoprevention has gained further attention in recent years. Deep understanding of the tumor/immune system interplay and successful prevention of virally-induced malignancies by vaccines have paved the way toward broadening cancer immunoprevention application. The identification of tumor antigens in premalignant lesions was the turning point in cancer immunoprevention that led to designing preventive vaccines for various malignancies including multiple myeloma, colorectal, and breast cancer. In addition to vaccines, immune checkpoint inhibitors are also being tested for the prevention of oral squamous cell carcinoma (SCC), and imiquimod which is an established drug for the prevention of skin SCC, is a non-specific immunomodulator. Herein, to provide a bench-to-bedside understanding of cancer immunoprevention, we will review the role of the immune system in suppression and promotion of tumors, immunoprevention of virally-induced cancers, identification of tumor antigens in premalignant lesions, and clinical advances of cancer immunoprevention.

Chimeric antigen receptor T-cell therapy for melanoma.

INTRODUCTION: In recent years, chimeric antigen receptor (CAR) T cell therapy has emerged as a cancer treatment. After initial therapeutic success for hematologic malignancies, this approach has been extended for the treatment of solid tumors including melanoma. AREAS COVERED: T cells need to be reprogramed to recognize specific antigens expressed only in tumor cells, a difficult problem since cancer cells are simply transformed normal cells. Tumor antigens, namely, CSPG4, CD70, and GD2 have been targeted by CAR-T cells for melanoma. Moreover, different co-stimulatory signaling domains need to be selected to direct T cell fate. In this review, various approaches for the treatment of melanoma and their effectiveness are comprehensively reviewed and the current status, challenges, and future perspective of CAR-T cell therapy for melanoma are discussed. Literature search was accomplished in three databases (PubMed, Google scholar, and Clinicaltrials.gov). Published papers and clinical trials were screened and relevant documents were included by checking pre-defined eligibility criteria. EXPERT OPINION: Despite obstacles and the risk of adverse events, CAR T cell therapy could be used for patients with treatment-resistant cancer. Clinical trials are underway to determine the efficacy of this approach for the treatment of melanoma.