Prevalence of Hypertension and Diabetes in Severe COVID-19: A Cross-Sectional Study from Single Center, Kabul.

Introduction: Previous studies have reported an association between certain medical conditions, such as hypertension and diabetes, and severe COVID-19. Objective: To determine the prevalence of hypertension and diabetes among severe COVID-19 patients who were admitted to the only specialized center for COVID-19 in Kabul, Afghan-Japan Hospital Kabul, Afghanistan. Methods: A cross-sectional design was utilized, including 202 patients, admitted to Afghan-Japan Hospital during the first six months of 2022. Medical records of patients tested positive for COVID-19 via Polymerase chain reaction (PCR) with oxygen saturation levels below 90% at the time of admission were included in the study. Age, sex, and the presence of hypertension and diabetes were the studied variables. Descriptive statistics were used for analysis. Results: The median age of the patients were 63 (IQR=54.75-75) years. Males and females each accounting for 50% of the total, and the majority of the patients (50.5%) were in the age group 60-79. Of 202 patients, 143 (70.8%) had hypertension, 42 (20.8%) had diabetes, 147 patients (72.77%) had at least one of these comorbidities. Fifty-five patients (27.22%) were without diabetes and without hypertension. The prevalence of hypertension and diabetes was higher among female, ie, 57.1% and 54.5% respectively. Patients in the 40-59 year old group had the highest rate of hypertension (75.6%). The highest prevalence of diabetes was seen in the 60-79 year old group. Conclusion: The study found a higher prevalence of hypertension in severe COVID-19 cases compared to global reports and the general adult population in Afghanistan. The relationship between hypertension and COVID-19 risk needs further investigation. The prevalence of diabetes was also higher, consistent with findings from other countries.

Common Reasons for Permanent Tooth Extraction and Its Correlation with Demographical Factors in Kabul, Afghanistan.

Objective: The aim of this survey was to investigate the main reasons for extraction of permanent teeth, and its correlation with age, gender, education level, smoking habits, and time of last dental visit, family income, and professions in Kabul, Afghanistan. Subjects and Methods: The study proposal was approved by Research Ethics Committee of Khatam AL Nabieen and was conducted over a period of 5 months; its population consisted 594 patients, aged 10-70 years, who underwent extraction. The frequency distribution was calculated using X2 test, ANOVA and t-test for differences in mean number of patients. Results: A total of 594 patients underwent extraction. The highest rate (53.8%) of extraction occurred for those 21-40 years old. Females compromised 51.3% of patients. Two hundred (33.6%) patients were uneducated. Tooth loss due to caries was 30.1%; patient-request was 18.3%; impacted teeth was 14.4%. Other causes were periodontal reasons, failed root canal therapy (RCT), Tooth mobility, and Root fractures. Conclusion: The result of this survey indicated that caries, patient request, and impaction were the leading reasons for tooth extraction. The majority of patients were uneducated, and had insufficient family income. Most of the patients were housewives and laborers.

Emerging treatment options for prostate cancer.

INTRODUCTION: Prostate cancer treatment has rapidly evolved in the past few years. Androgen deprivation therapy has been the backbone of treatment for locally advanced and metastatic prostate cancer, but incremental benefits in survival have been shown by adding androgen-receptor pathway inhibitors (ARPI) across various spectrums of disease state. In addition, docetaxel chemotherapy remains the first-line chemotherapy regimen available with survival benefits shown with triplet therapy in those who are chemotherapy eligible. However, disease progression remains inevitable and novel agents such as radioligand therapy with lutetium have shown improvement in survival. AREAS COVERED: This review discusses the pivotal trials that led to the U.S. FDA approval of agents utilized in metastatic prostate cancer and explores the use of novel agents including prostate-specific membrane antigen-targeting agents, radioligands, cell-based therapy, chimeric antigen receptor T-cell, BiTE, and antibody drug conjugates. EXPERT OPINION: Treatment landscape for metastatic castrate-resistant prostate cancer (mCRPC) has evolved beyond additional agents with ARPI and/or docetaxel, including other treatments with sipuleucel-T, radium, cabazitaxel, PARP inhibitors, and lutetium, which have specific indications and roles in sequencing. Novel therapies remain critically needed after progression from lutetium.

First-line pembrolizumab plus androgen deprivation therapy for locally advanced microsatellite instability-high prostate cancer in a patient with Muir-Torre syndrome: A case report.

The risks of development of colorectal and endometrial cancers in individuals with Lynch syndrome (LS) are well known and have been widely studied. In recent years, the potential association of other malignancies, including prostate cancer, with LS has been considered. Decision-making regarding screening for prostate cancer in the generalized population can be complicated; accounting for the possibility of a higher risk of cancer conferred by a potential genetic predisposition confounds the creation of salient guidelines even further. Although tissue-agnostic treatment approvals have been granted to several immune checkpoint inhibitors (ICIs) for their use in the treatment of subsets of patients whose tumors exhibit high levels of microsatellite instability or high tumor mutational burden, a paucity of data exists regarding the use of ICIs in the first line treatment of patients with locally advanced prostate cancer harboring these features. A significant reduction in tumor volume in response to the combination of immune checkpoint inhibition and androgen deprivation therapy is described in this report of a male with Muir-Torre syndrome who was found to have locally advanced adenocarcinoma of the prostate. While anecdotal, the anti-tumor activity of this combination of therapy is notable and calls attention to the importance of considering further investigation of the use of immune checkpoint blockade as a primary therapeutic option in patients with localized prostate cancer.

Acceptance and Hesitancy Toward the Covid-19 Vaccine Among Medical Students in Kabul, Afghanistan.

Introduction: Vaccine hesitancy is defined as "delay in acceptance or refusal of vaccination despite the availability of vaccination services". The low acceptance rate of covid-19 vaccination, reported in many countries, is a big challenge in efforts toward putting end to the pandemic. Objective: In this study, we aim to find the acceptance and hesitancy rates toward Covid-19 vaccine along with its reasons among medical students in Kabul. Methodology: In this cross-sectional study that was conducted among medical students of five randomly selected universities in Kabul, a total of 459 medical students completed the questionnaire. Results: The hesitancy rate for covid-19 vaccine among medical students was 42.3%, hesitancy rate in males was more than in female students. The essential reason for refusing of the vaccine was concerns about safety and adverse effect of the vaccine (62.3%). More than half of the participants (51.5%) have already been vaccinated. In 60.2% of participants, protection against the COVID-19 virus was the main reason for accepting the vaccine. This study indicates that social media was the leading source (64.3%) of information about vaccine hesitancy. Conclusion: This study indicates a high level of hesitancy toward the COVID-19 vaccine among medical students. It is strongly advised to deliver accurate information on the safety and effectiveness of COVID-19 vaccines to the community especially, medical students.

Adverse Effects of the COVID-19 Vaccine Reported by Lecturers and Staff of Kabul University of Medical Sciences, Kabul, Afghanistan.

PURPOSE: To evaluate the occurrence, extent, and severity of adverse reactions associated with the vaccine of COVID-19 (ChAdOx1 nCoV-19 vaccine or AstraZeneca) among Kabul University of Medical Sciences staff. PATIENTS AND METHODS: A retrospective observational, interview-based study was conducted from 4 to 20 April, 2021, to evaluate the adverse reactions associated with the vaccine of COVID-19 (ChAdOx1 nCoV-19 vaccine or AstraZeneca) among the staff and lecturers of the Kabul University of Medical Sciences, Kabul, Afghanistan. Participants were interviewed following the administration of the first dose of the AstraZeneca vaccines. They were asked to report any adverse reactions that occurred within 8-10 days after vaccination. The frequency, duration, severity, and outcome of the reactions were recorded. Association of the adverse reactions was analysed with the ages of participants and previous infection with SARS CoV-2. RESULTS: The most common adverse reactions reported by the participants were muscle pain (68.3%), local pain (58.8%) at the site of injection (68.3%), fever (66.3%) and fatigue (66.3%). Almost half of the respondents reported chills, joint pain and headache after receiving the first shot of the vaccine. The frequency of adverse reactions was higher in participants aged 40 years or less, and in those previously infected with SARS CoV-2. The severity of most adverse reactions was mild to moderate. No serious case or death was reported. CONCLUSION: The adverse reactions reported by the participants were mild to moderate in severity, and for a short duration. The findings of this study help us to address the vaccine hesitancy caused by worries about severe adverse effects associated with the COVID-19 vaccine.

Attenuation of SRC Kinase Activity Augments PARP Inhibitor-mediated Synthetic Lethality in BRCA2-altered Prostate Tumors.

PURPOSE: Alterations in DNA damage repair (DDR) pathway genes occur in 20%-25% of men with metastatic castration-resistant prostate cancer (mCRPC). Although PARP inhibitors (PARPis) have been shown to benefit men with mCRPC harboring DDR defects due to mutations in BRCA1/2 and ATM, additional treatments are necessary because the effects are not durable. EXPERIMENTAL DESIGN: We performed transcriptomic analysis of publicly available mCRPC cases, comparing BRCA2 null with BRCA2 wild-type. We generated BRCA2-null prostate cancer cells using CRISPR/Cas9 and treated these cells with PARPis and SRC inhibitors. We also assessed the antiproliferative effects of combination treatment in 3D prostate cancer organoids. RESULTS: We observed significant enrichment of the SRC signaling pathway in BRCA2-altered mCRPC. BRCA2-null prostate cancer cell lines had increased SRC phosphorylation and higher sensitivity to SRC inhibitors (e.g., dasatinib, bosutinib, and saracatinib) relative to wild-type cells. Combination treatment with PARPis and SRC inhibitors was antiproliferative and had a synergistic effect in BRCA2-null prostate cancer cells, mCRPC organoids, and Trp53/Rb1-null prostate cancer cells. Inhibition of SRC signaling by dasatinib augmented DNA damage in BRCA2-null prostate cancer cells. Moreover, SRC knockdown increased PARPi sensitivity in BRCA2-null prostate cancer cells. CONCLUSIONS: This work suggests that SRC activation may be a potential mechanism of PARPi resistance and that treatment with SRC inhibitors may overcome this resistance. Our preclinical study demonstrates that combining PARPis and SRC inhibitors may be a promising therapeutic strategy for patients with BRCA2-null mCRPC.

Pembrolizumab-Induced Cold Agglutinin Disease.

BACKGROUND The introduction of immunotherapy in the management of metastatic lung cancer appears to be changing their natural history. Most patients tolerate immunotherapy without any significant adverse events. Nevertheless, a significant number of patients still experience adverse effects. Autoimmune hemolytic anemia has been described as mostly related to warm autoantibodies. The following case report describes cold agglutinin disease with hemolysis secondary to Pembrolizumab therapy for the treatment of metastatic lung cancer. CASE REPORT A 58-year-old woman noted a left neck mass 4 months prior to her presentation. A biopsy confirmed the presence of metastatic adenocarcinoma, consistent with primary lung cancer. Further evaluation revealed the tumor to be PDL-1-positive. She was started on Pembrolizumab, Pemetrexed, and carboplatin chemotherapy regimen. Her CBC was within normal limits when she started therapy, but within 4 weeks hemoglobin dropped to 4.3 g/dL. Further evaluation showed high cryoglobulin levels and a high cold agglutinin titer. Complement C3 DAT was positive. A peripheral smear showed clumps of red cells and the serum IgM was elevated. The diagnosis of CAD was made. She was then started on Rituximab. Imaging showed a significant response, with decreased disease burden. CONCLUSIONS Our case shows a unique presentation of CAD, initially presumed to be myelosuppression secondary to chemotherapy. Instead, a peripheral smear revealed Pembrolizumab to be the cause of cold agglutinin disease. Due to the relatively unknown association between these 2 entities, patient care was delayed. Finally, after initiation of Rituximab therapy, the patient's CBC began to recover.

Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer.

Although there are molecularly distinct subtypes of prostate cancer, no molecular classification system is used clinically. The ribonucleotide reductase small subunit M2 (RRM2) gene plays an oncogenic role in many cancers. Our previous study elucidated comprehensive molecular mechanisms of RRM2 in prostate cancer (PC). Given the potent functions of RRM2, we set out to determine whether the RRM2 signature can be used to identify aggressive subtypes of PC. We applied gene ontology and pathway analysis in RNA-seq datasets from PC cells overexpressing RRM2. We refined the RRM2 signature by integrating it with two molecular classification systems (PCS and PAM50 subtypes) that define aggressive PC subtypes (PCS1 and luminal B) and correlated signatures with clinical outcomes in six published cohorts comprising 4000 cases of PC. Increased expression of genes in the RRM2 signature was significantly correlated with recurrence, high Gleason score, and lethality of PC. Patients with high RRM2 levels showed higher PCS1 score, suggesting the aggressive PC feature. Consistently, RRM2-regulated genes were highly enriched in the PCS1 signature from multiple PC cohorts. A simplified RRM2 signature (12 genes) was identified by intersecting the RRM2 signature, PCS1 signature, and the PAM50 classifier. Intriguingly, inhibition of RRM2 specifically targets PCS1 and luminal B genes. Furthermore, 11 genes in the RRM2 signature were correlated with enzalutamide resistance by using a single-cell RNA-seq dataset from PC circulating tumor cells. Finally, high expression of RRM2 was associated with an immunosuppressive tumor-immune microenvironment in both primary prostate cancer and metastatic prostate cancer using CIBERSORT analysis and LM22, a validated leukocyte gene signature matrix. These data demonstrate that RRM2 is a driver of aggressive prostate cancer subtypes and contributes to immune escape, suggesting that RRM2 inhibition may be of clinical benefit for patients with PC.

Significance of BRCA2 and RB1 Co-loss in Aggressive Prostate Cancer Progression.

PURPOSE: Previous sequencing studies revealed that alterations of genes associated with DNA damage response (DDR) are enriched in men with metastatic castration-resistant prostate cancer (mCRPC). BRCA2, a DDR and cancer susceptibility gene, is frequently deleted (homozygous and heterozygous) in men with aggressive prostate cancer. Here we show that patients with prostate cancer who have lost a copy of BRCA2 frequently lose a copy of tumor suppressor gene RB1; importantly, for the first time, we demonstrate that co-loss of both genes in early prostate cancer is sufficient to induce a distinct biology that is likely associated with worse prognosis. EXPERIMENTAL DESIGN: We prospectively investigated underlying molecular mechanisms and genomic consequences of co-loss of BRCA2 and RB1 in prostate cancer. We used CRISPR-Cas9 and RNAi-based methods to eliminate these two genes in prostate cancer cell lines and subjected them to in vitro studies and transcriptomic analyses. We developed a 3-color FISH assay to detect genomic deletions of BRCA2 and RB1 in prostate cancer cells and patient-derived mCRPC organoids. RESULTS: In human prostate cancer cell lines (LNCaP and LAPC4), loss of BRCA2 leads to the castration-resistant phenotype. Co-loss of BRCA2-RB1 in human prostate cancer cells induces an epithelial-to-mesenchymal transition, which is associated with invasiveness and a more aggressive disease phenotype. Importantly, PARP inhibitors attenuate cell growth in human mCRPC-derived organoids and human CRPC cells harboring single-copy loss of both genes. CONCLUSIONS: Our findings suggest that early identification of this aggressive form of prostate cancer offers potential for improved outcomes with early introduction of PARP inhibitor-based therapy.See related commentary by Mandigo and Knudsen, p. 1784.

A Novel Mechanism Driving Poor-Prognosis Prostate Cancer: Overexpression of the DNA Repair Gene, Ribonucleotide Reductase Small Subunit M2 (RRM2).

PURPOSE: Defects in genes in the DNA repair pathways significantly contribute to prostate cancer progression. We hypothesize that overexpression of DNA repair genes may also drive poorer outcomes in prostate cancer. The ribonucleotide reductase small subunit M2 (RRM2) is essential for DNA synthesis and DNA repair by producing dNTPs. It is frequently overexpressed in cancers, but very little is known about its function in prostate cancer. EXPERIMENTAL DESIGN: The oncogenic activity of RRM2 in prostate cancer cells was assessed by inhibiting or overexpressing RRM2. The molecular mechanisms of RRM2 function were determined. The clinical significance of RRM2 overexpression was evaluated in 11 prostate cancer clinical cohorts. The efficacy of an RRM2 inhibitor (COH29) was assessed in vitro and in vivo. Finally, the mechanism underlying the transcriptional activation of RRM2 in prostate cancer tissue and cells was determined. RESULTS: Knockdown of RRM2 inhibited its oncogenic function, whereas overexpression of RRM2 promoted epithelial mesenchymal transition in prostate cancer cells. The prognostic value of RRM2 RNA levels in prostate cancer was confirmed in 11 clinical cohorts. Integrating the transcriptomic and phosphoproteomic changes induced by RRM2 unraveled multiple oncogenic pathways downstream of RRM2. Targeting RRM2 with COH29 showed excellent efficacy. Thirteen putative RRM2-targeting transcription factors were bioinformatically identified, and FOXM1 was validated to transcriptionally activate RRM2 in prostate cancer. CONCLUSIONS: We propose that increased expression of RRM2 is a mechanism driving poor patient outcomes in prostate cancer and that its inhibition may be of significant therapeutic value.

The Role of Immunotherapy and Radiation Therapy in Tumor Chemosensitivity in Advanced Head and Neck Cancer.

BACKGROUND Cancer is the second leading cause of death internationally, resulting in millions of deaths each year. While treatment in the past has heavily relied on surgery and radiotherapy, chemotherapy and immunotherapy are being increasingly utilized depending on disease presentation. CASE REPORT A 56-year-old male presented to the Emergency Department with a 3-week history of a rapidly enlarging left supraclavicular neck mass. Computed tomography scan revealed a 12×13 cm mass extending from the angle of the mandible to the supraclavicular area. A biopsy confirmed advanced stage squamous cell carcinoma of the head and neck. The patient was started on a chemotherapy regimen of docetaxel, cisplatin, and 5-fluorouracil (TCF). The tumor progressed through chemotherapy, which was switched to cetuximab; however, this therapy was discontinued after an anaphylactic reaction. Palliative radiation treatment was begun along with pembrolizumab. Pembrolizumab was continued, and after 9 cycles, the patient's cancer was almost in complete remission. Three months later, disease progression was once again noted with pembrolizumab treatment, which was subsequently discontinued. The patient was started on paclitaxel and carboplatin chemotherapy regimen as a last resort, despite failure of prior TCF treatment, and the patient responded, this time with complete remission in 4 months. CONCLUSIONS This case demonstrates a unique outcome in which a patient who previously was resistant to chemotherapy, later responded to chemotherapy after a trial of radiation therapy and immunotherapy. Immunotherapy may have a synergistic effect with radiation therapy and play a role in tumor sensitivity to chemotherapy in head and neck cancer treatment.

Breast Cancer Immunotherapy: An Update.

The immune system plays a major role in cancer surveillance. Harnessing its power to treat many cancers is now a reality that has led to cures in hopeless situations where no other solutions were available from traditional anticancer drugs. These spectacular achievements rekindled the oncology community's interest in extending the benefits to all cancers including breast cancer. The first section of this article reviews the biological foundations of the immune response to different subtypes of breast cancer and the ways cancer may overcome the immune attack leading to cancer disease. The second section is dedicated to the actual immune treatments including breast cancer vaccines, checkpoint inhibitors, monoclonal antibodies, and the "unconventional" immune role of chemotherapy.

A Unique Case of Severe Anemia Secondary to Copper Deficiency in an Adult Patient.

Anemia is a frequently encountered problem in the healthcare system. Common causes of anemia include blood loss, followed by impaired red blood cell production and red blood cell destruction. This case demonstrates the need for cognizance of the less frequent causes of anemia. A 27-year-old male with a history of traumatic brain injury and quadriplegia with chronic respiratory failure on home ventilator support presented to the emergency department with dyspnea and no bowel movements for three days. The patient received nutrition via percutaneous endoscopic gastostromy (PEG) tube. He was hypotensive with a mean arterial pressure (MAP) of 54 mm/Hg. There was no evidence of acute or ongoing blood loss. Initial lab data revealed hyperkalemia (K+ 6.1), severe anemia (Hb 1.5 g/dL), leukopenia (2.53 K/uL), neutropenia (ANC 700), and normal platelets. Peripheral smear revealed leukopenia with absolute neutropenia, marked anemia with anisopoikilocytosis with rare dacrocytes but no evidence of schistocytes. He responded to transfusion with improvement in hemoglobin from 1.5 to 9.1 within 24 hours. There was no evidence of hemolysis or vitamin deficiency. Ferritin and triglyceride levels were ordered to rule out hemophagocytic lymphohistiocytosis (HLH). Ferritin was elevated at 6506 ng/mL and triglycerides were 123 mg/dL. Soluble IL-2 receptor level was sent and found to be significantly elevated; however, this was felt to be more likely secondary to infection and inflammation, as the patient had no other clinical features of HLH, apart from cytopenias. Zinc supplementation was part of his wound care regimen. Copper levels were <10 ug/dL (normal: 70-140). Zinc supplements were stopped, and the patient was started on copper supplementation. At his three month follow-up clinic appointment, his anemia and leukopenia had resolved. Micronutrient deficiency is a potential cause of anemia, especially in a risk population and must be considered, as it is often easily correctible.