Diminution of STING Expression in the Blood of Patients with Severe or Critical COVID-19 Pneumonia.

INTRODUCTION: Cytokine storm and critical COVID-19 pneumonia are caused in at least 10% of patients by inborn errors of or auto-Abs to type I IFNs. The pathogenesis of life-threatening COVID-19 pneumonia in other patients remains unknown. METHODS: This study was conducted at Masih Daneshvari Hospital, Tehran, Iran. In the period of study, 75 confirmed cases of COVID-19 with presentations ranging from mild upper respiratory tract infection to lower respiratory tract infection, including moderate, severe, and critical disease, were recruited. Expression of STING mRNA was measured in peripheral blood mononuclear cells (PBMCs) and compared between patients with different severity and outcome. RESULTS: There was a significant negative correlation between age and STING expression level (p value = 0.010). Patients with "severe to critical" illness had a 20-fold lower STING expression level compared to the "mild to moderate" group (p value = 0.001). Also, the results showed lower expressions of STING in the patients admitted to the ICU (p value = 0.015). Patients who finally died had lower expression of STING at the time of sampling (p value = 0.041). CONCLUSION: STING mRNA expression in PBMCs was significantly lower in older COVID-19 cases, the patients with more severe illness, who needed intensive care, and who eventually died.

Co-infection of Klebsiella pneumonia, Cytomegalovirus, Aspergillus and Zygomycete in a patient with SARS-CoV-2.

Co-infection between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other pathogens has become a serious threat. There are the reports of fungal, bacterial, and viral co-infections with SARS-CoV-2. We report the unusual case of concomitant aspergillosis, mucormycosis, cytomegalovirus pneumonia, and also klebsiella pneumoniae empyema as the complication of SARS-CoV-2.

Coinfection by Aspergillus and Mucoraceae Species in Two Cases of Acute Rhinosinusitis as a Complication of COVID-19.

Acute invasive fungal rhinosinusitis (AIFR) is a life-threatening infection often found in immunocompromised patients. In the COVID-19 era, reports of AIFR have emerged, with high mortality and morbidity rate. This paper presents two cases of COVID-19 associated AIFR with the combined proven fungal etiology of Aspergillus flavus and Rhizopus arrhizus in case 1 and Aspergillus fumigatus and Rhizopus arrhizus in case 2. Both patients received liposomal amphotericin B then posaconazole combined with aggressive surgical debridement of necrotic tissues with a favorable clinical outcome. Mixed etiology AIFR can influence the outcome; hence, further studies are required upon this new threat.

Mixed etiology COVID-19 associated acute rhinosinusitis caused by two Aspergillus species.

INTRODUCTION: Acute invasive fungal rhino-sinusitis (AIFR) is a life-threatening infection that is mostly found in immunocompromised patients with serious morbidity and mortality. Recently, reports of AIFR have also emerged among SARS-CoV-2 infected patients. CASE PRESENTATION: A 50-year-old diabetic woman, previously diagnosed with COVID-19 pneumonia, was presented to the hospital with left facial pain on day 12 after discharge. Paranasal sinuses computed tomography was performed and according to the mucosal thickening in both maxillary sinuses and ethmoidal air cells, the patient underwent functional endoscopic sinus surgery (FESS) and necrosis were observed. The histopathologic examination revealed mycelium with septation suspected to Aspergillus and the culture was consistent with Aspergillus flavus and also Aspergillus niger . We reported a case of COVID-19 associated AIFR with two combined Aspergillus species from Iran. The patient received liposomal amphotericin B, which then switched to voriconazole combined with aggressive surgical debridement of necrotic tissues with a clinically favorable outcome. CONCLUSION: Mixed etiology AIFR can influence the outcome. However, further investigation is required upon this new threat.

Primary Pleuropulmonary Synovial Sarcoma: Report of Two Cases and a Comprehensive Review of the Literature.

Primary sarcomas of the lung represent less than 0.5% of all primary lung tumors and comprise a heterogeneous group of malignancies including synovial sarcoma (SS). Primary pleuropulmonary SS has non-specific presentations, such as chest pain, shortness of breath and cough, and its associated imaging features resemble those of other intrathoracic malignancies. The diagnosis of these tumors needs to be confirmed by cytogenetic and molecular studies. Here, we describe two rare cases of primary pleuropulmonary SS who were admitted to our hospital. We also provide a concise review of clinical, radiological, and histopathological characteristics of pleuropulmonary SS after exploring 168 studies (415 corresponding patients) that were identified through a literature search.

Fatal invasive pulmonary aspergillosis in an immunocompetent patient with COVID-19 due to Aspergillus terreus: A case study.

Case reports of CAPA emerged. In most of the reports, the predominant species is Aspergillus fumigatus. Uncommon species are less reported. Due to poor clinical outcome with Aspergillus terreus, the increasing reports with this agent require attention.

Not all that is miliary is tuberculosis: Metastatic medullary thyroid carcinoma mimicking miliary tuberculosis.

Medullary carcinoma of the thyroid should be considered in the differential diagnosis of miliary pattern of micronodules on chest imaging, irrespective of clinical features.

The Frequency of Human Papillomavirus Positivity in Iranian Patients with Head and Neck Squamous Cell Carcinoma.

BACKGROUND & OBJECTIVE: Human papillomavirus (HPV) has been associated with prognosis in patients with head and neck squamous cell carcinoma (HNSCC). Similar to the global studies, different prevalence rates of this viral infection have been reported in Iran. Therefore, we aimed to report the prevalence of this virus and its significance in HNSCC patients. METHODS: Patients who were referred to the five hospitals of Tehran city from May 2018 to May 2019 were enrolled in this study. All patients were diagnosed with HNSCC based on pathologic study. The pathologic disease staging was defined, and DNAs were extracted from the fresh tissue samples via kits. After polymerase chain reaction (PCR), HPV positive samples were evaluated for determining genotypes and data analysis. RESULTS: Of the 46 patients, three patients (6.5%) showed positive HPV results with the following subtypes: 18 (in two patients), 52 (in three patients), 61 (in two patients), 67, and 73.Comparison of variables between the groups with and without HPV showed a significant difference based on the tumor's lymphatic invasion (P=0.041), peripheral lymph node involvement (P=0.008), and histologic grade (P=0.011), but no statistically significant difference in terms of other variables such as age, primary tumor site, size, pathologic stage, vascular or perineural invasion, metastasis, smoking, and alcohol consumption was found.

Primary Gastrointestinal Involvement in a Case of Extranodal-Extranasal Natural Killer T Cell Lymphoma.

Extra-nasal types of Extra-nodal natural killer cell lymphoma (ENKL) have been known with poorer prognoses than nasal type with the worst responses to treatment. The current work introduces a case of ENKL with GI involvement with no nasal manifestations. We report a 56-year male farmer with fever, productive cough, dyspnea, anorexia, vomiting and chill in addition to malaise and cachexia of three months duration referred to a hospital with acute abdominal pain, and was diagnosed as peritonitis due to perforated terminal ileum ulcer before experiencing surgery as a case of acute abdomen. The pathologic study of the relevant biopsy showed "ulceration and necrosis with dense fibrinoleukocytic exudation and granulation tissue formation. CT scan determined a bilateral mass like haziness which was more likely to be metastatic. The review of the previous pathologic specimens raised Natural Killer/T cell Lymphoma (NKTL), the reason for which we focused on the patient's sinuses and nasal area as well as nasopharynx. There was no finding in examination and endoscopy of sinuses. Pathology also found malignant high grade non-Hodgkin T cell lymphoma in specimens obtained from debridement of ulcer at terminal ileum. It also showed that most of the tumor cells were positive for CD3, CD56, CD8, and LCA but negative for CD19, CD20 and AE1/AE3. Positive reactions for CD30 were shown by some cells. CD56, CD3, and CD8 were expressed by neoplastic cells and CD30 were positive in few cells. Proliferative activity (Ki67 index) was high (60-70%). This was the main base to diagnose an extra-nodal extra-nasal NK/T cell lymphoma. In conclusion, Intestinal changes at middle age, especially in men with nonspecific clinical manifestations is highly advised to be studied pathologically and genetically for T cell types like CD30 positive T cells which are usually engaged in ENKTL.

Promising effects of tocilizumab in COVID-19: A non-controlled, prospective clinical trial.

BACKGROUND: The clinical presentation of SARS-CoV-2 infection ranges from mild symptoms to severe complications, including acute respiratory distress syndrome. In this syndrome, inflammatory cytokines are released after activation of the inflammatory cascade, with the predominant role of interleukin (IL)-6. The aim of this study was to evaluate the effects of tocilizumab, as an IL-6 antagonist, in patients with severe or critical SARS-CoV-2 infection. METHODS: In this prospective clinical trial, 76 patients with severe or critical SARS-CoV-2 infection were evaluated for eligibility, and ultimately, 42 patients were included. Tocilizumab was administered at a dose of 400 mg as a single dose via intravenous infusion. Primary outcomes included changes in oxygenation support, need for invasive mechanical ventilation, and death. Secondary outcomes included radiological changes in the lungs, IL-6 plasma levels, C-reactive protein levels, and adverse drug reactions. The data were analyzed using SPSS software. RESULTS: Of the 42 included patients, 20 (48%) patients presented the severe infection stage and 22 (52%) were in the critical stage. The median age of patients was 56 years, and the median IL-6 level was 28.55 pg/mL. After tocilizumab administration, only 6 patients (14%) required invasive ventilation. Additionally, 35 patients (83.33%) showed clinical improvement. By day 28, a total of 7 patients died (6 patients in the critical stage and 1 patient in the severe stage). Neurological adverse effects were observed in 3 patients. CONCLUSIONS: Based on the current results, tocilizumab may be a promising agent for patients with severe or critical SARS-CoV-2 infection, if promptly initiated during the severe stage.

The incidence of mTOR marker in tracheal adenoid cystic carcinoma by immunohistochemical staining.

INTRODUCTION: There is an association between the activation of mammalian target of rapamycin (mTOR) signaling and aggressive tumor growth in multiple forms of cancer,including adenoid cystic carcinoma (ACC). ACCs are uncommon yet a malignant form of neoplasms that arises within the secretory glands. Therefore, the aim of this study was to investigate the increase of mTOR in the ACC tumors in order to survey the possibility of treating these tumors with mTOR inhibitors. MATERIAL AND METHODS: Samples from known cases of the lung and tracheal ACC were retrievedfrom the archives of the pa-thology department of Masih Daneshvari hospital, and immunohistochemical (IHC) staining for mTOR was performed on them. After preparation of the blocks with specific antibodies, tumor cells with cytoplasmic and/or nuclear expression of mTOR were considered as positive cells by applying a specific scoring method introduced in this study. RESULTS: The paraffin blocks of 26 patients were surveyed and the IHC marker of mTOR was positive in the tumors of 10 patients (38.5%). Out of 10 mTOR positive cases, 5 were females and 5 were males. The primary site of the surveyed tumors was the trachea and bronchus in 12 cases (46%), salivary glands in 7 individuals (27%), and lung tissue in 7 cases (27%), and there was no significant correlation between the primary site of the ACC tumors and the existence of the mTOR markers in them (P = 0.67). From all cases, 13 patients (50%) had cribriform and tubular cells without solid components, 9 cases (34.6%) had cribriform and tubular with less than 30% of solid components, and 4 cases (15.4%) had cribriform and tubular cells with more than 30% of solid com-ponents. There was no significant difference between the morphologies and the existence of mTOR markers in them (P = 0.741). CONCLUSIONS: As the incidence of mTOR markers is seen in patients with tracheal ACC, evaluation and scoring of mTOR in these persons can be helpful as further studies can distinguish the use of it in the treatment of the disease. .

Diffuse alveolar damage and thrombotic microangiopathy are the main histopathological findings in lung tissue biopsy samples of COVID-19 patients.

BACKGROUND: Since the outbreak of the novel coronavirus disease-2019 (COVID-19) in December 2019, limited studies have investigated the histopathologic findings of patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). MATERIAL AND METHODS: This study was conducted on 31 deceased patients who were hospitalized for COVID-19 in a tertiary hospital in Tehran, Iran. A total of 52 postmortem tissue biopsy samples were obtained from the lungs and liver of decedents. Clinical characteristics, laboratory data, and microscopic features were evaluated. Reverse transcription polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 was performed on specimens obtained from nasopharyngeal swabs and tissue biopsies. RESULTS: The median age of deceased patients was 66 years (range, 30-87 years) and 25 decedents (81 %) were male. The average interval from symptom onset to death was 13 days (range, 6-34 days). On histopathologic examination of the lung specimens, diffuse alveolar damage and thrombotic microangiopathy were the most common findings (80 % and 60 %, respectively). Liver specimens mainly showed macrovesicular steatosis, portal lymphoplasmacytic inflammation and passive congestion. No definitive viral inclusions were observed in any of the specimens. In addition, 92 % of lung tissue samples tested positive for SARS-CoV-2 by RT-PCR. CONCLUSIONS: Further studies are needed to investigate whether SARS-CoV-2 causes direct cytopathic changes in various organs of the human body.

Reappraisal of Frequency of Common Cystic Fibrosis Transmembrane Conductance Regulator Gene Mutations in Iranian Cystic Fibrosis Patients.

BACKGROUND: Cystic Fibrosis (CF) is a life-threatening recessive genetic disorder resulting from mutations in the gene encoding the fibrosis transmembrane conductance regulator protein (CFTR). The CF clinical phenotype shows wide variation ranging from severe disease in early childhood in those homozygous for the p.Phe508del mutation to absence of the vas deferens in otherwise healthy men homozygous for the p.Arg117His mutation. MATERIALS AND METHODS: DNA was extracted from whole blood from 62 patients with CF. The CFTR mutation was determined by Allele-Specific PCR assay. The spearman and linear regression analysis were used to obtain the correlation between phenotype and genotype relationship. RESULTS: Out of total 62 patients, 35 (56.4%) were male. The mean age of the patients was 15.56 ± 6.65 years. Mutations in CFTR were detected in 64.5% of the patients. The commonest mutations were p.Phe508del (33.9%), p.Arg117His; [5T] (5.64%), p.Arg117His; [7T] (4.03%) and p.Trp1282X (5.64%). Mutations p.Ile507del (4%), p.Gly542X (4%), p.Asn1303Lys (2.42%), c.489+1G>T (1.6%), p.Gly551Asp (1.6%) and c.1585-1G>A (1.6%) were also detected. Most mutations were detected in west and south of Iran, while p.Phe508del mutation was dominant mutation (75%) in east and southeast of Iran. The study showed either an association between this mutation with severity of disease and sex or an association between p.Arg117His mutations and age at diagnosis. CONCLUSION: The geographic distribution of gene mutation in Iranian cystic fibrosis patients was very heterogenic. In spite of the study that showed a correlation between p.Phe508del and severity of disease, to find any correlation between genotype and phenotype a broad and multi-centered study is recommended.

Pathology Results at Autopsy in Brain-Dead Patients with Brain Tumors.

OBJECTIVES: Brain tumors are the most challenging causes of brain deaths due to the lack of pathology results in many cases. It is not uncommon to find a brain tumor in a brain-dead patient with no pathology results or neuroradiology reports available; this would exclude the deceased from organ donation. The mortality that occurs while patients are on transplant wait lists motivated us to find a solution to prevent losing brain-dead patients as potential donors. We present our experiences in autopsy examinations of brain tumors and the results of frozen-section pathology. MATERIALS AND METHODS: We performed autopsy examinations of 8 brain-dead patients who were suspected of having highly malignant brain tumors and in whom there were no pathology or radiology reports available. The autopsy process began at the conclusion of organ retrieval. First, we performed a complete brain dissection; the tumor was then removed with its adjacent brain tissue and sent for examination by an expert pathologist. Organ transplant was deferred until the pathology examination was completed. RESULTS: Organ transplant was cancelled if the frozen sections revealed a high-grade tumor. For all other results, the transplant was performed. If a medulloblastoma was confirmed, only the heart was transplanted. The duration of the delay for pathologic examination was 30 to 45 minutes. A total of 21 organs were donated that would otherwise have been rejected. CONCLUSIONS: It is worth performing an autopsy and frozen-section pathology examination to prevent losing potential organs from donors with brain tumors who are suspected of having a high-grade neoplasm but have no pathology or neuroradiology reports. This process is simple and has the potential to save lives.

What Do We Know about Anthracofibrosis? A Literature Review.

Recently, the significance of anthracosis in the tracheobronchial tree, lung parenchyma, and even non-respiratory organs has been postulated and discussed in association with other diseases, especially tuberculosis. We reviewed the current literature by using the following key words in Medline/PubMed, Embase, and Google Scholar databases: anthracosis, anthracofibrosis, anthracotic bronchitis, biomass fuels, and mixed-dust pneumoconiosis. The bibliographies of eligible papers were also reviewed for further relevant articles. A total of 37 studies were assessed. The content of these studies was then divided into specific categories. Considering the pathogenesis, along with histopathological, radiological, and bronchoscopic results regarding anthracotic lesions, we suggest these findings be defined as "ANTHRACOSIS SYNDROME". For the first time, we describe a syndrome involving black pigmentation, which was previously thought to involve only the tracheobronchial tree. Until recently, it was not considered to be a single syndrome with different sites of involvement.

Prognostic value of rare and complex mutations in EGFR and serum levels of soluble EGFR and its ligands in non-small cell lung carcinoma patients.

BACKGROUND: A number of complex and rare mutations in epidermal growth factor receptor (EGFR) gene have been identified and the clinical implication of serum EGFR ligands has also been reported. However, the prognostic significance of these mutations and also the serum EGFR and its ligands in Non-Small Cell Lung Carcinoma (NSCLC) has remained a challenging issue. This study is aimed at finding the prognostic importance of EGFR rare mutations and serum EGFR, amphiregulin (AR), and TGF-α (Transforming Growth Factor-alpha) in NSCLC. MATERIALS AND METHOD: NSCLC patients (n=98) with mean age of 59±10.5 were enrolled (M/F: 75/23). DNA was extracted from formalin fixed paraffin embedded tissues. Exons 19 and 21 were amplified using polymerase chain reaction followed by direct sequencing for identification of mutations. Serum EGFR, AR, and TGF-α were measured by ELISA. RESULTS: EGFR mutation rate in patients was 37% (exon 19 deletions: 72.2%, exon 21 substitutions: 27.8%). The E872K in exon 21 mutation-positive cases was the most frequent rare mutation detected (90%; 9/10 samples). A significant relationship was found between EGFR exon 21mutations and serum EGFR and TGF-α (P<0.05). Increased serum AR (>3pg/ml) and TGF-α (>10.5pg/ml) were associated with shorter overall survival (P<0.05). CONCLUSIONS: The data clearly show that elevation of serum TGF-α and AR are associated with poor prognosis of NSCLC. In addition to the close relationship between EGFR mutations and serum EGFR, serum TGF-α changes was associated with the gene mutations. These findings could be implicated in clinical decision making related to EGFR-TKIs.