Ancillary findings on high resolution CT chest associated with typical features of COVID-19 pneumonia (Observational descriptive study at a tertiary care hospital).

OBJECTIVE: To determine the frequency of ancillary pulmonary signs and their relation to the severity of disease seen on high-resolution computed tomography of chest in patients of coronavirus disease-2019 pneumonia. METHODS: The observational descriptive study was conducted at the Armed Forces Institute of Radiology and Imaging, Rawalpindi, Pakistan, from March to July 2020, and included in place of comprised all coronavirus disease-2019 patients who were found positive on reverse transcription-polymerase chain reaction-and were referred to have high-resolution computed tomography of chest. Ancillary pulmonary findings in addition to typical features of coronavirus disease-2019 pneumonia were recorded. These included vacuole sign, halo sign, reverse halo sign, subpleural white line, subpleural translucent line, microvascular dilatation, fibrotic streaks and bronchiectasis. Relative frequency of these signs were determined for mild versus and severe disease, as determined by the computed tomography severity score. Data was analysed using SPSS 26. RESULTS: Of the 1645 patients, 1286(78.2%) were males and 359(21.8%) were females. The overall mean age was 47.5±15.7 years (range: 1-92). High-resolution computed tomography was normal in 418(25.4%) patients, typical findings for coronavirus disease-2019 were seen in 1110(67.5%), indeterminate in 113(16.9%) and atypical in 4(0.2%). Vacuole sign, subpleural white line, subpleural translucent sign, microvascular dilatation and fibrotic streaks were more commonly seen in severe disease (p<0.001), while discrete pulmonary nodule was identified more in the milder form (p<0.05). Halo and reverse halo signs as well as bronchiectatic changes demonstrated no significant propensity to the degree of disease severity (p>0.05). CONCLUSIONS: Coronavirus disease-2019 pneumonia demonstrated various ancillary pulmonary features on high resolution computed tomography of the chest in addition to typical findings more commonly described; radiologists should be aware of these signs and their relation to disease severity.

Smoking and COVID-19: Adding Fuel to the Flame.

The coronavirus disease 2019 (COVID-19) pandemic, an infection caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), has led to more than 771,000 deaths worldwide. Tobacco smoking is a major known risk factor for severe illness and even death from many respiratory infections. The effects of smoking on COVID-19 are currently controversial. Here, we provide an overview of the current knowledge on the effects of smoking on the clinical manifestations, disease progression, inflammatory responses, immunopathogenesis, racial ethnic disparities, and incidence of COVID-19. This review also documents future directions of smoking related research in COVID-19. The current epidemiological finding suggests that active smoking is associated with an increased severity of disease and death in hospitalized COVID-19 patients. Smoking can upregulate the angiotensin-converting enzyme-2 (ACE-2) receptor utilized by SARS-CoV-2 to enter the host cell and activate a 'cytokine storm' which can lead to worsen outcomes in COVID-19 patients. This receptor can also act as a potential therapeutic target for COVID-19 and other infectious diseases. The COVID-19 pandemic sheds light on a legacy of inequalities regarding gender, racial, and ethnic health disparities associated with active smoking, thus, smoking cessation may help in improving outcomes. In addition, to flatten the COVID-19 curve, staying indoors, avoiding unnecessary social contact, and bolstering the immune defense system by maintaining a healthy diet/living are highly desirable.

Androgen receptor agonists increase lean mass, improve cardiopulmonary functions and extend survival in preclinical models of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a neuromuscular disease that predominantly affects boys as a result of mutation(s) in the dystrophin gene. DMD is characterized by musculoskeletal and cardiopulmonary complications, resulting in shorter life-span. Boys afflicted by DMD typically exhibit symptoms within 3-5 years of age and declining physical functions before attaining puberty. We hypothesized that rapidly deteriorating health of pre-pubertal boys with DMD could be due to diminished anabolic actions of androgens in muscle, and that intervention with an androgen receptor (AR) agonist will reverse musculoskeletal complications and extend survival. While castration of dystrophin and utrophin double mutant (mdx-dm) mice to mimic pre-pubertal nadir androgen condition resulted in premature death, maintenance of androgen levels extended the survival. Non-steroidal selective-AR modulator, GTx-026, which selectively builds muscle and bone was tested in X-linked muscular dystrophy mice (mdx). GTx-026 significantly increased body weight, lean mass and grip strength by 60-80% over vehicle-treated mdx mice. While vehicle-treated castrated mdx mice exhibited cardiopulmonary impairment and fibrosis of heart and lungs, GTx-026 returned cardiopulmonary function and intensity of fibrosis to healthy control levels. GTx-026 elicits its musculoskeletal effects through pathways that are distinct from dystrophin-regulated pathways, making AR agonists ideal candidates for combination approaches. While castration of mdx-dm mice resulted in weaker muscle and shorter survival, GTx-026 treatment increased the muscle mass, function and survival, indicating that androgens are important for extended survival. These preclinical results support the importance of androgens and the need for intervention with AR agonists to treat DMD-affected boys.

Protein kinase D1 regulates subcellular localisation and metastatic function of metastasis-associated protein 1.

BACKGROUND: Cancer progression and metastasis is profoundly influenced by protein kinase D1 (PKD1) and metastasis-associated protein 1 (MTA1) in addition to other pathways. However, the nature of regulatory relationship between the PKD1 and MTA1, and its resulting impact on cancer metastasis remains unknown. Here we present evidence to establish that PKD1 is an upstream regulatory kinase of MTA1. METHODS: Protein and mRNA expression of MTA1 in PKD1-overexpressing cells were determined using western blotting and reverse-transcription quantitative real-time PCR. Immunoprecipitation and proximity ligation assay (PLA) were used to determine the interaction between PKD1 and MTA1. PKD1-mediated nucleo-cytoplasmic export and polyubiquitin-dependent proteosomal degradation was determined using immunostaining. The correlation between PKD1 and MTA1 was determined using intra-tibial, subcutaneous xenograft, PTEN-knockout (PTEN-KO) and transgenic adenocarcinoma of mouse prostate (TRAMP) mouse models, as well as human cancer tissues. RESULTS: We found that MTA1 is a PKD1-interacting substrate, and that PKD1 phosphorylates MTA1, supports its nucleus-to-cytoplasmic redistribution and utilises its N-terminal and kinase domains to effectively inhibit the levels of MTA1 via polyubiquitin-dependent proteosomal degradation. PKD1-mediated downregulation of MTA1 was accompanied by a significant suppression of prostate cancer progression and metastasis in physiologically relevant spontaneous tumour models. Accordingly, progression of human prostate tumours to increased invasiveness was also accompanied by decreased and increased levels of PKD1 and MTA1, respectively. CONCLUSIONS: Overall, this study, for the first time, establishes that PKD1 is an upstream regulatory kinase of MTA1 status and its associated metastatic activity, and that the PKD1-MTA1 axis could be targeted for anti-cancer strategies.

Clinical significance of MUC13 in pancreatic ductal adenocarcinoma.

BACKGROUND: Poor prognosis of pancreatic cancer (PanCa) is associated with lack of an effective early diagnostic biomarker. This study elucidates significance of MUC13, as a diagnostic/prognostic marker of PanCa. METHODS: MUC13 was assessed in tissues using our in-house generated anti-MUC13 mouse monoclonal antibody and analyzed for clinical correlation by immunohistochemistry, immunoblotting, RT-PCR, computational and submicron scale mass-density fluctuation analyses, ROC and Kaplan Meir curve analyses. RESULTS: MUC13 expression was detected in 100% pancreatic intraepithelial neoplasia (PanIN) lesions (Mean composite score: MCS = 5.8; AUC >0.8, P < 0.0001), 94.6% of pancreatic ductal adenocarcinoma (PDAC) samples (MCS = 9.7, P < 0.0001) as compared to low expression in tumor adjacent tissues (MCS = 4, P < 0.001) along with faint or no expression in normal pancreatic tissues (MCS = 0.8; AUC >0.8; P < 0.0001). Nuclear MUC13 expression positively correlated with nodal metastasis (P < 0.05), invasion of cancer to peripheral tissues (P < 0.5) and poor patient survival (P < 0.05; prognostic AUC = 0.9). Submicron scale mass density and artificial intelligence based algorithm analyses also elucidated association of MUC13 with greater morphological disorder (P < 0.001) and nuclear MUC13 as strong predictor for cancer aggressiveness and poor patient survival. CONCLUSION: This study provides significant information regarding MUC13 expression/subcellular localization in PanCa samples and supporting the use anti-MUC13 MAb for the development of PanCa diagnostic/prognostic test.

Diffuse Large B-Cell Lymphoma Version 1.2016.

Diffuse large B-cell lymphomas (DLBCL) are now considered a heterogeneous group of distinct molecular subtypes (germinal center B-cell DLBCL, activated B-cell DLBCL, and primary mediastinal large B-cell lymphoma (PMBL) with varied natural history and response to therapy. In addition, a subset of patients with DLBCL have concurrent MYC and/or BCL2 gene rearrangements (double-hit lymphomas; DHL) and others have a dual expression of both MYC and BCL2 proteins (double-expressing DLBCL; DEL). The standard of care for the treatment of patients with PMBL, DHL, or DEL has not been established. Adequate immunophenotyping and molecular testing (in selected circumstances) are necessary for the accurate diagnosis of different subtypes of DLBCL. The NCCN Guidelines included in this issue, part of the NCCN Guidelines for non-Hodgkin's lymphomas, address the diagnosis and management of DLBCL and its subtypes.

NCCN Guidelines Insights: Non-Hodgkin's Lymphomas, Version 3.2016.

Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL.

Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease, which are managed in the same way. The advent of novel monoclonal antibodies (ofatumumab and obinutuzumab) led to the development of effective chemoimmunotherapy regimens. The recently approved small molecule kinase inhibitors (ibrutinib and idelalisib) are effective treatment options for CLL in elderly patients with decreased tolerance for aggressive regimens and in patients with poor prognostic features who do not benefit from conventional chemoimmunotherapy regimens. This portion of the NCCN Guidelines for Non-Hodgkin's Lymphomas describes the recent specific to the incorporation of recently approved targeted therapies for the management of patients with newly diagnosed and relapsed or refractory CLL/SLL.

DRY TAP: A DIAGNOSTIC ALERT FOR UNDERLYING BONE MARROW PATHOLOGY.

BACKGROUND: Dry tap is an annoying experience in bone marrow (BM) findings, especially in cases where the diagnosis may hinge on BM findings. This study was conducted to determine, on, the basis of bone marrow (BM) trephine biopsy, the frequency of various underlying conditions causing a dry tap, among different age groups. METHODS: It was a descriptive study carried out at PAF hospital Mianwali, Pakistan from 1" Jan 2009 to 31 Dec 2012. Record of all BM aspirations and trephine biopsies performed during 4 years was retrieved from hospital's laboratory. Total number of BM aspirations and trephines were counted and the subject's ages and genders recorded. Frequencies and percentages of patients with dry tap, in paediatric group (<15 years of age), young to middle-aged group (15-59 years) and the elderly (> or = 60 years) were calculated. Diagnoses of patients with dry tap made on BM biopsy were noted for each group and their frequencies calculated. RESULTS: Of 548 BM aspirations, dry tap was encountered in 52 (9.5%) cases. Acute lymphoblastic leukaemia (ALL) was the commonest cause of dry tap in paediatric age, seen in 6 (60%) of 10 children. In young to middle-aged group, non Hodgkin lymphoma (NHL) was the commonest cause, found in 6 (30%) of 20 cases. NHL and metastatic tumours, seen in 8 (36.4%) and 6 (27.3%) of 22 patients respectively, were the most frequent causes of dry tap in the elderly. CONCLUSION: Dry tap, in most of the cases, is like a diagnostic alert for the presence of an underlying BM pathology, nature of which depends upon age group.

Non-Hodgkin's lymphomas, version 4.2014.

Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Mantle cell lymphoma (MCL) accounts for approximately 6% of all newly diagnosed NHL cases. Radiation therapy with or without systemic therapy is a reasonable approach for the few patients who present with early-stage disease. Rituximab-based chemoimmunotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR) is recommended for patients presenting with advanced-stage disease. Induction therapy followed by rituximab maintenance may provide extended disease control for those who are not candidates for HDT/ASCR. Ibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of relapsed or refractory disease. This manuscript discusses the recommendations outlined in the NCCN Guidelines for NHL regarding the diagnosis and management of patients with MCL.

Non-Hodgkin's lymphomas, version 2.2014.

Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Follicular lymphoma (FL) is the most common subtype of indolent NHL, accounting for approximately 22% of all newly diagnosed cases of NHL. The incorporation of rituximab to chemotherapy regimens has become a widely accepted standard of care for first-line therapy for patients with FL. Maintenance and consolidation therapy with rituximab and radioimmunotherapy have also been associated with improved progression-free survival in patients experiencing response to first-line therapy. Despite therapeutic advances that have improved outcomes, FL is generally considered a chronic disease characterized by multiple recurrences with current therapies. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with FL.

Incorporating Halal Into Healthy and Equitable Dietary Patterns to Address Food and Nutrition Security Among K-12 and University Students: A Perspective.

Food and nutrition insecurity exist at an alarming rate in the US educational system, ranging from 17% among K-12 students up to 58.8% among university students. Many Muslim American students face food and nutrition insecurity due, in part, to a lack of acknowledgment of student adherence to halal dietary guidelines and the availability of certified halal options at school. This has implications for health, learning, and social outcomes. In this perspective paper, we provide short-term, mid-term, and long-term recommendations to address food and nutrition insecurity among halal-observant students to advance healthy dietary patterns.

Exosomes derived from tumor adjacent fibroblasts efficiently target pancreatic tumors.

The application of extracellular vesicles, particularly exosomes (EXs), is rapidly expanding in the field of medicine, owing to their remarkable properties as natural carriers of biological cargo. This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues (NAF-EXs) for personalized medicine, which can be derived at the time of diagnosis by endoscopic ultrasound. Herein, we show that exosomes (EXs) derived from NAFs demonstrate differential bio-physical characteristics, efficient cellular internalization, drug loading efficiency, pancreatic tumor targeting and delivery of payloads. NAF-derived EXs (NAF-EXs) were used for loading ormeloxifene (ORM), a potent anti-cancer and desmoplasia inhibitor as a model drug. We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype, which may be due to regulation of Ca2+ influx in fibroblast cells. NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition (EMT) and repressed tumor growth in xenograft mouse model. In conclusion, our data suggests preferential tropism of NAF-EXs for PDAC tumors, thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs. Additionally, it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.

Non-Hodgkin's lymphomas, version 1.2013.

These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Non-Hodgkin's Lymphomas (NHL) and provide a discussion of the clinical evidence that support the updates. The updates discussed in this article feature recommendations for additional treatment options in patients with chronic lymphocytic leukemia and guidance surrounding the management of hepatitis virus reactivation/infections in high-risk patients with NHL undergoing antitumor therapy.

Oropharyngeal Squamous Cell Carcinoma Outcomes by p16INK4a Antigen Status in a Veteran Population.

Background: The correlation between head and neck squamous cell carcinoma (SCC) and human papillomavirus (HPV) has been of great interest. We aimed to study immunoexpression of the p16INK4a (p16) antigen, a surrogate marker for high-risk HPV infection, in oropharyngeal SCC among veterans to estimate HPV-related cancer and survival. Secondary aims included stratification of race and ethnicity, degree of tobacco and alcohol use, tumor location, stage, and age at diagnosis. Methods: A retrospective electronic health record review was performed between January 1, 2000, and December 31, 2008, at a tertiary-level US Department of Veterans Affairs (VA) medical center for veterans who were treated for oropharyngeal SCC, had follow-up for a minimum of 2 years, and for whom paraffin-embedded tissue was available. Paraffin-embedded tissue was analyzed for p16 expression. Results: We identified 66 veterans who met the inclusion criteria. p16 expression was observed in 29% of the patients. All patients were male with no difference in age at diagnosis between the groups. Among patients with p16-negative status, 60% were African American, whereas among patients with p16-postive status, 32% were African American (P = .04). Among patients with p16-postive status, 22% were tobacco-naïve, and 18% were alcohol-naïve vs 0% and 4%, respectively, of patients with p16-negative status (P = .005 and P = .12, respectively). Two-year survival was the same for both groups (P = .52). Conclusions: We observed p16 expression in 29% of VA patients with oropharnygeal SCC, which was less than observed in non-VA populations. At presentation, both groups demonstrated a predilection for tonsil location and late stage without significant difference in age or disease-specific survival. Disparities in racial distribution and tobacco use between patients with and without p16-positive status appear like that reported in non-VA populations; however, the frequently reported younger age at presentation, lower stage, and improved prognosis were not observed.

Role Of Cd8+ Tumour-Infiltrating Lymphocytes In Predicting Regional Lymph Node Metastasis In Lip And Oral Cavity Squamous Cell Carcinoma.

BACKGROUND: Lip and oral squamous cell carcinoma maintains a significant disease burden in Pakistan. The latest research on cancer focuses more on the role of body's immune response in tumour progression and spread rather than on the nature of neoplastic cells. Tumour-infiltrating lymphocytes constitute a major part of the tumour microenvironment and infiltration of tumour stroma by cytotoxic T-cells are known to limit the tumour progression in various malignancies, such as colorectal and stomach cancers. In our study, we aim to establish the prognostic role of CD8+ tumour-infiltrating lymphocytes in lip and oral squamous cell carcinoma. METHODS: Clinico-pathological data and paraffin-embedded blocks were obtained for 100 cases of lip and oral squamous cell carcinoma. These cases were selected through non-probability, convenience sampling at the Histopathology department of A.F.I.P., Rawalpindi. Fresh sections from the tumour proper were taken and CD8 immuno-marker was applied. Data was recorded, entered and analysed with S.P.S.S. version 27.0 and Microsoft Excel. Qualitative variables were represented as frequency/percentages and quantitative variables were represented as mean and standard deviation. Chi-squared test was applied to test association between categorical data. A p-value of <0.05 was taken as significant. RESULTS: Increased CD8 T.I.L. density was significantly associated with pN stage (p-value= .000) and early clinical stage (p-value= .014). No significant association with other clinico-pathological parameters was established. CONCLUSIONS: CD8 T.I.L. density is a reliable marker for predicting absence or presence of cervical nodal metastasis in lip and oral S.C.C. Its predictive role in determining overall survival rate should be evaluated in future studies.

MUC13 drives cancer aggressiveness and metastasis through the YAP1-dependent pathway.

Anchorage-independent survival after intravasation of cancer cells from the primary tumor site represents a critical step in metastasis. Here, we reveal new insights into how MUC13-mediated anoikis resistance, coupled with survival of colorectal tumor cells, leads to distant metastasis. We found that MUC13 targets a potent transcriptional coactivator, YAP1, and drives its nuclear translocation via forming a novel survival complex, which in turn augments the levels of pro-survival and metastasis-associated genes. High expression of MUC13 is correlated well with extensive macrometastasis of colon cancer cells with elevated nuclear YAP1 in physiologically relevant whole animal model systems. Interestingly, a positive correlation of MUC13 and YAP1 expression was observed in human colorectal cancer tissues. In brief, the results presented here broaden the significance of MCU13 in cancer metastasis via targeting YAP1 for the first time and provide new avenues for developing novel strategies for targeting cancer metastasis.

The next phase in patient safety education: Towards a standardized, tools-based pathology patient safety curriculum: A call to action from the Association of Pathology Chairs' Residency Program Directors Section Training Residents in Patient Safety Workgroup.

Patient safety education is a mandated Common Program Requirement of the Accreditation Council for Graduate Medical Education and for the Royal College of Physicians and Surgeons of Canada in all medical residency and fellowship programs. Although many hospitals and healthcare environments have general patient safety education tools for trainees, few to none focus on the unique training milieu of pathologists, including a mix of highly automated and manual error-prone processes, frequent multiplicity of events, and lack of direct patient relationships for error disclosure. We established a national Association of Pathology Chairs-Program Directors Section Workgroup focused on patient safety education for pathology trainees entitled Training Residents in Patient Safety (TRIPS). TRIPS included diverse representatives from across the United States, as well as representatives from pathology organizations including the American Board of Pathology, the American Society for Clinical Pathology, the United States and Canadian Academy of Pathology, the College of American Pathologists, and the Society to Improve Diagnosis in Medicine. Objectives of the workgroup included developing a standardized patient safety curriculum, designing teaching and assessment tools, and refining them with pilot sites. Here we report the establishment of TRIPS as well as data from national needs assessment of Program Directors across the country, who confirmed the need for a standardized patient safety curriculum.

Non-Hodgkin's Lymphomas, version 3.2012.

These NCCN Guidelines Insights summarize several key updates to the 2012 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin's Lymphomas (NHL) and describe the clinical evidence supporting the updates. The featured updates include changes to the recommendations for treatment options in patients with chronic lymphocytic leukemia (including in elderly or frail patients and patients with poor-risk cytogenetics), guidance surrounding surveillance imaging for follow-up of patients with NHL, and the addition of first-line consolidation options for patients with mantle cell lymphoma.