Atypical Site of Presentation of a Rare Type of SMARCA4-Positive Cutaneous Squamous Cell Carcinoma of the Skin: Case Report and Review of the Literature.

Cutaneous squamous cell carcinoma (cSCC) comprises 20% of cases of nonmelanoma skin cancers in the United States. In total, 3% to 5% of squamous cell carcinoma (SCC) are metastatic at the time of presentation, associated with significant mortality due to a lack of standardized treatment options. In total, 95% of these tumors are amenable to the initial standard of treatment, which is surgical resection. However, a small percentage of them require systemic therapy as they are either locally advanced to regional lymph nodes or have distant metastasis. The common sites of presentation of cSCC are the scalp and the face with predictable spread to the intra-parotid, upper jugular, and perifacial lymph nodes. In our case report, however, our patient had a large lump lesion on the upper back, an unusual site of presentation of cSCC, with locally advanced metastasis to the left axillary lymph nodes. Subsequently, the tumor marker study revealed a positive SMARCA4 variant (the essential ATPase subunit of the Switch (SWI)/Sucrose Nonfermenting (SNF) chromatin-remodeling complex) that is even rarer in the context of cSCC. Furthermore, abnormalities in SWI/SNF chromatin-remodeling complex subunits have shown promising results as a target therapy for immune checkpoint inhibitor (ICI) therapy. We present an atypical presentation site of locally advanced rare variant SMARCA4-positive cSCC in a patient who received treatment with chemoradiation and systemic therapy with ICI after primary surgical resection. To date, only 2 cases of SMARCA4-positive cSCC were found in the literature with no details of the treatment received. Our case is unique in its atypical site of presentation as well as showing partial response to radiotherapy (RT) and systemic therapy with ICI.

A framework for exclusion of alternative diagnoses in sarcoidosis.

Sarcoidosis is a multisystem granulomatous syndrome that arises from a persistent immune response to a triggering antigen(s). There is no "gold standard" test or algorithm for the diagnosis of sarcoidosis, making the diagnosis one of exclusion. The presentation of the disease varies substantially between individuals, in both the number of organs involved, and the manifestations seen in individual organs. These qualities dictate that health care providers diagnosing sarcoidosis must consider a wide range of possible alternative diagnoses, from across a range of presentations and medical specialties (infectious, inflammatory, cardiac, neurologic). Current guideline-based diagnosis of sarcoidosis recommends fulfillment of three criteria: 1) compatible clinical presentation and/or imaging 2) demonstration of granulomatous inflammation by biopsy (when possible) and, 3) exclusion of alternative causes, but do not provide guidance on standardized strategies for exclusion of alternative diagnoses. In this review, we provide a summary of the most common differential diagnoses for sarcoidosis involvement of lung, eye, skin, central nervous system, heart, liver, and kidney. We then propose a framework for testing to exclude alternative diagnoses based on pretest probability of sarcoidosis, defined as high (typical findings with sarcoidosis involvement confirmed in another organ), moderate (typical findings in a single organ), or low (atypical/findings suggesting of an alternative diagnosis). This work highlights the need for informed and careful exclusion of alternative diagnoses in sarcoidosis.

Racial disparities in the incidence and survival outcomes in diffuse large B-cell lymphoma in adolescents and young adults.

Diffuse large B-cell Lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL). The disease generally occurs in older patients. Although at a lower prevalence, the disease also occurs in the adolescent and young adult group (AYA). There is paucity of data in the literature on racial and ethnic disparities in the incidence and survival outcomes of DLBCL in the AYA group. The objective of our study is to demonstrate the disparities in these outcomes. Utilizing SEER, we obtained data on patient demographics, incidence, and survival from 2000 to 2020. We observed statistically significant reduced incidence of DLBCL in all racial groups, except the non-Hispanic Asian and Pacific Islander group (NHAPI). The non-Hispanic Black group (NHB) had one of the lowest survival despite showing the largest decrease in incidence in DLBCL. The differences in the survival could be secondary to socioeconomic factors, however other reasons need to be explored. The increased incidence among the NHAPI group mirrors that of large population-based studies in East Asian countries, however, underlying reasons have not been elucidated.

The textures of sarcoidosis: quantifying lung disease through variograms.

Objective: Sarcoidosis is a granulomatous disease affecting the lungs in over 90% of patients. Qualitative assessment of chest CT by radiologists is standard clinical practice and reliable quantification of disease from CT would support ongoing efforts to identify sarcoidosis phenotypes. Standard imaging feature engineering techniques such as radiomics suffer from extreme sensitivity to image acquisition and processing, potentially impeding generalizability of research to clinical populations. In this work, we instead investigate approaches to engineering variogram-based features with the intent to identify a robust, generalizable pipeline for image quantification in the study of sarcoidosis. Approach: For a cohort of more than 300 individuals with sarcoidosis, we investigated 24 feature engineering pipelines differing by decisions for image registration to a template lung, empirical and model variogram estimation methods, and feature harmonization for CT scanner model, and subsequently 48 sets of phenotypes produced through unsupervised clustering. We then assessed sensitivity of engineered features, phenotypes produced through unsupervised clustering, and sarcoidosis disease signal strength to pipeline. Main results: We found that variogram features had low to mild association with scanner model and associations were reduced by image registration. For each feature type, features were also typically robust to all pipeline decisions except image registration. Strength of disease signal as measured by association with pulmonary function testing and some radiologist visual assessments was strong (optimistic AUC ≈ 0.9, p ≪ 0.0001 in models for architectural distortion, conglomerate mass, fibrotic abnormality, and traction bronchiectasis) and fairly consistent across engineering approaches regardless of registration and harmonization for CT scanner. Significance: Variogram-based features appear to be a suitable approach to image quantification in support of generalizable research in pulmonary sarcoidosis.

Application of Artificial Intelligence in Neuroendocrine Lung Cancer Diagnosis and Treatment: A Systematic Review.

Neuroendocrine tumors (NETs) represent a heterogeneous group of neoplasms with diverse clinical presentations and prognoses. Accurate and timely diagnosis of these tumors is crucial for appropriate management and improved patient outcomes. In recent years, exciting advancements in artificial intelligence (AI) technologies have been revolutionizing medical diagnostics, particularly in the realm of detecting and characterizing pulmonary NETs, offering promising avenues for improved patient care. This article aims to provide a comprehensive overview of the role of AI in diagnosing lung NETs. We discuss the current challenges associated with conventional diagnostic approaches, including histopathological examination and imaging modalities. Despite advancements in these techniques, accurate diagnosis remains challenging due to the overlapping features with other pulmonary lesions and the subjective interpretation of imaging findings. AI-based approaches, including machine learning and deep learning algorithms, have demonstrated remarkable potential in addressing these challenges. By leveraging large datasets of radiological images, histopathological samples, and clinical data, AI models can extract complex patterns and features that may not be readily discernible to human observers. Moreover, AI algorithms can continuously learn and improve from new data, leading to enhanced diagnostic accuracy and efficiency over time. Specific AI applications in the diagnosis of lung NETs include computer-aided detection and classification of pulmonary nodules on CT scans, quantitative analysis of PET imaging for tumor characterization, and integration of multi-modal data for comprehensive diagnostic assessments. These AI-driven tools hold promise for facilitating early detection, risk stratification, and personalized treatment planning in patients with lung NETs.

High-resolution CT phenotypes in pulmonary sarcoidosis: a multinational Delphi consensus study.

One view of sarcoidosis is that the term covers many different diseases. However, no classification framework exists for the future exploration of pathogenetic pathways, genetic or trigger predilections, patterns of lung function impairment, or treatment separations, or for the development of diagnostic algorithms or relevant outcome measures. We aimed to establish agreement on high-resolution CT (HRCT) phenotypic separations in sarcoidosis to anchor future CT research through a multinational two-round Delphi consensus process. Delphi participants included members of the Fleischner Society and the World Association of Sarcoidosis and other Granulomatous Disorders, as well as members' nominees. 146 individuals (98 chest physicians, 48 thoracic radiologists) from 28 countries took part, 144 of whom completed both Delphi rounds. After rating of 35 Delphi statements on a five-point Likert scale, consensus was achieved for 22 (63%) statements. There was 97% agreement on the existence of distinct HRCT phenotypes, with seven HRCT phenotypes that were categorised by participants as non-fibrotic or likely to be fibrotic. The international consensus reached in this Delphi exercise justifies the formulation of a CT classification as a basis for the possible definition of separate diseases. Further refinement of phenotypes with rapidly achievable CT studies is now needed to underpin the development of a formal classification of sarcoidosis.

Miller-Fisher Syndrome Unveiled in the Presence of Cholangiocarcinoma.

Miller-Fisher syndrome (MFS) is a rare variant of Guillain-Barré syndrome, characterized by ataxia, areflexia, ophthalmoplegia, and possible facial, swallowing and limb weakness alongside respiratory failure. Variations within MFS may include respiratory and limb weakness and Bickerstaff brainstem encephalitis (BBE), marked by altered consciousness, ataxia, ophthalmoparesis, and paradoxical hyperreflexia. MFS can emerge in both children and adults, often following bacterial or viral illness. While autoimmune-driven nerve damage occurs, most MFS patients recover within six months without specific treatment, with a low risk of lasting neurological deficits or relapses. Rarely fatal, MFS's co-occurrence with cholangiocarcinoma (CCA) presents unique management challenges. CCA, primarily affecting bile ducts, has a bleak prognosis; surgical resection offers limited cure potential due to late-stage detection and high recurrence rates. Advances in CCA's molecular understanding have led to novel diagnostic and therapeutic approaches, requiring a comprehensive interdisciplinary care approach for optimal MFS and CCA management outcomes. Herein, we present a 50-year-old male with a complex medical history who was admitted to the hospital due to abdominal discomfort, nausea, vomiting, and ascites. Imaging revealed pneumonia and secondary bacterial peritonitis. Later, he developed neurological symptoms, including weakness, gait abnormalities, and brainstem symptoms, leading to the diagnosis of MFS. Despite treatment efforts, his condition deteriorated, leading to acute liver failure and unexplained anasarca. N-acetyl cysteine was initiated for liver issues. Neurologically, he showed quadriparesis and areflexia. Intravenous immunoglobulin (IVIG) treatment improved his neurological symptoms but worsened gastrointestinal issues, including ileus and elevated CA19-9 levels, suggesting a potential carcinoma. A liver biopsy was performed. After IVIG treatment, he experienced widespread discomfort, emotional unresponsiveness, swallowing difficulties, and aspiration risk, ultimately leading to his demise.

Diagnostic Yield, Radiation Exposure, and the Role of Clinical Decision Rules to Limit Computed Tomographic Pulmonary Angiography-Associated Complications.

OBJECTIVES: Computed tomographic pulmonary angiography (CT-PA) is associated with significant cost, contrast, and radiation exposure. Clinical decision rules (CDRs) reduce the need for diagnostic imaging; however, their utility in the medical intensive care unit (MICU) remains unknown. We explored the diagnostic yield and complications associated with CT-PA (radiation exposure and contrast-induced acute kidney injury [AKI]) while investigating the efficacy of CDRs to reduce unnecessary testing. METHODS: All CT-PAs performed in an academic MICU for 4 years were retrospectively reviewed. The Wells and revised Geneva scores (CDRs) and radiation dose per CT-PA were calculated, and the incidence of post-CT-PA AKI was recorded. RESULTS: A total of 439 studies were analyzed; the diagnostic yield was 11% (48 PEs). Positive CT-PAs were associated with a higher Wells score (5.8 versus 3.2, P < 0.001), but similar revised Geneva scores (6.4 versus 6.0, P = 0.32). A Wells score of ≥4 had a positive likelihood ratio of 2.1 with a negative predictive value of 98.2. More than half (88.9%) of patients with a Wells score of ≤4 developed an AKI, with 55.6% of those having recovery of renal function. CONCLUSIONS: There is overutilization of CT-PA in the MICU. The Wells score retains its negative predictive value in critically ill adult patients and may aid to limit radiation exposure and contrast-induced AKI in MICU.

Cystic fibrosis autoantibody signatures associate with Staphylococcus aureus lung infection or cystic fibrosis-related diabetes.

Introduction: While cystic fibrosis (CF) lung disease is characterized by persistent inflammation and infections and chronic inflammatory diseases are often accompanied by autoimmunity, autoimmune reactivity in CF has not been studied in depth. Methods: In this work we undertook an unbiased approach to explore the systemic autoantibody repertoire in CF using autoantibody microarrays. Results and discussion: Our results show higher levels of several new autoantibodies in the blood of people with CF (PwCF) compared to control subjects. Some of these are IgA autoantibodies targeting neutrophil components or autoantigens linked to neutrophil-mediated tissue damage in CF. We also found that people with CF with higher systemic IgM autoantibody levels have lower prevalence of S. aureus infection. On the other hand, IgM autoantibody levels in S. aureus-infected PwCF correlate with lung disease severity. Diabetic PwCF have significantly higher levels of IgA autoantibodies in their circulation compared to nondiabetic PwCF and several of their IgM autoantibodies associate with worse lung disease. In contrast, in nondiabetic PwCF blood levels of IgA autoantibodies correlate with lung disease. We have also identified other autoantibodies in CF that associate with P. aeruginosa airway infection. In summary, we have identified several new autoantibodies and associations of autoantibody signatures with specific clinical features in CF.

Airway Injury Caused by Aspiration of Iron Sulfate Pills: A Series of 11 Cases.

It is not widely recognized that iron (ferrous sulfate) pill aspiration causes airway damage. Clinical diagnosis is challenging because patients are often unaware that they have aspirated a pill. The literature on this entity consists mainly of case reports. The aim of this study is to describe the clinical and pathologic features of iron pill aspiration in a series of 11 patients. A retrospective review of our pathology archives was performed to identify cases of iron pill aspiration (2013-2023). All available histologic and cytologic material was rereviewed. Clinical information was collected from the electronic medical record, and imaging studies were rereviewed. Eighteen endobronchial biopsies were identified from 11 patients (7 women and 4 men; mean age, 70 years; range, 44-82 years). Eight patients had corresponding cytology (20 specimens). Medication history was available in 9 of 11 patients, all of whom were taking iron sulfate pills. Two patients reported possible aspiration episodes; 4 had risk factors for aspiration. The diagnosis of iron pill aspiration was suspected prior to biopsy in only 1 case. Histologically, iron pill particles were yellow, golden brown, or gray, were elongated and crystal or fiber like, and stained strongly with an iron stain. Common histologic findings included mucosal ulceration, acute and/or chronic inflammation, fibrosis, and squamous metaplasia. Iron pill particles were also identified in 11 cytology specimens from 6 patients. On Papanicolaou staining, iron pill particles were yellow to golden, fiber like, refractile, and crystalline. Reactive epithelial cells, squamous metaplasia, and acute inflammation were common. The combination of iron pill intake and discolored mucosa on bronchoscopy is a potential clue to the diagnosis of iron pill aspiration. Pathologists should familiarize themselves with the appearance of iron pill particles in endobronchial biopsies and cytology specimens from the respiratory tract as this diagnosis is seldom suspected on clinical grounds, and most patients lack a history of aspiration.

Simultaneous Thoracic Spine Metastatic Melanoma and Pre-existing Prostate Adenocarcinoma: A Unique Case Presentation and Literature Review.

In melanoma patients, distant metastases frequently manifest in the skin, lung, brain, liver, bone, and intestine. Notably, bone metastasis predominantly occurs within the axial skeleton, with the lumbar and thoracic spines being the most affected regions. Conversely, prostate cancer often disseminates to the bone, lung, liver, pleura, and adrenal glands. The spinal column, particularly the lumbar region, frequently harbors metastases in prostate cancer cases. Given the proximity of axial lesions to the spinal cord, patients commonly experience pain, weakness, and urinary dysfunction. This article presents a compelling case report of a patient initially diagnosed with metastatic prostate cancer, who later exhibited a metastatic lesion in the thoracic spine, subsequently identified as originating from acral melanoma on the plantar surface of the right foot. Histopathological examination confirmed the presence of acral melanoma in both the spine and the right foot. The patient received comprehensive treatment for advanced melanoma from a multidisciplinary team comprising medical and radiation oncologists. Considering the overlapping pathophysiology of prostate cancer and melanoma, simultaneous screening for both diseases in cases where one is detected could yield significant benefits, including enhanced morbidity and mortality outcomes and the facilitation of early detection for secondary malignancies.

Role of Next Generation Immune Checkpoint Inhibitor (ICI) Therapy in Philadelphia Negative Classic Myeloproliferative Neoplasm (MPN): Review of the Literature.

The Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are enduring and well-known conditions. These disorders are characterized by the abnormal growth of one or more hematopoietic cell lineages in the body's stem cells, leading to the enlargement of organs and the manifestation of constitutional symptoms. Numerous studies have provided evidence indicating that the pathogenesis of these diseases involves the dysregulation of the immune system and the presence of chronic inflammation, both of which are significant factors. Lately, the treatment of cancer including hematological malignancy has progressed on the agents aiming for the immune system, cytokine environment, immunotherapy agents, and targeted immune therapy. Immune checkpoints are the molecules that regulate T cell function in the tumor microenvironment (TME). The first line of primary immune checkpoints are programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Immune checkpoint inhibitor therapy (ICIT) exerts its anti-tumor actions by blocking the inhibitory pathways in T cells and has reformed cancer treatment. Despite the impressive clinical success of ICIT, tumor internal resistance poses a challenge for oncologists leading to a low response rate in solid tumors and hematological malignancies. A Phase II trial on nivolumab for patients with post-essential thrombocythemia myelofibrosis, primary myelofibrosis, or post-polycythemia myelofibrosis was performed (Identifier: NCT02421354). This trial tested the efficacy of a PD-1 blockade agent, namely nivolumab, but was terminated prematurely due to adverse events and lack of efficacy. A multicenter, Phase II, single-arm open-label study was conducted including pembrolizumab in patients with primary thrombocythemia, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib. This study showed that pembrolizumab treatment did not have many adverse events, but there were no pertinent clinical responses hence it was terminated after the first stage was completed. To avail the benefits from immunotherapy, the paradigm has shifted to new immune checkpoints in the TME such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain immunoglobulin-containing suppressor of T cell activation (VISTA), and human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) forming the basis of next-generation ICIT. The primary aim of this article is to underscore and elucidate the significance of next-generation ICIT in the context of MPN. Specifically, we aim to explore the potential of monoclonal antibodies as targeted immunotherapy and the development of vaccines targeting specific MPN epitopes, with the intent of augmenting tumor-related immune responses. It is anticipated that these therapeutic modalities rooted in immunotherapy will not only expand but also enhance the existing treatment regimens for patients afflicted with MPN. Preliminary studies from our laboratory showed over-expressed MDSC and over-expressed VISTA in MDSC, and in progenitor and immune cells directing the need for more clinical trials using next-generation ICI in the treatment of MPN.

Amyloidoma and Plasmacytoma Presented as a Solitary Lung Nodule in a Patient of Multiple Myeloma With AL-Amyloidosis: A Case Report and Review of Literature.

Nodular amyloidoma in the lungs is a rare entity, also the occurrence of extramedullary plasmacytoma (EMP) in the lungs is rare. To have concomitant EMP and amyloidoma presented as a single lung mass is even rarer. There was only one similar case reported in the abstract form previously. Our case did not respond to many novel chemotherapy agents, suggesting that this combination of amyloidoma and plasmacytoma belonged to a poor prognosis entity, requiring different treatment modalities, such as early bone marrow transplantation or CART (chimeric antigen receptors T) therapy.

The Role of Dual Antiplatelet Therapy (DAPT) vs Surgery in a Case of Moyamoya Disease: A Case Report and Review of the Literature.

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by non-atherosclerotic and non-inflammatory progressive narrowing of the intracranial part of the carotid artery and its proximal branches. The disease process is commonly associated with the development of weak, dilated collateral blood vessels at the base of the brain. This gives it a classic smoky appearance on cerebral angiograms and hence the name "Moyamoya" which means "puff of smoke" in Japanese. When a patient has similar vasculopathy in the setting of another disease then it is known as Moyamoya syndrome (MMS). The associated diseases are sickle cell anemia, neurofibromatosis, long-standing diabetes, uncontrolled hypertension, or chemotherapy. Despite being known as a disease of the East Asian population, the disease is no longer exclusive to Asians, as evidenced by the rising incidence among non-Asian groups such as Caucasians, Hispanics, and African Americans. Patients can remain asymptomatic or present with ischemic or hemorrhagic stroke, headache, seizures, or recurrent transient ischemic attacks. Conventional cerebral angiography is considered the gold standard for diagnosing MMD. Treatment may be supportive, medical, or surgical. We present the case of a 42-year-old African American woman with several comorbidities who presented with sudden onset of ischemic stroke and upon further workup was found to have MMD. Equally important is to identify the most effective therapeutic approaches based on individual patients to achieve better clinical outcomes. Our case report highlights the importance of surgery in symptomatic MMD with a lack of supporting evidence indicating the benefits of dual antiplatelet therapy (DAPT).

Workup and Management of Recurrent Attacks of Post-bariatric Hypoglycemia in a Patient With Non-alcoholic Steatohepatitis.

Bariatric surgery is an established treatment option for patients with non-alcoholic fatty liver disease (NAFLD) as well as non-alcoholic steatohepatitis (NASH) and is said to effectively reduce hepatic inflammation as well as steatosis in these patients. However, bariatric surgery is associated with multiple complications, including nutritional deficiencies, malnutrition, post-bariatric hypoglycemia (PBH), anastomotic leaks, and bowel strictures. This case report describes a rare but significant complication of post-bariatric surgery hypoglycemia in a patient with NASH, which started almost six months after Roux-en-Y gastric bypass (RYGB) surgery. This 55-year-old male patient presented with recurrent episodes of severe hypoglycemia, which, on further work-up, were found to be predominantly nocturnal as well as occurring two to three hours after meals. We report the successful treatment of the patient with an unconventional approach using nifedipine and acarbose. Our findings emphasize the importance of careful evaluation of patients who have undergone bariatric surgery, as this complication can occur as early as six months following the bariatric surgery as well as several years after the surgery. Our case report highlights the need for early recognition, relevant workup, and appropriate management of resistant hypoglycemic events using calcium channel blockers and acarbose, thus adding to the existing literature on this topic.

Chemotherapy and Immune Checkpoint Inhibitors in a Case of SMARCA4-dUT: A Case Report and Review of Literature.

SMARCA4-deficient undifferentiated tumors (SMARCA4-dUT) are infrequently occurring aggressive neoplasms found predominantly in young male smokers. These tumors are distinguished by the loss of expression of Brahma-related gene 1 (BRG1) due to a deactivating mutation of SMARCA4. Immunophenotype can be variable but characteristically lack the expression of BRG1. SMARCA4-dUT has a poor prognosis and generally progresses or recurs. The median survival is around 6 months. Here, we report a case of a 36-year-old male smoker who presents with multiple right-sided lung masses. The patient was found to have a loss of SMARAC4 and SMARCA2 along with the absence of markers of vascular, melanocytic, lymphoid, keratin, or myogenic origin. Tumor size was reduced significantly after 3 cycles of carboplatin and 1 cycle of pembrolizumab. From reviewing the literature and the clinical course in our case, we suggest combination chemotherapy plus immune checkpoint inhibitor (ICI) therapy to be the first choice of therapy for treating SMARCA4-dUT of lungs. Further research and studies are needed to evaluate the response to ICI therapy alone or combination therapy (chemotherapy plus ICI).

Smoking-Related Interstitial Fibrosis (SRIF) in Patients Presenting With Diffuse Parenchymal Lung Disease.

OBJECTIVES: To describe the clinical, radiologic, and pathologic findings in cases where smoking-related interstitial fibrosis (SRIF) was diagnosed in surgical lung biopsy specimens from patients with clinical and imaging features of diffuse parenchymal lung disease (DPLD). METHODS: Cases were included in this study if patients had clinical and imaging evidence of DPLD and surgical lung biopsy specimens revealed SRIF. A dedicated multidisciplinary conference was held to correlate clinical, radiologic, and pathologic findings. RESULTS: Six cases met inclusion criteria; all six (five women/one man, aged 42-57 years, mean age 47 years) were either current smokers (five of six) or ex-smokers (one of six) and were evaluated for respiratory symptoms and abnormal pulmonary function tests, most commonly reduced forced vital capacity (n = 3) and diffusing capacity for carbon monoxide (n = 6). The most common imaging abnormalities were bilateral ground-glass opacities, which correlated with histopathologic SRIF. Follow-up of up to 10 years showed stable or improved clinical symptoms, pulmonary function tests, and radiologic findings with smoking cessation (three patients) or a decrease in smoking (three patients). No specific treatments were given, and those treated with empiric corticosteroid tapers did not show discernible responses. CONCLUSIONS: SRIF can present as clinically meaningful diffuse parenchymal lung disease in relatively young heavy smokers, characterized by bilateral ground-glass opacities and a stable clinical course.

Biochemical and structural insights into SARS-CoV-2 polyprotein processing by Mpro.

SARS-CoV-2, a human coronavirus, is the causative agent of the COVID-19 pandemic. Its genome is translated into two large polyproteins subsequently cleaved by viral papain-like protease and main protease (Mpro). Polyprotein processing is essential yet incompletely understood. We studied Mpro-mediated processing of the nsp7-11 polyprotein, whose mature products include cofactors of the viral replicase, and identified the order of cleavages. Integrative modeling based on mass spectrometry (including hydrogen-deuterium exchange and cross-linking) and x-ray scattering yielded a nsp7-11 structural ensemble, demonstrating shared secondary structural elements with individual nsps. The pattern of cross-links and HDX footprint of the C145A Mpro and nsp7-11 complex demonstrate preferential binding of the enzyme active site to the polyprotein junction sites and additional transient contacts to help orient the enzyme on its substrate for cleavage. Last, proteolysis assays were used to characterize the effect of inhibitors/binders on Mpro processing/inhibition using the nsp7-11 polyprotein as substrate.

Prospective cohort of cryobiopsy in interstitial lung diseases: a single center experience.

RATIONALE: Transbronchial cryobiopsy has been increasingly used to diagnose interstitial lung diseases. However, there is uncertainty regarding its accuracy and risks, mainly due to a paucity of prospective or randomized trials comparing cryobiopsy to surgical biopsy. OBJECTIVES: To evaluate the diagnostic yield and complications of cryobiopsy in patients selected by multidisciplinary discussion. METHODS: This was a prospective cohort from 2017 to 2019. We included consecutive patients with suspected interstitial lung diseases being considered for lung biopsy presented at our multidisciplinary meeting. MEASUREMENTS AND MAIN RESULTS: Of 112 patients, we recommended no biopsy in 31, transbronchial forceps biopsy in 16, cryobiopsy in 54 and surgical biopsy in 11. By the end of the study, 34 patients had had cryobiopsy and 24 patients, surgical biopsy. Overall pathologic and multidisciplinary diagnostic yield of cryobiopsy was 47.1% and 61.8%, respectively. The yield increased over time for both pathologic (year 1: 28.6%, year 2: 54.5%, year 3: 66.7%, p = 0.161) and multidisciplinary (year 1: 50%, year 2: 63.6%, year 3: 77.8%, p = 0.412) diagnosis. Overall rate of grade 4 bleeding after cryobiopsy was 11.8%. Cryobiopsy required less chest tube placement (11.8% vs 100%, p < 0.001) and less hospitalizations compared to surgical biopsy (26.5% vs 95.7%, p < 0.001), but hospitalized patients had a longer median hospital stay (2 days vs 1 day, p = 0.004). CONCLUSIONS: Diagnostic yield of cryobiopsy increased over time but the overall grade 4 bleeding rate was 11.8%.

SMARCA4-Deficient Undifferentiated Tumor of Lung Mass-A Rare Tumor With the Rarer Occurrence of Brain Metastasis: A Case Report and Review of the Literature.

Among thoracic tumors, these include subsets of a relatively newly described and yet to be fully characterized tumor entity: SMARCA4-deficient Undifferentiated Tumor (SMARCA4-dUT). Mutations of SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene and loss of BRG1 (Brahma-related gene-1) is the underlying molecular hallmark of SMARCA4-dUT. They mostly involved the mediastinum, lung, and/or pleura showing undifferentiated round cell or rhabdoid morphology associated with aggressive clinical behavior. The pathogenesis of these tumors is still not clear. Morphologically, SMARAC4-dUT is differentiated from SMARCA4-dNSCLC by the presence of squamous and solid components in the latter. Immunohistochemically SMARC4-dUT has characteristic loss of SMARCA4 and SMARCA2 and strong expression of SOX2, CD34, and SALL4. Common sites of metastasis include lymph nodes, bones, and adrenal glands but rarely brain metastasis. We present a unique and rare case of a 76-year-old male with a right lung mass with documented pathology of SMARCA4-dUT and was found to have multiple brain metastases.