RET gene fusion and emergent Selpercatinib resistance in a calcitonin-rich neuroendocrine carcinoma: a case report.

Metastatic lung neuroendocrine carcinomas provide diagnostic challenges in identifying the cell of origin. High level calcitonin expression is not pathognomonic for medullary thyroid cancer. Tumor mutation analysis may provide essential clues regarding tissue origin and treatment targets. Oncogenic RET gene fusions have been identified in non-small cell lung cancer and non-medullary thyroid cancers, whereas RET point mutations are the key genetic finding in both inherited and sporadic MTC. Patients who receive radiation for the treatment of other cancers have an increased risk of developing a second malignancy, including a neuroendocrine carcinoma. Herein, we present a case of calcitonin-rich neuroendocrine carcinoma emerging on a background of prior radiation and chemotherapy for the treatment of Hodgkin's disease. Identification of a RET gene rearrangement (KIF5B-RET) led to initial successful treatment with selpercatinib, with eventual resistance associated with an activating mutation involving the MEK1 protein (MAP2K1 p. E102-I103 del) that led to relapse and progression of the disease.

Assessment of Advanced Diagnostic Bronchoscopy Outcomes for Peripheral Lung Lesions: A Delphi Consensus Definition of Diagnostic Yield and Recommendations for Patient-centered Study Designs. An Official American Thoracic Society/American College of Chest Physicians Research Statement.

Background: Advanced diagnostic bronchoscopy targeting the lung periphery has developed at an accelerated pace over the last two decades, whereas evidence to support introduction of innovative technologies has been variable and deficient. A major gap relates to variable reporting of diagnostic yield, in addition to limited comparative studies. Objectives: To develop a research framework to standardize the evaluation of advanced diagnostic bronchoscopy techniques for peripheral lung lesions. Specifically, we aimed for consensus on a robust definition of diagnostic yield, and we propose potential study designs at various stages of technology development. Methods: Panel members were selected for their diverse expertise. Workgroup meetings were conducted in virtual or hybrid format. The cochairs subsequently developed summary statements, with voting proceeding according to a modified Delphi process. The statement was cosponsored by the American Thoracic Society and the American College of Chest Physicians. Results: Consensus was reached on 15 statements on the definition of diagnostic outcomes and study designs. A strict definition of diagnostic yield should be used, and studies should be reported according to the STARD (Standards for Reporting Diagnostic Accuracy Studies) guidelines. Clinical or radiographic follow-up may be incorporated into the reference standard definition but should not be used to calculate diagnostic yield from the procedural encounter. Methodologically robust comparative studies, with incorporation of patient-reported outcomes, are needed to adequately assess and validate minimally invasive diagnostic technologies targeting the lung periphery. Conclusions: This American Thoracic Society/American College of Chest Physicians statement aims to provide a research framework that allows greater standardization of device validation efforts through clearly defined diagnostic outcomes and robust study designs. High-quality studies, both industry and publicly funded, can support subsequent health economic analyses and guide implementation decisions in various healthcare settings.

Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and Immune Cell Compartment Tracking in Lung Cancer.

PURPOSE: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE). EXPERIMENTAL DESIGN: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. RESULTS: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE. CONCLUSIONS: Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.

Ablative radiation alone in stage I lung cancer produces an adaptive systemic immune response: insights from a prospective stud.

Stereotactic ablative body radiation (SABR) delivers high rates of local control in early-stage non-small cell lung cancer (NSCLC); however, systemic immune effects are poorly understood. Here, we evaluate the early pathologic and immunologic effects of SABR. Blood/core-needle tumor biopsies were collected from six patients with stage I NSCLC before and 5-7 days after SABR (48 Gy/4 or 50 Gy/5 fractions). Serial blood was collected up to 1-year post-SABR. We used immunohistochemistry to evaluate pathological changes, immune-cell populations (CD8, FoxP3), and PD-L1/PD-1 expression within the tumor. We evaluated T-cell receptor (TCR) profile changes in the tumor using TCR sequencing. We used the MANAFEST (Mutation-Associated Neoantigen Functional Expansion of Specific T-cells) assay to detect peripheral neoantigen-specific T-cell responses and dynamics. At a median follow-up of 40 months, 83% of patients (n=5) were alive without tumor progression. Early post-SABR biopsies showed viable tumor and similar distribution of immune-cell populations as compared with baseline samples. Core-needle samples proved insufficient to detect population-level TCR-repertoire changes. Functionally, neoantigen-specific T-cells were detected in the blood prior to SABR. A subset of these patients had a transient increase in the frequency of neoantigen-specific T-cells between 1 week and 3-6 months after SABR. SABR alone could induce a delayed, transient neoantigen-specific T-cell immunologic response in patients with stage I NSCLC.

Intravenous BCG vaccination reduces SARS-CoV-2 severity and promotes extensive reprogramming of lung immune cells.

Bacillus Calmette-Guérin (BCG) confers heterologous immune protection against viral infections and has been proposed as vaccine against SARS-CoV-2 (SCV2). Here, we tested intravenous BCG vaccination against COVID-19 using the golden Syrian hamster model. BCG vaccination conferred a modest reduction on lung SCV2 viral load, bronchopneumonia scores, and weight loss, accompanied by a reversal of SCV2-mediated T cell lymphopenia, and reduced lung granulocytes. BCG uniquely recruited immunoglobulin-producing plasma cells to the lung suggesting accelerated local antibody production. BCG vaccination also recruited elevated levels of Th1, Th17, Treg, CTLs, and Tmem cells, with a transcriptional shift away from exhaustion markers and toward antigen presentation and repair. Similarly, BCG enhanced recruitment of alveolar macrophages and reduced key interstitial macrophage subsets, that show reduced IFN-associated gene expression. Our observations indicate that BCG vaccination protects against SCV2 immunopathology by promoting early lung immunoglobulin production and immunotolerizing transcriptional patterns among key myeloid and lymphoid populations.

Elucidating the heterogeneity of immunotherapy response and immune-related toxicities by longitudinal ctDNA and immune cell compartment tracking in lung cancer.

Purpose: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect -especially in the setting of stable disease-call for the development of molecularly-informed real-time minimally invasive predictive biomarkers. In addition to capturing tumor regression, liquid biopsies may be informative in evaluating immune-related adverse events (irAEs). Experimental design: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response for each patient. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. Results: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank p=0.0003) and overall survival (log-rank p=0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, peripheral blood T-cell repertoire reshaping, assessed by significant TCR clonotypic expansions and regressions were noted on-treatment. Conclusions: Molecular responses assist with interpretation of heterogeneous clinical responses especially for patients with stable disease. Our complementary assessment of the tumor and immune compartments by liquid biopsies provides an approach for monitoring of clinical benefit and immune-related toxicities for patients with NSCLC receiving immunotherapy. Statement of translational relevance: Longitudinal dynamic changes in cell-free tumor load and reshaping of the peripheral T-cell repertoire capture clinical outcomes and immune-related toxicities during immunotherapy for patients with non-small cell lung cancer.

Five-Year Clinical Outcomes after Neoadjuvant Nivolumab in Resectable Non-Small Cell Lung Cancer.

PURPOSE: Neoadjuvant anti-PD-1 therapy has shown promise for resectable non-small cell lung cancer (NSCLC). We reported the first phase I/II trial of neoadjuvant nivolumab in resectable NSCLC, finding it to be safe and feasible with encouraging major pathological responses (MPR). We now present 5-year clinical outcomes from this trial, representing to our knowledge, the longest follow-up data for neoadjuvant anti-PD-1 in any cancer type. PATIENTS AND METHODS: Two doses of nivolumab (3 mg/kg) were administered for 4 weeks before surgery to 21 patients with Stage I-IIIA NSCLC. 5-year recurrence-free survival (RFS), overall survival (OS), and associations with MPR and PD-L1, were evaluated. RESULTS: With a median follow-up of 63 months, 5-year RFS and OS rates were 60% and 80%, respectively. The presence of MPR and pre-treatment tumor PD-L1 positivity (TPS ≥1%) each trended toward favorable RFS; HR, 0.61 [95% confidence interval (CI), 0.15-2.44] and HR, 0.36 (95% CI, 0.07-1.85), respectively. At 5-year follow-up, 8 of 9 (89%) patients with MPR were alive and disease-free. There were no cancer-related deaths among patients with MPR. In contrast, 6/11 patients without MPR experienced tumor relapse, and 3 died. CONCLUSIONS: Five-year clinical outcomes for neoadjuvant nivolumab in resectable NSCLC compare favorably with historical outcomes. MPR and PD-L1 positivity trended toward improved RFS, though definitive conclusions are limited by cohort size.

Cytopathology of rare gastric mesenchymal neoplasms: A series of 25 cases and review of literature.

BACKGROUND: Gastrointestinal stromal tumour (GIST) is the most common mesenchymal neoplasm arising in the stomach. However, a number of other rare mesenchymal neoplasms do occur at this anatomic site, which often presents a diagnostic challenge for cytopathologists on endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). Our study aims to selectively present the clinico-radiological and cytopathological characteristics of these rare "non-GIST" neoplasms, as well as their differential diagnoses. MATERIAL AND METHODS: We performed a 20 year retrospective search in the cytopathology database of our two large medical institutions for non-GIST mesenchymal neoplasms arising in the stomach and diagnosed on EUS-FNA. Data regarding the patients' demographics and radiological findings were analysed. All available cytopathology specimens were reviewed. The cytomorphological characteristics and the accompanying immunohistochemical stains, when available, were subsequently analysed. RESULTS: Twenty-five cases of gastric mesenchymal tumours were selectively included in the study after excluding all cases of GIST (n = 113) diagnosed on FNA. These cases included 10 leiomyomas (40%), eight schwannomas (32%), five glomus tumours (20%), one perivascular epithelioid cell neoplasm, and one desmoid tumour. The specimen cellularity was variable and ranged from hypocellular to highly cellular. Most smears were composed of spindle cells with a few showing epithelioid morphology. Cell blocks were available in 20 cases and a range of immunohistochemical ancillary studies were performed. DOG-1, c-KIT, smooth muscle actin (SMA), and S100-protein were the most common immunomarkers done. CONCLUSION: Our study highlights important cytomorphological characteristics of rare mesenchymal neoplasms arising in the stomach. In the appropriate clinical setting and with the help of immunohistochemistry, an accurate diagnosis of these neoplasms can be achieved.

Bronchoalveolar Lavage (BAL) and Pathologic Assessment of Electronic Cigarette or Vaping Product Use-associated Lung Injury (EVALI): The EVALI-BAL Study, A Multicenter Cohort.

BACKGROUND: E-cigarette or vaping-use related acute lung injury (EVALI) is a spectrum of radiographic and histologic patterns consistent with acute to subacute lung injury. However, limited data exist characterizing bronchoalveolar lavage (BAL) findings. The goal of this study is to further define the pathologic findings from BAL and biopsy samples of subjects with EVALI across 7 institutions. METHODS: A multicentered registry of patients admitted with EVALI who underwent flexible bronchoscopy with BAL+/-transbronchial biopsy from July 2019 to April 2021 was compiled for retrospective evaluation from 7 academic institutions throughout the United States. Radiographic and cytopathologic findings and frequencies were correlated with the substance vaped. RESULTS: Data from 21 subjects (42.9% women) who were predominantly White (76.2%) with a median age of 25 years (range, 16 to 68) with EVALI were included in this study. Sixteen patients (76.2%) reported use of tetrahydrocannabinol; the remainder used nicotine. BAL was performed in 19 of the 21 subjects, and transbronchial lung biopsy was performed in 7 subjects. BAL findings revealed neutrophilic predominance (median, 59.5%, range, 3.1 to 98) in most cases. Ten BAL samples demonstrated pulmonary eosinophilia ranging from 0.2% to 49.1% with one subject suggesting a diagnosis of acute eosinophilic pneumonia associated with the use of e-cigarettes. Lipid-laden macrophages were noted in 10 of 15 reports (66.7%). Transbronchial biopsy most frequently demonstrated patterns of organizing pneumonia (57.1%). CONCLUSION: EVALI-associated BAL findings typically demonstrate a spectrum of nonspecific inflammatory changes, including neutrophilia, lipid-laden macrophages, and in some cases eosinophilia.

Safety and Feasibility of a Sheath Cryoprobe for Bronchoscopic Transbronchial Biopsy: The FROSTBITE Trial.

BACKGROUND: Bronchoscopic lung biopsy is typically performed using transbronchial forceps. However, this method is limited by small sample size and presence of crush artifact. Cryobiopsy offers the potential to overcome these limitations with larger artifact-free samples but has not been widely adopted due to concerns over increased rates of bleeding and pneumothorax. A new, smaller 1.1-mm cryoprobe has been developed that operates in a similar fashion to forceps, though the safety profile of this cryoprobe has not yet been prospectively studied. OBJECTIVE: The aim of this study was to investigate the safety of transbronchial biopsy using a novel 1.1-mm cryoprobe. METHODS: This prospective, single-arm study enrolled patients referred for transbronchial biopsy. All procedures were performed using the 1.1-mm cryoprobe with oversheath. The primary outcome was the composite of significant complications related to the cryobiopsy procedure (bleeding Grade ≥3, pneumothorax Grade ≥2, and respiratory failure). Bleeding and pneumothorax were graded according to previously published scales. RESULTS: Fifty participants from two academic medical centers underwent transbronchial cryobiopsy. Indications for biopsy included evaluation of lung transplant allograft (50%), diffuse lung disease (44%), and pulmonary parenchymal lesion (6%). There were two pneumothoraces (4%), neither of which required aspiration or chest tube placement. There were no Grade 3 or 4 bleeding events. Mild bleeding (Grade ≤2) was observed in 25 cases (50%). No complications occurred that met the a priori primary outcome of bleeding Grade ≥3, pneumothorax Grade ≥2, and respiratory failure. CONCLUSIONS: Transbronchial cryobiopsy using a 1.1-mm cryoprobe is feasible with an acceptable safety profile.

Lung Cancer Recurrence Risk Prediction through Integrated Deep Learning Evaluation.

Background: Prognostic risk factors for completely resected stage IA non-small-cell lung cancers (NSCLCs) have advanced minimally over recent decades. Although several biomarkers have been found to be associated with cancer recurrence, their added value to TNM staging and tumor grade are unclear. Methods: Features of preoperative low-dose CT image and histologic findings of hematoxylin- and eosin-stained tissue sections of resected lung tumor specimens were extracted from 182 stage IA NSCLC patients in the National Lung Screening Trial. These features were combined to predict the risk of tumor recurrence or progression through integrated deep learning evaluation (IDLE). Added values of IDLE to TNM staging and tumor grade in progression risk prediction and risk stratification were evaluated. Results: The 5-year AUC of IDLE was 0.817 ± 0.037 as compared to the AUC = 0.561 ± 0.042 and 0.573 ± 0.044 from the TNM stage and tumor grade, respectively. The IDLE score was significantly associated with cancer recurrence (p < 0.0001) even after adjusting for TNM staging and tumor grade. Synergy between chest CT image markers and histological markers was the driving force of the deep learning algorithm to produce a stronger prognostic predictor. Conclusions: Integrating markers from preoperative CT images and pathologist's readings of resected lung specimens through deep learning can improve risk stratification of stage 1A NSCLC patients over TNM staging and tumor grade alone. Our study suggests that combining markers from nonoverlapping platforms can increase the cancer risk prediction accuracy.

Rapidly progressive interstitial lung disease in patients with anti-melanoma differentiation-associated gene 5-positive dermatomyositis: serial changes on HRCT.

BACKGROUND: Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibodies in patients with dermatomyositis are associated with rapidly progressive interstitial lung disease (RP-ILD). Computed tomography (CT) plays a central role in the diagnosis of RP-ILD and may help characterize the temporal changes. METHODS: We report five anti-MDA5-positive dermatomyositis patients with serial CT scans spanning their acute RP-ILD disease course. RESULTS: Our case series highlights the variable imaging pattern that can manifest in this setting, including diffuse alveolar damage and nonspecific interstitial pneumonia patterns. Three patients in our series died within 4 months of their disease onset, whereas the other two patients survived. CONCLUSION: The serial CT changes in anti-MDA5 disease are dynamic and variable; therefore, it is imperative to maintain a broad differential when faced with these HRCT patterns to improve the diagnosis and management of this underrecognized entity.

Dynamic single-cell RNA sequencing reveals BCG vaccination curtails SARS-CoV-2 induced disease severity and lung inflammation.

COVID-19 continues to exact a toll on human health despite the availability of several vaccines. Bacillus Calmette Guérin (BCG) has been shown to confer heterologous immune protection against viral infections including COVID-19 and has been proposed as vaccine against SARS-CoV-2 (SCV2). Here we tested intravenous BCG vaccination against COVID-19 using the golden Syrian hamster model together with immune profiling and single cell RNA sequencing (scRNAseq). We observed that BCG reduced both lung SCV2 viral load and bronchopneumonia. This was accompanied by an increase in lung alveolar macrophages, a reversal of SCV2-mediated T cell lymphopenia, and reduced lung granulocytes. Single cell transcriptome profiling showed that BCG uniquely recruits immunoglobulin-producing plasma cells to the lung suggesting accelerated antibody production. BCG vaccination also recruited elevated levels of Th1, Th17, Treg, CTLs, and Tmem cells, and differentially expressed gene (DEG) analysis showed a transcriptional shift away from exhaustion markers and towards antigen presentation and repair. Similarly, BCG enhanced lung recruitment of alveolar macrophages and reduced key interstitial macrophage subsets, with both cell-types also showing reduced IFN-associated gene expression. Our observations indicate that BCG vaccination protects against SCV2 immunopathology by promoting early lung immunoglobulin production and immunotolerizing transcriptional patterns among key myeloid and lymphoid populations.

Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial.

Mesothelioma is a rare and fatal cancer with limited therapeutic options until the recent approval of combination immune checkpoint blockade. Here we report the results of the phase 2 PrE0505 trial ( NCT02899195 ) of the anti-PD-L1 antibody durvalumab plus platinum-pemetrexed chemotherapy for 55 patients with previously untreated, unresectable pleural mesothelioma. The primary endpoint was overall survival compared to historical control with cisplatin and pemetrexed chemotherapy; secondary and exploratory endpoints included safety, progression-free survival and biomarkers of response. The combination of durvalumab with chemotherapy met the pre-specified primary endpoint, reaching a median survival of 20.4 months versus 12.1 months with historical control. Treatment-emergent adverse events were consistent with known side effects of chemotherapy, and all adverse events due to immunotherapy were grade 2 or lower. Integrated genomic and immune cell repertoire analyses revealed that a higher immunogenic mutation burden coupled with a more diverse T cell repertoire was linked to favorable clinical outcome. Structural genome-wide analyses showed a higher degree of genomic instability in responding tumors of epithelioid histology. Patients with germline alterations in cancer predisposing genes, especially those involved in DNA repair, were more likely to achieve long-term survival. Our findings indicate that concurrent durvalumab with platinum-based chemotherapy has promising clinical activity and that responses are driven by the complex genomic background of malignant pleural mesothelioma.

Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers.

PD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a 'barcode' to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein-Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.

Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.

BACKGROUND: Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis. METHODS: Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression. RESULTS: Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone. CONCLUSIONS: Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).

Renal medullary carcinoma involving serous cavity fluids: a cytomorphologic study of 12 cases.

INTRODUCTION: Renal medullary carcinoma (RMC) is a highly lethal adenocarcinoma with a propensity for widespread metastatic disease in young patients. It is strongly associated with sickle cell trait and shows the loss of SMARCB1 (also known as INI1 or BAF47) protein expression. In the present study, we reviewed a series of 12 patients for whom the cytology specimens played a significant role in patient treatment. MATERIALS AND METHODS: We performed a retrospective case review of patients with a history of RMC from 3 large tertiary care pathology practices. RESULTS: A total of 12 patients were identified with histologically confirmed RMC who had had pleural, pericardial, or urine specimens involved by their disease or had undergone initial kidney fine needle aspiration. Patient age ranged from 13 to 37 years (median, 21.5 years). All 12 patients were black or of African descent, and 10 had a confirmed history of sickle cell trait. Of the 12 patients, 11 (92%) had fluid specimens involved by metastatic tumor at some point in their clinical course, and 4 (33%) had initially presented with pericardial and/or pleural effusions or urine specimens that were positive for malignancy. Cytologic examination predominantly showed fragments of 3-dimensional "tumor balls" with smooth borders, fine pale cytoplasm with vacuolization, and highly pleomorphic nuclei with irregular nuclear membranes and coarse to vesicular chromatin and single prominent nucleoli. CONCLUSIONS: The cytomorphology of RMC involving serous fluids is nonspecific and in keeping with metastatic high-grade adenocarcinoma. In a young patient presenting with no history of malignancy and a pleural or pericardial effusion, triaging the material for ancillary studies and a nuanced assessment of patient history and radiologic findings will be critical.

Chronic immune checkpoint inhibitor pneumonitis.

BACKGROUND: Pneumonitis from immune checkpoint inhibitors (ICI) is a potentially fatal immune-related adverse event (irAE) from antiprogrammed death 1/programmed death ligand 1 immunotherapy. Most cases of ICI pneumonitis improve or resolve with 4-6 weeks of corticosteroid therapy. Herein, we report the incidence, clinicopathological features and management of patients with non-small cell lung cancer (NSCLC) and melanoma who developed chronic ICI pneumonitis that warrants ≥12 weeks of immunosuppression. METHODS: Patients with ICI pneumonitis were identified from institutional databases of ICI-treated patients with advanced melanoma and NSCLC between January 2011 and July 2018. ICI pneumonitis was defined as clinical/radiographic evidence of lung inflammation without alternative diagnoses, adjudicated by a multidisciplinary team. Chronic ICI pneumonitis was defined as pneumonitis that persists or worsens with steroid tapering, and necessitates ≥12 weeks of immunosuppression, after ICI discontinuation. Serial chest CT was used to assess radiological features, and tumor response by Response EvaluationCriteria for Solid Tumors V.1.1. Bronchoalveolar lavage fluid (BALF) samples were assessed by cell differential. Lung biopsy samples were evaluated by H&E staining and multiplex immunofluorescence (mIF), where available. RESULTS: Among 299 patients, 44 developed ICI pneumonitis (NSCLC: 5/205; melanoma: 1/94), and of these, 6 experienced chronic ICI pneumonitis. The overall incidence of chronic ICI pneumonitis was thus 2%. Of those who developed chronic ICI pneumonitis: the majority had NSCLC (5/6), all sustained disease control from ICIs, and none had other concurrent irAEs. Timing of chronic ICI pneumonitis development was variable (range: 0-50 months), and occurred at a median of 12 months post ICI start. Recrudescence of ICI pneumonitis occurred at a median of 6 weeks after initial steroid start (range: 3-12 weeks), with all patients requiring steroid reintroduction when tapered to ≤10 mg prednisone/equivalent. The median total duration of steroids was 37 weeks (range: 16-43+weeks). Re-emergence of radiographic ICI pneumonitis occurred in the same locations on chest CT, in most cases (5/6). All patients who developed chronic ICI pneumonitis had BALF lymphocytosis on cell differential and organising pneumonia on lung biopsy at initial ICI pneumonitis presentation, with persistent BALF lymphocytosis and brisk CD8+ infiltration on mIF at pneumonitis re-emergence during steroid taper. CONCLUSIONS: A subset of patients who develop pneumonitis from ICIs will develop chronic ICI pneumonitis, that warrants long-term immunosuppression of ≥12 weeks, and has distinct clinicopathological features.