Samir S. Makani

Surgical Management of Endobronchial Inflammatory Myofibroblastic Tumors

BACKGROUND Endobronchial myofibroblastic tumors are neoplasms composed of clonal populations of smooth muscle cells and a variable lymphocytic inflammatory component. They represent a challenge with respect to diagnosis, classification, and surgical resection due to their infrequent occurrence. METHODS We retrospectively reviewed our experience with patients who had myofibroblastic tumors in the major airways over a 15-year period, in order to understand the incidence, natural biology, treatment, and long-term outcome of individuals with this type of neoplasm in an endobronchial location. RESULTS Between 1995 and 2010, 11 patients (9 female, 2 male) underwent surgical resection of a myofibroblastic tumor arising within the tracheobronchial tree. The mean age was 39.6 years (range, 22.3 to 53.6 years). All patients were symptomatic, with cough and dyspnea as the most common presenting complaints. Rigid bronchoscopy with endobronchial biopsy was utilized to establish the diagnosis in 9 of 11 patients. Laser-mechanical debulking was performed to relieve airway obstruction prior to operation in 10 of 11 patients. Because of wide submucosal infiltration of the neoplasms, surgical resection for complete removal was required for all individuals. Tracheal resection was performed in 3 patients, carinal resection in 1 patient, mainstem bronchial resection in 2 patients, sleeve resection in 3 patients, bilobectomy in 1 patient, and right lower lobectomy in 1 patient. Resection with tumor-free margins was accomplished in all patients. Mean tumor size was 2.3 cm (range, 1.5 to 3.5 cm). There were no operative deaths, with all patients alive and disease-free at a mean of 6.1 ± 3.7 years. CONCLUSIONS Complete surgical resection of inflammatory myofibroblastic tumors presenting in a major airway is safe and leads to excellent survival for patients with this uncommon disease.

CD45RB ligation inhibits allergic pulmonary inflammation by inducing CTLA4 transcription.

CD45, a type I transmembrane protein tyrosine phosphatase expressed on nucleated hemopoietic cells, is prominently involved in T cell activation. Ligation of CD45RB isoforms has been associated with transplant tolerance. A recent genotyping analysis of asthma indicates a correlation with CD45 splicing. In this study, we administered an anti-CD45RB mAb (aCD45) in a murine model of allergic asthma and found that CD45RB ligation decreases allergic responses. aCD45 decreases allergen-induced pulmonary eosinophilia, bronchoalveolar lavage IL-13, IgE, and airway responses. Also, aCD45 increases the expression of CTLA4, a negative regulator of T cell activation. Furthermore, CD45RB signals no longer decrease allergic inflammation when CTLA4 is inhibited. These data support a role for CTLA4 in CD45RB-mediated inhibition of allergic inflammation. T cells and splenocytes stimulated with aCD45 exhibited increased CTLA4 levels, and analysis of CTLA4 promoter gene constructs identified a CD45RB-inducible regulatory region localized from −335 to –62 bp relative to the transcription start site. Together, these findings suggest that CD45RB signals mediate a novel role in the modulation of allergic inflammation, orchestrated by T cells through induction of CTLA4 transcription.

Immunomodulation of allergic responses by targeting costimulatory molecules

Purpose of review This review focuses on putative targets, including costimulatory and additional pathways involving T regulatory cells, that may be critical for modifying allergic responses. Recent findings Multiple costimulatory signals including CD28/CTLA4: CD80/CD86, ICOS: ICOSL, OX40:OX40L and PD-1: PD-L1/PD-L2 have been identified and implicated in the regulation of immune disorders. Recent studies indicate that T regulatory cells may also suppress T cell costimulation by the secretion of TGF-β and IL-10, suggesting an important role of T regulatory cells in the regulation of allergic disorders. Summary Immune-mediated disorders, including allergic diseases, have been increasing in prevalence. Unravelling these immune pathways may suggest new targets for immunomodulation.

Lung cancer screening, version 3.2018

Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. Early detection of lung cancer is an important opportunity for decreasing mortality. Data support using low-dose computed tomography (LDCT) of the chest to screen select patients who are at high risk for lung cancer. Lung screening is covered under the Affordable Care Act for individuals with high-risk factors. The Centers for Medicare & Medicaid Services (CMS) covers annual screening LDCT for appropriate Medicare beneficiaries at high risk for lung cancer if they also receive counseling and participate in shared decision-making before screening. The complete version of the NCCN Guidelines for Lung Cancer Screening provides recommendations for initial and subsequent LDCT screening and provides more detail about LDCT screening. This manuscript focuses on identifying patients at high risk for lung cancer who are candidates for LDCT of the chest and on evaluating initial screening findings.

Comparison of outcomes following stereotactic body radiotherapy for non-small cell lung cancer in patients with and without pathological confirmation.

Purpose/objective: Treatment of presumed early-stage lung cancer with definitive radiation therapy in the absence of a pathologically confirmed specimen frequently occurs. However, it is not well described in the literature, and there are few North American series reporting on this patient population. We report outcomes in patients treated with stereotactic body radiotherapy (SBRT) for presumed lung cancer and compare them to outcomes in patients treated with SBRT with pathologically confirmed non-small cell lung cancer (NSCLC). Materials/methods: This study is based on a retrospective review of 55 patients with presumed or confirmed lung cancer: 23 patients had nondiagnostic or absent pathologic specimens while 32 patients had pathologically confirmed NSCLC. All patients had hypermetabolic primary lesions on a positron emission tomography (PET) or PET/computed tomography (CT) scan. SBRT was delivered as 48–56 Gy in four to five fractions via a four-dimensional CT treatment plan. Results: Of the patients without pathological confirmation, the mean age was 78 (range 63–89 years) and 17 (74%) were men. The mean tumor size was 2.5 cm (range 1.0–5.1). Reasons for not having confirmed pathologic diagnosis included indeterminate biopsy specimen or an inability to tolerate a biopsy procedure due to poor respiratory status. SBRT was chosen due to noncandidacy for surgery in 17 patients (74%) or patient refusal of surgery in six (26%). Median follow up was 24.2 months (range 1.9–64.6): 2 of the 23 patients (8.7%) had local failure at the site of SBRT and 3 (13%) had regional failure. The actuarial 12-month overall survival was 83%. The median overall survival was 30.2 months. At last follow up, 12 patients (52%) were alive up to 64.6 months after treatment. SBRT was tolerated well in this series. Acute toxicity was noted in two patients (8.7%) and chronic toxicity in three (13%). These patient characteristics and results were shown to be similar to the 32 patients with pathologically confirmed NSCLC. On Kaplan–Meier analysis, there was no significant difference (p = 0.27) in overall survival between patients with pathologically confirmed NSCLC and those with presumed lung cancer (which was deemed most likely NSCLC). Conclusion: While biopsy confirmation remains a goal in the workup of suspected NSCLC, SBRT without pathologic confirmation may represent a safe and effective option for the treatment of presumed NSCLC among patients who cannot tolerate or refuse surgery.

Simulation for Skills-based Education in Pulmonary and Critical Care Medicine

The clinical practice of pulmonary and critical care medicine requires procedural competence in many technical domains, including vascular access, airway management, basic and advanced bronchoscopy, pleural procedures, and critical care ultrasonography. Simulation provides opportunities for standardized training and assessment in procedures without placing patients at undue risk. A growing body of literature supports the use and effectiveness of low-fidelity and high-fidelity simulators for procedural training and assessment. In this manuscript by the Skills-based Working Group of the American Thoracic Society Education Committee, we describe the background, available technology, and current evidence related to simulation-based skills training within pulmonary and critical care medicine. We outline working group recommendations for key procedural domains.

Cellular Expression of PD-L1 in the Peripheral Blood of Lung Cancer Patients is Associated with Worse Survival

Background: Lung cancer treatment has become increasingly dependent upon invasive biopsies to profile tumors for personalized therapy. Recently, tumor expression of programmed death-ligand 1 (PD-L1) has gained interest as a potential predictor of response to immunotherapy. Circulating biomarkers present an opportunity for tumor profiling without the risks of invasive procedures. We characterized PD-L1 expression within populations of nucleated cells in the peripheral blood of lung cancer patients in hopes of expanding the role of liquid biopsy in this setting. Methods: Peripheral blood samples from a multi-institutional prospective study of patients with clinical diagnosis of lung cancer were subjected to cytomorphometric and immunohistochemical evaluation using single-cell, automated slide-based, digital pathology. PD-L1 expression was determined by immunofluorescence. Results: PD-L1 expression was detected within peripheral circulating cells associated with malignancy (CCAM) in 26 of 112 (23%) non–small cell lung cancer patients. Two distinct populations of nucleated, nonhematolymphoid, PD-L1–expressing cells were identified; cytokeratin positive (CK+, PD-L1+, CD45−) and cytokeratin negative (CK−, PD-L1+, CD45−) cells, both with cytomorphometric features (size, nuclear-to-cytoplasm ratio) consistent with tumor cells. Patients with >1.1 PD-L1(+) cell/mL (n = 14/112) experienced worse overall survival than patients with ≤1.1 PD-L1(+) cell/mL (2-year OS: 31.2% vs. 78.8%, P = 0.00159). In a Cox model adjusting for stage, high PD-L1(+) cell burden remained a significant predictor of mortality (HR = 3.85; 95% confidence interval, 1.64–9.09; P = 0.002). Conclusions: PD-L1 expression is detectable in two distinct cell populations in the peripheral blood of lung cancer patients and is associated with worse survival. Impact: These findings could represent a step forward in the development of minimally invasive liquid biopsies for the profiling of tumors. Cancer Epidemiol Biomarkers Prev; 26(7); 1139–45. ©2017 AACR.

Pulmonary langerhans cell histiocytosis diagnosed in a cervical lymph node: a case report.

BACKGROUND Pulmonary Langerhans cell histiocytosis (PLCH) is usually confined to the lungs and is therefore an unexpected finding in a cervical lymph node. CASE A 52-year-old male with a 40-pack-year smoking history presented to our clinic with cough, fever and cervical lymphadenopathy. Chest computed tomography (CT) showed bilateral pulmonary nodules and enlarged mediastinal lymph nodes, worrisome for an infectious or malignant process. Bronchioloalveolar lavage was nondiagnostic. Fine needle aspiration cytology of the enlarged cervical lymph node revealed atypical histiocytoid cells, suspicious for malignancy. Immunohistochemistry revealed CD1a- and S-100-positive Langerhans cells. These findings, along with the patients extensive smoking history and characteristic radiographic nodules, favored a diagnosis of PLCH with cervical lymph node involvement. The patient was advised to cease smoking, and no therapy was administered. Months later, follow-up chest CT showed spontaneous resolution of the lung nodules. CONCLUSION The demonstration of Langerhans cells by immunohistochemical staining of CD1a and S-100 on a fine needle aspiration cell block is a useful diagnostic adjunct. In this case, definitive cytology for Langerhans cells in the appropriate clinical and radiologic setting allowed us to arrive at the correct diagnosis of PLCH in a minimally invasive manner.

New Costimulatory Families: Signaling Lymphocytic Activation Molecule in Adaptive Allergic Responses

The generation of an allergic immune response requires at least two signals for complete activation of T cells. Costimulatory molecules are integral to the second signal. In this review, we analyze the costimulatory molecule signaling lymphocytic activation molecule (SLAM) and other recently described SLAM family members. We highlight recent findings that position SLAM as critical for allergic inflammation and its role in modulation of cytokine secretion. Furthermore, a possible role of SLAM as a link between the adaptive and innate immune response is also discussed. Understanding the role of costimulatory molecules, including SLAM and SLAM family members, may elucidate mechanisms involved in the allergic immune response, and suggest potential therapeutic opportunities.

Spontaneous Pneumothorax Complicating Chronic Hepatic Hydrothorax: Successful Treatment by Small Bore Chest Tube.

To the Editor: To our knowledge, spontaneous pneumothorax (PTX) complicating hepatic pleural effusion has never been described. Here we report spontaneous PTX secondary to emphysematous bleb rupture that complicated hepatohydrothorax. Historically, performing a tube thoracostomy in the setting of hepatohydrothorax has not been recommended. This case demonstrates successful management of hepatohydropneumothorax with a small bore chest tube. A 62-year-old man with cirrhosis and chronic pleural effusion, presumed to be hepatic hydrothorax, presented with acute dyspnea on exertion. He reported dietary indiscretions, with increases in abdominal girth and lower extremity edema, and a new productive cough. Vital signs: 101.51F, respiratory rate=18, heart rate=110, blood pressure=128/73, and O2 sat 94% on 4L n.c. He was dyspneic with minimal exertion and had dullness to percussion 2/3 up his posterior right chest wall. Labs were significant for white blood cell count=9.4/mm, hemoglobin= 16.4g/dL, platelets=94,000/ mm, albumin=2.6g/dL, and international normalized ratio= 1.4. chest X-ray showed PTX superimposed on chronic pleural effusion (Figs. 1A, B). Chest computed tomography demonstrated apical emphysematous changes, large right pleural effusion displacing the diaphragm, and right PTX with leftward mediastinal shift (Figs. 1C, D). He was prepped for diagnostic thoracentesis to rule-out empyema; however, he suddenly became more hypoxic and tachycardic, raising concern for tension physiology. A 14-Fr thoracostomy tube was placed with immediate return of air and 4L of serous fluid. Oxygen saturation and tachycardia improved immediately. Pleural fluid studies were consistent with a transudate, and cultures were negative. Diagnosis of secondary, spontaneous PTX due to emphysema was made. An intermittent air leak persisted, but he was able to tolerate water seal drainage without lung collapse. Pleural fluid output remained 3.6 to 6L/d, thus aggressive diuresis and albumin transfusions were used to decrease fluid accumulation and prevent hypotension. On hospital day (HD) 7 the air leak resolved and output dropped to 600mL/d. The tube was clamped on HD 8 and removed on HD 9. Repeat chest X-ray noted PTX resolution with mild pleural fluid reaccumulation. Electrolytes and creatinine were stable throughout. Hepatic hydrothorax is a transudative pleural effusion >500mL in a patient with portal hypertension, in the absence of other cardiopulmonary diseases. It occurs in 5% to 10% of patients with advanced cirrhosis. Salt restriction and diuretics are the main stay of management, but liver transplantation remains the only definitive therapy.1 Chest tube placement for hepatic hydrothorax is contraindicated due to an exceptionally high rate of complications. A small, retrospective review demonstrated at least one complication in 94% of patients with chest tubes placed for hepatic hydrothorax, and 35% mortality at 3 months.2 Renal failure, encephalopathy, and electrolyte derangements are the most common complications due to massive and prolonged fluid loss. Video-assisted thoracic surgery repair and pleurodesis have been described in hepatic hydrothorax as a bridge to transplant, but not for the management of PTX.1 Both of these techniques have high rates of failure, as it is difficult to achieve pleurodesis due to rapid fluid accumulation and lack of inflamed pleural surfaces. A small case series described the simultaneous use of peritoneal catheter placement with pleurodesis to slow fluid reaccumulation. This was successful, but 4 of the 5 patients required hospitalizations of 3 weeks or longer.3 Another case report described the use of continuous positive airway pressure (CPAP) to increase intrathoracic pressure, thus lowering the peritoneal to pleural pressure gradient.4 This would not have been a good option in our patient, as the increase in transpulmonary pressure may have encouraged his Disclosure: L.E.C.A. salary was supported by VA Career Development Award (CDA)-2, award #1IK2BX001313, PI Crotty Alexander, from the US Department of Veterans Affairs, Biomedical Laboratory Research and Development (BLR&D) Program, and an American Heart Association, Beginning Grant-in-Aid, #16BGIA 27790079, PI Crotty Alexander. LE Crotty Alexander is the corresponding author. The remaining authors declare no conflict of interest or other disclosures. DOI: 10.1097/LBR.0000000000000324