Sertraline-Associated Interstitial Lung Disease: A case series and Literature Review.

Sertraline-associated interstitial lung disease (ILD) is a rare entity. A search of the English medical literature retrieved only 9 such cases. We report herein on an additional 12 patients who developed ILD during treatment with sertraline. The patients met the criteria for drug-induced pulmonary toxicity such as exposure to drug, correlation of the drug with clinical symptoms, lung imaging, lung biopsy findings, exclusion of other potential causes and improvement after drug removal. We review the available data and discuss various aspects of this entity. The possibility of drug-induced ILD should be considered in an individual who during treatment with sertraline develops dyspnea, cough, and radiographic findings compatible with ILD. Further epidemiological studies should be conducted to explore the association of sertraline treatment with ILD, and to delineate, substantiate, and broaden our knowledge of this rare entity.

Mucormycosis in lung transplant recipients: A systematic review of the literature and a case series.

BACKGROUND: Mucormycosis is a rare infection in lung transplant recipients (LTR). Our objective was to better define the clinical presentation and optimal management of this frequently lethal infection. METHODS: A systematic review of the literature was performed to identify all published cases of mucormycosis in LTR using PubMed/MEDLINE. These cases were analyzed together with a new case series from our clinic. RESULTS: Literature search yielded 44 articles matching the inclusion criteria, describing 121 cases. Six additional cases were identified from our clinic. Data regarding infection site and outcome were available for a total of 53 patients. The lungs were the most common site of infection (62%), followed by rhinocerebral and disseminated disease. Most cases (78%) developed in the first post-transplant year, with over 40% of them in the first month. Additional risk factors for mucormycosis were identified in over half of the patients. Surgical debridement was uncommon in pulmonary infection (9%). Posaconazole therapy was used in 35% of cases, mostly in combination with amphotericin B. Overall mortality was 32% but varied according to site of infection. CONCLUSION: Mucormycosis in LTRs tends to be an early post-surgical infection, associated with additional risk factors and intensified immunosuppressive states, and most often affects the lungs, where surgical debridement is rarely feasible. Posaconazole as first-line therapy should be further explored.

High Diagnostic Accuracy of Transbronchial Cryobiopsy in Fibrotic Interstitial Lung Diseases Compared to Final Explant Diagnosis.

BACKGROUND: A diagnostic lung biopsy may be required in some cases of fibrotic interstitial lung diseases (ILD). Transbronchial cryobiopsy has been suggested as a possible alternative to surgical lung biopsy. However, previous estimates of its diagnostic yield were not validated compared to the definitive diagnosis in explanted lungs. OBJECTIVES: We aimed to assess the diagnostic accuracy of cryobiopsy in fibrotic ILD patients who subsequently had lung transplantation. METHODS: All 197 patients who underwent lung transplantation at our Center due to fibrotic ILD from January 2010 to May 2018, were screened for the presence of a pre-transplant cryobiopsy. Fourteen patients who underwent cryobiopsy before transplantation were identified. Two expert lung pathologists blindedto the explant diagnoses, independently examined these cryobiopsy specimens to decide if they match guideline criteria for usual interstitial pneumonia (UIP) pattern or an alternative diagnosis. The primary measure was the diagnostic accuracy of cryobiopsy to detect or refute a UIP pattern, as compared to the final explant diagnosis. RESULTS: Median time between cryobiopsy and transplantation was 1.4 years. All 14 cryobiopsy samples contained adequate alveolar tissue. The explant diagnosis of 13/14 patients was UIP. The two pathologists correctly diagnosed or refuted UIP in the cryobiopsy specimen in 12/14 cases (85.7%) and 11/14 cases (78.6%), respectively. The level of diagnostic agreement between pathologists was good (kappa 0.59, p = 0.016). CONCLUSIONS: Compared to the final explant diagnosis, transbronchial cryobiopsy had high diagnostic accuracy and good inter-observer agreement for UIP pattern. These findings support a potential diagnostic role for cryobiopsy in experienced centers.

Rare targetable drivers (RTDs) in non-small cell lung cancer (NSCLC): Outcomes with immune check-point inhibitors (ICPi).

OBJECTIVES: Efficacy of immune check-point inhibitors (ICPi) in NSCLC with rare targetable drivers (RTDs) is largely unknown. MATERIALS AND METHODS: Consecutive patients with NSCLC and RTDs (non-EGFR/ALK, n-82) were selected from the Davidoff Cancer Center database. ORR, PFS, OS with ICPi, OS since advanced disease diagnosis, TMB, MSI, and PD-L1 expression were analyzed; uni- and multivariate PFS and OS analyses were done. OS with ICPi was compared between the RTD cohort and the non-selected NSCLC cohort (n-278). RESULTS: Of 50 tumors tested, 32%, 38%, and 30% were associated with ≥50%, 1-49% and <1% PD-L1 expression, respectively. Median TMB (n-48) comprised 4 muts/Mb (0-57); TMB ≥ 10 muts/Mb was seen in 19% of tumors. Both TMB and PD-L1 expression varied across different RTDs. All the 47 tumors were MSI stable. ORR with ICPi (n-44) was 16%, median PFS was 3.2 months (95% CI, 2.6-5.0), median OS was 16.2 months (95% CI, 8.4-NR). No correlation was seen between OS with ICPi and PD-L1 expression (p > 0.4), TMB (p > 0.8), or RTD type (p > 0.3). In the multivariate analysis, ECOG PS (p-0.005), targeted agents exposure (p-0.005), and ICPi exposure (p-0.04) were the only variables which correlated with OS since advanced disease diagnosis. Median OS since advanced disease diagnosis comprised 32 months (95% CI, 19.9-44.9) and 13 months (95% CI, 6.6-15.9) for patients who were and were not exposed to ICPi, respectively (log-rank test-6.3; p-0.01). In the inter-cohort comparison, for patients matched for ECOG PS (0/1), median OS with ICPi comprised 17.5 months (95% CI, 8.1-NR) and 8.6 months (95% CI, 6.7-NR) for RTD and non-selected patients, respectively (log-rank test-2.4, p-0.1). CONCLUSION: In NSCLC with RTD, ICPi have favorable efficacy and independent impact on OS. NSCLC with RTD is associated with MSI stable status and variable levels of PD-L1 expression and TMB; their predictive value remains to be determined.

Efficacy and safety of trans-bronchial cryo in comparison with forceps biopsy in lung allograft recipients: Analysis of 402 procedures.

BACKGROUND: Trans-bronchial forceps biopsy (TBFB) is the gold standard to establish the presence of allograft rejection or infection after lung transplantation. We aimed to analyze the diagnostic yield and safety of trans-bronchial cryobiopsy (TBCB) in lung allografts. METHODS: Retrospective analysis of 402 TBB procedures in 362 lung recipients was performed between 2011 and 2016. Half of the cases (201) were performed by TBCB and the other half by TBFB. One hundred random slides of TBB specimens from lung allografts were reviewed for artifacts, bleeding, and histological evidence. RESULTS: Both TBB groups were comparable in age, gender distribution, and time following transplantation. Acute rejection was diagnosed in 21.9% of the TBCB group vs 14.9% in the TBFB group (P = .09) and only 2 cases (1%) of nondiagnostic tissue in TBCB group and 4 cases (2%) in TBFB group (P = .685). Complications of pneumothorax and bleeding occurred in 9 (4.5%) vs 8 (4%) and 5 (2.5%) vs 4 (2%) in TBCB vs TBFB groups, respectively. The TBCB specimens were larger than TBFB (average 16.6 vs 6.6 mm2 ; P < .001). Crush and bleeding artifacts were seen in 11 (22%) and 23 (46%) of TBFB, respectively, yet none in TBCB group (P < .001). CONCLUSION: Trans-bronchial cryobiopsy is safe and effective for diagnosis of lung allograft rejection.

ALK-Rearranged Non-Small-Cell Lung Cancer Is Associated With a High Rate of Venous Thromboembolism.

BACKGROUND: Patients with lung cancer are at increased risk for venous thromboembolism (VTE), particularly those receiving chemotherapy. It is estimated that 8% to 15% of patients with advanced non-small-cell lung cancer (NSCLC) experience a VTE in the course of their disease. The incidence in patients with specific molecular subtypes of NSCLC is unknown. We undertook this review to determine the incidence of VTE in patients with ALK (anaplastic lymphoma kinase)-rearranged NSCLC. PATIENTS AND METHODS: We identified all patients with ALK-rearranged NSCLC diagnosed and/or treated at the Princess Margaret Cancer Centre (PM CC) in Canada between July 2012 and January 2015. Retrospective data were extracted from electronic medical records. We then included a validation cohort comprising all consecutive patients with ALK-rearranged NSCLC treated in 2 tertiary centers in Israel. RESULTS: Within the PM CC cohort, of 55 patients with ALK-rearranged NSCLC, at a median follow-up of 22 months, 23 (42%) experienced VTE. Patients with VTE were more likely to be white (P = .006). The occurrence of VTE was associated with a trend toward worse prognosis (overall survival hazard ratio = 2.88, P = .059). Within the validation cohort (n = 43), the VTE rate was 28% at a median follow-up of 13 months. Combining the cohorts (n = 98), the VTE rate was 36%. Patients with VTE were younger (age 52 vs. 58 years, P = .04) and had a worse Eastern Cooperative Oncology Group performance status (P = .04). VTE was associated with shorter overall survival (hazard ratio = 5.71, P = .01). CONCLUSION: The rate of VTE in our ALK-rearranged cohort was 3- to 5-fold higher than previously reported for the general NSCLC population. This warrants confirmation in larger cohorts.

A Harmonization Study for the Use of 22C3 PD-L1 Immunohistochemical Staining on Ventana's Platform.

INTRODUCTION: Immunotherapy is a novel treatment for lung cancer. Pembrolizumab (Merck Sharp and Dohme, Kenilworth, NJ) is a monoclonal antibody against programmed cell death 1 that has been approved for use with NSCLC together with a companion diagnostic by Dako (Carpinteria, CA). Ventana's BenchMark XT (Ventana Medical Systems, Tucson, AZ) is a widely used immunohistochemical (IHC) platform. However, data on its reliability and reproducibility with the 22C3 antibody are scant. METHODS: We performed a comprehensive calibration of 22C3 programmed cell death ligand 1 (PD-L1) staining on the BenchMark XT platform using Dako's prediluted 22C3 anti-PD-L1 primary antibody with two of Ventana's detection systems. Forty-one random cases of NSCLC were then independently evaluated by two pathologists. Each case was scored using Dako- or Ventana-stained slides. The scores obtained with the two 22C3 Ventana assays were compared with those obtained using the Dako 22C3 IHC platform. RESULTS: The Dako IHC platform stratified eight, seven, and 26 cases as being strongly positive, weakly positive, and negative for PD-L1, respectively, whereas 36 of 41 cases (87.8%) had the same results with Ventana's UltraView 22C3 protocol (Pearson's correlation score 0.91, p < 0.0001). Moreover, 35 of 41 cases (85.3%) had the same results with Ventana's OptiView 22C3 protocol (Pearson's correlation score 0.89, p < 0.0001). CONCLUSIONS: The results of this study demonstrate that the same PD-L1 IHC algorithm can be reliably applied to Ventana's BenchMark XT platform. Furthermore, we were able to detect all of the strongly positive cases with high interobserver and intraobserver agreement by using the Ventana platform. These findings suggest that the Ventana platform can be used to stratify patients for pembrolizumab-based immunotherapy.

Successful Rituximab Therapy in Steroid-Resistant, Cryptogenic Organizing Pneumonia: A Case Series.

Cryptogenic organizing pneumonia (COP) is an interstitial lung disease that is usually responsive to corticosteroid treatment. The treatment of COP has not been studied in randomized controlled trials; thus, treatment decisions are based on practice guidelines. We herein present, for the first time, 4 cases of patients with biopsy-proven COP who did not respond to corticosteroids but benefited from rituximab therapy. This report consists of a retrospective case series of patients who experienced steroid-resistant, biopsy-proven COP. Patients included in this case series suffered from acute or chronic COP and did not respond to corticosteroid treatment for a few weeks to months but later responded to rituximab. In a series of 4 patients, 1 patient had a complete radiological and clinical response after rituximab therapy, and the steroids could be gradually tapered. Three patients had a chronic course but had been able to lower steroid dosage or even discontinue the drug after being treated with rituximab. Since 40% of the patients with COP do not respond to or stay dependent on steroids, we think that even the ability to lower the steroid dosage by using rituximab as a steroid-sparing agent with a good safety profile is worth the effort. However, further studies are warranted.

Safety of Cryo-Transbronchial Biopsy in Diffuse Lung Diseases: Analysis of Three Hundred Cases.

BACKGROUND: Transbronchial biopsy (TBB) which is performed with metal forceps (forceps TBB) has been accepted as a useful technique in establishing diagnoses of diffuse lung diseases (DLDs). The use of cryoprobes to obtain alveolar tissue (cryo-TBB) is a new method which is currently used by our institute as well as others with excellent results. OBJECTIVES: To assess the safety of cryo-TBB compared with conventional forceps TBB. METHODS: We performed a retrospective data evaluation of 300 consecutive patients who underwent cryo-TBB between January 2012 and April 2014 and compared them with historical cases treated with forceps TBB between 2010 and 2012. The results of both diagnostic modalities were compared based on pathological reports. The major complications (significant bleeding and pneumothorax) were compared, along with postprocedural hospitalization. RESULTS: Pneumothorax was observed in 15 cases (4.95%) treated with cryo-TBB versus 9 cases (3.15%) treated with forceps TBB, with no significant difference (p = 0.303). The insertion of a chest tube was necessary in 6 (2%) and 4 (1.3%) of the cases having undergone cryo-TBB or forceps TBB, respectively (p = 0.8). In the cryo-TBB group, bleeding was encountered in 16 cases (5.2%), and it occurred in 13 cases (4.5%) of the forceps TBB group, with no significant difference in rates (p = 0.706). Also, there was no significant difference in hospital admission rates between the groups [cryo-TBB: 10 (3.3%); forceps TBB: 4 (1.44%); p = 0.181]. The safety profile of cryo- and forceps TBB remained the same even when stratified according to indications for TBB, i.e. immunocompromised hosts, patients after lung transplantation and those with DLDs. CONCLUSION: In patients with DLDs, cryo-TBB is as safe as forceps TBB.

Histological diagnosis of interstitial lung diseases by cryo-transbronchial biopsy.

BACKGROUND AND OBJECTIVE: The gold standard for the histological diagnosis of interstitial lung diseases (ILD) is an open lung biopsy (OLB). Tissue samples obtained by forceps transbronchial lung biopsies (TBB) are usually too small. We aim to evaluate the efficacy and safety of cryo-TBB for the diagnosis of ILD and to explore its role as substitute for OLB. METHODS: Seventy-five patients (mean age 56.2 years) with clinical and radiological features suggestive of ILD underwent cryo-TBB under moderate sedation. The diagnostic contribution on the work-up of suspected ILD was assessed. RESULTS: No major complications occurred during cryo-TBB procedures. The mean cross-sectional area of the biopsy specimen obtained was 9 mm2 with an average of 70% alveolated tissue. The most common pathological diagnoses were idiopathic nonspecific interstitial pneumonitis (n = 22), cryptogenic organizing pneumonia (n = 11) and usual interstitial pneumonitis (n = 7). There were three patients of pulmonary Langerhans cell histiocytosis and one patient of pulmonary lymphangioleiomyomatosis. A definite and probable clinicopathological consensus diagnosis was possible in 70% and 28% of patients, respectively. In only 2% of patients' diagnosis could not be established. CONCLUSIONS: Cryo-TBB is a safe and effective minimally invasive modality for the diagnosis of ILD. No OLB is needed in the majority of patients.

Transbronchial cryobiopsy in immunocompromised patients with pulmonary infiltrates: a pilot study.

BACKGROUND: In immunocompromised patients with pulmonary infiltrates, transbronchial lung biopsies (TBB) obtained by forceps has been shown to increase the diagnostic yield over simple bronchoalveolar lavage. Cryo-TBB is a novel modality for obtaining lung biopsies. We aimed to evaluate for the first time the efficacy and safety of cryo-TBB in immunocompromised patients. METHODS: Fifteen immunocompromised patients with pulmonary infiltrates underwent cryo-TBB. During the procedure two to three biopsy samples were taken. Procedure characteristics, complications, and the diagnostic yield were retrospectively evaluated. RESULTS: Most patients (n = 11) were immunocompromised due to hematological malignancies. The remaining four patients were receiving chronic immunosuppressive treatment due to previous solid-organ transplantation (n = 2) or collagen-vascular disease (n = 2). No major complications occurred in the cryo-TBB group. The mean surface area of the specimen taken by cryo-TBB was 9 mm(2). The increase in surface area and quality of biopsy samples translated to a high percentage of alveolated tissue (70 %) that enabled a clear histological detection of the following diagnoses: noncaseating granulomatous inflammation (n = 2), acute interstitial pneumonitis consistent with drug reaction (n = 5), nonspecific interstitial pneumonia fibrotic variant (n = 1), diffuse alveolar damage (n = 3), organizing pneumonia (n = 3), and pulmonary cryptococcal pneumonia (n = 1). Diagnostic information obtained by cryo-TBB led to change in the management of 12 patients (80 %). CONCLUSION: Cryo-TBB in immunocompromised patients with pulmonary infiltrates provides clinically important diagnostic data with a low complication rate. These advantages should be further compared with traditional forceps TBB in a prospective randomized trial.

[Pathology of organ transplantation: experience of the Rabin Medical Center].

Solid organ transplantation is currently the treatment of choice for renal, heart, and pancreas insufficiency and selected bowel diseases. Thanks to advances in medical technology, the lifespan of transplanted organs is currently about 10 years. To prevent graft rejection, patients need to take immunosuppressive drugs, usually for the rest of their Lives. Pathologists play a crucial role in organ transplantation. They are responsible for recognizing allograft rejection, both acute and chronic, differentiating rejection from drug toxicity, and identifying recurrent disease. In addition, pathologists identify new diseases in the graft, opportunistic infections in the transplanted organ or other organs, and the development of malignant tumors, which are more common in immunocompromised patients. Accordingly, transplant pathologists require a wide range of knowledge in many complex laboratory techniques, such as immunofluorescence, electron microscopy, immunohistochemical analysis, and molecular pathology. These tests are performed in dedicated Laboratories in departments of pathology. TranspLant pathology is an inseparable part of the field of transplantation medicine and greatly assists clinicians in the diagnosis of disease processes in transplanted organs and in the selection of appropriate treatment.

Transbronchial cryo-biopsy in lung transplantation patients: first report.

BACKGROUND AND OBJECTIVE: Transbronchial lung biopsies remain the gold standard to establish the presence of allograft rejection or infection after lung transplantation. The aim of this study was to evaluate the efficacy and safety of cryo-transbronchial biopsies (cryo-TBB) in lung transplantation patients. METHODS: Forty lung transplantation patients (mean age 58.3 years) underwent cryo-TBB, either routine post lung transplantation surveillance bronchoscopy (n = 27), or clinically indicated bronchoscopy (n = 13). During the procedure, two to three biopsy samples were taken. Procedure characteristics, complications and the diagnostic yield were compared with 40 matched controls who underwent conventional forceps-TBB. RESULTS: No major complications occurred in the cryo-TBB group. The mean diameter of the specimen taken by cryo-TBB was 10 mm(2) compared with only 2 mm(2) using forceps-TBB (P < 0.05). The increased size and quality of biopsy samples in the study group translated to a significant increase in the percentage of alveolated tissue (65% vs 34% respectively, P < 0.05) that enabled a clear histological detection of acute rejection (n = 4), pneumonitis (n = 3), diffuse alveolar damage (n = 1) and confident exclusion of acute rejection, infection or pneumonitis (n = 32). Fluoroscopy time was significantly shorter in the cryo-biopsy patients compared with controls (25 s vs 90 s, respectively, P < 0.05). CONCLUSIONS: Cryo-TBB for both surveillance and clinically indicated bronchoscopy in lung transplantation patients provides larger and more diagnostic lung parenchyma specimens with low complication rate and shorter intervention time than traditional forceps biopsies.