Samjot Singh Dhillon

The Case for a Pre-Cancer Genome Atlas (PCGA)

Understanding the earliest molecular and cellular events associated with cancer initiation remains a key bottleneck to transforming our approach to cancer prevention and detection. While TCGA has provided unprecedented insights into the genomic events associated with advanced stage cancer, there have been few studies comprehensively profiling premalignant and early-stage disease or elucidating the role of the microenvironment in premalignancy and tumor initiation. In this article, we make a call for development of a “Pre-Cancer Genome Atlas (PCGA),” a concerted initiative to characterize the molecular alterations in premalignant lesions and the corresponding changes in the microenvironment associated with progression to invasive carcinoma. This initiative will require a multicenter coordinated effort to comprehensively profile (cellular and molecular) premalignant lesions and their corresponding “field of injury” collected longitudinally as the lesion progresses towards or regresses from frank malignancy across multiple tumor types. Genomic characterization of alterations in premalignant lesions and their microenvironment, for both bulk tissue and single cells, will enable development of biomarkers for early detection and risk stratification as well as allow for the development of novel targeted cancer interception strategies. The multi-institutional and multidisciplinary collaborative “big-data” effort underlying the PCGA will help usher in a new era of precision medicine for cancer detection and prevention. Cancer Prev Res; 9(2); 119–24. ©2016 AACR.

MiR-205 and MiR-375 MicroRNA Assays to Distinguish Squamous Cell Carcinoma from Adenocarcinoma in Lung Cancer Biopsies

Introduction: Identification of adenocarcinoma (AC) and squamous cell carcinoma (SCC) histology of non–small-cell lung cancer (NSCLC) in biopsies is clinically important but can be inaccurate by routine histopathologic examination. We quantify this inaccuracy at a cancer center, and evaluate the utility of a microRNA-based method to histotype AC/SCC in biopsies. Methods: RNA was extracted from tissue sections with greater than 90% tumor content that were macro- or micro-dissected from formalin-fixed, paraffin-embedded biopsy specimens. MicroRNAs in RNA from the biopsies and from resected tumors were quantified by TaqMan reverse transcription-polymerase chain reaction assays and normalized against the RNU6B housekeeping RNA. Publicly available microRNA expression datasets were examined. Results: NSCLC subtyping of small biopsy specimens by routine histopathologic examination either failed or mistyped the histology of 21% of 190 cases. Using 77 resectates, an reverse transcription-polymerase chain reaction-based assay of microRNAs miR-21, miR-205, and miR-375 was developed to identify AC and SCC subtypes of NSCLC. This method identified the AC/SCC histotypes of 25 biopsies with an accuracy of 96%, and correctly histotyped all 12 cases for which the histology had been mistyped by routine histopathologic examination of the biopsy. Examination of publicly available datasets identified miR-205 and miR-375 as microRNAs with the best ability to histotype AC and SCC, and that levels of the two microRNAs in AC or SCC are unaffected by the pathologic stage of the tumor or the age or race of the patient. Conclusions: Histotypic microRNA assays can aid the subtyping of NSCLC biopsies as AC or SCC by standard histopathologic methods.

A Phase I Study of Light Dose for Photodynamic Therapy Using 2-[1-Hexyloxyethyl]-2 Devinyl Pyropheophorbide-a for the Treatment of Non–Small Cell Carcinoma In Situ or Non–Small Cell Microinvasive Bronchogenic Carcinoma: A Dose Ranging Study

Introduction: We report a phase I trial of photodynamic therapy (PDT) of carcinoma in situ (CIS) and microinvasive cancer (MIC) of the central airways with the photosensitizer (PS) 2‐[1‐hexyloxyethyl]‐2‐devinyl pyropheophorbide‐a (HPPH). HPPH has the advantage of minimal general phototoxicity over the commonly used photosensitizer porfimer sodium (Photofrin; Pinnacle Biologics, Chicago, IL). Methods: The objectives of this study were (1) to determine the maximally tolerated light dose at a fixed photosensitizer dose and (2) to gain initial insight into the effectiveness of this treatment approach. Seventeen patients with 21 CIS/MIC lesions were treated with HPPH with light dose escalation starting from 75 J/cm2 and increasing to 85, 95,125, and 150 J/cm,2 respectively. Follow‐up bronchoscopy for response assessment was performed at 1 and 6 months, respectively. Results: The rate of pathological complete response (CR) was 82.4% (14 of 17 evaluable lesions; 14 patients) at 1 month and 72.7% (8/11 evaluable lesions; 8 patients) at 6 months. Only four patients developed mild skin erythema. One of the three patients in the 150 J/cm2 light dose group experienced a serious adverse event. This patient had respiratory distress caused by mucus plugging, which precipitated cardiac ischemia. Two additional patients treated subsequently at this light dose had no adverse events. The sixth patient in this dose group was not recruited and the study was terminated because of delays in HPPH supply. However, given the observed serious adverse event, it is recommended that the light dose does not exceed 125 J/cm2. Conclusions: PDT with HPPH can be safely used for the treatment of CIS/MIC of the airways, with potential effectiveness comparable to that reported for porfimer sodium in earlier studies.

Leiomyosarcoma of the pulmonary artery diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration

Leiomyosarcoma of the pulmonary vasculature is an extremely rare condition that has not been previously diagnosed by endobronchial ultrasound (EBUS) bronchoscopy. We present the case of a 43-year-old white male with a history of leiomyosarcoma who was diagnosed with pulmonary embolism 2 years ago. As the filling defects on follow-up chest computed tomography continued to worsen despite anticoagulation, EBUS-guided transbronchial needle aspiration (EBUS-TBNA) of the right pulmonary artery lesion was safely and successfully performed. Cytopathological examination revealed the “thrombus” to be metastatic leiomyosarcoma. In experienced hands, and carefully selected cases, EBUS-TBNA seems to be a safe and effective in diagnosing thoracic endovascular lesions.

Endobronchial ultrasound-guided transbronchial needle aspiration of pulmonary artery tumors: A systematic review (with video).

Convex probe endobronchial ultrasound (CP-EBUS) was originally introduced as a diagnostic and staging tool for lung cancer and subsequently utilized for diagnosis of other malignant and benign mediastinal diseases such as melanoma, lymphoma, and sarcoidosis. More recently, CP-EBUS has been successfully used for the visualization and diagnosis of pulmonary emboli and other vascular lesions including primary and metastatic pulmonary artery (PA) tumors. In this review, we will underline the role of EBUS-guided transbronchial needle aspiration (EBUS-TBNA) for the diagnosis of pulmonary arterial tumors such as sarcomas and tumor emboli. We will concisely discuss the clinical applications of EBUS-TBNA and the types of pulmonary arterial tumors and their different diagnostic modalities. We searched the Cochrane Library and PubMed from 2004 to 2014 to provide the most comprehensive review. Only 10 cases of EBUS-TBNA for intravascular lesions were identified in the literature. Although many cases of EBUS and EUS-guided transvascular tumor biopsies were described in the literature, there were no reported cases of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for intravascular tumor biopsies. Except for one paper, all cases were published as case reports.

Mediastinal staging of non-small-cell lung cancer.

Accurate mediastinal staging is the hallmark of a sound thoracic oncology program. Mediastinal staging remains the most important validated tool for making treatment decisions for patients with non-small-cell lung cancer. The last few years have seen the emergence of several new techniques to improve mediastinal staging. This article summarizes the current state of the art of this rapidly evolving field.

Management of Benign Pleural Effusions Using Indwelling Pleural Catheters: A Systematic Review and Meta-analysis

BACKGROUND: The indwelling pleural catheter (IPC), which was initially introduced for the management of recurrent malignant effusions, could be a valuable management option for recurrent benign pleural effusion (BPE), replacing chemical pleurodesis. The purpose of this study is to analyze the efficacy and safety of IPC use in the management of refractory nonmalignant effusions. METHODS: We conducted a systematic review and meta‐analysis on the published literature. Retrospective cohort studies, case series, and reports that used IPCs for the management of pleural effusion were included in the study. RESULTS: Thirteen studies were included in the analysis, with a total of 325 patients. Congestive heart failure (49.8%) was the most common cause of BPE requiring IPC placement. The estimated average rate of spontaneous pleurodesis was 51.3% (95% CI, 37.1%‐65.6%). The estimated average rate of all complications was 17.2% (95% CI, 9.8%‐24.5%) for the entire group. The estimated average rate of major complications included the following: empyema, 2.3% (95% CI, 0.0%‐4.7%); loculation, 2.0% (95% CI, 0.0%‐4.7%); dislodgement, 1.3% (95% CI, 0.0%‐3.7%); leakage, 1.3% (95% CI, 0.0%‐3.5%); and pneumothorax, 1.2% (95% CI, 0.0%‐4.1%). The estimated average rate of minor complications included the following: skin infection, 2.7% (95% CI, 0.6%‐4.9%); blockage and drainage failure, 1.1% (95% CI, 0.0%‐3.5%); subcutaneous emphysema, 1.1% (95% CI, 0.0%‐4.0%); and other, 2.5% (95% CI, 0.0%‐5.2%). One death was directly related to IPC use. CONCLUSIONS: IPCs are an effective and viable option in the management of patients with refractory BPE. The quality of evidence to support IPC use for BPE remains low, and high‐quality studies such as randomized controlled trials are needed.

Lung cancer screening update

Lung cancer is the leading cause of cancer-related mortality globally and the American cancer society estimates approximately 226,160 new cases and 160,340 deaths from lung cancer in the USA in the year 2012. The majority of lung cancers are diagnosed in the later stages which impacts the overall survival. The 5-year survival rate for pathological st age IA lung cancer is 73% but drops to only 13% for stage IV. Thus, early detection through screening and prevention are the keys to reduce the global burden of lung cancer. This article discusses the current state of lung cancer screening, including the results of the National Lung Cancer Screening Trial, the consideration of implementing computed tomography screening, and a brief overview of the role of bronchoscopy in early detection and potential biomarkers that may aid in the early diagnosis of lung cancer.

Detecting the Presence and Progression of Premalignant Lung Lesions via Airway Gene Expression

Purpose: Lung cancer is the leading cause of cancer-related death in the United States. The molecular events preceding the onset of disease are poorly understood, and no effective tools exist to identify smokers with premalignant lesions (PMLs) that will progress to invasive cancer. Prior work identified molecular alterations in the smoke-exposed airway field of injury associated with lung cancer. Here, we focus on an earlier stage in the disease process leveraging the airway field of injury to study PMLs and its utility in lung cancer chemoprevention. Experimental Design: Bronchial epithelial cells from normal appearing bronchial mucosa were profiled by mRNA-Seq from subjects with (n = 50) and without (n = 25) PMLs. Using surrogate variable and gene set enrichment analysis, we identified genes, pathways, and lung cancer–related gene sets differentially expressed between subjects with and without PMLs. A computational pipeline was developed to build and test a chemoprevention-relevant biomarker. Results: We identified 280 genes in the airway field associated with the presence of PMLs. Among the upregulated genes, oxidative phosphorylation was strongly enriched, and IHC and bioenergetics studies confirmed pathway findings in PMLs. The relationship between PMLs and squamous cell carcinomas (SCC) was also confirmed using published lung cancer datasets. The biomarker performed well predicting the presence of PMLs (AUC = 0.92, n = 17), and changes in the biomarker score associated with progression/stability versus regression of PMLs (AUC = 0.75, n = 51). Conclusions: Transcriptomic alterations in the airway field of smokers with PMLs reflect metabolic and early lung SCC alterations and may be leveraged to stratify smokers at high risk for PML progression and monitor outcome in chemoprevention trials. Clin Cancer Res; 23(17); 5091–100. ©2017 AACR.

Yellow Nail Syndrome

A 73-year-old womanwith rheumatoid arthritis treated withmethotrexate and infliximab presented with worsening abdominal distension. A previous computed tomography scan of the chest showed bilateral bronchiectasis and small left pleural effusion (Figure 1A). Physical examination revealed tense ascites, nonpitting ankle edema, and dystrophic yellow nails (Figure 1B). Paracentesis revealed milky creamywhite fluid (Figure 1C) confirmed to be chylous by laboratory evaluation. Nail cultures were negative for fungus. Lymphangioscintigraphy showed absence of lymphatics in lower extremities. Yellow nail syndrome is a rare syndromewith a classic triad of yellow nails, lymphedema, and pleural effusions and is believed to be due to anatomic/functional lymphatic or microvascular abnormalities. The effusions are mostly lymphocytic exudative and sometimes chylous (1). Additional manifestations include recurrent sinupulmonary infections and bronchiectasis. Few cases have been reported in association with rheumatoid arthritis (1, 2). Chylous ascites as seen in this case is an extremely unusual presentation and likely related to underlying intestinal lymphangiectasia.