Case Report Bilateral Vocal Cord Paralysis and Cervicolumbar Radiculopathy as the Presenting Paraneoplastic Manifestations of Small Cell Lung Cancer: A Case Report and Literature Review

Introduction. Bilateral vocal cord paralysis (BVCP) is a potential medical emergency. The Otolaryngologist plays a crucial role in the diagnosis and management of BVCP and must consider a broad differential diagnosis. We present a rare case of BVCP secondary to anti-Hu paraneoplastic syndrome. Case Presentation. A 58-year-old female presented to an Otolaryngology clinic with a history of progressive hoarseness and dysphagia. Flexible nasolaryngoscopy demonstrated BVCP. Cross-sectional imaging of the brain and vagus nerves was negative. An antiparaneoplastic antibody panel was positive for anti-Hu antibodies. This led to an endobronchial biopsy of a paratracheal lymph node, which confirmed the diagnosis of small cell lung cancer. Conclusion. Paraneoplastic neuropathy is a rare cause of BVCP and should be considered when more common pathologies are ruled out. This is the second reported case of BVCP as a presenting symptom of paraneoplastic syndrome secondary to small cell lung cancer

Choline transporter-like protein 4 (CTL4) links to non-neuronal acetylcholine synthesis.

Synthesis of acetylcholine (ACh) by non-neuronal cells is now well established and plays diverse physiologic roles. In neurons, the Na(+) -dependent, high affinity choline transporter (CHT1) is absolutely required for ACh synthesis. In contrast, some non-neuronal cells synthesize ACh in the absence of CHT1 indicating a fundamental difference in ACh synthesis compared to neurons. The aim of this study was to identify choline transporters, other than CHT1, that play a role in non-neuronal ACh synthesis. ACh synthesis was studied in lung and colon cancer cell lines focusing on the choline transporter-like proteins, a five gene family choline-transporter like protein (CTL)1-5. Supporting a role for CTLs in choline transport in lung cancer cells, choline transport was Na(+) -independent and CTL1-5 were expressed in all cells examined. CTL1, 2, and 5 were expressed at highest levels and knockdown of CTL1, 2, and 5 decreased choline transport in H82 lung cancer cells. Knockdowns of CTL1, 2, 3, and 5 had no effect on ACh synthesis in H82 cells. In contrast, knockdown of CTL4 significantly decreased ACh secretion by both lung and colon cancer cells. Conversely, increasing expression of CTL4 increased ACh secretion. These results indicate that CTL4 mediates ACh synthesis in non-neuronal cell lines and presents a mechanism to target non-neuronal ACh synthesis without affecting neuronal ACh synthesis

Comparative study of post pneumonectomy compensatory lung response in growing male and female rats

Male and female Sprague-Dawley rats matched for litter and body weight, were subjected to left pneumonectomy and sham operations at four weeks of age. Three weeks following surgery, rats were sacrificed, and somatic and lung growth, pressure-volume curves, biochemical, and morphometric parameters were measured. Females weighed 48% less than males at the end of the experiment. Somatic growth of neither sex was effected by pneumonectomy. Following pneumonectomy, lung weight and lung volume increased significantly and matched that of both lungs of the sham-operated group in both sexes. The absolute amount of DNA and protein content also increased but was significantly less than that of both lungs of shams. Since females weighed less, absolute lung weight, lung volume, DNA and protein content increased more in males but specific parameters (i. e. values/ 100 g body weight) increased significantly less compared to females. This occurred because specific lung weight and volume decreased with increasing body weight. Mean linear intercept and mean chord length of alveoli were increased. Alveolar surface area increased by 51% in males and 31% in females, and matched that of both lungs of shams in males but not in females. The total number of alveoli increased 15% and 18% in males and females respectively and was significantly less compared to both lungs of shams in both sexes. After pneumonectomy, the post-caval lobe increased in volume 70% and 73% in males and females respectively as compared to a 60% and 47% increase in total lung volume. The mean linear intercept and mean chord length of alveoli increased less in the upper and lower lobes compared to the middle and post-caval lobes in males as well as in females. The number of alveoli per unit volume decreased more in middle and post-caval lobes compared to the upper and lower lobes in both sexes. In sham-operated male rats the upper and lower lobes had a smaller mean linear intercept and mean chord length of alveoli compared to the post-caval lobe. Postpneumonectomy, loss of elastic lung recoil at mid-volumes was observed in females. It was inferred that compensatory response following pneumonectomy was in general similar in males and females. While there was an evidence of alveolar multiplication, simple dilation of airspaces occurred and this was the dominant effect especially in females. In certain aspects (weight, volume) compensatory growth was complete but in most (DNA. protein, morphometry) was not. Male and female differences could not account for differing results in the literature concerning completeness or otherwise of lung compensatory growth.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat

Adaptive lung growth following exposure to simulated high altitude

Altered oxygen balance in the body at high altitude and in some physiological and pathological conditions may induce adaptive changes in the body which may be organ specific. Because gas exchange is the primary function of the lungs, they may undergo structural changes to adapt to the imbalance of oxygen. High altitude residents have large lungs and short body stature. Whether these adaptive changes are caused by hypobaric pressure or hypoxia (low oxygen) or hypobaric hypoxia is not known. In hypoxic conditions, somatic growth retardation occurs due to undernutrition, but the effect of undernutrition on growth of lung and other organs is not known. In this thesis, the influence of hypobaric normoxia (410 mm Hg, oxygen enriched to correspond the fraction of oxygen (Fo2) to0.21 at sea level), normobaric hypoxia (Fo2 0.11), hypobaric hypoxia (410 mm Hg, Fo2 equivalent to 0.11 at sea level) and diminished somatic growth (equivalent to that occurs in hypobaric hypoxia, food restriction) on lung growth (including biochemical, morphometric, cytokinetic and functional aspects) in rats from 4 to 7 weeks of age was studied. After 3 weeks of exposure, somatic growth was diminished in hypobaric hypoxic and normobarichypoxic animals, but lung growth was accelerated. All absolute biochemical and morphometric measurements in hypobaric hypoxic and normobaric hypoxic rats were higher than undernourished animals indicating that augmented lung growth occurred by hyperplastic and hypertrophic changes with increased accumulation of collagen and elastin. Lung weight, lung volume, DNA, RNA, protein and desmosine were also increased compared to general controls. Maximal tritiated thymidine uptake occurred on day 3 and declined thereafter suggesting that lung growth stimulation occurred during early exposure. With the exception of endothelial cells (alveolar wall, arterial), the maximum response in other cells (type II pneumonocytes, interstitial cells, unidentifiable cells) in the central alveoli wall cells lagged behind and was lower than in the peripheral alveoli. After 3 day recovery, lung DNA synthesis reached the control levels. Pulmonary function tests showed that hypobaric hypoxia caused a decrease in expiratory flow rates (FEF corrected for FVC) and an increase in specific upstream airway resistance while in normobaric hypoxia, FEV0.1/FVC%, expiratory flow rates (absolute and FEF corrected for FVC, and PEER) decreased but both absolute and specific upstream airway resistance increased. However, static compliance remained unchanged. In addition to above parameters, hypobaric hypoxia also caused an increase in collagen and alveolar surface area. These changes did not occur in normobaric hypoxia instead enlargement of airspaces occurred indicating over inflation of the lungs. The collagen concentration and elastic lung recoil at high lung volumes were also decreased in normobaric hypoxic animals. Hypobaric normoxia caused slight reduction in somatic growth which was associated with decreased lung volume, but biochemical and morphometric parameters did not change. Morphometric unit structures were smaller. Peak lung growth stimulation occurred on day 5 in all the main cell types, but not in endothelial cells. Undernutrition impaired both somatic and lung growth as lung weight and volume, cell number and size, accumulation of connective tissue proteins, alveolar number, and alveolar surface area were decreased compared to controls. DNA synthetic activity in all the main cell types diminished. However, body weight normalized lung weight, DNA, alveolar surface area and total alveolar number were higher in undernourished animals than general controls. These data suggest that lung growth stimulation occurs in normobaric hypoxia and hypobarichypoxia despite an inhibitory effect of undernutrition. Accelerated lung growth at high altitude is primarily induced by low oxygen tension. However, the differences in hypobaric hypoxia and normobaric hypoxia and changes in normobaric hypoxia indicate that hypobaric pressure per se may play a role in lung growth adaptation at high altitude. Geometrical location of the central alveoli may limit their adaptive response compared to the peripheral alveoli. Synchronous endothelial cell stimulation in each component of the lung suggests that endothelial cells may respond to hemodynamic changes while the other cells respond to functional demand of the lungs. Although lung growth was increased in normobaric hypoxic and hypobaric hypoxic animals, pulmonary function tests observations suggested that it may be dysanaptic. The response to hypoxic stress is organ specific as growth of lung, heart and spleen increased, but liver and kidney followed the growth patterns of undernourished animals. Increased specific parameters of lung growth in undernourished animals suggest that in conditions which compromise somatic growth, corrections made for body weight may lead to misinterpretation of true changes.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat

An Algorithmic Approach for Assessment of Mediastinal Lesions Using Conventional Transbronchial Needle Aspiration and Endoscopic Ultrasonography in a Single Procedure

Background. In the era of endobronchial/esophageal ultrasound (EBUS-TBNA/EUS-FNA), many centers forgo conventional transbronchial needle aspiration (C-TBNA) in favour of EBUS-TBNA/EUS-FNA despite no conclusive evidence showing better yields with EBUS-TBNA/EUS-FNA. Objectives. Assess the feasibility of an algorithmic approach for mediastinal sampling beginning with C-TBNA utilizing rapid onsite cytologic evaluation. Methods. Descriptive analysis of 92 consecutive patients referred for adenopathy that underwent C-TBNA and subsequent EBUS-TBNA/EUS-FNA if C-TBNA was negative or nondiagnostic. Results. 92 procedures were analyzed. In 50 (54.3%) of cases, C-TBNA alone was sufficient. EBUS-TBNA was performed after C-TBNA in 27 (29.3%) of cases and EUS-FNA in 33 (35.9%) of cases. The yield was 92.9% for C-TBNA, 92.5% for EBUS-TBNA, and 89.7% for EUS-FNA. There were no statistically significant differences in yields by LN station (), the relationship between yield and LN size (), or time difference in procedures following the algorithm compared to EBUS/EUS only procedures (33.7 minutes versus 32.4 minutes on average [95% CI for difference: −9.1 to 11.7], ). Conclusions. An algorithmic approach to assess the mediastinum using C-TBNA initially is feasible without sacrificing yield or procedure times. C-TBNA was sufficient for diagnosis in 54.3% of cases and can be efficiently taught in an IP training program.Peer Reviewe

Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non–Small Cell Lung Carcinoma Cells

Non–small cell lung carcinoma (NSCLC) is the most common cause of cancer deaths, with platin-based combination chemotherapy the most efficacious therapies. Gains in overall survival are modest, highlighting the need for novel therapeutic approaches including the development of next-generation platin combination regimens. The goal of this study was to identify novel regulators of platin-induced cytotoxicity as potential therapeutic targets to further enhance platin cytotoxicity. Employing RNA-seq transcriptome analysis comparing two parental NSCLC cell lines Calu6 and H23 to their cisplatin-resistant sublines, Calu6cisR1 and H23cisR1, activating transcription factor 3 (ATF3) was robustly induced in cisplatin-treated parental sensitive cell lines but not their resistant sublines, and in three of six tumors evaluated, but not in their corresponding normal adjacent lung tissue (0/6). Cisplatin-induced JNK activation was a key regulator of this ATF3 induction. Interestingly, in both resistant sublines, this JNK induction was abrogated, and the expression of an activated JNK construct in these cells enhanced both cisplatin-induced cytotoxicity and ATF3 induction. An FDA-approved drug compound screen was employed to identify enhancers of cisplatin cytotoxicity that were dependent on ATF3 gene expression. Vorinostat, a histone deacetylase inhibitor, was identified in this screen and demonstrated synergistic cytotoxicity with cisplatin in both the parental Calu6 and H23 cell lines and importantly in their resistant sublines as well that was dependent on ATF3 expression. Thus, we have identified ATF3 as an important regulator of cisplatin cytotoxicity and that ATF3 inducers in combination with platins are a potential novel therapeutic approach for NSCLC

Costs of Next-Generation Sequencing Assays in Non-Small Cell Lung Cancer: A Micro-Costing Study

Background: Next-generation sequencing (NGS) of tumor genomes has changed and improved cancer treatment over the past few decades. It can inform clinicians on the optimal therapeutic approach in many of the solid and hematologic cancers, including non-small lung cancer (NSCLC). Our study aimed to determine the costs of NGS assays for NSCLC diagnostics. Methods: We performed a micro-costing study of four NGS assays (Trusight Tumor 170 Kit (Illumina), Oncomine Focus (Thermo Fisher), QIAseq Targeted DNA Custom Panel and QIASeq Targeted RNAscan Custom Panel (Qiagen), and KAPA HyperPlus/SeqCap EZ (Roche)) at the StemCore Laboratories, the Ottawa Hospital, Canada. We used a time-and-motion approach to measure personnel time and a pre-defined questionnaire to collect resource utilization. The unit costs were based on market prices. The cost data were reported in 2019 Canadian dollars. Results: Based on a case throughput of 500 cases per year, the per-sample cost for TruSight Tumor 170 Kit, QIASeq Targeted DNA Custom Panel and QIASeq Targeted RNAscan Custom Panel, Oncomine Focus, and HyperPlus/SeqCap EZ were CAD 1778, CAD 599, CAD 1100 and CAD 1270, respectively. The key cost drivers were library preparation (34–60%) and sequencing (31–51%), followed by data analysis (6–13%) and administrative support (2–7%). Conclusions: Trusight Tumor 170 Kit was the most expensive NGS assay for NSCLC diagnostics; however, an economic evaluation is required to identify the most cost-effective NGS assay. Our study results could help inform decisions to select a robust platform for NSCLC diagnostics from fine needle aspirates, and future economic evaluations of the NGS platforms to guide treatment selections for NSCLC patients