Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2.

Human transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative pathogen of the COVID-19 pandemic, exerts a massive health and socioeconomic crisis. The virus infects alveolar epithelial type 2 cells (AT2s), leading to lung injury and impaired gas exchange, but the mechanisms driving infection and pathology are unclear. We performed a quantitative phosphoproteomic survey of induced pluripotent stem cell-derived AT2s (iAT2s) infected with SARS-CoV-2 at air-liquid interface (ALI). Time course analysis revealed rapid remodeling of diverse host systems, including signaling, RNA processing, translation, metabolism, nuclear integrity, protein trafficking, and cytoskeletal-microtubule organization, leading to cell cycle arrest, genotoxic stress, and innate immunity. Comparison to analogous data from transformed cell lines revealed respiratory-specific processes hijacked by SARS-CoV-2, highlighting potential novel therapeutic avenues that were validated by a high hit rate in a targeted small molecule screen in our iAT2 ALI system.

Graph Perceiver Network for Lung Tumor and Bronchial Premalignant Lesion Stratification from Histopathology.

Bronchial premalignant lesions (PMLs) precede the development of invasive lung squamous cell carcinoma (LUSC), posing a significant challenge in distinguishing those likely to advance to LUSC from those that might regress without intervention. This study followed a novel computational approach, the Graph Perceiver Network, leveraging hematoxylin and eosin-stained whole slide images to stratify endobronchial biopsies of PMLs across a spectrum from normal to tumor lung tissues. The Graph Perceiver Network outperformed existing frameworks in classification accuracy predicting LUSC, lung adenocarcinoma, and nontumor lung tissue on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium datasets containing lung resection tissues while efficiently generating pathologist-aligned, class-specific heatmaps. The network was further tested using endobronchial biopsies from two data cohorts, containing normal to carcinoma in situ histology. It demonstrated a unique capability to differentiate carcinoma in situ lung squamous PMLs based on their progression status to invasive carcinoma. The network may have utility in stratifying PMLs for chemoprevention trials or more aggressive follow-up.

Pandemic Response Requires Research Samples: A U.S. Safety-Net Hospital's Experience and Call for National Action.

Biorepositories provide a critical resource for gaining knowledge of emerging infectious diseases and offer a mechanism to rapidly respond to outbreaks; the emergence of the novel coronavirus, SARS-CoV-2, has proved their importance. During the COVID-19 pandemic, the absence of centralized, national biorepository efforts meant that the onus fell on individual institutions to establish sample repositories. As a safety-net hospital, Boston Medical Center (BMC) recognized the importance of creating a COVID-19 biorepository to both support critical science at BMC and ensure representation in research for its urban patient population, most of whom are from underserved communities. This article offers a realistic overview of the authors' experience in establishing this biorepository at the onset of the COVID-19 pandemic during the height of the first surge of cases in Boston, Massachusetts, with the hope that the challenges and solutions described are useful to other institutions. Going forward, funders, policymakers, and infectious disease and public health communities must support biorepository implementation as an essential element of future pandemic preparedness.

Profiling microRNA from nephrectomy and biopsy specimens: predictors of progression and survival in clear cell renal cell carcinoma.

OBJECTIVE: To identify microRNA (miRNA) characteristic of metastatic clear cell renal cell carcinoma (ccRCC) and those indicative of cancer-specific survival (CSS) in nephrectomy and biopsy specimens. We also sought to determine if a miRNA panel could differentiate benign from ccRCC tissue. MATERIALS AND METHODS: RNA was isolated from nephrectomy and kidney biopsy specimens (n = 156 and n = 46, respectively). Samples were grouped: benign, non-progressive, and progressive ccRCC. MiRNAs were profiled by microarray and validated by quantitative reverse transcription-polymerase chain reaction. Biomarker signatures were developed to predict cancer status in nephrectomy and biopsy specimens. CSS was examined using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Microarray analysis revealed 20 differentially expressed miRNAs comparing non-progressive with progressive tumours. A biomarker signature validated in nephrectomy specimens had a sensitivity of 86.7% and a specificity of 92.9% for differentiating benign and ccRCC specimens. A second signature differentiated non-progressive vs progressive ccRCC with a sensitivity of 93.8% and a specificity of 83.3%. These biomarkers also discriminated cancer status in biopsy specimens. Levels of miR-10a-5p, -10b-5p, and -223-3p were associated with CSS. CONCLUSION: This study identified miRNAs differentially expressed in ccRCC samples; as well as those correlating with CSS. Biomarkers identified in this study have the potential to identify patients who are likely to have progressive ccRCC, and although preliminary, these results may aid in differentiating aggressive and indolent ccRCC based on biopsy specimens.

Does reevaluation of colorectal cancers with inadequate nodal yield lead to stage migration or the identification of metastatic lymph nodes?

BACKGROUND: The National Comprehensive Cancer Network recommends routine reevaluation of all stage II colon cancer specimens with fewer than 12 lymph nodes. However, there are few data demonstrating the effect of reevaluation on stage. OBJECTIVE: The aim of this study was to demonstrate the effect of pathologic reevaluation for colorectal cancers with fewer than 12 lymph nodes on stage. DESIGN: This study entailed a retrospective review of pathology reports. SETTINGS: This study was conducted at 2 large multispecialty referral centers. INTERVENTIONS: Pathologic reevaluation was performed to look for additional lymph nodes. PATIENTS: All patients with stage I through III colorectal cancers with inadequate lymph node yields who underwent reevaluation from January 1, 2007 through March 31, 2011 were identified. MAIN OUTCOME MEASURES: We recorded initial pathologic stage and new stage following reevaluation. The following variables before and after reevaluation were also recorded: 1) total lymph node count, 2) metastatic node count, 3) negative node count, and 4) lymph node ratio. RESULTS: Eighty-three patients underwent pathologic reevaluation from a total of 1682 cancer specimens. Mean nodal yields were 7.2 ± 2.6 on the first pathologic review. On reevaluation, 80% of patients had one or more newly identified nodes. On average, 6.9 ± 9.6 more lymph nodes were identified with a metastatic node detected in 4 of 83 patients (4.8%). After pathologic reevaluation, 1 patient (1.2%) had a change in TNM stage from N1 to N2 disease. The lymph node ratio changed in 13 of 15 patients (87% of stage III cancers). Only 4 of these had a change in lymph node quartile. LIMITATIONS: The study was limited by its retrospective nature and small sample size. CONCLUSION: Few patients have a newly discovered metastatic node or stage change following pathologic reevaluation. The effect of pathologic reevaluation on treatment and outcome should be further investigated.

Pulmonary adenocarcinoma of low malignant potential defines indolent NSCLC associated with overdiagnosis in the national lung screening trial.

BACKGROUND: The national lung screening trial (NLST) demonstrated a reduction in lung cancer mortality with lowdose CT (LDCT) compared to chest x-ray (CXR) screening. Overdiagnosis was high (79%) among bronchoalveolar carcinoma (BAC) currently replaced by adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and adenocarcinoma of low malignant potential (LMP) exhibiting 100% disease specific survival (DSS). OBJECTIVE: Compare the outcomes and proportions of BAC, AIS, MIA, and LMP among NLST screendetected stage IA NSCLC with overdiagnosis rate. METHODS: Whole slide images were reviewed by a thoracic pathologist from 174 of 409 NLST screen-detected stage IA LUAD. Overdiagnosis rates were calculated from follow-up cancer incidence rates. RESULTS: Most BAC were reclassified as AIS/MIA/LMP (20/35 = 57%). The 7-year DSS was 100% for AIS/MIA/LMP and 94% for BAC. Excluding AIS/MIA/LMP, BAC behaved similarly to NSCLC (7-year DSS: 86% vs. 83%, p= 0.85) The overdiagnosis rate of LDCT stage IA NSCLC was 16.6% at 11.3-years, matching the proportion of AIS/MIA/LMP (16.2%) but not AIS/MIA (3.5%) or BAC (22.8%). CONCLUSIONS: AIS/MIA/LMP proportionally matches the overdiagnosis rate among stage IA NSCLC in the NLST, exhibiting 100% 7-year DSS. Biomarkers designed to recognize AIS/MIA/LMP preoperatively, would be useful to prevent overtreatment of indolent screen-detected cancers.

Graph Attention-Based Fusion of Pathology Images and Gene Expression for Prediction of Cancer Survival.

Multimodal machine learning models are being developed to analyze pathology images and other modalities, such as gene expression, to gain clinical and biological insights. However, most frameworks for multimodal data fusion do not fully account for the interactions between different modalities. Here, we present an attention-based fusion architecture that integrates a graph representation of pathology images with gene expression data and concomitantly learns from the fused information to predict patient-specific survival. In our approach, pathology images are represented as undirected graphs, and their embeddings are combined with embeddings of gene expression signatures using an attention mechanism to stratify tumors by patient survival. We show that our framework improves the survival prediction of human non-small cell lung cancers, outperforming existing state-of-the-art approaches that leverage multimodal data. Our framework can facilitate spatial molecular profiling to identify tumor heterogeneity using pathology images and gene expression data, complementing results obtained from more expensive spatial transcriptomic and proteomic technologies.

A computed tomography-based score indicative of lung cancer aggression (SILA) predicts lung adenocarcinomas with low malignant potential or vascular invasion.

BACKGROUND: Histologic grading of lung adenocarcinoma (LUAD) is predictive of outcome but is only possible after surgical resection. A radiomic biomarker predictive of grade has the potential to improve preoperative management of early-stage LUAD. OBJECTIVE: Validate a prognostic radiomic score indicative of lung cancer aggression (SILA) in surgically resected stage I LUAD (n= 161) histologically graded as indolent low malignant potential (LMP), intermediate, or aggressive vascular invasive (VI) subtypes. METHODS: The SILA scores were generated from preoperative CT-scans using the previously validated Computer-Aided Nodule Assessment and Risk Yield (CANARY) software. RESULTS: Cox proportional regression showed significant association between the SILA and 7-year recurrence-free survival (RFS) in a univariate (p< 0.05) and multivariate (p< 0.05) model incorporating age, gender, smoking status, pack years, and extent of resection. The SILA was positively correlated with invasive size (spearman r= 0.54, p= 8.0 × 10 - 14) and negatively correlated with percentage of lepidic histology (spearman r=-0.46, p= 7.1 × 10 - 10). The SILA predicted indolent LMP with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.74 and aggressive VI with an AUC of 0.71, the latter remaining significant when invasive size was included as a covariate in a logistic regression model (p< 0.01). CONCLUSIONS: The SILA scoring of preoperative CT scans was prognostic and predictive of resected pathologic grade.

Identification of a gene expression signature of vascular invasion and recurrence in stage I lung adenocarcinoma via bulk and spatial transcriptomics.

Microscopic vascular invasion (VI) is predictive of recurrence and benefit from lobectomy in stage I lung adenocarcinoma (LUAD) but is difficult to assess in resection specimens and cannot be accurately predicted prior to surgery. Thus, new biomarkers are needed to identify this aggressive subset of stage I LUAD tumors. To assess molecular and microenvironment features associated with angioinvasive LUAD we profiled 162 resected stage I tumors with and without VI by RNA-seq and explored spatial patterns of gene expression in a subset of 15 samples by high-resolution spatial transcriptomics (stRNA-seq). Despite the small size of invaded blood vessels, we identified a gene expression signature of VI from the bulk RNA-seq discovery cohort (n=103) and found that it was associated with VI foci, desmoplastic stroma, and high-grade patterns in our stRNA-seq data. We observed a stronger association with high-grade patterns from VI+ compared with VI- tumors. Using the discovery cohort, we developed a transcriptomic predictor of VI, that in an independent validation cohort (n=60) was associated with VI (AUROC=0.86; p=5.42×10-6) and predictive of recurrence-free survival (HR=1.98; p=0.024), even in VI- LUAD (HR=2.76; p=0.003). To determine our VI predictor's robustness to intra-tumor heterogeneity we used RNA-seq data from multi-region sampling of stage I LUAD cases in TRACERx, where the predictor scores showed high correlation (R=0.87, p<2.2×10-16) between two randomly sampled regions of the same tumor. Our study suggests that VI-associated gene expression changes are detectable beyond the site of intravasation and can be used to predict the presence of VI. This may enable the prediction of angioinvasive LUAD from biopsy specimens, allowing for more tailored medical and surgical management of stage I LUAD.

Vascular Invasion Predicts Recurrence in Stage IA2-IB Lung Adenocarcinoma but not Squamous Cell Carcinoma.

BACKGROUND: Lymphovascular invasion (LVI) is an adverse prognostic feature in resected stage I non-small cell lung cancer (NSCLC); however, it is unclear if the prognostic significance applies to both lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). MATERIALS AND METHODS: A retrospective review of H&E-stained slides from surgically resected AJCC 8th ed. stage IA2-IB LUAD (n = 344) and LUSC (n = 102) from two institutions was performed. LVI was defined as either lymphatic (LI) or vascular (VI) invasion. Outcomes were assessed by 5-year recurrence-free survival (RFS) estimates using the Kaplan-Meier method. RESULTS: The cohorts of LUAD and LUSC showed no significant differences in 5-year RFS (81% each), stage, age, race, or surgical procedure. The presence of LVI, VI, and LI was predictive of 5-year RFS for LUAD (LVI + 71% vs. LVI - 92%, P < 0.001; VI + 64% vs. VI - 90%, P < 0.001; LI + 75% vs. LI - 84%, P = 0.030) but not LUSC (LVI + 84% vs. LVI - 79%, P = 0.740; VI + 83% vs. VI- 80%, P = 0.852; LI + 84% vs. LI - 81%, P = 0.757). Among LUAD with LVI, VI was a stronger predictor of 5-year RFS than the remaining subset of VI-LI + tumors (64% vs. 87%, P = 004). Subset analysis of LI among LUAD stratified by VI showed no significant prognostic advantage to adding LI for risk stratification (VI-LI + 87% vs. VI-LI - 92%, P = 0.347 & VI+LI + 62% vs. VI + LI- 66%, P = 0.422). VI was present in 36% of LUAD. CONCLUSION: Vascular invasion is a strong predictor of recurrence in stage IA2-IB LUAD but not in LUSC. Adjuvant therapy trials should be directed at this subgroup.

An additive destabilising effect of compound T60I and V122I substitutions in ATTRv amyloidosis.

BACKGROUND: The amyloidogenic transthyretin (TTR) variant, V122I, occurs in 4% of the African American population and frequently presents as a restricted cardiomyopathy. While heterozygosity for TTR V122I predominates, several compound heterozygous cases have been previously described. Herein, we detail features of ATTRv amyloidosis associated with novel compound heterozygous TTR mutation, T60I/V122I and provide evidence supporting the amyloidogenecity of T60I. METHODS: A 63-year-old African American female presented with atrial fibrillation, congestive heart failure, autonomic and peripheral neuropathy. In vitro studies of TTR T60I and V122I were undertaken to compare the biophysical properties of the proteins. RESULTS: Congophilic deposits in a rectal biopsy were immunohistochemically positive for TTR. Serum screening by isoelectric focussing revealed two TTR variants in the absence of wild-type protein. DNA sequencing identified compound heterozygous TTR gene mutations, c.239C > T and c.424G > A. Adipose amyloid deposits were composed of both T60I and V122I. While kinetic stabilities of T60I and V122I variants were similar, distinct thermodynamic stabilities and amyloid growth kinetics were observed. CONCLUSIONS: This report provides clinical and experimental results supporting the amyloidogenic nature of a novel TTR T60I variant. In vitro data indicate that the destabilising effect of individual T60I and V122I variants appears to be additive rather than synergistic.

Vascular invasion predicts the subgroup of lung adenocarcinomas ≤2.0 cm at risk of poor outcome treated by wedge resection compared to lobectomy.

Background: Recent randomized control trials (JCOG0802 and CALGB140503) have shown sublobar resection to be noninferior to lobectomy for non-small cell lung cancer (NSCLC) ≤2.0 cm. We have previously proposed histologic criteria stratifying lung adenocarcinoma into indolent low malignant potential (LMP) and aggressive angioinvasive adenocarcinomas, resulting in better prognostication than provided by World Health Organization grade. Here we determine whether pathologic classification is reproducible and whether subsets of adenocarcinomas predict worse outcomes when treated by wedge resection compared to lobectomy. Methods: A retrospective cohort of 108 recipients of wedge resection and 187 recipients of lobectomy for stage I/0 lung adenocarcinomas ≤2.0 cm was assembled from 2 institutions. All tumors were classified by a single pathologist, and interobserver reproducibility was assessed in a subset (n = 92) by 5 pathologists. Results: Angioinvasive adenocarcinoma (21%-27% of cases) was associated with worse outcomes when treated with wedge resection compared to lobectomy (5-year recurrence-free survival, 57% vs 85% [P = .007]; 5-year disease-free survival [DSS], 70% vs 90% [P = .043]; 7-year overall survival, 37% vs 58% [P = .143]). Adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and LMP exhibited 100% 5-year DSS regardless of the surgical approach. Multivariable analysis showed that angioinvasion, tumor size, margin status, and extent of nodal sampling were significantly associated with recurrence but not with surgical procedure. There was substantial interobserver reproducibility among the pathologists for the diagnosis of angioinvasive adenocarcinoma (κ = 0.71) and the combined indolent AIS/MIA/LMP group (κ = 0.74). Conclusions: The majority (∼75%) of lung adenocarcinomas ≤2 cm are adequately managed with wedge resection; however, angioinvasive adenocarcinomas (∼25%) treated by wedge resection with suboptimal nodal sampling exhibit poor outcomes, with a 40% to 45% rate of recurrence within 5 years and 60% to 65% overall mortality at 7 years.

Lung Cancer Risk in Suspicious Lung Nodules With Negative Positron Emission Tomography.

BACKGROUND: Lung CT Screening Reporting and Data System (LungRADS) Category 4 represents lung nodules with the highest likelihood of cancer. For LungRADS-4 lesions, if positron emission tomography (PET) is negative, no uniform guideline currently exists on subsequent follow-up, particularly whether the surveillance interval can be extended. We sought to investigate the incidence of cancer, our surveillance practice, and any clinical factors associated with cancer in this patient subset. METHODS: We retrospectively stratified LungRADS-4 patients screened at our institution from March 2015 to February 2019 into subgroups: PET positive, PET negative, and no PET performed. PET negativity was defined as the absence of a radiologist's suspicion or a maximum standardized uptake value at or below the mediastinal value. RESULTS: Of the 191 LungRADS-4 patients identified, 67 (35.1%) met the criteria for PET negativity. Cancer was diagnosed in 28.8% of the entire cohort (55/191), 77.8% of the PET-positive subgroup (35/45), 22.4% of the PET-negative subgroup (15/67), and 6.3% of the no PET subgroup (5/79). The most common follow-up modality after a negative PET was a computed tomography (47/67, 70.1%), with a median interval of 3.1 months. Clinical variables including nodule location/size, chronic obstructive pulmonary disease, family history of lung cancer, pack-years, and number of years quit in former smokers were not significantly associated with greater cancer risk among the PET-negative subgroup. CONCLUSIONS: For LungRADS-4/PET-negative lesions the cancer risk remained high despite a lack of activity on PET. As such we believe the current surveillance practice of continuing to follow LungRADS-4/PET-negative patients as LungRADS-4 patients is appropriate.

A Graph-Transformer for Whole Slide Image Classification.

Deep learning is a powerful tool for whole slide image (WSI) analysis. Typically, when performing supervised deep learning, a WSI is divided into small patches, trained and the outcomes are aggregated to estimate disease grade. However, patch-based methods introduce label noise during training by assuming that each patch is independent with the same label as the WSI and neglect overall WSI-level information that is significant in disease grading. Here we present a Graph-Transformer (GT) that fuses a graph-based representation of an WSI and a vision transformer for processing pathology images, called GTP, to predict disease grade. We selected 4,818 WSIs from the Clinical Proteomic Tumor Analysis Consortium (CPTAC), the National Lung Screening Trial (NLST), and The Cancer Genome Atlas (TCGA), and used GTP to distinguish adenocarcinoma (LUAD) and squamous cell carcinoma (LSCC) from adjacent non-cancerous tissue (normal). First, using NLST data, we developed a contrastive learning framework to generate a feature extractor. This allowed us to compute feature vectors of individual WSI patches, which were used to represent the nodes of the graph followed by construction of the GTP framework. Our model trained on the CPTAC data achieved consistently high performance on three-label classification (normal versus LUAD versus LSCC: mean accuracy = 91.2 ± 2.5%) based on five-fold cross-validation, and mean accuracy = 82.3 ± 1.0% on external test data (TCGA). We also introduced a graph-based saliency mapping technique, called GraphCAM, that can identify regions that are highly associated with the class label. Our findings demonstrate GTP as an interpretable and effective deep learning framework for WSI-level classification.

Vascular invasion identifies the most aggressive histologic subset of stage I lung adenocarcinoma: Implications for adjuvant therapy.

OBJECTIVES: Approximately 15% of stage I lung adenocarcinomas will recur despite adequate surgical therapy. Adjuvant therapy may benefit specific high-risk subsets; however, it is unclear which patients are sufficiently predisposed to recurrence to warrant intensified therapy. MATERIALS AND METHODS: 517 AJCC 8th edition stage I/0 lung adenocarcinomas ≤ 4 cm total size were graded (WHO-2015 and WHO-2021) and compared to stage subgroupings using 7-year recurrence free (RFS), disease specific (DSS), and overall survival (OS). Low malignant potential (LMP) adenocarcinoma was assigned as previously defined. Univariate/multivariate analysis was performed to assess risk factors associated with aggressive behavior. RESULTS: Vascular invasion was the most significant histologic feature on multivariate analysis for both RFS (HR = 4.68, p < 0.001) and DSS (HR = 3.67, p = 0.001) and nearly reached significance for OS (HR = 1.47, p = 0.060). Angioinvasive adenocarcinomas comprised 26 % of the cohort and exhibited a 7-year 64 % RFS, 73 % DSS, and 50 % OS; in contrast to 20 % WHO-2015-G3 (7-year 71 % RFS, 79 % DSS, & 54 % OS), 44 % WHO-2021-G3 (7-year 79 % RFS, 85 % DSS, & 56 % OS), and 21 % stage IB (7-year 72 % RFS, 79 % DSS, and 50 % OS) adenocarcinomas. The majority (>50 %) of overall mortality was disease specific for angioinvasive adenocarcinoma whereas ≤25 % of overall mortality was disease specific for the remaining tumors. Angioinvasive adenocarcinomas were proportionally more common among those still smoking at diagnosis (49 %), male sex (49 %), and black race (16 %) than other subtypes. CONCLUSION: Patients with AJCC 8th ed. stage I angioinvasive lung adenocarcinomas are at high-risk of cancer-specific mortality and should be considered for clinical trials evaluating benefit of adjuvant therapy.

MicroRNA Associated with the Invasive Phenotype in Clear Cell Renal Cell Carcinoma: Let-7c-5p Inhibits Proliferation, Migration, and Invasion by Targeting Insulin-like Growth Factor 1 Receptor.

Differential microRNA (miRNA) expression can portend clear cell renal cell carcinoma (ccRCC) progression. In a previous study, we identified a subset of dysregulated miRNA in small renal masses, pT1 ccRCC (≤5 cm) that are associated with an aggressive phenotype. The present study investigated miRNA expression in clinical stage I (cT1) tumors (≤5 cm), comparing pathologic stage I (pT1) tumors to those upstaged to pathologic stage 3 (pT3) after surgery following identification of renal vein invasion or invasion into adjacent fat tissue within Gerota's fascia. Twenty cT1 tumors were examined in an miRNA screening, 10 pT1 and 10 pT3 tumors. The ccRCC cell lines 786-O and Caki-1 were used to assess the impact of let-7c-5p and its protein target insulin-like growth factor 1 receptor (IGF1R). Cells were transfected with pre-let-7c-5p and assessed through cell proliferation, migration, and invasion assays. IGF1R expression was evaluated through Simple Western, and interaction between let-7c-5p and IGF1R was confirmed via luciferase reporter assay. Screening identified 20 miRNA, including let-7c-5p, that were dysregulated between pT1 and pT3 upstaged tumors. This miRNA was also downregulated in our previous study of pT1 tumors that progressed to metastatic disease. Transfection of ccRCC cells with pre-let-7c-5p significantly inhibited proliferation, migration, invasion, and IGF1R expression. These findings suggest that miRNA dysregulation is involved in ccRCC progression, specifically through invasion, and that let-7c-5p downregulation contributes to the aggressiveness of small ccRCC tumors, in part, through its regulation of IGF1R.

Risk Factors for Lung Cancer in an Underrepresented Safety-Net Screening Cohort.

INTRODUCTION/BACKGROUND: The USPSTF (United States Preventive Services Task Force) guidelines suggest criteria centering on smoking status and age to select patients for lung cancer screening. Despite the significant advances in screening with low-dose computed tomography (LDCT), cancer detection rate is low (1.1%), highlighting the need to investigate possible ways to refine the current lung cancer screening strategy. Our aim was to determine clinical risk factors predictive of lung cancer in an urban safety-net hospital. MATERIALS AND METHODS: We performed a retrospective chart review of 2847 patients who received LDCT screening for lung cancer between 3/1/2015 and 12/31/2019. Patient demographics and medical history were collected. A bivariate logistic regression was used to evaluate predictors of lung cancer. RESULTS: Compared to the National Lung Cancer Screening Trial (NLST) population, our screening cohort had significantly more African Americans (38.2% vs. 4.5%, P < .0001), more obesity (32.7% vs. 28.3%, P < .0001), and higher rates of chronic obstructive pulmonary disease (COPD) (45.9% vs. 5.0%, P < .0001). The strongest predictors of lung cancer were COPD (odds ratio [OR] = 2.14, P < .0001) and a family history of lung cancer (OR = 2.77, P < .0001). Age (OR = 1.04, P< .001) and pack years (OR = 1.01, P< .001) were less predictive. CONCLUSION: A diagnosis of COPD and family history of lung cancer were most predictive of lung cancer in a screening cohort at our urban safety-net hospital. Future studies should focus on whether inclusion of these additional risk-factors improves proportion of lung cancer detected via screening.

A novel substitution of proline (P32L) destabilises ß2-microglobulin inducing hereditary systemic amyloidosis.

BACKGROUND: ß2-microglobulin amyloidosis was first described in the 1980s as a protein deposition disease associated with long-term haemodialysis. More recently, two inherited forms resulting from separate point mutations in the ß2-microglobulin gene have been identified. In this report, we detail a novel ß2M variant, P32L, caused by a unique dinucleotide mutation that is linked to systemic hereditary ß2-microglobulin amyloidosis. METHODS: Three family members from a Portuguese kinship featured cardiomyopathy, requiring organ transplantation in one case, along with soft tissue involvement; other involvements included gastrointestinal, neuropathic and sicca syndrome. In vitro studies with recombinant P32L, P32G, D76N and wild-type ß2-microglobulin were undertaken to compare the biophysical properties of the proteins. RESULTS: The P32L variant was caused by the unique heterozygous dinucleotide mutation c.154_155delinsTT. Amyloid disease featured lowered serum ß2-microglobulin levels with near equal amounts of circulating P32L and wild-type proteins; amyloid deposits were composed exclusively of P32L variant protein. In vitro studies of P32L demonstrated thermodynamic and chemical instability and enhanced susceptibility to proteolysis with rapid formation of pre-fibrillar oligomeric structures by N- and C-terminally truncated species under physiological conditions. CONCLUSIONS: This work provides both clinical and experimental evidence supporting the critical role of P32 residue replacement in ß2M amyloid fibrillogenesis.

Lung adenocarcinoma and pulmonary actinomycosis: a cautionary tale.

BACKGROUND: Pulmonary actinomycosis is a rare and slowly progressive bacterial infection that is often mistaken for lung cancer. Multiple case reports caution against premature diagnosis of malignancy without proper consideration of potential Actinomyces infection. However, no cases in the English literature have been reported that demonstrate the possible coexistence of Actinomyces and lung cancer. CASE DESCRIPTION: We present two cases of patients with culture-positive Actinomyces who were later found to have concomitant biopsy-proven lung adenocarcinoma. CONCLUSIONS: In the workup of a newly identified lung mass, positive culture for Actinomyces does not rule out an underlying malignancy.