Faculty Bibliography

BACKGROUND/UNASSIGNED:Evidence suggests that patients critically ill with COVID-19 have a dysregulated host immune response that contributes to end-organ damage. Extracorporeal membrane oxygenation (ECMO) has been used in this population with varying degrees of success. This study was performed to evaluate the impact of ECMO on the host immunotranscriptomic response in these patients. METHODS/UNASSIGNED:Eleven patients critically ill with COVID-19 requiring ECMO underwent an analysis of cytokines and immunotranscriptomic pathways before ECMO (T1), after ECMO for 24 hours (T2), and 2 hours after ECMO decannulation (T3). A Multiplex Human Cytokine panel was used to identify cytokine changes, and immunotranscriptomic changes in peripheral leukocytes were evaluated by PAXgene and NanoString nCounter. RESULTS/UNASSIGNED:, which code for binding ligands for the activation of toll-like receptors 2 and 4. Reactome analyses of differential gene expression demonstrated an impact on many of the body's most important immune inflammatory pathways. CONCLUSIONS/UNASSIGNED:These findings suggest a temporal impact of ECMO on the host immunotranscriptomic response in patients critically ill with COVID-19.

BACKGROUND:The increased detection of small-sized peripheral non-small-cell lung cancer (NSCLC) has renewed interest in sublobar resection in lieu of lobectomy. METHODS:We conducted a multicenter, noninferiority, phase 3 trial in which patients with NSCLC clinically staged as T1aN0 (tumor size, ≤2 cm) were randomly assigned to undergo sublobar resection or lobar resection after intraoperative confirmation of node-negative disease. The primary end point was disease-free survival, defined as the time between randomization and disease recurrence or death from any cause. Secondary end points were overall survival, locoregional and systemic recurrence, and pulmonary functions. RESULTS:From June 2007 through March 2017, a total of 697 patients were assigned to undergo sublobar resection (340 patients) or lobar resection (357 patients). After a median follow-up of 7 years, sublobar resection was noninferior to lobar resection for disease-free survival (hazard ratio for disease recurrence or death, 1.01; 90% confidence interval [CI], 0.83 to 1.24). In addition, overall survival after sublobar resection was similar to that after lobar resection (hazard ratio for death, 0.95; 95% CI, 0.72 to 1.26). The 5-year disease-free survival was 63.6% (95% CI, 57.9 to 68.8) after sublobar resection and 64.1% (95% CI, 58.5 to 69.0) after lobar resection. The 5-year overall survival was 80.3% (95% CI, 75.5 to 84.3) after sublobar resection and 78.9% (95% CI, 74.1 to 82.9) after lobar resection. No substantial difference was seen between the two groups in the incidence of locoregional or distant recurrence. At 6 months postoperatively, a between-group difference of 2 percentage points was measured in the median percentage of predicted forced expiratory volume in 1 second, favoring the sublobar-resection group. CONCLUSIONS:In patients with peripheral NSCLC with a tumor size of 2 cm or less and pathologically confirmed node-negative disease in the hilar and mediastinal lymph nodes, sublobar resection was not inferior to lobectomy with respect to disease-free survival. Overall survival was similar with the two procedures. (Funded by the National Cancer Institute and others; CALGB 140503 ClinicalTrials.gov number, NCT00499330.).

Malignant pleural effusions (MPE) complicate malignancies and portend worse outcomes. MPE is comprised of various components, including immune cells, cancer cells, and cell-free DNA/RNA. There have been investigations into using these components to diagnose and prognosticate MPE. We hypothesize that the microbiome of MPE is unique and may be associated with diagnosis and prognosis. We compared the microbiota of MPE against microbiota of pleural effusions from non-malignant and paramalignant states. We collected a total of 165 pleural fluid samples from 165 subjects; Benign (n = 16), Paramalignant (n = 21), MPE-Lung (n = 57), MPE-Other (n = 22), and Mesothelioma (n = 49). We performed high throughput 16S rRNA gene sequencing on pleural fluid samples and controls. We showed that there are compositional differences among pleural effusions related to non-malignant, paramalignant, and malignant disease. Furthermore, we showed differential enrichment of bacterial taxa within MPE depending on the site of primary malignancy. Pleural fluid of MPE-Lung and Mesothelioma were associated with enrichment with oral and gut bacteria that are commonly thought to be commensals, including Rickettsiella, Ruminococcus, Enterococcus, and Lactobacillales. Mortality in MPE-Lung is associated with enrichment in Methylobacterium, Blattabacterium, and Deinococcus. These observations lay the groundwork for future studies that explore host-microbiome interactions and their influence on carcinogenesis.

BACKGROUND:Cancer recurrence after tumor resection in early-stage non-small cell lung cancer (NSCLC) is common, yet difficult to predict. The lung microbiota and systemic immunity may be important modulators of risk for lung cancer recurrence, yet biomarkers from the lung microbiome and peripheral immune environment are understudied. Such markers may hold promise for prediction as well as improved etiologic understanding of lung cancer recurrence. METHODS:In tumor and distant normal lung samples from 46 stage II NSCLC patients with curative resection (39 tumor samples, 41 normal lung samples), we conducted 16S rRNA gene sequencing. We also measured peripheral blood immune gene expression with nanoString®. We examined associations of lung microbiota and peripheral gene expression with recurrence-free survival (RFS) and disease-free survival (DFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression, and examined predictive accuracy using time-dependent receiver operating characteristic (ROC) curves. RESULTS:Over a median of 4.8 years of follow-up (range 0.2-12.2 years), 43% of patients experienced a recurrence, and 50% died. In normal lung tissue, a higher abundance of classes Bacteroidia and Clostridia, and orders Bacteroidales and Clostridiales, were associated with worse RFS, while a higher abundance of classes Alphaproteobacteria and Betaproteobacteria, and orders Burkholderiales and Neisseriales, were associated with better RFS. In tumor tissue, a higher abundance of orders Actinomycetales and Pseudomonadales were associated with worse DFS. Among these taxa, normal lung Clostridiales and Bacteroidales were also related to worse survival in a previous small pilot study and an additional independent validation cohort. In peripheral blood, higher expression of genes TAP1, TAPBP, CSF2RB, and IFITM2 were associated with better DFS. Analysis of ROC curves revealed that lung microbiome and peripheral gene expression biomarkers provided significant additional recurrence risk discrimination over standard demographic and clinical covariates, with microbiome biomarkers contributing more to short-term (1-year) prediction and gene biomarkers contributing to longer-term (2-5-year) prediction. CONCLUSIONS:We identified compelling biomarkers in under-explored data types, the lung microbiome, and peripheral blood gene expression, which may improve risk prediction of recurrence in early-stage NSCLC patients. These findings will require validation in a larger cohort.

PURPOSE/OBJECTIVE:Lung adenocarcinoma (LUAD) is a clinically heterogenous disease, which is highlighted by the unpredictable recurrence in low-stage tumors and highly variable responses observed in patients treated with immunotherapies, which cannot be explained by mutational profiles. DNA methylation-based classification and understanding of microenviromental heterogeneity may allow stratification into clinically relevant molecular subtypes of LUADs. EXPERIMENTAL DESIGN/METHODS:We characterize the genome-wide DNA methylation landscape of 88 resected LUAD tumors. Exome sequencing focusing on a panel of cancer-related genes was used to genotype these adenocarcinoma samples. Bioinformatic and statistical tools, the immune cell composition, DNA methylation age (DNAm age), and DNA methylation clustering were used to identify clinically relevant subgroups. RESULTS:Deconvolution of DNA methylation data identified immunologically hot and cold subsets of lung adenocarcinomas. Additionally, concurrent factors were analyzed that could affect the immune microenvironment, such as smoking history, ethnicity, or presence of KRAS or TP53 mutations. When the DNAm age was calculated, a lower DNAm age was correlated with the presence of a set of oncogenic drivers, poor overall survival, and specific immune cell populations. Unsupervised DNA methylation clustering identified 6 molecular subgroups of LUAD tumors with distinct clinical and microenvironmental characteristics. CONCLUSIONS:Our results demonstrate that DNA methylation signatures can stratify lung adenocarcinoma into clinically relevant subtypes, and thus such classification of LUAD at the time of resection may lead to better methods in predicting tumor recurrence and therapy responses.

Background: For resectable NSCLC, surgery (often with neoadjuvant or adjuvant CT), is the standard of care. However, benefit is modest and there is need to improve outcomes. Atezo (anti-PD-L1) has shown promising efficacy as monotherapy and in combination with CT in NSCLC. Inhibition of the PD-L1 pathway may be amplified by inhibition of TIGIT signaling. In CITYSCAPE (phase II; NCT03563716), tira (anti-TIGIT) + atezo was well tolerated and improved objective response rate vs atezo alone in 1L metastatic PD-L1+ NSCLC. Hypothesis: tira + atezo may provide clinical benefit in the neoadjuvant setting by enhancing anti-tumour immune response and eradicating micrometastases, reducing risk of disease recurrence. SKYSCRAPER-05 (NCT04832854) will evaluate safety, tolerability and preliminary efficacy of neoadjuvant tira + atezo +/- CT in pts with resectable NSCLC. Trial design: In this global, open-label study, ~82 pts with histologically/cytologically confirmed, resectable Stage II, IIIA, or select IIIB (T3N2 only) NSCLC who are eligible for R0 resection with curative intent; without EGFR/ALK mutations; ECOG PS 0-1; with no prior cancer immunotherapy, CT or radiotherapy for NSCLC will be enrolled into two cohorts. Cohort A: pts with PD-L1 TC >=50% tumours or Cohort B: pts independent of PD-L1 status. Pts will receive 4 cycles of neoadjuvant tira 600 mg IV + atezo 1200 mg IV Q3W (Cohort A) (CT-free option) or in combination with platinum-doublet CT Q3W (Cohort B). Following resection, pts will receive adjuvant tira + atezo or platinum-based CT Q3W (Cohort A) or adjuvant tira + atezo for 16 cycles (Cohort B) until disease recurrence or unacceptable toxicity. Investigator-selected CT options are cisplatin or carboplatin + pemetrexed, carboplatin + paclitaxel, and cisplatin or carboplatin + gemcitabine. Primary endpoints: central pathology laboratory-assessed major pathological response, treatment-related surgical delays, cancellations/complications and safety. Secondary endpoints: pathological complete response and event-free survival. Exploratory biomarkers will be evaluated. Recruitment is ongoing. Clinical trial identification: NCT04832854. Editorial acknowledgement: Medical writing assistance, under the direction of the authors, was provided by Ashfield MedComms, an Ashfield Health company. Legal entity responsible for the study: F. Hoffmann-La Roche Ltd.
Funding(s): F. Hoffmann-La Roche Ltd. Disclosure: H. Pass: Financial Interests, Speaker's Bureau: BeiGene, Genentech Inc; Financial Interests, Royalties: NIH cell lines, Mesothelioma Book; Financial Interests, Advisory Board: genentech/Roche; Financial Interests, Research Grant: NCI/NIH, AACR; Financial Interests, Funding: NCI/NIH, AACR; Financial Interests, Advisory Role: Genentech/Roche. A.W. Kim: Non-Financial Interests, Advisory Board: Roche/Genentech Inc. E. Felip: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristrol Meyers Squibb, Eli Lilly, Glaxo Smith Kline, Janssen, Medical Trends, Merck Sharp & Dohme, Pfizer, Puma, Sanofi, Takeda, Merck Serono, Peptomyc, Regeneron, Syneos Health, F. Hoffmann-La Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristrol Meyers Squibb, Eli Lilly, Medscape, Merck Sharp & Dome, Peervoice, Pfizer, Springer, Touch Medical, Amgen, F. Hoffmann-La Roche, Janssen, Medical Trends, Merck Serono; Financial Interests, Personal, Invited Speaker, Independent member: Grifols; Financial Interests, Institutional, Invited Speaker, Clinical Trial: F. Hoffmann-La Roche Ltd, Merck Sharp & Dohme Corp, AstraZeneca AB, Daiichi Sankyo Inc, Exelixis Inc, Merck KGAA, Janssen Cilag International NV, GlaxoSmithKline Research & Development Limited, AbbVie Deutschland GmbH & Co KG, Novartis Farmaceutica SA, Bayer Consumer Care AG, Takeda Pharmaceuticals International, Boehringer Ingelheim International GmbH, Pfizer S.L.U., Amgen Inc, Bristol-Myers Squibb International Corporation (BMS), Mirati Therapeutics Inc; Non-Financial Interests, Leadership Role, President Elect (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of ESMO Nominating Committee and Compliance Committee: ESMO; Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Leadership Role, Member of Board of Directors and the Executive Committee (2017-Sept 2021): IASLC (International Association for the Study of Lung Cancer). C.A. Shu: Financial Interests, Advisory Board: Genentech Inc, Mirati, AstraZeneca, Janssen. M. Frueh: Financial Interests, Advisory Board: Roche. B.J. Gitlitz: Financial Interests, Full or part-time Employment: Roche/Genentech; Financial Interests, Stocks/Shares: Roche/Genentech. S. Troutman: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Stocks/Shares: Roche. X. Liu: Financial Interests, Full or part-time Employment: Genentech Inc. J. Hsu: Financial Interests, Full or part-time Employment: Roche/Genentech Inc; Financial Interests, Stocks/Shares: Roche/Genentech. N. Patil: Financial Interests, Full or part-time Employment: Roche/Genentech Inc. R.D. Meng: Financial Interests, Full or part-time Employment: Genentech Inc; Financial Interests, Stocks/Shares: Genentech Inc. All other authors have declared no conflicts of interest.
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The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma; less frequently breast cancer, several types of skin carcinomas and other tumor types. Mesotheliomas in these patients are significantly less aggressive and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, significant medical, social and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life and is also cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges and our recommendations of how to best care for these patients and their family members, as well as the potential economic and psychosocial impact.

BACKGROUND: Coronavirus disease-19 (COVID-19) remains a public health crisis. The epidemiology of COVID-19-associated large- and medium-sized-vessel pathology is not well characterized. The aim of this study is to identify patients with possible COVID-19-associated large- and medium-sized-vessel pathology based on computed tomography (CT) imaging to provide insight into this rare, but potentially devastating, cardiovascular manifestation. METHODS: This is a single-center retrospective review of patients with CT chest, abdomen, and/or pelvis concerning for large- and medium-vessel pathology and confirmed COVID-19 infection from March 1, 2020 to October 31, 2020. RESULTS: During the study period, 6,553 CT reports were reviewed and pertinent imaging was identified in 139 patients. Of these, 8 patients (median age: 59 years, range 51-82) were COVID-19 positive. All patients had preexisting cardiovascular risk factors and three (37.5%) had an autoimmune disease. Four patients were never hospitalized for COVID-19. Among these, two presented to the hospital at a median of 39 days (range: 27-50) after their initial COVID-19 test with chest and back pain where imaging revealed extensive aortic pathology. One patient required surgical management for aortic pathology. All other patients were treated with expectant management and outpatient follow-up. CONCLUSION/CONCLUSIONS: The clinical and radiological presentations of COVID-19-associated large- and medium-vessel pathology are heterogeneous and can be a late finding after COVID-19 recovery. Close clinical follow-up and surveillance imaging for large- and medium-sized-vessel pathology may be warranted in COVID-19 patients.