Publications by authors named "Boris Sepesi"

140 Publications

Single-Cell Expression Landscape of SARS-CoV-2 Receptor and Host Proteases in Normal and Malignant Lung Tissues from Pulmonary Adenocarcinoma Patients.

Cancers (Basel) 2021 Mar 12;13(6). Epub 2021 Mar 12.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

The novel coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Severely symptomatic COVID-19 is associated with lung inflammation, pneumonia, and respiratory failure, thereby raising concerns of elevated risk of COVID-19-associated mortality among lung cancer patients. Angiotensin-converting enzyme 2 (ACE2) is the major receptor for SARS-CoV-2 entry into lung cells. The single-cell expression landscape of and other SARS-CoV-2-related genes in pulmonary tissues of lung cancer patients remains unknown. We sought to delineate single-cell expression profiles of and other SARS-CoV-2-related genes in pulmonary tissues of lung adenocarcinoma (LUAD) patients. We examined the expression levels and cellular distribution of and SARS-CoV-2-priming proteases and in 5 LUADs and 14 matched normal tissues by single-cell RNA-sequencing (scRNA-seq) analysis. scRNA-seq of 186,916 cells revealed epithelial-specific expression of , , and . Analysis of 70,030 LUAD- and normal-derived epithelial cells showed that levels were highest in normal alveolar type 2 (AT2) cells and that was expressed in 65% of normal AT2 cells. Conversely, the expression of was highest and most frequently detected (75%) in lung cells with malignant features. -positive cells co-expressed genes implicated in lung pathobiology, including COPD-associated , and the scavengers and . Notably, the viral scavenger was significantly positively correlated with expression in AT2 cells. We describe normal and tumor lung epithelial populations that express SARS-CoV-2 receptor and proteases, as well as major host defense genes, thus comprising potential treatment targets for COVID-19 particularly among lung cancer patients.
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http://dx.doi.org/10.3390/cancers13061250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998226PMC
March 2021

Impact of Psychiatric Comorbidities on Surgical Outcomes for Non-Small Cell Lung Cancer.

Ann Thorac Surg 2021 Mar 24. Epub 2021 Mar 24.

Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Background: Psychiatric comorbidities (PC) have been associated with poor surgical outcomes in several malignancies. However, the impact of PC on surgical outcomes for non-small cell lung cancer (NSCLC) remains largely unknown.

Methods: NSCLC patients who underwent pulmonary resection at a single institution between 2006-2017 were included. Presence of preoperative PC was identified by documented diagnostic codes. Demographic, histopathologic, perioperative, and survival data were analyzed. Categorical variables were compared using chi-squared or Fisher's exact test. Overall and disease-free survival were analyzed using Kaplan-Meier method. Univariable and multivariable logistic regression analyses were performed for 30-day readmission.

Results: Among 2907 patients, PC were present preoperatively in 180 (6%), including 130 (72%) anxiety, 52 (29%) depression, 28 (16%) adjustment disorder, 16 (9%) alcohol abuse, 8 (4%) sleep disorder, and 3 (2%) schizophrenia. Patients with PC were younger, with fewer cardiovascular complications. There were no differences in length of stay. However, PC led to increased 30-day readmission (12% vs 6%, p=0.004). Reasons for readmission did not differ between groups (p=0.679). Upon multivariable analysis, PC independently predicted 30-day readmission (OR: 2.00, p=0.005). Importantly, there were no differences in 30- or 90-day mortality (p=0.495 and 0.748, respectively), overall survival (p=0.439), or disease-free survival (p=0.924).

Conclusions: NSCLC patients with and without PC experienced similar perioperative and long-term outcomes, suggesting that individuals should not be denied surgical care on the basis of such comorbidities. However, further research should seek to identify reasons for increased risk of readmission for patients with PC and validate these findings in other settings.
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http://dx.doi.org/10.1016/j.athoracsur.2021.03.034DOI Listing
March 2021

Simultaneous versus staged resections for bilateral pulmonary metastases.

J Surg Oncol 2021 Mar 8. Epub 2021 Mar 8.

Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: For patients with bilateral pulmonary metastases, staged resections have historically been the preferred surgical intervention. During the spring of 2020, the COVID-19 pandemic made patient travel to the hospital challenging and necessitated reduction in operative volume so that resources could be conserved. We report our experience with synchronous bilateral metastasectomies for the treatment of disease in both lungs.

Methods: Patients with bilateral pulmonary metastases who underwent simultaneous bilateral resections were compared with a cohort of patients who underwent staged resections. We used nearest-neighbor propensity score (1:1) matching to adjust for confounders. Perioperative outcomes were compared between groups using paired statistical analysis techniques.

Results: Between 1998 and 2020, 36 patients underwent bilateral simultaneous metastasectomies. We matched 31 pairs of patients. The length of stay was significantly shorter in patients undergoing simultaneous resection (median 3 vs. 8 days, p < .001) and operative time was shorter (156 vs. 235.5 min, p < .001) when compared to the sum of both procedures in the staged group. The groups did not significantly differ with regard to postoperative complications.

Conclusion: In a carefully selected patient population, simultaneous bilateral metastasectomy is a safe option. A single procedure confers benefits for both the patient as well as the hospital resource system.
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http://dx.doi.org/10.1002/jso.26392DOI Listing
March 2021

Identification of distinct immune landscapes using an automated nine-color multiplex immunofluorescence staining panel and image analysis in paraffin tumor tissues.

Sci Rep 2021 Feb 25;11(1):4530. Epub 2021 Feb 25.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Unit 9512130 Holcombe Blvd, Houston, TX, 77030, USA.

Immune profiling is becoming a vital tool for identifying predictive and prognostic markers for translational studies. The study of the tumor microenvironment (TME) in paraffin tumor tissues such as malignant pleural mesothelioma (MPM) could yield insights to actionable targets to improve patient outcome. Here, we optimized and tested a new immune-profiling method to characterize immune cell phenotypes in paraffin tissues and explore the co-localization and spatial distribution between the immune cells within the TME and the stromal or tumor compartments. Tonsil tissues and tissue microarray (TMA) were used to optimize an automated nine-color multiplex immunofluorescence (mIF) panel to study the TME using eight antibodies: PD-L1, PD-1, CD3, CD8, Foxp3, CD68, KI67, and pancytokeratin. To explore the potential role of the cells into the TME with this mIF panel we applied this panel in twelve MPM cases to assess the multiple cell phenotypes obtained from the image analysis and well as their spatial distribution in this cohort. We successful optimized and applied an automated nine-color mIF panel to explore a small set of MPM cases. Image analysis showed a high degree of cell phenotype diversity with immunosuppression patterns in the TME of the MPM cases. Mapping the geographic cell phenotype distribution in the TME, we were able to identify two distinct, complex immune landscapes characterized by specific patterns of cellular distribution as well as cell phenotype interactions with malignant cells. Successful we showed the optimization and reproducibility of our mIF panel and their incorporation for comprehensive TME immune profiling into translational studies that could refine our ability to correlate immunologic phenotypes with specific patterns of cells distribution and distance analysis. Overall, this will improve our ability to understand the behavior of cells within the TME and predict new treatment strategies to improve patient outcome.
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http://dx.doi.org/10.1038/s41598-021-83858-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907283PMC
February 2021

Controversies and challenges in the pathologic examination of lung resection specimens after neoadjuvant treatment.

Lung Cancer 2021 Apr 17;154:76-83. Epub 2021 Feb 17.

Department of Cardiovascular and Thoracic Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA.

New therapy approaches in the treatment of surgically resectable non-small cell lung cancer (NSCLC) challenge the traditional handling and examination of pathology specimens. The increasingly common use of neoadjuvant therapies before surgical resection, due to advantages in novel drug administration, tolerance, and measurement of radiographic and pathologic response compared to adjuvant treatment, has the potential to alter the microscopic tumor appearance and its biology. Currently, many clinical trials use pathologic response as a surrogate endpoint of clinical efficacy, since the extent of residual viable tumor appears to correlate with outcome in patients treated with neoadjuvant chemotherapy. Consequently, pathologic assessment of the extent of residual viable tumor is of paramount importance. However, high level evidence-based guidelines on how to process and evaluate such specimens are lacking. Moreover, while pathologic response has been shown to be associated with survival after chemotherapy, its significance after immunotherapy remains to be determined. Additionally, many clinical trials do not routinely include pathologists in trial design, which may lead to non-standardized evaluation of pathologic response. Although recently, several algorithms have been proposed to address these issues, none of them represents evidence-based recommendations or is universally applied. Therefore, controversies and challenges continue to exist, raising concerns about the validity, reproducibility, and comparability of the results of many neoadjuvant clinical trials. Herein, we discuss the current difficulties in pathologic specimen evaluation following neoadjuvant therapy in NSCLC and propose potential approaches to overcome these challenges.
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http://dx.doi.org/10.1016/j.lungcan.2021.02.014DOI Listing
April 2021

Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.

Nat Med 2021 03 18;27(3):504-514. Epub 2021 Feb 18.

Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.
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http://dx.doi.org/10.1038/s41591-020-01224-2DOI Listing
March 2021

Emerging biomarkers for neoadjuvant immune checkpoint inhibitors in operable non-small cell lung cancer.

Transl Lung Cancer Res 2021 Jan;10(1):590-606

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The advent of immune checkpoint inhibitors (ICIs) has dramatically changed the treatment of patients with locally advanced unresectable and metastatic non-small cell lung cancer (NSCLC). Now, ICIs are undergoing evaluation as neoadjuvant therapy in patients with early-stage, resectable NSCLC using candidate surrogate endpoints of clinical efficacy, i.e., major pathologic response (MPR, ≤10% viable tumor cells in resected tumors). The initial results from early, small-scale trials are encouraging; however, they also reveal that a substantial number of patients with operable disease may not benefit from neoadjuvant ICIs. Consequently, much investigative effort is currently directed toward identifying mechanisms of resistance to ICI therapy in resectable NSCLC. There is also an urgent need for biomarkers that could be used to guide the clinical decision-making process and maximize the clinical benefit of ICIs in patients with early-stage, resectable NSCLC. Here, we summarize the initial results from the trials of neoadjuvant ICIs in patients with early-stage and locally advanced operable NSCLC and review the findings of studies investigating emerging biomarkers associated with those trials.
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http://dx.doi.org/10.21037/tlcr-20-573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867746PMC
January 2021

Intestinal Metaplasia in the Esophageal Remnant Is Rare After Ivor Lewis Esophagectomy.

J Gastrointest Surg 2021 Feb 8. Epub 2021 Feb 8.

Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas, 77030, USA.

Background: Most patients undergoing esophagectomy will experience intermittent reflux of gastric and biliary content into the remnant esophagus postoperatively. The incidence of new or recurrent intestinal metaplasia following chemoradiation and surgery has not been well-described. Furthermore, post-resection guidelines do not exist regarding surveillance for metaplasia in the esophageal remnant.

Methods: Patients undergoing Ivor Lewis esophagectomy after concurrent chemoradiation for a diagnosis of esophageal adenocarcinoma from 2006 to 2018 were identified. Pathology records were reviewed for the presence of intestinal metaplasia on pretreatment biopsies, surgical specimen, or post-resection biopsies.

Results: In total, 619 patients met inclusion criteria, including 267 (43%) who had intestinal metaplasia noted either prior to or at the time of esophagectomy. The median duration of metaplastic disease prior to resection was 4.4 months. During a median follow-up time of 28 months (interquartile range, 12-60), intestinal metaplasia was noted in the remnant esophagus in 12 (2%) patients, 7 of whom had a prior history of metaplasia. Local recurrence of adenocarcinoma was also uncommon, and occurred in 37/577 (6%) of patients with complete resections, with similar event rates among those with and without a prior history of metaplasia (14/249 [6%] vs. 23/328 [7%], p = 0.614).

Conclusions: Our findings suggest that despite several factors predisposing to mucosal damage following esophagectomy, occurrence of new intestinal metaplasia after trimodality therapy in our patient population appears to be rare, even among patient with a previous history of this pathologic finding, which may have significant implications for surveillance and cost-savings after resection.
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http://dx.doi.org/10.1007/s11605-021-04909-2DOI Listing
February 2021

Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas.

Nat Commun 2021 01 29;12(1):687. Epub 2021 Jan 29.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

The evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of methylation aberrations and significantly higher level of methylation ITH in later-stage lesions. The phylogenetic patterns inferred from methylation aberrations resemble those based on somatic mutations suggesting parallel methylation and genetic evolution. De-convolution reveal higher ratio of T regulatory cells (Tregs) versus CD8 + T cells in later-stage diseases, implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation is associated with higher mutation burden, copy number variation burden and AI burden as well as higher Treg/CD8 ratio, highlighting the potential impact of methylation on chromosomal instability, mutagenesis and tumor immune microenvironment during early carcinogenesis of lung adenocarcinomas.
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http://dx.doi.org/10.1038/s41467-021-20907-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846738PMC
January 2021

CD73 expression defines immune, molecular, and clinicopathological subgroups of lung adenocarcinoma.

Cancer Immunol Immunother 2021 Jan 8. Epub 2021 Jan 8.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 2130 West Holcombe Boulevard, Houston, TX, 77030, USA.

Introduction: CD73 is a membrane-bound enzyme crucial in adenosine generation. The adenosinergic pathway plays a critical role in immunosuppression and in anti-tumor effects of immune checkpoint inhibitors (ICI). Here, we interrogated CD73 expression in a richly annotated cohort of human lung adenocarcinoma (LUAD) and its association with clinicopathological, immune, and molecular features to better understand the role of this immune marker in LUAD pathobiology.

Materials And Methods: Protein expression of CD73 was evaluated by immunohistochemistry in 106 archived LUADs from patients that underwent surgical treatment without neoadjuvant therapy. Total CD73 (T +) was calculated as the average of luminal (L +) and basolateral (BL +) percentage membrane expression scores for each LUAD and was used to classify tumors into three groups based on the extent of T CD73 expression (high, low, and negative).

Results: CD73 expression was significantly and progressively increased across normal-appearing lung tissue, adenomatous atypical hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and LUAD. In LUAD, BL CD73 expression was associated with an increase in PD-L1 expression in tumor cells and increase of tumor-associated immune cells. Stratification of LUADs based on T CD73 extent also revealed that tumors with high expression of this enzyme overall exhibited significantly elevated immune infiltration and PD-L1 protein expression. Immune profiling demonstrated that T-cell inflammation and adenosine signatures were significantly higher in CD73-expressing lung adenocarcinomas relative to those lacking CD73.

Conclusion: Our study suggests that higher CD73 expression is associated with an overall augmented host immune response, suggesting potential implications in the immune pathobiology of early stage lung adenocarcinoma. Our findings warrant further studies to explore the role of CD73 in immunotherapeutic response of LUAD.
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http://dx.doi.org/10.1007/s00262-020-02820-4DOI Listing
January 2021

Characterization of the Immune Landscape of EGFR-Mutant NSCLC Identifies CD73/Adenosine Pathway as a Potential Therapeutic Target.

J Thorac Oncol 2021 Apr 31;16(4):583-600. Epub 2020 Dec 31.

Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Introduction: Lung adenocarcinomas harboring EGFR mutations do not respond to immune checkpoint blockade therapy and their EGFR wildtype counterpart. The mechanisms underlying this lack of clinical response have been investigated but remain incompletely understood.

Methods: We analyzed three cohorts of resected lung adenocarcinomas (Profiling of Resistance Patterns of Oncogenic Signaling Pathways in Evaluation of Cancer of Thorax, Immune Genomic Profiling of NSCLC, and The Cancer Genome Atlas) and compared tumor immune microenvironment of EGFR-mutant tumors to EGFR wildtype tumors, to identify actionable regulators to target and potentially enhance the treatment response.

Results: EGFR-mutant NSCLC exhibited low programmed death-ligand 1, low tumor mutational burden, decreased number of cytotoxic T cells, and low T cell receptor clonality, consistent with an immune-inert phenotype, though T cell expansion ex vivo was preserved. In an analysis of 75 immune checkpoint genes, the top up-regulated genes in the EGFR-mutant tumors (NT5E and ADORA1) belonged to the CD73/adenosine pathway. Single-cell analysis revealed that the tumor cell population expressed CD73, both in the treatment-naive and resistant tumors. Using coculture systems with EGFR-mutant NSCLC cells, T regulatory cell proportion was decreased with CD73 knockdown. In an immune-competent mouse model of EGFR-mutant lung cancer, the CD73/adenosine pathway was markedly up-regulated and CD73 blockade significantly inhibited tumor growth.

Conclusions: Our work revealed that EGFR-mutant NSCLC has an immune-inert phenotype. We identified the CD73/adenosine pathway as a potential therapeutic target for EGFR-mutant NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2020.12.010DOI Listing
April 2021

Predictors of survival following surgical resection of limited-stage small cell lung cancer.

J Thorac Cardiovasc Surg 2021 Mar 27;161(3):760-771.e2. Epub 2020 Nov 27.

Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Tex. Electronic address:

Background: Adjuvant chemotherapy, postoperative radiation (PORT), and prophylactic cranial irradiation (PCI) have been individually examined in limited-stage small cell lung cancer (SCLC). There is a paucity of data on the effectiveness of each adjuvant treatment modality when used in combination after surgical resection of SCLC.

Methods: Data were collected from 5 cancer centers on all patients with limited-stage SCLC who underwent surgical resection between 1986 and 2019. Univariate and multivariable models were conducted to identify predictors of long-term outcomes, focusing on freedom from recurrence and survival benefit of adjuvant chemotherapy, PORT, and PCI.

Results: A total of 164 patients were analyzed. Multivariable Cox regression analysis did not identify any adjuvant therapies to significantly influence recurrence in this cohort. Specifically, PORT was not associated with a significant influence on locoregional recurrence and PCI was not significantly associated with intracranial outcomes. Adjuvant chemotherapy improved survival in all stage I through III disease (hazard ratio, 0.49; 95% confidence interval, 0.29-0.81; P = .005) and even in pathologically node negative patients (hazard ratio, 0.49; 95% confidence interval, 0.27-0.91; P = .024). Although PCI was found to improve survival in univariate analysis, it was not significant in a multivariable model. PORT was not found to affect survival on either univariate or multivariable analysis.

Conclusions: This is among the largest multi-institutional studies on surgically resected limited-stage SCLC. Our results highlight survival benefit of adjuvant chemotherapy, but did not identify a statistically significant influence from mediastinal PORT or PCI in our cohort. Larger prospective studies are needed to determine the benefit of PORT or PCI in a surgically resected limited-stage SCLC population.
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http://dx.doi.org/10.1016/j.jtcvs.2020.10.148DOI Listing
March 2021

Liposomal Bupivacaine Intercostal Block is Important for Reduction of Pulmonary Complications.

Ann Thorac Surg 2020 Oct 28. Epub 2020 Oct 28.

Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas, USA 77030. Electronic address:

Background: We have previously demonstrated that Enhanced Recovery After Surgery protocols are associated with a reduction in pulmonary complications. As a component of enhanced recovery pathways, intercostal nerve blocks with liposomal bupivacaine are increasingly utilized, but the extent to which this element may contribute to such outcomes has not been evaluated.

Methods: Patients undergoing lung resection for stage I-III non-small cell lung cancer at a single institution from 2006-2017 were examined for major postoperative pulmonary morbidity, defined as pneumonia, acute respiratory distress syndrome, respiratory arrest, reintubation, bronchoscopy, or need for discharge with oxygen. Pharmacy records were queried for administration of liposomal bupivacaine via posterior intercostal nerve block. Patients treated with and without liposomal bupivacaine were compared in a logistic regression to determine the impact upon pulmonary morbidity.

Results: 2865 patients were identified, including 860 (30%) who were treated with liposomal bupivacaine via posterior intercostal block. Pulmonary morbidity occurred in 455 (16%). Adoption of liposomal bupivacaine analgesia occurred over several years, beginning in 2012 to full adoption by 2017. Liposomal bupivacaine management was associated with a reduction in pulmonary complications, as compared to nonuse (odds ratio, 0.63, p=0.006). Additional factors associated with the occurrence of pulmonary morbidity were age, body mass index, smoking, spirometry values, and operative blood loss.

Conclusions: As a component of an active enhanced recovery program, liposomal bupivacaine is associated with a reduction in major pulmonary complications, and utilization should be evaluated on a hospital-by-hospital basis.
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http://dx.doi.org/10.1016/j.athoracsur.2020.09.017DOI Listing
October 2020

Neoadjuvant Chemotherapy Increases Cytotoxic T Cell, Tissue Resident Memory T Cell, and B Cell Infiltration in Resectable NSCLC.

J Thorac Oncol 2021 01 21;16(1):127-139. Epub 2020 Oct 21.

Department of Oncology, Queens' University and the Canadian Cancer Trials Group, Kingston, Ontario, Canada; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Introduction: The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade.

Methods: Genomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73).

Results: NCT was associated with increased infiltration of cytotoxic CD8 T cells and CD20 B cells. Moreover, NCT was associated with increases in CD8CD103 and CD4CD103PD-1TIM3 tissue resident memory T cells. Gene expression profiling supported memory function of CD8 and CD4 T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery.

Conclusions: Our study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8 and CD4 memory helper T cells.
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http://dx.doi.org/10.1016/j.jtho.2020.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775914PMC
January 2021

Esophageal adenocarcinoma with any component of signet ring cells portends poor prognosis and response to neoadjuvant therapy.

J Thorac Cardiovasc Surg 2020 Sep 5. Epub 2020 Sep 5.

Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Tex.

Background: Multiple investigations have shown inferior outcomes for esophageal cancer patients with signet ring cell (SRC) histology. Traditionally, SRC adenocarcinoma has been defined by ≥50% of the tumor composed of SRC. We hypothesized that patients with SRC even <50% would show resistance to standard multimodality therapy with poorer long-term outcomes.

Methods: Patients treated with trimodality therapy for adenocarcinoma from 2006 to 2018 were evaluated for SRC on pretreatment biopsy specimens. Available hematoxylin and eosin slides containing SRC tumors were re-reviewed by an esophageal pathologist to quantify the percent composition of SRC.

Results: SRC histology was identified on at least 1 pathologic specimen in 106 of 819 (13%) patients. Rates of pathologic complete response (pCR) among usual-type and SRC tumors were 25% (177/713) and 10% (11/106), respectively (P = .006). The pretreatment SRC components did not independently affect the rate of pCR (1%-10% SRC: 4% [2/46] pCR; 11%-49% SRC: 25% [7/28] pCR; 50%-100% SRC: 7% [2/30] pCR). Kaplan-Meier analysis demonstrated worse survival among patients with any degree of SRC present on pretreatment biopsy, as compared with usual-type esophageal adenocarcinoma (P < .0001). Cox multivariable analysis failed to identify a relationship between increasing SRC component and poorer survival.

Conclusions: We present the only known evaluation of the percentage of SRC component in esophageal carcinoma. Our data support the hypothesis that esophageal adenocarcinoma with any component of SRC are more resistant to chemoradiation with poorer survival. Pathologic reporting of esophageal adenocarcinoma should include any component of SRC. Alternative therapies in patients with any SRC component may be indicated.
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http://dx.doi.org/10.1016/j.jtcvs.2020.08.108DOI Listing
September 2020

Perioperative outcomes among chronic opioid users who receive lobectomy for non-small cell lung cancer.

J Thorac Cardiovasc Surg 2020 02 27;159(2):691-702.e5. Epub 2019 Sep 27.

Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Tex. Electronic address:

Objective: We sought to identify whether chronic opioid users are at increased risk for complications or hospital readmission following lobectomy for non-small cell lung cancer.

Methods: The National Cancer Institute Surveillance, Epidemiology, and End Results-Medicare database was queried to identify patients older than age 65 years who received a lobectomy for non-small cell lung cancer. Chronic opioid users were identified through Medicare Part D records and were defined as those with >120 cumulative days of opioid supply for the year before surgery. A systematic 1:2 propensity matching was performed among chronic opioid users.

Results: Six thousand four hundred thirty-seven patients were identified, among whom 3627 (56%) were opioid naïve, 1866 (29%) were intermittent opioid users, and 944 (15%) were chronic opioid users. After propensity matching, 30-day mortality and 90-day mortality were nearly 2-fold higher among chronic opioid users compared with nonchronic users. In addition, length of stay and hospital charges were increased among chronic opioid users (median, 6 vs 7 days and mean increase, $12,526, respectively). Multivariable analysis revealed that intermittent opioid users and chronic opioid users were associated with an increased risk of 90-day hospital readmission compared with opioid-naïve patients (odds ratio, 1.35; 95% confidence interval, 1.07-1.71 and odds ratio, 1.72; 95% confidence interval, 1.40-2.12, respectively), predominantly burdened by infectious, renal, and pulmonary causes.

Conclusions: Patients who chronically use opioids before lobectomy represent high-risk patients. The risk of 30- and 90-day mortality, length of stay, hospital charges, and 90-day readmission after lobectomy among chronic opioid users are substantially elevated.
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http://dx.doi.org/10.1016/j.jtcvs.2019.09.059DOI Listing
February 2020

Postoperative Bleeding and Acute Kidney Injury in Esophageal Cancer Patients Receiving Ketorolac.

Ann Thorac Surg 2021 04 24;111(4):1111-1117. Epub 2020 Sep 24.

Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Background: As strategies promoting enhanced recovery protocols and opioid minimization techniques are increasingly prioritized, use of nonsteroidal antiinflammatory drugs continues to rise. Whether this prevalent use poses increased risk for bleeding or renal dysfunction in surgical populations after extensive dissection and fluid shifts is unclear.

Methods: We reviewed records of patients undergoing esophagectomy for a diagnosis of esophageal adenocarcinoma at a single institution from 2006 to 2018 for ketorolac administration during the postoperative hospital admission, as well as the occurrence of postoperative events, defined as the need for blood product transfusion and/or acute kidney injury.

Results: We identified 1019 patients, 123 of whom experienced postoperative events (12%). Ketorolac was administered to 686 (67%). Furthermore, ketorolac use steadily increased over the study period; 36 of 72 patients received this medication in 2006 (49%), and 76 of 83 in 2018 (92%). Multivariable logistic regression failed to identify a relationship between ketorolac administration (assessed as a binary covariate) and postoperative events (P = .657). Additional examination for a dose-response relationship using the cumulative total dose from the time of surgery to discharge also did not demonstrate a relationship with postoperative events (P = .829). In an effort to evaluate a more homogeneous population, we performed a subgroup analysis using only patients treated with trimodality therapy, which showed similar findings.

Conclusions: Ketorolac has become a staple of multimodal postesophagectomy analgesic regimens. Importantly, this medication does not pose risk for acute kidney injury or bleeding after surgery.
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http://dx.doi.org/10.1016/j.athoracsur.2020.07.028DOI Listing
April 2021

Emerging Therapies in Thoracic Malignancies-Immunotherapy, Targeted Therapy, and T-Cell Therapy in Non-Small Cell Lung Cancer.

Surg Oncol Clin N Am 2020 10 29;29(4):555-569. Epub 2020 Jul 29.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

Immunotherapy, targeted therapy, and adoptive T-cell therapy have been revolutionary advancements in cancer research. Some of these therapies have become the standard of care for lung cancer and replaced older treatment algorithms; some continue to be studied in clinical trials. This article discusses the current state of novel treatment options for non-small cell lung cancer patients with metastatic and locoregional disease, with focus on immunotherapy, targeted therapy, and adoptive T-cell therapy.
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http://dx.doi.org/10.1016/j.soc.2020.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388816PMC
October 2020

Pathological nodal disease defines survival outcomes in patients with lung cancer with tumour major pathological response following neoadjuvant chemotherapy.

Eur J Cardiothorac Surg 2021 Jan;59(1):100-108

Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Objectives: Major pathological response (MPR) is prognostic of outcomes for patients with non-small-cell lung cancer following neoadjuvant chemotherapy and is used as the primary end point in neoadjuvant immunotherapy trials. We studied the influence of pathological nodal disease on patterns and timing of recurrence among patients with MPR.

Methods: Patients treated with neoadjuvant chemotherapy for stages I-III non-small-cell lung cancer were identified. Surgical specimens were histopathologically examined for tumour viability, categorized as ≤10% viability (MPR) or >10% (NoMPR). Overall survival and disease-free survival were evaluated with emphasis upon MPR and pathological nodal disease.

Results: Among 307 patients, 58 (19%) had MPR within primary tumour and 42 (14%) had MPRypN0. In the MPR group, the frequency of cN0 and cN+ disease was 18 (31%) and 40 (69%); similarly, the frequency of ypN0, ypN1 and ypN2 was 72% (42/58), 16% (9/58) and 12% (7/58), respectively. When evaluating only those with MPR, recurrence rates among those with MPRypN0, MPRypN1 and MPRypN2 were 33% (14/42), 44% (4/9) and 71% (5/7) (P = 0.16). The median time-to-recurrence in MPRypN0, MPRypN1 and MPRypN2 was 40, 10 and 14 months (P = 0.006). Distant recurrences were less common among those with MPRypN0 [MPRypN0, 26% (11/42); MPRypN1, 44% (4/9); MPRypN2, 71% (5/7); P = 0.047]. Though the median disease-free survival was prolonged among those with MPR vs NoMPR (120 vs 25 months, P < 0.0001), only those with MPRypN0 had prolonged disease-free survival in comparison to other groups upon pairwise comparisons, while MPRypN+ experienced no benefit.

Conclusions: MPRypN0 represents the most favourable surrogate end point following neoadjuvant chemotherapy. Patients with ypN1-2 are at the risk of early recurrence regardless of primary tumour MPR, warranting intensive surveillance and consideration for additional adjuvant therapy. We highlight that MPRypN0 is the most rigorous end point and should be considered as a surrogate end point in future neoadjuvant trials.
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http://dx.doi.org/10.1093/ejcts/ezaa290DOI Listing
January 2021

Modified En Bloc Esophagectomy Compared With Standard Resection After Neoadjuvant Chemoradiation.

Ann Thorac Surg 2021 04 25;111(4):1133-1140. Epub 2020 Aug 25.

Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Background: Surgeons have shifted away from the practice of en bloc esophagectomy, particularly in the era of neoadjuvant therapies. Although some still advocate for this radical approach, contemporary data establishing its superiority are sparse. We hypothesized that a more complete, radical resection could be completed in the setting of chemoradiation without adding morbidity.

Methods: Patients undergoing esophagectomy after neoadjuvant chemoradiation for esophageal adenocarcinoma from 2006-2018 were evaluated. Outcomes after right transthoracic en bloc esophagectomy were compared with standard esophagectomy to determine the impact on outcomes. A Cox proportional hazard model was evaluated, and logistic regression was performed to determine the impact of en bloc resection on postoperative morbidity.

Results: A total of 604 patients were identified, including 133 (22%) who underwent modified en bloc esophagectomy. Positive margins were most likely to occur in standard esophagectomy (35 of 471, 7%) vs en bloc (3 of 133, 2%) (P = .026). En bloc resection yielded a greater lymph node harvest (27; interquartile range, 22-36), as compared to standard esophagectomy (22; interquartile range, 17-28), P < .001. Multivariable analysis demonstrated prolonged progression-free survival with en bloc resection (hazard ratio, 0.74; P = .041), with 3-year freedom from locoregional recurrences of 78% and 90% for standard and en bloc approaches (P = .044). There were no differences in cardiopulmonary, gastrointestinal, or wound complications, as well as leak or chylothorax.

Conclusions: Our experience demonstrates improved locoregional disease control with en bloc esophagectomy, with equivalent morbidity. Although these results may be multifactorial, including adequate clearance of both primary tumor and nodal micrometastases, this approach is safe and feasible.
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http://dx.doi.org/10.1016/j.athoracsur.2020.06.054DOI Listing
April 2021

Evolution of Genomic and T-cell Repertoire Heterogeneity of Malignant Pleural Mesothelioma Under Dasatinib Treatment.

Clin Cancer Res 2020 Oct 14;26(20):5477-5486. Epub 2020 Aug 14.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Malignant pleural mesothelioma (MPM) is considered an orphan disease with few treatment options. Despite multimodality therapy, the majority of MPMs recur and eventually become refractory to any systemic treatment. One potential mechanism underlying therapeutic resistance may be intratumor heterogeneity (ITH), making MPM challenging to eradicate. However, the ITH architecture of MPM and its clinical impact have not been well studied.

Experimental Design: We delineated the immunogenomic ITH by multiregion whole-exome sequencing and T-cell receptor (TCR) sequencing of 69 longitudinal MPM specimens from nine patients with resectable MPM, who were treated with dasatinib.

Results: The median total mutation burden before dasatinib treatment was 0.65/Mb, similar with that of post-dasatinib treatment (0.62/Mb). The median proportion of mutations shared by any given pair of two tumor regions within the same tumors was 80% prior to and 83% post-dasatinib treatment indicating a relatively homogenous genomic landscape. T-cell clonality, a parameter indicating T-cell expansion and reactivity, was significantly increased in tumors after dasatinib treatment. Furthermore, on average, 82% of T-cell clones were restricted to individual tumor regions, with merely 6% of T-cell clones shared by all regions from the same tumors indicating profound TCR heterogeneity. Interestingly, patients with higher T-cell clonality and higher portion of T cells present across all tumor regions in post-dasatinib-treated tumors had significantly longer survival.

Conclusions: Despite the homogeneous genomic landscape, the TCR repertoire is extremely heterogeneous in MPM. Dasatinib may potentially induce T-cell response leading to improved survival.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709879PMC
October 2020

Female Gender Predicts Augmented Immune Infiltration in Lung Adenocarcinoma.

Clin Lung Cancer 2020 Jun 14. Epub 2020 Jun 14.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Introduction: Immune infiltration in lung adenocarcinomas (LUADs) has been associated with response to immune checkpoint inhibitors. Clinical features underlying differential responses of patients with LUADs to immunotherapy are not well understood. Here, we analyzed the association between LUAD immune infiltration and clinicopathologic variables.

Materials And Methods: Intratumoral CD3, CD8, and CD68 cell densities (tumor-associated immune cells [TAICs]) were immunohistochemically assessed in 146 surgically resected LUADs. LUADs were classified into 2 groups, low and high TAICs, based on the median values of cell densities for CD3, CD8, and CD68. Somatic mutation burden and driver gene mutation status were analyzed in a subset of the cases (n = 92). We statistically analyzed the association between the TAIC groups and various clinicopathologic and molecular variables by using the χ/Fisher and Wilcoxon sum tests and multivariable logistic regression models.

Results: Patient gender, tumor size, and STK11 mutations were significantly associated with TAIC levels in LUAD. Female patients exhibited significantly elevated TAIC levels (P = .005) compared with male patients. Tumor size was inversely associated with TAIC levels (P = .012). STK11 mutated tumors were associated with lower TAICs (P = .008). Higher TAICs were consistently observed in female patients with LUADs after adjusting for stage, tumor size, and age. Multivariable regression models confirmed female gender as an independent variable associated with TAIC levels in LUAD (P = .0141).

Conclusion: Immune infiltration in LUADs was significantly higher in female patients, warranting further exploration into the association between this clinical variable and immunotherapeutic response in LUAD.
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http://dx.doi.org/10.1016/j.cllc.2020.06.003DOI Listing
June 2020

Perioperative considerations for neoadjuvant immunotherapy in non-small cell lung cancer.

J Thorac Cardiovasc Surg 2020 Nov 5;160(5):1376-1382. Epub 2020 Jul 5.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.

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http://dx.doi.org/10.1016/j.jtcvs.2020.05.119DOI Listing
November 2020

Genomic assessment distinguishes intrapulmonary metastases from synchronous primary lung cancers.

J Thorac Dis 2020 May;12(5):1952-1959

Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Multiple synchronous lung tumors (MSLT), particularly within a single lobe, represent a diagnostic and treatment challenge. While histologic assessment was once the only method to possibly distinguish multiple primary lung cancers, there is a growing interest in identifying unique genomic features or mutations to best characterize these processes.

Methods: In order to differentiate multiple primary lung malignancies from intrapulmonary metastases in patients with MSLT, we performed whole exome sequencing (WES) on 10 tumor samples from 4 patients with MSLT.

Results: Shared mutations between tumors from the same patient varied from 0-91%. Patient 3 shared no common mutations; however, in Patients 2 and 4, identical mutations were identified among all tumors from each patient, suggesting that the three tumors identified in Patient 3 represent separate primary lung cancers, while those of Patients 1, 2 and 4 signify hematogenous and lymphatic spread.

Conclusions: A high proportion of shared mutations between different lung tumors is likely indicative of intrapulmonary metastatic disease, while tumors with distinct genomic profiles likely represent multiple primary malignancies driven by distinct molecular events. Application of genomic profiling in the clinical setting may prove to be important to precise management of patients with MSLT.
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http://dx.doi.org/10.21037/jtd-20-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330333PMC
May 2020

Peripheral cytokines are not influenced by the type of surgical approach for non-small cell lung cancer by four weeks postoperatively.

Lung Cancer 2020 08 27;146:303-309. Epub 2020 Jun 27.

Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, United States. Electronic address:

Objectives: The influence of surgical approach on systemic inflammatory response and the subsequent oncologic impact for non-small cell lung cancer is debated. We aimed to measure the effects of thoracic surgical approach on peripheral cytokine milieu over time.

Methods: Patients undergoing primary lung resection without neoadjuvant therapy (2016-2018) were evaluated. A panel of 43 cytokines, angiogenic factors, and inflammatory molecules (CAFs) were evaluated in peripheral blood preoperatively, at 24 -hs and 4-weeks postoperatively. Differences between CAFs in patients undergoing thoracotomy versus video-assisted thoracoscopic surgery (VATS) at all timepoints were assessed using Student's t-test.

Results: 76 patients with available peripheral CAF panels met inclusion criteria. Thoracotomy was performed in 53 (70 %) patients while VATS was undertaken in 23 (30 %). Upon examination of known inflammatory CAFs, including IL-1β, IL-6, IL-8, IL-10, IFN-γ, and soluble (s) CD27, no differences were detected at 24 h or 4 weeks postoperatively between surgical groups. Examination of trends over time did not demonstrate any temporal derangements for these CAFs, with return to baseline levels by 4 weeks postoperatively for both groups. Evaluation of soluble (s) checkpoint molecules, including sPD-1, sPD-L1, sTIM-3, and sCTLA-4, did not reveal any differences in the immediate postoperative or long-term recovery period.

Conclusions: Peripheral immune profiles following pulmonary resection do not appear to differ between VATS and thoracotomy postoperatively. CAF fluctuations are transient and recover rapidly. These results, at the peripheral cytokine level, suggest that the surgical approach for lung cancer is unlikely to alter the effectiveness of novel immune-modulating systemic therapies, although more studies are needed to validate these findings.
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http://dx.doi.org/10.1016/j.lungcan.2020.06.022DOI Listing
August 2020

Importance of resection for locoregional disease control in Masaoka stage IVA thymic neoplasms.

J Surg Oncol 2020 Sep 28;122(3):515-522. Epub 2020 May 28.

Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas.

Background And Objectives: It is unclear if a specific strategy for simultaneous treatment of primary thymic neoplasms and pleural metastases confers benefit for Masaoka stage IVA disease. We reviewed our experience with thymic neoplasms with concurrent pleural metastases to identify factors influencing outcomes.

Methods: Records of patients who presented with stage IVA thymic neoplasms from 2000 to 2018 were assessed. Multivariate Cox proportional hazards analyses were completed to determine predictors of progression-free and overall survival.

Results: Forty-eight patients were identified, including 34 (71%) who underwent surgery. Median overall and progression-free survival were 123 and 21 months, respectively. The extent of resection varied, and was most commonly thymectomy plus partial pleurectomy (22, 65%). Median progression-free survival for patients who underwent surgical resection versus those who had not was 24 versus 12 months (P = .018). Following surgical resection, mediastinal recurrence was uncommon (2, 6%, vs 7, 50% nonoperatively). Five-year survival rates in these groups were suggestive of possible benefit to surgery (87% vs 68%).

Conclusions: Thymic neoplasms with pleural dissemination represents a treatment challenge. As part of a multidisciplinary approach, surgery appears to be associated with more favorable long-term results, although selection bias may account for some of the survival differences observed.
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http://dx.doi.org/10.1002/jso.25981DOI Listing
September 2020

Effects of Surgery on Survival of Early-Stage Patients With SCLC: Propensity Score Analysis and Nomogram Construction in SEER Database.

Front Oncol 2020 24;10:626. Epub 2020 Apr 24.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Medical Oncology, Peking University Cancer Hospital & Institute, Beijing, China.

We aimed to assess the survival benefit of surgery for patients with stage IA-IIB small cell lung cancer (SCLC) and construct a nomogram for predicting overall survival (OS). Patients who had been diagnosed with stage IA-IIB SCLC between 2004 and 2014 and who had received active treatment were selected from the Surveillance, Epidemiology, and End Results database. The primary endpoint was OS. Cox proportional hazards models and propensity score (PS) analyses were used to compare the associations between surgery and OS. The probability of 1- and 3-year OS was predicted using a nomogram. We reviewed 2,246 patients. The median OS of the surgery and non-surgery groups was 35 months and 19 months, respectively. Multivariable Cox proportional hazards models showed a survival benefit in the surgery group (hazards ratio [HR], 0.642; 95% confidence interval [CI], 0.557-0.740; < 0.001). To balance the between-group measurable confounders, the impact of surgery on OS was assessed using PS matching. After PS matching, OS analysis still favored surgical resection. The PS-stratification, PS-weighting, and PS-adjustment models showed similar results to demonstrate a statistically significant benefit for surgery. Further, the nomogram was well calibrated and had good discriminative ability (Harrell's -index = 0.645). Our analysis suggests that surgery is a viable option for patients with early-stage SCLC. Our nomogram is a viable tool for quantifying treatment trade-off assumptions and may assist clinicians in decision-making. Future work is needed to validate our results and improve our tools.
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http://dx.doi.org/10.3389/fonc.2020.00626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193096PMC
April 2020

Programmed Death-Ligand 1 Heterogeneity and Its Impact on Benefit From Immune Checkpoint Inhibitors in NSCLC.

J Thorac Oncol 2020 09 8;15(9):1449-1459. Epub 2020 May 8.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Introduction: Programmed death-ligand 1 (PD-L1) expression may vary in different disease sites and at different time points of the disease course. We aimed to investigate PD-L1 heterogeneity and its usefulness as a predictive value for immune checkpoint inhibitor (ICI) therapy in patients with NSCLC.

Methods: PD-L1 expression was analyzed in 1398 patients with NSCLC. The predictive value of PD-L1 for ICIs in 398 patients with metastatic NSCLC was assessed.

Results: PD-L1 was significantly associated with biopsy sites (p = 0.004). Adrenal, liver, and lymph node (LN) metastases had the highest PD-L1 expression as a continuous variable and at 1% or 50% cutoff. PD-L1 expression was lower in bone and brain metastases. Among 112 patients with two specimens tested, 55 (49%) had major changes in PD-L1 falling into different clinically relevant categories (<1%, 1%-49%, ≥50%) at different time points. Previous ICI therapy was associated with significant decrease in PD-L1 compared with treatment-naive counterparts (p = 0.015). Patients with metastatic NSCLC treated with ICI (n = 398) were divided into three cohorts on the basis of biopsy sites: lung (n = 252), LN (n = 85), and distant metastasis (n = 61). Higher PD-L1 in lung or distant metastasis specimens was associated with higher response rate, longer progression-free survival, and overall survival. However, PD-L1 in LN biopsies was not associated with either response or survival.

Conclusions: PD-L1 varies substantially across different anatomical sites and changes during the clinical course. PD-L1 from different biopsy sites may have different predictive values for benefit from ICIs in NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2020.04.026DOI Listing
September 2020

Time trends and predictors of survival in surgically resected early-stage non-small cell lung cancer patients.

J Surg Oncol 2020 Sep 30;122(3):495-505. Epub 2020 Apr 30.

Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: The improvement in the management of lung cancer have the potential to improve survival in patients undergoing resection for early-stage (stage I and II) non-small cell lung cancer (NSCLC), but few studies have evaluated time trends and identified predictors of overall survival (OS).

Methods: We identified surgically resected early-stage NSCLC between 1998 and 2016. The 3-year OS (1998-2014) and 5-year OS (1998-2012) rates were calculated for each year. Joinpoint regression was used to calculate annual percentage changes (APC) and to test time trends in OS. Multivariable Cox regression was used to identify predictors of OS.

Results: There was a significant upward trend in the 3-year (1998, 56%; 2014, 83%; APC = 1.8) and 5-year (1998, 47%; 2012, 76%; APC = 3.1) OS. Older age; male sex; history of diabetes, coronary artery disease, and chronic obstructive pulmonary disease; high ASA score; smoking pack-years; high-grade tumor; pneumonectomy; thoracotomy; neoadjuvant therapy; nodal disease; and positive tumor margin were predictors of poor OS.

Conclusion: The upward time trend in OS suggests that improved staging, patient selection, and management have conferred a survival benefit in early-stage NSCLC patients. The prediction model of OS could be used to refine selection criteria for resection and improve survival outcomes.
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http://dx.doi.org/10.1002/jso.25966DOI Listing
September 2020