An atlas of epithelial cell states and plasticity in lung adenocarcinoma.

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8+ cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention.

Perioperative Nivolumab in Resectable Lung Cancer.

BACKGROUND: Standard treatment with neoadjuvant nivolumab plus chemotherapy significantly improves outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative treatment (i.e., neoadjuvant therapy followed by surgery and adjuvant therapy) with nivolumab may further improve clinical outcomes. METHODS: In this phase 3, randomized, double-blind trial, we assigned adults with resectable stage IIA to IIIB NSCLC to receive neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary outcome was event-free survival according to blinded independent review. Secondary outcomes were pathological complete response and major pathological response according to blinded independent review, overall survival, and safety. RESULTS: At this prespecified interim analysis (median follow-up, 25.4 months), the percentage of patients with 18-month event-free survival was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (hazard ratio for disease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% confidence interval [CI], 0.42 to 0.81; P<0.001). A pathological complete response occurred in 25.3% of the patients in the nivolumab group and in 4.7% of those in the chemotherapy group (odds ratio, 6.64; 95% CI, 3.40 to 12.97); a major pathological response occurred in 35.4% and 12.1%, respectively (odds ratio, 4.01; 95% CI, 2.48 to 6.49). Grade 3 or 4 treatment-related adverse events occurred in 32.5% of the patients in the nivolumab group and in 25.2% of those in the chemotherapy group. CONCLUSIONS: Perioperative treatment with nivolumab resulted in significantly longer event-free survival than chemotherapy in patients with resectable NSCLC. No new safety signals were observed. (Funded by Bristol Myers Squibb; CheckMate 77T ClinicalTrials.gov number, NCT04025879.).

Early Interventional Treatment of High Output Chyle Leak After Esophagectomy is Associated With Improved Survival.

OBJECTIVE: To investigate overall survival and length of stay (LOS) associated with differing management for high output (>1 L over 24 hours) leaks (HOCL) after cancer-related esophagectomy. BACKGROUND: Although infrequent, chyle leak after esophagectomy is an event that can lead to significant perioperative sequelae. Low-volume leaks appear to respond to nonoperative measures, whereas HOCLs often require invasive therapeutic interventions. METHODS: From a prospective single-institution database, we retrospectively reviewed patients treated from 2001 to 2021 who underwent esophagectomy for esophageal cancer. Within that cohort, we focused on a subgroup of patients who manifested a HOCL postoperatively. Clinicopathologic and operative characteristics were collected, including hospital LOS and survival data. RESULTS: A total of 53/2299 patients manifested a HOCL. These were mostly males (77%), with a mean age of 62 years. Of this group, 15 patients received nonoperative management, 15 patients received prompt (<72 hours from diagnosis) interventional management, and 23 received late interventional management. Patients in the late intervention group had longer LOSs compared with early intervention (slope = 9.849, 95% CI: 3.431-16.267). Late intervention (hazard ratio: 4.772, CI: 1.384-16.460) and nonoperative management (hazard ratio: 4.731, CI: 1.294-17.305) were associated with increased mortality compared with early intervention. Patients with early intervention for HOCL had an overall survival similar to patients without chyle leaks in survival analysis. CONCLUSIONS: Patients with HOCL should receive early intervention to possibly reverse the prognostic implications of this potentially detrimental complication.

Pathologic Processing of Lung Cancer Resection Specimens After Neoadjuvant Therapy.

Neoadjuvant treatment of non-small cell lung cancer challenges the traditional processing of pathology specimens. Induction therapy before resection allows evaluation of the efficacy of neoadjuvant agents at the time of surgery. Many clinical trials use pathologic tumor response, measured as major pathologic response (MPR, ≤10% residual viable tumor [RVT]) or complete pathologic response (CPR, 0% RVT) as a surrogate of clinical efficacy. Consequently, accurate pathologic evaluation of RVT is crucial. However, pathologic assessment has not been uniform, which is particularly true for sampling of the primary tumor, which instead of the traditional processing, requires different tissue submission because the focus has shifted from tumor typing alone to RVT scoring. Using a simulation study, we analyzed the accuracy rates of %RVT, MPR, and CPR of 31 pretreated primary lung tumors using traditional grossing compared with the gold standard of submitting the entire residual primary tumor and identified the minimum number of tumor sections to be submitted to ensure the most accurate scoring of %RVT, MPR, and CPR. Accurate %RVT, MPR, and CPR calls were achieved in 52%, 87%, and 81% of cases, respectively, using the traditional grossing method. Accuracy rates of at least 90% for these parameters require either submission of all residual primary tumor or at least 20 tumor sections. Accurate %RVT, MPR, and CPR scores cannot be achieved with traditional tumor grossing. Submission of the entire primary tumor, up to a maximum of 20 sections, is required for the most accurate reads.

Do resected colorectal cancer patients need early chest imaging? Impact of clinicopathologic characteristics on time to development of pulmonary metastases.

BACKGROUND AND OBJECTIVES: For patients with colorectal cancer (CRC), the lung is the most common extra-abdominal site of distant metastasis. However, practices for chest imaging after colorectal resection vary widely. We aimed to identify characteristics that may indicate a need for early follow-up imaging. METHODS: We retrospectively reviewed charts of patients who underwent CRC resection, collecting clinicopathologic details and oncologic outcomes. Patients were grouped by timing of pulmonary metastases (PM) development. Analyses were performed to investigate odds ratio (OR) of PM diagnosis within 3 months of CRC resection. RESULTS: Of 1600 patients with resected CRC, 233 (14.6%) developed PM, at a median of 15.4 months following CRC resection. Univariable analyses revealed age, receipt of systemic therapy, lymph node ratio (LNR), lymphovascular and perineural invasion, and KRAS mutation as risk factors for PM. Furthermore, multivariable regression showed neoadjuvant therapy (OR: 2.99, p < 0.001), adjuvant therapy (OR: 6.28, p < 0.001), LNR (OR: 28.91, p < 0.001), and KRAS alteration (OR: 5.19, p < 0.001) to predict PM within 3 months post-resection. CONCLUSIONS: We identified clinicopathologic characteristics that predict development of PM within 3 months after primary CRC resection. Early surveillance in such patients should be emphasized to ensure timely identification and treatment of PM.

Octreotide's role in the management of post-esophagectomy chylothorax.

The use of octreotide in managing intrathoracic chyle leak following esophagectomy has gained popularity in the adult population. While the benefits of octreotide have been confirmed in the pediatric population, there remains limited evidence to support its use in the adults post-esophagectomy. Thus, we performed a single-institution cohort study to characterize its efficacy. The study was performed using a prospective, single-center database, from which clinicopathologic characteristics were extracted of patients who had post-esophagectomy chyle leaks. Kaplan-Meier and multivariable Cox regression analyses were performed to investigate the effect of octreotide use on chest tube duration (CTD), hospital length of stay (LOS), and overall survival (OS). In our cohort, 74 patients met inclusion criteria, among whom 27 (36.5%) received octreotide. Kaplan-Meier revealed no significant effect of octreotide on CTD (P = 0.890), LOS (P = 0.740), or OS (P = 0.570). Multivariable Cox regression analyses further corroborated that octreotide had no effect on CTD (HR = 0.62, 95% confidence interval [CI]: 0.32-1.20, P = 0.155), LOS (HR = 0.64, CI: 0.34-1.21, P = 0.168), or OS (1.08, CI: 0.53-2.19, P = 0.833). Octreotide use in adult patients with chyle leak following esophagectomy lacks evidence of association with meaningful clinical outcomes. Level 1 evidence is needed prior to further consideration in this population.

Financial Toxicity in Patients With Resected Lung Cancer.

OBJECTIVES: To describe financial toxicity (FT) in patients with resected lung cancer and identify risk factors in this population. BACKGROUND: FT describes the financial burden associated with cancer care and its impact on the quality of survivorship. Few prior studies have examined FT in patients with lung cancer. METHODS: Patients who underwent lung cancer resection at our institution between January 1, 2016 and December 31, 2021, were surveyed to gather demographic information and evaluate FT using a validated questionnaire. A multivariable model was built to identify risk factors for FT. RESULTS: Of the total, 1477 patients were contacted, of whom 463 responded (31.3%). Most patients were stage I (n = 349, 75.4%) and lobectomy was performed often (n = 290, 62.8%). There were 196 patients (42.3%) who experienced FT. Upon multivariable analyses, divorced marital status [odds ratio (OR) = 3.658, 95% CI: 1.180-11.337], household income <$40,000 (OR = 2.544, 95% CI: 1.003-6.455), credit score below 739 (OR = 2.744, 95% CI: 1.326-5.679), clinical stage >I (OR = 2.053, 95% CI: 1.088-3.877), and change in work hours or work cessation (all P < 0.05) were associated with FT. Coping mechanisms, such as decreased spending on food or clothing and increased use of savings or borrowing money, were more likely to be reported by patients experiencing FT than those who did not ( P < 0.001). CONCLUSIONS: Patients undergoing lung cancer resection often experienced significant financial stress with several identifiable risk factors. FT should be considered early in the care of these patients to alleviate detrimental coping mechanisms and enhance their quality of survivorship.

High-Risk Features of Esophageal Adenocarcinoma Following Neoadjuvant Chemoradiation: Patients for Whom Surgery Should Not Be Delayed.

OBJECTIVE: Clinical predictors of pathological complete response have not reliably identified patients for whom an organ-sparing approach following neoadjuvant chemoradiation be undertaken for esophageal cancer patients. We sought to identify high-risk predictors of residual carcinoma that may preclude patients from a selective surgical approach. BACKGROUND: Patients treated with neoadjuvant chemoradiation followed by esophagectomy for esophageal adenocarcinoma were identified. PATIENTS AND METHODS: Correlation between clinical and pathologic complete responses were examined. Regression models and recursive partitioning were utilized to identify features associated with residual carcinoma. External validation of these high-risk factors was performed on a data set from an independent institution. RESULTS: A total of 326 patients were identified, in whom clinical complete response was noted in 104/326 (32%). Pathologic complete response was noted in only 33/104 (32%) of these clinical complete responders. Multivariable analysis identified that the presence of stricture ( P =0.011), positive biopsy ( P =0.010), and signet ring cell histology ( P =0.019) were associated with residual cancer. Recursive partitioning corroborated a 94% probability of residual disease, or greater, for each of these features. The positive predictive value was >90% for these characteristics. A SUV max >5.4 at the esophageal primary in the absence of esophagitis was also a high-risk factor for residual carcinoma. External validation confirmed these high-risk factors to be implicated in the finding of residual carcinoma. CONCLUSIONS: Clinical parameters of response are poor predictors of complete pathologic response leading to challenges in selecting candidates for active surveillance. However, we characterize several high-risk features for residual carcinoma which indicate that esophagectomy should not be delayed.

Analysis of Immune Intratumor Heterogeneity Highlights Immunoregulatory and Coinhibitory Lymphocytes as Hallmarks of Recurrence in Stage I Non-Small Cell Lung Cancer.

Our understanding of the molecular mechanisms underlying postsurgical recurrence of non-small cell lung cancer (NSCLC) is rudimentary. Molecular and T cell repertoire intratumor heterogeneity (ITH) have been reported to be associated with postsurgical relapse; however, how ITH at the cellular level impacts survival is largely unknown. Here we report the analysis of 2880 multispectral images representing 14.2% to 27% of tumor areas from 33 patients with stage I NSCLC, including 17 cases (relapsed within 3 years after surgery) and 16 controls (without recurrence ≥5 years after surgery) using multiplex immunofluorescence. Spatial analysis was conducted to quantify the minimum distance between different cell types and immune cell infiltration around malignant cells. Immune ITH was defined as the variance of immune cells from 3 intratumor regions. We found that tumors from patients having relapsed display different immune biology compared with nonrecurrent tumors, with a higher percentage of tumor cells and macrophages expressing PD-L1 (P =.031 and P =.024, respectively), along with an increase in regulatory T cells (Treg) (P =.018), antigen-experienced T cells (P =.025), and effector-memory T cells (P =.041). Spatial analysis revealed that a higher level of infiltration of PD-L1+ macrophages (CD68+PD-L1+) or antigen-experienced cytotoxic T cells (CD3+CD8+PD-1+) in the tumor was associated with poor overall survival (P =.021 and P =.006, respectively). A higher degree of Treg ITH was associated with inferior recurrence-free survival regardless of tumor mutational burden (P =.022), neoantigen burden (P =.021), genomic ITH (P =.012) and T cell repertoire ITH (P =.001). Using multiregion multiplex immunofluorescence, we characterized ITH at the immune cell level along with whole exome and T cell repertoire sequencing from the same tumor regions. This approach highlights the role of immunoregulatory and coinhibitory signals as well as their spatial distribution and ITH that define the hallmarks of tumor relapse of stage I NSCLC.

The role of immunotherapy and targeted therapy in the multimodal therapy for resectable lung cancer.

As the immunotherapeutic milieu in resectable nonsmall cell lung cancer continues to evolve, the field of thoracic oncology actively moves towards better patient selection based on biomarkers and oncogenic drivers. In this article, we review the current standard of oncologic care in this population and discuss the ongoing phase III clinical trials investigating the use of immunotherapy or targeted therapy in the perioperative period. We also discuss genotyping initiatives, biomarkers, and trial endpoints.

Optimal Combination of Neuroendocrine Markers for the Detection of High-Grade Neuroendocrine Tumors of the Sinonasal Tract and Lung.

PURPOSE OF REVIEW: Identification of neuroendocrine (NE) differentiation is critical to the classification of head and neck (HN) and lung tumors. In combination with tumor morphology, immunohistochemical (IHC) documentation of NE differentiation is necessary for the diagnosis of NE tumors. The purpose of this study is to determine the sensitivity and concordance of two novel NE markers (mASH1, INSM1) across a group of high-grade NE tumors of the sinonasal tract and lung, and to compare their expression with the current widespread use of conventional NE markers, synaptophysin (SYN) and chromogranin A (CGA). In addition, expression of PARP1 is examined as a potential novel therapeutic target. RECENT FINDINGS: Thirty-nine high-grade NE tumors, 23 of the HN and 16 of the lung, were reevaluated by two subspecialized HN and thoracic pathologists, and subsequently stained with mASH1, INSM1, and PARP1. Sensitivity and degree of concordance of all possible combinations of markers were assessed. Sensitivities (standard error) were as follows: mASH1 41% (0.08), INSM1 44% (0.08), SYN 56% (0.08), and CGA 42% (0.09); combination of all four NE markers: 73% (0.08). Sensitivity and standard error for PARP1 was 90% and 0.05, respectively. Highest sensitivity to detect NE differentiation in high-grade NE tumors of the HN and thoracic region was achieved with a combination of four NE markers. Moderate concordance was found with combinations of mASH1 and INSM1 and traditional NE markers, respectively. Consistent overexpression of PARP1 in high-grade tumors with NE differentiation in the HN and lung opens eligibility for PARP1 inhibitor trials.

The Role of Surgery in the Treatment of Melanoma Pulmonary Metastases in the Modern Era.

INTRODUCTION: The lung represents a frequent site of spread for metastatic melanoma, which has historically been managed with surgical resection achieving promising outcomes. We hypothesized that the role of surgery in the management of melanoma pulmonary metastases (MPM) is evolving among the development of less invasive diagnostic and novel systemic therapeutic strategies. MATERIALS AND METHODS: A single-center thoracic surgery database was reviewed and patients who underwent surgical resection of MPM between 1998 and 2019 were identified. Demographic, clinicopathologic, and surgical data were collected and analyzed, as were the annual volumes and indications for surgical resection. A Cochran-Armitage test was used to assess the trend in surgical indication. RESULTS: Three hundred and seventy seven surgical procedures for MPM were performed during the years of study in the care of 347 patients. Patients were predominantly male, with a mean age of 59.3 y. The mean number of annual resections was 17 and while this number initially increased from six in 1998 to a peak of 39 cases in 2008, a decline was subsequently observed. Diagnostic resection decreased from 22% in 1998-1999 to 5% at the peak of procedures in 2008-2009 and to 0 in 2018-2019 (P = 0.02). Curative resection increased from 44% in 1998-1999 to 73% in 2008-2009 (P < 0.001) and remained the dominant reason for surgery in later years. CONCLUSIONS: Surgical indications in the management of MPM have transformed in conjunction with systemic modalities, and the volume of resections has decreased in the modern era. Despite innovations in systemic management and shifting goals of operative interventions, surgeons continue to play a vital role in caring for these patients with an advanced disease.

Single Chest Drain Practice Reduces Discharge Opioid Prescriptions in Thoracic Surgery.

INTRODUCTION: Chest drains are placed following pulmonary resection to promote lung re-expansion. The superiority of two chest drains at preventing postoperative complications has not been established, and practice remains largely dictated by surgeon preference. We sought to compare patient outcomes based on number of chest drains used. METHODS: This is a retrospective analysis including patients undergoing lobectomies and segmentectomies between March 2016 and April 2020. Patients were categorized based on number of chest drains placed and were matched 1:1 using the nearest neighbor (greedy) technique. Our primary outcome was opioid prescriptions at discharge (in morphine equivalent daily dose [MEDD]). Associations were tested using multilevel mixed-effects regression to account for variability between surgeons. RESULTS: A total of 1,094 patients met inclusion criteria. Single chest drain was used in 922 patients, whereas 172 had two chest tubes. After matching, there were 111 patients in each group. In multilevel mixed-effects logistic regression, patients treated with a single chest drain received fewer opioid prescriptions (ß: -194 MEDD, 95% confidence interval [CI]: -302 to -86 MEDD, p < 0.01), were more likely to be opioid-free at hospital discharge (odds ratio [OR] = 2.11, 95% CI: 1.08-4.12, p = 0.03), and had lower readmission rates within 30 days (OR = 0.33, 95% CI: 0.13-0.84, p = 0.02). Single chest drain practice did not affect the risk of pulmonary complications and there was no statistically significant difference in length of hospital stay (3 days [interquartile range: 2-5] vs. 4 days [3-6], p = 0.08). CONCLUSION: Single chest drain practice in lobectomies and segmentectomies was associated with less opioid prescription requirement without any increase in complications.

Prolonged neutrophilia is associated with worse outcomes after Esophagectomy.

Neutrophilia is a potential biomarker for postoperative complications and oncologic outcomes. There is a paucity of data regarding neutrophilia in patients with esophageal adenocarcinoma. Our Institutional Database was queried for esophageal adenocarcinoma patients who underwent esophagectomy from 2006 to 2019. Complete blood counts (CBC), demographic characteristics, perioperative and oncologic outcomes were evaluated. Two groups were created based on the presence of prolonged neutrophilia (PN, >7,000 absolute neutrophils 90 days after surgery). Univariate, multivariable, and survival analysis were performed (P-value < 0.05). We identified 686 patients with complete CBC data: 565 in the no prolonged neutrophilia (NPN) and 121 in the PN groups (17.6%). The mean age was 54 versus 48 years in the NPN and PN groups (P = 0.01). There was no difference in height, weight, gender, race, tumor size, histology, pTNM, PS, ASA, salvage procedure, neoadjuvant treatment and comorbidities. On multivariable analysis, the PN group had increased transfusions (19.8% vs. 11.9%; P = 0.02), aspiration (13.2% vs. 2.5%; P = 0.002), pulmonary embolus (3.3% vs. 0.4%; P = 0.02), cardiac arrest (5% vs. 0.4%; P = 0.02) and hematologic complications (23.1% vs. 12.6%; P = 0.01). After controlling for any postoperative complication, PN had increased distant recurrence (24% vs. 12.7%; hazard ration [HR]: 2.3, 95% confidence interval [CI] 1.42-3.9; P = 0.001) and decreased OS (33.8% vs. 49.7%, HR: 1.83, 95% CI: 1.19-2.81; P = 0.006); median follow up 77 months (46-109). PN was predictive of distant recurrence and decreased overall survival. Further work investigating these neutrophil populations represents a potential area for biomarker research, immunomodulation, and may guide postoperative surveillance strategies.

Matched Pairs Comparison of an Enhanced Recovery Pathway Versus Conventional Management on Opioid Exposure and Pain Control in Patients Undergoing Lung Surgery.

OBJECTIVE: The aim of this study was to assess the effect of an enhanced recovery after surgery (ERAS) pathway on pain and opioid use following lung resection. SUMMARY BACKGROUND DATA: A major component ERAS pathways is opioid-sparing analgesia; however, the effect on postoperative pain and opioid use in patients undergoing lung resection is unknown. METHODS: Following implementation of an ERAS pathway for lung resection, 123 consecutive patients were identified. Patients were propensity-matched 1:1 with a group of consecutive patients (n = 907) undergoing lung resection before ERAS. Differences regarding in-hospital opioid consumption, discharge prescribing of opioids, and postoperative pain scores were examined. Morphine milligram equivalents were separately calculated including and excluding tramadol as an opioid medication. RESULTS: There were no significant differences between matched patients regarding age, sex, performance status, receipt of preoperative treatment, extent of lung resection, or operative approach. Epidural analgesia was used in 66% of controls and in none of the ERAS group (P < 0.001). The number of adjunct analgesics used postoperatively was greater in the ERAS group (median 3 vs 2, P < 0.001). There was a major reduction in morphine milligram equivalents in the ERAS group whether tramadol was included (median 14.2 vs 57.8, P < 0.001) or excluded (median 2.7 vs 57.8, P < 0.001) and regardless of surgical approach. Average daily pain scores were lower in the ERAS group (median 1.3 vs 1.8, P = 0.004); however, this difference was present only among patients undergoing thoracotomy. The proportion of patients who were prescribed discharge opioids varied whether tramadol was included (96% each group, P = 1.00) or excluded (39% vs 80%, P < 0.001) in the analysis. CONCLUSIONS: Implementation of an ERAS pathway was associated with effective post-operative analgesia, major reductions in in-hospital consumption of opioids, and reduced pain, compared to conventional management.

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

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.

Simultaneous versus staged resections for bilateral pulmonary metastases.

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.

Pulmonary resection for tissue harvest in adoptive tumor-infiltrating lymphocyte therapy: Safety and feasibility.

BACKGROUND AND OBJECTIVES: Adoptive T-cell therapies (ACTs) using expansion of tumor-infiltrating lymphocyte (TIL) populations are of great interest for advanced malignancies, with promising response rates in trial settings. However, postoperative outcomes following pulmonary TIL harvest have not been widely documented, and surgeons may be hesitant to operate in the setting of widespread disease. METHODS: Patients who underwent pulmonary TIL harvest were identified, and postoperative outcomes were studied, including pulmonary, cardiovascular, infectious, and wound complications. RESULTS: 83 patients met inclusion criteria. Pulmonary TIL harvest was undertaken primarily via a thoracoscopy with a median operative blood loss and duration of 30 ml and 65 min, respectively. The median length of stay was 2 days. Postoperative events were rare, occurring in only five (6%) patients, including two discharged with a chest tube, one discharged with oxygen, one episode of urinary retention, and one blood transfusion. No reoperations occurred. The median time from TIL harvest to ACT infusion was 37 days. CONCLUSIONS: Pulmonary TIL harvest is safe and feasible, without major postoperative events in our cohort. All patients were able to receive intended ACT infusion without delays. Therefore, thoracic surgeons should actively participate in ongoing ACT trials and aggressively seek to enroll patients on these protocols.

18F-fluorodeoxyglucose positron emission tomography correlates with tumor immunometabolic phenotypes in resected lung cancer.

Enhanced tumor glycolytic activity is a mechanism by which tumors induce an immunosuppressive environment to resist adoptive T cell therapy; therefore, methods of assessing intratumoral glycolytic activity are of considerable clinical interest. In this study, we characterized the relationships among tumor 18F-fluorodeoxyglucose (FDG) retention, tumor metabolic and immune phenotypes, and survival in patients with resected non-small cell lung cancer (NSCLC). We retrospectively analyzed tumor preoperative positron emission tomography (PET) 18F-FDG uptake in 59 resected NSCLCs and investigated correlations between PET parameters (SUVMax, SUVTotal, SUVMean, TLG), tumor expression of glycolysis- and immune-related genes, and tumor-associated immune cell densities that were quantified by immunohistochemistry. Tumor glycolysis-associated immune gene signatures were analyzed for associations with survival outcomes. We found that each 18F-FDG PET parameter was positively correlated with tumor expression of glycolysis-related genes. Elevated 18F-FDG SUVMax was more discriminatory of glycolysis-associated changes in tumor immune phenotypes than other 18F-FDG PET parameters. Increased SUVMax was associated with multiple immune factors characteristic of an immunosuppressive and poorly immune infiltrated tumor microenvironment, including elevated PD-L1 expression, reduced CD57+ cell density, and increased T cell exhaustion gene signature. Elevated SUVMax identified immune-related transcriptomic signatures that were associated with enhanced tumor glycolytic gene expression and poor clinical outcomes. Our results suggest that 18F-FDG SUVMax has potential value as a noninvasive, clinical indicator of tumor immunometabolic phenotypes in patients with resectable NSCLC and warrants investigation as a potential predictor of therapeutic response to immune-based treatment strategies.