Commission on Cancer Standards for Lymph Node Sampling and Oncologic Outcomes after Lung Resection.

BACKGROUND: The newest Commission on Cancer (CoC) standards recommend sampling 3 mediastinal and 1 hilar lymph node station, 3(N2)1(N1), for lung cancer resections. However, the relationship between the CoC standards and outcomes has not been thoroughly investigated. METHODS: A prospective institutional database was queried for clinical stage I-III lung resections prior to the implementation of the new standards. The relationship between the 3(N2)1(N1) standard ("guideline concordant") and outcomes (upstaging, complications, receipt of adjuvant therapy, locoregional/distant recurrence, and survival) were assessed using multivariable models and stratified by stage. RESULTS: Of 9,289 pulmonary resections 3048 (33%) were guideline concordant and 6241 (67%) were not. Compared to non-concordant, those who were guideline-concordant had higher rates of nodal upstaging (21% vs 13%; OR 1.32 [95% CI 1.14-1.51] p<0.001) and in-hospital complications (34% vs 27%), (OR 1.17 [95% CI 1.05-1.30], p=0.004), but similar adjuvant systemic therapy administration (19% vs 13%; OR 1.09 [95% CI 0.95-1.24], p=0.2), (98% chemotherapy). Locoregional and distant recurrence were not significantly improved with guideline concordance across clinical stage I, II and III subsets. Overall survival was similar in clinical stages I and II but improved survival was observed among guideline concordant clinical stage III patients (HR 0.85 [95% CI 0.74-0.97], p=0.02). CONCLUSIONS: Sampling 3(N2)1(N1) was associated with increased upstaging and complications but not with decreased recurrence or mortality in clinical stage I or II patients. Survival was improved among concordant, clinical stage III patients. Further study is indicated to determine the ideal lymph node sampling strategy across heterogeneous lung cancer patients.

Determinants of successful minimally invasive surgery for resectable non-small cell lung cancer after neoadjuvant therapy.

OBJECTIVE: Minimally invasive surgery (MIS) (video-assisted thoracoscopic surgery and robot-assisted thoracoscopic surgery) for pulmonary resection is standard in early-stage non-small cell lung cancer because it is associated with better perioperative outcomes than thoracotomy. MIS for resection of more advanced non-small cell lung cancer (Stages IB-IIIB) treated with neoadjuvant therapy has been utilized. However, the determinants of success are not well defined. METHODS: A single institution retrospective review of a prospectively maintained database was conducted, querying for patients with clinical Stage IB through IIIB non-small cell lung cancer who had resection after neoadjuvant systemic therapy without radiation from 2013 to 2022. Patients were grouped by surgical approach; that is, open versus MIS. Successful MIS was defined by no conversion, R0 resection, and no major (grade 3 or greater) morbidity. Analyses by intent-to-treat assessed outcomes by Wilcoxon rank-sum test and Fisher exact test. (Multivariable regression analysis identified variables that contributed to successful MIS resection.) RESULTS: Of 627 eligible patients, 360 (57%) had open and 267 (43%) had MIS procedures. Most patients (79.1%) received neoadjuvant platinum-based chemotherapy, and 21.9% were treated with immunotherapy or targeted therapy alone or combined with chemotherapy. Among MIS resections, 179 (67%) were performed by video-assisted thoracoscopic surgery and 88 (33%) by robot-assisted thoracoscopic surgery. The conversion rate was 16% (n = 43). Successful MIS resection was achieved in 77% of patients. Multivariable regression analysis showed that pretreatment clinical N stage was a significant determinant of success, but not pretreatment clinical T stage or type of neoadjuvant therapy. CONCLUSIONS: Following neoadjuvant systemic therapy for clinical stage IB or IIIB non-small cell lung cancer, MIS resection can be successfully accomplished and should be considered in appropriate patients. Presence of pretreatment nodal disease is associated with higher odds of conversion, major morbidity, and incomplete resection.

Late recurrence of completely resected stage I to IIIA lung adenocarcinoma.

OBJECTIVE: Research into the risk factors associated with late recurrence (>2 years after surgery) of lung adenocarcinoma is limited. We investigated the incidence of and clinicopathologic and genomic features associated with late recurrence of resected stage I-IIIA lung adenocarcinoma. METHODS: We performed a retrospective analysis of patients with completely resected pathologic stage I-IIIA lung adenocarcinoma (2010-2019). Patients with a history of lung cancer, neoadjuvant therapy, or mucinous or noninvasive lung adenocarcinoma, or with follow-up of less than 2 years were excluded. Cox and logistic regression modeling were used to compare clinicopathologic variables among patients with no, early (≤2 years), and late recurrence. Comparisons of genomic mutations were corrected for multiple testing. RESULTS: Of the 2349 patients included, 537 developed a recurrence during follow-up. Most recurrences (55% [297/537]) occurred early; 45% (240/537) occurred late. A larger proportion of late recurrences than early recurrences were locoregional (37% vs 29%; P = .047). Patients with late recurrence had more aggressive pathologic features (International Association for the Study of Lung Cancer grade 2 and 3, lymphovascular invasion, visceral pleural invasion) and higher stage than patients without recurrence. Pathologic features were similar between patients with early and late recurrence, except stage IIIA disease was more common in the early cohort. No genomic mutations were associated with late recurrence. CONCLUSIONS: Late recurrence of lung adenocarcinoma after resection is more common than previously reported. Patients without disease more than 2 years after surgery who had aggressive pathologic features at the time of resection have an elevated risk of recurrence and may benefit from more aggressive follow-up.

Minimally Invasive Ivor Lewis Esophagectomy.

Minimally invasive Ivor Lewis esophagectomy is a technically demanding operation that requires an experienced surgeon, assistant, and anesthesiologist. The preoperative workup should focus on the extent of disease and extent of resection required, as well as the cardiopulmonary fitness of the patient. Surgical outcomes show decreased postoperative pain, decreased morbidity largely due to a reduction in respiratory complications, and decreased length of stay. Quality metrics and 5-year overall survival are equivalent to traditional open esophagectomy.

A New Functional Threshold for Minimally Invasive Lobectomy.

OBJECTIVE: To assess the performance of a lower predicted postoperative (ppo) forced expiratory volume in 1 second (FEV1) or diffusion capacity of the lung for carbon monoxide (DLCO) (ppoFEV1/ppoDLCO) threshold to predict cardiopulmonary complications after minimally invasive surgery (MIS) lobectomy. SUMMARY BACKGROUND DATA: Although MIS is associated with better postoperative outcomes than open surgery, MIS uses risk-assessment algorithms developed for open surgery. Moreover, several different definitions of cardiopulmonary complications are used for assessment. METHODS: All patients who underwent MIS lobectomy for clinical stage I-II lung cancer from 2018 to 2022 at our institution were considered. The performance of a ppoFEV1/ppoDLCO threshold of <45% was compared against that of the current guideline threshold of <60%. Three different definitions of cardiopulmonary complications were compared: Society of Thoracic Surgeons (STS), European Society of Thoracic Surgeons (ESTS), and Berry et al. RESULTS: In 946 patients, the ppoFEV1/ppoDLCO threshold of <45% was associated with a higher proportion correctly classified (79% [95% CI, 76%-81%] vs. 65% [95% CI, 62%-68%]; P<0.001). The complication with the biggest difference in incidence between ppoFEV1/ppoDLCO of 45%-60% and >60% was prolonged air leak (33 [13%] vs. 34 [6%]; P<0.001). The predicted probability curves for cardiopulmonary complications were higher for the STS definition than for the ESTS or Berry definitions across ppoFEV1 and ppoDLCO values. CONCLUSIONS: The ppoFEV1/ppoDLCO threshold of <45% more accurately classified patients for cardiopulmonary complications after MIS lobectomy, emphasizing the need for updated risk-assessment guidelines for MIS lobectomy to optimize additional cardiopulmonary function evaluation.

Immunotherapy for Resectable Locally Advanced Esophageal Carcinoma.

BACKGROUND: The current standard of care for locally advanced esophageal and gastroesophageal junction (GEJ) cancers includes neoadjuvant chemoradiotherapy or perioperative chemotherapy with surgical resection; however, disease-free survival in these patients remains poor. Immune checkpoint inhibitors (ICIs) are approved for adjuvant treatment of locally advanced esophageal and GEJ cancers, but their benefit in the perioperative and neoadjuvant settings remains under investigation. METHODS: We used the PubMed online database to conduct a literature search to identify studies that investigated immunotherapy for locally advanced esophageal and GEJ carcinoma. A review of ClinicalTrials.gov yielded a list of ongoing trials. RESULTS: Adjuvant nivolumab for residual disease after neoadjuvant chemoradiotherapy and surgery is the only approved immunotherapy regimen for locally advanced esophageal cancer. Early-phase trials investigating the addition of neoadjuvant or perioperative ICIs to standard-of-care multimodality approaches have observed pathologic complete response rates as high as 60%. Response rates are highest for ICIs plus chemoradiotherapy for esophageal squamous cell carcinoma and dual checkpoint inhibition in mismatch repair-deficient adenocarcinomas. Safety profiles are acceptable, with a pooled adverse event rate of 27%. Surgical morbidity and mortality with immunotherapy are similar to historical controls with no immunotherapy, and R0 resection rates are high. When reported, disease-free survival among patients treated with perioperative immunotherapy is promising. CONCLUSIONS: Outside of clinical trials, immunotherapy for resectable esophageal carcinoma is limited to the adjuvant setting. Phase III trials investigating neoadjuvant and perioperative immunotherapy are now underway and will provide much-needed data on survival that may ultimately lead to practice-changing recommendations.

Activation of the JAK/STAT Pathway Leads to BRAF Inhibitor Resistance in BRAFV600E Positive Thyroid Carcinoma.

A subset of thyroid cancers, recurrent differentiated thyroid cancers and anaplastic thyroid cancer (ATC), are difficult to treat by thyroidectomy and systemic therapy. A common mutation in thyroid cancer, BRAFV600E, has targetable treatment options; however, the results have been disappointing in thyroid cancers compared with BRAFV600E melanoma, as thyroid cancers quickly become resistant to BRAFV600E inhibitor (BRAFi). Here, we studied the molecular pathway that is induced in BRAFV600E thyroid cancer cells and patient-derived tumor samples in response to BRAFi, vemurafenib, using RNA-sequencing and molecular analysis. Both inducible response to BRAFi and acquired BRAFi resistance in BRAFV600E thyroid cancer cells showed significant activation of the JAK/STAT pathway. Functional analyses revealed that the combination of BRAFi and inhibitors of JAK/STAT pathway controlled BRAFV600E thyroid cancer cell growth. The Cancer Genome Atlas data analysis demonstrated that potent activation of the JAK/STAT signaling was associated with shorter recurrence rate in patients with differentiated thyroid cancer. Analysis of tumor RNA expression in patients with poorly differentiated thyroid cancer and ATC also support that enhanced activity of JAK/STAT signaling pathway is correlated with worse prognosis. Our study demonstrates that JAK/STAT pathway is activated as BRAFV600E thyroid cancer cells develop resistance to BRAFi and that this pathway is a potential target for anticancer activity and to overcome drug resistance that commonly develops to treatment with BRAFi in thyroid cancer. IMPLICATIONS: Dual inhibition of BRAF and JAK/STAT signaling pathway is a potential therapeutic treatment for anticancer activity and to overcome drug resistance to BRAFi in thyroid cancer.

Improved Preoperative Risk Assessment Tools Are Needed to Guide Informed Decision Making before Esophagectomy.

OBJECTIVE: We sought to evaluate the performance of 2 commonly used prediction models for postoperative morbidity in patients undergoing open and minimally invasive esophagectomy. SUMMARY BACKGROUND DATA: Patients undergoing esophagectomy have a high risk of postoperative complications. Accurate risk assessment in this cohort is important for informed decision-making. METHODS: We identified patients who underwent esophagectomy between January 2016 and June 2018 from our prospectively maintained database. Predicted morbidity was calculated using the American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator (SRC) and a 5-factor National Surgical Quality Improvement Programderived frailty index. Performance was evaluated using concordance index (C-index) and calibration curves. RESULTS: In total, 240 consecutive patients were included for analysis. Most patients (85%) underwent Ivor Lewis esophagectomy. The observed overall complication rate was 39%; the observed serious complication rate was 33%.The SRC did not identify risk of complications in the entire cohort (C-index, 0.553), patients undergoing open esophagectomy (C-index, 0.569), or patients undergoing minimally invasive esophagectomy (C-index, 0.542); calibration curves showed general underestimation. Discrimination of the SRC was lowest for reoperation (C-index, 0.533) and highest for discharge to a facility other than home (C-index, 0.728). Similarly, the frailty index had C-index of 0.513 for discriminating any complication, 0.523 for serious complication, and 0.559 for readmission. CONCLUSIONS: SRC and frailty index did not adequately predict complications after esophagectomy. Procedure-specific risk-assessment tools are needed to guide shared patient-physician decision-making in this high-risk population.

Exposure to Polybrominated Diphenyl Ether Flame Retardants Causes Deoxyribonucleic Acid Damage in Human Thyroid Cells In Vitro.

INTRODUCTION: The incidence of papillary thyroid cancer (PTC) in the United States has tripled in the past 30 y. Polybrominated diphenyl ethers (PBDEs) are flame retardants that were ubiquitously used over that time period, and exposure to PBDEs has been associated with PTC prevalence. They are potential carcinogens via their induction of reactive oxygen species (ROS) formation and resultant deoxyribonucleic acid (DNA) damage. We sought to determine the effects of PBDE and tris(2-chloroethyl) phosphate (TCEP), another flame retardant implicated in PTC incidence, on thyrocytes in vitro and measure PBDE levels in human thyroid tissue to determine their carcinogenic potential. METHODS: Nthy-Ori, an immortalized benign human thyroid follicular cell line was used as a model of normal human thyroid. MTT assays were used to measure cell viability after exposure to PBDEs and TCEP. ROS levels and double-stranded and single-stranded DNA breaks were measured to determine genotoxicity. DNA damage response protein levels were measured with immunoblotting. RESULTS: Exposure to 20µM PBDE or TCEP for 48 h had minimal effects on thyrocyte viability. There was no significant increase in intracellular ROS up to 6 h following PBDE or TCEP exposure in thyrocytes; however, cells exposed to PBDE 47 showed evidence of DNA single-stranded and double-stranded breaks. There was a dose-dependent increase in γH2AX levels following exposure to PBDEs 47 and 209 in Nthy-Ori cells but not with TCEP treatment. CONCLUSIONS: PBDE 47 and 209 demonstrated genotoxicity but not cytotoxicity in follicular thyrocytes in vitro. Therefore, PBDE 47 and 209 may be carcinogenic in human thyroid cells.

The American College of Surgeons Surgical Risk Calculator performs well for pulmonary resection: A validation study.

OBJECTIVE: The American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator (NSQIP SRC) was developed to estimate the risk of postoperative morbidity and mortality within 30 days of an operation. We sought to externally evaluate the performance of the NSQIP SRC for patients undergoing pulmonary resection. METHODS: Patients undergoing pulmonary resection at our center between January 2016 and December 2018 were included. Using data from our institution's prospectively maintained Society of Thoracic Surgeons General Thoracic Database, we identified 2514 patients. We entered requisite patient demographic information, preoperative risk factors, and procedural details into the online calculator. Predicted performance of the calculator versus observed outcomes was assessed by discrimination (concordance index [C-index]) and calibration. RESULTS: The observed and predicted probabilities of any complication were 8.3% and 9.9%, respectively, and of serious complications were 7.4% and 9.2%, respectively. Observed and predicted 30-day mortality were 0.5% and 0.9%, respectively. The C-index for readmission was 0.644; the C-indices corresponding to all other outcomes in the NSQIP SRC ranged from 0.703 to 0.821. Calibration curves indicated excellent calibration for all binary end points, with the exception of renal failure (predicted underestimated observed probabilities), discharge to a nursing or rehabilitation facility (overestimated), and sepsis (overestimated). Correlation between predicted and observed length of stay was moderate (Spearman coefficient, 0.562), and calibration was good. CONCLUSIONS: Except for readmission, renal failure, discharge to a location other than home, and sepsis, the NSQIP SRC can be used to reasonably predict postoperative complications in patients undergoing pulmonary resection.

Implementing a High-Value Care Discharge Protocol in Patients Undergoing CABG Reduces Readmission.

BACKGROUND: Readmission after coronary artery bypass grafting (CABG) is associated with adverse outcomes and increased cost. We evaluated the impact of a high-value care discharge protocol on readmission, length of stay (LOS), and discharge destination in patients undergoing isolated CABG. METHODS: In 2016, a comprehensive, patient-centered discharge protocol was implemented. A nurse practitioner was the fulcrum of this program, which focused on improving health literacy, disease management, and rigorous follow-up. All patients undergoing isolated CABG between 2012 and 2019 were retrospectively analyzed with regard to 30-day readmission, LOS, and discharge disposition. Differences were analyzed by Mann-Whitney, chi-square, and t tests. Analyses were repeated using propensity matching. RESULTS: A total of 910 consecutive patients undergoing isolated CABG were included in the analyses: 353 preprotocol and 557 postprotocol. Preprotocol patients had a readmission rate of 14.4% (n = 51), compared with 6.8% (n = 38) in the postprotocol patients (P < .001). Median postoperative LOS before implementation was 6 (interquartile range, 5-8) days compared with 5 (interquartile range, 4-6) days postimplementation (P < .001). Postimplementation, a higher proportion of patients were discharged to home compared with a skilled nursing facility (82.7% [n = 461] vs 73.9% [n = 261]; P = .002). After propensity matching, 298 well-balanced patients were included for analysis and these significant reductions in LOS, readmission, and discharge destination persisted. CONCLUSIONS: Implementation of a new discharge protocol was significantly associated with reduced readmission and LOS, along with higher rates of discharge to home in isolated CABG patients. Importantly, the results were sustainable and did not require additional resources, delivering high-value care.

Performance Comparison Between SURPAS and ACS NSQIP Surgical Risk Calculator in Pulmonary Resection.

BACKGROUND: Accurate preoperative risk assessment is critical for informed decision making. The Surgical Risk Preoperative Assessment System (SURPAS) and the National Surgical Quality Improvement Program (NSQIP) Surgical Risk Calculator (SRC) predict risks of common postoperative complications. This study compares observed and predicted outcomes after pulmonary resection between SURPAS and NSQIP SRC. METHODS: Between January 2016 and December 2018, 2514 patients underwent pulmonary resection and were included. We entered the requisite patient demographics, preoperative risk factors, and procedural details into the online NSQIP SRC and SURPAS formulas. Performance of the prediction models was assessed by discrimination and calibration. RESULTS: No statistically significant differences were found between the 2 models in discrimination performance for 30-day mortality, urinary tract infection, readmission, and discharge to a nursing or rehabilitation facility. The ability to discriminate between a patient who will develop a complication and a patient who will not was statistically indistinguishable between NSQIP and SURPAS, except for renal failure. With a C index closer to 1.0, the NSQIP performed significantly better than the SURPAS SRC in discriminating risk of renal failure (C index, 0.798 vs 0.694; P = .003). The calibration curves of predicted and observed risk for each model demonstrate similar performance with a tendency toward overestimation of risk, apart from renal failure. CONCLUSIONS: Overall, SURPAS and NSQIP SRC performed similarly in predicting outcomes for pulmonary resections in this large, single-center validation study with moderate to good discrimination of outcomes. Notably, SURPAS uses a smaller set of input variables to generate the preoperative risk assessment. The addition of thoracic-specific input variables may improve performance.

External Validation of Surgical Risk Preoperative Assessment System in Pulmonary Resection.

BACKGROUND: Accurate preoperative risk assessment is necessary for informed decision making for patients and surgeons. Several preoperative risk calculators are available but few have been examined in the general thoracic surgical patient population. The Surgical Risk Preoperative Assessment System (SURPAS), a risk-assessment tool applicable to a wide spectrum of surgical procedures, was developed to predict the risks of common adverse postoperative outcomes using a parsimonious set of preoperative input variables. We sought to externally validate the performance of SURPAS for postoperative complications in patients undergoing pulmonary resection. METHODS: Between January 2016 and December 2018, 2514 patients underwent pulmonary resection at our center. Using data from our institution's prospectively maintained database, we calculated the predicted risks of 12 categories of postoperative outcomes using the latest version of SURPAS. Performance of SURPAS against observed patient outcomes was assessed by discrimination (concordance index) and calibration (calibration curves). RESULTS: The discrimination ability of SURPAS was moderate across all outcomes (concordance indices, 0.640 to 0.788). Calibration curves indicated good calibration for all outcomes except infectious and cardiac complications, discharge to a location other than home, and mortality (all overestimated by SURPAS). CONCLUSIONS: SURPAS demonstrates outcomes for pulmonary resections with reasonable predictive ability. Discretion should be applied when assessing risk for postoperative infectious and cardiac complications, discharge to a location other than home, and mortality. Although the parsimonious nature of SURPAS is one of its strengths, its performance might be improved by including additional factors known to influence outcomes after pulmonary resection, such as sex and pulmonary function.

Ablation therapy using a low dose of radioiodine may be sufficient in low- to intermediate-risk patients with follicular variant papillary thyroid carcinoma.

OBJECTIVES: Follicular variant papillary thyroid carcinoma (FVPTC) is treated similarly to classical variant papillary thyroid carcinoma (cPTC). However, FVPTC has unique tumour features and behaviours. We investigated whether a low dose of radioiodine was as effective as a high dose for remnant ablation in patients with FVPTC and evaluated the recurrence of low-intermediate risk FVPTC. METHODS: Data from cPTC and FVPTC patients treated with I-131 from 2004 to 2014 were reviewed. Demographics, tumour behaviour, lymph node metastasis, and local recurrence data were compared between FVPTC and cPTC patients. Then, low-intermediate risk FVPTC patients were divided into low, intermediate, and high I-131 dose groups, and postoperative I-131 activities were analysed to evaluate the effectiveness of I-131 therapy for thyroid remnant ablation. RESULTS: In total, 799 cases of FVPTC (n = 168) and cPTC (n = 631) treated with I-131 were identified. Patients with FVPTC had a larger primary nodule size than cPTC, but lymph node metastases and local recurrence were more prevalent in cPTC than in FVPTC. For the low-, intermediate-, and high-dose groups, success rates of ablation did not differ (82.0%, 80%, and 81.3%, respectively). CONCLUSION: FVPTC differs from cPTC in behaviour. Low-dose ablation may be sufficient in FVPTC patients with low-intermediate disease risk.

Chimeric Antigen Receptor T Cell Therapy Targeting ICAM-1 in Gastric Cancer.

Cancer therapy utilizing adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated remarkable clinical outcomes in hematologic malignancies. However, CAR T cell application to solid tumors has had limited success, partly due to the lack of tumor-specific antigens and an immune-suppressive tumor microenvironment. From the tumor tissues of gastric cancer patients, we found that intercellular adhesion molecule 1 (ICAM-1) expression is significantly associated with advanced stage and shorter survival. In this study, we report a proof-of-concept study using ICAM-1-targeting CAR T cells against gastric cancer. The efficacy of ICAM-1 CAR T cells showed a significant correlation with the level of ICAM-1 expression in target cells in vitro. In animal models of human gastric cancer, ICAM-1-targeting CAR T cells potently eliminated tumors that developed in the lungs, while their efficacy was more limited against the tumors in the peritoneum. To augment CAR T cell activity against intraperitoneal tumors, combinations with paclitaxel or CAR activation-dependent interleukin (IL)-12 release were explored and found to significantly increase anti-tumor activity and survival benefit. Collectively, ICAM-1-targeting CAR T cells alone or in combination with chemotherapy represent a promising strategy to treat patients with ICAM-1+ advanced gastric cancer.