ERAS following Gastrectomy for Octo- and Nonagenarians: A Single-Center Retrospective Analysis.

Background: The safety and efficacy of enhanced recovery after surgery (ERAS) following elective gastrectomy for gastric cancer in patients >80 years of age are not well described. The aim of this study was to explore whether an ERAS protocol following gastrectomy in this age group can be safely implemented and reduce postoperative length of stay. Methods: A retrospective, single-center analysis was performed. All patients >80 years of age with gastric cancer undergoing elective subtotal and total gastrectomy between January 2010 and December 2021 were identified. With the implementation of an ERAS protocol in January 2016, patients treated beforehand were allocated to Group A (pre-ERAS) and Group B (ERAS). The length of stay, incidence of postoperative complications and representation/readmission to the hospital were compared between the groups. Results: Of the 221 patients identified, 56 met the inclusion criteria with 22 patients (39.3%) allocated to Group A and 34 patients (60.7%) to Group B. There were no differences with regard to the type of resection and surgical approach. Length of stay was shorter in Group B (5 days, range 2-27 versus 10 days, 3-109, P = .040). A trend toward more discharges by postoperative day 3 was noted among patients in Group B (7/34, 20.6% versus 2/22, 9.1%, P = .253). There were no differences in the incidence of postoperative complications or readmission hospital between the groups. Conclusion: Among patients >80 years of age, ERAS following gastrectomy for cancer is associated with a reduced length of stay and can be safely implemented.

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.).

Survival in esophageal cancer with nonregional lymphadenopathy: a propensity score-matched analysis.

BACKGROUND: Survival among patients with esophageal cancer with stage IV nonregional lymphadenopathy treated with neoadjuvant therapy and surgical resection is not well described. This study aimed to compare the survival outcomes of patients with nonregional lymphadenopathy with a propensity-matched cohort of patients with locoregional disease. METHODS: This was a retrospective cohort analysis of a prospectively maintained database from a regional upper gastrointestinal cancer network in Quebec, Canada. From January 2010 to December 2022, patients with radiologically suspicious nonregional retroperitoneal or supraclavicular lymphadenopathy were identified. Using 1:1 propensity score matching, a control group without nonregional disease was created. RESULTS: Of the 1235 patients identified, 39 met the inclusion criteria and were allocated to the study group of whom 35 of 39 (89%) had adenocarcinoma. Retroperitoneal and supraclavicular lymphadenopathy occurred in 26 of 39 patients (67%) and 13 of 39 patients (33%). Of the 39 patients, 34 (87%) received neoadjuvant chemotherapy, and 5 (13%) received chemoradiotherapy. After resection, ypN0 of nonregional lymph node stations occurred in 21 of 39 patients (54%). When comparing the study group with a matched non-stage IV control group, the median overall survival was similar in patients with retroperitoneal lymphadenopathy (21.0 months [95% CI, 8.0-21.0] vs 27.0 months [95% CI, 13.0-41.0]; P = .262) but not with supraclavicular disease (13.0 months; 95% CI, 8.0-18.0; P = .039). The median follow-up intervals were 40.1 months (95% CI, 1.0-83.0) for the study group and 70.0 (95% CI, 33.0-106.0) for the control groups. CONCLUSION: Compared with a matched cohort of patients with similar disease burden but not stage IV disease, retroperitoneal lymphadenopathy did not negatively affect survival outcomes. Multimodal curative intent therapy may be appropriate in select cases.

Perioperative Immunotherapy for Node-Negative Non-Small Cell Lung Cancer-Current Evidence and Future Directions.

Neoadjuvant immunotherapy has gone from an idea to an indication in locally advanced lung cancer. Several phase III trials have demonstrated the superiority of neoadjuvant chemoimmunotherapy compared with chemotherapy in this setting. Although such progress has revolutionized the treatment of locally advanced disease, the unmet needs of stage I and stage II patients without lymph node disease have largely been underrepresented in existing trials. Up-front resection with few patients going on to complete adjuvant therapy remains the norm for most stage I and II patients. Emerging evidence now supports the exploration of supplemental checkpoint blockade in well-selected early-stage, node-negative patients with large tumors and no actionable driver mutations. Although concerns surrounding safety and risk exist, patient selection could be substantially improved using novel biomarker approaches that leverage our understanding of the tumor immune microenvironment of lung cancer. This review provides a comprehensive overview of the opportunities and controversies of perioperative immunotherapy in node-negative lung cancer.

Enhanced recovery after surgery after radical gastrectomy: Improved compliance over time is associated with a shorter postoperative hospital stay.

BACKGROUND: Changing adherence over time to enhanced recovery after surgery (ERAS) protocols following radical gastrectomy and the impact this has on length of stay (LoS) is not well described. This study aimed to explore the changes in adherence to core ERAS elements over time and the relationship between compliance and LoS. METHODS: A retrospective, single center cohort study was performed between 01/2016-12/2021. An ad hoc analysis revealed the point at which a significant difference in the number of patients being discharge on postoperative day (PoD) 3 was noted allowing allocation of patients to Group A (01/2016-12/2019) or B (01/2020-12/2021). Compliance with core ERAS elements was compared and the relationship between compliance and discharge by (PoD) 3 assessed. Variables significant on univariate analysis were assessed using binary multivariate regression. RESULTS: Of the 268 patients identified, 187 met the inclusion criteria (Group A 112 and Group B 75). More patients in Group B mobilized on PoD 1 (60.0 vs. 31.3%, p = <0.001), tolerated postgastrectomy diet by PoD 3 (84.6 vs. 62.5%, p = 0.049), and were discharged by PoD 3 (34.7 vs. 20.5%, p = 0.002). Protocol compliance of >75% was associated with discharge on PoD 3 (area under the curve, 0.726). Active mobilization on PoD 1 (OR 3.5, p = 0.009), compliance ≥75% (OR 3.3, p = 0.036), and preoperative nutritional consult (OR 0.2, p = 0.002) were independently associated with discharge on PoD 3. Discharge on PoD 3 did not increase readmission or representation to hospital. CONCLUSION: Early mobilization, protocol compliance >75%, and preoperative nutritional consult were associated with discharge on PoD 3 after radical gastrectomy.

Neoadjuvant Chemoimmunotherapy for NSCLC: A Systematic Review and Meta-Analysis.

Importance: To date, no meta-analyses have comprehensively assessed the association of neoadjuvant chemoimmunotherapy with clinical outcomes in non-small cell lung cancer (NSCLC) in randomized and nonrandomized settings. In addition, there exists controversy concerning the efficacy of neoadjuvant chemoimmunotherapy for patients with NSCLC with programmed cell death 1 ligand 1 (PD-L1) levels less than 1%. Objective: To compare neoadjuvant chemoimmunotherapy with chemotherapy by adverse events and surgical, pathological, and efficacy outcomes using recently published randomized clinical trials and nonrandomized trials. Data Sources: MEDLINE and Embase were systematically searched from January 1, 2013, to October 25, 2023, for all clinical trials of neoadjuvant chemoimmunotherapy and chemotherapy that included at least 10 patients. Study Selection: Observational studies and trials reporting the use of neoadjuvant radiotherapy, including chemoradiotherapy, molecular targeted therapy, or immunotherapy monotherapy, were excluded. Main Outcomes and Measures: Surgical, pathological, and efficacy end points and adverse events were pooled using a random-effects meta-analysis. Results: Among 43 eligible trials comprising 5431 patients (4020 males [74.0%]; median age range, 55-70 years), there were 8 randomized clinical trials with 3387 patients. For randomized clinical trials, pooled overall survival (hazard ratio, 0.65; 95% CI, 0.54-0.79; I2 = 0%), event-free survival (hazard ratio, 0.59; 95% CI, 0.52-0.67; I2 = 14.9%), major pathological response (risk ratio, 3.42; 95% CI, 2.83-4.15; I2 = 31.2%), and complete pathological response (risk ratio, 5.52; 95% CI, 4.25-7.15; I2 = 27.4%) favored neoadjuvant chemoimmunotherapy over neoadjuvant chemotherapy. For patients with baseline tumor PD-L1 levels less than 1%, there was a significant benefit in event-free survival for neoadjuvant chemoimmunotherapy compared with chemotherapy (hazard ratio, 0.74; 95% CI, 0.62-0.89; I2 = 0%). Conclusion and Relevance: This study found that neoadjuvant chemoimmunotherapy was superior to neoadjuvant chemotherapy across surgical, pathological, and efficacy outcomes. These findings suggest that patients with resectable NSCLC with tumor PD-L1 levels less than 1% may have an event-free survival benefit with neoadjuvant chemoimmunotherapy.

Comparing immediate postoperative outcomes of different VATS approaches for anatomical lung resection: a single-centre retrospective study.

BACKGROUND: Video-assisted thoracic surgery (VATS) can be performed through 1 or more intercostal or subxiphoid ports. The aim of this study was to evaluate whether number and location of ports had an impact on early perioperative outcomes and postoperative pain after anatomical lung resection (ALR). METHODS: A search of the departmental electronic database identified all patients who underwent VATS ALR between June 2018 and June 2019. We stratified patients according to the surgical approach: 2-port VATS, 3-port VATS, and subxiphoid VATS. We extracted demographic and clinicopathologic data. We used univariate analysis with unpaired t tests and χ2 tests to compare these variables between the subgroups. RESULTS: We included 201 patients in the analysis. When patients were stratified by surgical approach, there was no difference in terms of age, disease load, length of surgery, postoperative complications, duration of pleural drainage, and length of hospital stay. Postoperative pain and morphine equivalent usage were also comparable between the groups. According to these results, number and location of VATS ports seemingly has no clinical impact on early postoperative outcomes. Limitations of the study include its retrospective nature, small sample size, and short follow-up interval. CONCLUSION: Our results suggest that incision location and the number of VATS ports is not associated with differences in the incidence of perioperative complications or postoperative pain. Given the limitations described above, further studies with longer follow-up intervals are required to explore the lasting impact of this surgical approach on quality of life.

Transitioning to Neoadjuvant Therapy for Resectable Non-Small Cell Lung Cancer: Trends and Surgical Outcomes in a Regionalized Pulmonary Oncology Network.

BACKGROUND: Several regulatory agencies have approved the use of the neoadjuvant chemo-immunotherapy for resectable stage II and III of non-small cell lung cancer (NSCLC) and numerous trials investigating novel agents are underway. However, significant concerns exist around the feasibility and safety of offering curative surgery to patients treated within such pathways. The goal in this study was to evaluate the impact of a transition towards a large-scale neoadjuvant therapy program for NSCLC. METHODS: Medical charts of patients with clinical stage II and III NSCLC who underwent resection from January 2015 to December 2020 were reviewed. The primary outcome was perioperative complication rate between neoadjuvant-treated versus upfront surgery patients. Multivariable logistic regression estimated occurrence of postoperative complications and overall survival was assessed as an exploratory secondary outcome by Kaplan-Meier and Cox-regression analyses. RESULTS: Of the 428 patients included, 106 (24.8%) received neoadjuvant therapy and 322 (75.2%) upfront surgery. Frequency of minor and major postoperative complications was similar between groups (P = .22). Occurrence in postoperative complication was similar in both cohort (aOR = 1.31, 95% CI 0.73-2.34). Neoadjuvant therapy administration increased from 10% to 45% with a rise in targeted and immuno-therapies over time, accompanied by a reduced rate of preoperative radiation therapy use. 1-, 2-, and 5-year overall survival was higher in neoadjuvant therapy compared to upfront surgery patients (Log-Rank P = .017). CONCLUSIONS: No significant differences in perioperative outcomes and survival were observed in resectable NSCLC patients treated by neoadjuvant therapy versus upfront surgery. Transition to neoadjuvant therapy among resectable NSCLC patients is safe and feasible from a surgical perspective.

Nunavimmi puvakkut kaggutimik aanniaqarniq: Qanuilirqitaa? Lung cancer in Nunavik: How are we doing? A retrospective matched cohort study.

BACKGROUND: Whether Inuit in Canada experience disparities in lung cancer survival remains unknown. When requiring investigation and treatment for lung cancer, all residents of Nunavik, the Inuit homeland in Quebec, are sent to the McGill University Health Centre (MUHC), in Montréal. We sought to compare survival among patients with lung cancer at the MUHC, who were residents of Nunavik and Montréal, Quebec, respectively. METHODS: We conducted a retrospective cohort study. Using lung cancer registry data, we identified Nunavik residents with histologically confirmed lung cancer diagnosed between 2005 and 2017. We aimed to match 2 Montréal residents to each Nunavik resident on sex, age, calendar year of diagnosis, and histology (non-small cell lung cancer v. small cell lung cancer). We reviewed medical records for data on additional patient characteristics and treatment, and obtained vital status from a provincial registry. We compared survival using Kaplan-Meier analysis and Cox proportional hazards regression. RESULTS: We included 95 residents of Nunavik and 185 residents of Montréal. For non-small cell lung cancer, median survival times were 321 (95% confidence interval [CI] 184-626) days for Nunavik (n = 71) and 720 (95% CI 536-1208) days for Montréal residents (n = 141). For small cell lung cancer, median survival times were 190 (95% CI 159-308) days for Nunavik (n = 24) and 270 (95% CI 194-766) days for Montréal residents (n = 44). Adjusting for matching variables, stage, performance status, and comorbidity, Nunavik residents had a higher hazard of death (hazard ratio 1.68, 95% CI 1.17-2.41). INTERPRETATION: Nunavik residents experience disparities in survival after lung cancer diagnosis. Although studies in other Inuit Nunangat regions are needed, our findings point to an urgent need to ensure that interventions aimed at improving lung cancer survival, including lung cancer screening, are accessible to Inuit Nunangat residents.

The Emerging Role of Immunotherapy in Resectable Non-Small Cell Lung Cancer.

BACKGROUND: Despite surgical resection, long-term survival of patients with resectable non-small cell lung cancer (NSCLC) remains poor. Adjuvant chemotherapy, the standard of care for locally advanced NSCLC, provides a marginal 5.4% benefit in survival. Immune checkpoint inhibitors (ICIs) have shown a significant survival benefit in some patients with advanced NSCLC and are being evaluated for perioperative use in resectable NSCLC. METHODS: We conducted a literature search using the PubMed online database to identify clinical trials of immunotherapy in resectable NSCLC and studies analyzing biomarkers and immune priming strategies. RESULTS: Building on previous phase I and II trials, randomized phase III trials have shown efficacy of neoadjuvant nivolumab, perioperative pembrolizumab, adjuvant atezolizumab, and adjuvant pembrolizumab in the treatment of NSCLC with improvement of event-free/disease-free survival of 24% to 42%, leading to United States Food and Drug Administration approval of these drugs in the treatment of resectable NSCLC. Three additional phase III trials have also recently reported the use of immunotherapy both before and after surgery, with pathologic complete response rates of 17% to 25%, significantly better than chemotherapy alone. Perioperative ICI therapy has comparable perioperative morbidity to chemotherapy alone and does not impair surgical outcomes. CONCLUSIONS: Perioperative immunotherapy, in combination with chemotherapy, is safe and improves outcomes in patients with resectable NSCLC. Questions regarding patient selection, the need for adjuvant ICI therapy after neoadjuvant chemoimmunotherapy, and the duration of perioperative immunotherapy remain to be answered by future trials.

Cotargeting CDK4/6 and BRD4 Promotes Senescence and Ferroptosis Sensitivity in Cancer.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for breast cancer treatment and show activity against other malignancies, including KRAS-mutant non-small cell lung cancer (NSCLC). However, the clinical efficacy of CDK4/6 inhibitors is limited due to frequent drug resistance and their largely cytostatic effects. Through a genome-wide cDNA screen, we identified that bromodomain-containing protein 4 (BRD4) overexpression conferred resistance to the CDK4/6 inhibitor palbociclib in KRAS-mutant NSCLC cells. Inhibition of BRD4, either by RNA interference or small-molecule inhibitors, synergized with palbociclib to induce senescence in NSCLC cells and tumors, and the combination prolonged survival in a KRAS-mutant NSCLC mouse model. Mechanistically, BRD4-inhibition enhanced cell-cycle arrest and reactive oxygen species (ROS) accumulation, both of which are necessary for senescence induction; this in turn elevated GPX4, a peroxidase that suppresses ROS-triggered ferroptosis. Consequently, GPX4 inhibitor treatment selectively induced ferroptotic cell death in the senescent cancer cells, resulting in tumor regression. Cotargeting CDK4/6 and BRD4 also promoted senescence and ferroptosis vulnerability in pancreatic and breast cancer cells. Together, these findings reveal therapeutic vulnerabilities and effective combinations to enhance the clinical utility of CDK4/6 inhibitors. SIGNIFICANCE: The combination of cytostatic CDK4/6 and BRD4 inhibitors induces senescent cancer cells that are primed for activation of ferroptotic cell death by targeting GPX4, providing an effective strategy for treating cancer.

Association between pathologic response and survival after neoadjuvant therapy in lung cancer.

Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS) and pathologic complete response (0% residual viable tumor (RVT) in primary tumor (PT) and lymph nodes (LNs)), and is approved for treatment of resectable lung cancer. Pathologic response assessment after neoadjuvant therapy is the potential analog to radiographic response for advanced disease. However, %RVT thresholds beyond pathologic complete response and major pathologic response (≤10% RVT) have not been explored. Pathologic response was prospectively assessed in the randomized, phase 3 CheckMate 816 trial (NCT02998528), which evaluated neoadjuvant nivolumab (anti-programmed death protein 1) plus chemotherapy in patients with resectable lung cancer. RVT, regression and necrosis were quantified (0-100%) in PT and LNs using a pan-tumor scoring system and tested for association with EFS in a prespecified exploratory analysis. Regardless of LN involvement, EFS improved with 0% versus >0% RVT-PT (hazard ratio = 0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (area under the curve = 0.74); 2-year EFS rates were 90%, 60%, 57% and 39% for patients with 0-5%, >5-30%, >30-80% and >80% RVT, respectively. Each 1% RVT associated with a 0.017 hazard ratio increase for EFS. Combining pathologic response from PT and LNs helped differentiate outcomes. When compared with radiographic response and circulating tumor DNA clearance, %RVT best approximated EFS. These findings support pathologic response as an emerging survival surrogate. Further assessment of the full spectrum of %RVT in lung cancer and other tumor types is warranted. ClinicalTrials.gov registration: NCT02998528 .

Docetaxel-Based Neoadjuvant Chemotherapy Followed by En Bloc Resection for Esophageal Adenocarcinoma: A 15-Year Retrospective Analysis from a Regional Upper Gastrointestinal Cancer Network.

BACKROUND: Real-world, long-term survival outcomes of neoadjuvant, docetaxel-based therapy for esophageal and junctional adenocarcinoma are lacking. This study describes the long-term survival outcomes of patients with esophageal and junctional adenocarcinoma treated with neoadjuvant docetaxel-based chemotherapy and en bloc transthoracic esophagectomy. METHODS: A retrospective cohort analysis of a prospectively maintained database from a regional upper gastrointestinal cancer network in Quebec, Canada, was performed. From January 2007 to December 2021, all patients with locally advanced (cT3 and/or N1) esophageal/Siewert I/II adenocarcinoma treated with neoadjuvant DCFx3 (Docetaxel/Cisplatin/5FU) or FLOTx4 (5FU/Leucovorin/Oxaliplatin/Docetaxel) and transthoracic en bloc esophagectomy were identified. Postoperative, pathological, and survival outcomes were compared. RESULTS: Overall, 236 of 420 patients met the inclusion criteria. Tumor location was esophageal/Siewert I/Siewert II (118/33/85), most were cT3-4 (93.6%) and cN+ (61.0%). DCF and FLOT were used in 127 of 236 (53.8%) and 109 of 236 (46.2%). All neoadjuvant cycles were completed in 87.3% with no difference between the regimens. Operative procedures included Ivor Lewis (81.8%), left thoraco-abdominal esophagectomy (10.6%) and McKeown (7.6%) with an R0 resection in 95.3% and pathological complete response in 9.7% (DCF 12.6%/FLOT 6.4%, p = 0.111). The median lymph node yield was 32 (range 4-79), and 60.6% were ypN+. Median follow-up was longer for the DCF group (74.8 months 95% confidence interval [CI] 4-173 vs. 37.8 months 95% CI 2-119, p <0.001. Overall survival was similar between the groups (FLOT 97.3 months, 78.6-115.8 vs. DCF 92.9, 9.2-106.5, p = 0.420). CONCLUSIONS: Neoadjuvant DCF and FLOT followed by transthoracic en bloc resection are both highly effective regimens for locally advanced esophageal adenocarcinoma with equivalent survival outcomes despite high disease load.

Esophagectomy versus observation following endoscopic submucosal dissection of pT1b esophageal adenocarcinoma.

BACKGROUND: Management following endoscopic submucosal dissection (ESD) of pT1b esophageal adenocarcinoma (EAC) remains controversial. This study compared pathological and survival outcomes of patients after endoscopic resection (ER) of pT1b EAC followed by either en bloc esophagectomy or observation. METHODS: From 1/12 to 12/22, all patients with pT1b EAC treated with ER were identified from a prospectively maintained departmental database. ESD was curative (all of: Submucosal invasion < 500 µm; G1/2, LVI/PNI-; deep margin-) or non-curative (one or more of Submucosal invasion ≥ 500 µm; G3; LVI/PNI+; deep margin+). Patients were allocated to observation (OBS) or esophagectomy (SURG) based on patient factors/preference and pathological variables. RESULTS: 56/171 ERs met the inclusion criteria. ER was curative in 8/56 (14%) and non-curative in 48/56 (86%). OBS was undertaken after 8/27 (30%) curative and 19/27 (70%) non-curative resections. All 29 SURG patients had non-curative ERs and were younger, had lower Charlson comorbidity scores and had more deep margin + lesions than OBS patients. Post-esophagectomy, 15/29 (52%) had no residual disease within the surgical specimen while pT+N-/pT-N+/pT+N+ occurred in 5/3/6 (17%/10%/21%) patients. Of those with residual disease in the surgical specimen, 12/14 (86%) had deep margin + ERs; however, only ESD instead of EMR was independently associated with a lower risk of residual disease (OR 0.431, 95% CI - 0.016 to 1.234, p = 0.045). OBS and SURG patients had equivalent overall survival outcomes and recurrence was low in both groups even following non-curative ER. Follow-up was 28 months (0-102) and 30 months (0-97), respectively. CONCLUSION: In select patients, including some of those with a non-curative ESD resection of pT1B EAC, surveillance alone may be appropriate. Alternatives beyond traditional pathological features is needed to direct patient care more accurately.

Canadian Consensus Recommendations for the Management of Operable Stage II/III Non-Small-Cell Lung Cancer: Results of a Modified Delphi Process.

The treatment paradigm for patients with stage II/III non-small-cell lung cancer (NSCLC) is rapidly evolving. We performed a modified Delphi process culminating at the Early-stage Lung cancer International eXpert Retreat (ELIXR23) meeting held in Montreal, Canada, in June 2023. Participants included medical and radiation oncologists, thoracic surgeons and pathologists from across Quebec. Statements relating to diagnosis and treatment paradigms in the preoperative, operative and postoperative time periods were generated and modified until all held a high level of consensus. These statements are aimed to help guide clinicians involved in the treatment of patients with stage II/III NSCLC.

Transabdominal Management of Epiphrenic Diverticula in the Setting of Achalasia: A Single-center Review.

BACKGROUND: The perioperative and functional outcomes of patients with epiphrenic diverticula (ED) on a background of achalasia managed via a minimally invasive transabdominal approach are under-reported. We describe our center's experience over 10 years of treating such patients. METHODS: A single-center, retrospective chart of a prospectively maintained hospital database was performed. All patients with a diagnosis of ED and manometrically proven achalasia were identified. Demographic, clinical, and surgical data were extracted from the institution's medical records. Patients were stratified by whether they underwent myotomy only or myotomy plus diverticulectomy and compared in a univariate manner. RESULTS: There were 18 patients who met the inclusion criteria. The median age of the cohort was 67.1 years (range 53.1 to 77.8), the maximal size of the diverticula was 3.5 cm (range 2.0 to 7.0), and the distance of the proximal lip of the diverticulum to the incisors was 33.5 cm (range 28.0 to 38.0). In terms of surgical intervention, 14 patients (77.8%) underwent myotomy plus diverticulectomy, and 4 (22.2%) underwent myotomy alone. The duration of surgery was significantly longer in the former (177.5 vs. 75.0 min, P =0.031). In total, 9/18 (50.0%) of patients were discharged on the day of surgery. There was a trend to more major postoperative complications following diverticulectomy plus myotomy, with 2/13 (15.4%) patients suffering staple line leaks. Excellent long-term functional outcomes were achieved, with 81.3% of patients having sustained resolution of their symptoms. CONCLUSIONS: Laparoscopic transabdominal approach for the treatment of ED offers an acceptable risk profile and favorable functional outcomes in patients with underlying achalasia.

Lung tumor-infiltrating Treg have divergent transcriptional profiles and function linked to checkpoint blockade response.

Regulatory T cells (Treg) are conventionally viewed as suppressors of endogenous and therapy-induced antitumor immunity; however, their role in modulating responses to immune checkpoint blockade (ICB) is unclear. In this study, we integrated single-cell RNA-seq/T cell receptor sequencing (TCRseq) of >73,000 tumor-infiltrating Treg (TIL-Treg) from anti-PD-1-treated and treatment-naive non-small cell lung cancers (NSCLC) with single-cell analysis of tumor-associated antigen (TAA)-specific Treg derived from a murine tumor model. We identified 10 subsets of human TIL-Treg, most of which have high concordance with murine TIL-Treg subsets. Only one subset selectively expresses high levels of TNFRSF4 (OX40) and TNFRSF18 (GITR), whose engangement by cognate ligand mediated proliferative programs and NF-κB activation, as well as multiple genes involved in Treg suppression, including LAG3. Functionally, the OX40hiGITRhi subset is the most highly suppressive ex vivo, and its higher representation among total TIL-Treg correlated with resistance to PD-1 blockade. Unexpectedly, in the murine tumor model, we found that virtually all TIL-Treg-expressing T cell receptors that are specific for TAA fully develop a distinct TH1-like signature over a 2-week period after entry into the tumor, down-regulating FoxP3 and up-regulating expression of TBX21 (Tbet), IFNG, and certain proinflammatory granzymes. Transfer learning of a gene score from the murine TAA-specific TH1-like Treg subset to the human single-cell dataset revealed a highly analogous subcluster that was enriched in anti-PD-1-responding tumors. These findings demonstrate that TIL-Treg partition into multiple distinct transcriptionally defined subsets with potentially opposing effects on ICB-induced antitumor immunity and suggest that TAA-specific TIL-Treg may positively contribute to antitumor responses.

Neoadjuvant Durvalumab Alone or Combined with Novel Immuno-Oncology Agents in Resectable Lung Cancer: The Phase II NeoCOAST Platform Trial.

Neoadjuvant chemoimmunotherapy improves pathologic complete response rate and event-free survival in patients with resectable non-small cell lung cancer (NSCLC) versus chemotherapy alone. NeoCOAST was the first randomized, multidrug platform trial to examine novel neoadjuvant immuno-oncology combinations for patients with resectable NSCLC, using major pathologic response (MPR) rate as the primary endpoint. Eighty-three patients received a single cycle of treatment: 26 received durvalumab (anti-PD-L1) monotherapy, 21 received durvalumab plus oleclumab (anti-CD73), 20 received durvalumab plus monalizumab (anti-NKG2A), and 16 received durvalumab plus danvatirsen (anti-STAT3 antisense oligonucleotide). MPR rates were higher for patients in the combination arms versus durvalumab alone. Safety profiles for the combinations were similar to those of durvalumab alone. Multiplatform immune profiling suggested that improved MPR rates in the durvalumab plus oleclumab and durvalumab plus monalizumab arms were associated with enhanced effector immune infiltration of tumors, interferon responses and markers of tertiary lymphoid structure formation, and systemic functional immune cell activation. SIGNIFICANCE: A neoadjuvant platform trial can rapidly generate clinical and translational data using candidate surrogate endpoints like MPR. In NeoCOAST, patients with resectable NSCLC had improved MPR rates after durvalumab plus oleclumab or monalizumab versus durvalumab alone and tumoral transcriptomic signatures indicative of augmented immune cell activation and function. See related commentary by Cooper and Yu, p. 2306. This article is featured in Selected Articles from This Issue, p. 2293.