Novel Approaches to Thoracic Malignancies

Abstract

Reduction in muscle contractile force associated with many clinical conditions incurs serious morbidity and increased mortality. Here, we report the first evidence that JAK inhibition impacts contractile force in normal human muscle. Muscle biopsies were taken from patients who were randomized to receive tofacitinib (n = 16) or placebo (n = 17) for 48 h. Single-fiber contractile force and molecular studies were carried out. The contractile force of individual diaphragm myofibers pooled from the tofacitinib group (n = 248 fibers) was significantly higher than those from the placebo group (n = 238 fibers), with a 15.7% greater mean maximum specific force (P = 0.0016). Tofacitinib treatment similarly increased fiber force in the serratus anterior muscle. The increased force was associated with reduced muscle protein oxidation and FoxO-ubiquitination-proteasome signaling, and increased levels of smooth muscle MYLK. Inhibition of MYLK attenuated the tofacitinib-dependent increase in fiber force. These data demonstrate that tofacitinib increases the contractile force of skeletal muscle and offers several underlying mechanisms. Inhibition of the JAK-STAT pathway is thus a potential new therapy for the muscle dysfunction that occurs in many clinical conditions.

View details for DOI 10.26508/lsa.202402885

View details for PubMedID 39122555

View details for PubMedCentralID PMC11316201

Abstract

Multidisciplinary lung cancer screening (LCS) programs that perform shared decision-making visits (SDMV) and follow up annual low dose computed tomography (LDCT) have been emerging. We hypothesize that primary care providers (PCPs) prefer to refer patients to LCS programs instead of facilitating the screening process themselves.This is a mixed-methods, cross-sectional study in which an online survey was administered to PCPs between April 2023 and June 2023.58 PCPs in the same hospital network participated in the study with a median age of 43 (34-51), predominance of women (77.6%), and clinicians of white and Asian race (44.8% and 48.3%). Respondents estimated that 26.1% (SD 32.4%) of their eligible patients participate in LCS screening. PCPs thought that an LCS program was equally convenient to performing screening themselves for identifying eligible patients and ordering LDCT. However, 63.8% of participants preferred an LCS program for performing SDMVs, 62.1% for ensuring annual follow-up on negative LDCTs, 70.7% for deciding next steps on positive LDCTs, and 60.4% for performing smoking cessation counseling. PCPs agreed that an LCS program saves time (69%), allows patients to receive specialty care (65.6%), addresses patient concerns (70.7%), ensures annual follow-up (77.6%), and manages abnormal findings (79.3%). However, they also expressed concerns about an additional visit for the patient (48.2%) and patient cost (46.5%).Most PCPs believe that formal LCS programs have many benefits including providing specialized care and follow up, although there were concerns about patient time and cost.

View details for DOI 10.1016/j.cllc.2024.10.002

View details for PubMedID 39472235

Abstract

Sublobar resection of early-stage non-small cell lung cancer (NSCLC) is increasingly considered appropriate but may compromise margins compared to lobectomy. This study evaluated resection extent, margin status, and survival for clinical stage I NSCLC patients.Clinical T1-2N0M0 NSCLC patients in the National Cancer Database (2006-2020) treated with primary surgery were compared stratified by margin status. The potential benefit of radiation was explored in subgroup analysis of sublobar resection patients with positive margins.Positive margins occurred in 5,089 (2.8%) of 181,824 patients and were more common in sublobar resections compared to lobectomy (4.3% vs 2.4%,p<0.001). Sublobar resection had the strongest association with positive margins in multivariable analysis (OR 2.06 [95% CI 1.91-2.23],p<0.001). Patients with positive margins were more likely to undergo both adjuvant chemotherapy (16% vs 13%,p<0.001) and radiation (17% vs 1%,p<0.001) but had worse survival in univariate (44.0% 5-year OS vs 69.2%,p<0.001) and multivariable Cox analysis (HR 1.71 [95% CI 1.63-1.78, p<0.001) in the entire cohort, as well as in univariate subset analysis of lobectomy (46.9% vs 70.4%, p<0.001) and sublobar (37.5% vs 64.1%,p<0.001). Postoperative radiation for sublobar patients with positive margins did not improve 5-year OS (36.3% for irradiated patients vs 38.3% for non-irradiated patients,p=0.57), and positive margin sublobar patients treated with radiation had inferior survival to negative margin lobectomy patients.Positive margins occur more frequently after sublobar resection of clinical stage I NSCLC compared to lobectomy. Patients with positive margins have worse survival than complete resection patients and are not rescued by post-operative radiation.

View details for DOI 10.1016/j.athoracsur.2024.05.032

View details for PubMedID 38866199

Abstract

Sublobar resection offers non-inferior survival vs. lobectomy for ≤2cm NSCLC and is commonly employed for subsolid tumors. While data exists for solid tumors, the minimum adequate margin of resection for subsolid adenocarcinomas remains unclear.Retrospective review of 1101 adenocarcinoma resections at our institution, 2006-2022.tumors≤3cm with ≥10% radiographic ground glass, excised by sublobar resection.positive nodes, positive or unreported margin. The primary outcome was rate of local recurrence(LR) at multiple thresholds of margin distance. Relationship between margin distance and solid-component size was also explored.194 patients met inclusion criteria. Median(IQR) tumor diameter and margin distance were 12(9-17)mm and 10(5-17)mm, respectively. Median follow-up was 42.5 months. There was a progressive increase in LR with diminishing margin (0.1cm decrements) from 1.5cm to 0.5cm. The difference in the rate of LR between "over"(n=143) and "under"(n=51) was most significant at 0.5cm [8/51(15.7%) vs. 6/143(4.2%),p=0.01] but did not reach α adjusted for multiple comparisons. On Cox regression for LR-free survival (LRFS), margin ≤0.5cm(p=0.19) and %solid component (p=0.14) trended to significance. Combining these using margin-distance-to-solid-component-size ratio, a ratio≤1 did show a significantly higher rate of local recurrence [7(14.3%) vs. 2(2.0%),p=0.009]. Treatment of local recurrences provided at least intermediate-term survival in 87% of recurrences (median post-recurrence follow-up 44 months).During sublobar resection of subsolid lung adenocarcinomas, margin-to-solid-component-size ratio>1.0 appears to be a more reliable factor than margin distance alone to minimize local recurrence. Local recurrence, however, may not impact survival in patients with subsolid adenocarcinomas if timely treatment is administered.

View details for DOI 10.1016/j.athoracsur.2024.04.018

View details for PubMedID 38734402

Abstract

Annual low-dose computed tomography (LDCT) screening has been shown to reduce lung cancer mortality in high-risk individuals by detecting the disease at an earlier stage. This study aims to assess the barriers to completing LDCT in a cohort of patients who were determined eligible for lung cancer screening (LCS).We performed a single institution, mixed methods, cross-sectional study of patients who had a LDCT ordered from July to December 2022. We then completed phone surveys with patients who did not complete LDCT to assess knowledge, attitude, and perceptions toward LCS.We identified 380 patients who met inclusion criteria, including 331 (87%) who completed LDCT and 49 (13%) who did not. Patients who completed a LDCT and those who did not were similar regarding age, sex, race, primary language, household income, body mass index, median pack years, and quit time. Positive predictors of LDCT completion were: meeting USPSTF guidelines (97.9% vs 81.6%), being married (58.3% vs 44.9%), former versus current smokers (55% vs 41.7%), personal history of emphysema (60.4% vs 42.9%), and family history of lung cancer (13.9% vs 4.1%) (all P < .05). Of the patients who participated in the phone survey, only 7% of respondents thought they were high risk for developing lung cancer despite attending a shared decision-making visit and only 10% wanted to re-schedule their LDCT.There exist barriers to completing LDCT even after patients are identified as eligible and complete a shared decision-making visit secondary to knowledge barriers, misperceptions, and patient disinterest.

View details for DOI 10.1016/j.cllc.2024.04.014

View details for PubMedID 38749902

Abstract

Randomized control trials are considered the highest level of evidence, yet the scalability and practicality of implementing randomized control trials in the thoracic surgical oncology space are not well described. The aim of this study is to understand what types of randomized control trials have been conducted in thoracic surgical oncology and ascertain their success rate in completing them as originally planned.The ClinicalTrials.gov database was queried in April 2023 to identify registered randomized control trials performed in patients with lung cancer who underwent surgery (by any technique) as part of their treatment.There were 68 eligible randomized control trials; 33 (48.5%) were intended to examine different perioperative patient management strategies (eg, analgesia, ventilation, drainage) or to examine different intraoperative technical aspects (eg, stapling, number of ports, port placement, ligation). The number of randomized control trials was relatively stable over time until a large increase in randomized control trials starting in 2016. Forty-four of the randomized control trials (64.7%) were open-label studies, 43 (63.2%) were conducted in a single facility, 66 (97.1%) had 2 arms, and the mean number of patients enrolled per randomized control trial was 236 (SD, 187). Of 21 completed randomized control trials (31%), the average time to complete accrual was 1605 days (4.4 years) and average time to complete primary/secondary outcomes and adverse events collection was 2125 days (5.82 years).Given the immense investment of resources that randomized control trials require, these findings suggest the need to scrutinize future randomized control trial proposals to assess the likelihood of successful completion. Future study is needed to understand the various contributing factors to randomized control trial success or failure.

View details for DOI 10.1016/j.xjon.2024.01.008

View details for PubMedID 38690441

View details for PubMedCentralID PMC11056451

Abstract

Lepidic-type adenocarcinomas (LPA) can be multi-focal, and treatment is often deferred until there is observed growth. This study investigated the potential downside of that strategy by evaluating the relationship of nodal involvement with tumor size and survival.The impact of tumor size on lymph node involvement and survival was evaluated for National Cancer Database patients who received surgery without induction therapy as primary treatment for cT1-3N0M0 histologically confirmed LPA from 2006-2019 using logistic regression, Kaplan-Meier, and Cox analyses.Positive nodes occurred in 442 (5.3%) of 8,286 patients. The incidence of having positive nodes approximately doubled with each 1cm increment increase in size. Patients with positive nodes were more likely to have larger tumors (27mm vs 20mm,p<0.001) and clinical T2+ disease (40.7% vs 26.8%,p<0.001) compared to node-negative patients, but tumor size was the only significant independent predictor of having positive nodal disease in logistic regression analysis; this association grew stronger with each incremental centimeter increase in size. Patients with positive nodes were more likely to undergo adjuvant radiation (23.5% vs 1.1%,p<0.001) and chemotherapy (72.9% vs 7.9%,p<0.001), and expectedly had worse survival compared to the node negative group in univariate (5-year overall survival 50.9% vs 81.1%,p<0.001) and multivariable (Hazard ratio 2.56 [95% CI 2.14-3.05],p<0.001) analyses.Nodal involvement is relatively uncommon in early-stage LPAs but steadily increases with tumor size and is associated with dramatically worse survival. This data can be used to inform treatment decisions when evaluating LPA patients.

View details for DOI 10.1016/j.athoracsur.2024.03.003

View details for PubMedID 38490310

View details for DOI 10.1016/j.gassur.2023.12.024

View details for PubMedID 38445922

Abstract

Multiple clinical trials have revealed the benefit of immunotherapy (IO) for NSCLC, including unresectable stage III disease. Our aim was to investigate the impact of IO use on treatment and outcomes of potentially resectable stage IIIA NSCLC in a broader nationwide patient cohort.We queried the National Cancer Database (2004-2019) for patients with stage IIIA (T1-2N2) NSCLC. Treatment and survival were evaluated with descriptive statistics, logistic regression, Kaplan-Meier analysis, and Cox proportional hazards modeling.Overall, 5.5% (3777 of 68,335) of patients received IO. IO use was uncommon until 2017, but by 2019, it was given to 40.1% (1544 of 2308) of stage IIIA patients. The increased use of IO after 2017 was associated with increased definitive chemoradiation treatment (54.2% [6800 of 12,535] from years 2017 to 2019 versus 46.9% [26,251 of 55,914] from 2004 to 2016, p < 0.001) and less use of surgery (18.1% [2266 of 12,535] from years 2017 to 2019 versus 22.0% [12,300 of 55,914] from 2004 to 2016, p < 0.001). IO treatment was associated with significantly better 5-year survival in the entire cohort (36.9% versus 23.4%, p < 0.001) and the subsets of patients treated with chemoradiation (37.2% versus 22.7%, p < 0.001) and surgery (48.6% versus 44.3%, p < 0.001). Pneumonectomy use decreased with increased IO treatment (5.1% of surgical patients [116 of 2266] from years 2017 to 2019 versus 9.2% [1127 of 12,300] from 2004 to 2016, p < 0.001).Increased use of IO was associated with a change in treatment patterns and improved survival for patients with stage IIIA(N2) NSCLC.

View details for DOI 10.1016/j.jtocrr.2024.100654

View details for PubMedID 38496376

View details for PubMedCentralID PMC10941003

Abstract

Background: Radiotherapy (RT) is integral to breast cancer treatment, especially in the current era that emphasizes breast conservation. The aim of our study was to determine the incidence of subsequent primary lung cancer after RT exposure for breast cancer over a time span of 3decades to quantify this risk over time as modern oncologic treatment continues to evolve.Methods: The SEER (Surveillance, Epidemiology, and End Results) database was queried from 1988 to 2014 for patients diagnosed with nonmetastatic breast cancer. Patients who subsequently developed primary lung cancer were identified. Multivariable regression modeling was performed to identify independent factors associated with the development of lung cancer stratified by follow up intervals of 5 to 9years, 10 to 15years, and >15years after breast cancer diagnosis.Results: Of the 612,746 patients who met our inclusion criteria, 319,014 (52%) were irradiated. primary lung cancer developed in 5556 patients (1.74%) in the RT group versus 4935 patients (1.68%) in the non-RT group. In a multivariable model stratified by follow-up duration, the overall HR of developing subsequent ipsilateral lung cancer in the RT group was 1.14 (P=.036) after 5 to 9years of follow-up, 1.28 (P=.002) after 10 to 15years of follow-up, and 1.30 (P=.014) after >15years of follow-up. The HR of contralateral lung cancer was not increased at any time interval.Conclusions: The increased risk of developing a primary lung cancer secondary to RT exposure for breast cancer is much lower than previously published. Modern RT techniques may have contributed to the improved risk profile, and this updated study is important for counseling and surveillance of breast cancer patients.

View details for DOI 10.1016/j.xjon.2023.10.031

View details for PubMedID 38204675