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.

High-risk features associated with recurrence in stage I lung adenocarcinoma.

OBJECTIVE: There is a lack of knowledge regarding the use of prognostic features in stage I lung adenocarcinoma (LUAD). Thus, we investigated clinicopathologic features associated with recurrence after complete resection for stage I LUAD. METHODS: We performed a retrospective analysis of patients with pathologic stage I LUAD who underwent R0 resection from 2010 to 2020. Exclusion criteria included history of lung cancer, induction or adjuvant therapy, noninvasive or mucinous LUAD, and death within 90 days of surgery. Fine and Gray competing-risk regression assessed associations between clinicopathologic features and disease recurrence. RESULTS: In total, 1912 patients met inclusion criteria. Most patients (1565 [82%]) had stage IA LUAD, and 250 developed recurrence: 141 (56%) distant and 109 (44%) locoregional only. The 5-year cumulative incidence of recurrence was 12% (95% CI, 11%-14%). Higher maximum standardized uptake value of the primary tumor (hazard ratio [HR], 1.04), sublobar resection (HR, 2.04), higher International Association for the Study of Lung Cancer grade (HR, 5.32 [grade 2]; HR, 7.93 [grade 3]), lymphovascular invasion (HR, 1.70), visceral pleural invasion (HR, 1.54), and tumor size (HR, 1.30) were independently associated with a hazard of recurrence. Tumors with 3 to 4 high-risk features had a higher cumulative incidence of recurrence at 5 years than tumors without these features (30% vs 4%; P < .001). CONCLUSIONS: Recurrence after resection for stage I LUAD remains an issue for select patients. Commonly reported clinicopathologic features can be used to define patients at high risk of recurrence and should be considered when assessing the prognosis of patients with stage I disease.

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.

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.

Lung resection after initial nonoperative treatment for non-small cell lung cancer.

OBJECTIVES: The study objectives were to assess the outcomes of lung resection in patients with non-small cell lung cancer previously treated with nonoperative treatment and to identify prognostic factors associated with survival. METHODS: Patients who underwent surgery (2010-2022) after initial nonoperative treatment at a single institution were identified from a prospectively maintained database. Exclusion criteria included metachronous cancer, planned neoadjuvant therapy, and surgery for diagnostic or palliative indications. Cox models were constructed for overall survival and event-free survival. Survival of patients with stage IV disease was compared with survival of a nonstudy cohort who did not undergo surgery. RESULTS: In total, 120 patients met the inclusion criteria. Initial clinical stage was early stage in 16%, locoregionally advanced in 25%, and metastatic in 59% of patients. The indication for surgery was recurrence in 18%, local persistent disease in 23%, oligoprogression in 22%, and local control of oligometastatic disease in 38% of patients. Grade 3 or greater complications occurred in 5% of patients; 90-day mortality was 3%. Three-year event-free survival and overall survival were 39% and 73%, respectively. Male sex and lymphovascular invasion were associated with shorter event-free survival and overall survival; younger age and prior radiation therapy were associated with shorter overall survival. Patients with stage IV disease who received salvage lung resection had better overall survival than similar patients who received subsequent systemic therapy and no surgery. CONCLUSIONS: In this selected, heterogeneous population, lung resection after initial nonoperative treatment for non-small cell lung cancer was safe. Surgery as local consolidative therapy was associated with encouraging outcomes and should be considered for these patients.

Mediastinal Staging in Non-Small-Cell Lung Cancer: Saying Goodbye to Mediastinoscopy.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.Accurate staging of the mediastinal lymph nodes in resectable non-small-cell lung cancer (NSCLC) is critically important to determine the overall stage of the tumor and guide subsequent management. The staging process typically begins with positron emission tomography (PET) or computed tomography imaging; however, imaging alone is inadequate, and tissue acquisition is required for confirmation of nodal disease. Mediastinoscopy was long considered the gold standard for staging of mediastinal lymph nodes, but, recently, endobronchial ultrasound-guided (EBUS) fine-needle aspiration (FNA) has become the standard of care. EBUS-FNA, in combination with supplementary technologies, such as intranodal forceps biopsy and esophageal ultrasonography, has a high sensitivity and specificity for the diagnosis of nodal metastases. EBUS-FNA is also capable of assessing N1 disease and obtaining adequate tissue for tumor genomic analysis to help guide treatment. In the case of negative findings on EBUS, a confirmatory video mediastinoscopy is still recommended by the European Society of Thoracic Surgeons guidelines. However, whether confirmatory mediastinoscopy is necessary is a matter of debate, and it is not commonly performed in North America. To address this question, Bousema and colleagues performed a randomized noninferiority trial to determine rates of unforeseen nodal metastases after EBUS alone versus EBUS with confirmatory mediastinoscopy in patients with resectable NSCLC. The authors concluded that EBUS alone is noninferior to EBUS with confirmatory mediastinoscopy. These findings affirm our current practice to forgo confirmatory mediastinoscopy after negative findings on EBUS.

Genomic mapping of metastatic organotropism in lung adenocarcinoma.

We analyzed 2,532 lung adenocarcinomas (LUAD) to identify the clinicopathological and genomic features associated with metastasis, metastatic burden, organotropism, and metastasis-free survival. Patients who develop metastasis are younger and male, with primary tumors enriched in micropapillary or solid histological subtypes and with a higher mutational burden, chromosomal instability, and fraction of genome doublings. Inactivation of TP53, SMARCA4, and CDKN2A are correlated with a site-specific shorter time to metastasis. The APOBEC mutational signature is more prevalent among metastases, particularly liver lesions. Analyses of matched specimens show that oncogenic and actionable alterations are frequently shared between primary tumors and metastases, whereas copy number alterations of unknown significance are more often private to metastases. Only 4% of metastases harbor therapeutically actionable alterations undetected in their matched primaries. Key clinicopathological and genomic alterations in our cohort were externally validated. In summary, our analysis highlights the complexity of clinicopathological features and tumor genomics in LUAD organotropism.

A Word of Caution for Future Studies in Patellofemoral Pain: A Systematic Review With Meta-analysis.

BACKGROUND: Patellar maltracking is widely accepted as an underlying mechanism of patellofemoral pain. However, methodological differences in the literature hinder our ability to generate a universal quantitative definition of pathological patellofemoral kinematics (patellar maltracking) in patellofemoral pain, leaving us unable to determine the cause of patellofemoral pain. PURPOSE: To systematically review the literature to provide evidence regarding the influence of confounding variables on patellofemoral kinematics. STUDY DESIGN: Systematic review and random effects meta-analysis of control-case studies. METHODS: A literature search of case-control studies that evaluated patellofemoral kinematics at or near full extension and were written in English was conducted using Embase, PubMed, Scopus, and Web of Science up to September 2019. Cases were defined as patients with patellofemoral pain. Studies were eliminated if they lacked quantitative findings; had a primary aim to assess therapy efficacy; or included participants with osteoarthritis and/or previous trauma, pathology, or surgery. A quality assessment checklist was employed to evaluate each study. Meta-analyses were conducted to determine the influence of confounding variables on measures of patellofemoral kinematics. RESULTS: Forty studies met the selection criteria, with quality scores ranging from 13% to 81%. Patient characteristics, data acquisition, and measurement methods were the primary sources of methodological variability. Active quadriceps significantly increased lateral shift (standardized mean difference [SMD]shift = 0.33; P = .0102) and lateral tilt (SMDtilt = 0.43; P = .006) maltracking. Individuals with pain secondary to dislocation had greater effect sizes for lateral maltracking than had those with isolated patellofemoral pain (ΔSMDshift = 0.71, P = .0071; ΔSMDtilt = 1.38, P = .0055). CONCLUSION: This review exposed large methodological variability across the literature, which not only hinders the generalization of results, but ultimately mitigates our understanding of the underlying mechanism of patellofemoral pain. Although our meta-analyses support the diagnostic value of maltracking in patellofemoral pain, the numerous distinct methods for measuring maltracking and the limited control for cofounding variables across the literature prohibit defining a single quantitative profile. Compliance with specific standards for anatomic and outcome measures must be addressed by the scientific and clinical community to establish methodological uniformity in this field.

The American Association for the Surgery of Trauma renal injury grading scale: Implications of the 2018 revisions for injury reclassification and predicting bleeding interventions.

BACKGROUND: In 2018, the American Association for the Surgery of Trauma (AAST) published revisions to the renal injury grading system to reflect the increased reliance on computed tomography scans and non-operative management of high-grade renal trauma (HGRT). We aimed to evaluate how these revisions will change the grading of HGRT and if it outperforms the original 1989 grading in predicting bleeding control interventions. METHODS: Data on HGRT were collected from 14 Level-1 trauma centers from 2014 to 2017. Patients with initial computed tomography scans were included. Two radiologists reviewed the scans to regrade the injuries according to the 1989 and 2018 AAST grading systems. Descriptive statistics were used to assess grade reclassifications. Mixed-effect multivariable logistic regression was used to measure the predictive ability of each grading system. The areas under the curves were compared. RESULTS: Of the 322 injuries included, 27.0% were upgraded, 3.4% were downgraded, and 69.5% remained unchanged. Of the injuries graded as III or lower using the 1989 AAST, 33.5% were upgraded to grade IV using the 2018 AAST. Of the grade V injuries, 58.8% were downgraded using the 2018 AAST. There was no statistically significant difference in the overall areas under the curves between the 2018 and 1989 AAST grading system for predicting bleeding interventions (0.72 vs. 0.68, p = 0.34). CONCLUSION: About one third of the injuries previously classified as grade III will be upgraded to grade IV using the 2018 AAST, which adds to the heterogeneity of grade IV injuries. Although the 2018 AAST grading provides more anatomic details on injury patterns and includes important radiologic findings, it did not outperform the 1989 AAST grading in predicting bleeding interventions. LEVEL OF EVIDENCE: Prognostic and Epidemiological Study, level III.

The associations between initial radiographic findings and interventions for renal hemorrhage after high-grade renal trauma: Results from the Multi-Institutional Genitourinary Trauma Study.

BACKGROUND: Indications for intervention after high-grade renal trauma (HGRT) remain poorly defined. Certain radiographic findings can be used to guide the management of HGRT. We aimed to assess the associations between initial radiographic findings and interventions for hemorrhage after HGRT and to determine hematoma and laceration sizes predicting interventions. METHODS: The Genitourinary Trauma Study is a multicenter study including HGRT patients from 14 Level I trauma centers from 2014 to 2017. Admission computed tomography scans were categorized based on multiple variables, including vascular contrast extravasation (VCE), hematoma rim distance (HRD), and size of the deepest laceration. Renal bleeding interventions included angioembolization, surgical packing, renorrhaphy, partial nephrectomy, and nephrectomy. Mixed-effect Poisson regression was used to assess the associations. Receiver operating characteristic analysis was used to define optimal cutoffs for HRD and laceration size. RESULTS: In the 326 patients, injury mechanism was blunt in 81%. Forty-seven (14%) patients underwent 51 bleeding interventions, including 19 renal angioembolizations, 16 nephrectomies, and 16 other procedures. In univariable analysis, presence of VCE was associated with a 5.9-fold increase in risk of interventions, and each centimeter increase in HRD was associated with 30% increase in risk of bleeding interventions. An HRD of 3.5 cm or greater and renal laceration depth of 2.5 cm or greater were most predictive of interventions. In multivariable models, VCE and HRD were significantly associated with bleeding interventions. CONCLUSION: Our findings support the importance of certain radiographic findings in prediction of bleeding interventions after HGRT. These factors can be used as adjuncts to renal injury grading to guide clinical decision making. LEVEL OF EVIDENCE: Prognostic and Epidemiological Study, Level III and Therapeutic/Care Management, Level IV.

Optimal timing of delayed excretory phase computed tomography scan for diagnosis of urinary extravasation after high-grade renal trauma.

BACKGROUND: Excretory phase computed tomography (CT) scan is used for diagnosis of renal collecting system injuries and accurate grading of high-grade renal trauma. However, optimal timing of the excretory phase is not well established. We hypothesized that there is an association between excretory phase timing and diagnosis of urinary extravasation and aimed to identify the optimal excretory phase timing for diagnosis of urinary extravasation. METHODS: The Genito-Urinary Trauma Study collected data on high-grade renal trauma (grades III-V) from 14 Level I trauma centers between 2014 and 2017. The time between portal venous and excretory phases at initial CT scans was recorded. Poisson regression was used to measure the association between excretory phase timing and diagnosis of urinary extravasation. Predictive receiver operating characteristic analysis was used to identify a cutoff point optimizing detection of urinary extravasation. RESULTS: Overall, 326 patients were included; 245 (75%) had excretory phase CT scans for review either initially (n = 212) or only at their follow-up (n = 33). At initial CT with excretory phase, 46 (22%) of 212 patients were diagnosed with urinary extravasation. Median time between portal venous and excretory phases was 4 minutes (interquartile range, 4-7 minutes). Time of initial excretory phase was significantly greater in those diagnosed with urinary extravasation. Increased time to excretory phase was positively associated with finding urinary extravasation at the initial CT scan after controlling for multiple factors (risk ratio per minute, 1.15; 95% confidence interval, 1.09-1.22; p < 0.001). The optimal delay for detection of urinary extravasation was 9 minutes. CONCLUSION: Timing of the excretory phase is a significant factor in accurate diagnosis of renal collecting system injury. A 9-minute delay between the early and excretory phases optimized detection of urinary extravasation. LEVEL OF EVIDENCE: Diagnostic tests/criteria study, level III.