Impact of Comorbidities on Lung Cancer Screening Evaluation.

OBJECTIVES: We used data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial to examine the impact of self-reported chronic obstructive pulmonary disease, coronary artery disease, stroke, and diabetes mellitus on diagnostic complications in lung cancer screening evaluation. METHODS: In our analysis, we included individuals from the usual care and intervention (annual chest x-ray) of the lung cancer screening trial with equal or greater than 55 years of age with a 20 pack-year smoking history who had undergone an invasive procedure. We performed multivariate logistic regression analysis to estimate the association of comorbidity on procedure complication. Our primary outcome was the incidence of major or moderate complications. RESULTS: Features associated with high-risk complication included older age (OR = 1.03 per year, P = .001), history of coronary artery disease (OR = 1.40, P = .03), history of diabetes mellitus (OR = 0.41, P < .001, current smoking status (OR = 1.46, P ≤ .001), surgical biopsy (OR = 7.39, P < .001), needle biopsy (OR = 1.94, P < .001), and other invasive procedure (OR = 1.58, P < .001). We did not find an associated with complication and history of stroke (OR = 0.84, P = .53) or chronic obstructive pulmonary disease (OR = 1.27, P = .06). CONCLUSION: Patient and procedure-level factors may alter the benefits of lung cancer screening. Data concerning individual risk factors and high-risk complications should therefore be incorporated into diagnostic algorithms to optimize clinical benefit and minimize harm. Further study and validation of the risk factors identified herein are warranted.

Lymph Node Ratio in HPV-Associated Oropharyngeal Cancer: Identification of a Prognostic Threshold.

OBJECTIVE: To evaluate the utility of lymph node ratio (LNR) as a prognostic factor for survival and recurrence in surgically treated patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). STUDY DESIGN: Retrospective cohort study. METHODS: In this retrospective cohort study of a tertiary healthcare system in a major metropolitan area, we reviewed 169 consecutive patients with HPV-related OPSCC treated using transoral robotic surgery. Univariable and multivariable Cox proportional hazards regression analysis with stratified models were used to compare LNR with other traditional clinicopathologic risk factors forrecurrence and survival. An LNR cutoff was found using the minimal P approach. RESULTS: Multivariable Cox regression models showed that each additional percentage increase in LNR corresponded to an adjusted hazard ratio (HR) of 1.04 (confidence interval [CI] 1.02-1.07). LNR was more significant when adjusted for adequate lymph node yield of ≥ 18 nodes (HR 5.05, 95% confidence interval [CI] 1.38-18.47). The minimal P generated cutoff point at LNR ≥ 17% demonstrated a HR 4.34 (95% CI 1.24-15.2) for disease-free survival. CONCLUSION: For HPV-related OPSCC, continuous LNR and an LNR threshold of 17% could be helpful in identifying recurrent disease in addition to measures such as lymph node number alone. LEVEL OF EVIDENCE: 4.

Prevalence of Occult Peribronchial N1 Nodal Metastasis in Peripheral Clinical N0 Small (≤2 cm) Non-Small Cell Lung Cancer.

BACKGROUND: There has been growing interest in limited resection and nonsurgical treatment for small lung cancers. We examined the pattern and rate of occult N1 nodal metastasis in patients with peripheral, small (≤2 cm), clinically node-negative non-small cell lung cancer (NSCLC). METHODS: Patients with peripheral small (≤2 cm) NSCLC with no evidence of locally advanced or metastatic disease (clinical T1a-b N0 M0, American Joint Committee on Cancer 8th Edition Cancer Staging Manual), who were deemed eligible for lobectomy or sublobar resection, were identified from preregistration eligibility screening logs for the Alliance/Cancer and Leukemia Group B 140503 trial at our institution. Pathologic outcomes were examined in all patients undergoing anatomic resection with mediastinal and hilar lymphadenectomy. RESULTS: Included were 58 patients treated between November 2014 and January 2017 who met the inclusion criteria: 51 underwent lobectomy, and 7 underwent segmentectomy. Mean tumor diameter on computed tomography was 1.5 cm, and mean positron emission tomography maximal standardized uptake value was 3.9. The mean consolidation-to-tumor ratio was 0.77. Occult nodal metastases in N1 stations were found in 8 of 58 patients (14%), and most of these nodes were found in interlobar or peribronchial stations (11 or 12). An additional 2 patients (3%) had occult positive N2 nodes. Overall, the false-negative rate for clinical staging was 16%. CONCLUSIONS: Occult nodal disease was frequently identified in peripheral N1 stations (11-13) in patients with small (≤2 cm) clinical N0 NSCLC. Hilar lymphadenectomy is essential for accurate staging in the management of patients with small clinical N0 NSCLC.

Thoracotomy and VATS Surgery in Local Non-Small-Cell Lung Cancer: Differences in Long-Term Health-Related Quality Of Life.

BACKGROUND: As a result of routine low-dose computed tomographic screening, lung cancer is more frequently diagnosed at earlier, operable stages of disease. In treating local non-small-cell lung cancer, video-assisted thoracoscopic surgery (VATS), a minimally invasive surgical approach, has replaced thoracotomy as the standard of care. While short-term quality-of-life outcomes favor the use of VATS, the impact of VATS on long-term health-related quality of life (HRQoL) is unknown. PATIENTS AND METHODS: We studied patients who underwent lobectomy for the treatment of non-small-cell lung cancer from January 2006 to January 2013 at a single institution (n = 456). Patients who underwent segmentectomy (n = 27), who received neoadjuvant therapy (n = 13), or who were found to have clinical stage > T2 or > N0 disease (n = 45) were excluded from analysis. At time of HRQoL assessment, 199 patients were eligible for study and were mailed the generic HRQoL instrument 15D. RESULTS: A total of 180 patients (90.5%) replied; 92 respondents underwent VATS while 88 underwent open thoracotomy. The VATS group more often had adenocarcinoma (P = .006), and lymph node stations were sampled to a lesser extent (P = .004); additionally, hospital length of stay was shorter among patients undergoing VATS (P = .001). No other clinical or pathologic differences were observed between the 2 groups. Surprisingly, patients who underwent VATS scored significantly lower on HRQoL on the dimensions of breathing, speaking, usual activities, mental function, and vitality, and they reported a lower total 15D score, which reflects overall quality of life (P < .05). CONCLUSION: In contrast to earlier short-term reports, long-term quality-of-life measures are worse among patients who underwent VATS compared to thoracotomy.

Association between Ki-67 expression and clinical outcomes among patients with clinically node-negative, thick primary melanoma who underwent nodal staging.

BACKGROUND: Patients with thick primary melanomas (≥4 mm) have highly variable survival outcomes. Cell proliferation marker Ki-67 has been identified as promising biomarker in thick melanoma but has not been evaluated since the wide spread adoption of sentinel lymph node biopsy. We revisit its prognostic relevance in the sentinel node era. METHODS: We studied patients with thick (≥4 mm) primary melanoma prospectively enrolled in a clinicopathological biospecimen database from 2002 to 2015, and evaluated the prognostic value of Ki-67 expression while controlling for features included in the existing staging criteria. RESULTS: We analyzed 68 patients who underwent lymph node sampling and who had an available tumor for Ki-67 immunohistochemical (IHC) staining. The median tumor thickness was 6.0 mm; the median follow-up was 2.6 years. In multivariable analysis including nodal status and primary tumor ulceration, Ki-67 expression was an independent predictor of worse recurrence-free survival (HR 2.19, P = 0.024) and overall survival (HR 2.49, P = 0.028). Natural log-transformed tumor thickness (ln [thickness]) was also significantly associated with worse OS (HR 2.39, P = 0.010). CONCLUSION: We identify Ki-67 and ln (thickness) as potential biomarkers for patients with thick melanoma who have undergone nodal staging. If validated in additional studies, these biomarkers could be integrated into the staging criteria to improve risk-stratification.

Outcomes in Melanoma Patients Treated with BRAF/MEK-Directed Therapy or Immune Checkpoint Inhibition Stratified by Clinical Trial versus Standard of Care.

OBJECTIVES: Since 2011, metastatic melanoma treatment has evolved with commercial approval of BRAF- and MEK-targeted therapy and CTLA-4- and PD-1-blocking antibodies (immune checkpoint inhibitors, ICI). While novel therapies have demonstrated improved prognosis in clinical trials, few studies have examined the evolution of prognosis and toxicity of these drugs among an unselected population. We assess whether survival and toxicity reported in trials, which typically exclude most patients with brain metastases and poor performance status, are recapitulated within a commercial access population. METHODS: 182 patients diagnosed with stage IV melanoma from July 2006 to December 2013 and treated with BRAF- and/or MEK-targeted therapy or ICI were prospectively studied. Outcomes and clinicopathologic differences between trial and commercial cohorts were assessed. RESULTS: Patients receiving commercial therapy (vs. on trial) had poorer prognostic features (i.e., brain metastases) and lower median overall survival (mOS) when assessed across all treatments (9.2 vs. 17.5 months, p = 0.0027). While toxicity within trial and commercial cohorts did not differ, patients who experienced toxicity had increased mOS (p < 0.001), irrespective of stratification by trial status or therapy. CONCLUSION: Metastatic melanoma patients receiving commercial treatment may represent a different clinical population with poor prognostic features compared to trial patients. Toxicity may prognosticate treatment benefit.

Identification of a Novel Pathogenic Germline KDR Variant in Melanoma.

PURPOSE: The application of pan-cancer next-generation sequencing panels in the clinical setting has facilitated the identification of low frequency somatic mutations and the testing of new therapies in solid tumors using the "basket trial" scheme. However, little consideration has been given to the relevance of nonsynonymous germline variants, which are likely to be uncovered in tumors and germline and which may be relevant to prognostication and prediction of treatment response. EXPERIMENTAL DESIGN: We analyzed matched tumor and normal DNA from 34 melanoma patients using an Ion Torrent cancer-associated gene panel. We elected to study the germline variant Q472H in the kinase insert domain receptor (KDR), which was identified in 35% of melanoma patients in both a pilot and an independent 1,223 patient cohort. Using patient-derived melanoma cell lines and human samples, we assessed proliferation, invasion, VEGF levels, and angiogenesis by analyzing tumor microvessel density (MVD) using anti-CD34 antibody. RESULTS: Serum VEGF levels and tumor MVD were significantly higher in Q472H versus KDR wild-type (WD) patients. Primary cultures derived from melanomas harboring the KDR variant were more proliferative and invasive than KDR wild type. Finally, using a VEGFR2 antibody, we showed that KDR Q472H cells were sensitive to targeted inhibition of VEGFR2, an effect that was not observed in KDR WT cells. CONCLUSIONS: Our data support the integration of germline analysis into personalized treatment decision-making and suggest that patients with germline KDR variant might benefit from antiangiogenesis treatment. Clin Cancer Res; 22(10); 2377-85. ©2015 AACR.