High-Risk Features of Esophageal Adenocarcinoma Following Neoadjuvant Chemoradiation: Patients for Whom Surgery Should Not Be Delayed.

OBJECTIVE: Clinical predictors of pathological complete response have not reliably identified patients for whom an organ-sparing approach following neoadjuvant chemoradiation be undertaken for esophageal cancer patients. We sought to identify high-risk predictors of residual carcinoma that may preclude patients from a selective surgical approach. BACKGROUND: Patients treated with neoadjuvant chemoradiation followed by esophagectomy for esophageal adenocarcinoma were identified. PATIENTS AND METHODS: Correlation between clinical and pathologic complete responses were examined. Regression models and recursive partitioning were utilized to identify features associated with residual carcinoma. External validation of these high-risk factors was performed on a data set from an independent institution. RESULTS: A total of 326 patients were identified, in whom clinical complete response was noted in 104/326 (32%). Pathologic complete response was noted in only 33/104 (32%) of these clinical complete responders. Multivariable analysis identified that the presence of stricture ( P =0.011), positive biopsy ( P =0.010), and signet ring cell histology ( P =0.019) were associated with residual cancer. Recursive partitioning corroborated a 94% probability of residual disease, or greater, for each of these features. The positive predictive value was >90% for these characteristics. A SUV max >5.4 at the esophageal primary in the absence of esophagitis was also a high-risk factor for residual carcinoma. External validation confirmed these high-risk factors to be implicated in the finding of residual carcinoma. CONCLUSIONS: Clinical parameters of response are poor predictors of complete pathologic response leading to challenges in selecting candidates for active surveillance. However, we characterize several high-risk features for residual carcinoma which indicate that esophagectomy should not be delayed.

Diverse tumorigenic consequences of human papillomavirus integration in primary oropharyngeal cancers.

Human papillomavirus (HPV) causes 5% of all cancers and frequently integrates into host chromosomes. The HPV oncoproteins E6 and E7 are necessary but insufficient for cancer formation, indicating that additional secondary genetic events are required. Here, we investigate potential oncogenic impacts of virus integration. Analysis of 105 HPV-positive oropharyngeal cancers by whole-genome sequencing detects virus integration in 77%, revealing five statistically significant sites of recurrent integration near genes that regulate epithelial stem cell maintenance (i.e., SOX2, TP63, FGFR, MYC) and immune evasion (i.e., CD274). Genomic copy number hyperamplification is enriched 16-fold near HPV integrants, and the extent of focal host genomic instability increases with their local density. The frequency of genes expressed at extreme outlier levels is increased 86-fold within ±150 kb of integrants. Across 95% of tumors with integration, host gene transcription is disrupted via intragenic integrants, chimeric transcription, outlier expression, gene breaking, and/or de novo expression of noncoding or imprinted genes. We conclude that virus integration can contribute to carcinogenesis in a large majority of HPV-positive oropharyngeal cancers by inducing extensive disruption of host genome structure and gene expression.

Independent association of marijuana use and poor oral hygiene with HPV-negative but not HPV-positive head and neck squamous cell carcinomas.

BACKGROUND: Sexual behavior is associated with human papillomavirus (HPV)-positive head and neck cancer, whereas tobacco and alcohol use are associated with HPV-negative cancer. A case-control study was designed to investigate additional demographic and behavioral factors independently associated with these distinct oral cancers. METHODS: From 2011 to 2014, 249 newly diagnosed oral cavity and oropharyngeal squamous cell carcinoma (OSCC) cases were matched (1:2) on age, gender, and self-identified race to 498 controls without a cancer history attending the outpatient otolaryngology clinic at The Ohio State University in Columbus. Cases were stratified by detection of high-risk HPV DNA and RNA in tumors. Demographic and behavioral data were collected using an audio computer-assisted self-interview, and associations with HPV-positive versus HPV-negative OSCCs were investigated by use of univariable and multivariable conditional logistic regression models. RESULTS: After adjustment for oral sexual behavior, the odds of HPV-positive cancer decreased with the patient's years of education. Annual income, tobacco smoking, alcohol drinking, marijuana smoking, and poor oral hygiene were not associated with HPV-positive OSCC. In contrast, the odds of HPV-negative OSCC increased independently with decreased annual income, decreased with a high number of marijuana hit-years, and increased with fewer than annual dental visits after adjustment for lifetime tobacco and alcohol use. Sexual behavior and education were not associated with HPV-negative OSCC. CONCLUSIONS: The distinct risk-factor profiles for HPV-positive and HPV-negative OSCC are confirmed and extended in this case-control study, thus supporting 2 principal etiological pathways for OSCC development. LAY SUMMARY: Sexually acquired human papillomavirus (HPV) infection is an established cause of tonsil and base of tongue cancers. This study compared and contrasted risk factors for HPV-positive and HPV-negative oral cancers. Low number of years of education and sexual behavior are associated with HPV-positive cancer. In contrast, low annual income, infrequent dental visits, and tobacco and alcohol use are associated with HPV-negative cancers. Long-term marijuana use appears protective for HPV-negative cancer. Public health efforts to address these modifiable risk factors may prevent oral cancer.

Time trends and predictors of survival in surgically resected early-stage non-small cell lung cancer patients.

BACKGROUND: The improvement in the management of lung cancer have the potential to improve survival in patients undergoing resection for early-stage (stage I and II) non-small cell lung cancer (NSCLC), but few studies have evaluated time trends and identified predictors of overall survival (OS). METHODS: We identified surgically resected early-stage NSCLC between 1998 and 2016. The 3-year OS (1998-2014) and 5-year OS (1998-2012) rates were calculated for each year. Joinpoint regression was used to calculate annual percentage changes (APC) and to test time trends in OS. Multivariable Cox regression was used to identify predictors of OS. RESULTS: There was a significant upward trend in the 3-year (1998, 56%; 2014, 83%; APC = 1.8) and 5-year (1998, 47%; 2012, 76%; APC = 3.1) OS. Older age; male sex; history of diabetes, coronary artery disease, and chronic obstructive pulmonary disease; high ASA score; smoking pack-years; high-grade tumor; pneumonectomy; thoracotomy; neoadjuvant therapy; nodal disease; and positive tumor margin were predictors of poor OS. CONCLUSION: The upward time trend in OS suggests that improved staging, patient selection, and management have conferred a survival benefit in early-stage NSCLC patients. The prediction model of OS could be used to refine selection criteria for resection and improve survival outcomes.

Time Trends of Perioperative Outcomes in Early Stage Non-Small Cell Lung Cancer Resection Patients.

BACKGROUND: Advances in perioperative and operative management hold great promise for improving perioperative outcomes in patients undergoing resection for early stage non-small cell lung cancer (NSCLC). The objective of this study was to evaluate time trends in the incidence of perioperative outcomes and to identify predictors of pulmonary complication in early stage NSCLC resection patients. METHODS: An institutional database was reviewed to identify patients with primary, clinical stage I and II NSCLC who underwent resection from 1998 to 2016. Rates of perioperative pulmonary complication, pneumonia, and cardiovascular complication; and 30-day and 90-day mortality were calculated for each year. Joinpoint regression was used to calculate annual percentage change (APC) and to evaluate time trends in rates of these outcomes. Multivariable logistic regression was conducted to identify predictors of pulmonary complication. RESULTS: Of the 3045 patients identified, 80% had stage I and 20% had stage II NSCLC. From 1998 to 2016, there was no trend in the rate of pulmonary complication, but there was a significant downward trend in the rates of pneumonia (APC -3.7), cardiovascular complication (APC -3.5), 30-day mortality (APC -9.8), and 90-mortality (APC -7.4). Older age, male sex, smoking status, percentage of predicted forced expiratory volume in 1 second and percentage of diffusion capacity of lung for carbon monoxide, and intraoperative blood transfusion were identified as predictors of pulmonary complication. CONCLUSIONS: Decrease in the rates of perioperative outcomes parallels improvements in patient selection and perioperative management of early stage NSCLC resection patients. Predictors of pulmonary complication could be used to improve selection criteria for surgery and to reduce the incidence of pulmonary complication in these patients.

Dynamic factors affecting HPV-attributable fraction for head and neck cancers.

Head and neck squamous cell carcinoma (HNSCC) is attributable to carcinogen and oncogenic virus exposure and rates are driven by the prevalence, intensity, and duration of exposures. Recent dramatic shifts in human behavior have resulted in substantial heterogeneity in HNSCC incidence trends over calendar time. For example, changes in sexual behavior during the 1900s likely increased exposure to oral human papillomavirus (HPV) infection and, consequently, rates of HPV-positive HNSCC. Shifting rate-ratios for HPV-positive versus negative HNSCC determine the HPV attributable fraction (AF), best measured by direct tumor testing for HPV DNA and RNA. Potential high efficacy of HPV vaccines against oral HPV infections will affect future incidence trends, depending on calendar time of introduction, male and female coverage, and herd protection. Accurate estimates of HPV AF for all cancers, including HNSCC, may inform HPV immunization policy and surveillance of effectiveness.

Multimodality Therapy for N2 Non-Small Cell Lung Cancer: An Evolving Paradigm.

BACKGROUND: Induction chemoradiation for resectable N2 non-small cell lung cancer (NSCLC) is used with the intent to optimize locoregional control, whereas induction chemotherapy given in systemic doses is meant to optimally target potential distant disease. However, the optimal preoperative treatment regimen is still unknown and practice patterns continue to vary widely. We compared multiinstitutional oncologic outcomes for N2 NSCLC from 4 experienced lung cancer treatment centers. METHODS: This collaborative retrospective study unites 4 major thoracic oncology centers. Patients with N2 NSCLC undergoing surgical resection after induction chemotherapy (CxT) or concurrent chemoradiation (CxRT) were included. Primary outcomes were overall and disease-free survival (OS and DFS). RESULTS: 822 patients were identified (CxT = 662 and CxRT = 160). There were no differences in 5-year OS (CxT 39.9% versus CxRT 42.9%, p = 0.250) nor in DFS (CxT 28.7% versus 29.8%, p = 0.207). Recurrence rates (CxT 46.8% versus CxRT 51.6%, p = 0.282) and recurrence patterns were not significantly different (Local: CxT 9.8% versus CxRT 9.7%; and Distant: CxT 30.4% versus CxRT 33.1%, p = 0.764). There was no difference in perioperative mortality. In the analyses of patients who underwent pretreatment invasive mediastinal staging (n = 555), there were still no significant differences in OS (p = 0.341) and DFS (p = 0.455) between the 2 treatment strategies. CONCLUSIONS: Both treatment strategies produce equivalent and better than expected outcomes compared with historical controls for N2 NSCLC, with no differences in recurrence patterns. How these conventional therapeutic strategies will compare with those involving immunotherapy combined with surgical locoregional disease control for N2 disease remains to be determined.

Predictors of survival after resection of primary sarcomas of the chest wall-A large, single-institution series.

BACKGROUND AND OBJECTIVES: Chest wall sarcomas are rare and may demonstrate heterogeneous features. Surgery remains the mainstay of treatment with chemotherapy and radiotherapy used as adjuncts. Herein, we report outcomes of a large cohort of patients with primary chest wall sarcoma who underwent resection. METHODS: Records of 121 patients who underwent resection for primary chest wall sarcoma between 1998 and 2013 were reviewed. A thoracic pathologist reexamined all tumors and categorized them according to grade. Univariable and multivariable Cox analyses were conducted to identify predictors of overall survival (OS). RESULTS: The median age was 45.0 (range, 11-81) years, and most tumors (63.6%, 77) were high grade. The median tumor size was 7 cm (range, 1-21 cm). Fifty-nine (48.8%) patients received neoadjuvant chemotherapy and 12 (9.9%) received neoadjuvant radiotherapy. A complete resection was achieved in 103 (85.1%) patients. Neoadjuvant chemotherapy (P = 0.532) and radiation ( P = 1.000) were not associated with a complete resection. Five-year OS among patients undergoing R0 and R1 resections was 61.9% and 27.8%, respectively. Multivariable analysis identified high grade (HR, 15.21; CI, 3.57-64.87; P < 0.001), R1 (HR, 3.10; CI, 1.40-6.86; P = 0.005), R2 resection (HR, 5.18; CI, 1.91-14.01; P = 0.001), and age (HR, 1.02; CI, 1.01-1.03; P = 0.002) as predictors of OS. CONCLUSIONS: In this series of resected chest wall sarcomas, complete resection and tumor grade remain the most important survival predictors. Individual decisions are required for the utilization of neoadjuvant therapy.

Clinicoradiographic Predictors of Aggressive Biology in Lung Cancer With Ground Glass Components.

BACKGROUND: Ground glass opacities pose diagnostic challenges, and even after malignancy is confirmed, prognosis is often unclear. We sought to identify clinicoradiographic features that could predict aggressive tumor biology in lung adenocarcinoma with associated ground glass components. METHODS: A retrospective review of patients with resected lung adenocarcinoma from 2008 to 2013 was performed. Detailed radiographic features were reviewed by two radiologists. Logistic regression was used to identify risks of poor differentiation or a composite outcome of nodal metastases and lymphovascular invasion. RESULTS: In all, 79 patients met criteria for analysis. Larger tumor size (p = 0.04), increasing solid component (p = 0.01), pleural tags (p = 0.03), spiculation (p = 0.01), lobulation (p < 0.05), history of coronary artery disease (p = 0.04), and increasing number of pack-years smoking (p < 0.05) were associated with poorly differentiated tumors. However, after adjustment for size of the solid component, the associations between pleural tags, spiculation, and lobulation with poorly differentiated tumors were negated, whereas number of pack-years and history of coronary artery disease remained statistically significant (p = 0.01 and p = 0.03, respectively). There were no identified clinical or radiographic features associated with lymphovascular invasion/nodal metastasis. CONCLUSIONS: Several radiographic features were associated with aggressive tumor biology, a well-known finding. However, we found that none of these radiographic features remained relevant after we adjusted for the size of the solid component, indicating that radiographic features are not as important as previously believed. Further research will be required to identify reliable markers associated with favorable tumor biology. These studies will ultimately be critical in informing prognosis or guiding extent of resection.

Natural History of Ground-Glass Lesions Among Patients With Previous Lung Cancer.

BACKGROUND: Among patients with previous lung cancer, the malignant potential of subsequent ground-glass opacities (GGOs) on computed tomography remains unknown, with a lack of consensus regarding surveillance and intervention. This study sought to describe the natural history of GGO in patients with a history of lung cancer. METHODS: A retrospective review was performed of 210 patients with a history of lung cancer and ensuing computed tomography evidence of pure or mixed GGOs between 2007 and 2013. Computed tomography reports were reviewed to determine the fate of the GGOs, by classifying all lesions as stable, resolved, or progressive over the course of the study. Multivariable analysis was performed to identify predictors of GGO progression and resolution. RESULTS: The mean follow-up time was 13 months. During this period, 55 (26%) patients' GGOs were stable, 131 (62%) resolved, and 24 (11%) progressed. Of the 24 GGOs that progressed, three were subsequently diagnosed as adenocarcinoma. Patients of black race (odds ratio [OR], 0.26) and other races besides white (OR, 0.89) had smaller odds of GGO resolution (p = 0.033), whereas patients with previous lung squamous cell carcinoma (OR, 5.16) or small cell carcinoma (OR, 5.36) were more likely to experience GGO resolution (p < 0.001). On multivariable analysis, only a history of adenocarcinoma was an independent predictor of GGO progression (OR, 6.9; p = 0.011). CONCLUSIONS: Among patients with a history of lung cancer, prior adenocarcinoma emerged as a predictor of GGO progression, whereas a history of squamous cell carcinoma or small cell carcinoma and white race were identified as predictors of GGO resolution.

Correlating mammographic and pathologic findings in clinical decision support using natural language processing and data mining methods.

BACKGROUND: A key challenge to mining electronic health records for mammography research is the preponderance of unstructured narrative text, which strikingly limits usable output. The imaging characteristics of breast cancer subtypes have been described previously, but without standardization of parameters for data mining. METHODS: The authors searched the enterprise-wide data warehouse at the Houston Methodist Hospital, the Methodist Environment for Translational Enhancement and Outcomes Research (METEOR), for patients with Breast Imaging Reporting and Data System (BI-RADS) category 5 mammogram readings performed between January 2006 and May 2015 and an available pathology report. The authors developed natural language processing (NLP) software algorithms to automatically extract mammographic and pathologic findings from free text mammogram and pathology reports. The correlation between mammographic imaging features and breast cancer subtype was analyzed using one-way analysis of variance and the Fisher exact test. RESULTS: The NLP algorithm was able to obtain key characteristics for 543 patients who met the inclusion criteria. Patients with estrogen receptor-positive tumors were more likely to have spiculated margins (P = .0008), and those with tumors that overexpressed human epidermal growth factor receptor 2 (HER2) were more likely to have heterogeneous and pleomorphic calcifications (P = .0078 and P = .0002, respectively). CONCLUSIONS: Mammographic imaging characteristics, obtained from an automated text search and the extraction of mammogram reports using NLP techniques, correlated with pathologic breast cancer subtype. The results of the current study validate previously reported trends assessed by manual data collection. Furthermore, NLP provides an automated means with which to scale up data extraction and analysis for clinical decision support. Cancer 2017;114-121. © 2016 American Cancer Society.

The Influence of Reconstructive Technique on Perioperative Pulmonary and Infectious Outcomes Following Chest Wall Resection.

BACKGROUND: Emerging technologies for prosthetic reconstruction after chest wall resection have yielded a wide variety of reconstructive options for thoracic surgeons. The ideal chest wall reconstruction and its impact on perioperative outcomes has not been well defined. Our goal was to determine whether mesh characteristics such as rigidity or absorbability altered perioperative pulmonary and infectious outcomes. METHODS: Our institutional database was queried for patients who underwent chest wall resection and reconstruction for primary or secondary chest wall tumors between the years 1998 and 2013. A focused chart review supplied clinical and perioperative variables. The main study outcomes focused on perioperative pulmonary and wound/implant infectious complications. Univariate and multivariate analyses were performed to identify variables associated with outcome. RESULTS: We identified 1,096 patients who underwent chest wall resection during the study period, of which 427 required chest wall reconstruction. Pulmonary complications occurred in 24% (n = 102 of 427) of patients. We observed no significant difference in pulmonary complications between those that had a rigid versus flexible chest wall reconstruction (p = 0.401; OR, 1.43; 95% CI, 0.83-2.43). The odds of pulmonary complications increased with each additional resected rib (OR, 1.43; 95% CI, 1.2-1.71). Multivariable analysis identified the number of resected ribs (OR, 1.26; 95% CI, 1.00-1.59) and concomitant lobectomy (OR, 3.59; 95% CI, 1.62-7.92) as variables associated with perioperative pulmonary morbidity. Infectious complications occurred in 13 patients and were not predicted by the use of permanent versus absorbable prosthetic materials (p = 0.575). CONCLUSIONS: The type of reconstructive material, whether with rigid, flexible, permanent, or biologic characteristics, does not appear to influence perioperative pulmonary or infectious wound complications. Rather, the number of resected ribs and the concomitant lung parenchymal resection predict pulmonary morbidity following chest wall resection. Depending on the circumstances, an effective chest wall reconstruction can be achieved with either rigid or flexible prosthetic material.

Impact of a Fast-track Esophagectomy Protocol on Esophageal Cancer Patient Outcomes and Hospital Charges.

OBJECTIVE: To evaluate the effects of a fast-track esophagectomy protocol (FTEP) on esophageal cancer patients' safety, length of hospital stay (LOS), and hospital charges. BACKGROUND: FTEP involved transferring patients to the telemetry unit instead of the surgical intensive care unit (SICU) after esophagectomy. METHODS: We retrospectively reviewed 708 consecutive patients who underwent esophagectomy for primary esophageal cancer during the 4 years before (group A; 322 patients) or 4 years after (group B; 386 patients) the institution of an FTEP. Postoperative morbidity and mortality, LOS, and hospital charges were reviewed. RESULTS: Compared with group A, group B had significantly shorter median LOS (12 days vs 8 days; P < 0.001); lower mean numbers of SICU days (4.5 days vs 1.2 days; P < 0.001) and telemetry days (12.7 days vs 9.7 days; P < 0.001); and lower rates of atrial arrhythmia (27% vs 19%; P = 0.013) and pulmonary complications (27% vs 20%; P = 0.016). Multivariable analysis revealed FTEP to be associated with shorter LOS (P < 0.001) even after adjustment for predictors like tumor histology and location. FTEP was also associated with a lower rate of pulmonary complications (odds ratio = 0.655; 95% confidence interval = 0.456, 0.942; P = 0.022). In addition, the median hospital charges associated with primary admission and readmission within 90 days for group B ($65,649) were lower than that for group A ($79,117; P < 0.001). CONCLUSIONS: These findings suggest that an FTEP reduces patients' LOS, perioperative morbidity, and hospital charges.