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The NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC) provide recommendations for management of disease in patients with NSCLC. These NCCN Guidelines Insights focus on neoadjuvant and adjuvant (also known as perioperative) systemic therapy options for eligible patients with resectable NSCLC.

The NCCN Guidelines for Lung Cancer Screening recommend criteria for selecting individuals for screening and provide recommendations for evaluation and follow-up of lung nodules found during initial and subsequent screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.

Gene promoter methylation amplification curves

Variable importance plot for random forest prediction

Purpose: CT screening can reduce death from lung cancer. We sought to improve the diagnostic accuracy of lung cancer screening using ultrasensitive methods and a lung cancer–specific gene panel to detect DNA methylation in sputum and plasma.Experimental Design: This is a case–control study of subjects with suspicious nodules on CT imaging. Plasma and sputum were obtained preoperatively. Cases (n = 150) had pathologic confirmation of node-negative (stages I and IIA) non–small cell lung cancer. Controls (n = 60) had non-cancer diagnoses. We detected promoter methylation using quantitative methylation-specific real-time PCR and methylation-on-beads for cancer-specific genes (SOX17, TAC1, HOXA7, CDO1, HOXA9, and ZFP42).Results: DNA methylation was detected in plasma and sputum more frequently in people with cancer compared with controls (P < 0.001) for five of six genes. The sensitivity and specificity for lung cancer diagnosis using the best individual genes was 63% to 86% and 75% to 92% in sputum, respectively, and 65% to 76% and 74% to 84% in plasma, respectively. A three-gene combination of the best individual genes has sensitivity and specificity of 98% and 71% using sputum and 93% and 62% using plasma. Area under the receiver operating curve for this panel was 0.89 [95% confidence interval (CI), 0.80–0.98] in sputum and 0.77 (95% CI, 0.68–0.86) in plasma. Independent blinded random forest prediction models combining gene methylation with clinical information correctly predicted lung cancer in 91% of subjects using sputum detection and 85% of subjects using plasma detection.Conclusions: High diagnostic accuracy for early-stage lung cancer can be obtained using methylated promoter detection in sputum or plasma. Clin Cancer Res; 23(8); 1998–2005. ©2016 AACR.

Supplemental Tables and figures legends

Receiver operator classification curves for lung cancer detection for the genes obtained from Plasma

Receiver operator classification curves for lung cancer detection for the genes obtained from sputum

This study sought to identify disparities in the timing of alveolar bone grafting (ABG) surgery and the replacement strategy for missing maxillary lateral incisors for patients with clefts. A retrospective record review identified patients who underwent ABG. Multivariable regression analyzed the independent contribution of each variable. This institutional study was performed at the University of California, San Francisco. Patients who presented under age 12 and underwent secondary ABG between 2012 and 2020 (n = 160). The age at secondary ABG and the recommended dental replacement treatment for each patient, either dental implantation or canine substitution. The average age at ABG was 10.8 ± 2.1 years, 106 (66.3%) patients were not White, and 80 (50.0%) had private insurance. Independent predictors of older age at ABG included an income below $ 50 000 as estimated from ZIP code (β = 15.0 months, 95% CI, 5.7-24.3, P = .002) and identifying as a race other than White (β = 10.1 months, 95% CI, 2.1-18.0, P = .01). After ABG, patients were more likely to undergo dental implantation over canine substitution if they were female (odds ratio [OR] = 4.3, 95% CI, 1.3-17.1, P = .02) or had private insurance (OR = 12.5, 95% CI, 2.2-143.2, P = .01). Patients who were low-income or not White experienced delays in ABG, whereas dental implantation was more likely to be recommended for patients with private insurance. Understanding the sources of disparities in dental reconstruction of cleft deformities may reveal opportunities to improve equity.

The US Health and Human Services Pain Management Best Practices Inter-Agency Task Force initiated a public–private partnership which led to the publication of its report in 2019. The report emphasized the need for individualized, multimodal, and multidisciplinary approaches to pain management that decrease the over-reliance on opioids, increase access to care, and promote widespread education on pain and substance use disorders. The Task Force specifically called on specialty organizations to work together to develop evidence-based guidelines. In response to this report’s recommendations, a consortium of 14 professional healthcare societies committed to a 2-year project to advance pain management for the surgical patient and improve opioid safety. The modified Delphi process included two rounds of electronic voting and culminated in a live virtual event in February 2021, during which seven common guiding principles were established for acute perioperative pain management. These principles should help to inform local action and future development of clinical practice recommendations.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.

Cancer recurrence after surgery remains an unresolved clinical problem1–3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4–6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy. In mouse models of pulmonary metastasis, adjuvant epigenetic therapy targeting myeloid-derived suppressor cells disrupts the premetastatic microenvironment after resection of primary tumours and inhibits the dissemination of residual tumour cells.

The purpose of this study was to identify racial and socioeconomic disparities in craniosynostosis evaluation and treatment, from referral to surgery. Patients diagnosed with craniosynostosis between 2012 and 2020 at a single center were identified. Chart review was used to collect demographic variables, age at referral to craniofacial care, age at diagnosis, age at surgery, and surgical technique (open versus limited incision). Multivariable linear and logistic regression models with lasso regularization assessed the independent effect of each variable. A total of 298 patients were included. Medicaid insurance was independently associated with a delay in referral of 83 days [95% confidence interval (CI) 4-161, P=0.04]. After referral, patients were diagnosed a median of 21 days later (interquartile range 7-40), though this was significantly prolonged in patients who were not White (β 23 d, 95% CI 9-38, P=0.002), had coronal synostosis (β 24 d, 95% CI 2-46, P=0.03), and had multiple suture synostosis (β 47 d, 95% CI 27-67, P0.001). Medicaid insurance was also independently associated with diagnosis over 3 months of age (risk ratio 1.3, 95% CI 1.1-1.4, P=0.002) and undergoing surgery over 1 year of age (risk ratio 3.9, 95% CI 1.1-9.4, P=0.04). In conclusion, Medicaid insurance was associated with a 3-month delay in referral to craniofacial specialists and increased risk of diagnosis over 3 months of age, limiting surgical treatment options in this group. Patients with Medicaid also faced a 4-fold greater risk of delayed surgery, which could result in neurodevelopmental sequelae.

To establish expert consensus regarding the domains and topics for senior surgery residents (PGY-4) to make critical decisions and assume senior-level responsibilities, and to develop the formative American College of Surgeons Senior Resident Readiness Assessment (ACS SRRA) Program.The American College of Surgeons (ACS) education leadership team conducted a focus group with surgical experts to identify the content for an assessment tool to evaluate senior residents' readiness for their increased levels of responsibility. After the focus group, national experts were recruited to develop consensus on the topics through three rounds of surveys using Delphi methodology. The Delphi participants rated topics using Likert-type scales and their comments were incorporated into subsequent rounds. Consensus was defined as ≥ 80% agreement with internal-consistency reliability (Cronbach's alpha) ≥ 0.8. In a stepwise fashion, topics that did not achieve consensus for inclusion were removed from subsequent survey rounds.The surveys were administered via an online questionnaire.Twelve program directors and assistant program directors made up the focus group. The 39 Delphi participants represented seven different surgical subspecialties and were from diverse practice settings. The median length of experience in general surgery resident education was 20 years (IQR 14.3-30.0) with 64% of the experts being either current or past general surgery residency program directors.The response rate was 100% and Cronbach's alpha was ≥ 0.9 for each round. The Delphi participants contributed a large number of comments. Of the 201 topics that were evaluated initially, 120 topics in 25 core clinical areas were included to create the final domains of ACS SRRA.National consensus on the domain of the ACS SRRA has been achieved via the modified Delphi method among expert surgeon educators. ACS SRRA will identify clinical topics and areas in which each senior resident needs improvement and provide data to residents and residency programs to develop individualized learning plans. This would help in preparing the senior residents to assume their responsibilities and support their readiness for future fellowship training or surgical practice.

Introduction: There is a critical need to incorporate molecular assessments of minimal residual disease (MRD) during neoadjuvant immunotherapy, in order to identify individuals at high risk for disease recurrence based on analyses of circulating cell-free tumor DNA (ctDNA) landscapes. Here we employed longitudinal liquid biopsies to dynamically assess clinical outcomes with neoadjuvant immuno-chemoradiotherapy in patients with esophageal/gastroesophageal junction (E/GEJ) cancer. Methods: We utilized targeted error-correction sequencing to perform high-depth ctDNA next-generation sequencing for 141 serial plasma and 32 matched white blood cell (WBC) DNA samples from 32 patients with operable stage II/III E/GEJ cancer that received neoadjuvant immune checkpoint blockade (ICB) with chemoradiotherapy prior to surgery (NCT03044613). ctDNA analyses were performed at baseline, post-ICB induction, after completion of chemoradiotherapy (pre-op), and post-operatively (post-op). Using a tumor-agnostic WBC DNA-informed panel NGS approach we determined the cellular origin of plasma variants, filtering out germline and clonal hematopoiesis (CH) variants and evaluated ctDNA clonal dynamics over time. Molecular MRD was evaluated post-ICB, pre-op and post-op and correlated with recurrence-free (RFS) and overall survival (OS). Results: Twenty out of 32 patients had detectable ctDNA at any timepoint. Of the 12 patients with undetectable ctDNA, 9 had only CH- and/or germline-derived variants, while 3 patients had no detectable variants of any origin. ctDNA clearance post-ICB was correlated with tumor regression >80% at the time of resection (Fischer’s exact p=0.04). The subset of patients that did not attain complete pathologic response was heterogeneous with respect to ctDNA dynamics; such that ctDNA clearance pre-op identified patients with longer OS despite residual tumor of >0% at the time of resection (log rank p=0.06). Patients with undetectable ctDNA or ctDNA clearance pre-op had a longer RFS (log rank p=0.007) and OS (log rank p=0.03). Molecular MRD was associated with RFS and OS such that patients with ctDNA clearance post-op had longer RFS (log-rank p=0.007) and OS (log-rank p=0.017). Conclusion: ctDNA clearance post-ICB, pre-op and post-op reflects differential clinical outcomes for patients with E/GEJ cancer receiving neoadjuvant immuno-chemoradiotherapy. Understanding ctDNA dynamics and their relationship with pathological response and long-term outcomes can help identify patients at higher risk for recurrence and open a therapeutic window for future intervention. Citation Format: Blair V. Landon, Ronan J. Kelly, Ali H. Zaidi, Archana Balan, Jenna V. Canzoniero, Gavin Pereira, Zineb Belcaid, Russell K. Hales, K Ranh Voong, Richard J. Battafarano, Blair A. Jobe, Stephen C. Yang, Stephen Broderick, Jinny Ha, Kellie N. Smith, Elizabeth Thompson, Fyza Y. Shaikh, James R. White, Cynthia L. Sears, Eun J. Shin, Ali I. Amjad, Benny Weksler, Josephine L. Feliciano, Chen Hu, Vincent K. Lam, Valsamo Anagnostou. Circulating cell-free tumor DNA dynamics capture minimal residual disease with neoadjuvant immune checkpoint blockade plus chemoradiotherapy for patients with operable esophageal/gastroesophageal junction cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3374.

Surgical specialties, including oral and maxillofacial surgery (OMS), are traditionally male-dominated fields. This study aimed to analyze the proportions of female surgeons on specialty society boards and journal editorial boards in OMS in the United States and to assess whether they were proportionate with female representation in OMS academic faculty between 2011 and 2020.A retrospective cohort study was performed using information obtained from the websites of two major OMS journals and information obtained directly from six American specialty societies for OMS. The predictor variable was time. The outcome variable was gender. Temporal changes in the proportion of women on society and journal editorial boards were compared with those amongst full-time board-certified faculty. Chi-squared test and simple linear regression were used for statistical analyses.Between 2011 and 2020, the proportion of women on editorial and society boards was 6.7% (31 women among 463 editorial board members) and 7.8% (43 women among 553 society board members), respectively. The proportion of women on editorial boards increased from 4.5% in 2011 to 10.6% in 2020 (β = 0.656 [95% confidence interval, 0.336-0.975], P = .001) and that of women on society boards increased from 4.3% in 2011 to 10.3% in 2020 (β = 0.645 [95% confidence interval, 0.252-1.037], P = .005). The proportion of women on editorial boards in 2011-2012 was significantly lower than that in full-time board-certified faculty positions (4.3% vs 11.0%, P = .045), whereas by 2019-2020, there was no difference between the 2 groups (9.8% vs 12.5%, P = .454). Similarly, the proportion of women on society boards in 2011-2012 tended to be lower than that in full-time board-certified faculty positions (5.6% vs 11.0%, P = .111), while in 2019-2020, no difference was observed between the 2 groups (10.4% vs 12.5%, P = .531).The proportion of women on society and journal editorial boards in OMS remains low but has progressively increased from 2011 to 2020, resulting in proportionate female representation in these positions compared with the gender composition of academic faculty in recent years. The current upward trend of female representation in leadership positions will hopefully present more diverse opportunities and mentorship/role models for trainees.

Medical students and general surgery residents often do not get exposure to cardiothoracic surgery (CTS) because of a decreased emphasis on CTS rotations during their training. The Southern Thoracic Surgical Association (STSA) began offering the Brooks Scholarship to medical students in 2010 and general surgery residents in 2014 to promote CTS. This study examines the impact of the scholarship.We examined the history of the award and how STSA administers the award. Next we examined the impact of the award by evaluating the number of medical students and residents who are tracked to complete a CTS program. Finally we performed an analysis of the academic output of the awardees who have completed or were tracked to complete a CTS program.The scholarship was developed to honor the memory of past STSA President Dr James W. Brooks. The award is administered through the STSA scholarship committee and provides medical students and residents funds to attend the STSA annual meeting and the opportunity to spend time with a mentor during the meeting. Eighty-eight percent of medical student recipients (21/24) and 100% of general surgery resident recipients (15/15) have completed or are on track to complete a CTS program. The 36 recipients going into CTS have published a total of 823 papers and 9240 articles have cited those papers.The STSA medical student and general surgery Brooks scholarship awards were associated with completing or pursuing a career in CTS. STSA should continue the Brooks scholarship to attract talented medical students and residents to CTS.

Thoracic meningoceles and dural ectasia are less commonly recognized manifestations of neurofibromatosis 1 (NF1). Rarely, large thoracic meningoceles may become compressive and lead to respiratory compromise secondary to lung compression. Surgical goals aim to increase lung aeration through decreasing the size of the meningocele through shunting, excision or repair of the meningocele, and varying degrees of dural tube reconstruction. There is no agreement on the best approach for large, symptomatic meningoceles. Here, we discuss the case of a 41-year-old woman with NF1 who presented with dyspnea and enlargement of a large, 19 cm thoracic meningocele. A multidisciplinary team of thoracic, plastic, and neurological surgery participated in the operation to excise the meningocele and reconstruct the dural tube without the need for subsequent shunting of spinal fluid. We also systematically review the literature on thoracic meningoceles in NF1 to understand the optimal treatment of this pathology.

The NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates in immunotherapy. For the 2020 update, all of the systemic therapy regimens have been categorized using a new preference stratification system; certain regimens are now recommended as “preferred interventions,” whereas others are categorized as either “other recommended interventions” or “useful under certain circumstances.”

Surgical training has focused on the development of technical competency. Interpersonal and cognitive skills are essential to working as an interdisciplinary team, which translates into safety for the patient and well-being for the surgeon and colleagues. This article offers an "alternative" surgical curriculum topic list to augment the technical skill sets traditionally taught to trainees.

Aquatic activities are some of the most widely enjoyed sports and recreational activities in the United States. This study aimed to analyze the risks and types of craniofacial injuries associated with various aquatic activities.We retrospectively analyzed aquatic activity-related craniofacial injuries between 2010 and 2019 using the National Electronic Injury Surveillance System database. Aquatic activities included swimming, diving, surfing, water skiing, and water tubing. Risks and types of craniofacial injuries were analyzed according to the types of aquatic activities, age, and sex.Among 48,112 patients with aquatic activity-related injuries, 9,529 (19.8%) had craniofacial injuries. In decreasing order of frequency, the causes of craniofacial injuries were swimming (79.6%), diving (7.5%), surfing (5.9%), water skiing (3.6%), and water tubing (3.5%). The proportion of craniofacial injuries among all injuries was higher in males than in females (22.8 vs 16.3%, P.001), and decreased with age: 27.7% in 0 to 5 years, 21.5% in 6 to 11 years, 20.5% in 12 to 17 years, and 15.2% in ≥18 years (P.001). Additionally, the proportion of craniofacial injuries was highest in diving (38.7%), and lowest in swimming (18.1%, P.001). The male-to-female ratio in the proportion of patients with craniofacial injuries was highest in swimming at 1.42, and close to unity (0.97-1.13) in other activities. The most common type of craniofacial injury was laceration (43.5%), followed by concussion/internal organ injury (38.9%), contusion/abrasion (11.3%), and fracture (3%). Among all craniofacial injuries, the proportion of craniofacial fractures was highest in water tubing (8.5%) and lowest in swimming (2.2%, P.001).Craniofacial injuries are a frequent cause of morbidity related to aquatic activities. Substantial variability exists in the risk and pattern of craniofacial injuries depending on the type of activity, age, and sex. These findings may aid in instituting educational programs and preventive measures against aquatic activity-related craniofacial injuries.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.

Background: Preclinical and clinical data indicate that neoadjuvant chemoradiotherapy (CRT) may prime an anti-tumor immunological response in esophageal cancer driven by intratumoral CD8+ T cells and PD-L1 expression. LAG-3 is also highly expressed in esophagogastric cancers. The microbiome, a novel and potentially modifiable, biomarker of IO response, has not yet been examined in the neoadjuvant setting in esophageal cancer and is the goal of our study. Methods: Fecal samples were collected from patients with stage II/III esophageal or gastroesophageal junction carcinoma eligible for curative resection treated with the standard of care regimen of carboplatin paclitaxel (50mg/m2), radiation 50.4 Gy in 28 fractions and an Ivor-Lewis esophagectomy 6-10 weeks after last CRT and immunotherapy (IO) dose. Patients on arm A (n=11) received 2 cycles of induction with nivolumab plus 3 additional cycles on week 1, 3 and 5 of CRT. Patients on arm B (n=8) received nivolumab plus relatlimab on the same schedule (Clinical trial: NCT03044613). We examined longitudinal fecal samples from n=19 patients across both arms (n=90 samples) using 16S rRNA amplicon sequencing. Patients were classified based on pathological response: complete response (CR) and grades 1, 2, and 3 (G1, G2, G3) with increasing residual tumor visible in the resected specimen. Sequencing data was trimmed and filtered for contaminants, followed by high-resolution taxonomic assignment and normalization of reads across all samples. Analysis was performed using multiple metrics for alpha diversity and beta-diversity, with principal coordinates analysis/PERMANOVA, and pathway analysis using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Results: Patients with improved response in the neoadjuvant setting (CR/G1 vs G2/G3) grouped in distinct clusters using Bray-Curtis (p < 0.001). Patients with CR had higher alpha diversity, using both measures of richness and evenness, compared to patients with a G3 responses (p < 0.03). Specifically, family Bacteroidaceae and genus Bacteroides were enriched in patients with CR vs G3 (p < 0.02). At the species level, B. finegoldii, B. ovatus, and B. uniformis were enriched in patients with CR vs G3 (p < 0.02). In contrast, genus Klebsiella and Clostridium termitidis were enriched in patients with a poor response, G3 (p Conclusions: Patients with operable esophageal cancer and improved responses to combined CRT and IO had distinct microbiome profiles enriched in multiple Bacteroides species. Further analyses and validation efforts are underway to confirm metabolomic pathways. Citation Format: Fyza Y. Shaikh, James R. White, Ronan J. Kelly, Ali H. Zaidi, Jenna V. Canzoniero, Josephine L. Feliciano, Russell K. Hales, K Ranh Voong, Richard J. Battafarano, Blair A. Jobe, Stephen C. Yang, Stephen Broderick, Jinny Ha, Kellie N. Smith, Elizabeth Thompson, Eun J. Shin, Ali I. Amjad, Patrizia Guerrieri, Benny Weksler, Chen Hu, Valsamo Anagnostou, Vincent K. Lam, Cynthia L. Sears. Patients with operable esophageal cancer and improved responses to combined chemoradiotherapy and immunotherapy display distinct microbiome profiles enriched in multiple Bacteroides species [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1973.

BACKGROUND: Patients on maintenance hemodialysis are particularly vulnerable to infection and hospitalization from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to immunocompromised patients and the clustering that occurs in outpatient dialysis units, the seroprevalence of COVID-19 antibodies in this population is unknown and has significant implications for public health. Also, little is known about their risk factors for hospitalization. METHODS: Three outpatient maintenance hemodialysis units affiliated with a major teaching hospital in the New York area were studied. We determined rates of SARS-CoV-2 positivity via nasopharyngeal, real-time, reverse-transcriptase PCR (RT-PCR); SARS-CoV-2 IgG seropositivity; hospitalization; and mortality. RESULTS: Of 367 patients, 28% had either SARS-CoV-2 seropositivity or PCR positivity. Prevalence across the three respective units was 7%, 32%, and 70%. Those who were either antibody or PCR positive were significantly younger (65 versus 69 years, P=0.05), and had a higher prevalence of Black race (43% versus 30%, P=0.001) and Hispanic ethnicity (32% versus 12%, P

BackgroundWe conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab.MethodsPatients with resectable stage IB (≥4 cm)–IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint.ResultsWhile the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations.ConclusionsThough treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.

Background With the recent introduction of Integrated Cardiothoracic Surgery Residency Programs (IPs), limited data exist on unmatched applicants. We aimed to determine the dropout rate in individuals who applied for IP but did not match. Methods An online Institutional Review Board–approved survey was sent to current residents (n = 409), provided by the Thoracic Surgery Directors Association, to evaluate preferences and pathway to cardiothoracic surgery (CTS). Descriptive analysis was performed on quantitative data. Main Residency Match Data from 2008 to 2017 were collected. Results Of 250 respondents, 89 (36%) were in IPs. In the cohort, 110 (44%) applied for at least one IP, whereas only 10 of the remaining 140 CTS residents had contemplated applying. From written comments of those 140 residents, the most common reasons against applying for IP programs were (1) uncertainty of IP training/belief that general surgery offered more well-rounded training and (2) uncommitted to CTS as a medical student. Interestingly, 96% of IP residents were set on a cardiac career, whereas a larger proportion of 4/3 and traditional residents were interested in general thoracic (36%). According to the National Resident Matching Program, 147 individuals applied to IP programs from 2008 to 2011 and were unmatched. Only 20 of those individuals (14%), from our results, ended up in a CTS residency program. Conclusions Only a small percentage of applicants that did not match to an IP from 2008 to 2011 have ended up in CTS. As IPs continue to develop and improve, the concerns brought about by current CTS residents must be addressed to attract the next generation of exceptional surgeons.

Purpose In patients with non-small cell lung cancer (NSCLC) who undergo trimodality therapy (chemoradiation followed by surgical resection), it is unknown whether limiting preoperative radiation dose to the uninvolved lung reduces postsurgical morbidity. This study evaluated whether radiation fall-off dose parameters to the contralateral lung that is unaffected by NSCLC are associated with postoperative complications in NSCLC patients treated with trimodality therapy. Methods and materials We retrospectively reviewed NSCLC patients who underwent trimodality therapy between March 2008 and October 2016, with available restored digital radiation plans. Fischer's exact test was used to assess associations between patient and treatment characteristics and the development of treatment-related toxicity. Spearman rank correlation was used to measure the strength of association between dosimetric parameters. Results Forty-six patients were identified who received trimodality therapy with intensity modulated radiation (median, 59.4 Gy; range, 45-70) and concurrent platinum doublet chemotherapy, followed by surgical resection. The median age was 64.9 years (range, 45.6-81.6). The median follow-up time was 1.9 years (range, 0.3-8.4). Twenty-four (52.2%) patients developed any-grade pulmonary toxicity and 14 (30.4%) patients developed grade 2+ pulmonary toxicity. There was an increased incidence of any-grade pulmonary toxicity in patients with contralateral lung volume receiving at least 20 Gy (V20) ≥7% compared with P = .01). Similarly, contralateral lung V10 ≥20% was associated with an increased rate of any-grade pulmonary toxicity compared with V10 P = .01). Pneumonectomy/bilobectomy was associated with grade 2+ pulmonary toxicity ( P = .04). Conclusions Patients who received a higher radiation fall-off dose volume parameter (V20 ≥7% and V10 ≥20%) to the contralateral uninvolved lung had a higher incidence of any-grade postoperative pulmonary toxicity. Limiting radiation fall-off dose to the uninvolved lung may be an important modifiable radiation parameter in limiting postoperative toxicity in trimodality patients.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the targeted therapy and immunotherapy sections in the NCCN Guidelines. For the 2018 update, a new section on biomarkers was added.

OBJECTIVES: The tendency for patients with primary focal hyperhidrosis (PFH), characterized by excessive sweating, to experience psycho-social deficits is well documented. In addition, although endoscopic thoracic sympathectomy (ETS) effectively corrects PFH, its role in the psycho-social management of these patients remains unclear. Here, we examined changes in psychiatric symptomatology and psychotropic medication usage in PFH patients following ETS. METHODS: In total, 106 PFH patients underwent ETS and were compared against 213 matched controls. Information on psychiatric diagnosis and prescription was obtained through a retrospective chart review. Prospectively, PFH patients completed Hyperhidrosis Impact Questionnaires, Leibowitz Social Anxiety Scales and Center for Epidemiological Studies Depression Scales to evaluate pre- and postoperative quality-of-life and psycho-social impairment. RESULTS: A significantly greater proportion of PFH patients had been prescribed psychotropic medication (37.7%) compared to controls (14.1%) despite no differences in the proportion of psychiatric diagnoses. Following ETS, 52.5% of the PFH patients who were using psychotropic medications reduced their prescription regimen, compared to only 10% of control patients (P

Background Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non–small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. Methods In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses. Results Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed...

Simple Summary The role of exosomes in HIV (human immunodeficiency virus) as well as in cancer patients seems to be pivotal. The aim of our retrospective study was to assess the potential clinical value of CD9-positive plasma exosomes in lung cancer patients, patients with lung granulomas, healthy individuals, and HIV-positive patients with or without lung cancer. This study shows that CD9-positive plasma exosome concentrations differ between healthy controls, patients with immunocompetent pulmonary granulomas and patients with lung cancer. In addition, CD9-positive plasma exosomes are increased in HIV seropositive and HIV seronegative lung cancer patients compared to healthy controls, while chemotherapy-treated lung cancer patients have lower plasma exosome levels. This study also shows that in chemotherapy-naïve patients, plasma exosome levels are directly correlated with a prognosis with higher concentrations being associated with a longer, overall survival. These findings further support previous literature on the translational significance of total plasma exosomes in cancer patients, despite different immunological contexts. Abstract Recently, the role of exosomes in the progression of both cancer and HIV (human immunodeficiency virus) has been described. This study investigates the clinical significance of CD9-positive plasma exosomes in lung cancer patients, healthy individuals, and HIV-positive patients with or without lung cancer. Using a verified with transmission electron microscopy double-sandwich ELISA technique, plasma-derived exosomes were isolated and quantified from 210 lung cancer patients (including 44 metastatic patients with progressive disease after chemotherapy), 49 healthy controls, 20 patients with pulmonary granulomas, 19 HIV+ patients with lung cancer, 31 HIV+ patients without cancer, and 3 HIV+ patients with pulmonary granulomas. Plasma exosome concentrations differed between healthy controls, patients with immunocompetent pulmonary granulomas and patients with lung cancer even after chemotherapy (p < 0.001). Lung cancer patients after chemotherapy had lower exosome concentrations compared to patients with untreated lung cancer or granuloma (p < 0.001 for both). HIV+ patients without lung cancer had significantly higher exosome concentrations compared to HIV+ patients with lung cancer (p = 0.016). Although exosome concentrations differed between all different lung cancer histologies and healthy controls (p < 0.001 for all histologies), adjusted statistical significance was oµy retained for patients with granulomas and SCLC (Small-cell lung cancer, p < 0.001). HIV-induced immunodeficient patients with or without lung cancer had lower plasma exosomes compared to immunocompetent granuloma and lung cancer patients (p < 0.001). Finally, higher plasma exosomes were associated both on univariate (p = 0.044), and multivariate analysis (p = 0.040) with a better 3-year survival in stage II and III NSCLC (Non-small-cell lung carcinoma) patients. In conclusion, our study shows that CD9-positive plasma exosomes are associated with both lung cancer and HIV, prior chemotherapy, as well as with survival, suggesting a possible prognostic value.

// Lauren M. Rosati 1,* , Megan N. Kummerlowe 1,* , Justin Poling 2 , Amy Hacker-Prietz 1 , Amol K. Narang 1 , Eun J. Shin 3 , Dung T. Le 4 , Elliot K. Fishman 5 , Ralph H. Hruban 2 , Stephen C. Yang 6 , Matthew J. Weiss 6 and Joseph M. Herman 1,7 1 Department of Radiation Oncology & Molecular Radiation Sciences, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 3 Department of Gastroenterology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 4 Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 5 Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 6 Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 7 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA * These authors have contributed equally to this manuscript Correspondence to: Joseph M. Herman, email: // Keywords : pancreatic cancer, pancreatic ductal adenocarcinoma, metastatic, esophagus, esophageal metastasis Received : April 28, 2017 Accepted : May 20, 2017 Published : June 12, 2017 Abstract Purpose: We report a very unique case of an esophageal metastasis from a pancreatic ductal adenocarcinoma (PDAC) primary. Methods: After obtaining consent from the patient, all relevant records of the case were obtained and retrospectively reviewed. Results: At presentation, the patient was diagnosed with synchronous pancreatic and esophageal cancer. He received six months of neoadjuvant therapy including FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) and stereotactic body radiation therapy (SBRT) to the pancreatic tumor followed by a combined pancreaticoduodenectomy and Ivor Lewis esophagectomy. Review of the final esophageal specimen revealed normal overlying squamous mucosa with an underlying focus of metastatic PDAC. The patient remains alive with no evidence of disease 17 months from surgery and 25 months from diagnosis. Conclusions: Differentiating an esophageal metastasis from a PDAC primary versus a synchronous esophageal carcinoma is very difficult despite state-of-the-art diagnostic techniques performed at a high-volume tertiary cancer center. Extensive evaluation and continued follow-up of PDAC patients presenting with a synchronous esophageal lesion in a multidisciplinary setting may help ensure efficient and accurate management. In our case, neoadjuvant FOLFIRINOX and SBRT to the primary PDAC tumor followed by surgery has been an effective approach for this patient.

This selection from the NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) focuses on targeted therapies and immunotherapies for metastatic NSCLC, because therapeutic recommendations are rapidly changing for metastatic disease. For example, new recommendations were added for atezolizumab, ceritinib, osimertinib, and pembrolizumab for the 2017 updates.

Oral cancer patients report severe function-induced pain; severity is greater in females. We hypothesize that a neutrophil-mediated endogenous analgesic mechanism is responsible for sex differences in nociception secondary to oral squamous cell carcinoma (SCC). Neutrophils isolated from the cancer-induced inflammatory microenvironment contain β-endorphin protein and are identified by the Ly6G+ immune marker. We previously demonstrated that male mice with carcinogen-induced oral SCC exhibit less nociceptive behavior and a higher concentration of neutrophils in the cancer microenvironment compared to female mice with oral SCC. Oral cancer cells secrete granulocyte colony stimulating factor (G-CSF), a growth factor that recruits neutrophils from bone marrow to the cancer microenvironment. We found that recombinant G-CSF (rG-CSF, 5 μg/mouse, intraperitoneal) significantly increased circulating Ly6G+ neutrophils in the blood of male and female mice within 24 h of administration. In an oral cancer supernatant mouse model, rG-CSF treatment increased cancer-recruited Ly6G+ neutrophil infiltration and abolished orofacial nociceptive behavior evoked in response to oral cancer supernatant in both male and female mice. Local naloxone treatment restored the cancer mediator-induced nociceptive behavior. We infer that rG-CSF-induced Ly6G+ neutrophils drive an endogenous analgesic mechanism. We then evaluated the efficacy of chronic rG-CSF administration to attenuate oral cancer-induced nociception using a tongue xenograft cancer model with the HSC-3 human oral cancer cell line. Saline-treated male mice with HSC-3 tumors exhibited less oral cancer-induced nociceptive behavior and had more β-endorphin protein in the cancer microenvironment than saline-treated female mice with HSC-3 tumors. Chronic rG-CSF treatment (2.5 μg/mouse, every 72 h) increased the HSC-3 recruited Ly6G+ neutrophils, increased β-endorphin protein content in the tongue and attenuated nociceptive behavior in female mice with HSC-3 tumors. From these data, we conclude that neutrophil-mediated endogenous opioids warrant further investigation as a potential strategy for oral cancer pain treatment.