Integrating genomic features for non-invasive early lung cancer detection.

Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

Impact of Treatment Sequencing on Survival for Patients with Locally Advanced Gastric Cancer.

BACKGROUND: Data are limited concerning the survival outcomes of locally advanced gastric cancer patients according to the multimodality therapy (MMT) administered. METHODS: Single institution, retrospective analysis of 235 patients with locally advanced gastric cancer from 2001 to 2015. All patients met criteria for curative-intent surgery and chemotherapy ± radiation therapy. Treatment regimens were: (1) surgery first with adjuvant chemoradiation therapy (S + Adj); (2) perioperative chemotherapy + surgery (Periop); and (3) total neoadjuvant therapy followed by surgery (TNT + S). RESULTS: One hundred twenty-eight (60.0%) patients received S + Adj, 69 (26.8%) Periop, and 38 (13.2%) TNT + S. Of the 235 patients, 222 (94.5%) received surgery. All intended therapy was received by 81.6% of TNT + S, 44.5% of S + Adj, and 42.0% of Periop patients. MMT was significantly more likely to be completed by TNT + S patients (HR 6.67, p < 0.001). At a median follow-up of 37 months, survival rates on an intention-to-treat basis with TNT + S, Periop, and S + Adj were 52.6%, 59.4%, and 45.3%, respectively. Regimen and completion of MMT significantly affected overall mortality risk. Compared with Periop, TNT + S had similar mortality risk (hazard ratio [HR] 1.28, p = 0.421), whereas S + Adj had increased mortality risk (HR 1.64, p = 0.027). CONCLUSIONS: The choice of treatment sequencing has a major impact on completion rates of multimodal therapy in patients with locally advanced gastric cancer. Less than 50% of patients treated with upfront surgery or perioperative chemotherapy receive all intended therapies. TNT has higher intended therapy completion rates and comparable survival compared with perioperative therapy in our data. Further prospective investigations of TNT are warranted.

Recurrence After Complete Resection for Non-Small Cell Lung Cancer in the National Lung Screening Trial.

BACKGROUND: The objective of this study was to evaluate patterns, predictors, and long-term outcomes of recurrent disease after complete resection for early-stage non-small cell lung cancer (NSCLC) using the National Lung Screening Trial (NLST). METHODS: The frequency of recurrence in patients with pathologic stage I-II NSCLC who underwent complete resection (lobectomy or bilobectomy) in the NLST was evaluated. Predictors of increased risk of recurrence were assessed by Fine-Gray competing risks regression. RESULTS: Of the 497 patients meeting study inclusion criteria, 94 experienced a recurrence-a rate of 4.9 (95% CI, 4.0-6.0) per 100 person-years. The 5-year cumulative incidence of recurrence was 20.1% (95% CI, 16.5%-23.9%). Most patients experienced recurrences at distant sites alone (n = 47 [50.0%]) or at both locoregional and distant sites (n = 30 [31.9%]). The median time from resection to recurrence was 18.8 (10.6-30.7) months. The incidence rate of recurrence was significantly lower among patients with lung cancer detected by low-dose computed tomography screening during one of the three screening rounds of the NLST when compared with patients with lung cancer detected by chest radiography screening and patients with lung cancer not detected by any form of screening (ie, those diagnosed after a negative or missed screening exam and those diagnosed during follow-up after the three screening rounds of the NLST were completed) (P < .001). Median survival (from the date of recurrence) of patients with pathologic stage I and stage II disease who had recurrences at locoregional, distant, or both sites was 63.0, 23.1, and 9.8 months and 28.9, 8.7, and 10.2 months, respectively. CONCLUSIONS: In this analysis of NLST participants with completely resected stage I-II NSCLC, the 5-year cumulative incidence of recurrence was 20%. Nearly 82% of recurrences were at distant sites and associated with poor survival.

Germline mutations and developmental mosaicism underlying EGFR-mutant lung cancer.

While the development of multiple primary tumors in smokers with lung cancer can be attributed to carcinogen-induced field cancerization, the occurrence of multiple primary tumors in individuals with EGFR-mutant lung cancer who lack known environmental exposures remains unexplained. We identified ten patients with early-stage, resectable non-small cell lung cancer who presented with multiple anatomically distinct EGFR-mutant tumors. We analyzed the phylogenetic relationships among multiple tumors from each patient using whole exome sequencing (WES) and hypermutable poly-guanine (poly-G) repeat genotyping, as orthogonal methods for lineage tracing. In two patients, we identified germline EGFR variants, which confer moderately enhanced signaling when modeled in vitro. In four other patients, developmental mosaicism is supported by the poly-G lineage tracing and WES, indicating a common non-germline cell-of-origin. Thus, developmental mosaicism and germline variants define two distinct mechanisms of genetic predisposition to multiple EGFR-mutant primary tumors, with implications for understanding their etiology and clinical management.

A Network of Anomalies Prompting VACTERL Workup in a Trisomy 21 Newborn.

VACTERL (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities) association is a condition defined by having at least three of the following congenital malformations: vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities. While diagnosing the VACTERL association is rare, the conditions that make up the VACTERL core-component features among other congenital abnormalities are even more unique. We present a case of a 34-week-old premature infant with trisomy 21 in addition to esophageal atresia, tracheoesophageal fistula, laryngeal cleft, vascular ring, Hirschsprung's disease, atrioventricular canal defect, ventricular septal defect, and other related conditions diagnosed at birth. To our knowledge, this case represents the first of its kind in relation to the constellation of anomalies diagnosed in one individual at birth of which may or may not be related to Down syndrome, and the associated interventions necessary to continue postnatal living.

Surgical Technique: Minimally Invasive First-Rib Resection.

Minimally invasive surgical approaches to the treatment of thoracic outlet syndrome (TOS) will become increasingly common as more surgeons gain experience in thoracoscopic and robotic technique. Robotic surgery may be more technically advantageous because of improved visualization and maneuverability of wristed instruments. Longer-term outcome data are necessary to definitively establish the equivalency or superiority of minimally invasive TOS compared with open surgery in the treatment of TOS.

Extended Pulmonary Resection by Sleeve Lobectomy and Carinal Pneumonectomy: Selection and Technique.

Minimally invasive surgical approaches for extended pulmonary resections are becoming increasingly common as more surgeons gain experience in thoracoscopic and robotic technique. Outcome studies demonstrate improved decreased morbidity as compared with an open surgery.

Naturally occurring K vitamins inhibit pancreatic cancer cell survival through a caspase-dependent pathway.

BACKGROUND AND AIMS: Available medical therapies against pancreatic cancer are largely ineffective and have many side-effects. Physiologically, vitamins K1 and K2 (VK) act as co-factors for gamma-carboxylation of prothrombin and other coagulation factors. In previous studies, VK analogs have been found to have potent negative effects on the survival of various cancer cells. We hypothesized that the well-tolerated and naturally occurring VK1 and VK2 may be used to inhibit pancreatic cancer cell survival. METHODS: Four pancreas cancer cell lines were tested. Two of these (MiaPaCa2 and PL5) were found to be sensitive to VK1 and VK2 (IC50 values < or =150 microM). To address the mechanisms of this effect on cell survival, we performed cell cycle and apoptosis studies using VK2 (the more potent compound). RESULTS: We found that VK induced caspase-dependent apoptosis in over 60% of cells in the sensitive lines at the half maximal inhibitory concentration (IC(50)) range. Further, this induction in apoptosis was antagonized by a caspase inhibitor. Accompanying apoptosis, a dose- and time-dependent induction of extracellular signal-regulated kinase (ERK) phosphorylation occurred when sensitive lines were treated with either VK1 or VK2 at inhibitory doses. Simultaneous co-treatment of cells with a MEK1 inhibitor and VK prevented both the induction of ERK phosphorylation and the apoptosis, showing that the mitogen-activated protein (MAP) kinase pathway is central for VK-mediated apoptosis in pancreatic cancer cells. CONCLUSION: These data show that naturally-occurring, non-toxic K vitamins can inhibit the survival of some pancreatic cancer cell lines. These novel, safe and clinically-utilized agents initiate a caspase-dependent apoptosis via the MAP kinase pathway and could potentially benefit patients with pancreatic cancer either as a single agent or in combination with chemotherapy for treatment, or for prevention of recurrence of pancreas cancer post resection.

Outcomes of Laparoscopic Heller Myotomy for Achalasia: 22-Year Experience.

INTRODUCTION: Laparoscopic Heller Myotomy is the most effective treatment of achalasia. We examined the durability of symptomatic relief, with and without fundoplication. METHODS: A single institution database between 1995 and 2017 was reviewed. Achalasia symptom severity was assessed by Eckardt scores (ES) obtained at 3-time points via patient questionnaire. Primary outcome was treatment success defined as ES of < 3. RESULTS: Completed surveys were returned by 130 patients (median follow-up of 6.6 years). A partial fundoplication was performed in 86%. At both 1-year and late follow-up, patients reported a significant improvement in ES compared to baseline (p < 0.05). Of those followed for ≥ 10 years (n = 44), 82% reported ES < 3 at 1-year (p < 0.001), and 78% at last follow-up (p < .001). Of patients who reported treatment success 1-year postoperatively (103/130), 85% continued to report symptomatic relief at last follow-up. Five-year cohort analysis did not show deterioration of dysphagia relief over time. The presence or absence of fundoplication had no impact on long-term outcome (p > 0.05). CONCLUSIONS: LHM provides immediate and durable symptomatic relief, with very few patients requiring further therapeutic intervention. Fundoplication does not appear to influence the durability of symptom relief. Treatment success at 1-year is predictive of long-lasting symptomatic relief.

ATRAID regulates the action of nitrogen-containing bisphosphonates on bone.

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase, resulting in defects in protein prenylation. Yet, it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID Loss of ATRAID function results in selective resistance to N-BP-mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Last, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare nonsynonymous coding variants in patients with ONJ or an AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people.

Adenosquamous carcinoma of the pancreas harbors KRAS2, DPC4 and TP53 molecular alterations similar to pancreatic ductal adenocarcinoma.

Adenosquamous carcinoma of the pancreas is one of the most aggressive forms of pancreatic cancer. Molecular characterizations of this rare tumor subtype are sparse. Understanding the common molecular and pathologic features of pancreatic adenosquamous carcinomas could provide critical information for identifying therapeutic targets. Herein, we analyzed the pathologic and molecular features of our series of eight pancreatic adenosquamous carcinomas. We found KRAS2 gene mutations at codon 12 in all eight cases. All the cases showed loss of p16 protein. In three of these cases the loss was attributed to an exon 2 homozygous deletion in the p16/CDKN2a gene. The majority of the cases had loss of Dpc4 protein and strong nuclear p53 positivity, similar to the molecular signature found in pancreatic ductal adenocarcinoma. We found that E-cadherin was either lost or reduced in all cases and that epidermal growth factor receptor was overexpressed in all cases. The squamous component was positive for p63 staining and thus p63 labeling was helpful in identifying squamous differentiation in adenosquamous carcinomas with an acantholytic growth pattern. In summary, although pancreatic adenosquamous carcinoma and ductal adenocarcinoma have overlapping pathologic and molecular characteristics, there are distinct differences that may be helpful in diagnostic and therapeutic strategies.

Minimally Invasive Gastric Cancer Surgery.

Minimally invasive surgical approaches to the treatment of gastric cancer have become increasingly common as more data have demonstrated the safety, feasibility, and oncologic equivalency of such approaches compared with conventional open gastrectomy. East Asia has produced the majority of these data, encouraging Western high-volume centers to expand their application of minimally invasive techniques to patients despite more advanced tumor stages at presentation and a lower volume of cases. More randomized, controlled trials and longer term outcome data are necessary to definitively establish the superiority of minimally invasive gastrectomy to open gastrectomy for the treatment of gastric cancer.

Morbidity and Mortality of Total Gastrectomy: a Comprehensive Analysis of 90-Day Outcomes.

BACKGROUND: Total gastrectomy (TG) is a complex procedure that carries a high risk of morbidity and mortality and in which patients may experience post-operative sequelae well past the standard 30-day follow-up period. Large studies from high-volume centers with detailed 90-day follow-up data are needed to provide benchmarks for high-quality care for this complex procedure. METHODS: Single-institution, retrospective review of a comprehensive gastric cancer database of 148 patients undergoing curative intent TG from 2000 to 2017. Clinicopathologic and treatment factors were analyzed for their impact on 90-day outcomes. RESULTS: The median age of the cohort was 66 years, and 61% were male. Neoadjuvant chemotherapy and radiation therapy were delivered to 32% and 11% of patients, respectively. Open and laparoscopic TG were performed in 93% (n = 137) and 7% (n = 11) of patients, respectively. Extended lymphadenectomy, pancreatectomy, and splenectomy were performed in 37%, 4.7%, and 19% of patients, respectively. The 30- and 90-day mortality rates were 2.0% and 3.4%, respectively. At least one 90-day complication was experienced by 43.9% (n = 65) of patients, and 14% (n = 21) experienced a Clavien-Dindo grade 3 or 4 complication. Anastomotic leak occurred in 5.4% (n = 8) of patients, half of which required an invasive intervention. Median length of stay was 8 days. The readmission rate was 22%, and most readmissions were due to dehydration and/or nutritional compromise. CONCLUSIONS: This study defines 30- and 90-day post-operative outcomes after total gastrectomy in a high-volume center. These outcomes data are critical to the improvement of the informed consent process and as benchmarks for future quality improvement initiatives.

Outcomes of Extended Lymphadenectomy for Gastroesophageal Carcinoma: A Large Western Series.

BACKGROUND: The extent of lymph node dissection for patients with gastroesophageal carcinoma remains controversial. We sought to examine the perioperative risk and survival outcomes in a large Western series of patients undergoing limited (D0/D1) vs extended (D1+/D2) lymphadenectomy (LAD) for gastroesophageal carcinoma. STUDY DESIGN: Clinicopathologic and treatment factors for 520 patients with gastroesophageal carcinoma undergoing potentially curative resection at a single institution from 1995 to 2017 were analyzed for their impact on perioperative morbidity and mortality, lymph node yield, and overall survival. RESULTS: A total of 362 (70%) patients underwent D0/D1 LAD and 158 (30%) underwent D1+/D2 LAD. Median follow-up was 3.1 years. Patients undergoing D1+/D2 LAD were more likely to have distal tumors, to undergo distal/subtotal/total gastrectomy, and to undergo operation at a more contemporary time than patients undergoing D0/D1 LAD. The median number of lymph nodes examined and the percentage of patients with 16 or more lymph nodes examined was 16 and 53%, respectively, in the D0/D1 group vs 27 and 89%, respectively, in the D1+/D2 group. There were no differences in the rates of major complications (16.6% vs 14.6%) or operative mortality (2.8% vs 0.6%) between the D0/D1 and D1+/D2 groups, respectively. Patients undergoing D1+/D2 LAD had significantly improved overall survival (hazard ratio 0.74; p = 0.035) compared with those undergoing D0/D1 LAD on univariate analysis, but this survival benefit disappeared when controlling for the time period of operation. CONCLUSIONS: Gastrectomy with extended (D1+/D2) LAD can be performed safely at a high-volume Western center, and it improves nodal yield significantly and ensures accurate pathologic staging.

Carinal surgery: A single-institution experience spanning 2 decades.

OBJECTIVES: Complete resection of neoplasms involving the carina are technically challenging and have high operative morbidity and mortality. This study examines the last 2 decades of clinical experience at our institution. METHODS: Medical records were retrospectively reviewed between 1997 and 2017 to identify all patients who underwent carinal resection. Primary outcome measures include risk factors for complications and overall survival. RESULTS: In total, 45 carinal resections were performed with a median follow-up of 3.4 years (interquartile range 0.8-8.5). Procedures included 21 neocarinal reconstructions (48%), 14 right carinal pneumonectomies (30%), 9 left carinal pneumonectomies (20%), and 1 carinal plus lobar resection (2%). Age ranged from 27 to 74 years, and 23 of 45 patients were female. Eight received neoadjuvant chemotherapy and 6 preoperative radiation. Extracorporeal membrane oxygenation and cardiopulmonary bypass were intraoperatively used for 4 patients with no mortality. Four patients underwent superior vena cava resection and reconstruction. Anastomotic complications occurred in 5 patients, all of which were managed conservatively: 1 required stent placement and a second underwent hyperbaric oxygen therapy. Postoperative events were observed in 26 patients (58%), including pneumonia (n = 11), blood transfusion (n = 8), and atrial arrhythmias (n = 8). More serious complications, such as acute respiratory distress syndrome, occurred in 3 patients. Postoperative events were most closely associated with pulmonary resection (P = .040). There were 3 deaths, yielding an overall operative 30- and 90-day mortality of 6.8% and 7%, respectively. CONCLUSIONS: Despite advances in perioperative management, carinal resection poses challenges for both patient and surgeon. Preoperative chemotherapy, radiation, and concomitant pulmonary resection were associated with increased risk of complications. Patient selection and meticulous surgical technique contribute to reduction in morbidity and mortality.

"Yes, I'm the Doctor": One Department's Approach to Assessing and Addressing Gender-Based Discrimination in the Modern Medical Training Era.

While gender-based bias and discrimination (GBD) is known to exist in medical training, there is limited guidance for training programs on how to understand and combat this issue locally. The Massachusetts General Hospital Department of Surgery established the Gender Equity Task Force (GETF) to address GBD in the local training environment. In 2017, members of the GETF surveyed residents in surgery, anesthesia, and internal medicine at 2 academic hospitals to better understand perceived sources, frequency, forms, and effects of GBD. Overall, 371 residents completed the survey (60% response rate, 197 women). Women trainees were more likely to endorse personal experience of GBD and sexual harassment than men (P < .0001), with no effect of specialty on rates of GBD or sexual harassment. Patients and nursing staff were the most frequently identified groups as sources of GBD. While an overwhelming majority of both men (86%) and women (96%) respondents either experienced or observed GBD in the training environment, less than 5% of respondents formally reported such experiences, most frequently citing a belief that nothing would happen. Survey results served as the basis for a variety of interventions addressing nursing staff and patients as sources of GBD, low confidence in formal reporting mechanisms, and the pervasiveness of GBD, including sexual harassment, across specialties. These results reproduce other studies' findings that GBD and sexual harassment disproportionately affect women trainees while demonstrating how individual training programs can incorporate local GBD data when planning interventions to address GBD.

Subglottic Stenosis in Granulomatosis With Polyangiitis: The Role of Laryngotracheal Resection.

BACKGROUND: Granulomatosis with polyangiitis (GPA) is associated with development of subglottic stenosis in about one-fourth of all patients. Although endoscopic management is the primary treatment method for tracheobronchial stenosis, some patients have refractory disease, and tracheostomy is required. It is unclear if laryngotracheal resection and reconstruction (LTRR) can be safely performed in patients with GPA. METHODS: A retrospective review was performed of 11 patients with GPA undergoing LTRR. RESULTS: Eleven female patients with GPA and a median age of 47 years underwent LTRR. Six patients were diagnosed with GPA after LTRR and had not received any induction immunosuppression regimen. Five patients had received induction immunosuppression regimen and were in clinical remission before LTRR. LTRR was performed with a protective tracheostomy in 3 patients, which was eventually removed in all. There were no major complications and no postoperative deaths. One patient (9%) failed surgical management and had replacement of a permanent tracheostomy 4 months after LTRR. Six patients (55%) required additional tracheal dilations after LTRR. Ten patients (91%) had durable control of symptoms and freedom from tracheostomy with a median follow-up of 9.7 years. Two patients (18%) experienced subsequent lower airway stenoses. CONCLUSIONS: Surgical treatment of subglottic stenosis in highly selected patients with GPA is effective and associated with minimal morbidity. Although long-term outcomes are encouraging, additional procedures may be necessary, and patients are at risk of experiencing lower airway disease.

Idiopathic laryngotracheal stenosis.

Idiopathic laryngotracheal stenosis (ILTS) is a rare inflammatory disease of unknown etiology. Infectious, traumatic and immunologic processes must first be excluded. The majority of patients affected are female who present with progressive symptoms of upper airway obstruction, which can extend over a number of years. ILTS is characterized by short segment, circumferential stenotic lesions, located particularly at the level of the cricoid. Bronchoscopic evaluation is essential for establishing the diagnosis and operative planning. Various temporizing interventions have historically been utilized, including dilation and laser ablation, for symptomatic management. However these interventions have demonstrated diminishing returns and poor long-term outcomes. Patients with ILTS should be considered early for definitive surgical intervention to minimize complications and optimize outcomes. Laryngotracheal resection and reconstruction is a viable intervention, which has demonstrated good long-term results and low recurrence rates for this patient population.

Alton Ochsner, MD (1896-1981): surgical pioneer and legacy linking smoking and disease.

Edward William Alton Ochsner kept a plain, metal card file in which he recorded close to 50 years worth of medical experiences, research, and insights. The most populated topics were filed as "Cancer, Lung" and "Cancer, Bronchogenic." These reflected his areas of greatest interest, for which he would go on to produce groundbreaking work. Of his many lifetime accomplishments, he is perhaps best known for being the first to report a link between cigarette smoking and lung cancer. This was just one of the many ways in which Ochsner worked to effect social change. The establishment of the Ochsner Health System in New Orleans was born from this similar passion. Ochsner went on to become one of the giants of his generation as a result of this tireless work as a leader, educator, and mentor.