Large Cell Neuroendocrine Carcinoma of the Lung: Current Understanding and Challenges

Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare and highly aggres-sive type of lung cancer, with a complex biology that shares similarities with both small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). The prognosis of LCNEC is poor, with a median overall survival of 8–12 months. The diagnosis of LCNEC requires the identification of neuroendocrine morphology and the expression of at least one of the neuroendocrine markers (chromogranin A, synaptophysin or CD56). In the last few years, the introduction of next-generation sequencing allowed the identification of molecular subtypes of LCNEC, with prognostic and potential therapeutic implications: one subtype is similar to SCLC (SCLC-like), while the other is similar to NSCLC (NSCLC-like). Because of LCNEC rarity, most evidence comes from small retrospective studies and treatment strategies that are extrapolated from those adopted in patients with SCLC and NSCLC. Nevertheless, limited but promising data about targeted therapies and immune checkpoint inhibitors in patients with LCNEC are emerging. LCNEC clinical management is still controversial and standardized treatment strategies are currently lacking. The aim of this manuscript is to review clinical and molecular data about LCNEC to better understand the optimal management and the potential prognostic and therapeutic implications of molecular subtypes

Lymph node ratio predicts efficacy of postoperative radiation therapy in nonmetastatic Merkel cell carcinoma: A population-based analysis

Background: After radical resection of a nonmetastatic Merkel cell carcinoma (M0 MCC), postoperative radiation therapy (RT) is recommended as it improves survival. However, the role of RT in specific subgroups of M0 MCC is unclear. We sought to identify whether there is a differential survival benefit from RT in specific M0 MCC patient subgroups. Methods: M0 MCC patients from the Surveillance, Epidemiology, and End Results (SEER) database registry were collected. The best prognostic age, tumor size, and lymph node ratio (LNR, ratio between positive lymph nodes and resected lymph nodes) cutoffs were calculated. The primary endpoint was overall survival (OS). Results: A total of 5644 M0 MCC patients (median age 77 years, 62% male) were included: 4022 (71%) node-negative (N0) and 1551 (28%) node-positive (N+). Overall, 2682 patients (48%) received RT. Age > 76.5 years, tumor size >13.5 mm, and LNR >0.215 were associated with worse OS. RT was associated with longer OS in the M0 MCC, N0, and N+ group and independently associated with a 25%, 27%, and 26% reduction in the risk for death, respectively. RT benefit on survival was increased in tumor size >13.5 mm in the N0 group and LNR >0.215 in the N+ group. No OS benefit from RT was observed in T4 tumors (N0 and N+ groups). Conclusions: RT was associated with improved survival in M0 MCC, irrespective of the nodal status. LNR >0.215 is a useful prognostic factor for clinical decision-making and for stratification and interpretation of clinical trials

Sudden cardiac death in patients with ischemic heart failure undergoing coronary artery bypass grafting results from the STICH randomized clinical trial (Surgical Treatment for Ischemic Heart Failure)

Background—The risk of sudden cardiac death (SCD) in patients with heart failure following CABG has not been examined in a contemporary clinical trial of surgical revascularization. This analysis describes the incidence, timing and clinical predictors of SCD after CABG. Methods—Patients enrolled in the Surgical Treatment of Ischemic Heart Failure (STICH) trial who underwent CABG with or without surgical ventricular reconstruction (SVR) were included. We excluded patients with prior ICD and those randomized only to medical therapy. The primary outcome was SCD as adjudicated by a blinded committee. A Cox model was used to examine and identify predictors of SCD. The Fine and Gray method was used to estimate the incidence of SCD accounting for the competing risk of other deaths. Results—Over a median follow-up of 46 months, 113 patients of 1411 patients who received CABG without (n = 934) or with SVR (n = 477) had SCD; 311 died of other causes. The mean LVEF at enrollment was 28±9%. The 5-year cumulative incidence of SCD was 8.5%. Patients who had SCD and those who did not die were younger and had fewer comorbid conditions than those who died for reasons other than SCD. In the first 30 days after CABG, SCD (n=5) accounted for 7% of all deaths. The numerically greatest monthly rate of SCD was in the 31-90 day time period. In a multivariable analysis including baseline demographics, risk factors, coronary anatomy and LV function, ESVI and BNP were most strongly associated with SCD. Conclusions—The monthly risk of SCD shortly after CABG among patients with a low LVEF is highest between the first and third month, suggesting that risk stratification for SCD should occur early in the postoperative period, particularly in patients with increased preoperative ESVI and/or BNP

Durability of bioprosthetic aortic valves in patients under the age of 60 years - Rationale and design of the international INDURE registry

Background: There is an ever-growing number of patients requiring aortic valve replacement (AVR). Limited data is available on the long-term outcomes and structural integrity of bioprosthetic valves in younger patients undergoing surgical AVR. Methods: The INSPIRIS RESILIA Durability Registry (INDURE) is a prospective, open-label, multicentre, international registry with a follow-up of 5 years to assess clinical outcomes of patients younger than 60 years who undergo surgical AVR using the INSPIRIS RESILIA aortic valve. INDURE will be conducted across 20-22 sites in Europe and Canada and intends to enrol minimum of 400 patients. Patients will be included if they are scheduled to undergo AVR with or without concomitant root replacement and/or coronary bypass surgery. The primary objectives are to 1) determine VARC-2 defined time-related valve safety at one-year (depicted as freedom from events) and 2) determine freedom from stage 3 structural valve degeneration (SVD) presenting as morphological abnormalities and severe haemodynamic valve degeneration at 5 years. Secondary objectives include the assessment of the haemodynamic performance of the valve, all stages of SVD, potential valve-in-valve procedures, clinical outcomes (in terms of New York Heart Association [NYHA] function class and freedom from valve-related rehospitalisation) and change in patient quality-of-life. Discussion: INDURE is a prospective, multicentre registry in Europe and Canada, which will provide much needed data on the long-term performance of bioprosthetic valves in general and the INSPIRIS RESILIA valve in particular. The data may help to gather a deeper understanding of the longevity of bioprosthetic valves and may expand the use of bioprosthetic valves in patients under the age of 60 years. Trial registration: ClinicalTrials.gov identifier: NCT03666741 (registration received September, 12th, 2018)

A machine learning-based chemoproteomic approach to identify drug targets and binding sites in complex proteomes

Chemoproteomics is a key technology to characterize the mode of action of drugs, as it directly identifies the protein targets of bioactive compounds and aids in the development of optimized small-molecule compounds. Current approaches cannot identify the protein targets of a compound and also detect the interaction surfaces between ligands and protein targets without prior labeling or modification. To address this limitation, we here develop LiP-Quant, a drug target deconvolution pipeline based on limited proteolysis coupled with mass spectrometry that works across species, including in human cells. We use machine learning to discern features indicative of drug binding and integrate them into a single score to identify protein targets of small molecules and approximate their binding sites. We demonstrate drug target identification across compound classes, including drugs targeting kinases, phosphatases and membrane proteins. LiP-Quant estimates the half maximal effective concentration of compound binding sites in whole cell lysates, correctly discriminating drug binding to homologous proteins and identifying the so far unknown targets of a fungicide research compound

Durability of bioprosthetic aortic valves in patients under the age of 60 years - Rationale and design of the international INDURE registry

Background: There is an ever-growing number of patients requiring aortic valve replacement (AVR). Limited data is available on the long-term outcomes and structural integrity of bioprosthetic valves in younger patients undergoing surgical AVR. Methods: The INSPIRIS RESILIA Durability Registry (INDURE) is a prospective, open-label, multicentre, international registry with a follow-up of 5 years to assess clinical outcomes of patients younger than 60 years who undergo surgical AVR using the INS

Tailored postoperative treatment of prostate cancer: final results of a phase I/II trial.

BACKGROUD: The European Organization for Research and Treatment of Cancer (EORTC) trial 22,911 reported 74% 5-year biochemical disease-free survival (bDFS) in patients with prostate carcinoma treated with radical prostatectomy (RP) followed by postoperative radiotherapy (RT). This study aimed to improve these outcomes by using a combined-intensified-modulated-adjuvant treatment, including RT and hormone therapy (HT) after RP. MATERIALS AND METHODS: This phase I/II trial treatment was designed to improve 5-year bDFS from ~\u200975 to 90%. Patients were consecutively enrolled using the following inclusion criteria: age\u2009<\u200980 years, histological diagnosis of prostate adenocarcinoma without known metastases, stage pT2-4N0-1, and Eastern Cooperative Oncology Group performance status of 0-2. All patients had at least one of these pathologic features: capsular perforation, positive surgical margins, seminal vesicle invasion, and pelvic lymph nodes involvement. A minimum dose of 64.8\u2009Gy to the tumor bed was delivered in all patients. Depending on tumor characteristics at diagnosis, patients received a higher dose (70.2\u2009Gy; 85.4%) and/or prophylactic pelvic lymph nodes irradiation (57.7%) and/or HT (69.1%). Biochemical relapse was defined as two consecutive rising prostate-specific antigen (PSA) values\u2009>\u20090.2\u2009ng/ml. RESULTS: A total of 123 patients were enrolled in the study and completed the scheduled treatment. Median preoperative and postoperative PSA were: 8.8 and 0.06\u2009ng/mL, respectively. The percentages of patients with pathologically involved nodes and positive resection margins were: 14.6% and 58.5%, respectively. With a median follow-up of 67 months (range: 37-120 months), the actuarial 5-year bDFS, local control, metastasis-free survival, and overall survival (OS) were: 92.9%, 98.7%, 96.1%, and 95.1%, respectively. CONCLUSION: A higher 5-year bDFS (92.9%) was recorded compared to studies based on standard adjuvant RT, even though patients with nodal disease and detectable postoperative PSA were enrolled. Clinical end points, as long-term disease-free survival and OS, will require further assessments

AOSpine Consensus Paper on Nomenclature for Working-Channel Endoscopic Spinal Procedures

Study Design: International consensus paper on a unified nomenclature for full-endoscopic spine surgery. Objectives: Minimally invasive endoscopic spinal procedures have undergone rapid development during the past decade. Evolution of working-channel endoscopes and surgical instruments as well as innovation in surgical techniques have expanded the types of spinal pathology that can be addressed. However, there is in the literature a heterogeneous nomenclature defining approach corridors and procedures, and this lack of common language has hampered communication between endoscopic spine surgeons, patients, hospitals, and insurance providers. Methods: The current report summarizes the nomenclature reported for working-channel endoscopic procedures that address cervical, thoracic, and lumbar spinal pathology. Results: We propose a uniform system that defines the working-channel endoscope (full-endoscopic), approach corridor (anterior, posterior, interlaminar, transforaminal), spinal segment (cervical, thoracic, lumbar), and procedure performed (eg, discectomy, foraminotomy). We suggest the following nomenclature for the most common full-endoscopic procedures: posterior endoscopic cervical foraminotomy (PECF), transforaminal endoscopic thoracic discectomy (TETD), transforaminal endoscopic lumbar discectomy (TELD), transforaminal lumbar foraminotomy (TELF), interlaminar endoscopic lumbar discectomy (IELD), interlaminar endoscopic lateral recess decompression (IE-LRD), and lumbar endoscopic unilateral laminotomy for bilateral decompression (LE-ULBD). Conclusions: We believe that it is critical to delineate a consensus nomenclature to facilitate uniformity of working-channel endoscopic procedures within academic scholarship. This will hopefully facilitate development, standardization of procedures, teaching, and widespread acceptance of full-endoscopic spinal procedures

Total disc replacement surgery for symptomatic degenerative lumbar disc disease: a systematic review of the literature

The objective of this study is to evaluate the effectiveness and safety of total disc replacement surgery compared with spinal fusion in patients with symptomatic lumbar disc degeneration. Low back pain (LBP), a major health problem in Western countries, can be caused by a variety of pathologies, one of which is degenerative disc disease (DDD). When conservative treatment fails, surgery might be considered. For a long time, lumbar fusion has been the “gold standard” of surgical treatment for DDD. Total disc replacement (TDR) has increased in popularity as an alternative for lumbar fusion. A comprehensive systematic literature search was performed up to October 2008. Two reviewers independently checked all retrieved titles and abstracts, and relevant full text articles for inclusion. Two reviewers independently assessed the risk of bias of included studies and extracted relevant data and outcomes. Three randomized controlled trials and 16 prospective cohort studies were identified. In all three trials, the total disc replacement was compared with lumbar fusion techniques. The Charité trial (designed as a non-inferiority trail) was considered to have a low risk of bias for the 2-year follow up, but a high risk of bias for the 5-year follow up. The Charité artificial disc was non-inferior to the BAK® Interbody Fusion System on a composite outcome of “clinical success” (57.1 vs. 46.5%, for the 2-year follow up; 57.8 vs. 51.2% for the 5-year follow up). There were no statistically significant differences in mean pain and physical function scores. The Prodisc artificial disc (also designed as a non-inferiority trail) was found to be statistically significant more effective when compared with the lumbar circumferential fusion on the composite outcome of “clinical success” (53.4 vs. 40.8%), but the risk of bias of this study was high. Moreover, there were no statistically significant differences in mean pain and physical function scores. The Flexicore trial, with a high risk of bias, found no clinical relevant differences on pain and physical function when compared with circumferential spinal fusion at 2-year follow up. Because these are preliminary results, in addition to the high risk of bias, no conclusions can be drawn based on this study. In general, these results suggest that no clinical relevant differences between the total disc replacement and fusion techniques. The overall success rates in both treatment groups were small. Complications related to the surgical approach ranged from 2.1 to 18.7%, prosthesis related complications from 2.0 to 39.3%, treatment related complications from 1.9 to 62.0% and general complications from 1.0 to 14.0%. Reoperation at the index level was reported in 1.0 to 28.6% of the patients. In the three trials published, overall complication rates ranged from 7.3 to 29.1% in the TDR group and from 6.3 to 50.2% in the fusion group. The overall reoperation rate at index-level ranged from 3.7 to 11.4% in the TDR group and from 5.4 to 26.1% in the fusion group. In conclusion, there is low quality evidence that the Charité is non-inferior to the BAK cage at the 2-year follow up on the primary outcome measures. For the 5-year follow up, the same conclusion is supported only by very low quality evidence. For the ProDisc, there is very low quality evidence for contradictory results on the primary outcome measures when compared with anterior lumbar circumferential fusion. High quality randomized controlled trials with relevant control group and long-term follow-up is needed to evaluate the effectiveness and safety of TDR