Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer.

BACKGROUND: Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and CD3, showed promising antitumor activity in a phase 1 trial in patients with previously treated small-cell lung cancer. METHODS: In this phase 2 trial, we evaluated the antitumor activity and safety of tarlatamab, administered intravenously every 2 weeks at a dose of 10 mg or 100 mg, in patients with previously treated small-cell lung cancer. The primary end point was objective response (complete or partial response), as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Overall, 220 patients received tarlatamab; patients had previously received a median of two lines of treatment. Among patients evaluated for antitumor activity and survival, the median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% (97.5% confidence interval [CI], 29 to 52) of the patients in the 10-mg group and in 32% (97.5% CI, 21 to 44) of those in the 100-mg group. Among patients with an objective response, the duration of response was at least 6 months in 59% (40 of 68 patients). Objective responses at the time of data cutoff were ongoing in 22 of 40 patients (55%) in the 10-mg group and in 16 of 28 patients (57%) in the 100-mg group. The median progression-free survival was 4.9 months (95% CI, 2.9 to 6.7) in the 10-mg group and 3.9 months (95% CI, 2.6 to 4.4) in the 100-mg group; the estimates of overall survival at 9 months were 68% and 66% of patients, respectively. The most common adverse events were cytokine-release syndrome (in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group), decreased appetite (in 29% and 44%, respectively), and pyrexia (in 35% and 33%). Cytokine-release syndrome occurred primarily during treatment cycle 1, and events in most of the patients were grade 1 or 2 in severity. Grade 3 cytokine-release syndrome occurred less frequently in the 10-mg group (in 1% of the patients) than in the 100-mg group (in 6%). A low percentage of patients (3%) discontinued tarlatamab because of treatment-related adverse events. CONCLUSIONS: Tarlatamab, administered as a 10-mg dose every 2 weeks, showed antitumor activity with durable objective responses and promising survival outcomes in patients with previously treated small-cell lung cancer. No new safety signals were identified. (Funded by Amgen; DeLLphi-301 ClinicalTrials.gov number, NCT05060016.).

FAMetA: a mass isotopologue-based tool for the comprehensive analysis of fatty acid metabolism.

The use of stable isotope tracers and mass spectrometry (MS) is the gold standard method for the analysis of fatty acid (FA) metabolism. Yet, current state-of-the-art tools provide limited and difficult-to-interpret information about FA biosynthetic routes. Here we present FAMetA, an R package and a web-based application (www.fameta.es) that uses 13C mass isotopologue profiles to estimate FA import, de novo lipogenesis, elongation and desaturation in a user-friendly platform. The FAMetA workflow covers the required functionalities needed for MS data analyses. To illustrate its utility, different in vitro and in vivo experimental settings are used in which FA metabolism is modified. Thanks to the comprehensive characterization of FA biosynthesis and the easy-to-interpret graphical representations compared to previous tools, FAMetA discloses unnoticed insights into how cells reprogram their FA metabolism and, when combined with FASN, SCD1 and FADS2 inhibitors, it enables the identification of new FAs by the metabolic reconstruction of their synthesis route.

Outpatient Surgery and Unplanned Overnight Admission in Bilateral Inguinal Hernia Repair: A Population-based Study.

PURPOSE: The use of outpatient surgery in inguinal hernia is heterogeneous despite clinical recommendations. This study aimed to analyze the utilization trend of outpatient surgery for bilateral inguinal hernia repair (BHIR) in Spain and identify the factors associated with outpatient surgery choice and unplanned overnight admission. METHODS: A retrospective observational study of patients undergoing BIHR from 2016 to 2021 was conducted. The clinical-administrative database of the Spanish Ministry of Health RAE-CMBD was used. Patient characteristics undergoing outpatient and inpatient surgery were compared. A multivariable logistic regression analysis was performed to identify factors associated with outpatient surgery choice and unplanned overnight admission. RESULTS: A total of 30,940 RHIBs were performed; 63% were inpatient surgery, and 37% were outpatient surgery. The rate of outpatient surgery increased from 30% in 2016 to 41% in 2021 (p < 0.001). Higher rates of outpatient surgery were observed across hospitals with a higher number of cases per year (p < 0.001). Factors associated with outpatient surgery choice were: age under 65 years (OR: 2.01, 95% CI: 1.92-2.11), hospital volume (OR: 1.59, 95% CI: 1.47-1.72), primary hernia (OR: 1.89, 95% CI: 1.71-2.08), and laparoscopic surgery (OR: 1.47, 95% CI: 1.39-1.56). Comorbidities were negatively associated with outpatient surgery. Open surgery was associated (OR: 1.26, 95% CI: 1.09-1.47) with unplanned overnight admission. CONCLUSIONS: Outpatient surgery for BHIR has increased in recent years but is still low. Older age and comorbidities were associated with lower rates of outpatient surgery. However, the laparoscopic repair was associated with increased outpatient surgery and lower unplanned overnight admission.

Long Non-Coding RNAs and Alzheimer's Disease: Towards Personalized Diagnosis.

Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive cognitive decline, is the most common form of dementia. Currently, there is no single test that can diagnose AD, especially in understudied populations and developing countries. Instead, diagnosis is based on a combination of medical history, physical examination, cognitive testing, and brain imaging. Exosomes are extracellular nanovesicles, primarily composed of RNA, that participate in physiological processes related to AD pathogenesis such as cell proliferation, immune response, and neuronal and cardiovascular function. However, the identification and understanding of the potential role of long non-coding RNAs (lncRNAs) in AD diagnosis remain largely unexplored. Here, we clinically, cognitively, and genetically characterized a sample of 15 individuals diagnosed with AD (cases) and 15 controls from Barranquilla, Colombia. Advanced bioinformatics, analytics and Machine Learning (ML) techniques were used to identify lncRNAs differentially expressed between cases and controls. The expression of 28,909 lncRNAs was quantified. Of these, 18 were found to be differentially expressed and harbored in pivotal genes related to AD. Two lncRNAs, ENST00000608936 and ENST00000433747, show promise as diagnostic markers for AD, with ML models achieving > 95% sensitivity, specificity, and accuracy in both the training and testing datasets. These findings suggest that the expression profiles of lncRNAs could significantly contribute to advancing personalized AD diagnosis in this community, offering promising avenues for early detection and follow-up.

Bilateral inguinal hernia repair by laparoscopic totally extraperitoneal (TEP) vs. laparoscopic transabdominal preperitoneal (TAPP).

BACKGROUND: The guidelines recommend laparoscopic repair for bilateral inguinal hernia. However, few studies compare the totally extraperitoneal (TEP) and transabdominal preperitoneal (TAPP) techniques in bilateral inguinal hernias. This study aimed to compare the outcomes of TEP and TAPP in bilateral inguinal hernia. METHODS: We conducted a retrospective cohort study of patients operated on for bilateral inguinal hernia by TEP and TAPP repair from 2016 to 2020. Intraoperative complications, operative time, acute postoperative pain, hospital stay, postoperative complications, chronic inguinal pain, and recurrence were compared. RESULTS: A total of 155 patients were included in the study. TEP was performed in 71 patients (46%) and TAPP in 84 patients (54%). The mean operative time was longer in the TAPP group than in the TEP group (107 min vs. 82 min, p < 0.001). The conversion rate to open surgery was higher in the TEP group than in the TAPP group (8.5% vs. 0%, p = 0.008). The mean hospital stay was longer in the TAPP group than in the TEP group (p < 0.001). We did not observe significant differences in the proportion of postoperative complications (p = 0.672), postoperative pain at 24 h (p = 0.851), chronic groin pain (p = 0.593), and recurrence (p = 0.471). We did not observe an association between the choice of surgical technique (TEP vs. TAPP) with conversion rate, operative time, hospital stay, postoperative complications, chronic inguinal pain, or hernia recurrence when performing a multivariable analysis adjusted for the male sex, age, BMI, ASA, recurrent hernia repair, surgeon, and hernia size > 3cm. CONCLUSIONS: Bilateral inguinal hernia repair by TEP and TAP presented similar outcomes in our study.

The role of specialist nurses in detecting spasticity and related symptoms in multiple sclerosis.

BACKGROUND: Spasticity is a frequent symptom of multiple sclerosis (MS), which may negatively influence daily living activities (ADL). OBJECTIVES: To (1) explore the feasibility to conduct a structured interview by specialist nurses about limitations in ADL; (2) determine the percentage of people with MS (PwMS) with limitations in ADL related to spasticity; (3) to assess the knowledge about spasticity and describe its clinical features. DESIGN: Observational, cross-sectional, multicentre study in 16 MS units of Catalonia (Spain). Participants were recruited from the outpatient facility and day-care hospital between July 2018 and June 2019 and met the following criteria: (1) age 18 or older, (2) diagnosis of MS according to McDonald criteria 2010 and (3) no clinical relapse in previous 30 days. METHODS: Specialist nurses conducted a structured interview divided in two parts: the assessment of (1) limitations in the ADL and (2) the presence of spasticity and associated symptoms. The usefulness of this intervention was requested. This study met the STROBE reporting guidelines checklist for observational studies. RESULTS: Three hundred sixty eight pwMS (244 women) with a mean age of 46 years and a median Expanded Disability Status Scale score of 2.5 (range, 0-8.5) were included. 262 (71%) pwMS had limitations in the ADL, and spasticity was reported as the most limiting symptom in 59 (23%). As a result of the interview, spasticity was observed in 199 (76%) participants; 47 (24%) of them were unaware that they had spasticity and 102 (51%) would not have reported it spontaneously. The level of the interview satisfaction was high (90%). CONCLUSIONS: Spasticity is a complex and limiting symptom in MS. The structured interview conducted by specialist nurses is feasible and has good acceptance. PATIENT CONTRIBUTION: Specialist nurses can be proactive in MS clinical assessment, which may help to detect symptoms with negative impact on quality of life.

RESILIENT part 1: a phase 2 dose-exploration and dose-expansion study of second-line liposomal irinotecan in adults with small cell lung cancer.

BACKGROUND: RESILIENT (NCT03088813) is a phase 2/3 study assessing the safety, tolerability, and efficacy of liposomal irinotecan monotherapy in patients with small cell lung cancer and disease progression on/after first-line platinum-based therapy. Here, we present results from RESILIENT part 1. METHODS: This open-label, single-arm, safety run-in evaluation with dose-exploration and dose-expansion phases included patients ≥18 years old with Eastern Cooperative Oncology Group performance status of 0/1; those with asymptomatic central nervous system metastases were eligible. The primary objectives were to evaluate safety and tolerability and recommend a dose for further development. Efficacy end points were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: During dose exploration, 5 patients received intravenous liposomal irinotecan at 85 mg/m2 (deemed not tolerable; dose-limiting toxicity) and 12 patients received 70 mg/m2 (deemed tolerable). During dose expansion, 13 additional patients received intravenous liposomal irinotecan at 70 mg/m2 . Of these 25 patients (median age [range], 59.0 [48.0-73.0] years, 92.0% with metastatic disease), 10 experienced grade ≥3 treatment-related treatment-emergent adverse events (TEAEs), most commonly diarrhea (20.0%) and neutropenia (16.0%), and 3 had serious treatment-related TEAEs, of whom 2 died. ORR was 44.0% (95% confidence interval [CI]: 24.40-65.07; 1 complete response, 10 partial responses) and median (95% CI) PFS and OS were 3.98 (1.45-4.24) months and 8.08 (5.16-9.82) months, respectively. CONCLUSION: Overall, no new safety signals were identified with liposomal irinotecan, and antitumor activity was promising. RESILIENT part 2, a randomized, controlled, phase 3 study of liposomal irinotecan versus topotecan, is ongoing. LAY SUMMARY: Small cell lung cancer (SCLC) is an aggressive disease with few treatment options after platinum-based therapy. Administering 1 option, irinotecan, as a "liposomal" formulation, may extend drug exposure and improve outcomes. The RESILIENT part 1 trial assessed the safety and efficacy of liposomal irinotecan in 25 adults with SCLC after disease progression despite platinum-based therapy. No new safety concerns were reported. The most common moderate-to-severe side effects were diarrhea (20% of patients) and neutropenia (16%). Tumors responded to treatment in 44% of patients. Average survival was 8.08 months, and time to disease progression was 3.98 months. Liposomal irinotecan trials are ongoing.

Determination of essential biomarkers in lung cancer: a real-world data study in Spain with demographic, clinical, epidemiological and pathological characteristics.

BACKGROUND: The survival of patients with lung cancer has substantially increased in the last decade by about 15%. This increase is, basically, due to targeted therapies available for advanced stages and the emergence of immunotherapy itself. This work aims to study the situation of biomarker testing in Spain. PATIENTS AND METHODS: The Thoracic Tumours Registry (TTR) is an observational, prospective, registry-based study that included patients diagnosed with lung cancer and other thoracic tumours, from September 2016 to 2020. This TTR study was sponsored by the Spanish Lung Cancer Group (GECP) Foundation, an independent, scientific, multidisciplinary oncology society that coordinates more than 550 experts and 182 hospitals across the Spanish territory. RESULTS: Nine thousand two hundred thirty-nine patients diagnosed with stage IV non-small cell lung cancer (NSCLC) between 2106 and 2020 were analysed. 7,467 (80.8%) were non-squamous and 1,772 (19.2%) were squamous. Tumour marker testing was performed in 85.0% of patients with non-squamous tumours vs 56.3% in those with squamous tumours (p-value < 0.001). The global testing of EGFR, ALK, and ROS1 was 78.9, 64.7, 35.6% respectively, in non-squamous histology. PDL1 was determined globally in the same period (46.9%), although if we focus on the last 3 years it exceeds 85%. There has been a significant increase in the last few years of all determinations and there are even close to 10% of molecular determinations that do not yet have targeted drug approval but will have it in the near future. 4,115 cases had a positive result (44.5%) for either EGFR, ALK, KRAS, BRAF, ROS1, or high PDL1. CONCLUSIONS: Despite the lack of a national project and standard protocol in Spain that regulates the determination of biomarkers, the situation is similar to other European countries. Given the growing number of different determinations and their high positivity, national strategies are urgently needed to implement next-generation sequencing (NGS) in an integrated and cost-effective way in lung cancer.

In vitro biological activity of extracts from marine bacteria cultures against Toxoplasma gondii and Mycobacterium tuberculosis.

AIMS: To evaluate the biological activity of extracts from cultures of marine bacteria against Toxoplasma gondii and Mycobacterium tuberculosis. METHODS AND RESULTS: Ethyl acetate extracts obtained from seven marine bacteria were tested against T. gondii GFP-RH and M. tuberculosis H37Rv. The cytotoxicity on HFF-1 cells was measured by a microplate resazurin fluorescent approach, and the haemolytic activity was determined photometrically. The extracts from Bacillus sp. (INV FIR35 and INV FIR48) affected the tachyzoite viability. The extracts from Bacillus, Pseudoalteromonas, Streptomyces and Micromonospora exhibited effects on infection and proliferation processes of parasite. Bacillus sp. INV FIR48 extract showed an minimum inhibitory concentration value of 50 µg ml-1 against M. tuberculosis H37Rv. All the extracts exhibited relatively low toxicity to HFF-1 cells and the primary culture of erythrocytes, except Bacillus sp. INV FIR35, which decreased cell viability under 20%. Liquid chromatography coupled to mass spectrometry analysis of the most active bacterial extract Bacillus sp. INV FIR48 showed the presence of peptide metabolites related to surfactin. CONCLUSIONS: The extract from culture of deep-sea Bacillus sp. INV FIR48 showed anti-T. gondii and anti-tuberculosis (TB) biological activity with low cytotoxicity. In addition, peptide metabolites were detected in the extract. SIGNIFICANCE AND IMPACT OF THE STUDY: Toxoplasmosis and TB are among the most prevalent diseases worldwide, and the current treatment drugs exhibit side effects. This study confirm that marine bacteria are on hand sources of anti-infective natural products.

Synthesis, Anticancer and Antitubercular Properties of New Chalcones and Their Nitrogen-Containing Five-Membered Heterocyclic Hybrids Bearing Sulfonamide Moiety.

A new series of sulfonamides, 8a-b, 10, 12, and 14a-b, were synthesized by N-sulfonation reaction with sulfonyl chlorides 6a-b. Five new series of chalcone-sulfonamide hybrids (16-20)a-f were prepared via Claisen-Schmidt condensation of the newly obtained sulfonamides with aromatic aldehydes 15a-f in basic medium. Chalcones substituted with chlorine at position 4 of each series were used as precursors for the generation of their five-membered heterocyclic pyrazoline (22-23)a-d, (24-25)a-b and carbothioamide 27a-f derivatives. The synthesized compounds were evaluated for their anticancer and antituberculosis activities. To determine their anticancer activity, compounds were screened against sixty human cancer cell lines at a single dose (10 µM). Compounds 17a-c were highly active against LOX IMVI (melanoma), with IC50 values of 0.34, 0.73 and 0.54 µM, respectively. Chalcone 18e showed remarkable results against the entire panel of leukemia cell lines with IC50 values between 0.99-2.52 µM. Moreover, compounds 20e and 20f displayed growth inhibition of Mycobacterium tuberculosis H37Rv at concentrations below 10 µM. Although they showed low selectivity in cytotoxicity tests against the Vero cell line, further optimization could advance the potential biological activity of the selected compounds.

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial.

BACKGROUND: First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to investigate whether the addition of a limited course (two cycles) of chemotherapy to this combination would further enhance the clinical benefit. METHODS: This randomised, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomisation was stratified by tumour histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analysed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis. This study is active but no longer recruiting patients, and is registered with ClinicalTrials.gov, number NCT03215706. FINDINGS: Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358 [50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR 6·4-12·8]), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2-16·2] vs 10·7 months [9·5-12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55-0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months [IQR 6·4-17·0]), median overall survival was 15·6 months (95% CI 13·9-20·0) in the experimental group versus 10·9 months (9·5-12·6) in the control group (HR 0·66 [95% CI 0·55-0·80]). The most common grade 3-4 treatment-related adverse events were neutropenia (in 24 [7%] patients in the experimental group vs 32 [9%] in the control group), anaemia (21 [6%] vs 50 [14%]), diarrhoea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three [1%]), and asthenia (tjree [1%] vs eight [2%]). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anaemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related. INTERPRETATION: Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk-benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC. FUNDING: Bristol Myers Squibb.

Prognostic model of long-term advanced stage (IIIB-IV) EGFR mutated non-small cell lung cancer (NSCLC) survivors using real-life data.

BACKGROUND: There is a lack of useful diagnostic tools to identify EGFR mutated NSCLC patients with long-term survival. This study develops a prognostic model using real world data to assist clinicians to predict survival beyond 24 months. METHODS: EGFR mutated stage IIIB and IV NSCLC patients diagnosed between January 2009 and December 2017 included in the Spanish Lung Cancer Group (SLCG) thoracic tumor registry. Long-term survival was defined as being alive 24 months after diagnosis. A multivariable prognostic model was carried out using binary logistic regression and internal validation through bootstrapping. A nomogram was developed to facilitate the interpretation and applicability of the model. RESULTS: 505 of the 961 EGFR mutated patients identified in the registry were included, with a median survival of 27.73 months. Factors associated with overall survival longer than 24 months were: being a woman (OR 1.78); absence of the exon 20 insertion mutation (OR 2.77); functional status (ECOG 0-1) (OR 4.92); absence of central nervous system metastases (OR 2.22), absence of liver metastases (OR 1.90) or adrenal involvement (OR 2.35) and low number of metastatic sites (OR 1.22). The model had a good internal validation with a calibration slope equal to 0.781 and discrimination (optimism corrected C-index 0.680). CONCLUSIONS: Survival greater than 24 months can be predicted from six pre-treatment clinicopathological variables. The model has a good discrimination ability. We hypothesized that this model could help the selection of the best treatment sequence in EGFR mutation NSCLC patients.

EDC-induced mechanisms of immunotoxicity: a systematic review.

Endocrine-disrupting chemicals (EDCs) refer to a group of chemicals that cause adverse effects in human health, impairing hormone production and regulation, resulting in alteration of homeostasis, reproductive, and developmental, and immune system impairments. The immunotoxicity of EDCs involves many mechanisms altering gene expression that depend on the activation of nuclear receptors such as the aryl hydrocarbon receptor (AHR), the estrogen receptor (ER), and the peroxisome proliferator-activated receptor (PPAR), which also results in skin and intestinal disorders, microbiota alterations and inflammatory diseases. This systematic review aims to review different mechanisms of immunotoxicity and immunomodulation of T cells, focusing on T regulatory (Treg) and Th17 subsets, B cells, and dendritic cells (DCs) caused by specific EDCs such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), bisphenols (BPs) and polyfluoroalkyl substances (PFASs). To achieve this objective, a systematic study was conducted searching various databases including PubMed and Scopus to find in-vitro, in-vivo, and biomonitoring studies that examine EDC-dependent mechanisms of immunotoxicity. While doing the systematic review, we found species- and cell-specific outcomes and a translational gap between in-vitro and in-vivo experiments. Finally, an adverse outcome pathway (AOP) framework is proposed, which explains mechanistically toxicity endpoints emerging from different EDCs having similar key events and can help to improve our understanding of EDCs mechanisms of immunotoxicity. In conclusion, this review provides insights into the mechanisms of immunotoxicity mediated by EDCs and will help to improve human health risk assessment.

Quality of life with second or third line nab-paclitaxel-based regimens in advanced non-small-cell lung cancer.

Aim: Evaluate quality of life (QoL) in patients with advanced non-small cell lung cancer treated with second or third line nab-paclitaxel ± durvalumab. Patients & methods: Longitudinal QoL was assessed using Lung Cancer Symptom Scale, EuroQoL Five-Dimensions Five-Levels and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core. Results: QoL was generally stable through eight treatment cycles (both arms). Clinically meaningful improvement from baseline was noted in Lung Cancer Symptom Scale (overall constitutional score and three-item index [nab-paclitaxel + durvalumab]) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core (global health status/QoL and emotional functioning [both arms] and pain [nab-paclitaxel + durvalumab]) analyses. EuroQoL Five-Dimensions Five-Levels domains were stable/improved or completely resolved at least once in 19-56% and 9-51% of patients, respectively. Conclusion: While QoL trends were promising, additional data are required to support these regimens in this setting.

Risk factors for open conversion of lateral transperitoneal laparoscopic adrenalectomy: retrospective cohort study of the Spanish Adrenal Surgery Group (SASG).

BACKGROUND: Laparoscopic adrenalectomy has become the standard of care for treating adrenal tumors. Conversion from laparoscopic adrenalectomy to an open approach during surgery may be necessary in some cases. This study aimed to identify the risk factors for open conversion of laparoscopic adrenalectomy. METHODS: Retrospective analysis of all consecutive patients undergoing lateral transperitoneal laparoscopic adrenalectomy in six endocrine surgery units of the Spanish Adrenal Surgery Group (SASG) between January 2005 and December 2017. Demographic, clinical, surgical, and histopathologic characteristics were recorded. Risk factors for conversion were assessed by logistic regression analysis. RESULTS: Of a total of 865 patients included in the study, 58 (6.7%) required conversion to open surgery. In the univariate analysis, factors associated with conversion from laparoscopic to open adrenalectomy were body mass index (BMI) ≥ 30 kg/m2 (P = 0.002), previous abdominal surgery (P = 0.015), tumor size > 5 cm (P = 0.001), and surgery for pheochromocytoma (P = 0.034). In the multivariate analysis, independent risk factors were BMI ≥ 30 kg/m2 [odds ratio (OR) 4.26, 95% confidence interval (CI) 2.81-8.75; P = 0.001], tumor size > 5 cm (OR 10.15, 95% CI 4.24-28.31; P < 0.001), and surgery for pheochromocytoma (OR 2.96, 95% CI 1.89-11.55; P = 0.015). CONCLUSIONS: Obesity, tumor size, and pheochromocytoma as the type of adrenal tumor were predictive factors for intraoperative conversion from laparoscopic to open adrenalectomy. Preoperative assessment of these characteristics should be valuable to clinicians in discussing conversion risk in patients and for surgical planning.

Development of an ontology for laparoscopic transabdominal adrenalectomy via a comprehensive modified Delphi survey and its validation on a multicentric pilot data set for surgical training and future video analysis with machine learning algorithms.

Surgical technique is essential to ensure safe minimally invasive adrenalectomy. Due to the relative rarity of adrenal surgery, it is challenging to ensure adequate exposure in surgical training. Surgical video analysis supports auto-evaluation, expert assessment and could be a target for automatization. The developed ontology was validated by a European expert consensus and is applicable across the surgical techniques encountered in all participating centres, with an exemplary demonstration in bi-centric recordings. Standardization of adrenalectomy video analysis may foster surgical training and enable machine learning training for automated safety alerts.

Volume-outcome correlation in adrenal surgery-an ESES consensus statement.

BACKGROUND: Published data in the last decade showed that a majority of adrenal operations are done by surgeons performing only one such case per year and based on the distribution of personal workloads 'high-volume' surgeons are defined as those doing 4 or more cases/year. PURPOSE: This paper summarises literature data identified by a working group established by the European Society of Endocrine Surgeons (ESES). The findings were discussed during ESES-2019 conference and members agreed on a consensus statement. RESULTS: The annual of adrenal operations performed yearly in individual countries was reported to be 800/year in UK and over 1600/year in France. The learning curve of an individual surgeon undertaking laparoscopic, retroperitoneoscopic or robotic adrenalectomy is estimated to be 20-40 cases. Preoperative morbidity and length of stay are more favourable in high-volume centres. CONCLUSION: The main recommendations are that adrenal surgery should continue only in centres performing at least 6 cases per year, surgery for adrenocortical cancer should be restricted to centres performing at least 12 adrenal operations per year, and an integrated multidisciplinary team should be established in all such centres. Clinical information regarding adrenalectomies should be recorded prospectively and contribution to the established EUROCRINE and ENSAT databases is strongly encouraged. Surgeons wishing to develop expertise in this field should seek mentorship and further training from established adrenal surgeons.

ABOUND.2L+: A randomized phase 2 study of nanoparticle albumin-bound paclitaxel with or without CC-486 as second-line treatment for advanced nonsquamous non-small cell lung cancer (NSCLC).

BACKGROUND: This randomized phase 2 trial compared the efficacy and safety of second-line nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without the addition of CC-486 (an oral formulation of 5-azacytidine) in patients with advanced-stage, nonsquamous non-small cell lung cancer. METHODS: Patients were randomized to receive either nab-paclitaxel 100 mg/m2 on days 8 and 15 plus CC-486 200 mg daily on days 1 to 14 or single-agent nab-paclitaxel 100 mg/m2 on days 1 and 8, with both regimens administered every 21 days until tumor progression or unacceptable toxicity. The primary endpoint was progression-free survival. Secondary endpoints included the overall response rate, the disease control rate, and overall survival. RESULTS: Between January 2015 and August 2016, 161 patients were randomized (81 to the combination arm and 80 to the single-agent nab-paclitaxel arm). There was no benefit from the addition of CC-486 to nab-paclitaxel. The median progression-free survival was 3.2 months for the combination and 4.2 months for single-agent nab-paclitaxel (hazard ratio, 1.3; 95% confidence interval, 0.9-1.9). The median overall survival was 8.1 months in the combination arm and 17 months in the single-agent nab-paclitaxel arms (hazard ratio, 1.7; 95% confidence interval, 1.08-2.57). Grade 3 or greater treatment-related, emergent adverse events were reported by 40.5% of patients in the combination arm and by 31.6% of those in the single-agent nab-paclitaxel arm. CONCLUSIONS: Single-agent nab-paclitaxel was associated with promising outcomes and a tolerable safety profile as second-line treatment for patients with advanced-stage, nonsquamous non-small cell lung cancer. There was no benefit from the addition of CC-486 to nab-paclitaxel.

Translational evidence of prothrombotic and inflammatory endothelial damage in Cushing syndrome after remission.

OBJECTIVE: Sustained evidence from observational studies indicates that after remission of Cushing syndrome (CS) a cardiovascular risk phenotype persists. Here, we performed a translational study in active CS and CS in remission (RCS) to evaluate the subclinical cardiometabolic burden and to explore the direct pro-inflammatory and prothrombotic potential of their sera on the endothelium in an in vitro translational atherothrombotic cell model. PATIENTS: Cross sectional study. The groups were (n = 9/group): I. RCS; II. Active CS (ACS) and III. Controls (CTR), all matched for age, body mass index, sex, without other hormonal deficits. DESIGN: We evaluated in vivo: cardiometabolic profile; endothelial markers (sVCAM-1, NO); endothelial dysfunction (FMD); intima-media thickness and body composition (DEXA). In vitro endothelial cells (EC) were exposed to sera taken from the different subjects to evaluate inflammatory EC response (tisVCAM) and thrombogenicity of the generated extracellular matrix (ECM): von Willebrand factor (VWF) and platelet reactivity. RESULTS: Three of the 9 RCS subjects were on glucocorticoid replacement therapy (GC-RT). Patients on GC-RT had a shorter period of time in stable remission. In vivo analysis ACS showed typically metabolic features, while cardiometabolic markers reached statistical significance for RCS only for Hs-CRP (P < .01). In vitro:EC exposed to ACS and RCS sera displayed increased tisVCAM-1 (P < .01 for ACS and P < .05 for RCS vs CTR), VWF (P < .01 for ACS and P < .05 for RCS vs CTR) and platelet adhesion on ECM (P < .01 for ACC and P < .05 for RCS vs CTR). No statistically significant differences were observed between GC-RT RSC and RCS without GC-RT. CONCLUSIONS: The sera of premenopausal women with CS in remission, without atherothrombotic disease, contain circulatory endothelial deleterious factors with a direct thrombogenic and pro-inflammatory endothelial effect that could increase cardiovascular risk.

Geriatric assessment in clinical practice for patients with stage IV non-small-cell lung cancer: The Grup de Investigació I Divulgació Oncològica experience.

Therapeutic decision-making for older patients with stage IV non-small-cell lung cancer (NSCLC) with no identifiable activating mutation is complex. In this prospective study, we evaluated the usefulness of geriatric assessment (GA) in identifying frail patients. Stage IV NSCLC patients ≥70 years of age were evaluated with GA and classified according to this evaluation into three different groups: fit, vulnerable and frail. Classifications based on GA, treatment decision, toxicity and overall survival were analysed. In total, 93 patients were included. Median age was 76 (70-92) years and 90% were men. Most patients had performance status (PS) 0 or 1 (82%), unrelated to their GA (p = 0.006). GA groups were associated with overall survival (p = 0.000), treatment decision (p = 0.0001), and toxicity (p = 0.0001). Chemotherapy was delivered to 100% of fit patients, to 48% of vulnerable patients, and to only 8% of frail patients (p = 0.000). Toxicity was higher in vulnerable patients than in fit individuals (p = 0.000). Multivariable analysis showed PS (p = 0.001), active treatment (p < 0.001) and GA group (p = 0.001) to be prognostic factors related to survival. Our results suggest that GA identified patients with poor natural prognosis.