Afatinib in the first-line treatment of patients with non-small cell lung cancer: clinical evidence and experience

Epidermal growth factor receptor (EGFR) gene mutations identify a molecularly defined subset of non-small cell lung cancer (NSCLC) patients who display an excellent sensitivity to EGFR tyrosine kinase inhibitors (TKIs). First-generation reversible EGFR TKIs, gefitinib and erlotinib have been proven to improve the objective response rate and to prolong the progression-free survival compared with standard chemotherapy in large phase III trials. Unfortunately, virtually all patients develop resistance to treatment, usually within 9–12 months. Afatinib is an irreversible ErbB family inhibitor initially designed to overcome the development of resistance. Compared with gefitinib in a first-line setting, afatinib prolonged progression-free survival and time to treatment failure, without impacting on overall survival in the general population of EGFR-mutant patients. However, afatinib has been shown to prolong overall survival in the subset of patients with an EGFR exon 19 deletion compared with chemotherapy. The aim of this review is to summarize the clinical evidence available to date and to critically discuss the place in therapy of afatinib in the rapidly expanding landscape of EGFR-mutant NSCLC first-line therapy

FROM 3D SURVEYING DATA TO BIM TO BEM: THE INCUBE DATASET

In recent years, the improvement of sensors and methodologies for 3D reality-based surveying has exponentially enhanced the possibility of creating digital replicas of the real world. LiDAR technologies and photogrammetry are currently standard approaches for collecting 3D geometric information of indoor and outdoor environments at different scales. This information can potentially be part of a broader processing workflow that, starting from 3D surveyed data and through Building Information Models (BIM) generation, leads to more complex analyses of buildings’ features and behavior (Figure 1). However, creating BIM models, especially of historic and heritage assets (HBIM), is still resource-intensive and time-consuming due to the manual efforts required for data creation and enrichment. Improve 3D data processing, interoperability, and the automation of the BIM generation process are some of the trending research topics, and benchmark datasets are extremely helpful in evaluating newly developed algorithms and methodologies for these scopes. This paper introduces the InCUBE dataset, resulting from the activities of the recently funded EU InCUBE project, focused on unlocking the EU building renovation through integrated strategies and processes for efficient built-environment management (including the use of innovative renewable energy technologies and digitalization). The set of data collects raw and processed data produced for the Italian demo site in the Santa Chiara district of Trento (Italy). The diversity of the shared data enables multiple possible uses, investigations and developments, and some of them are presented in this contribution

Osimertinib in patients with advanced epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer: Rationale, evidence and place in therapy

The identification of epidermal growth factor receptor (EGFR) mutations represented a fundamental step forward in the treatment of advanced non-small cell lung cancer (NSCLC) as they define a subset of patients who benefit from the administration of specifically designed targeted therapies. The inhibition of mutant EGFR through EGFR-tyrosine kinase inhibitors (TKIs), either reversible, first-generation gefitinib and erlotinib, or irreversible, second-generation afatinib, has dramatically improved the prognosis of patients harboring this specific genetic alteration, leading to unexpected clinical benefit. Unfortunately, virtually all patients who initially respond to treatment develop acquired resistance to EGFR-TKIs within 9-14 months. The EGFR T790M secondary mutation has emerged as a cause of treatment failure in approximately 60% of resistant cases. To date, several compounds designed with the aim to overcome T790M-mediated resistance are under clinical investigation. The aim of this review is to discuss emerging data regarding the third-generation EGFR-TKI, osimertinib, for the treatment of EGFR T790M mutant advanced NSCLC

Androgen-deprivation therapy and SARS-Cov-2 infection: the potential double-face role of testosterone

To analyze possible effect of androgen deprivation therapy in preventing SARS-Cov-2 infection and respiratory complication

Transcriptional Regulation of Sorghum Stem Composition : Key Players Identified Through Co-expression Gene Network and Comparative Genomics Analyses

Most sorghum biomass accumulates in stem secondary cell walls (SCW). As sorghum stems are used as raw materials for various purposes such as feed, energy and fiber reinforced polymers, identifying the genes responsible for SCW establishment is highly important. Taking advantage of studies performed in model species, most of the structural genes contributing at the molecular level to the SCW biosynthesis in sorghum have been proposed while their regulatory factors have mostly not been determined. Validation of the role of several MYB and NAC transcription factors in SCW regulation in Arabidopsis and a few other species has been provided. In this study, we contributed to the recent efforts made in grasses to uncover the mechanisms underlying SCW establishment. We reported updated phylogenies of NAC and MYB in 9 different species and exploited findings from other species to highlight candidate regulators of SCW in sorghum. We acquired expression data during sorghum internode development and used co-expression analyses to determine groups of co-expressed genes that are likely to be involved in SCW establishment. We were able to identify two groups of co-expressed genes presenting multiple evidences of involvement in SCW building. Gene enrichment analysis of MYB and NAC genes provided evidence that while NAC SECONDARY WALL THICKENING PROMOTING FACTOR NST genes and SECONDARY WALL-ASSOCIATED NAC DOMAIN PROTEIN gene functions appear to be conserved in sorghum, NAC master regulators of SCW in sorghum may not be as tissue compartmentalized as in Arabidopsis. We showed that for every homolog of the key SCW MYB in Arabidopsis, a similar role is expected for sorghum. In addition, we unveiled sorghum MYB and NAC that have not been identified to date as being involved in cell wall regulation. Although specific validation of the MYB and NAC genes uncovered in this study is needed, we provide a network of sorghum genes involved in SCW both at the structural and regulatory levels

Which factors can influence post-operative renal function preservation after nephron-sparing surgery for kidney cancer: a critical review

Introduction: The aim of this article was to compare different surgical approaches to perform nephron-sparing surgery (NSS) in terms of preservation of renal function. Material and methods: We critically reviewed the literature from January 2000 to December 2020 including studies comparing different surgical techniques. Results: A total of 51 studies met the inclusion criteria. Functional outcomes were evalutated in terms of percentual change of estimated glomerular filtration rate (eGFR) and impaired renal function (IRF) on scintigraphy. In cases with a mean age <60 years, the mean decrease in eGFR after NSS was 11.7% and that of IRF 10.0%, whereas higher changes were found in cases with a mean age ≥60 years. For open NSS, the mean eGFR and IRF changes were 15.3% and 21.1%, respectively; using the laparoscopic approach, the mean percentual eGFR and IRF changes were 13.9% and 11.1%, respectively; in robotic cases, the mean eGFR and IRF changes were 10.8% and 13.1%, respectively. In cases performed with global ischemia, the mean eGFR and IRF changes were 12.7% and 15.1%, respectively. Similar results were found distinguishing ischemia time ≤20 and >20 minutes, whereas using the off-clamp technique the mean decreases in eGFR and IRF were only 4.2% and 6%, respectively. Conclusions: Patients' age, tumor size, off-clamp technique, and robot-assisted approach were significant independent predictive factors able to influence renal function changes after NSS. A lower reduction of eGFR and IRF after NSS was reported in patients aged <60 years, submitted to a robot-assisted procedure, and using selective and cold ischemia <20 minutes or an off-clamp technique

Resumption of immune checkpoint inhibitor therapy after immune-mediated colitis

PURPOSE: Immune checkpoint inhibitor (ICI) therapy often is suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the rate of and risk factors for IMDC recurrence after ICI resumption. METHODS: This retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between January 2010 and November 2018. Univariable and multivariable logistic regression analyses assessed the association of clinical covariates and IMDC recurrence. RESULTS: Of the 167 patients in our analysis, 32 resumed an anti-cytotoxic T-cell lymphocyte-4 (CTLA-4) agent, and 135 an anti-programmed cell death 1 or ligand 1 (PD-1/L1) agent. The median age was 60 years (interquartile range [IQR], 50-69 years). The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136 days). IMDC recurred in 57 patients (34%) overall (44% of those receiving an anti-CTLA-4 and 32% of those receiving an anti-PD-1/L1); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC, and all required permanent discontinuation of ICI therapy. The median duration from ICI resumption to IMDC recurrence was 53 days (IQR, 22-138 days). On multivariable logistic regression, patients who received anti-PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45; 95% CI, 1.59 to 7.69; P = .002). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95% CI, 1.08 to 9.62; P = .019) or had a longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95% CI, 1.00 to 1.03; P = .031). Risk of IMDC recurrence was lower after resumption of anti-PD-1/L1 therapy than after resumption of anti-CTLA-4 therapy (OR, 0.30; 95% CI, 0.11 to 0.81; P = .019). CONCLUSION: One third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. Recurrence of IMDC was less frequent after resumption of anti-PD-1/L1 than after resumption of anti-CTLA-4

Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis

PURPOSE: Immune checkpoint inhibitor (ICI) therapy often is suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the rate of and risk factors for IMDC recurrence after ICI resumption. METHODS: This retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between January 2010 and November 2018. Univariable and multivariable logistic regression analyses assessed the association of clinical covariates and IMDC recurrence. RESULTS: Of the 167 patients in our analysis, 32 resumed an anti–cytotoxic T-cell lymphocyte-4 (CTLA-4) agent, and 135 an anti–programmed cell death 1 or ligand 1 (PD-1/L1) agent. The median age was 60 years (interquartile range [IQR], 50-69 years). The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136 days). IMDC recurred in 57 patients (34%) overall (44% of those receiving an anti–CTLA-4 and 32% of those receiving an anti–PD-1/L1); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC, and all required permanent discontinuation of ICI therapy. The median duration from ICI resumption to IMDC recurrence was 53 days (IQR, 22-138 days). On multivariable logistic regression, patients who received anti–PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45; 95% CI, 1.59 to 7.69; P = .002). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95% CI, 1.08 to 9.62; P = .019) or had a longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95% CI, 1.00 to 1.03; P = .031). Risk of IMDC recurrence was lower after resumption of anti–PD-1/L1 therapy than after resumption of anti–CTLA-4 therapy (OR, 0.30; 95% CI, 0.11 to 0.81; P = .019). CONCLUSION: One third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. Recurrence of IMDC was less frequent after resumption of anti–PD-1/L1 than after resumption of anti–CTLA-

Characteristics of Sepsis or Acute Pyelonephritis Combined with Ureteral Stone in the United States: A Retrospective Analysis of Large National Cohort

To identify the characteristics of patients with sepsis or acute pyelonephritis (APN) combined with ureteral calculi and to analyze the risk factors in its causation. Methods: We included patients with sepsis or APN caused by ureteral calculi who received treatment in the United States from January 2003 to December 2017 using the Optum® deidentified Clinformatics® Datamart. Demographic factors and risk factors for the receipt of sepsis or APN were subsequently analyzed for statistical significance. Results: Of 467,502 urinary stone patients, age-matched multivariate analysis revealed that a history of urinary tract infection (OR 11.31, 95% CI 10.68–11.99, p < 0.0001) and female gender (OR 2.73, 95% CI 2.62–2.84, p < 0.0001) were significantly related to an increased risk of sepsis or APN. Conversely, a previous past medical history of urolithiasis (OR 0.91, 95% CI 0.87–0.95, p < 0.0001) and cancer (OR 0.91, 95% CI 0.87–0.95, p < 0.0001) were associated with a decreased risk of sepsis or APN. With regards to comorbidities, when more than one comorbidity was present, there was an additive effect with higher OR point estimates, rising to 11.31 (10.68–11.99) when three or more comorbidities present. History of urinary tract infection and female gender are risk factors for sepsis or APN in patients with ureteral calculi. Conclusions: This large national cohort reveals the characteristics of sepsis or APN combined with ureteral stone and provides an important baseline for the treatment of urolithiasis in the future

Female heterozygotes for the hypomorphic R40H mutation can have ornithine transcarbamylase deficiency and present in early adolescence: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Ornithine transcarbamylase deficiency is the most common hereditary urea cycle defect. It is inherited in an X-linked manner and classically presents in neonates with encephalopathy and hyperammonemia in males. Females and males with hypomorphic mutations present later, sometimes in adulthood, with episodes that are frequently fatal.</p> <p>Case presentation</p> <p>A 13-year-old Caucasian girl presented with progressive encephalopathy, hyperammonemic coma and lactic acidosis. She had a history of intermittent regular episodes of nausea and vomiting from seven years of age, previously diagnosed as abdominal migraines. At presentation she was hyperammonemic (ammonia 477 μmol/L) with no other biochemical indicators of hepatic dysfunction or damage and had grossly elevated urinary orotate (orotate/creatinine ratio 1.866 μmol/mmol creatinine, reference range <500 μmol/mmol creatinine) highly suggestive of ornithine transcarbamylase deficiency. She was treated with intravenous sodium benzoate and arginine and made a rapid full recovery. She was discharged on a protein-restricted diet. She has not required ongoing treatment with arginine, and baseline ammonia and serum amino acid concentrations are within normal ranges. She has had one further episode of hyperammonemia associated with intercurrent infection after one year of follow up. An R40H (c.119G>A) mutation was identified in the ornithine transcarbamylase gene (<it>OTC</it>) in our patient confirming the first symptomatic female shown heterozygous for the R40H mutation. A review of the literature and correspondence with authors of patients with the R40H mutation identified one other symptomatic female patient who died of hyperammonemic coma in her late teens.</p> <p>Conclusions</p> <p>This report expands the clinical spectrum of presentation of ornithine transcarbamylase deficiency to female heterozygotes for the hypomorphic R40H <it>OTC </it>mutation. Although this mutation is usually associated with a mild phenotype, females with this mutation can present with acute decompensation, which can be fatal. Ornithine transcarbamylase deficiency should be considered in the differential diagnosis of unexplained acute confusion, even without a suggestive family history.</p