New generation anaplastic lymphoma kinase inhibitors

Anaplastic lymphoma kinase (ALK) gene translocations are pro-tumoral driver alterations that encompass 3*7% of non-squamous non-small cell lung cancer (NSCLC) with specific, clinic and histologic features. The therapeutic strategy depends on anti-ALK tyrosine kinase inhibitors (TKIs) of which crizotinib was the first approved for clinical use. Despite its use improved significantly progression-free survival, overall response rate and duration of response of this illness, after a median period of 10.9 months all patients progress due to the development of acquired resistance mutations in the ALK tyrosine kinase domain in approximately one third of patients. Moreover, 60-90% of patients treated with crizotinib has a progression in the central nervous system (CNS) in absence of extracranial worsening of the disease. This is primarily attributed to poor CNS penetration by crizotinib as many pre-clinical and clinical models suggest. For instance, in order to overtake acquired resistance to crizotinib, prolong the control of the disease and manage CNS localizations, several II and III generation TKIs have been developed. Some of them were approved after the failure of crizotinib (ceritinib, alectinib, brigatinib and lorlatinib) and in first line setting (ceritinib, alectinib and brigatinib) while others are still under evaluation for TKI-naive patients such as lorlatinib, ensartinib and entrectinib. In this review we will discuss the most recent results of new TKIs in order to describe a fast growing therapeutic landscape in this setting

Endoscopic ultrasound fine-needle biopsy vs fine-needle aspiration for lymph nodes tissue acquisition: A systematic review and meta-Analysis

Background: Endoscopic ultrasound (EUS)-guided tissue acquisition represents the choice of methods for suspected lymph nodes (LNs) located next to the gastrointestinal tract. This study aimed to compare the pooled diagnostic performance of EUS-guided fine-needle biopsy (EUS-FNB) and fine-needle aspiration (EUS-FNA) for LNs sampling. Methods: We searched PubMed/MedLine and Embase databases through August 2021. Primary outcome was diagnostic accuracy; secondary outcomes were sensitivity, specificity, sample adequacy, optimal histological core procurement, number of passes, and adverse events. We performed a pairwise meta-Analysis using a random-effects model. The results are presented as odds ratio (OR) or mean difference along with 95% confidence interval (CI). Results: We identified nine studies (1,276 patients) in this meta-Analysis. Among these patients, 66.4% were male; the median age was 67 years. Diagnostic accuracy was not significantly different between the two approaches (OR, 1.31; 95% CI, 0.81-2.10; P = 0.270). The accuracy of EUS-FNB was significantly higher when being performed with newer end-cutting needles (OR, 1.87; 95% CI, 1.17-3.00; P = 0.009) and in abdominal LNs (OR, 2.48; 95% CI, 1.52-4.05; P < 0.001) than that of EUS-FNA. No difference in terms of sample adequacy was observed between the two approaches (OR, 1.40; 95% CI, 0.46-4.26; P = 0.550); however, histological core procurement and diagnostic sensitivity with EUS-FNB were significantly higher than those with EUS-FNA (OR, 6.15; 95% CI, 1.51-25.07; P = 0.010 and OR, 1.87; 95% CI, 1.27-2.74, P = 0.001). The number of needle passes needed was significantly lower in the EUS-FNB group than in the EUS-FNA group (mean difference,-0.54; 95% CI,-0.97 to-0.12; P = 0.010). Conclusions: EUS-FNA and EUS-FNB perform similarly in LN sampling; however, FNB performed with end-cutting needles outperformed FNA in terms of diagnostic accuracy

Diagnostic performance of endoscopic ultrasound-guided tissue acquisition of splenic lesions: systematic review with pooled analysis

Background: Focal splenic lesions are usually incidentally discovered on radiological assessments. Although percutaneous tissue acquisition (TA) under trans-abdominal ultrasound guidance is a well-established technique for obtaining cyto-histological diagnosis of focal splenic lesions, endoscopic ultrasound (EUS)-guided TA has been described in several studies, reporting different safety and outcomes. The aim was to assess the pooled safety, adequacy, and accuracy of EUS-TA of splenic lesions. Methods: A comprehensive review of available evidence was conducted at the end of November 2021. All studies including more than five patients and reporting about the safety, adequacy, and accuracy of EUS-TA of the spleen were included. Results: Six studies (62 patients) were identified; all studies have been conducted using fine-needle aspiration (FNA) needles. Pooled specimen adequacy and accuracy of EUS-TA for spleen characterization were 92.8% [95% confidence interval (CI), 86.3%-99.3%] and 88.2% (95% CI, 79.3%-97.1%), respectively. The pooled incidence of adverse events (six studies, 62 patients) was 4.7% (95% CI, 0.4%-9.7%). Conclusion: EUS-FNA of the spleen is a safe technique with high diagnostic adequacy and accuracy. The EUS-guided approach could be considered a valid alternative to the percutaneous approach for spleen TA

Methods for Drainage of Distal Malignant Biliary Obstruction after ERCP Failure: A Systematic Review and Network Meta‐Analysis

There is scarce evidence on the comparison between different methods for the drainage of distal malignant biliary obstruction (DMBO) after endoscopic retrograde cholangiopancreatography (ERCP) failure. Therefore, we performed a network meta‐analysis to compare the outcomes of these techniques. We searched main databases through September 2021 and identified five randomized controlled trials. The primary outcome was clinical success. The secondary outcomes were technical success, overall and serious adverse event rate. Percutaneous trans‐hepatic biliary drainage was found to be inferior to other interventions (PTBD: RR 1.01, 0.88– 1.17 with EUS‐choledochoduodenostomy (EUS‐CD); RR 1.03, 0.86–1.22 with EUS-hepaticogastrostomy (EUS‐HG); RR 1.42, 0.90–2.24 with surgical hepaticojejunostomy). The comparison between EUS‐HG and EUS‐CD was not significant (RR 1.01, 0.87–1.17). Surgery was not superior to other interventions (RR 1.40, 0.91–2.13 with EUS‐CD and RR 1.38, 0.88–2.16 with EUS‐HG). No difference in any of the comparisons concerning adverse event rate was detected, although PTBD showed a slightly poorer performance on ranking analysis (SUCRA score 0.13). In conclusion, all interventions seem to be effective for the drainage of DMBO, although PTBD showed a trend towards higher rates of adverse events

Prognostic impact of alternative splicing-derived hMENA isoforms in resected, node-negative, non-small-cell lung cancer

Risk assessment and treatment choice remain a challenge in early non-small-cell lung cancer (NSCLC). Alternative splicing is an emerging source for diagnostic, prognostic and therapeutic tools. Here, we investigated the prognostic value of the actin cytoskeleton regulator hMENA and its isoforms, hMENA(11a) and hMENA Delta v6, in early NSCLC. The epithelial hMENA(11a) isoform was expressed in NSCLC lines expressing E-CADHERIN and was alternatively expressed with hMENA Delta v6. Enforced expression of hMENA Delta v6 or hMENA(11a) increased or decreased the invasive ability of A549 cells, respectively. hMENA isoform expression was evaluated in 248 node-negative NSCLC. High pan-hMENA and low hMENA(11a) were the only independent predictors of shorter disease-free and cancer-specific survival, and low hMENA(11a) was an independent predictor of shorter overall survival, at multivariate analysis. Patients with low pan-hMENA/high hMENA(11a) expression fared significantly better (P <= 0.0015) than any other subgroup. Such hybrid variable was incorporated with T-size and number of resected lymph nodes into a 3-class-risk stratification model, which strikingly discriminated between different risks of relapse, cancer-related death, and death. The model was externally validated in an independent dataset of 133 patients. Relative expression of hMENA splice isoforms is a powerful prognostic factor in early NSCLC, complementing clinical parameters to accurately predict individual patient risk

Tuberous sclerosis with pulmonary lymphangioleiomyomatosis and renal angiomyolipomas. Computed tomographic findings: a case report

The authors describe a case of a 31-year-old female with tuberous sclerosis, a genetic, rare, variably expressed disease. Clinical symptoms were chest pain, and progressive dyspnea. Computed tomography scan of the chest showed bilateral, diffuse, small thin-walled cysts scattered throughout the lungs characteristic for pulmonary lymphangioleiomyomatosis. Computed tomography scan of the abdomen revealed enlarged, heterogeneous kidneys, with low density tumors corresponding to angiomyolipomas. Pulmonary lymphangioleiomyomatosis and bilateral renal angiomyolipomas are some presentations of tuberous sclerosis and the coexistence of both conditions may cause devastating morbidity and mortality

Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73.

We describe a novel nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum among 30 children (ages 1.0 to 28 years) from diverse Amish demes. Children with nephrocerebellar syndrome had progressive microcephaly, visual impairment, stagnant psychomotor development, abnormal extrapyramidal movements and nephrosis. Fourteen died between ages 2.7 and 28 years, typically from renal failure. Post-mortem studies revealed (i) micrencephaly without polymicrogyria or heterotopia; (ii) atrophic cerebellar hemispheres with stunted folia, profound granule cell depletion, Bergmann gliosis, and signs of Purkinje cell deafferentation; (iii) selective striatal cholinergic interneuron loss; and (iv) optic atrophy with delamination of the lateral geniculate nuclei. Renal tissue showed focal and segmental glomerulosclerosis and extensive effacement and microvillus transformation of podocyte foot processes. Nephrocerebellar syndrome mapped to 700 kb on chromosome 15, which contained a single novel homozygous frameshift variant (WDR73 c.888delT; p.Phe296Leufs*26). WDR73 protein is expressed in human cerebral cortex, hippocampus, and cultured embryonic kidney cells. It is concentrated at mitotic microtubules and interacts with α-, β-, and γ-tubulin, heat shock proteins 70 and 90 (HSP-70; HSP-90), and the carbamoyl phosphate synthetase 2/aspartate transcarbamylase/dihydroorotase multi-enzyme complex. Recombinant WDR73 p.Phe296Leufs*26 and p.Arg256Profs*18 proteins are truncated, unstable, and show increased interaction with α- and β-tubulin and HSP-70/HSP-90. Fibroblasts from patients homozygous for WDR73 p.Phe296Leufs*26 proliferate poorly in primary culture and senesce early. Our data suggest that in humans, WDR73 interacts with mitotic microtubules to regulate cell cycle progression, proliferation and survival in brain and kidney. We extend the Galloway-Mowat syndrome spectrum with the first description of diencephalic and striatal neuropathology