Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Heterogeneity of EGFR activating and resistance mutations in lung adenocarcinoma: clinical relevance

In lung adenocarcinoma, activating mutation of EGFR (aEGFR) and EGFR-T790M can coexist. T790M confers resistance to 1st and 2nd generation TKIs. T790M may also be observed at diagnosis (preT790M+) in 0,5-3% cases using standard techniques and up to 30% with highly sensitive ones. FDA and EMA approved osimertinib, a 3rd generation TKI overcoming T790M resistance, for 2nd-line in patients T790M+; FDA approved it also for 1st-line of aEGFR+ metastatic disease. Current guidelines make no distinction in aEGFR patients with or without preT790M+. Aim of this study was to find differences in terms of survival and response rate between preT790M+ and wild-type for T790M (WT), detecting T790M at diagnosis with a highly sensitive technique (RainDrop Digital PCR). We selected 28 aEGFR+ lung adenocarcinoma that received 1st or 2nd generation TKI in 1st line. For statistical analysis we used Kaplan-Meyer method and log-rank test. At diagnosis, all were WT for T790M with standard techniques. With RainDrop Digital PCR, preT790M+ were 28,6% (n=8). In ≥2nd lines 50% of preT790M+ and 30% of WT received osimertinib. 1-yr and 2-yr survival were, respectively, 100% and 89% for preT790M+; 68% and 60% for WT. Median OS (mOS) of preT790M+ was not reached at the end of follow-up and 32.7 months for WT (p=0.098). There were no differences in mOS stratifying by osimertinib use the study population (p=0.792) and preT790M+ subgroup (p=1.000). RR was 87,5% for preT790M+, 60% for WT (p=0.241). The coexistence at diagnosis of aEGFR and T790M is not negligible. PreT790M+ seems to be an independent prognostic factor; preT790M+ tumors could represent a more indolent disease. Further studies are needed to define the optimal timing for osimertinib in these patients

IMPATTO DEL SISTEMA TNM NELLA STADIAZIONE DEL MICROCITOMA POLMONARE: LA NOSTRA CASISTICA.

BACKGROUND: Il microcitoma polmonare (SCLC, small-cell lung cancer, tumore a piccole cellule del polmone) costituisce circa il 13-20 % di tutte le neoplasie polmonari ed è un tumore altamente aggressivo e rapidamente evolutivo: la malattia non trattata ha una sopravvivenza mediana di 2-4 mesi dalla diagnosi. Le sue peculiarità sono quelle di disseminare precocemente e di dare segno di sè tardivamente. Sono proprio le stesse caratteristiche negative del microcitoma a renderlo altamente responsivo ai trattamenti chemioterapici e radiotrapici, ma a caratterizzare,purtroppo, le risposte ad essi di breve durata. L’aggressività e rapida evolutività del microcitoma hanno rappresentato il razionale per la suddivisione della malattia in solo due stadi: - LD, limited-disease, malattia limitata: tumore di qualsiasi dimensione confinato ad un emitorace, compreso un eventuale coinvolgimento linfonodale omolaterale toracico; - ED, estended-disease, malattia estesa: tumore con metastasi ematogene a distanza. Questo sistema fu introdotto originariamente dal Veterans Administration Lung Study Group (VALG) e i due stadi rappresentavano lo spartiacque per dividere i pazienti in quelli che avrebbero ricevuto e beneficiato di chemioterapia più radioterapia, (LD), e in coloro che sarebbero stati trattati con la sola terapia farmacologica. L’ International Association for the Study of Lung Cancer (IASLC), nel 1989, rivisitò per la prima volta questo sitema definendo: • LD-SCLC come malattia confinata ad un emitorace con eventuale presenza di metastasi linfonodali locoregionali, ovvero i linfonodi ilari, mediastinici e sopraclaveari ipsilaterali e controlaterali; • ED-SCLC come malattia disseminata. Questa revisione fa corrispondere la malattia limitata a un campo radioterapico. I pazienti con versamento pleurico ipsilaterale , neoplastico o reattivo, sono da considerare in malattia limitata, salvo evidenza di metastasi extratoraciche. A questo punto LD-SCLC corrisponderebbe precisamente agli stadi del sistema TNM dall’I al IIIB e ED-SCLC allo stadio IV, ovvero qualsiasi neoplasia con paramentro M1. (tabella) Il TNM (Tumor-Node-Metastasis) è il sistema di stadiazione usato per i tumori non a piccole cellule e per i carcinoidi. La IASLC propone di introdurre quest'ultimo come sistema stadiativo anche per il microcitoma, revisione che sarà presente nella settima edizione del sistema TNM, avendone dimostrato l'impatto attraverso metanalisi pubblicate nel 2007 e nel 2009. SCOPO DELLO STUDIO: raccogliendo i pazienti afferiti al nostro centro dal 2004 al 2008 abbiamo confrontato i nostri risultati in termini di sopravvivenza per stadio con quelli ricavati dall'analisi eseguita dalla IASCL. RISULTATI: i risultati sono concordanti, ovvero i pazienti T1 hanno una sopravvivenza migliore dei pazienti T2 e ,in particolar modo, dei T3 e T4, inoltre quelli in stadio I e II avevano una prognosi differente da quelli in stadio III con coinvolgimento linfonodale N2 o N3 e di quelli in stadio IV. CONCLUSIONI:Usare il sistema TNM per la stratificazione dei pazienti comporta sia vantaggi in termini di management , che la possibilità di stabilire classi di prognosi più precise e individualizzate. Ciò è molto importante per i soggetti con SCLC, neoplasia dove i progressi terapeutici sono ancora, purtroppo, insoddisfacenti

Noninvasive ventilation and renal replacement therapy in do-not-intubate order critically ill patients: A brief report

Introduction: Multiple organ failure has been considered a contraindication for noninvasive ventilation (NIV). Materials and methods: We described the outcome of Do-not-Intubate (DNI) patients with acute respiratory failure, treated with NIV and, subsequently, necessitating renal replacement therapy (RRT). Results and discussion: Seven patients admitted to our Respiratory Intensive Care Unit, developed Acute Kidney Injury (AKI) during NIV treatment and received RRT for 12.8 \ub1 8 days together with NIV. All the patients but one, discontinued renal support because they regained a satisfactory urinary output; nevertheless mortality rate was high (71%). Conclusion: Our data suggest that RRT could be feasible together with NIV. RRT was associated with an acute improvement in renal function but did not modify the mortality rate

Small cell lung cancer transformation and the T790M mutation: A case report of two acquired mechanisms of TKI resistance detected in a tumor rebiopsy and plasma sample of EGFR-mutant lung adenocarcinoma

The present study describes the case of a 45-year-old man diagnosed with metastatic lung adenocarcinoma, which harbored a deletion within exon 19 of the epidermal growth factor receptor (EGFR) gene. The patient was subsequently treated with gefitinib (250 mg/day orally from May 2013 to March 2014), but developed acquired resistance to the drug following 11 months of treatment. Tumor burden molecular analysis was performed on a tumor rebiopsy and plasma sample, and histological analysis was also performed on the tumor rebiopsy. A small cell transformation retaining the original EGFR mutation was detected in the tumor rebiopsy, while the T790M mutation together with the activating ex19del mutation were identified only in the plasma sample. The patient was treated with cytotoxic chemotherapy (off-label schedule with epirubicin 80 mg/mq and paclitaxel 160 mg/mq every 21 days for 6 cycles) and radiation (50.4 Gy administered in 28 fractions of 1.8 Gy once daily for 5.5 weeks) specific for small cell lung cancer, and may also have benefitted from treatment with a third generation T790M-specific EGFR-TKI. To better describe the mechanisms of resistance to TKI inhibitors and to optimize therapeutic regimens, the simultaneous analysis of tumor biopsies and circulating tumor DNA should be considered

Effects of high-flow nasal cannula in patients with persistent hypercapnia after an acute COPD exacerbation: a prospective pilot study

BACKGROUND: Persistent hypercapnia after COPD exacerbation is associated with excess mortality and early rehospitalization. High Flow Nasal cannula (HFNC), may be theoretically an alternative to long-term noninvasive ventilation (NIV), since physiological studies have shown a reduction in PaCO2 level after few hours of treatment. In this clinical study we assessed the acceptability of HFNC and its effectiveness in reducing the level of PaCO2 in patients recovering from an Acute Hypercapnic Respiratory Failure (AHRF) episode. We also hypothesized that the response in CO2 clearance is dependent on baseline level of hypercapnia. METHODS: Fifty COPD patients recovering from an acute exacerbation and with persistent hypercapnia, despite having attained a stable pH (i.e. pH > 7,35 and PaCO2 > 45 mmHg on 3 consecutive measurements), were enrolled and treated with HFNC for at least 8 h/day and during the nighttime RESULTS: HFNC was well tolerated with a global tolerance score of 4.0 ± 0.9. When patients were separated into groups with or without COPD/OSA overlap syndrome, the “pure” COPD patients showed a statistically significant response in terms of PaCO2 decrease (p = 0.044). In addition, the subset of patients with a lower pH at enrolment were those who responded best in terms of CO2 clearance (score test for trend of odds, p = 0.0038). CONCLUSIONS: HFNC is able to significantly decrease the level of PaCO2 after 72 h only in “pure” COPD patients, recovering from AHRF. No effects in terms of CO2 reduction were found in those with overlap syndrome. The present findings will help guide selection of the best target population and allow a sample size calculation for future long-term randomized control trials of HFNC vs NIV

Effects of non-invasive respiratory supports on inspiratory effort in moderate-severe COVID-19 patients. A randomized physiological study

Rationale and objective: Various forms of Non-invasive respiratory support (NRS) have been used during COVID-19, to treat Hypoxemic Acute Respiratory Failure (HARF), but it has been suggested that the occurrence of strenuous inspiratory efforts may cause Self Induced Lung Injury(P-SILI). The aim of this investigation was to record esophageal pressure, when starting NRS application, so as to better understand the potential risk of the patients in terms of P-SILI and ventilator induced lung injury (VILI).Methods and measurements: 21 patients with early de-novo respiratory failure due to COVID-19, underwent three 30 min trials applied in random order: high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), and non-invasive ventilation (NIV). After each trial, standard oxygen therapy was reinstituted using a Venturi mask (VM). 15 patients accepted a nasogastric tube placement. Esophageal Pressure (Delta Pes) and dynamic transpulmonary driving pressure (Delta PLDyn), together with the breathing pattern using a bioelectrical impedance monitor were recorded. Arterial blood gases were collected in all patients.Main results: No statistically significant differences in breathing pattern and PaCO2 were found. PaO2/FiO(2) ratio improved significantly during NIV and CPAP vs VM. NIV was the only NRS to reduce significantly Delta Pes vs. VM (-10,2 +/- 5 cmH20 vs -3,9 +/- 3,4). No differences were found in Delta PLDyn between NRS (10,2 +/- 5; 9,9 +/- 3,8; 7,6 +/- 4,3; 8,8 +/- 3,6 during VM, HFNC, CPAP and NIV respectively). Minute ventilation (Ve) was directly dependent on the patient's inspiratory effort, irrespective of the NRS applied. 14% of patients were intubated, none of them showing a reduction in Delta Pes during NRS.Conclusions: In the early phase of HARF due to COVID-19, the inspiratory effort may not be markedly elevated and the application of NIV and CPAP ameliorates oxygenation vs VM. NIV was superior in reducing Delta Pes, maintaining Delta PLDyn within a range of potential safety