Integrating Liquid Biopsy and Radiomics to Monitor Clonal Heterogeneity of EGFR-Positive Non-Small Cell Lung Cancer

Background: EGFR-positive Non-small Cell Lung Cancer (NSCLC) is a dynamic entity and tumor progression and resistance to tyrosine kinase inhibitors (TKIs) arise from the accumulation, over time and across different disease sites, of subclonal genetic mutations. For instance, the occurrence of EGFR T790M is associated with resistance to gefitinib, erlotinib, and afatinib, while EGFR C797S causes osimertinib to lose activity. Sensitive technologies as radiomics and liquid biopsy have great potential to monitor tumor heterogeneity since they are both minimally invasive, easy to perform, and can be repeated over patient’s follow-up, enabling the extraction of valuable information. Yet, to date, there are no reported cases associating liquid biopsy and radiomics during treatment. Case presentation: In this case series, seven patients with metastatic EGFR-positive NSCLC have been monitored during target therapy. Plasma-derived cell free DNA (cfDNA) was analyzed by a digital droplet PCR (ddPCR), while radiomic analyses were performed using the validated LifeX® software on computed tomography (CT)-images. The dynamics of EGFR mutations in cfDNA was compared with that of radiomic features. Then, for each EGFR mutation, a radiomic signature was defines as the sum of the most predictive features, weighted by their corresponding regression coefficients for the least absolute shrinkage and selection operator (LASSO) model. The receiver operating characteristic (ROC) curves were computed to estimate their diagnostic performance. The signatures achieved promising performance on predicting the presence of EGFR mutations (R2 = 0.447, p <0.001 EGFR activating mutations R2 = 0.301, p = 0.003 for T790M; and R2 = 0.354, p = 0.001 for activating plus resistance mutations), confirmed by ROC analysis. Conclusion: To our knowledge, these are the first cases to highlight a potentially promising strategy to detect clonal heterogeneity and ultimately identify patients at risk of progression during treatment. Together, radiomics and liquid biopsy could detect the appearance of new mutations and therefore suggest new therapeutic management

Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications

BACKGROUND Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. OBJECTIVES To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. DESIGN This was a prospective international 1-week observational study using the ‘Assess Respiratory Risk in Surgical Patients in Catalonia risk score’ (ARISCAT score) for PPC for risk stratification. PATIENTS AND SETTING Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. MAIN OUTCOME MEASURES The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. RESULTS A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (VT) size was 500 ml, or 7 to 9 ml kg1 predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P < 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P < 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. CONCLUSION The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high VT and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome

Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications: LAS VEGAS - An observational study in 29 countries

BACKGROUND Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. OBJECTIVES To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. DESIGN This was a prospective international 1-week observational study using the ‘Assess Respiratory Risk in Surgical Patients in Catalonia risk score’ (ARISCAT score) for PPC for risk stratification. PATIENTS AND SETTING Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. MAIN OUTCOME MEASURES The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. RESULTS A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (V T) size was 500 ml, or 7 to 9 ml kg−1 predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P ˂ 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P ˂ 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. CONCLUSION The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high V T and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome.</p

Indagini Geofisiche

Nell'ambito del progetto per la Microzonazione sismica dell'area aquilana, coordinata dal DPC, il Gruppo di Lavoro ha condotto le indagini di MS nella Conca di Roio.Published336-3854T. Sismologia, geofisica e geologia per l'ingegneria sismic

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P &lt; 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P &lt; 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Thyroid blood flow evaluation by color-flow Doppler sonography distinguishes Graves' disease from Hashimoto's thyroiditis.

Thyroid hypoechogenicity at ultrasound is a characteristic of autoimmune thyroid diseases, with an overlap of this echographic pattern in patients affected by Graves' disease or Hashimoto's thyroiditis. Aim of the present paper was to study the thyroid blood flow (TBF) by color-flow doppler (CFD) and peak systolic velocity (PSV) at the inferior thyroid artery in 37 Graves' and 45 goitrous Hashimoto's thyroiditis patients. CFD pattern was defined as normal (or type 0): TBF limited to peripheral thyroid arteries (PSV = 17.7 +/- 3 cm/sec, mean +/- SD); type I: TBF mildly increased; type II: TBF clearly increased; type III: TBF markedly increased. The CFD was in direct relationship to the PSV. Out of 18 patients with Graves' disease and untreated active hyperthyroidism CFD pattern was type III in 17 and type II in 1. The PSV was 42.1 +/- 15 cm/sec. In 17 patients euthyroid under methimazole, the CFD pattern was type 0 in 3 (17%) type I in 5 (30%), type II in 5 (30%), type III in 4 (23%). In this group of Graves' patients the PSV was 36 +/- 14 cm/sec. In two patients, hypothyroid after radioiodine treatment, the CFD pattern was type 0 in 1 and type I in 1. In the group of Hashimoto's patients TBF was in no relationship with thyroid status or treatment and was type 0 in 22 (49%), type I in 20 (44%), type II in 3 (7%), while none had type III CFD pattern. Thyroid hypoechogenicity at ultrasound was present in 32/37 (86%) Graves' and 41/45 (91%) Hashimoto's patients. All the four patients with Hashimoto's thyroiditis and normal thyroid ultrasound pattern had also a normal CFD pattern, while 4/5 patients with Graves' disease and normal echographic pattern had an increased TBF. In conclusion, a diffusely increased thyroid blood flow is pathognomonic of untreated Graves' disease and an abnormal CFD pattern identifies the majority of Graves' patients with a normal thyroid ultrasound pattern. Thus, CFD sonography may be useful in distinguishing patients with Graves' disease and Hashimoto's thyroiditis having a similar thyroid echographic pattern at ultrasound

Clinical Impact of Radioguided Localization in the Treatment of Solitary Pulmonary Nodule: A 20-Year Retrospective Analysis

Purpose Incidental solitary pulmonary nodules (SPNs) have become an increasingly common CT finding worldwide. Although there are currently many imaging strategies for evaluating SPNs, the differential diagnosis and management of SPNs remains complex because of overlap between benign and malignant processes. Moreover, transbronchial or percutaneous CT-guided biopsies do not always allow definitive diagnoses. In such cases, video-assisted thoracic surgery (VATS) has become the preferred surgical procedure for diagnosis and, in selected cases, for treatment of indeterminate SPNs. The difficulties in localizing smaller, deeper, and ground-glass nodules have been approached with different techniques. The aim of this study was to report 20 years of experience with radioguided thoracoscopic resection of SPNs at the Regional Centre of Nuclear Medicine of Pisa. Methods Three hundred ninety-five patients with SPNs less than 2 cm and deeper than 5 mm below the visceral pleura underwent CT-guided injection of a suspension composed of 0.1 to 0.2 mL99mTc-labeled human albumin macroaggregates (99mTc-MAA) and of 0.2 to 0.3 mL of nonionic contrast medium into or adjacent to the SPN. During VATS, the pulmonary area with the highest target/background ratio identified by an 11-mm-diameter collimated thoracoscopic gamma probe was resected. Results From 1997 to 2016, approximately 395 patients with SPN underwent VATS wedge resection using the radioguided technique. Mean SPN size was 13 mm (range, 5-20 mm) with mean distance of 15 mm (range, 6-39 mm) from the visceral pleura. Mean VATS procedural time was 40 minutes (range, 20-90 minutes), with an average time of 3 minutes (range, 1-5 minutes) to localize the nodule. Neither mortality nor major perioperative complication was reported. The success rate of VATS with radioguidance in our series was 99%. Histological examination revealed 206 benign lesions (52%), 59 primary lung tumors (15%), and 130 metastatic nodules (33%). Conclusions This study demonstrates that radioguided SPN localization by VATS is a feasible, safe, and rapid procedure with highly successful rate of SPN resection