Resistance to osimertinib in advanced EGFR-mutated NSCLC: a prospective study of molecular genotyping on tissue and liquid biopsies.

BACKGROUND: Resistance to osimertinib in advanced EGFR-mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent therapeutic implications. METHODS: This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR-mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed. RESULTS: Sixty-five advanced EGFR-mutated NSCLC patients treated with osimertinib in first- (n = 56) or in second-line (n = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification (n = 8), EGFR C797S (n = 3), and SCLC transformation (n = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively. CONCLUSIONS: Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

Real-world experience of abiraterone acetate plus prednisone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: long-term results of the prospective ABItude study.

BACKGROUND: Limited real-world data exist on the effectiveness and safety of abiraterone acetate plus prednisone (abiraterone hereafter) in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) naive to chemotherapy. Most of the few available studies had a retrospective design and included a small number of patients. In the interim analysis of the ABItude study, abiraterone showed good clinical effectiveness and safety profile in the chemotherapy-naive setting over a median follow-up of 18 months. PATIENTS AND METHODS: We evaluated clinical and patient-reported outcomes (PROs) of chemotherapy-naive mCRPC patients treated with abiraterone as for clinical practice in the Italian, observational, prospective, multicentric ABItude study. mCRPC patients were enrolled at abiraterone start (February 2016-June 2017) and followed up for 3 years; clinical endpoints and PROs, including quality of life (QoL) and pain, were prospectively collected. Kaplan-Meier curves were estimated. RESULTS: Of the 481 patients enrolled, 454 were assessable for final study analyses. At abiraterone start, the median age was 77 years, with 58.6% elderly patients and 69% having at least one comorbidity (57.5% cardiovascular diseases). Visceral metastases were present in 8.4% of patients. Over a median follow-up of 24.8 months, median progression-free survival (any progression reported by the investigators), time to abiraterone discontinuation, and overall survival were, respectively, 17.3 months [95% confidence interval (CI) 14.1-19.4 months], 16.0 months (95% CI 13.1-18.2 months), and 37.3 months (95% CI 36.5 months-not estimable); 64.2% of patients achieved ≥50% reduction in prostate-specific antigen. QoL assessed by Functional Assessment of Cancer Therapy-Prostate, the European Quality of Life 5 Dimensions 3 Level, and European Quality of Life Visual Analog Scale remained stable during treatment. Median time to pain progression according to Brief Pain Inventory data was 31.1 months (95% CI 24.8 months-not estimable). Sixty-two patients (13.1%) had at least one adverse drug reaction (ADR) and 8 (1.7%) one serious ADR. CONCLUSION: With longer follow-up, abiraterone therapy remains safe, well tolerated, and active in a large unselected population.

Comparison of HER2 status in primary and paired metastatic sites of gastric carcinoma.

BACKGROUND: Trastuzumab has recently shown efficacy in the treatment of HER2-positive advanced gastric adenocarcinoma. Although antibody-based therapies target the metastatic disease, HER2 status is usually evaluated in the primary tumour because metastatic sites are rarely biopsied. The aim of this study was to compare HER2 status in primary and paired metastatic sites of gastric adenocarcinoma. METHODS: The HER2 status was assessed by fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in 72 secondary lesions of gastric adenocarcinoma and in the corresponding primary tumours. RESULTS: Concordance of FISH results, evaluable in 68 primary and matched metastatic sites, was 98.5%. Concordance of IHC results, available in 39 of the 72 paired cases, was 94.9%. Only one case showed discordance between primary tumour and metastasis, being negative by both IHC and FISH in the primary and showing HER2 overexpression and amplification in the corresponding pancreatic lymph node metastasis. CONCLUSION: The high concordance observed between HER2 results obtained by both IHC and FISH on primary tumours and corresponding metastases suggests that in gastric cancer HER2 status is maintained in most cases unchanged during the metastatic process.

Physiological effects of sleeping with the head of the bed elevated 18 in. in young healthy volunteers.

BACKGROUND: Sleeping with the head of bed tilted upwards (SHU) is recommended as a treatment of orthostatic hypotension though the supporting evidence is weak. AIM: To investigate the physiological effects of SHU amongst a group of young healthy volunteers. METHODS: Twenty-nine volunteers, mean age 22 years, underwent 1-week of SHU at 18-in. elevation. Before and after hemodynamic and non-haemodynamic parameters were recorded. RESULTS: After SHU, there were reductions in the systolic blood pressure drop on standing, upright total peripheral resistance, haemoglobin, nocturnal urinary volume, orthostatic dizziness and increases in weight, standing cardiac output and ankle circumference. There were no differences in heart rate, stroke volume, renin, aldosterone, pro-atrial natriuretic peptide or 24-h blood pressure. CONCLUSIONS: In these healthy subjects, SHU for 1 week had a nocturnal antidiuretic effect with both intra- and extra-vascular accumulation of fluid and was associated with reduced postural drop in SBP and improved orthostatic tolerance.

Early-onset type 2 diabetes in obese white subjects is characterised by a marked defect in beta cell insulin secretion, severe insulin resistance and a lack of response to aerobic exercise training.

AIMS/HYPOTHESIS: Early-onset type 2 diabetes is associated with marked visceral obesity and extreme insulin resistance, but its pathogenesis and response to treatment are not completely understood. We studied physical fitness, whole-body and hepatic glucose turnover, and insulin secretion in young obese Irish subjects before and after 3 months of aerobic exercise training. We hypothesised that exercise alone, with stable diet, should improve insulin sensitivity. MATERIALS AND METHODS: Anthropometric parameters and maximum volume of oxygen utilisation (VO(2max)) were measured in 13 subjects with type 2 diabetes and 18 non-diabetic control subjects, matched for age and BMI. Insulin sensitivity and hepatic glucose turnover were measured using the hyperinsulinaemic-euglycaemic clamp. Insulin secretion was assessed from an OGTT and a modified intravenous glucose tolerance test. Some subjects (seven type 2 diabetic, 14 non-diabetic control subjects) then completed a 12-week supervised aerobic exercise programme. All measurements were repeated on completion of the exercise programme. RESULTS: Type 2 diabetic subjects had higher WHR, systolic blood pressure and triacylglycerols than non-diabetic control subjects. They were significantly more insulin-resistant as measured both by the clamp and oral glucose insulin sensitivity. They also displayed marked defects in insulin secretion in response to oral and intravenous glucose challenges. Exercise intervention had no significant effect on whole-body or hepatic insulin sensitivity or insulin secretion. VO(2max) increased significantly in the non-diabetic control subjects, but not in the type 2 diabetic subjects after exercise training. CONCLUSIONS/INTERPRETATION: Young obese subjects with type 2 diabetes are severely insulin-resistant with marked loss of beta cell function compared with control subjects matched for age and obesity. Neither group responded metabolically to aerobic exercise intervention.

Exercise training increases insulin-stimulated glucose disposal and GLUT4 (SLC2A4) protein content in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Exercise enhances insulin-stimulated glucose transport in skeletal muscle through changes in signal transduction and gene expression. The aim of this study was to assess the impact of acute and short-term exercise training on whole-body insulin-mediated glucose disposal and signal transduction along the canonical insulin signalling cascade. METHODS: A euglycaemic-hyperinsulinaemic clamp, with vastus lateralis skeletal muscle biopsies, was performed at baseline and 16 h after an acute bout of exercise and short-term exercise training (7 days) in obese non-diabetic (n=7) and obese type 2 diabetic (n=8) subjects. RESULTS: Insulin-mediated glucose disposal was unchanged following acute exercise in both groups. Short-term exercise training increased insulin-mediated glucose disposal in obese type 2 diabetic (p<0.05), but not in obese non-diabetic subjects. Insulin activation of (1) IRS1, (2) IRS2, (3) phosphotyrosine-associated phosphatidylinositol-3 kinase activity and (4) the substrate of phosphorylated Akt, AS160, a functional Rab GTPase activating protein important for GLUT4 (now known as solute carrier family 2 [facilitated glucose transporter], member 4 [SLC2A4]) translocation, was unchanged after acute or chronic exercise in either group. GLUT4 protein content was increased in obese type 2 diabetic subjects (p<0.05), but not in obese non-diabetic subjects following chronic exercise. CONCLUSIONS/INTERPRETATION: Exercise training increased whole-body insulin-mediated glucose disposal in obese type 2 diabetic patients. These changes were independent of functional alterations in the insulin-signalling cascade and related to increased GLUT4 protein content.

A case of Resistance to Thyroid Hormone without mutation in the thyroid hormone receptor beta.

BACKGROUND: Resistance to Thyroid Hormone (RTH) is a condition caused by tissue hyposensitivity to the effects of circulating thyroid hormone, and may be misdiagnosed as hyperthyroidism. AIMS: We report the first case of RTH in an Irish patient highlighting the clinical features and the pathophysiological mechanism underlying the characteristic laboratory abnormalities found in the condition. METHODS: We describe an isolated case of RTH initially misdiagnosed as hyperthyroidism, and detail the investigations which ultimately led to the correct diagnosis. Genetic screening of the thyroid hormone receptor beta gene was performed. RESULTS: Thyroid function tests including T3 suppression test and TRH-stimulation test suggested a diagnosis of RTH. Genetic testing failed to demonstrate a mutation in the thyroid hormone receptor. CONCLUSION: RTH is a rare inherited condition that may be misdiagnosed as hyperthyroidism. The case we describe most likely results from a de novo mutation in an as yet undiscovered gene. RTH should be considered in patients with elevated thyroid hormone levels and normal TSH so that unnecessary and potentially harmful treatment can be avoided.

Catamenial variations in erythrocyte sodium-lithium countertransport and blood pressure.

1. We undertook a temporal study of external sodium-stimulated lithium efflux (sodium-lithium countertransport) in erythrocytes and blood pressure by measuring these two parameters in three phases of the menstrual cycle (menstrual, midcycle and luteal phases) in 22 healthy, non-medicated females with regular menstrual cycles. Plasma oestradiol and progesterone levels were also determined. 2. Sodium-lithium countertransport activity (activity in 140 mmol/l external NaCl) in the midcycle phase (0.176 +/- 0.017 mmol h-1 l-1 of cells) was lower than in the menstrual (0.192 +/- 0.016 mmol h-1 l-1 of cells, P < 0.030) and luteal (0.203 +/- 0.018 mmol h-1 l-1 of cells, P < 0.030) phases. The Vmax of the transporter changed similarly but the K(m) was unaltered. 3. The plasma oestradiol level was 628.9 +/- 39.1 pmol/l in the midcycle phase, higher than in the menstrual (232 +/- 18.5 pmol/l, P < 0.001) and luteal (372.5 +/- 28.1 pmol/l, P < 0.001) phases. The progesterone level was 28.6 +/- 2.1 nmol/l in the luteal phase, and values were lower in the menstrual (2.5 +/- 0.3 nmol/l, P < 0.001) and midcycle (2.8 +/- 0.4 nmol/l, P < 0.001) phases. 4. There was no correlation between plasma oestradiol and sodium-lithium countertransport activity or Vmax during the menstrual cycle, but plasma progesterone was positively correlated with sodium-lithium countertransport activity (r = 0.478, P < 0.025, n = 22) and Vmax (r = 0.551, P < 0.045, n = 14) in the luteal phase. 5. Systolic blood pressure did not change significantly during the menstrual cycle. However, the diastolic pressure showed variation similar to that in sodium-lithium countertransport activity/Vmax, its midcycle value of 66.6 +/- 1.4 mmHg being lower than that in the luteal (71.6 +/- 1.3 mmHg, P < 0.025) and menstrual (70.6 +/- 1.4 mmHg, P < 0.025) phases. 6. We conclude that sodium-lithium countertransport activity exhibits catamenial variation. Therefore we suggest, given this observation, that blood sampling for the assessment of the state of activity of the transport system be standardized in relation to a phase of the menstrual cycle in future studies involving females.