Combination atezolizumab, bevacizumab, pemetrexed and carboplatin for metastatic EGFR mutated NSCLC after TKI failure.

INTRODUCTION: Acquired resistance to TKI is an important unmet need in the management of EGFR mutated lung cancer. Recent clinical trial IMPower150 suggested that combination approach with VEGF inhibitor, check point inhibitor immunotherapy and platinum-based chemotherapy was effective in oncogene driven lung cancer. The current trial examined the efficacy of a modified regimen in an EGFR mutated cohort. METHODS: An open-labelled, single arm, phase II study was conducted in patients with EGFR mutated NSCLC who had progressed on at least one EGFR TKI. For those with T790M mutation, radiological progression on osimertinib was required for enrolment. Patients were treated with combination atezolizumab (1200 mg), bevacizumab (7.5 mg/kg), pemetrexed (500 mg/m2) and carboplatin (AUC 5) given once every 3 weeks until progression. RESULTS: Forty patients were enrolled. Median age was 62 (range 45-76) years. More than one half (23/40, 57.5%) had progressed on osimertinib. PD-L1 expression was < 1% in 52.5%. Median follow-up time was 17.8 months. ORR was 62.5%. Median PFS was 9.4 months (95% CI: 7.6 - 12.1). One year OS was 72.5% (95% CI: 0.56-0.83). Treatment related grade 3 or above adverse events (AE) occurred in 37.5% (15/40). Immune-related AE occurred in 32.5% (13/40) patients. Quality of life measures of function and symptoms did not change significantly throughout the course of treatments. Post-trial rechallenge with EGFR TKI containing regimen resulted in PFS of 5.8 months (95% CI 3.9-10.0 months). CONCLUSION: Combination approach of atezolizumab, bevacizumab, pemetrexed and carboplatin achieved promising efficacy in metastatic EGFR mutated NSCLC after TKI failure. The results were comparable with taxane based regimen of IMPower150 while toxicity profile was improved.

Lung disease severity in idiopathic pulmonary fibrosis is more strongly associated with impedance measures of bolus reflux than pH parameters of acid reflux alone.

BACKGROUND: Gastroesophageal reflux (GER) has been associated with idiopathic pulmonary fibrosis (IPF). Pathogenesis may be related to chronic micro-aspiration. We aimed to assess objective measures of GER on multichannel intraluminal impedance and pH study (MII-pH) and their relationship with pulmonary function testing (PFT) results, and to compare the performance of pH/acid reflux parameters vs corresponding MII/bolus parameters in predicting pulmonary dysfunction in IPF. METHODS: This was a retrospective cohort study of IPF patients undergoing prelung transplant evaluation with MII-pH off acid suppression, and having received PFT within 3 months. Patients with prior fundoplication were excluded. Severe pulmonary dysfunction was defined using diffusion capacity of the lung for carbon monoxide (DLCO) ≤40%. Six pH/acid reflux parameters with corresponding MII/bolus reflux measures were specified a priori. Multivariate analyses were applied using forward stepwise logistic regression. Predictive value of each parameter for severe pulmonary dysfunction was calculated by area-under-the-receiver-operating-characteristic-curve or c-statistic. KEY RESULTS: Forty-five subjects (67% M, age 59, 15 mild-moderate vs 30 severe) met criteria for inclusion. Patient demographics and clinical characteristics were similar between pulmonary dysfunction groups. Abnormal total reflux episodes and prolonged bolus clearance time were significantly associated with pulmonary dysfunction severity on univariate and multivariate analyses. No pH parameters were significant. The c-statistic of each pH parameter was lower than its MII counterpart in predicting pulmonary dysfunction. CONCLUSIONS & INFERENCES: MII/bolus reflux, but not pH/acid reflux, was associated with pulmonary dysfunction in prelung transplant patients with IPF. MII-pH may be more valuable than pH testing alone in characterizing GER in IPF.

Increased proximal acid reflux is associated with early readmission following lung transplantation.

BACKGROUND: Gastroesophageal reflux disease has been associated with poor outcomes following lung transplantation. However, the association between pretransplant reflux and post-transplant readmission, an indicator of early clinical outcome, has not been previously assessed. METHODS: This was a retrospective cohort study of lung transplant recipients undergoing pretransplant multichannel intraluminal impedance and pH (MII-pH) study off acid suppression at a tertiary care center since 2007. Subjects with pretransplant fundoplication were excluded. Time to readmission was defined as duration from post-transplant discharge to next hospital admission for any reason. Subgroup analysis was performed to exclude elective readmissions. Time-to-event analysis was performed using Cox proportional hazards model, with appropriate censoring. KEY RESULTS: Forty-three subjects (60% men, mean age: 57, median follow-up: 1.7 years) met inclusion criteria for the study. Patient demographics and pretransplant cardiopulmonary function were similar between readmission cohorts. Time to all-cause readmission was associated with increased distal acid episodes (HR: 3.15, p = 0.04) and proximal acid episodes (HR: 3.61, p = 0.008) on impedance, increased acid exposure on pH (HR: 2.22, p = 0.04), and elevated Demeester score (HR: 2.26, p = 0.03). When elective readmissions were excluded, early readmission remained significantly associated with increased proximal acid reflux episodes (HR: 2.49, p = 0.04). All findings were confirmed on Kaplan-Meier analysis. CONCLUSIONS & INFERENCES: Elevated proximal acid reflux on pretransplant MII-pH testing was associated with early readmission following lung transplantation, even after excluding elective readmissions. Exposure to severe acid reflux has measurable effects on early postoperative outcomes such as readmission, and aggressive early antireflux therapy should be considered.

GERD phenotypes from pH-impedance monitoring predict symptomatic outcomes on prospective evaluation.

BACKGROUND: Combinations of reflux parameters (acid exposure time, AET; symptom association probability, SAP) on pH-impedance monitoring describe varying confidence in reflux evidence. We compared outcomes between phenotypes with distinct pre-identified reflux parameters. METHODS: In this observational cohort study, patients undergoing pH-impedance testing over a 5-year period were phenotyped by strength of reflux evidence as strong (abnormal AET, positive SAP), good (abnormal AET, negative SAP), reflux hypersensitivity (RH, normal AET, positive SAP), and equivocal evidence of reflux, and compared to two historical institutional pH monitoring cohorts. Symptom burden (dominant symptom intensity, DSI; global symptom severity, GSS) was assessed by questionnaire at baseline and on prospective follow-up and compared between phenotypes. KEY RESULTS: Of 94 patients tested off proton pump inhibitor (PPI) therapy, baseline symptom burden was highest with strong reflux evidence and lowest when equivocal (DSI: p = 0.01; GSS: p = 0.03 across groups). After 3.1 ± 0.2 years follow-up, symptomatic improvement with surgical or medical therapy was highest with strong or good evidence, and lowest when equivocal (DSI: p = 0.008; GSS: p = 0.005 across groups). This was most pronounced for typical symptoms (DSI: p = 0.001; GSS: 0.016 across groups), but not atypical symptoms (DSI: p = 0.6; GSS: p = 0.2). For testing on PPI therapy, only GSS followed a similar trend (GSS: p = 0.057, DSI: p = 0.3). Compared to historical cohorts with pH monitoring alone, equivocal evidence for reflux was partly replaced by RH, especially off PPI (p < 0.0001). CONCLUSIONS & INFERENCES: Phenotyping gastroesophageal reflux disease by the strength of reflux evidence on pH-impedance testing off PPI efficiently stratifies symptomatic outcome, especially for typical symptoms, and could be useful in planning management.

Idiopathic pulmonary fibrosis is associated with increased impedance measures of reflux compared to non-fibrotic disease among pre-lung transplant patients.

BACKGROUND: Gastroesophageal reflux (GER) has been associated with idiopathic pulmonary fibrosis (IPF), although the mechanism remains unclear. Gastroesophageal reflux/microaspiration may lead to lung fibrosis, while increased pulmonary workload may also worsen GER. Comparing the GER profile of IPF patients to chronic obstructive pulmonary disease (COPD) patients with similar lung function may help delineate the role of GER in IPF pathogenesis. METHODS: This was a retrospective cohort study of IPF and COPD patients undergoing pre-lung transplant multichannel intraluminal impedance and pH study (MII-pH) off acid suppression at a tertiary center in 2008-2014. Patients with prior fundoplication were excluded. Baseline demographics, pulmonary function test, and MII-pH results were recorded. Univariate analyses were performed using Fisher's exact (binary variables) and Student's t (continuous variables) tests. Logistic regression was performed to adjust for potential confounders. KEY RESULTS: A total of 90 subjects (54 IPF, 36 COPD) met inclusion criteria. Compared to COPD, IPF patients had increased total reflux episodes (65.9 vs 46.1, p = 0.02), proximal reflux episodes (30.3 vs 20.3, p = 0.04), and prevalence of abnormal total reflux episodes (38.9% vs 16.7%, p = 0.02). On multivariate analyses, abnormal total reflux episodes (OR: 4.9, p = 0.05) and bolus reflux exposure time (OR: 4, p = 0.04) remained significantly associated with IPF. CONCLUSIONS & INFERENCES: Abnormal reflux was significantly more prevalent among IPF patients after controlling for lung disease severity. Gastroesophageal reflux/microaspiration likely plays a role in fibrosis in IPF. A significant portion of IPF patients had increased non-acid reflux. Therapies aiming to prevent reflux of gastric contents may be more beneficial than antisecretory medications alone in these patients.

How we identify and count Aboriginal people--does it make a difference in estimating their disease burden?

INTRODUCTION: We examined the concordance between the Canadian Community Health Survey (CCHS) "identity" and "ancestry" questions used to estimate the size of the Aboriginal population in Canada and whether the different definitions affect the prevalence of selected chronic diseases. METHODS: Based on responses to the "identity" and "ancestry" questions in the CCHS combined 2009-2010 microdata file, Aboriginal participants were divided into 4 groups: (A) identity only; (B) ancestry only; (C) either ancestry or identity; and (D) both ancestry and identity. Prevalence of diabetes, arthritis and hypertension was estimated based on participants reporting that a health professional had told them that they have the condition(s). RESULTS: Of participants who identified themselves as Aboriginal, only 63% reported having an Aboriginal ancestor; of those who claimed Aboriginal ancestry, only 57% identified themselves as Aboriginal. The lack of concordance also differs according to whether the individual was First Nation, Métis or Inuit. The different method of estimating the Aboriginal population, however, does not significantly affect the prevalence of the three selected chronic diseases. CONCLUSION: The lack of concordance requires further investigation by combining more cycles of CCHS to compare discrepancy across regions, genders and socio-economic status. Its impact on a broader list of health conditions should be examined.

TITRE: Forum pancanadien - Nos méthodes d'identification et de recension des Autochtones influent-elles sur l'évaluation du fardeau de la maladie de ce groupe de population? INTRODUCTION: Nous avons examiné la concordance entre les questions de l'Enquête sur la santé dans les collectivités canadiennes (ESCC) relatives à l'identité et à l'ascendance utilisées pour évaluer la taille de la population autochtone au Canada et avons cherché à déterminer si les différentes définitions ont une incidence sur la prévalence de certaines maladies chroniques. MÉTHODOLOGIE: D'après le fichier de microdonnées combinées sur les réponses aux questions sur l'identité et l'ascendance de l'ESCC de 2009-2010, les participants autochtones se divisent en quatre groupes : (A) identité seulement; (B) ascendance seulement; (C) ascendance ou identité et (D) ascendance et identité. La prévalence du diabète, de l'arthrite et de l'hypertension est évaluée à partir des déclarations des participants concernant le diagnostic reçu d'un professionnel de la santé. RÉSULTATS: Parmi les participants qui s'identifient comme autochtones, seuls 63 % déclarent avoir un ancêtre autochtone; parmi ceux qui se disent d'ascendance autochtone, seuls 57 % s'identifient comme Autochtones. Le manque de concordance diffère également selon que le sujet est membre des Premières nations, Métis ou Inuit. Cependant, les différences entre méthodes d'estimation de la population autochtone n'ont pas d'incidence significative sur la prévalence des trois maladies chroniques choisies. CONCLUSION: Le manque de concordance doit être étudié de plus près, en combinant plus de cycles de l'ESCC afin de comparer les écarts entre les régions, les sexes et les statuts socioéconomiques. Il serait bon aussi d'en examiner cette incidence sur d'autres problèmes de santé.

Incidence of diabetes among postmenopausal breast cancer survivors.

AIMS/HYPOTHESIS: Evidence is emerging of an association between breast cancer and diabetes; however, it is uncertain whether diabetes incidence is increased in postmenopausal breast cancer survivors compared with women without breast cancer. The objective of this study was to determine whether postmenopausal women who develop breast cancer have a higher incidence of diabetes than those who do not develop breast cancer. METHODS: We used population-based data from Ontario, Canada to compare the incidence of diabetes among women with breast cancer, aged 55 years or older, from 1996 to 2008, with that of age-matched women without breast cancer. We used Cox proportional hazard models to estimate the effect of breast cancer on the cause-specific hazard of developing diabetes overall and in the subgroup of women who received adjuvant chemotherapy. RESULTS: Of 24,976 breast cancer survivors and 124,880 controls, 9.7% developed diabetes over a mean follow-up of 5.8 years. The risk of diabetes among breast cancer survivors compared with women without breast cancer began to increase 2 years after diagnosis (HR 1.07 [95% CI, 1.02, 1.12]), and rose to an HR of 1.21 (95% CI, 1.09, 1.35) after 10 years. Among those who received adjuvant chemotherapy (n = 4,404), risk was highest in the first 2 years after diagnosis (HR 1.24 [95% CI 1.12, 1.38]) and then declined. CONCLUSIONS/INTERPRETATION: We found a modest increase in the incidence of diabetes among postmenopausal breast cancer survivors that varied over time. In most women the risk began to increase 2 years after cancer diagnosis but the highest risk was in the first 2 years in those who received adjuvant therapy. Our study suggests that greater diabetes screening and prevention strategies among breast cancer survivors may be warranted.

Mycobacterium heckeshornense peritonitis in a peritoneal dialysis patient: a case report and review of the literature.

We report the first case of peritonitis attributed to Mycobacterium heckeshornense. This is a rare, non-tuberculous mycobacterium that has been reported as an aetiological agent in a growing number and widening spectrum of infections.

Bisphosphonates and osteoporotic fractures: a cross-design synthesis of results among compliant/persistent postmenopausal women in clinical practice versus randomized controlled trials.

UNLABELLED: In a cross-design synthesis, total fractures were similarly reduced by bisphosphonates among postmenopausal women in randomized trials (23.8%) and highly compliant/persistent patients in observational studies of large databases from routine practice (20.3%). Bisphosphonates also reduced nonvertebral, vertebral and hip fractures in randomized trials and observational studies. In the real-word setting, compliant/persistent patients can gain a benefit from bisphosphonates comparable to that of randomized trial participants. INTRODUCTION: The purpose of the study was to determine whether clinical fracture risk reduction by bisphosphonate treatment in women with postmenopausal osteoporosis differs between randomized controlled trials and routine practice. METHODS: Randomized trials comparing bisphosphonate with placebo and observational studies comparing highly compliant/persistent with less compliant/persistent patients were sought by electronic searches and ancillary methods. Clinical fracture data were extracted from the study reports and quantitatively combined by random effects metaanalysis. RESULTS: The odds ratio (OR) for all clinical fractures in randomized trials of 0.762, with a 95% confidence interval (CI) of 0.680-0.855, was closely similar to that in the observational studies (OR, 0.797; CI, 0.748-0.850). Pooled clinical fracture reduction across both study designs was 22%. Nonvertebral, vertebral, and hip fractures were also significantly reduced by bisphosphonate treatment in both randomized trials and observational studies. CONCLUSIONS: Compliant/persistent patients in the "real-world" setting benefit from bisphosphonate treatment to a similar extent as patients in randomized trials.

Penetrating head injury caused by a dart.

In paediatric practice, head injury is a major public health hazard that places considerable demand on health services. It accounts for almost one third of all accidental deaths and for up to two thirds of all trauma deaths in hospital. Common house-hold objects are at times a source of penetrating head injuries in children. These include electric plugs, golf clubs, toys, nails, etc. Fortunately less than 10% of these eventually lead to permanent brain injury. We report a rare case of penetrating head injury caused by a dart.

Epigenetic dysregulation of the DAP kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in acute leukaemias.

BACKGROUND: Dysregulation of apoptosis is important in carcinogenesis. AIM AND METHODS: To analyse the potential inactivation of the DAP kinase/p14/HDM2/p53/Apaf-1 pathway by aberrant promoter methylation in acute leukaemias. RESULTS: Of five leukaemic lines examined, p14 was unmethylated in Raji, HL60 and U937, but completely deleted in Jurkat and NB4. DAP kinase was totally methylated in Raji and NB4, but unmethylated in HL60, Jurkat and U937. Apaf-1 was unmethylated in all the lines. At diagnosis, DAP kinase methylation occurred in eight (25%) APL patients and none of the other AML patients (8/32 vs 0/50, p = 0.001). DAP kinase methylation was detected in four (16%) ALL patients. p14 and Apaf-1 methylation was not detected in any of the 32 cases of acute promyelocytic leukaemia (APL), 50 cases of other subtypes of acute myeloid leukaemia (AML), and 25 cases of acute lymphoblastic leukaemia. CONCLUSION: Among AML subtypes, DAP kinase is preferentially hypermethylated in APL.

A review of the management of patients after percutaneous coronary intervention.

The exponential increase in the numbers of percutaneous coronary interventions (PCIs) has led to many clinicians having to care for post-PCI patients. We review the management of early problems seen in post-PCI patients, such as vascular access site complications, contrast nephropathy, drug-induced thrombocytopaenia and chest pain. The management of possible restenosis and the use of stress testing are discussed. The complications from dual antiplatelet therapy are addressed. The prognosis of the post-PCI patient, the implications of co-existent heart failure and the newer technologies of implantable defibrillator and cardiac resynchronisation therapy are reviewed. We conclude by emphasising the importance of secondary prevention by risk factor modification as well as the communication between the clinician and the cardiologist.

Integrator function in the oculomotor system is dependent on sensory context.

The oculomotor integrator is usually defined by the characteristics of decay in gaze after saccades to flashed targets or after spontaneous gaze shifts in the dark. This property is then presumed fixed and accessed by other ocular reflexes, such as the vestibuloocular reflex (VOR) or pursuit, to shape motoneural signals. An alternate view of this integrator proposes that it relies on a distributed network, which should change its properties with sensory-motor context. Here we demonstrate in 10 normal subjects that the function of integration can vary in an individual with the imposed test. The value of the time constant for the decay of gaze holding in the dark can be significantly different from the effective integration time constant estimated from VOR responses. Hence analytical tools for the study of dynamics in ocular reflexes must allow for nonideal and labile integrator function. The mechanisms underlying such labile integration remain to be explored and may be different in various ocular reflexes (e.g., visual versus vestibular).

Acupuncture for general veterinary practice.

Since the International Society of Veterinary Acupuncture (IVAS) was founded in 1974, acupuncture (AP) has received greater acceptance by veterinary professionals throughout the world. This article introduces some important animal diseases that respond well to AP therapy. These include resuscitation of small animals, treatment of anoestrous gilts and sows, bovine reproductive disease, canine vertebral problems and equine backpain, etc. Conventional medicine considers these to be difficult cases to treat. Veterinarians have become more aware of the benefits of AP especially for those diseases, thanks to the efforts of experienced practitioners and scientists, and the many published reports on veterinary AP that have introduced some good indications for AP therapy in veterinary practice. Possible mechanisms behind the effectiveness of AP are discussed. This article aims to introduce veterinarians to good indications for AP to initiate their interest in the practice of AP. Although this is a rapidly expanding field, a long march must begin with one step. We wish this article to be the shoes for such a march. For more information on veterinary AP, contact IVAS , P.O. Box 1478, Longmont, CO.. 80502, USA (http://www.ivas.org), or your national veterinary acupuncture society (http://www.komvet.at/ ivadkom/vapsocs.htm).

High-level expression and mutagenesis of recombinant human phosphatidylcholine transfer protein using a synthetic gene: evidence for a C-terminal membrane binding domain.

Phosphatidylcholine transfer protein (PC-TP) is a 214-amino acid cytosolic protein that promotes intermembrane transfer of phosphatidylcholines, but no other phospholipid class. To probe mechanisms for membrane interactions and phosphatidylcholine binding, we expressed recombinant human PC-TP in Escherichia coli using a synthetic gene. Optimization of codon usage for bacterial protein translation increased expression of PC-TP from trace levels to >10% of the E. coli cytosolic protein mass. On the basis of secondary structure predictions of an amphipathic alpha-helix (residues 198-212) in proximity to a hydrophobic alpha-helix (residues 184-193), we explored whether the C-terminus might interact with membranes and promote binding of phosphatidylcholines. Consistent with this possibility, truncation of five residues from the C-terminus shortened the predicted amphipathic alpha-helix and decreased PC-TP activity by 50%, whereas removal of 10 residues eliminated the alpha-helix, abolished activity, and markedly decreased the level of membrane binding. Circular dichroic spectra of synthetic peptides containing one ((196-214)PC-TP) or both ((183-214)PC-TP) predicted C-terminal alpha-helices in aqueous buffer were most consistent with random coil structures. However, both peptides adopted alpha-helical configurations in the presence of trifluoroethanol or phosphatidylcholine/phosphatidylserine small unilamellar vesicles. The helical content of (196-214)PC-TP increased in proportion to vesicle phosphatidylserine content, consistent with stabilization of the alpha-helix at the membrane surface. In contrast, the helical content of (183-214)PC-TP was not influenced by vesicle composition, implying that the more hydrophobic of the alpha-helices penetrated into the membrane bilayer. These studies suggest that tandem alpha-helices located near the C-terminus of PC-TP facilitate membrane binding and extraction of phosphatidylcholines.

Modeling directed design and biological evaluation of quinazolinones as non-peptidic growth hormone secretagogues.

Quinazolinone derivatives were synthesized and evaluated as non-peptidic growth hormone secretagogues. Modeling guided design of quinazolinone compound 21 led to a potency enhancement of greater than 200-fold compared to human growth hormone secretagogue affinity of a screening lead 4.