Tyrosine kinase domain mutations in chronic myelogenous leukemia patients: A single center experience.

INTRODUCTION: Despite the impressive responses achieved with tyrosine kinase inhibitor (TKI) therapy, treatment resistance develops in 16-33% of patients of chronic myelogenous leukemia (CML). Of the BCR-ABL1 dependent mechanisms, mutations in the tyrosine kinase domain (TKD) are the commonest cause of resistance. MATERIAL AND METHODS: Allele specific oligonucleotide - polymerase chain reaction (ASO-PCR) was done for testing the six common TKD mutations, T315I, G250E, E255K, M244V, M351T, and Y253F. RESULTS AND CONCLUSION: TKD mutation study was done on 83 patients. Of these 44 (53%) were positive for one or more mutations. On analyzing specific mutations, E255K was the commonest mutation seen in 24 (29%) cases, followed by T315I in 23(28%) cases. Y253F mutation was not seen in the present study sample. In the present cohort of 83 patients, 29 (35%) cases were positive for single mutation, 12 (14%) had two mutations and 3 (4%) had three mutations.

Acceptability of Neuroscientific Interventions in Education.

Researchers are increasingly applying neuroscience technologies that probe or manipulate the brain to improve educational outcomes. However, their use remains fraught with ethical controversies. Here, we investigate the acceptability of neuroscience applications to educational practice in two groups of young adults: those studying bioscience who will be driving future basic neuroscience research and technology transfer, and those studying education who will be choosing among neuroscience-derived applications for their students. Respondents rated the acceptability of six scenarios describing neuroscience applications to education spanning multiple methodologies, from neuroimaging to neuroactive drugs to brain stimulation. They did so from two perspectives (student, teacher) and for three recipient populations (low-achieving, high-achieving students, students with learning disabilities). Overall, the biosciences students were more favorable to all neuroscience applications than the education students. Scenarios that measured brain activity (i.e., EEG or fMRI) to assess or predict intellectual abilities were deemed more acceptable than manipulations of mental activity by drug use or stimulation techniques, which may violate body integrity. Enhancement up to the norm for low-achieving students and especially students with learning disabilities was more favorably viewed than enhancement beyond the norm for high-achieving students. Finally, respondents rated neuroscientific applications to be less acceptable when adopting the perspective of a teacher than that of a student. Future studies should go beyond the acceptability ratings collected here to delineate the role that concepts of access, equity, authenticity, agency and personal choice play in guiding respondents' reasoning.

Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial.

BACKGROUND: Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. PATIENTS AND METHODS: Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). RESULTS: Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. CONCLUSIONS: EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. TRIAL REGISTRATION: ACTRN12609000665235.

National survey of UK Dermatologists demonstrates significant variation in how to obtain consent for dermatological procedures.

Consent must be undertaken prior to any dermatological procedure; however, in doing this, the clinician needs to ensure consent is valid and satisfies the principles of determining material risk. We aimed to assess variations in obtaining consent in the UK and understanding of material risk through a nationally distributed survey to members of the British Society for Dermatological Surgery and British Association of Dermatologists. Of 165 responses, we found that written consent was being obtained for all procedures in 73.9% of cases and typically at the time of procedure in the operating room/theatre (78.8%). Fifty-seven per cent of respondents were not familiar with the term 'material risk' and almost one-third were not aware of the Montgomery vs. Lanarkshire ruling, which replaced the Bolam test in 2015. We would encourage readers to be aware of these changes to consent law in the UK and how it might affect their approach to obtaining consent.

Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway.

Preclinical changes that precede the onset of symptoms and eventual diagnosis of Alzheimer's disease (AD) are a target for potential preventive interventions. A large body of evidence suggests that inflammation is closely associated with AD pathogenesis and may be a promising target pathway for such interventions. However, little is known about the association between systemic inflammation and preclinical AD pathophysiology. We first examined whether the acute-phase protein, alpha-2 macroglobulin (A2M), a major component of the innate immune system, was associated with cerebrospinal fluid (CSF) markers of neuronal injury in preclinical AD and risk of incident AD in the predictors of cognitive decline among normal individuals (BIOCARD) cohort. We find that A2M concentration in blood is significantly associated with CSF concentrations of the neuronal injury markers, tau and phosphorylated tau, and that higher baseline serum A2M concentration is associated with an almost threefold greater risk of progression to clinical symptoms of AD in men. These findings were replicated in the Alzheimer's Disease Neuroimaging (ADNI) study. Then, utilizing a systems level approach combining large multi-tissue gene expression datasets with mass spectrometry-based proteomic analyses of brain tissue, we identified an A2M gene network that includes regulator of calcineurin (RCAN1), an inhibitor of calcineurin, a well-characterized tau phosphatase. A2M gene and protein expression in the brain were significantly associated with gene and protein expression levels of calcineurin. Collectively these novel findings suggest that A2M is associated with preclinical AD, reflects early neuronal injury in the disease course and may be responsive to tau phosphorylation in the brain through the RCAN1-calcineurin pathway.

Ion induced dewetting of Au-Si on a SiO2 surface: composite nanodot evolution and wettability transition.

A nanodot array morphology gradually develops on SiO2 surface when a thin bi-layer of Au and Si undergoes ion irradiation. An increasing amount of gold silicide is detected as islands on the insulator surface evolve into nanodots as a function of increasing ion fluence. Different stages of evolution from islands to nanodots are found to be driven by the localized melting of Au along the ion-track and dewetting of the metal film. Dewetting is accompanied by sputter-erosion and mixing of Au and Si at the bi-layer interface due to ion energy deposition. Interestingly, a gradual transition in wettability of the surface from the hydrophilic to the hydrophobic one is observed with the growth of nanodots, which is correlated with the compositional variation. The experimental results indicate a route towards the controlled growth of composite nanodots on an insulator surface having hydrophobic properties using ion irradiation.

A prospective comparison of times to presentation and treatment of regional and remote head and neck patients in North Queensland, Australia.

BACKGROUND/AIM: This study aims to examine differences between outer regional (OR) and remote/very remote (RVR) patients in northern Queensland, Australia in the times taken to receive various aspects of head and neck cancer management. METHODS: Our study prospectively recruited head and neck cancer patients presenting to three North Queensland regional hospitals from January 2009 to January 2011. Data on demographic and cancer-specific details, comorbidities and timing of presentation to various services, were collected using a self-administered questionnaire that included two questions in relation to possible reason for delays to health services. Multivariate linear regression analyses were conducted to assess the effects of various demographic characteristics on time delays. Survival and disease recurrence data were analysed in 2014. RESULTS: One hundred and fifty-eight patients participated. RVR patients had significantly longer median times between diagnosis and first treatment compared with OR patients (P = 0.015). Indigenous patients had significant delays from diagnosis to first treatment (P = 0.013) and visit to first specialist and treatment (P = 0.031) compared to non-Indigenous patients. Longer median times between symptoms and first treatment was associated with low income (P = 0.03) and lower education level (P = 0.04). Disease recurrence was higher for RVR patients compared with OR patients (P = 0.04), without significant differences in overall survival. Possible reasons for delays included patient and professional factors. CONCLUSION: Significant delays in various aspects of head and neck cancer management were associated with remoteness, Indigenous and socioeconomic status. While patient and professional factors could be addressed at local levels, sustainable improvement in outcomes requires a state and national level approach.

A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: the Australasian lung cancer trials group NITRO trial.

BACKGROUND: We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial. PATIENTS AND METHODS: Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point. RESULTS: Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86-1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79-1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82-1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin. CONCLUSION: The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further. CLINICAL TRIALS NUMBER: Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.

PIRO concept: staging of sepsis.

INTRODUCTION: Sepsis is common presenting illness to the emergency services and one of the leading causes of hospital mortality. Researchers and clinicians have realized that the systemic inflammatory response syndrome concept for defining sepsis is less useful and lacks specificity. The predisposition, infection (or insult), response and organ dysfunction (PIRO) staging of sepsis similar to malignant diseases (TNM staging) might give better information. MATERIALS AND METHODS: A prospective observational study was conducted in emergency medical services attached to medicine department of a tertiary care hospital in Northern India. Patients with age 18 years or more with proven sepsis were included in the first 24 hours of the diagnosis. Two hundred patients were recruited. Multivariate logistic regression analysis was done to assess the factors that predicted in-hospital mortality. RESULTS: Two hundred patients with proven sepsis, admitted to the emergency medical services were analysed. Male preponderance was noted (M: F ratio = 1.6:1). Mean age of study cohort was 50.50 ± 16.30 years. Out of 200 patients, 116 (58%) had in-hospital mortality. In multivariate logistic regression analysis, the factors independently associated with in-hospital mortality for predisposition component of PIRO staging were age >70 years, chronic obstructive pulmonary disease, chronic liver disease, cancer and presence of foley's catheter; for infection/ insult were pneumonia, urinary tract infection and meningitis/encephalitis; for response variable were tachypnea (respiratory rate >20/minute) and bandemia (band >5%). Organ dysfunction variables associated with hospital mortality were systolic blood pressure <90mm Hg, prolonged activated partial thromboplastin time, raised serum creatinine, partial pressure of oxygen in arterial blood/ fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio <300, decreased urine output in first two hours of emergency presentation and Glasgow coma scale ≤9. Each of the components of PIRO had good predictive capability for in-hospital mortality but the total score was more accurate than the individual score and increasing PIRO score was associated with higher in-hospital mortality. The area under receiver operating characteristic curve for cumulative PIRO staging system as a predictor of in-hospital mortality was 0.94. CONCLUSION: This study finds PIRO staging as an important tool to stratify and prognosticate hospitalised patients with sepsis at a tertiary care center. The simplicity of score makes it more practical to be used in busy emergencies as it is based on four easily assessable components.

Disintegration mediated controlled release supersaturating solid dispersion formulation of an insoluble drug: design, development, optimization, and in vitro evaluation.

The objective of this study was to develop a solid dispersion based controlled release system for drug substances that are poorly soluble in water. A wax-based disintegration mediated controlled release system was designed based on the fact that an amorphous drug can crystallize out from hydrophilic matrices. For this study, cilostazol (CIL) was selected as the model drug, as it exhibits poor aqueous solubility. An amorphous solid dispersion was prepared to assist the drug to attain a supersaturated state. Povidone was used as carrier for solid dispersion (spray drying technique), hydrogenated vegetable oil (HVO) as wax matrix former, and sodium carboxymethyl cellulose (NaCMC) as a disintegrant. The extreme vertices mixture design (EVMD) was applied to optimize the designed and developed composition. The optimized formulation provided a dissolution pattern which was equivalent to the predicted curve, ascertaining that the optimal formulation could be accomplished with EVMD. The release profile of CIL was described by the Higuchi's model better than zero-order, first-order, and Hixson-Crowell's model, which indicated that the supersaturation state of CIL dominated to allow drug release by diffusion rather than disintegration regulated release as is generally observed by Hixson-Crowell's model. The optimized composition was evaluated for disintegration, dissolution, XRD, and stability studies. It was found that the amorphous state as well as the dissolution profile of CIL was maintained under the accelerated conditions of 40°C/75% RH for 6 months.

Wetting Kinetics: an Alternative Approach Towards Understanding the Enhanced Dissolution Rate for Amorphous Solid Dispersion of a Poorly Soluble Drug.

Developing amorphous solid dispersions of water-insoluble molecules using polymeric materials is a well-defined approach to improve the dissolution rate and bioavailability. While the selected polymer plays a vital role in stabilizing the amorphous solid dispersion physically, it is equally important to improve the dissolution profile by inhibiting crystallization from the supersaturated solution generated by dissolution of the amorphous material. Furthermore, understanding the mechanism of dissolution rate enhancement is of vital importance. In this work, wetting kinetics was taken up as an alternative approach for understanding the enhanced dissolution rate for amorphous solid dispersion of a poorly soluble drug. While cilostazol (CIL) was selected as the model drug, povidone (PVP), copovidone, and hypromellose (HPMC) were the polymers of choice. The concentrations against time profiles were evaluated for the supersaturated solutions of CIL in the presence and absence of the selected polymers. The degree of supersaturation increased significantly with increase in polymer content within the solid dispersion. While povidone was found to maintain the highest level of supersaturation for the greatest length of time both in dissolution and solution crystallization experiments, copovidone and hypromellose were found to be the less effective as crystallization inhibitor. The ability of polymers to generate and maintain supersaturated drug solutions was assessed by dissolution studies. The wetting kinetics was compared against the solid dispersion composition to establish a correlation with enhanced dissolution rate.

Challenges and new horizons in the management of advanced basal cell carcinoma: a UK perspective.

Basal cell carcinoma (BCC) is a common malignancy with a good prognosis in the majority of cases. However, some BCC patients develop a more advanced disease that poses significant management challenges. Such cases include locally advanced, recurrent or metastatic BCC, or tumours that occur in anatomical sites where surgical treatment would result in significant deformity. Until recently, treatment options for these patients have been limited, but increased understanding of the molecular basis of BCC has enabled potential therapies, such as hedgehog signalling pathway inhibitors, to be developed. A clear definition of advanced BCC as a distinct disease entity and formal management guidelines have not previously been published, presumably because of the rarity, heterogeneity and lack of treatment options available for the disease. Here we provide a UK perspective from a multidisciplinary group of experts involved in the treatment of complex cases of BCC, addressing the key challenges associated with the perceived definition and management of the disease. With new treatments on the horizon, we further propose a definition for advanced BCC that may be used as a guide for healthcare professionals involved in disease diagnosis and management.

Sequestrated meningocoele within a naevus sebaceous of Jadassohn on the scalp of a child.

Sequestrated meningocoele is an uncommon developmental anomaly in which meningothelial elements are found in the skin or subcutaneous tissue without underlying bony defect. By contrast, naevus sebaceous of Jadassohn (NSJ) is a circumscribed hamartomatous lesion occurring in about 0.3% of newborns. We report a child with a histologically confirmed sequestrated meningocoele within an NSJ on his scalp vertex. Such an occurrence has not been reported previously.

Johnson square procedure for lentigo maligna and lentigo maligna melanoma.

BACKGROUND: Lentigo maligna (LM) and lentigo maligna melanoma (LMM) can be difficult to manage surgically. Predetermined margins can be inadequate because of subclinical spread, or can affect function when margins are adjacent to the eye or mouth. AIM: To describe our 5-year experience in Nottingham of using the staged square procedure (Johnson square) in excising difficult facial LM and LMM. METHODS: The square procedure is a staged technique useful for ill-defined lesions and for lesions that have a high recurrence rate due to subclinical spread. It uses paraffin wax-embedded peripheral vertical sections for margin control, ensuring complete clearance as the surgical margins are usually examined at distances of 2-5 mm from the periphery of the lesion. RESULTS: We treated 21 patients with LM or LMM with the staged square procedure over a 5-year period. Of the 21 patients, 10 needed only one stage of surgery, 6 needed two stages, 3 needed three stages and 2 needed four stages. To date, there has been only one recurrence, which was of an extensive lesion that crossed the medial canthus, making margin control impossible because of the anatomical limitations. CONCLUSIONS: The staged square procedure is an effective treatment for LM and LMM. It attempts to conserve tissue while ensuring a higher clearance rate. This offers favourable cosmetic outcomes and better prognosis, especially for facial LM and LMM.

Osseous sarcoid with lytic lesions in skull.

Sarcoidosis bone is uncommon, and involvement of the skull is exceptionally rare. We present a 65-year-old obese female who presented with a 2-month history of dryness of mouth, polyuria, fatigue, and anorexia. She had generalized lymphadenopathy, organomegaly, and hypercalcemia, and a skeletal survey revealed extensive osteolytic lesions in the skull and phalanges. Both lymph node biopsy from the cervical lymph node and bone marrow examination revealed non-caseating granulomas, suggesting sarcoidosis. She was started on 1 mg/kg oral corticosteroids; during a follow-up of 6 months, she achieved normocalcemia; however, the punched-out lesions in the skull remained unchanged. This case reiterates several important issues that all lymphadenopathy in emerging nations may not be tubercular, and presence of osteolytic lesions in skull are unusual for sarcoid, at an elderly age, necessitates evaluation for more common etiologies like metastases and myeloma. Finally, patients with osseous sarcoid should be on a close follow-up since due to the rarity of this presentation, no definite consensus on the management of such cases exists in the literature.