Medicine by Alexandros G.Sfakianakis: 01/22/19

Τρίτη 22 Ιανουαρίου 2019

Re-interpretation of PAM50 gene expression as quantitative tumor dimensions shows utility for clinical trials: application to prognosis and response to paclitaxel in breast cancer

Abstract

Background

We recently showed PAM50 gene expression data can be represented by five quantitative, orthogonal, multi-gene breast tumor traits. These novel tumor 'dimensions' were superior to categorical intrinsic subtypes for clustering in high-risk breast cancer pedigrees, indicating potential to represent underlying genetic susceptibilities and biological pathways. Here we explore the prognostic and predictive utility of these dimensions in a sub-study of GEICAM/9906, a Phase III randomized prospective clinical trial of paclitaxel in breast cancer.

Methods

Tumor dimensions, PC1–PC5, were calculated using pre-defined coefficients. Univariable and multivariable Cox proportional hazards (PH) models for disease-free survival (DFS) were used to identify associations between quantitative dimensions and prognosis or response to the addition of paclitaxel. Results were illustrated using Kaplan–Meier curves.

Results

Dimensions PC1 and PC5 were associated with DFS (Cox PH p = 6.7 \(\times\) 10⁻⁷ and p = 0.036), remaining significant after correction for standard clinical–pathological prognostic characteristics. Both dimensions were selected in the optimal multivariable model, together with nodal status and tumor size (Cox PH p = 1.4 \(\times\) 10⁻¹²). Interactions with treatment were identified for PC3 and PC4. Response to paclitaxel was restricted to tumors with low PC3 and PC4 (log-rank p = 0.0021). Women with tumors high for PC3 or PC4 showed no survival advantage.

Conclusions

Our proof-of-concept application of quantitative dimensions illustrated novel findings and clinical utility beyond standard clinical–pathological characteristics and categorical intrinsic subtypes for prognosis and predicting chemotherapy response. Consideration of expression data as quantitative tumor dimensions offers new potential to identify clinically important patient subsets in clinical trials and advance precision medicine.

http://bit.ly/2AWdCG0

Unknown primary (CUP) of the head and neck : No advantages of bilateral radiotherapy, the strategy of ipsilateral radiotherapy can be recommended for the adjuvant treatment

Bilateral vs ipsilateral adjuvant radiotherapy in patients with cancer of unknown primary of the head and neck: An analysis of the clinical outcome and radiation‐induced side effects

Nguyen‐Son Le Stefan Janik MD, PhD Helmut Simmel MD Boban M. Erovic MD, PD, MBA

First published: 19 January 2019 https://doi.org/10.1002/hed.25637

This work was presented at the 61st Annual Meeting of the Austrian Society of Oto‐Rhino‐Laryngology – Head and Neck Surgery, Vienna, Austria

Abstract

Background

The purpose of this study was to analyze and compare ipsilateral and bilateral adjuvant radiotherapy in patients with cancer of unknown primary (CUP) of the head and neck.

Methods

Overall survival, recurrence‐free survival, and radiation‐induced side effects were assessed in 76 patients with CUP who underwent ipsilateral (n = 29) or bilateral (n = 47) radiotherapy.

Results

At a median follow‐up of 41 months, the 5‐year overall survival and recurrence‐free rate were 67.9% and 71.5%, respectively. No statistically significant difference between ipsilateral and bilateral radiotherapy could be found regarding 5‐year overall survival, recurrence‐free survival, occurrence of a primary tumor, and distant metastasis. The analysis of radiation‐induced acute side effects showed a significant benefit of ipsilateral radiotherapy.

Conclusion

As the main parameters of the study regarding the outcome and radiation‐induced side effects showed no advantages of bilateral radiotherapy, the strategy of ipsilateral radiotherapy can be recommended for the adjuvant treatment of CUP patients.

Acanthosis Nigricans & Metabolic Syndrome : Metabolic syndrome refers to a clustering of metabolic risk factors including central obesity, glucose intolerance, hyperinsulinemia, low HDL cholesterol, high triglycerides and hypertension. High prevalence of Acanthosis Nigricans (AN) in subjects with metabolic syndrome. Also there was a positive correlation between severity of Acanthosis Nigricans (AN) and Metabolic syndrome.

Acanthosis nigricans: A cutaneous marker for metabolic syndrome p. 16

Nirali Girish Shah, Swapna S Khatu, Neeta R Gokhale, Yuvraj E More, Deepak Khismatrao

DOI:10.4103/mjdrdypu.mjdrdypu_44_18

Background: Acanthosis Nigricans (AN) is an easily identifiable dermatoses characterized by thickened, hyperpigmented plaques. Metabolic syndrome refers to a clustering of metabolic risk factors including central obesity, glucose intolerance, hyperinsulinemia, low HDL cholesterol, high triglycerides and hypertension. AN is a skin marker associated with this syndrome. Aims and Objectives: This study aimed to determine the relationship between AN and metabolic syndrome by studying its clinico-epidemiological features and also the relation of severity of AN over neck with metabolic syndrome. Methodology: This is a case-control study. One hundred consecutive patients of AN attending dermatology OPD of a tertiary care hospital were included in this study. They were evaluated for AN and severity of AN over neck was assessed. Age and sex matched 100 controls were included in the study. Epidemiological, clinical and anthropometric characteristics (height, weight, waist circumference) were measured of all the cases and controls. Body Mass Index (BMI) was calculated. Fasting Blood Sugar, High Density Lipoprotein and Serum Triglyceride levels were estimated. Result: The average age of the patients was 32.4 years and females (62%) were more than the males (38%). Neck was involved in all the patients. There was statistically significant correlation of increasing severity of AN with each component of Metabolic syndrome. On comparing between cases and controls, each component of metabolic syndrome was raised in cases as compared to the controls. 70% cases had Metabolic syndrome which was statistically significant. Conclusion: There was a high prevalence of AN in subjects with metabolic syndrome. Also there was a positive correlation between severity of AN and Metabolic syndrome.

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Annual Meeting Abstracts of the Society of Skeletal Radiology (SSR) 2019, Scottsdale, Arizona, USA

http://bit.ly/2sIwrrs

Highlights of the annual scientific meeting of the 25th congress of the European Society of Musculoskeletal Radiology (ESSR) 2018, Amsterdam, The Netherlands

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Sequelae of bilateral luxatio erecta in the acute post-reduction period demonstrated by MRI: a case report and literature review

Abstract

Luxatio erecta humeri (LEH), also known as inferior shoulder dislocation, is uncommon, comprising about 0.5% of all cases of shoulder dislocation. Synchronous bilateral LEH is exceedingly rare and, to our knowledge, there are no descriptions of axillary nerve injury on magnetic resonance imaging (MRI) following LEH. We present a case of traumatic bilateral LEH in a 59-year-old woman who fell from a fast-moving mobility scooter and sustained direct axial loading forces on the fully abducted shoulders. Both shoulders were successfully reduced using the traction–countertraction technique in the emergency department. In this article, we describe the characteristic features of LEH on plain radiography and the pattern of acute soft-tissue injuries on MRI. We emphasize the importance of reviewing the axillary neurovascular bundle, which by virtue of its location beneath the shoulder joint, is prone to injury in inferior shoulder dislocation and thus has a substantial impact on functional recovery. This important complication is unfortunately not routinely examined by radiologists, partly because of the paucity of literature highlighting its clinical significance.

http://bit.ly/2sJbe0M

Radiation dose reduction for musculoskeletal computed tomography of the pelvis with preserved image quality

Abstract

Objective

To analyze the impact of pelvic computed tomography (CT) technique optimization on estimated dose and subjective and objective image quality.

Materials and methods

An institutional review board (IRB)-approved retrospective records review was performed with waived informed consent. Five CT scanners (various manufacturers/models) were standardized to match the lowest dose profile on campus via subjective assessment of clinical images by experienced musculoskeletal radiologists. The lowest dose profile had previously been established through image assessment by experienced musculoskeletal radiologists after a department-wide radiation dose reduction initiative. A consecutive series of 60 pre- and 59 post-optimization bony pelvis CTs were analyzed by two residents, who obtained signal-to-noise ratio for femoral cortex and marrow, gluteus medius muscle, and subcutaneous and visceral fat in a standardized fashion. Two blinded attending radiologists ranked image quality from poor to excellent.

Results

Pre- and post-optimization subjects exhibited no difference in gender, age, or BMI (p > 0.2). Mean CT dose index (CTDIvol) and dose–length product (DLP) decreased by approximately 45%, from 39± 14 to 18± 12 mGy (p < 0.0001) and 1,227± 469 to 546± 384 mGy-cm (p < 0.0001). Lower body mass index (BMI) was associated with a larger dose reduction and higher BMI with higher DLP regardless of pre- or post-optimization examination. Inter-observer agreement was 0.64–0.92 for SNR measurements. Cortex SNR increased significantly for both observers (p < 0.02). Although qualitative image quality significantly decreased for one observer (p < 0.01), adequate mean quality (3.3 out of 5) was maintained for both observers.

Conclusion

Subjective and objective image quality for pelvic CT examination remains adequate, despite a substantially reduced radiation dose.

http://bit.ly/2MshhzJ

How we do it: shifting MR arthrogram compounding from the fluoroscopy suite to the sterile pharmacy

Abstract

Objective

To assess the impact of shifting arthrogram injectate compounding from the fluoroscopy suite to the main hospital sterile pharmacy on cost, examination delays, and infection rates.

Materials and Methods

All arthrograms from the 12 months before (629 in total) and the 12 months after (699 in total) the change in arthrogram preparation procedure were compared to identify differences in examination delays and infection rate. The arthrogram formulation was sent to the Compounder's International Analytical Laboratory for stability testing. Finally, cost per injection analysis was performed to compare fluoroscopy suite with sterile pharmacy compounding.

Results

In the 699 arthrograms performed in the 12 months following transfer of arthrogram preparation to the main hospital pharmacy, there were 0 reported examination delays, 0 reported infections, and a 53% decrease in the material cost per arthrogram. There were three recorded instances of fluoroscopy suite preparation of arthrogram injectate due to unexpected add-on patients. Outside stability testing determined that the arthrogram injectate retained at least 90% potency 30 h post-preparation.

Conclusion

Shifting the compounding of the arthrogram injectate from the fluoroscopy room to the main hospital sterile pharmacy provides a modest cost saving and can be accomplished without examination delays or any increase in infection rate. It brought our practice into compliance with USP797, which is the current guideline for compounding practitioners, by transferring the compounding preparation of the arthrogram injectate from a procedure room to the sterile pharmacy.

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4-year-old boy referring for diffuse joint stiffness and progressive bilateral visual impairment

http://bit.ly/2MuEPEg

Reliability of patellotrochlear index in patellar height assessment on MRI—correction for variation due to change in knee flexion

Abstract

Objectives

To assess the reliability of patellotrochlear Index (PTI) in patellar height assessment on successive MRI scans in asymptomatic patients.

Materials and methods

Sixty-four patients with two successive MRI scans (128 studies) of the same knee for non-patellofemoral joint symptoms were identified retrospectively. PTI and knee flexion angle were assessed independently by three observers to assess interobserver reliability. The effect of knee flexion on PTI was assessed by comparing the change in values of PTI in each patient correlated with change in knee flexion.

Results

Sixty-four MRIs of patients (M:F) aged between 18 and 35 years (mean 24.6) years were assessed. The mean PTI for initial scan group was 0.33% (95% CI: 0.29–0.37; SD: 0.15) and consecutive scan group was 0.30% (CI: 0.27–0.33; SD: 0.3). The difference was not significant (p = 0.097 using a paired t test) with high inter-observer correlation (0.9) in both sets. Spearman's rho for knee flexion angle and PTI was found to be positive and statistically significant (0.41; p = 0.001). A linear regression model was derived using a scatter chart of change in PTI with change in knee flexion for each patient. The gradient of the linear regression line was used to estimate a cPTI (corrected PTI) value (corrected to 0 degrees of knee flexion), defined as cPTI = PTI – 1.3a (a = knee flexion angle).

Conclusions

This study demonstrates high inter-observer correlation of PTI on MRI and high test–retest reliability indicating unconscious quadriceps contraction does not change the index sufficiently. Knee flexion significantly alters PTI, increased patellotrochlear engagement with flexion increases the index. We propose use of the formula cPTI = PTI -1.3a to correct the index to 0 degree knee flexion in clinical practice.

http://bit.ly/2sIPZMC

Thirteen patients with imaging of the primary tumor site were identified [eight female, five male; mean age, 15.9 years (range, 3–41 years)]. Plexiform fibrohistiocytic tumor typically manifested as a solitary, painless, firm, slow-growing lesion centered in the subcutaneous tissues, with a predilection for the upper extremity or head and neck region. Most tumors had a purely plaque-like or infiltrative morphology at MRI; some demonstrated no round or oval mass. Tumors were predominantly isointense to muscle on T1-weighted imaging and hyperintense on fluid-sensitive imaging, and enhanced after gadolinium contrast administration. Five patients (38%) had residual tumor after initial surgery, resembling postoperative changes. No patient had recurrent tumor. One patient (8%) developed metastases to local lymph nodes and to the lung. No patient died from plexiform fibrohistiocytic tumor.

Conclusions

Plexiform fibrohistiocytic tumor often manifests as a plaque-like or infiltrative process, sometimes without a round or oval mass, most commonly in the subcutaneous tissues of the upper extremity or head and neck region. Residual tumor is often present after initial surgery, and may be indistinguishable from postoperative changes.

http://bit.ly/2MsgZZF

Radiologic evaluation of fracture healing

Abstract

While assessment of fracture healing is a common task for both orthopedic surgeons and radiologists, it remains challenging due to a lack of consensus on imaging and clinical criteria as well as the lack of a true gold standard. Further complicating this evaluation are the wide variations between patients, specific fracture sites, and fracture patterns. Research into the mechanical properties of bone and the process of bone healing has helped to guide the evaluation of fracture union. Development of standardized scoring systems and identification of specific radiologic signs have further clarified the radiologist's role in this process. This article reviews these scoring systems and signs with regard to the biomechanical basis of fracture healing. We present the utility and limitations of current techniques used to assess fracture union as well as newer methods and potential future directions for this field.

http://bit.ly/2R8kWDI

Advances in Management of Psychosis in Neurodegenerative Diseases

Abstract

Purpose of the review

Psychosis is broadly defined as a disengagement from reality. It describes syndromes that impair both thought content and thought process. Psychosis negatively impacts an individual's quality of life, in addition to the families caring for them. Psychosis with different types of hallucinations and delusions occurs in the context of delirium. Neuropsychiatric symptoms (NPS) are almost universal in the course of common neurodegenerative disorders (NDD) like Alzheimer's disease (AD) or Parkinson's disease (PD).

In this paper, the authors took an effort to characterize AD and PD psychosis with a special focus on the most diagnostically reliable features. Effectiveness and limitations of pharmacological interventions are discussed.

Recent findings

Consensus diagnostic criteria have evolved for psychosis secondary to AD as well as psychosis in PD. Psychotropic medications can be effective in the treatment of NPS in NDD; however, clinicians must be mindful of the side effects. There is a consensus on benefit of initiating any acetylcholinesterase inhibitor (ACHI: donepezil, rivastigmine, and galantamine) as a first line of treatment for psychosis in AD, as it may reduce and/or avoid the need for the use antipsychotics. Pimavanserin, a selective-serotonin inverse agonist that preferentially targets 5-HT2A receptors, while avoiding activity at dopamine and other receptors commonly targeted by antipsychotics had recently been approved by FDA to treat hallucinations and delusions in PD. Quetiapine is widely prescribed for the treatment of psychosis in different NDD, but the data remains equivocal.

Summary

Psychosis with different types of hallucinations and delusions may occur in the context of delirium and is almost universal as a neuropsychiatric symptom in the course of PD and AD. Currently, pimavanserin remains the only pharmacologic agent approved for treatment of psychosis in PD. In cases of other NPS in other than Parkinson's diseases, atypical antipsychotics are commonly used off-label. More research is greatly needed to advance this field and address NPS especially psychosis in geriatric population.

http://bit.ly/2HpGSKY

UPDATED: Torrent Pharmaceuticals Limited Issues Voluntary Nationwide Recall of Losartan Potassium Tablets, USP and Losartan Potassium and Hydrochlorothiazide Tablets, USP

Audience: Consumer, Health Professional, Pharmacy. Torrent Pharmaceuticals Limited is expanding its voluntary recall from 10 lots of Losartan potassium tablets USP to include 6 lots of Losartan potassium and hydrochlorothiazide tablets, USP, to the...

http://bit.ly/2S5vCY4

Neuropsychiatric symptoms following sore throat in a young boy

A previously healthy 6-year-old boy was referred to us by his primary provider, with a history of sudden onset behavioural abnormalities including irritability, sleep disturbance and anxiety. Physical examination revealed no significant findings; further analyses were not suggestive of meningitis, encephalitis, metabolic abnormalities, toxicity or any other obvious cause. On rechecking the patient's history, an episode of throat pain 1 week prior to the symptom onset was noted. Therefore, the possibility of paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) was considered. The antistreptolysin O titre was high (1078 IU/mL), and it increased to 1194 IU/mL 4 weeks later, leading to a diagnosis of PANDAS. He was started on ampicillin and administered one dose of intravenous immunoglobulin. His abnormal behaviours subsided and he returned to a normal state within 48 hours of treatment. This report aims to provide insights into the symptomology and diagnosis of PANDAS in children.

http://bit.ly/2Mrfs6i

Urachal Mucinous Cystadenocarcinoma

A 57-year-old man presented with a 6-month history of pelvic fullness. He had no lower urinary tract symptoms or altered bowel habits. On examination, there was a non-tender pelvic mass which extended from the pubic symphysis to the level of the umbilicus. CT scan of the abdomen demonstrated a 22x11x11 cm cystic mass arising from the pelvis extending into the midline and superiorly to the umbilicus. Other than raised carcinoembryonic antigen of 7.6 ng/mL (<5.0), the remainder of his blood test were unremarkable. Flexible cystoscopy demonstrated a convex deformity of the bladder wall in keeping with the compression and displacement as seen on the CT. The patient underwent an open excision of the cystic structure (urachal remnant), partial cystectomy, partial excision of anterior abdominal wall and pelvic lymphadenectomy. A check cystogram performed 12 days following the initial operation was unremarkable.

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Correction: Exclusively plant, whole-food diet for polypharmacy due to persistent atrial fibrillation, ischaemic cardiomyopathy, hyperlipidaemia and hypertension in an octogenarian

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Rare cutaneous myiasis of the face due to Lunds fly (Cordylobia rodhaini) in a British traveller returning from Uganda

We present a rare cause for cutaneous furuncular myiasis in a 55-year-old British traveller returning from Uganda. Initially presenting with what appeared to be a cellulitic furuncle on her forehead, she returned to the emergency department 3 days later with extensive preseptal periorbital swelling and pain. Occlusive treatment with petroleum jelly was applied and one larva manually extracted and sent to London School of Tropical Medicine for examination. It was identified as Lund's Fly (Cordylobia rodhaini), a rare species from the rainforests of Africa with only one other case reported in the UK since 2015. Ultrasound imaging identified another larva, necessitating surgical exploration and cleaning. The lesion subsequently healed completely and the patient remains well.

http://bit.ly/2sGT27V

Phenytoin-induced hypothermia

A 60-year-old man with cerebral palsy and epilepsy was admitted with acute lethargy and deterioration in coordination. He was noted to be hypothermic at 35°C on admission. Routine work-up revealed toxic levels of phenytoin. No cause of hypothermia could be identified but as his phenytoin levels normalised, his body temperature also improved. There are three other reported cases of phenytoin- induced hypothermia in the literature. Could this be a rare cause of hypothermia?

http://bit.ly/2MqZZmB

Anaphylaxis to patent blue dye in a 17-year-old boy

Patent blue V dye (PBV) is frequently used as a perioperative drug for lymphangiography, as well as a food additive. Hypersensitivity to PBV is poorly documented in adults and had not been previously described in children. The diagnosis of PBV allergy depends on corroboration of history consistent with an IgE-mediated reaction and confirmatory skin tests. We present in this paper a paediatric case of PBV anaphylaxis and of biphasic reaction that exemplifies the challenges involved in diagnosing and managing this rare but potentially life-threatening allergic reaction.

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Floating fetus: a rare complication of balloon tamponade treatment of caesarean scar ectopic pregnancy

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Spontaneous subcapsular haematoma: a rare cause of acute kidney graft dysfunction

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Chylothorax in a patient with HIV-related Kaposis sarcoma

We present a case of a 33-year-old man with a background of HIV and Kaposi's sarcoma (KS), who presented with a right sided chylothorax. He was managed with percutaneous chest drainage and talc pleurodesis, in addition to his chemotherapy and antiretroviral therapy for KS and HIV, respectively. Good clinical control of the chylothorax remained 4 months post drainage. This case report summarises the approach to investigating and managing pleural effusion, and in particular chylothorax, in HIV patients.

http://bit.ly/2MqZUPP

Spontaneous spinal subdural haematoma in a patient on apixaban

A 68-year-old man on apixaban presented to the emergency department with back pain following a long-haul flight. Investigations for pulmonary embolus and aortic dissection were negative and he was discharged with analgesia for mechanical back pain. He presented three more times with worsening back pain, third time with urinary retention and the fourth time with lower limb weakness and loss of coordination. He was found to have a spinal subdural haematoma on MRI and transferred to a tertiary centre, where he was managed conservatively and discharged for rehabilitation with good neurological recovery.

http://bit.ly/2sEOn6m

Rectal adenocarcinoma presenting with thigh muscle metastasis as the only metastatic site

Rectal carcinoma with metastasis to skeletal muscle is a rare finding. According to literature review, 17 cases of skeletal muscle metastasis from colorectal carcinoma have been documented where only six cases were rectal carcinomas.

We discuss a case of a middle-aged man with a known history of high-grade mucinous adenocarcinoma of the rectum, status post abdominoperineal resection followed by adjuvant radiotherapy and chemotherapy. During the planned chemotherapy course, a right proximal thigh subcutaneous mass was incidentally found which on subsequent biopsy proved to be metastatic from rectal primary site. On subsequent 18F-FDG (Fluorodeoxyglucose) positron emission tomography (PET)/CT scan after completion of chemotherapy for the purpose of treatment response evaluation, only FDG-avid lesion was residual right proximal thigh metastatic mass without involvement of other common sites, such as liver and lung. In this case, the 18F-FDG-PET/CT scan was able to exclude additional metastatic sites and also evaluate the patient's treatment response.

http://bit.ly/2MoWvRv

Radiation induced valvular disease: the internists prospective

Radiation-induced cardiac injury entails a wide spectrum of cardiovascular complications such as cardiomyopathy and valvular diseases among others. We present the internist's perspective and the challenges faced in managing these patients. There are guidelines addressing radiation-induced valvular disease (RIVD) including screening and treatment, but are often unrecognised by most internist's practice. A thorough cardiovascular examination and screening echocardiography may detect RIVD at an earlier stage. Early screening with transthoracic echocardiogram should be considered in asymptomatic or low-risk patients and more frequently in symptomatic and high-risk patients. The internists should educate their patients with prior chest irradiation, regarding the possible radiation related adverse cardiovascular effects and recommended screening. Lifestyle changes and aggressive cardiovascular risk modification should be emphasised, as concomitant hypertension, coronary artery disease and cardiomyopathy can have unfavourable effects in these patients.

http://bit.ly/2sI7CMh

Sacral schwannoma with intraosseous extension

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Rare case report of idiopathic gingival fibromatosis in childhood and its management

Idiopathic gingival fibromatosis (GF), also known as gingivomatosis, is a rare condition in childhood, with an unknown aetiology. The oral manifestations of the condition are varied and depend on the severity and age of involvement. This paper describe the case of a 5-year-old male child with extensive gingival enlargement covering almost all the maxillary and mandibular teeth resulted in difficulty with speech, mastication and poor aesthetics. Clinical and radiographic examination along with haematological investigations ruled out any systemic association. The case was managed with conventional scalpel blade surgery along with electrocautery under general anaesthesia yielding good results without any recurrence after a 12-month follow-up. The results revealed that the oral manifestations of GF depend on its severity and the age of onset. Timely intervention can help to prevent associated complications in a growing child.

http://bit.ly/2sGvvUs

Primary isolated hepatosplenic sarcoidosis mimicking malignancy and causing symptomatic hypercalcaemia

This is a case of a 67-year-old woman, known to have multiple medical problems, mainly papillary thyroid cancer status post-total thyroidectomy and cervical neck dissection in addition to radioactive iodine currently in remission for 1 year, who presented to the hospital with severe weakness and fatigue. The initial workup showed significant hypercalcaemia and suppressed Parathyroid hormone (PTH). The patient was treated with hydration and pamidronate and her hypercalcaemia and symptoms improved. The differential was wide, however, a CT scan of the chest, abdomen and pelvis did show multiple liver and splenic nodular lesions; therefore, malignancy was the highest possible diagnosis. Biopsy of the splenic lesion confirmed the diagnosis of sarcoidosis. Therefore, the patient was diagnosed with primary isolated nodular hepatosplenic sarcoidosis mimicking malignancy and causing significant symptomatic hypercalcaemia.

http://bit.ly/2MpZyZI

Hearing Norton Sound: mixed methods protocol of a community randomised trial to address childhood hearing loss in rural Alaska

Introduction

Childhood hearing loss has implications for school achievement, economic outcomes and quality of life. This study will engage rural Alaska communities in research to improve the school hearing screening and referral process, partnering with stakeholders to develop a locally derived, evidence-based solution to improve timely identification and treatment of childhood hearing loss.

Methods and analysis

Mixed methods community randomised trial in 15 communities in the Norton Sound region of northwest Alaska. Data collection will span from April 2017 until February 2020. Qualitative and mixed methods components are described in this protocol and the community randomised trial in the companion protocol. Focus groups and community events will be held leading up to the randomised trial to obtain community perspectives on childhood hearing loss in Alaska and elicit community input during trial protocol refinement (exploratory sequential stage). Stakeholder groups, including parents, children, teachers, school administrators and community health aides, will participate, along with community leaders, tribal leaders and community members. The randomised trial will be combined with qualitative, semi-structured interviews to elicit stakeholder perspectives on the intervention (explanatory sequential stage). The five stakeholder groups described above will participate in interviews. The study will conclude with additional focus groups and community events to discuss results and provide community insight for future implementation. Concluding focus groups will include policymakers, healthcare administrators, and tribal and community leaders in addition to the stakeholder groups. Informed consent and child assent will be required. Recordings will be transcribed and deidentified, with only stakeholder group recorded. Analyses will include categorical coding as well as narrative and thematic analysis.

Ethics and dissemination

The Hearing Norton Sound study has been approved by the Institutional Review Boards of Alaska Area, Norton Sound, and Duke University, with trial registration on clinicaltrials.gov. Study results will be distributed with equal emphasis on scientific and community dissemination.

Trial registration number

NCT03309553; Results.

http://bit.ly/2Muh9jq

Did psychotropic drug consumption increase during the 2008 financial crisis? A cross-sectional population-based study in Spain

Objectives and setting

Although psychotropic drugs are used to treat mental health disorders, little evidence analyses the effects the 2008 economic downturn had on psychotropic drug consumption in the case of Spain. We analyse these effects, considering both gender and employment situation.

Participants

We used the microdata from the face-to-face cross-sectional population-based Spanish National Health Survey for two periods: 2006–2007 (n=28 954) and 2011–2012 (n=20 509). Our samples included adults (>15 years old).

Methods

The response variables are consumption (or not) of antidepressants or sedatives and the explanatory variables are the year of the survey, gender and employment status. Covariates are mental health problems, mental health index General Health Questionnaire (GHQ-12) and self-reported health outcome variables such as self-rated health, chronic diseases, smoking behaviour, sleeping hours, body mass index, physical activity in the workplace, medical visits during the past year, age, region of residence (autonomous communities), educational level, marital status and social class of the reference person. Finally, we include interactions between time period, gender and employment status. We specify random effects logistic regressions and use Bayesian methods for the inference.

Results

The economic crisis did not significantly change the probability of taking antidepressant drugs (OR=0.56, 95% CI 0.18 to 2.56) nor sedatives (OR=1.21, 95% CI 0.26 to 5.49). In general, the probability of consuming antidepressants among men and women decreases, but there are differences depending on employment status. The probability of consuming sedatives also depends on the employment status.

Conclusions

While the year of the financial crisis is not associated with the consumption of antidepressants nor sedatives, it has widened the gap in consumption differences between men and women. Although antidepressant use dropped, the difference in consumption levels between men and women grew significantly among the retired, and in the case of sedatives, risk of women taking sedatives increased in all groups except students.

http://bit.ly/2sJ5vYQ

Cancers, Vol. 11, Pages 131: Emerging Functional Imaging Biomarkers of Tumour Responses to Radiotherapy

Cancers, Vol. 11, Pages 131: Emerging Functional Imaging Biomarkers of Tumour Responses to Radiotherapy

Cancers doi: 10.3390/cancers11020131

Authors: Campbell Davis Wilkinson Hesketh

Tumour responses to radiotherapy are currently primarily assessed by changes in size. Imaging permits non-invasive, whole-body assessment of tumour burden and guides treatment options for most tumours. However, in most tumours, changes in size are slow to manifest and can sometimes be difficult to interpret or misleading, potentially leading to prolonged durations of ineffective treatment and delays in changing therapy. Functional imaging techniques that monitor biological processes have the potential to detect tumour responses to treatment earlier and refine treatment options based on tumour biology rather than solely on size and staging. By considering the biological effects of radiotherapy, this review focusses on emerging functional imaging techniques with the potential to augment morphological imaging and serve as biomarkers of early response to radiotherapy.

http://bit.ly/2HpemJ5

Cancers, Vol. 11, Pages 130: 3D Mammary Epithelial Cell Models: A Goldmine of DCIS Biomarkers and Morphogenetic Mechanisms

Cancers, Vol. 11, Pages 130: 3D Mammary Epithelial Cell Models: A Goldmine of DCIS Biomarkers and Morphogenetic Mechanisms

Cancers doi: 10.3390/cancers11020130

Authors: Stefano Rossetti Nicoletta Sacchi

Breast ductal carcinoma in situ (DCIS) has been typically recognized by pathologists on the basis of aberrant mammary duct morphology. Thus, there are increasing efforts to detect DCIS biomarkers and druggable targets. In this study we focused on the molecular mechanism involving Annexin A8 (ANXA8), a Ca2+ and phospholipid binding protein, which is regulated by all-trans Retinoic Acid (RA), and it is highly expressed in breast DCIS tissue samples relative to atypical ductal hyperplasia, and normal breast tissue. Using a panel of human mammary epithelial HME1 cell lines that share a common protein signature, and develop in vitro three dimensional (3D) “DCIS-like” amorphous structures, we identified by bioinformatics analysis protein-miRNA pairs, potentially involved in mammary morphogenetic mechanisms, including the ANXA8 mechanism. HME1 cells with genetic mutations hampering the physiological RA regulation of the RA receptor alpha (RARA) transcriptional function, but retain the RARA function controlling the PI3KCA-AKT signaling, develop 3D “DCIS-like” amorphous structures with upregulated ANXA8. Consistently, ectopic ANXA8 expression, by affecting the RARA transcriptional function, induced HME1 DCIS-like amorphous acini expressing phosphorylated AKT (P-AKT). Apparently, a RA-RARA-ANXA8 feedback loop fosters a vicious circle of aberrant morphogenesis. Interestingly, a few miRNAs regulated by RA are predicted to target ANXA8 mRNA. These miRNAs are candidate components of the RA-RARA-ANXA8 mechanism, and their deregulation might induce DCIS initiation.

http://bit.ly/2S0FAKs

Understanding Processes of Transformative Change: A Qualitative Inquiry into Empowering Sources and Outcomes Identified by Women in Rural Nicaragua

Abstract

Despite decades of research on women's human rights and empowerment across several academic disciplines, inequities between women and men persist at alarming rates across the globe. The current study employs an in-depth exploration of how programs intended for empowering purposes impact individual women's lives, focusing on the transformation promoted at multiple ecological levels. More specifically, the present study assesses how women involved in a feminist organization in rural Nicaragua were affected by their participation in the organization. Via analysis of qualitative interviews with 14 women, we identify aspects of the organization most associated with actualizing transformative change and assess how involvement in the organization affected women's sense of self and lived experience. Specifically, we identify and explicate two themes: (a) moving forward, which details aspects of the organization that facilitated positive changes for women, and (b) feminist autoconocimiento, which involved developing an understanding of oneself as capable of offering valuable contributions to their homes and communities. Findings have implications for promoting empowering contexts for women, with a focus on ensuring that desired empowering change is occurring for the women involved.

http://bit.ly/2HnkeTg

Low prevalence of Gram-positive isolates showing elevated lefamulin MIC results during the surveillance program for 2015-2016 and characterization of resistance mechanisms [Mechanisms of Resistance]

This study investigated the molecular mechanisms possibly associated with non-wildtype MICs for lefamulin among staphylococci and streptococci included in the lefamulin surveillance program for 2015-2016. A total of 2,919 Staphylococcus aureus, 276 coagulase-negative staphylococci (CoNS), 3,923 Streptococcus pneumoniae, 389 ß-hemolytic and 178 viridans group streptococci were included in the surveillance studies. Eleven (0.3% of all S. aureus) S. aureus with lefamulin MICs above the staphylococcal epidemiological cut-off (ECOFF) value (>0.25 μg/mL) were selected for this study. Eight (72.7%) S. aureus (lefamulin MIC, 0.5-4 μg/mL) carried vga(A or E), one isolate (MIC, 32 μg/mL) carried lsa(E), one isolate (MIC, 16 μg/mL) had an alteration in L4, and one strain (MIC, 0.5 μg/mL) did not carry any of the investigated resistance mechanisms. A total of 14 (5.1% of all CoNS) CoNS had lefamulin MICs (0.5 to >32 μg/mL) above ECOFF. Similar to S. aureus, 8 (57.1%) CoNS (lefamulin MIC, 1-8 μg/mL) carried vga(A or B), while 2 isolates (MIC, 4-32 μg/mL) carried cfr. High genetic diversity was observed among staphylococci, although 3 S. aureus belonged to ST398. Among 3 S. agalactiae and 3 viridans group streptococci (0.1% of all streptococci surveyed) selected for additional characterization, and all but 1 isolate carried lsa(E). This study documents a low occurrence of surveillance isolates exhibiting a non-wildtype MIC for lefamulin, and among these isolates, vga and lsa(E) prevailed in staphylococci and streptococci, respectively.

http://bit.ly/2R7i2Pf

Efficacy of Human-simulated Epithelial Lining Fluid Exposure of Meropenem-Nacubactam Combination against Class A Serine {beta}-lactamase-producing Enterobacteriaceae in the Neutropenic Murine Lung Infection Model [Experimental Therapeutics]

Nacubactam is a novel broad spectrum β-lactamase inhibitor that is currently under development as combination therapy with meropenem. This study evaluated the efficacy of human-simulated epithelial lining fluid (ELF) exposures of meropenem, nacubactam, and the combination meropenem-nacubactam against class A serine carbapenemase-producing Enterobacteriaceae isolates in the neutropenic murine lung infection model. Twelve clinical meropenem-resistant Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae isolates all harboring KPC or IMI-type β-lactamases were utilized in the study. Meropenem, nacubactam, and the combination meropenem-nacubactam (1:1) MICs were determined in triplicate via broth microdilution. At 2hr after intranasal inoculation, neutropenic mice were dosed with regimens that provided ELF profiles mimicking those observed in humans given meropenem 2g q8hr and nacubactam 2g q8hr (1.5hr infusions) alone or in combination. Efficacy was assessed as the change in log₁₀CFU/lung at 24hr compared with 0hr controls. Meropenem, nacubactam, and meropenem-nacubactam MICs were 8 – >64, 2 - >256 and 0.5 – 4 μg/mL, respectively. The average log₁₀CFU/lung at 0hr across all isolates was 6.31 ± 0.26. Relative to 0hr control, the mean bacterial growth at 24hr in the untreated control mice, meropenem human-simulated regimen (HSR), and nacubactam HSR treatment groups were 2.91 ± 0.27, 2.68 ± 0.42, and 1.73 ± 0.75 log₁₀CFU/lung, respectively. Meropenem-nacubactam combination HSR resulted in -1.50 ± 0.59 log₁₀CFU/lung reduction. Meropenem-nacubactam human-simulated ELF exposure produced enhanced efficacy against all class A serine carbapenemase-producing Enterobacteriaceae isolates tested in the neutropenic murine lung infection model.

http://bit.ly/2W81I4R

Antibacterial Activity of Lefamulin Against Pathogens Most Commonly Causing Community-Acquired Bacterial Pneumonia: SENTRY Antimicrobial Surveillance Program (2015-2016) [Susceptibility]

Lefamulin, the first semisynthetic pleuromutilin antibacterial for intravenous and oral treatment of community-acquired bacterial pneumonia (CABP), and comparators were evaluated for in vitro activity against a global collection of pathogens commonly causing CABP (n=8595) from the 2015–2016 SENTRY Antimicrobial Surveillance Program. Lefamulin was highly active against pathogens commonly Streptococcus pneumoniae including multidrug resistant and extensively drug resistant strains (MIC_50/90 for total and resistant subsets, 0.06/0.12 μg/mL; 100% inhibited at ≤1 μg/mL), Staphylococcus aureus including MRSA (both MIC_50/90, 0.06/0.12 μg/mL; 99.8% and 99.6% inhibited at ≤1 μg/mL, respectively), Haemophilus influenzae (MIC_50/90, 0.5/1 μg/mL; 93.8% inhibited at ≤1 μg/mL), and Moraxella catarrhalis (MIC_50/90, 0.06/0.12 μg/mL; 100% inhibited at ≤0.25 μg/mL), and its activity was unaffected by resistance to other antibacterial classes.

http://bit.ly/2R7hZ61

Software for Dosage Individualization of Voriconazole: a Prospective Clinical Study [Clinical Therapeutics]

Voriconazole is a first-line antifungal agent. Therapeutic drug monitoring is a standard of care. The best way to adjust dosages to achieve desired drug exposure endpoints is unclear due to nonlinear and variable pharmacokinetics. Previously described software was used to prospectively adjust voriconazole dosages. CYP2C19 and CYP3A4 and CYP3A5 genotype was determined. The primary endpoint was the proportion of patients with a Cmin at 120 hours in the range 1-3 mg/L using software to adjust voriconazole dosages. A total of 19 patients were enrolled and 14 were evaluable. Of these, 12/14 (85.7%, 95% CI 57.2 – 98.2%) had a Cmin at 120 hours post-treatment initiation of 1-3 mg/L, which was higher than the a priori expected proportion of 33%. There was no association of CYP genotype-derived metaboliser phenotype with voriconazole AUC. Software can be used to adjust the dosages of voriconazole to achieve drug exposures that are safe and effective.

http://bit.ly/2W81DOB

In vitro activity of Tedizolid against Mycobacterium tuberculosis [Susceptibility]

Tedizolid is a novel oxazolidinone with activities against Gram-positive microorganisms, including mycobacteria. We studied, the in vitro activity of Tedizolid against 120 M. tuberculosis strains, including susceptible, first-line-resistant and MDR isolates. Minimal Inhibitory Concentration (MIC) was tested using the Bactec 960 MGIT system. The MIC ₉₀ and MIC ₅₀ were 0,5 and 0.25 μg/ml respectively in both susceptible and resistant strains. Tedizolid could be an alternative in the treatment of resistant M.tuberculosis.

http://bit.ly/2RbmVXW

In vitro synergism of rifabutin with clarithromycin, imipenem and tigecycline against the Mycobacterium abscessus complex [Susceptibility]

Background

Infections caused by the difficult-to-treat Mycobacterium abscessus are increasing in frequency. Rifabutin, in contrast to rifampin, appears to be active in vitro against M. abscessus, especially against clarithromycin-resistant strains. However, exploring for potential synergy between rifabutin and available antimicrobials is currently limited.

Methods

In vitro synergism was evaluated by the checkerboard method for rifabutin and 10 antimicrobials in 31 mycobacterial strains. The fractional inhibitory concentration index (FICI) was calculated for each rifabutin-based combination. Colony morphology was recorded. Molecular subspeciation and macrolide resistance were determined by sequencing of the secA1, rpoB, hsp65, erm (41) and rrl genes.

Results

Rifabutin yielded an MIC₅₀ of 16 mg/L (range 2-32 mg/L) against 26 clinical M. abscessus isolates (comprising 13 M. abscessus subsp. abscessus and 13 M. abscessus subsp. massiliense) and 5 reference strains including M. abscessus subsp. abscessus ATCC 19977, M. abscessus subsp. bolletii BCRC 16915, M. abscessus subsp. massiliense BCRC 16916, M. chelonae ATCC 35752 and M. peregrinum ATCC 700686. Significant synergism as classified by an FICI≤0.5 was demonstrated for the combinations of rifabutin and imipenem in 100% of M. abscessus subsp. abscessus vs. 69% of M. abscessus subsp. massiliense isolates, and for rifabutin and tigecycline in 77% of M. abscessus subsp. abscessus vs. 69% of M. abscessus subsp. massiliense isolates. Among the 6 clarithromycin resistant (MIC ≥8 mg/L) M. abscessus subsp. abscessus isolates, the combination of rifabutin and clarithromycin was 100% synergistic.

Conclusions

Rifabutin showed promising in vitro synergism with first-line anti-M. abscessus agents, especially for macrolide-resistant M. abscessus subsp. abscessus.

http://bit.ly/2Wbtsp9

Novel Polymyxin Combination with Antiretroviral Zidovudine Exerts Synergistic Killing against NDM-producing MDR Klebsiella pneumoniae [Pharmacology]

Polymyxins are used as a last-line therapy against multidrug-resistant (MDR) New Delhi metallo-β-lactamase (NDM) producing Klebsiella pneumoniae. However, polymyxin resistance can emerge with monotherapy; therefore, novel strategies are urgently needed to minimize the resistance and maintain their clinical utility. This study aimed to investigate the pharmacodynamics of polymyxin B in combination with the antiretroviral drug zidovudine against K. pneumoniae. Three isolates were evaluated in static time-kill studies (0 – 64 mg/L) over 48 h. A one-compartment in vitro pharmacokinetic/pharmacodynamic (PK/PD) model (IVM) was used to simulate humanized dosage regimens of polymyxin B (4 mg/L as continuous infusion) and zidovudine (as bolus dose thrice daily to achieve C_max = 6 mg/L) against K. pneumoniae BM1 over 72 h. The antimicrobial synergy of the combination was further evaluated in a murine thigh infection model against K. pneumoniae 02. In the static time-kill studies, polymyxin B monotherapy produced rapid and extensive killing against all three isolates followed by extensive regrowth, whereas zidovudine produced modest killing followed by significant regrowth at 24 h. Polymyxin B in combination with zidovudine significantly enhanced the antimicrobial activity (≥ 4 log₁₀CFU/mL) and minimized bacterial regrowth. In the IVM, the combination was synergistic and the total bacterial loads were below the limit of detection for up to 72 h. In the murine thigh infection model, the bacterial burden at 24 h in the combination group was ≥ 3 log₁₀CFU/thigh lower compared to each monotherapy against K. pneumoniae 02. Overall, polymyxin B-zidovudine combination demonstrates superior antimicrobial efficacy and minimized emergence of resistance to polymyxins.

http://bit.ly/2R3PUNf

The Anti-Staphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood to Potentiate MRSA Bacteriolysis [Experimental Therapeutics]

Bacteriophage-derived lysins are cell wall hydrolytic enzymes which represent a potential new class of antibacterial therapeutics in development to address burgeoning antimicrobial resistance. CF-301, the lead compound in this class, is in clinical development as an adjunctive treatment to potentially improve clinical cure rates of Staphylococcus aureus bacteremia and infective endocarditis (IE) when used in addition to antibiotics. In order to profile CF-301's activity in a clinically relevant milieu, we assessed its in vitro activity in human blood vs. in a conventional testing medium (cation-adjusted Mueller Hinton Broth [caMHB]). CF-301 exhibited substantially greater potency (32-≥100-fold) in human blood vs. caMHB in three standard microbiologic testing formats (e.g. broth dilution MICs, checkerboard synergy and time-kill assays). We demonstrated that CF-301 acted synergistically with two key human blood factors, human serum lysozyme (HuLYZ) and albumin (HSA), which normally have no nascent antistaphylococcal activity, against a prototypic MRSA strain (MW2). Similar in vitro enhancement of CF-301 activity was also observed in rabbit, horse and dog (but not rat or mouse) blood. Two well-established MRSA IE models in rabbit and rat were used to validate these findings in vivo by demonstrating comparable synergistic efficacy with standard-of-care anti-MRSA antibiotics, at > 100-fold lower lysin doses in the rabbit vs the rat model. The unique properties of CF-301 which enable bactericidal potentiation of antimicrobial activity via activation of 'latent' host factors in human blood may have important therapeutic implications for the durable improvements in clinical outcomes of serious, antibiotic-resistant staphylococcal infections.

http://bit.ly/2W81sCV

Dose Selection and Validation for Ceftazidime-Avibactam in Adults with Complicated Intra-Abdominal Infections, Complicated Urinary Tract Infections and Nosocomial Pneumonia [Minireviews]

Avibactam is a non-β-lactam β-lactamase inhibitor that has been approved in combination with ceftazidime for the treatment of complicated intra-abdominal infections, complicated urinary tract infections and nosocomial pneumonia, including ventilator-associated pneumonia. In Europe, ceftazidime-avibactam is also approved for the treatment of Gram-negative infections with limited treatment options. Selection and validation of the ceftazidime-avibactam dosage regimen was guided by an iterative process of population pharmacokinetic (PK) modelling, whereby population PK models for ceftazidime and avibactam were developed using PK data from clinical trials and updated periodically. These models were used in probability of target attainment (PTA) simulations using joint pharmacodynamic (PD) targets for ceftazidime and avibactam derived from preclinical data. Joint PTA was calculated based on the simultaneous achievement of the individual PK/PD targets (50% free time above the ceftazidime-avibactam minimum inhibitory concentration (MIC) for ceftazidime and free time above a critical avibactam threshold concentration of 1 mg/l for avibactam). The joint PTA analyses supported a ceftazidime-avibactam dosage regimen of 2,000 + 500 mg every 8 h by 2-h intravenous infusion for patients with creatinine clearance (CrCL) >50 ml/min across all approved indications and modified dosage regimens for patients with CrCL ≤50 ml/min. Subgroup simulations for individual Phase III patients showed that the dosage regimen was robust, with high target attainment (>95%) against MICs ≤8 mg/l achieved regardless of older age, obesity, augmented renal clearance or severity of infection. This review summarizes how the approved ceftazidime-avibactam dosage regimens were developed and validated using PK/PD targets, population PK modeling, and PTA analyses.

http://bit.ly/2R5ERmz

Molecular Epidemiology of Emerging Carbapenem Resistance in Acinetobacter nosocomialis and Acinetobacter pittii in Taiwan, 2010-2014 [Epidemiology and Surveillance]

This study investigated the molecular epidemiology of carbapenem-resistant Acinetobacter nosocomialis and Acinetobacter pittii (ANAP). Clinical isolates of Acinetobacter spp. collected by the biennial nationwide Taiwan Surveillance of Antimicrobial Resistance program from 2010-2014 were subjected to species identification, antimicrobial susceptibility testing, and PCR for detection of carbapenemase genes. Whole genome sequencing or PCR mapping was performed to study the genetic surroundings of the carbapenemase genes. Among 1041 Acinetobacter isolates, the proportion of ANAP increased from 11% in 2010 to 22% in 2014. The rate of carbapenem resistance in these isolates increased from 7.5% (3/40) to 22% (14/64), with a concomitant increase in their resistance to other antibiotics. The bla_OXA-72 and bla_OXA-58 genes were highly prevalent in carbapenem-resistant ANAP. Various genetic structures were found upstream of bla_OXA-58 in different plasmids. Among the plasmids found to contain bla_OXA-72 flanked by XerC/XerD, pAB-NCGM253-like was identified in 8 of 10 isolates. Conjugations of plasmids carrying bla_OXA-72 or bla_OXA-58 to A. baumannii were successful. In addition, three isolates with chromosome-located bla_OXA-23 embedded in AbGRI1-type structure with disruption of genes other than comM were detected. Two highly similar plasmids carrying class I integron containing bla_IMP-1 and aminoglycoside resistance genes were also found. The universal presence of bla_{OXA-272/213-like} on A. pittii chromosomes and their lack of contribution to carbapenem resistance indicate its potential to be a marker for species identification. The increase of ANAP along with their diverse mechanisms of carbapenem resistance may herald their further spread and warrants close monitoring.

http://bit.ly/2Waa5fY

The Efficacy of Intranasal Administration of the Recombinant Endolysin, SAL200, in a Lethal Murine Staphylococcus aureus Pneumonia Model [Experimental Therapeutics]

SAL200 is derived from a phage endolysin and is a novel candidate drug for the treatment of Staphylococcus aureus infection. We investigated the efficacy of the recombinant endolysin SAL200 in a lethal murine pneumonia model. Lethal pneumonia was established by intranasally administering a methicillin-susceptible (Newman) or methicillin-resistant (LAC) S. aureus strain into BALB/c mice. The mice were treated with single intranasal administration of SAL200 or phosphate-buffered saline at 2 h after S. aureus infection. The survival rates were recorded until 60 h after the bacterial challenge. The bacterial loads in the lungs and blood, histopathology of lung tissues, and serum cytokine levels were evaluated following the S. aureus challenge. The SAL200-treated group and control group exhibited 90-95% and 10-40% survival rates, respectively. The bacterial loads in the lungs of the SAL200-treated group were significantly lower by ~10-fold than those of the control group as early as 1 h after treatment. Histopathologic recovery of pneumonia was observed in the SAL200-treated mice. The cytokine levels were comparable between groups. These results suggest that direct administration of SAL200 into the lungs could be a potential adjunct treatment against severe pneumonia caused by S. aureus.

http://bit.ly/2R8Yha4

A Novel {beta}-lactam Enhancer Zidebactam Augments the In vivo Pharmacodynamic Activity of Cefepime in Neutropenic Mouse Lung A. baumannii Infection Model [Mechanisms of Action]

WCK 5222 is a combination of cefepime and high-affinity PBP2-binding β-lactam enhancer, zidebactam. The cefepime-zidebactam combination is active against multi-drug resistant Gram-negatives including carbapenemases- expressing Acinetobacter baumannii. The mechanism of action of the combination involves concurrent multiple penicillin binding protein inhibition leading to enhanced bactericidal action of cefepime. The aim of the present study was to assess the impact of zidebactam-mediated enhanced in vitro bactericidal action in modulating the cefepime's %fT>MIC required for in vivo killing of A. baumannii. Cefepime and cefepime-zidebactam MICs were comparable and ranged between 2 to 16 mg/L for A. baumannii strains (n = 5) employed in the study. Against these strains, the time-kill studies revealed an improved killing with the cefepime-zidebactam combination as compared to standalone constituents. Employing neutropenic mouse lung infection model, exposure-response analyses for all the A. baumannii showed that cefepime fT>MIC required for 1 log₁₀ kill was 38.9%. In the presence of non-effective dose of zidebactam, cefepime fT>MIC dropped significantly to the extent of 15.5%, still rendering comparable bactericidal effect. Thus, zidebactam mediated improvement in cefepime's bactericidal effect observed in time-kill studies manifested in vivo through lowering of cefepime's pharmacodynamic requirement. This is a first ever study demonstrating β-lactam enhancer role of zidebactam that helps augment in vivo activity of cefepime by reducing the magnitude of its pharmacodynamically relevant exposures against A. baumannii.

http://bit.ly/2W81eM5

Synergistic antifungal effect of amphotericin B-loaded PLGA nanoparticle with ultrasound against C. albicans biofilms [Experimental Therapeutics]

C. albicans is a human opportunistic pathogen that causes superficial and life-threatening infections. An important reason for the failure of current antifungal drugs is related to biofilm formation, mostly associated with implanted medical devices. The present study investigated the synergistic antifungal efficacy of low-frequency and low-intensity ultrasound combined with amphotericin B-loaded PLGA nanoparticles (AmB-NPs) on C. albicans biofilms. AmB-NPs were prepared by a double emulsion method and demonstrated lower toxicity than free AmB. We then established biofilms and treated them with ultrasound and AmB-NPs separately or jointly in vitro and in vivo. The results demonstrated that the activity, biomass, and proteinase and phospholipase activities of biofilms were decreased significantly after the combination treatment of AmB-NPs with 42 KHz ultrasound irradiation at an intensity of 0.30 W/cm² for 15 min compared with the controls, with AmB alone, or with ultrasound treatment alone (P < 0.01). The morphology of the biofilms was altered remarkably after joint treatment based on confocal laser scanning microscopy (CLSM), especially in regard to reduced thickness and loosened structure. Furthermore, the same synergistic effects were found in a subcutaneous catheter biofilm rat model. The number of colony forming units from the catheter exhibited a significant reduction after AmB-NPs and ultrasound joint treatment for 7 continuous days, and CLSM and scanning electron microscopy (SEM) images revealed that the biofilm on the catheter surface was substantially eliminated. This method may provide a new noninvasive, safe, and effective therapy for C. albicans biofilm infection.

http://bit.ly/2R43MXK

DS86760016, a leucyl-tRNA synthetase inhibitor, with activity against Pseudomonas aeruginosa [Experimental Therapeutics]

DS86760016 is a new leucyl-tRNA-synthetase inhibitor in the preclinical development stage. DS86760016 showed potent activity against extended spectrum multidrug-resistant Pseudomonas aeruginosa isolated from clinical samples and in-vitro biofilms. In a murine catheter associated urinary tract infection model, DS86760016 treatment resulted in significant eradication of P. aeruginosa counts from kidney, bladder and catheter without developing drug-resistance. Our data suggest that DS86760016 has the potential to act as a new drug for the treatment of Pseudomonas infections.

http://bit.ly/2W81avP

Arylacetamide deacetylase (AADAC) gene polymorphism and HIV infection affect the exposure of Rifapentine: a population pharmacokinetics analysis. [Experimental Therapeutics]

Rifapentine is a rifamycin used to treat tuberculosis. As for rifampicin, plasma exposures of rifapentine are associated with treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, PXR, CAR, and AADAC on rifapentine exposure. Two studies evaluating novel regimens amongst Southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In RIFAQUIN, rifapentine was administered in the continuation phase of antituberculosis treatment in 1200mg once-weekly or 900mg twice-weekly doses. In Daily-RPE 450 or 600mg were given daily during the intensive-phase of treatment. Nonlinear mixed-effects modelling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1144 drug-concentration measurements, from 326 patients, were included in the analysis. Pharmacogenetic information was available for 162 patients. A one-compartment model with first-order elimination and transit compartment absorption described the data well. In a typical patient (body weight of 56kg, fat-free-mass of 45kg), the values of clearance and volume of distribution were 1.33L/h and 25L, respectively. Patients carrying the AA variant (65.4%) of AADAC rs1803155 were found to have 10.4% lower clearance. HIV+ infected patients had 21.9% lower bioavailability. Once weekly doses of 1200 mg were associated reduced clearance (-13.2%), compared to more frequently administered doses. Bioavailability was 23.3% lower amongst patients participating in the Daily-RPE study compared to RIFAQUIN. This is the first study to report the effect of AADAC rs1803155AA on rifapentine clearance. The observed increase in exposure is modest and unlikely to be of clinical relevance. The difference in bioavailability between the two studies is probably related to the different food concomitant to the dose. HIV coinfected patients had lower rifapentine exposures.

http://bit.ly/2R4pBWZ

Population Pharmacokinetic Analyses for Plazomicin Using Pooled Data from Phase 1, 2, and 3 Clinical Studies [Pharmacology]

Plazomicin is an aminoglycoside with activity against multidrug-resistant Enterobacteriaceae. Plazomicin is dosed on a mg/kg basis and administered by 30-min intravenous infusion every 24 h, with dose adjustments for renal impairment and body weight (BW) ≥125% of ideal BW. A population pharmacokinetic analysis was performed to identify patient factors that account for variability in pharmacokinetics and to determine if dose adjustments are warranted based on covariates. The analysis included 143 healthy adults and 421 adults with complicated urinary tract infection (cUTI), acute pyelonephritis, bloodstream infection, or hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) from seven studies (phases 1–3). A three-compartment structural pharmacokinetic model with a zero-order rate constant for the intravenous infusion and linear first-order elimination kinetics best described the plasma concentration–time profiles. The base structural model included creatinine clearance (CL_CR) as a time-varying covariate for clearance. The covariates included age, BW, height, body surface area, body mass index, sex, race, and disease-related factors. The range of α-, β-, and -phase half-lives for the analysis population are 0.328–1.58, 2.77–5.38, and 25.8–36.5 h, respectively. Total and renal clearance in a typical cUTI or HABP/VABP patient are 4.57 and 4.08 l/h, respectively. Starting dose adjustments for CL_CR are sufficient for minimizing variation in plasma exposure across patient populations; adjustments based on other covariates are not warranted. The results support initial dosing on a mg/kg basis with adjustments for CL_CR and BW. Subsequent adjustments based on therapeutic drug management are recommended in certain subsets of patients, including the critically ill and renal impaired.

http://bit.ly/2WbsY2j

Various evolutionary trajectories lead to loss of the tobramycin-potentiating activity of the quorum sensing inhibitor baicalin hydrate in Burkholderia cenocepacia biofilms [Mechanisms of Resistance]

Combining antibiotics with potentiators that increase their activity is a promising strategy to tackle infections caused by antibiotic-resistant bacteria. As potentiators do not interfere with essential processes, it has been hypothesized that they are less likely to induce resistance. However, evidence supporting this hypothesis is lacking. In the present study, we investigated whether Burkholderia cenocepacia J2315 biofilms develop reduced susceptibility towards one such adjuvant, baicalin hydrate (BH). Biofilms were repeatedly and intermittently treated with tobramycin (TOB) alone or in combination with BH for 24 h. After treatment, the remaining cells were quantified using plate counting. After 15 cycles, biofilm cells were less susceptible to TOB and TOB+BH, compared to the start population, and the potentiating effect of BH towards TOB was lost. WGS was performed to probe which changes were involved in the reduced effect of BH and mutations in 14 protein-coding genes were identified (including mutations in genes involved in central metabolism and in BCAL0296, encoding an ABC transporter). No changes in the MIC or MBC of TOB or changes in the number of persister cells were observed. However, basal intracellular levels of reactive oxygen species (ROS) and ROS levels found after treatment with TOB were markedly decreased in the evolved populations. In addition, in evolved cultures with mutations in BCAL0296, a significantly reduced uptake of TOB was observed. Our results indicate that B. cenocepacia J2315 biofilms rapidly loose susceptibility towards the antibiotic-potentiating activity of BH and point to changes in central metabolism, reduced ROS production, and reduced TOB uptake as mechanisms.

http://bit.ly/2R4pxGJ

CMCdG, a novel nucleoside analog, exerts potent activity against wild-type and entecavir-resistant HBV with favorable safety feature [Antiviral Agents]

We designed, synthesized, and characterized a novel nucleoside analog, (1S,3S,5S)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-5-hydroxy-1-(hydroxyl-methyl)-2-methylenecyclopentanecarbonitrile or 4'-cyano-methylenecarbocyclic-2'-deoxyguanosine (CMCdG) and evaluated its anti-HBV activity, safety, and related features. CMCdG's in vitro activity was determined using qPCR and Southern blotting assays and its cytotoxicity with MTT assay, while that of in vivo activity and safety were determined in wild-type HBV genotype-Ce (HBV_WT^Ce)- and ETV-resistant HBV (HBV_ETV-R^{L180M/S202G/M204V})-infected human-liver-chimeric mice. CMCdG potently inhibited HBV production in HepG2.2.15 cells (IC₅₀ ~30 nM) and HBV_WT^Ce-plasmid-transfected Huh7 cells (IC₅₀: 206 nM) and efficiently suppressed an ETV-resistant HBV_ETV-R^{L180M/S202G/M204V} (IC₅₀: 2,657 nM), while it showed no or least cytotoxicity (CC₅₀: >500 μM in most of hepatocytic cells examined). Two-week peroral administration of CMCdG (1 mg/kg/day, q.d.) to HBV_WT^Ce-infected human-liver-chimeric mice reduced viremia by ~2 logs. CMCdG also reduced HBV_ETV-R^{L180M/S202G/M204V} viremia by ~1 log in HBV_ETV-R^{L180M/S202G/M204V}-infected human-liver-chimeric mice, while ETV (1 mg/kg/day, q.d.) completely failed to reduce the viremia. None of the CMCdG-treated mice had significant drug-related changes in body-weights or serum human-albumin levels. Structural analyses using homology modeling, semi-empirical quantum methods, and molecular dynamics revealed that although ETV-triphosphates (TP) forms good van der Waals contacts with L180 and M204 of HBV_WT^Ce reverse transcriptase (RT), its contacts with M180 substitution are totally lost in the HBV_ETV-R^{L180M/S202G/M204V}-RT complex. However, CMCdG-TP retains good contacts with both HBV_WT^Ce- and HBV_ETV-R^{L180M/S202G/M204V}-RT complexes. The present data warrant further studies toward development of CMCdG as a potential therapeutic for infection with drug-resistant HBV and shed light on further development of more potent and safer anti-HBV agents.

http://bit.ly/2WbsR6T

APX001 Pharmacokinetic/Pharmacodynamic Target Determination against Aspergillus fumigatus in an in vivo Model of Invasive Pulmonary Aspergillosis [Experimental Therapeutics]

APX001, the prodrug of APX001A, is a first-in-class antifungal agent that has a potent activity against Aspergillus fumigatus. The goal of current study was to determine the pharmacodynamic (PD) index and target of APX001 in an immunocompromised murine model of invasive pulmonary aspergillosis against 6 A. fumigatus isolates. Minimum effective concentration (MEC) values ranged from 0.03 to 0.06 mg/liter. Dose fractionation was performed against isolate AF293 using total doses of APX001 ranging from 81 to 768 mg/kg/day fractionated into every 3-, 6-, and 8- hourly regimens over a 96-h treatment duration. Efficacy was assessed by A. fumigatus quantitative PCR (qPCR) of conidial equivalents from lung homogenates. Nonlinear regression analysis using the Hill equation demonstrated that the 24h AUC/MEC ratio was the PK/PD index that best correlated with efficacy (coefficient of determination [lsqb]R²[rsqb] = 0.79). Treatment studies with the remaining strains utilized regimens of 40 to 1536 mg/kg of APX001 administered every 3 h for a 96-h duration. Exposure-response relationships for all strains were similar and the median free drug AUC/MEC PK/PD targets for stasis and 1-log kill endpoint were 47.6 and 89.4, respectively. The present studies demonstrated in vitro and in vivo APX001A/APX001 potency against A. fumigatus. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints.

http://bit.ly/2R7hrwZ

Imidazole derivatives as promising agents for the treatment of Chagas disease{dagger} [Experimental Therapeutics]

More than 100 years later after being firstly described, Chagas disease remains endemic in 21 Latin American countries and has spread to other continents. Indeed, this disease, caused by the protozoan parasite Trypanosoma cruzi, is no longer just a problem for the American continent but has become a global health threat. Current therapies, nifurtimox and benznidazole (Bz), are far from being adequate due to undesirable effects and their lack of efficacy in the chronic phases of the disease. In this work, we present an in-depth phenotypical evaluation in T.cruzi of a new class of imidazole compounds, discovered in a previous phenotypic screening against different trypanosomatids and designed as potential inhibitors of cAMP phosphodiesterases (PDEs). The confirmation of several activities similar or superior to Bz prompted a synthesis program of hit optimization and extended SAR, aimed at improving drug-like properties such as aqueous solubility, resulting in additional hits with IC₅₀ similar to Bz. The cellular effects of one representative hit, compound 9, on bloodstream trypomastigotes were further investigated. Transmission electron microscopy revealed cellular changes, after just 2 h of incubation with the IC₅₀ concentration, that were consistent with induced autophagy and osmotic stress - mechanisms previously linked to cAMP signaling. Compound 9 induced highly significant increases in both cellular and medium cAMP, confirming that inhibition of T.cruzi PDE(s) is part of its mechanism of action. The potent and selective activity of this imidazole-based PDE inhibitor class against T.cruzi constitutes a successful repurposing of research into inhibitors of mammalian PDEs.

http://bit.ly/2WbFQ8B

The Short Chain Fatty Acid Butyrate Imprints an Antimicrobial Program in Macrophages

Macrophages maintain gut homeostasis by eliminating invasive pathogens and regulating inflammatory responses. Schulthess et al. demonstrate that butyrate, a bacterial fermentation product, imprints potent antimicrobial activity during macrophage differentiation through HDAC3i function.

http://bit.ly/2sPpgy1

Methylation Biomarker Panel Performance in EsophaCap Cytology Samples for Diagnosing Barrett's Esophagus: A Prospective Validation Study

Purpose: Barrett's esophagus (BE) is the only known precursor of esophageal adenocarcinoma (EAC). Although endoscopy and biopsy are standard methods for BE diagnosis, their high cost and risk limit their use as a screening modality. Here, we sought to develop a BE detection method based on methylation status in cytology samples captured by EsophaCap using a streamlined sensitive technique, methylation on beads (MOB). Experimental Design: We conducted a prospective cohort study on 80 patients (52 in the training set; 28 in the test set). We employed MOB to extract and bisulfite-convert DNA, followed by qMSP to assess methylation levels of 8 previously selected candidate markers. Lasso regression was applied to establish a prediction model in the training set, which was then tested on the independent test set. Results: In the training set, 5 of 8 candidate methylation biomarkers (p16, HPP1, NELL1, TAC1, and AKAP12) were significantly higher in BE patients than in controls. We built a 4-biomarker-plus-age lasso regression model for BE diagnosis. The AUC was 0.894, with sensitivity 94.4% (95% CI 71%~99%) and specificity 62.2% (95% CI 44.6%~77.3%) in the training set. This model also performed with high accuracy for BE diagnosis in an independent test set: AUC= 0.929 (P<0.001, 95% CI 0.810~1), with sensitivity = 78.6% (95% CI 48.8%~94.3%) and specificity = 92.8% (95% CI 64.1%~99.6%). Conclusions: EsophaCap, in combination with an epigenetic biomarker panel and the MOB method, is a promising, well-tolerated, low-cost esophageal sampling strategy for BE diagnosis. This approach merits further prospective studies in larger populations.

http://bit.ly/2U6XZ5y

Depression stresses the immune response and promotes prostate cancer growth

Depression induces secretion of neuropeptide Y from prostate cancer cells which, in turn, recruits MDSCs to the tumor; tumor cells and MDSC secrete IL-6, which activates STAT3 within cancer cells. Prostate cancer samples from depressed patients reveal a similar phenotype, suggesting new treatment strategies based upon blockade of β2 adrenergic receptors and/or neuropeptide Y.

http://bit.ly/2DswMVr

Agnostic-Histology Approval of new drugs in Oncology: are we already there?

Over the last years, several molecular aberrations have been unevenly described across cancers, although the distinct functional relevance in each biological context is not yet fully understood. Novel discoveries have led to the development of drugs tailored according to the molecular profile of patients, thus increasing the likelihood of response among biomarker-selected patients. In this context, there has been a progressive redefinition of a precision medicine framework where evidence-based development and earlier approvals might be now driven by this molecular information. Innovative trial designs have greatly facilitated the evaluation and approval of new drugs in small cohorts of orphan cancers in which histology-dependent molecularly-defined trials might be logistically difficult. However, accelerated approvals based on this agnostic-histology development model have brought new clinical, regulatory and reimbursement challenges. In this article we will highlight many of the biologic issues and clinical trial design challenges characterizing the development of tissue-agnostic compounds. Also, we will review some of the key factors involved in the development of pembrolizumab and larotrectinib, the first 2 drugs that have been approved by the US Food and Drug Administration in an histology-agnostic manner. Since we anticipate that agnostic-histology approvals will continue to grow, we aim to provide an insight into the current panorama of targeted drugs that are following this strategy and some premises to take into consideration. Clinicians and regulators should be prepared to overcome the associated potential hurdles, ensuring that uncertainties are dealt properly and allowing that new promising agents arrive faster into the market.

http://bit.ly/2U7Mxqn

Endogenous production of IL-1B by breast cancer cells drives metastasis and colonisation of the bone microenvironment.

Background: Breast cancer bone metastases are incurable highlighting the need for new therapeutic targets. After colonizing bone, breast cancer cells remain dormant, until signals from the microenvironment stimulate outgrowth into overt metastases. Here we show that endogenous production of IL-1B by tumor cells drives metastasis and growth in bone. Methods: Tumor/stromal IL-B and IL-1R1 expression was assessed in patient samples and effects of the IL-1R antagonist, Anakinra or the IL-1B antibody Canakinumab on tumor growth and spontaneous metastasis were measured in a humanized mouse model of breast cancer bone metastasis. Effects of tumor cell-derived IL-1B on bone colonisation and parameters associated with metastasis were measured in MDA-MB-231, MCF7 and T47D cells transfected with IL-1B/control. Results: In tissue samples from >1300 patients with stage II/III breast cancer, IL-1B in tumor cells correlated with relapse in bone (hazard ratio 1.85; 95% CI 1.05-3.26; P=0.02) and other sites (hazard ratio 2.09; 95% CI 1.26-3.48; P=0.0016). In a humanized model of spontaneous breast cancer metastasis to bone, Anakinra or Canakinumab reduced metastasis and reduced the number of tumor cells shed into the circulation. Production of IL-1B by tumor cells promoted EMT (altered E-Cadherin, N-Cadherin and G-Catenin), invasion, migration and bone colonisation. Contact between tumor and osteoblasts or bone marrow cells increased IL-1B secretion from all three cell types. IL-1B alone did not stimulate tumor cell proliferation. Instead, IL-1B caused expansion of the bone metastatic niche leading to tumor proliferation. Conclusion: Pharmacological inhibition of IL-1B has potential as a novel treatment for breast cancer metastasis.

http://bit.ly/2DtBIJO

L-Carnitine Mediated Tumor Cell Protection and Poor Patient Survival Associated with OCTN2 Overexpression in Glioblastoma Multiforme

Purpose: Apoptotic dysregulation, redox adaptive mechanisms and resilience to hypoxia are major causes of glioblastoma (GBM) resistance to therapy. Commonly known as crucial factors in energy metabolism, OCTN2 (SLC22A5) and its substrate L-carnitine (LC) are increasingly recognized as actors in cytoprotection. This study provides a comprehensive expression and survival analysis of the OCTN2/LC system in GBM and clarifies the system's impact on GBM progression. Experimental Design: OCTN2 expression and LC content were measured in 121 resected human GBM specimens and 10 healthy brain samples and analyzed for prognostic significance. Depending on LC administration, the effects of hypoxic, metabolic and cytotoxic stress on survival and migration of LN18 GBM cells were further studied in vitro. Finally, an orthotopic mouse model was employed to investigate inhibition of the OCTN2/LC system on in vivo GBM growth. Results: Compared to healthy brain, OCTN2 expression was increased in primary and even more so in recurrent GBM on mRNA and protein level. High OCTN2 expression was associated with a poor overall patient survival; the unadjusted hazard ratio for death was 2.7 (95%-CI, 1.47-4.91; p<0.001). LC administration to GBM cells increased their tolerance towards cytotoxicity whereas siRNA-mediated OCTN2 silencing led to a loss of tumor cell viability. In line herewith, OCTN2/LC inhibition by mildronate resulted in reduced tumor growth in an orthotopic GBM mouse model. Conclusions: Our data indicates a potential role of the OCTN2/LC system in GBM progression and resistance to therapy, and suggests OCTN2 as a prognostic marker in patients with primary GBM.

http://bit.ly/2Ud9qJ7

irRECIST for the Evaluation of Candidate Biomarkers of Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma: Analysis of a Phase II Prospective Clinical Trial

Purpose: irRECIST were designed to capture atypical responses seen with immunotherapy. We hypothesized that, in patients with metastatic clear cell Renal Cell Carcinoma (mccRCC), candidate biomarkers for nivolumab response would show improved association with clinical endpoints capturing atypical responders (irRECIST) compared to standard clinical endpoints (RECISTv1.1). Experimental Design: Endpoints based on RECISTv1·1 (ORR/PFS) or irRECIST (irORR/irPFS) were compared in patients enrolled in the CheckMate-010 trial. Pretreatment tumors were analyzed by PD-L1 and PD-L2 immunohistochemistry, and by multiplex-immunofluorescence for CD8, PD-1, TIM-3 and LAG-3. T-cell activation signatures were assessed by RNAseq. Results: Median irPFS was significantly longer than median PFS. irORR was not significantly different from ORR but irPD rate was significantly lower than PD rate. Tumor cell (TC) PD-L1 expression was not associated with PFS or ORR but patients with TC PD-L1 ≥ 1% had longer median irPFS and higher irORR. High percentage of CD8+ tumor infiltrating cells (TIC) that are PD-1+TIM-3-LAG-3- (% CD8+PD-1+TIM-3-LAG-3- TIC) correlated with high levels of T-cell activation and was associated with longer median irPFS and higher irORR. Notably, combination of TC PD-L1 expression with % CD8+PD-1+TIM-3-LAG-3- TIC identified 3 groups of patients for which irPFS and irORR were significantly different. Conclusions: Atypical responders to nivolumab were identified in the CheckMate-010 trial. We observed improved association of candidate biomarkers for nivolumab response with endpoints defined by irRECIST compared to RECISTv1.1. TC PD-L1 expression in combination with PD-1 expression on CD8+ TIC may predict outcome on nivolumab in mccRCC.

http://bit.ly/2DswKNj

Unstable genome and transcriptome dynamics during tumor metastasis contribute to therapeutic heterogeneity in colorectal cancers

Purpose: Genomic and transcriptomic alterations during metastasis are considered to affect clinical outcome of colorectal cancers (CRCs), but detailed clinical implications of metastatic alterations are not fully uncovered. We aimed to investigate the effect of metastatic evolution on in vivo treatment outcome, and identify genomic and transcriptomic alterations associated with drug responsiveness. Experimental Design: We developed and analyzed patient-derived xenograft (PDX) models from 35 CRC patients including five patients with multiple organ metastases (MOMs). We performed whole-exome, DNA methylation and RNA sequencing for patient and PDX tumors. With samples from patients with MOMs, we conducted phylogenetic and subclonal analysis and in vivo drug efficacy test on the corresponding PDX models. Results: Phylogenetic analysis using mutation, expression and DNA methylation data in patients with MOMs showed that mutational alterations were closely connected with transcriptomic and epigenomic changes during the tumor evolution. Subclonal analysis revealed that initial primary tumors with larger number of subclones exhibited more dynamic changes in subclonal architecture according to metastasis, and loco-regional and distant metastases occurred in a parallel or independent fashion. The PDX models from MOMs demonstrated therapeutic heterogeneity for targeted treatment, due to subclonal acquisition of additional mutations or transcriptomic activation of bypass signaling pathway during tumor evolution. Conclusions: This study demonstrated in vivo therapeutic heterogeneity of CRCs using PDX models, and suggests that acquired subclonal alterations in mutations or gene expression profiles during tumor metastatic processes can be associated with the development of drug resistance and therapeutic heterogeneity of CRCs.

http://bit.ly/2UasCqN

Role of Tumor Associated Macrophages in the Clinical Course of Pancreatic Neuroendocrine Tumors (PanNETs)

Purpose: This study evaluated the potential role of immune cells and molecules in the pathogenesis and clinical course of PanNET. Experimental Design: Surgically resected PanNETs (N=104) were immunohistochemically analyzed for Ki67 index, mitotic rate, macrophage, CD4+ cell, and CD8+ T cell infiltration, as well as HLA class I, PD-L1, and B7-H3 expression. Results were correlated with clinicopathological characteristics as well as with disease-free (DFS) and disease-specific (DSS) survival. Results: The median age of the 57 WHO grade 1 and 47 WHO grade 2 patients was 54.5 years. High intratumoral CD8+ T cell infiltration correlated with prolonged DFS (P=0.05), especially when the number of tumor-associated macrophages (TAMs) was low. In contrast, high peritumoral CD4+ cell and TAM infiltration were associated with a worse DFS and DSS. PD-L1 and B7-H3 were expressed in 53 and 78% PanNETs, respectively. HLA class I expression was defective in about 70% PanNETs. HLA-A class I expression correlated with favorable DSS in PD-L1-negative tumors (P=0.02). TAM infiltration (P=0.02), WHO grade (P=0.04), T stage (P=0.01), and lymph node positivity (P=0.04) were independent predictors of DFS. TAM infiltration (P=0.026) and T stage (P=0.012) continued to be predictors of DFS in WHO grade 1 PanNET patients. TAM infiltration was the sole independent predictor of DSS for WHO grade 1 and 2 patients (P=0.02). Therefore, this biomarker may contribute to identify WHO grade 1 patients with poor prognosis. Conclusions: TAM infiltration appears to be the most informative prognostic biomarker in PanNET. It may represent a useful immunotherapeutic target in PanNET patients.

http://bit.ly/2DtIWh0

The CD98 heavy chain is a marker and regulator of head and neck squamous cell carcinoma radiosensitivity

Purpose: The heavy chain of the CD98 protein (CD98hc) is encoded by the SLC3A2 gene. Together with the light subunit LAT1, CD98hc constitutes a heterodimeric transmembrane amino acid transporter. High SLC3A2 mRNA expression levels are associated with poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC) treated with radiochemotherapy. Little is known regarding the CD98hc protein mediated molecular mechanisms of tumor radioresistance. Experimental Design: CD98hc protein expression levels were correlated with corresponding tumor control dose 50 (TCD50) in HNSCC xenograft models. Expression levels of CD98hc and LAT1 in HNSCC cells were modulated by siRNA or CRISPR/Cas9 gene editing. HNSCC cell phenotypes were characterized by transcription profiling, plasma membrane proteomics, metabolic analysis and signaling pathway activation. Expression levels of CD98hc and LAT1 proteins were examined by immunohistochemical analysis of tumor tissues from patients with locally advanced HNSCC treated with primary radiochemotherapy (RCTx). Primary endpoint was loco-regional tumor control (LRC). Results: High expression levels of CD98hc resulted in an increase in mTOR pathway activation, amino acid metabolism and DNA repair as well as downregulation of oxidative stress and autophagy. High expression levels of CD98hc and LAT1 proteins were significantly correlated and associated with an increase in radioresistance in HNSCC in vitro and in vivo models. High expression of both proteins identified a poor prognosis subgroup in patients with locally advanced HNSCC after RCTx. Conclusions:

http://bit.ly/2U7Mueb

EGFR/Notch Antagonists Enhance the Response to Inhibitors of the PI3K-Akt Pathway by Decreasing Tumour-Initiating Cell Frequency

Purpose: Both EGFR and PI3K-Akt signalling pathway have been used as therapeutically actionable targets, but resistance is frequently reported. In this report, we show that enrichment of the cancer stem cell (CSC) subsets and dysregulation of Notch signalling underlie the challenges to therapy and describe the development of bispecific antibodies targeting both HER and Notch signalling. Experimental Design: We utilized cell-based models to study Notch signalling in drug induced CSC expansion. Both cancer cell line models and patient-derived xenograft tumours were used to evaluate the antitumour effects of bispecific antibodies. Cell assays, flow cytometry, qPCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts. Results: We found that EGFR/Notch targeting bispecific antibodies exhibited a notable anti-stem cell effect in both in vitro and in vivo assays. Bispecific antibodies delayed the occurrence of acquired resistance to EGFR inhibitors in TNBC cell-line based models and showed efficacy in patient-derived xenografts. Moreover, the EGFR/Notch bispecific antibody PTG12 in combination with GDC-0941 exerted a stronger antitumour effect than the combined therapy of PI3K inhibitor with EGFR inhibitors or tarextumab in a broad spectrum of epithelial tumours. Mechanistically, bispecific antibody treatment inhibits the stem cell-like subpopulation, reduces tumour-initiating cell frequency and downregulates the mesenchymal gene expression. Conclusions: These findings suggest that the co-blockade of EGFR and Notch signalling has the potential to increase the response to PI3K inhibition and PTG12 may gain clinical efficacy when combined with PI3K blockage in cancer treatment.

http://bit.ly/2DswIFb

YH25448, an irreversible EGFR-TKI with Potent Intracranial Activity in EGFR mutant non-small-cell lung cancer

Purpose:Given that osimertinib is the only approved third-generation EGFR-TKI against EGFR activating and resistant T790M mutated NSCLC, additional mutant-selective inhibitors with a higher efficacy, especially for brain metastases, with favorable toxicity profile are still needed. In this study, we investigated the antitumor efficacy of YH25448, an oral, mutant-selective, irreversible third-generation EGFR-TKI in preclinical models. Experimental Design:Antitumor activity of YH25448 was investigated in vitro using mutant EGFR-expressing Ba/F3 cells and various lung cancer cell lines. In vivo antitumor efficacy, ability to penetrate the blood-brain barrier (BBB), and skin toxicity of YH25448 were examined and compared with those of osimertinib using cell lines- and PDX model. Results:Compared to osimertinib, YH25448 showed a higher selectivity and potency in kinase assay and mutant EGFR-expressing Ba/F3 cells. In various cell line models harboring EGFR activating and T790M mutation, YH25448 effectively inhibited EGFR downstream signaling pathways, leading to cellular apoptosis. When compared in vivo at equimolar concentrations, YH25448 produced significantly better tumor regression than osimertinib. Importantly, YH25448 induced profound tumor regression in brain metastasis model with excellent brain/plasma and tumor/brain area under the concentration-time curve value. YH25448 rarely suppressed the levels of p-EGFR in hair follicles, leading to less keratosis than osimertinib in animal model. The potent systemic and intracranial activity of YH25448 has been shown in an ongoing phase I/II clinical trial for advanced EGFR T790M mutated NSCLC (NCT03046992). Conclusions:Our findings suggest that YH25448 is a promising third-generation EGFR inhibitor, which may be more effective and better tolerated than the currently approved osimertinib.

http://bit.ly/2U9tcVW

http://bit.ly/2FRAKIR

Editorial Board

http://bit.ly/2FIuLH2

How are Pediatric Tracheostomy Decisions Discussed? An Analysis of Pediatric Tracheostomy Decision Processes (S876)

Parents of critically ill children who are ventilator dependent are often asked to consider the placement of a tracheostomy. This decision has substantial implications over the life of the child and the family. Many healthcare professionals and parents find this decision process difficult. Understanding tracheostomy decision processes may inform researchers to develop decisions tools for promoting high-quality provider-parent communication and decision making.

http://bit.ly/2FS4Fk5

Cannabis Use Among Patients Prescribed Opioids in a Palliative Care Clinic (S875)

Cannabis use is increasing in the United States. Palliative care patients utilize it to manage various symptoms, but there is little data about its use in this population.

http://bit.ly/2FMgIAv

Bereavement Interventions for Grieving Family Members: A Systematic Review (S874)

Bereavement care is part of palliative care that continues after patient deaths. It is important to determine what interventions are helpful and contribute to positive outcomes since supporting the bereaved may prevent long-term negative problems. The purpose of this systematic review was to review and evaluate the evidence regarding bereavement interventions for bereaved adults during the first year of bereavement.

http://bit.ly/2FRB36t

Testing Usability and Acceptance of the Electronic Patient Visit Assessment (ePVA) for Head and Neck Cancer: An Iterative Process (S873)

Patients with head and neck cancer experience substantial symptom burden. A clinically useful tool is needed to evaluate symptoms for early detection of symptoms and functional limitations. Therefore, we developed a web-based electronic patient visit assessment (ePVA) for head and neck cancer. Using an iterative process to identify issues related to usability of the tool is imperative for the implementation of the ePVA in clinical settings.

http://bit.ly/2FKH45y

An Opportunity for Palliative Care: Symptom Burden in Patients with Amyloidosis (S872)

Although significant symptom burden has been described in patients with amyloidosis, few studies have used a validated tool to assess symptom burden or severity. Amyloidosis has many similarities to cancer; prognosis is poor, multiple organs may be involved, and treatment toxicities are common.

http://bit.ly/2FXRrCH

Αρχειοθήκη ιστολογίου

Αναζήτηση αυτού του ιστολογίου

Τρίτη 22 Ιανουαρίου 2019

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