Pharmacokinetic/pharmacodynamic analysis of adjunctive perampanel in subjects with partial-onset seizures

Objectives

Explore perampanel pharmacokinetics (PK) in all subjects (aged ≥12 years) vs adolescents (aged ≥12 to ≤17 years) with partial-onset seizures (POS) and identify factors explaining between-subject variability in efficacy using a population PK/pharmacodynamic (PD) analysis.

Materials & methods

Population PK analysis was performed using nonlinear mixed-effect modeling with data from phase II/III randomized, double-blind, placebo-controlled studies of adjunctive perampanel in POS. Perampanel exposure was predicted for all subjects and adolescents. Population PK/PD analyses were performed using data from phase III studies to explore the relationship between perampanel exposure and 28-day average seizure frequency and responder probability.

Results

Pooled perampanel PK data from 1318 subjects were described by a one-compartment disposition model. In the absence of antiepileptic drugs (AEDs) affecting perampanel PK, estimated perampanel apparent clearance (CL/F) was 0.668 L/h (all subjects) and 0.682 L/h (adolescent subjects). Co-administration of carbamazepine and oxcarbazepine/phenytoin reduced perampanel exposure. Gender, Asian race (excluding Japanese or Chinese), and increasing alanine aminotransferase lowered perampanel CL/F, but differences were small and not considered clinically relevant. Adolescent outcomes were similar to the total population. Based on PK/PD data from 1748 subjects, percent reduction in 28-day average seizure frequency from baseline and responder probability increased with increasing perampanel exposure; concomitant CYP3A-inducing AEDs lowered perampanel exposure but did not impact the slope for responder probability.

Conclusions

These results are consistent with previous analyses but expand on these through inclusion of a larger number of patients from different ethnic groups, and demonstrate that outcomes were similar between adults and adolescents.

http://ift.tt/2ia4jfi

Prognosis of status epilepticus in elderly patients

Purpose

To evaluate the clinical features and prognosis of status epilepticus (SE) in patients above 70 years old.

Methods

Retrospective analysis of all patients ≥70 years old with SE registered prospectively during 4 years. Follow-up after discharge was performed.

Results

Ninety patients were evaluated. Acute symptomatic etiology was the most prevalent. The mean number of antiepileptic drugs (AEDs) used was 2.7 ± 1.2, and 21% of the patients required sedation. A poor outcome was considered when death (31.1%) or developing of new neurological impairment at discharge (32.2%) occurred. After multivariate analysis, four variables predicted a poor outcome: acute symptomatic etiology (OR: 6.320; 95% CI: 1.976-20.217; P = .002), focal motor SE type (OR: 9.089; 95% CI: 2.482-33.283; P = .001), level of consciousness (OR: 4.596; 95% CI: 1.903-11.098; P = .001), and SE duration >12 hours (OR: 3.763; 95% CI: 1.130-12.530; P = .031). Independent predictive factors of mortality were SE duration >12 hours (OR: 4.306; 95% CI: 1.044-17.757; P = .043), modified Status Epilepticus Severity Score (mSTESS) (OR: 2.216; 95% CI: 1.313-3.740; P = .003), and development of complications (OR: 3.334; 95% CI: 1.004-11.070, P = .049). Considering long-term mortality, age (HR 1.036; 95% CI 1.001-1.071; P = .044), a potentially fatal underlying cause (HR 2.609; 95% CI 1.497- 4.548; P = .001), and mSTESS score >4 (HR 1.485; 95% CI 1.158-1.903; P = .002) remained as predictive factors. There was no association between sedation and the number of AEDs used with outcome at discharge or long-term mortality (P > .05). Conclusions: SE above 70 years old has a high morbimortality. Prognosis is not related to treatment aggressiveness.

http://ift.tt/2AenLym

Seizures, CSF neurofilament light and tau in patients with subarachnoid haemorrhage

Objectives

Patients with severe subarachnoid haemorrhage (SAH) often suffer from complications with delayed cerebral ischaemia (DCI) due to vasospasm that is difficult to identify by clinical examination. The purpose of this study was to monitor seizures and to measure cerebrospinal fluid (CSF) concentrations of neurofilament light (NFL) and tau, and to see whether they could be used for predicting preclinical DCI.

Methods

We prospectively studied 19 patients with aneurysmal SAH who underwent treatment with endovascular coiling. The patients were monitored with continuous EEG (cEEG) and received external ventricular drainage (EVD). CSF samples of neurofilament light (NLF) and total tau (T-tau) protein were collected at day 4 and day 10. Cox regression analysis was applied to evaluate whether seizures and protein biomarkers were associated with DCI and poor outcome.

Results

Seven patients developed DCI (37%), and 4 patients (21%) died within the first 2 months. Six patients (32%) had clinical seizures, and electrographic seizures were noted in one additional patient (4.5%). Increased tau ratio (proportion tau10/tau4) was significantly associated with DCI and hazard ratio [HR=1.33, 95% confidence interval (CI) 1.055-1.680. P = .016].

Conclusion

Acute symptomatic seizures are common in SAH, but their presence is not predictive of DCI. High values of the tau ratio in the CSF may be associated with development of DCI.

http://ift.tt/2ia3Idy

Serial electrophysiology in Guillain-Barré syndrome: A retrospective cohort and case-by-case multicentre analysis

Objectives

To assess the usefulness of serial electrophysiology in Guillain-Barré syndrome (GBS) in a multicenter setting and the reasons for change in electrodiagnostic subtypes with serial studies.

Methods

We retrospectively analysed serial electrophysiology of 51 patients with GBS from 4 European centres. Proportions of subtypes were determined at each timing. Individual case analyses were also performed where diagnostic changes occurred with either criteria, to ascertain if changes were due to disease progression or criteria inadequacy.

Results

At first study, comparing old vs new criteria, acute inflammatory demyelinating polyneuropathy (AIDP) was diagnosed in 70.6% vs 51%, axonal GBS in 15.7% vs 39.2%, equivocal forms in 11.8% vs 7.8%. At second study, AIDP was diagnosed in 72.5% vs 52.9%, axonal GBS in 9.8% vs 33.3%, equivocal forms in 15.7% vs 11.7%. Subtype proportions were unchanged, indicating serial studies did not, in the cohort, alter diagnostic rates for each subtype irrespective of criteria used. Individual review of cases where subtype electrodiagnosis changed indicated suboptimal specificity for AIDP/sensitivity for axonal GBS as main cause of diagnostic shifts with old criteria, whereas disease progression explained most changes with new criteria (55.6% vs 81.8%; P = .039).

Conclusions

Serial electrophysiology is unhelpful in GBS. Repeat studies cannot represent the gold standard as electrodiagnosis may alter due to disease progression. Changes in electrodiagnosis relate more often to disease progression with new criteria but are more frequently due to suboptimal sensitivity/specificity with old criteria. A single electrophysiological study using the most accurate available criteria appears sufficient in GBS.

http://ift.tt/2AcJDu9

Vocational outcome in cerebral venous thrombosis: Long-term follow-up study

Abstract

Objectives

Few studies have investigated long-term functional outcome in patients with cerebral venous thrombosis (CVT). We aimed to evaluate return to work (RTW) after CVT and its association with self-reported life satisfaction, quality of life, health, participation, fatigue, depression, and anxiety.

Methods

From hospital records, we identified all patients diagnosed with CVT in Sahlgrenska University Hospital between 1996 and 2016 and invited all survivors to a clinical follow-up visit >1 year after onset. Primary outcome was RTW within the follow-up period which was defined as ≥50% of gainful work or equivalent activity. Patients that were >62 years when they developed CVT were excluded. Cox regression analyses identified associated factors to RTW and Mann-Whitney U tests compared distributions of self-reported questionnaires on life satisfaction and health.

Results

Of 62 eligible and consenting patients (median age: 41.5 years (28.75-51.0); 61.3% female), 44 (71.0%) did RTW within the follow-up period (median 135 months, IQR 64-197). Median time to RTW was 7.0 months (IQR 1.4-12.7). Female sex (HR = 0.50, 95% CI = 0.25-0.99, P = .049) and parenchymal lesion detected during acute hospital stay (HR = 0.45, 95% CI = 0.24-0.82, P = .009) were significantly associated with no RTW. Patients with RTW reported significantly higher life satisfaction, quality of life, health, participation and lesser impact of fatigue, depression, and anxiety.

Conclusions

Return to work after CVT is associated with higher life satisfaction, participation, and health. Parenchymal lesion in acute phase and female sex were associated with no RTW. Despite the young age of the patients, a significant portion did not regain working ability.

http://ift.tt/2ia4bwk

Real-life clinical use of natalizumab and fingolimod in Austria

Objectives

To compare the efficacy of natalizumab or fingolimod in a nationwide observational cohort using prospectively collected data.

Materials and methods

We included all patients starting treatment with natalizumab or fingolimod documented in the Austrian MS Treatment Registry (AMSTR) from 2011 and staying on therapy for at least 24 months. We used propensity scores for several matching methods and as a covariate in multivariate models to correct for the bias of this non-randomized registry study.

Results

The study cohort includes 588 patients with RRMS. Ten patients did not produce a propensity score in the common support region, thus leaving 578 cases for final analyses, 332 in the fingolimod and 246 in the natalizumab group. Mean annualized relapse rates (ARR) during the 24 months observation period were 0.19 under fingolimod and 0.12 under natalizumab treatment (P = .005). No statistical significant differences were found analysing the log-transformed ARR, probability for experiencing a relapse, EDSS progression and EDSS regression. The hazard ratio for switching treatment from fingolimod comparing with natalizumab was 0.36 (95% CI: 0.247-0.523), P < .001.

Conclusions

The generalized linear model (GLM) for relapse count as Poisson distributed dependent variable and propensity score as covariate showed a statistically significant reduction for the mean relapse count in the natalizumab group compared with fingolimod. This effect was smaller in the analyses of log-transformed ARR with propensity score matching, loosing statistical significance although showing the same direction for the effect. We assume that the GLM was the more sensitive model analysing this question.

http://ift.tt/2AenF9Y

Aneuploidy, TP53 mutation, and amplification of MYC correlate with increased intratumor heterogeneity and poor prognosis of breast cancer patients

Abstract

The clinical course of breast cancer varies from one patient to another. Currently, the choice of therapy relies on clinical parameters and histological and molecular tumor features. Alas, these markers are informative in only a subset of patients. Therefore, additional predictors of disease outcome would be valuable for treatment stratification. Extensive studies showed that the degree of variation of the nuclear DNA content, i.e., aneuploidy determines prognosis. Our aim was to further elucidate the molecular basis of aneuploidy. We analyzed five diploid and six aneuploid tumors with more than 20 years of follow-up. By performing FISH with a multiplexed panel of 10 probes to enumerate copy numbers in individual cells, and by sequencing 563 cancer-related genes, we analyzed how aneuploidy is linked to intratumor heterogeneity. In our cohort, none of the patients with diploid tumors died of breast cancer during follow-up in contrast to four of six patients with aneuploid tumors (mean survival 86.4 months). The FISH analysis showed markedly increased genomic instability and intratumor heterogeneity in aneuploid tumors. MYC gain was observed in only 20% of the diploid cancers, while all aneuploid cases showed a gain. The mutation burden was similar in diploid and aneuploid tumors, however, TP53 mutations were not observed in diploid tumors, but in all aneuploid tumors in our collective.

We conclude that quantitative measurements of intratumor heterogeneity by multiplex FISH, detection of MYC amplification and TP53 mutation could augment prognostication in breast cancer patients. This article is protected by copyright. All rights reserved.

http://ift.tt/2AjKQO5

Functions of the multi-interacting protein KIDINS220/ARMS in cancer and other pathologies

Abstract

Development of an organ and subsequently the whole system from an embryo is a highly integrated process. Although there are evidence that different systems are interconnected during developmental stages, the molecular understanding of this relationship is either not known or only to a limited extent. Nervous system development, amongst all, is maybe the most crucial and complex process. It relies on the correct distribution of specific neuronal growth factors and hormones to the specific receptors. Among the plethora of proteins that are involved in downstream signalling of neuronal growth factors, we find the Kinase-D Interacting Substrate of 220 kDa (KIDINS220), also known as Ankyrin-rich Repeat Membrane Spanning (ARMS) protein. KIDINS220 has been shown to play a substantial role in the nervous system and vascular system development as well as in neuronal survival and differentiation. It serves as a downstream regulator for many important neuronal and vascular growth factors such as Vascular Endothelial Growth Factor (VEGF), the neurotrophin family, glutamate receptors and ephrin receptors. Moreover, activation and differentiation of B- and T-cells, as well as tumour cell proliferation has also shown to be related KIDINS220. This review comprehensively summarises the existing research data on this protein, with a particular interest in its role in cancer and in other pathologies. This article is protected by copyright. All rights reserved.

http://ift.tt/2zvCMs4

Serial lipase for pancreatitis: not enough evidence

Background

Lipase is both a sensitive and specific marker for diagnosing pancreatitis. However, the benefit of serial lipase in both monitoring and defining prognosis remains undetermined. This systematic review was conducted to further evaluate this potential application. In addition, this review also looked into the benefits of serial lipase in the subgroup of traumatic pancreatitis.

Methods

PubMed, Cochrane Library and Google Scholar were systematically searched for related articles, between January 1995 and December 2015, according to Preferred Reporting Items for Systematic Reviews and Meta-analyses standards. Data was extracted and analysed by two authors.

Results

Seven studies were included in the final analysis: six retrospective and one prospective studies were identified. Five studies (all retrospective) concluded no benefits in serial lipase for prognostication, while two studies identified serial lipase as a beneficial prognostic factor for acute pancreatitis. Of the included studies, only two involved traumatic pancreatitis (both dedicated to the paediatric population).

Conclusion

The evidence supporting or opposing serial lipase as a prognostic factor for pancreatitis is weak and consists mainly of retrospective analyses. The only prospective data identified suggested benefits to serial lipase in prognosis. Further prospective studies evaluating the prognostic value of serial lipase in the adult population with both traumatic and non-traumatic pancreatitis are required given the paucity of available evidence.

http://ift.tt/2zMh5bq

Phantom validation of quantitative Y-90 PET/CT-based dosimetry in liver radioembolization

Abstract

Background

PET/CT has recently been shown to be a viable alternative to traditional post-infusion imaging methods providing good quality images of ⁹⁰Y-laden microspheres after selective internal radiation therapy (SIRT). In the present paper, first we assessed the quantitative accuracy of ⁹⁰Y-PET using an anthropomorphic phantom provided with lungs, liver, spine, and a cylindrical homemade lesion located into the hepatic compartment. Then, we explored the accuracy of different computational approaches on dose calculation, including (I) direct Monte Carlo radiation transport using Raydose, (II) Kernel convolution using Philips Stratos, (III) local deposition algorithm, (IV) Monte Carlo technique (MCNP) considering a uniform activity distribution, and (V) MIRD (Medical Internal Radiation Dose) analytical approach. Finally, calculated absorbed doses were compared with those obtained performing measurements with LiF:Mg,Cu,P TLD chips in a liquid environment.

Results

Our results indicate that despite ⁹⁰Y-PET being likely to provide high-resolution images, the ⁹⁰Y low branch ratio, along with other image-degrading factors, may produce non-uniform activity maps, even in the presence of uniform activity. A systematic underestimation of the recovered activity, both for the tumor insert and for the liver background, was found. This is particularly true if no partial volume correction is applied through recovery coefficients. All dose algorithms performed well, the worst case scenario providing an agreement between absorbed dose evaluations within 20%. Average absorbed doses determined with the local deposition method are in excellent agreement with those obtained using the MIRD and the kernel-convolution dose calculation approach.

Finally, absorbed dose assessed with MC codes are in good agreement with those obtained using TLD in liquid solution, thus confirming the soundness of both calculation approaches. This is especially true for Raydose, which provided an absorbed dose value within 3% of the measured dose, well within the stated uncertainties.

Conclusions

Patient-specific dosimetry is possible even in a scenario with low true coincidences and high random fraction, as in ⁹⁰Y–PET imaging, granted that accurate absolute PET calibration is performed and acquisition times are sufficiently long. Despite Monte Carlo calculations seeming to outperform all dose estimation algorithms, our data provide a strong argument for encouraging the use of the local deposition algorithm for routine ⁹⁰Y dosimetry based on PET/CT imaging, due to its simplicity of implementation.

http://ift.tt/2jrFmsk

Management of hereditary breast and ovarian cancer

Abstract

Hereditary breast and ovarian cancer (HBOC) syndrome represents 5−10% of all breast cancers. In Japan, the HBOC syndrome is frequently diagnosed in patients with breast cancer. Therefore, a treatment strategy combining a plan for existing breast cancer and for reduction of future breast and ovarian cancer risk is necessary. Breast cancer risk-reducing management involves three options—surveillance, chemoprevention, and risk-reducing mastectomy (RRM). RRM can prevent >90% of new breast cancers. Ovarian cancer risk management options are more limited, and risk-reduction salpingo-oophorectomy is the only option since there is no proven effective early detection method available. The local recurrence rate following breast-conserving surgery in BRCA1/2 mutation-associated breast cancer is not significantly higher than that in sporadic breast cancer. Furthermore, there is no difference in prognosis between surgical methods. Clinicians should inform patients that there are no data on long-term monitoring and fully discuss risks of re-developing breast cancer with patients when choosing the surgical method. In HBOC, BRCA1/2 mutations lead to failure of double-strand DNA break repair, with poly ADP-ribose polymerase (PARP) playing an important role in single-strand DNA nick repair. Use of PARP inhibitors in HBOC prevents DNA repair (synthetic lethality) leading to cell death. This review summarizes management of the HBOC syndrome based on recent evidence.

http://ift.tt/2AhdG1n

Effect of Xylan Sulfates on Coagulation of Human Blood Plasma

Sulfated derivatives of xylan (isolated from Bétula pubéscens wood) with average molecular weight ~34 kDa, sulfur content of 11.3-17.5%, a degree of substitution of 0.74-1.64 are anticoagulants of direct type of action. Antithrombin and antifactor Xa activities in three tested xylan samples did not differ and reached 30.8-31.8 and 13.5-14.3 U/mg, respectively.

http://ift.tt/2ADmlyc

Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer

Abstract

Background

In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy (2 cycles of cisplatin 50 mg/m2 in week 1 and 4 of RT, followed by 4 cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required prior to patient enrolment. The aim of this analysis was to evaluate the role of central pathology review before randomisation.

Patients and methods

A total of 1295 cases underwent pathology review to confirm HR-EC in the Netherlands (n=395) and the United Kingdom (n=900), and for 1226/1295 (95%) matching review and original reports were available. 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the United Kingdom, comprising 48% of the total PORTEC-3 cohort of 686 participants. Areas of discrepancies were evaluated, and inter-observer agreement between original and review opinion was evaluated by calculating the kappa value (κ).

Results

In the 1226 pathology reviews, 6356 selected items were evaluable for both original and review pathology. In 43% of cases at least one pathology item changed after review. For 102 patients (8%), this discrepancy led to ineligibility for the PORTEC-3 trial, most frequently due to differences in the assessment of histological type (34%), endocervical stromal involvement (27%) and histological grade (19%). Lowest inter-observer agreement was found for histological type (κ = 0.72), lymph-vascular space invasion (κ = 0.72) and histological grade (κ = 0.70).

Conclusion

Central pathology review by expert gynaeco-pathologists changed histological type, grade or other items in 43% of women with HR-EC, leading to ineligibility for the PORTEC-3 trial in 8%. Upfront pathology review is essential to ensure enrolment of the target trial-population, and to avoid over- or undertreatment, especially when treatment modalities with substantial toxicity are involved.This study is registered with ISRCTN (ISRCTN14387080, http://ift.tt/HkCGY7) and with ClinicalTrials.gov (NCT00411138).

http://ift.tt/2zMrSSQ

Puff laddy: a 5-year-old-boy with forehead swelling

Description

A 5-year-old boy presented with forehead swelling in the setting of a recent sinus infection. His initial symptoms were fever and nasal congestion for which he was prescribed a 10-day course of antibiotics, completed 3 days prior to admission. He subsequently developed unsteady gait, photophobia, headache, vomiting and progressive forehead swelling. He was noted to have central forehead oedema and tenderness without overlying erythaema (figure 1). There were no neurological or ophthalmological deficits. Magnetic Resonance Imaging (MRI)/Magnetic Resonance Venography (MRV) of the head demonstrated a 3.5x1.2x3.9 cm subgaleal abscess with communication to the frontal sinuses as well as osteomyelitis of the frontal bone (figure 2). The patient underwent surgical drainage of the abscess with evacuation of purulent fluid (figure 3). Culture from the procedure grew Streptococcus anginosus. He clinically improved following surgery and was transitioned home to complete a 21-day total course of antibiotics.

...

http://ift.tt/2Aaows5

Brief psychotic episode in a patient with chromosome 2q37 microdeletion syndrome

A 21-year-old woman with moderate learning disability secondary to chromosome 2 microdeletion at q37 was admitted to a general adult psychiatric ward following a period of agitation with incessant pressure of speech, nihilistic delusions and worsening of sleep and eating patterns. Her presentation was preceded for a number of weeks by social stressors of an ill family member and another family member moving away. She had also been diagnosed and treated for a respiratory infection several weeks prior to presentation. Her presentation improved with low-dose antipsychotic medication and parallel input from the general adult mental health team and the psychiatry of intellectual disability team.

http://ift.tt/2icwH0x

Treatment of advanced colorectal cancer in a patient with cardiotoxic reactions to 5-fluorouracil and capecitabine using suboptimal doses

A 32-year-old female with stage IV colorectal cancer and metastasis to the liver experienced cardiotoxic reactions after treatment with 5-fluorouracil and its oral prodrug capecitabine even at two-thirds the recommended dose. After careful considerations, the decision was made to attempt capecitabine retrial at a further suboptimal dose with combination chemotherapy where she no longer experienced cardiac events. As a result, the liver tumour shrank and rectal mass stabilised, tumour markers dropped and she underwent surgical resection of both masses. Later there was local recurrence of disease near the previous liver tumour, so the suboptimal capecitabine therapy was restarted without complaint. The patient became a candidate for a NanoKnife procedure, offering a potentially curative therapy. This case report summarises a novel treatment strategy for those patients with advanced colorectal cancer who experience cardiotoxic reactions to fluoropyrimidines, the active agent of gold standard treatment.

http://ift.tt/2k3QBLr

Dying art of a history and physical: pulsatile tinnitus

Modern medicine often leaves the history and physical by the wayside. Physicians instead skip directly to diagnostic modalities like MRI and angiography. In this case report, we discuss a patient who presented with migraine symptoms. Auscultation revealed signs of pulsatile tinnitus. Further imaging concluded that it was secondary to a type I dural arteriovenous fistula. Thanks to a proper and thorough history and physical, the patient was streamlined into an accurate and efficient work-up leading to symptomatic relief and quality of life improvement. Imaging is a powerful adjunctive technique in modern medicine, but physicians must not rely on machines to diagnose their patients. If this trend continues, it will have a tremendous negative impact on the cost and calibre of healthcare. Our hope is that this case will spread awareness in the medical community, urging physicians to use the lost art of a history and physical.

http://ift.tt/2i9XXws

Inverse hypopyon (hyperoleon) at the posterior segment in pathological myopia

Description

A 54-year-old woman presented a year after vitreoretinal surgery with silicone oil injection in the left eye. The left eye showed emulsified silicone oil in the anterior chamber and a posterior chamber intraocular lens. The fundus revealed a posterior staphyloma, attached retina and whitish emulsified silicone bubbles with a horizontal lower border giving rise to inverse hypopyon in the posterior pole (figure 1).

Figure 1

The fundus photo shows chorioretinal atrophy temporal to the optic disc and emulsified silicone oil bubbles with a horizontal lower level suggestive of inverse hypopyon.

Inverted hypopyon at the posterior pole1 is a rare finding which can be seen in patients with posterior staphyloma and long-term silicone oil tamponade.2 The emulsified silicone oil being lighter than fluid floats superiorly giving rise to this appearance mostly in the anterior segment (hyperoleon).

http://ift.tt/2k3Qwr7

Rare and unusual case of perforated appendicitis in a Spigelian hernia

Background

Amyand hernia is a rare phenomenon, defined as an inguinal hernia containing the vermiform appendix. It is seen in less than 1% of inguinal hernias. Claudius Amyand first reported this interesting finding in 1735.

De Garengeot hernia: this is the clinical finding of the vermiform appendix within a femoral hernia sac; it occurs in less than 1% of all femoral hernias and is named after the French surgeon, Rene Jacques Croissant de Garengeot.

Unnamed: The clinical entity we describe in this case report is the last of the 'appendix in a hernia—yet to be eponymously named'. It is an interesting and intriguing clinical finding, yet without a referenced name it does not immediately come to mind as a potential differential diagnosis. Medical historians may well commence the search for the first description of the condition.

Case presentation

An 83-year-old woman was admitted to the...

http://ift.tt/2ibG5Bw

Fish hook injury: an easy removal using the string yank technique

Description

An embedded fish hook injury is a tough condition for clinical decision-making, as it needs to be determined whether to advance the hook or to pull it out. Patients or their friends usually attempt to remove a fish hook, causing more soft tissue trauma. There are many different sizes and types of fish hooks, and the four main techniques for their removal are (1) retrograde technique for barbless and superficially embedded hooks, (2) needle cover technique for large hooks with a single barb, (3) advance and cut technique for large fish hooks with potential additional trauma and (4) string yank technique for superficially embedded, small-sized to medium-sized fish hooks.1 The technique of removal should be selected based on the size and shape of a fish hook and the anatomical condition of the injury. Here, we report a useful technique for primary care physicians, accompanied by an instructional video given in the online...

http://ift.tt/2k3ZZyS

Paediatric Salter-Harris type IV injury of distal tibia with talus fracture

Fracture of talus with Salter-Harris injury of the distal end of tibia is a rare injury in paediatric age group. The authors report a case of a 13-year-old male child who sustained type IV Salter-Harris injury to the medial malleolus with coronal spilt along with spilt and depressed fracture of the neck of talus and fracture of the lateral process of talus with stable compression fracture of spine sustained due to fall from 6 meters height. CT scan delineated the morphology of fracture pattern and helped in preoperative planning. Talar articular fracture was reduced and fixed arthroscopically while distal tibial fracture was fixed under image intensifier. We observed favourable outcome following arthroscopic reduction at 4-year follow-up.

http://ift.tt/2ia7zY5

Lesion in the external auditory canal: an unusual site for basal cell carcinoma

Description

An 85-year-old woman presented to the ear, nose and throat clinic with a 2-week history of left-sided otorrhoea and pruritus of the ear. Examination of the left external auditory canal (EAC) revealed a polypoidal lesion and purulent discharge (figure 1). The tympanic membrane was intact. The suspicious lesion prompted imaging, including CT neck and thorax (figure 2). An ultrasound scan of the parotid and neck showed no metastatic disease. A biopsy was undertaken and histology demonstrated a basal cell carcinoma (BCC). The patient was managed with a staged procedure. Stage 1 consisted of a wide local excision of the BCC, with a 4 mm margin. Frozen section was not available; therefore, a second stage was needed to achieve clear margins using a sleeve resection. Fortunately, the disease was limited to the cartilaginous ear canal, hence did not require further resection or reconstruction. This management...

http://ift.tt/2k3ZMM6

Puzzling thyroid function test

A 13-1/2-year-old boy was referred to the Department of Endocrinology as a case of thyrotoxicosis for initiation of antithyroid medication. His chief complaint was a swelling in front of the neck, which was incidentally noted by his mother 2 weeks prior to presentation. He denied any history of symptoms suggestive of hyperthyroidism or ophthalmological involvement. His physical examination was unremarkable except for a grade 2 goitre. Thyroid function test revealed elevated free triiodothyronine and tetraiodothyronine in the face of an unsuppressed thyroid-stimulating hormone level. Technetium-99 uptake scan showed increased uptake indicating enhanced thyroid activity. However, he was clinically euthyroid. This raised the possibility of resistance to thyroid hormones, which was confirmed by documenting similar thyroid function test abnormalities in other members of his family and genetic testing. The family was reassured of the benign nature of the condition.

http://ift.tt/2i9XFpm

Cancer-related microangiopathic haemolytic anaemia

Description

A 71-year-old woman with widely metastatic breast cancer to liver and bone marrow presented with 2 weeks of fatigue. Examination revealed a severely ill-appearing woman in moderate distress with icterus and jaundice. Laboratory investigations revealed profound anaemia (haemoglobin 5.2 g/dL) with appropriate reticulocyte response (14.4%) and a normal platelet count (207x 10⁹/L). Additional tests revealed a lactate dehydrogenase of 2997 IU/L (normal: 140–297 IU/L), negative direct Coombs antiglobulin, an undetectable haptoglobin level, elevated total bilirubin, newly elevated prothrombin time (19.7 s, normal: <14.1 s), elevated fibrin split products and D-dimer (14.36 µg/dL, normal: <0.53 µg/dL) but normal fibrinogen level (322 mg/dL, normal: 193–488 mg/dL). Peripheral blood smear revealed marked schistocytosis (figure 1) with normal platelet count. The patient was diagnosed with cancer-associated microangiopathic haemolytic anaemia1 2 with laboratory evidence of disseminated intravascular coagulation, and she passed away on comfort measures 24 hours after admission.

Figure 1

Arrows showing marked schistocytes.

...

http://ift.tt/2k3ZHbg

Delayed presentation of iatrogenic bladder perforation

Description 

A 41-year-old lady presented to a district general hospital with a 24-hour history of abdominal pain, shoulder tip pain and anuria. No other symptoms were reported, and observations were stable. Her medical history included endometriosis, one normal vaginal delivery in 1998 and three caesarean sections dated 2003, 2010 and 2012. On examination, there was tenderness in the suprapubic region and left loin; the bladder was not palpable, and she did not elicit any signs of peritonitis. A Foley catheter was inserted. Urinalysis showed 4+ blood and 2+ ketones. She had raised inflammatory markers and a raised creatinine of 200 µmol/L.

The following day, creatinine had normalised, but there was no improvement in symptoms, despite antibiotics. A CT of her kidneys, ureters and bladder was reported as showing locules of free gas in the bladder consistent with recent catheterisation. There was free fluid in the pelvis, and a faecolith...

http://ift.tt/2icfjIY

Tuberculosis in Pap Samples with Emphasis on LBC: Caught Only When Thought

Despite being a commonly encountered infection, the clinical diagnosis of tuberculosis of the uterine cervix is elusive. Though a straightforward diagnosis on tissue sections, identification of typical features of tubercular infection on cervical Pap samples is challenging. In our experience, the infrequent pale staining collections of epithelioid cells are difficult to pick up on Pap stained smears, particularly LBC samples. In this series, 2 of the three samples were reported as atypical squamous cells of undetermined significance while 1 was reported as inflammatory at the initial diagnosis. Scattered Langhans' type giant cells may be seen as a subtle clue which should prompt the search for epithelioid cell granulomas. These cases may have a mass lesion clinically while no obvious signs of malignancy on the cervical samples.

http://ift.tt/2iYbEMf

Cysticercosis and cytodiagnosis

http://ift.tt/2Bj1X1v

Pharmacogenetics of drug-induced ototoxicity caused by aminoglycosides and cisplatin

Pharmacogenomics, Ahead of Print.


http://ift.tt/2AdkSy8

Impact of SNP–SNP interaction among ABCB1, ARRB2, DRD1 and OPRD1 on methadone dosage requirement in Han Chinese patients

Pharmacogenomics, Ahead of Print.


http://ift.tt/2ifyl1b

Pharmacogenetics and psoriasis: is targeted treatment a possibility?

Pharmacogenomics, Ahead of Print.


http://ift.tt/2AdydWR

Molecular network-selected pharmacogenomics in a case of bipolar spectrum disorder

Pharmacogenomics, Ahead of Print.


http://ift.tt/2ia0zuh

miR-509-3p promotes cisplatin-induced apoptosis in ovarian cancer cells through the regulation of anti-apoptotic genes

Pharmacogenomics, Ahead of Print.


http://ift.tt/2Ab70o1

Effect of dendritic cell-cytokine-induced killer cells in patients with advanced colorectal cancer combined with first-line treatment

Abstract

Background

Surgical resection combined with adjuvant chemotherapy is considered as the gold-standard treatment for advanced colorectal cancer patients. These patients have a poor 5-year survival rate of 5% or less. Furthermore, a large dose of chemotherapy can produce adverse side effects and severe toxicity. Therefore, this retrospective study aimed to evaluate the efficacy of dendritic cell-cytokine-induced killer (DC-CIK) cell infusion as an adjuvant therapy in patients with advanced colorectal cancer combined with first-line treatment.

Methods

A total of 142 patients with stage III/IV colorectal carcinoma who had been treated with first-line therapy were included in this study. Among these patients, 71 patients received first-line treatment only (non-DC-CIK group), while the other 71 patients who had similar demographic and clinical characteristics received a DC-CIK cell infusion combined with first-line treatment (DC-CIK group). These patients were followed up until August 2014. Data were analyzed by Kaplan-Meier and Cox regression.

Results

Our results showed that the 5-year overall survival (OS) rate for the DC-CIK group versus the non-DC-CIK group was 41.3 versus 19.4% (p = 0.001) and the 5-year progression-free survival (PFS) rate for the DC-CIK group versus the non-DC-CIK group was 57.4 versus 33.6% (p = 0.022).

Conclusions

Our results showed that patients with advanced colorectal cancer might benefit from DC-CIK immunotherapy combined with first-line therapy by significantly prolonging 5-year OS and PFS.

http://ift.tt/2Aczvl7

The Optimal Injection Solution for Endoscopic Submucosal Dissection: A Randomized Controlled Trial of Western Solutions in a Porcine Model

Abstract

Background

When performing endoscopic submucosal dissection (ESD), procedural safety increases with greater tissue elevation and efficiency increases with longer-lasting submucosal cushion. Fluids specifically developed for ESD in Asia aren't commercially available in the West, leading endoscopists to use a variety of injectable fluids off-label. To determine the optimal fluid available in the West, we compared commonly used fluids for Western ESD.

Methods

All phases were performed in an ex-vivo porcine stomach model. Phase-1 compared tissue elevation and duration of submucosal cushions produced by various standard volumes of various injectable solutions used for ESD. The two best performing solutions used off-label were tested head-to-head in ESD in Phase-2. Phase-3 compared the best solution from Phase-2 to Eleview^®, currently the only submucosal injection fluid approved in the United States. In Phase-2 and 3, 5 ESDs were performed with each solution. The solutions were randomized and the endoscopist blinded to the solution.

Results

The best performing solutions in Phase 1 were 0.4% hyaluronic acid, 6% hydroxyethyl starch (HES), and Eleview^®. Phase-2 compared 6% HES and hydroxypropyl methylcellulose (HPMC), demonstrating ESD with 6% HES was easier (p=0.007), faster (p=0.041) and required less injection volume (p=0.003). In Phase-3, resection speed, ease of ESD and total volume per area resected were comparable between 6% HES and Eleview^®.

Conclusions

Of the submucosal injection fluids currently available in the West, Eleview^® and 6% HES are the best-performing solutions for ESD in a porcine model.

This article is protected by copyright. All rights reserved.

http://ift.tt/2Ah4JFj

Tumor Invasion to the Arteries Feeding the Gallbladder as a Novel Risk Factor for Cholecystitis after Metallic Stent Placement in Distal Malignant Biliary Obstruction

Abstract

Objectives

Cholecystitis is a major complication after self-expandable metallic stent (SEMS) placement for malignant biliary obstruction. Ischemia is one of the risks for cholecystitis, but little is known about the influence of tumor invasion to the feeding artery of the gallbladder on the onset of cholecystitis after SEMS placement. The aim of this study was to identify risk factors for cholecystitis after SEMS placement.

Methods

The incidence and nine predictive factors of cholecystitis were retrospectively evaluated in 107 patients who underwent SEMS placement for unresectable distal malignant biliary obstruction at Kyoto University Hospital and Otsu Red Cross hospital between January 2012 and June 2016.

Results

Cholecystitis occurred in 13 of 107 patients (12.1%) after SEMS placement during the median follow-up period of 262 days. Univariate analyses showed that tumor invasion to the feeding artery of the gallbladder and tumor involvement to the orifice of the cystic duct were significant predictors of cholecystitis (P = 0.001 and P < 0.001). Multivariate analysis confirmed that these two factors were significant and independent risks for cholecystitis with odds ratios of 22.13 (95% CI, 3.57-137.18; P = 0.001) and 25.26 (95% CI, 4.12-154.98; P < 0.001), respectively.

Conclusions

This study demonstrated for the first time that tumor invasion to the feeding artery of the gallbladder as well as tumor involvement to the orifice of the cystic duct are independent risk factors for cholecystitis after SEMS placement.

This article is protected by copyright. All rights reserved.

http://ift.tt/2jv5ceS

Linked Color Imaging identified UC Associated Colorectal Cancer. A case report

Abstract

Ulcerative colitis (UC) associated colorectal cancer (CRC) is an important issue in long-term management of patients with UC. Lesions with chronic inflammatory mucosa as background may often be difficult to identify even by endoscopic observation. Traditionally, a random biopsy strategy was recommended, but problems with patient compliance, increased burden on endoscopic staff and pathologists, were left.

This article is protected by copyright. All rights reserved.

http://ift.tt/2AfVPrr

Life course evolution of body size and breast cancer survival in the E3N cohort

Abstract

Although adult obesity has been associated with poor breast cancer survival, data on adiposity at different periods in life and its lifelong evolution are scarce. Our aims were to assess the associations between breast cancer survival and body size during childhood, puberty, and early adulthood and body size trajectories from childhood to adulthood.

Self-assessed body size at age 8, at puberty, at age 20-25, and at age 35-40 and trajectories of body size of 4 662 breast cancer survivors from the prospective E3N cohort were studied in relation to risk of death from any cause, death from breast cancer and second invasive cancer event using multivariate Cox regression models.

Four trajectories of body size were identified (T1 "moderate increase", T2 "stable/low increase", T3 "increase at puberty", T4 "constantly high"). Compared with stable body size, an increase in body size during adult life was associated with an increased risk of death from any cause (HR T1 versus T2=1.27; 95% CI=1.01-1.60), and an increased risk of second invasive cancer event (HR T1 versus T2=1.25; 95% CI=1.06-1.47). Silhouettes at various ages were not associated with survival.

Our results suggest that the evolution of body size from childhood to adulthood has a long-term influence on breast cancer survival. Although these results need to be confirmed, this work sheds light on the need to combine lifelong approaches to current BMI to better identify breast cancer survivors who are at higher risk of recurrence or second primary cancer, or of death. This article is protected by copyright. All rights reserved.

http://ift.tt/2naSFCH

Preconditioned Augmented Lagrangian formulation for nearly incompressible cardiac mechanics

Summary

Computational modeling of the heart is a subject of substantial medical and scientific interest, which may contribute to increase the understanding of several phenomena associated with cardiac physiological and pathological states. Modeling the mechanics of the heart have led to considerable insights, but it still represents a complex and a demanding computational problem, especially in a strongly coupled electromechanical setting. Passive cardiac tissue is commonly modeled as hyperelastic, and is characterized by quasi-incompressible, orthotropic and non-linear material behavior. These factors are known to be very challenging for the numerical solution of the model. The near-incompressibility is known to cause numerical issues such as the well known locking phenomenon and ill-conditioning of the stiffness matrix. In this work, the Augmented Lagrangian method (ALG) is used to handle the nearly incompressible condition. This approach can potentially improve computational performance by reducing the condition number of the stiffness matrix and thereby improving the convergence of iterative solvers. We also improve the performance of iterative solvers by the use of an algebraic multigrid preconditioner. Numerical results of the ALG method combined with a preconditioned iterative solver for a cardiac mechanics benchmark suite are presented to show its improved performance. This article is protected by copyright. All rights reserved.

http://ift.tt/2iWZT8G

Placentophagy’s effects on mood, bonding, and fatigue: A pilot trial, part 2

Publication date: Available online 27 November 2017
Source:Women and Birth
Author(s): Sharon M. Young, Laura K. Gryder, Chad Cross, David Zava, David W. Kimball, Daniel C. Benyshek
BackgroundHuman maternal placentophagy is gaining popularity among a growing number of women who believe it provides maternal benefits, including prevention of postpartum blues/depression, improved maternal bonding, and reduced fatigue.MethodsWe conducted a randomized, double-blind, placebo-controlled pilot study (N=27) in which participants consumed either their processed, encapsulated placenta (n=12), or similarly prepared placebo (n=15). Maternal mood, bonding, and fatigue were assessed via validated scales across four time points during late pregnancy and early postpartum. Psychometric data were analyzed for changes between and within both groups over time.ResultsNo significant main effects related to maternal mood, bonding, or fatigue were evident between placenta and placebo group participants. However, examination of individual time points suggested that some measures had specific time-related differences between placenta and placebo groups that may warrant future exploration. Though statistical significance should not be interpreted in these cases, we did find some evidence of a decrease in depressive symptoms within the placenta group but not the placebo group, and reduced fatigue in placenta group participants at the end of the study compared to the placebo group.ConclusionsNo robust differences in postpartum maternal mood, bonding, or fatigue were detected between the placenta and placebo groups. This finding may be especially important for women considering maternal placentophagy as a 'natural' (i.e., non-pharmacological) means of preventing or treating blues/depression. Given the study limitations, these findings should be interpreted as preliminary. Small, time-related improvements in maternal mood and lower fatigue post-supplementation among placenta group participants may warrant further research.



http://ift.tt/2BiqJ1X

Bonding in neonatal intensive care units: Experiences of extremely preterm infants’ mothers

Publication date: Available online 27 November 2017
Source:Women and Birth
Author(s): Isabel María Fernández Medina, José Granero-Molina, Cayetano Fernández-Sola, José Manuel Hernández-Padilla, Marcos Camacho Ávila, María del Mar López Rodríguez
BackgroundThe birth of an extremely preterm infant can disrupt normal mother–infant physical contact and the care provided by the mother. This situation has an impact on the process of bonding between the mother and the child.AimThe objective of this study was to describe and understand the experiences of mothers who have extremely preterm infants admitted in Neonatal Intensive Care Units with regard to their bonding process.MethodsAn interpretive, qualitative research methodology using Gadamer's philosophical hermeneutics was carried out. A focus group and eleven in-depth, semi-structured interviews were conducted. Data were collected between June and September of 2016.FindingsSixteen women with a mean age of 34.4 years participated in the study. Two themes emerged from the data analysis: (1) premature labour and technological environment, a distorted motherhood, with the subthemes 'feeling of emptiness and emotional crisis' and 'the complexity of the environment and care generate an emotional swing'; (2) learning to be the mother of an extremely preterm infant, with the subthemes "the difficulty of relating to a stranger" and 'forming the bond in spite of difficulties'.ConclusionsThe bonding with extremely preterm infants is interrupted after giving birth. The maternal emotional state and the environment of the neonatal intensive care unit limit its development. Nursing care can facilitate mother–infant bonding by encouraging communication, participation in care, massaging or breastfeeding.



http://ift.tt/2iWyJ1M

Effects of placentophagy on maternal salivary hormones: A pilot trial, part 1

Publication date: Available online 27 November 2017
Source:Women and Birth
Author(s): Sharon M. Young, Laura K. Gryder, Chad Cross, David Zava, David W. Kimball, Daniel C. Benyshek
BackgroundRecent studies show that human placenta, processed and encapsulated for postpartum consumption, contains a host of trace minerals and hormones that could conceivably affect maternal physiology. Our objective was to investigate whether salivary hormone concentrations of women ingesting their own encapsulated placenta during the early postpartum differed from those of women consuming a placebo.MethodsRandomly assigned participants (N=27) were given a supplement containing either their dehydrated and homogenized placenta (n=12), or placebo (n=15). Saliva samples were collected during late pregnancy and early postpartum. Samples of participants' processed placenta, and the encapsulated placebo, were also collected. Hormone analyses were conducted on all samples utilizing liquid chromatography–tandem mass spectrometry.ResultsThere were no significant differences in salivary hormone concentrations between the placenta and placebo groups post-supplementation that did not exist pre-supplementation. There were, however, significant dose–response relationships between the concentration of all 15 detected hormones in the placenta capsules and corresponding salivary hormone measures in placenta group participants not seen in the placebo group. The higher salivary concentrations of these hormones in the placenta group reflects the higher concentrations of these hormones in the placenta supplements, compared to the placebo.ConclusionsSome hormones in encapsulated placenta lead to small but significant differences in hormonal profiles of women taking placenta capsules compared to those taking a placebo, although these dose–response changes were not sufficient to result in significant hormonal differences between groups. Whether modest hormonal changes due to placenta supplementation are associated with therapeutic postpartum effects, however, awaits further investigation.



http://ift.tt/2BiEaPq

Safety and Pharmacokinetics of the Aminomethylcycline Antibiotic Omadacycline Administered to Healthy Subjects in Oral Multiple Dose Regimens [PublishAheadOfPrint]

Omadacycline, a first-in-class aminomethylcycline antibiotic, is related to tetracyclines, but structurally modified to circumvent mechanisms of resistance to tetracyclines. Omadacycline demonstrates potent activity against a broad range of pathogens, including drug-resistant strains, and is in late-stage development for treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Previous studies support an intravenous-to-oral transition regimen with 300 mg once-daily oral dosing. This phase 1 study investigated the pharmacokinetics and safety/tolerability of multiple oral omadacycline doses higher than 300 mg. Using a 3-period crossover design, healthy adults were randomized to receive oral omadacycline 300, 450, and 600 mg in variable sequence (n = 26) or placebo (n = 7) once daily for 5 consecutive days per period. In plasma, omadacycline maximum concentration and total exposure increased with increasing dose, but were less than dose proportional. The kinetics of omadacycline plasma accumulation were similar between dose levels; exposure on Day 5 was ~50% higher than on Day 1. Omadacycline plasma concentrations on Day 1 of 450-mg dosing were similar to those on Day 5 of 300-mg dosing. All doses were generally well tolerated, but the 600-mg dose was associated with more gastrointestinal adverse events.

http://ift.tt/2iXOUf4

The ABC of biofilm drug tolerance: The MerR-like regulator BrlR is an activator of ABC transport systems, with PA1874-77 contributing to the tolerance by Pseudomonas aeruginosa biofilms to tobramycin [PublishAheadOfPrint]

A hallmark of biofilms is their tolerance to killing by antimicrobial agents. In P. aeruginosa, biofilm drug tolerance requires the c-di-GMP responsive, MerR transcriptional regulator BrlR. However, the mechanism by which BrlR mediates biofilm drug tolerance has not been elucidated. Here, we demonstrate that BrlR activates the expression of at least 7 ABC transport systems, including PA1874-77, with ChIP and DNA binding assays confirming BrlR binding to the promoter region of PA1874-77. Insertional inactivation of the 7 ABC transport systems rendered P. aeruginosa PAO1 biofilms susceptible to tobramycin or norfloxacin. Susceptibility was linked to drug accumulation, with BrlR contributing to norfloxacin accumulation in a manner dependent on multidrug efflux pumps and the ABC transport system PA1874-77. Inactivation of the respective ABC transport system furthermore eliminated the recalcitrance of biofilms to killing by tobramycin but not norfloxacin, indicating that drug accumulation is not linked to biofilm drug tolerance. Our findings indicate for the first time that BrlR, a MerR-type transcriptional activator, activates genes encoding several ABC transport systems, in addition to multiple multi-drug efflux pump genes. Moreover, our data confirm a BrlR target contributing to drug tolerance, likely countering the prevailing dogma that biofilm tolerance arises from a multiplicity of factors.

http://ift.tt/2BiFKRb

Integrated Resistance Analysis of CERTAIN-1 and CERTAIN-2 Studies in HCV Infected Patients Receiving Glecaprevir and Pibrentasvir in Japan [PublishAheadOfPrint]

Glecaprevir and pibrentasvir are hepatitis C virus (HCV) pangenotypic inhibitors targeting NS3/4A protease and NS5A, respectively. This once-daily, fixed-dose combination regimen demonstrated high SVR12 rates in CERTAIN-1 and CERTAIN-2 studies in Japanese HCV-infected patients, with a low virologic failure (VF) rate (1.2%). There were no VFs among direct acting antiviral (DAA)-treatment-naive genotype (GT)1a- (n=4), GT1b- (n=128), and GT2- (n=97) infected non-cirrhotic patients treated for 8 weeks, or GT1b- (n=38) or GT2- (n=20) infected patients with compensated cirrhosis treated for 12 weeks. Two of 33 DAA-experienced and 2/12 GT3-infected patients treated for 12 weeks experienced VF. Pooled resistance analysis, grouped by HCV subtype, treatment duration, prior treatment experience, and cirrhosis status was conducted. Among DAA-naïve GT1b-infected patients, the baseline prevalence of NS3-D168E was 1.2%, NS5A-L31M was 3.6%, and NS5A-Y93H was 17.6%. Baseline polymorphisms (BP) in NS3 or NS5A were less prevalent in GT2 with the exception of the common L/M31 polymorphism in NS5A. Among DAA-experienced GT1b-infected patients (30/32 experienced to daclatasvir and asunaprevir), the baseline prevalence of NS3-D168E/T/V was 48.4%, NS5A-L31F/I/M/V was 81.3%, NS5A-P32deletion was 6.3%, and NS5A-Y93H was 59.4%. Common BPs in NS3 and/or NS5A had no impact on treatment outcome in GT1- and GT2-infected patients; the impact in GT3-infected patients could not be assessed due to enrollment of diverse subtypes and limited number of patients. The glecaprevir/pibrentasvir combination regimen allows for a simplified treatment option without the need for HCV subtyping or baseline resistance testing for DAA-naïve GT1 or GT2-infected patients.

http://ift.tt/2iYD44t

Azithromycin Pharmacodynamics against 'Persistent Haemophilus influenza in Chronic Obstructive Pulmonary Disease [PublishAheadOfPrint]

The pharmacodynamic profile of azithromycin against persistent strains of non-typeable H. influenzae (NTHi) from COPD patients was characterized. Azithromycin displayed differential concentration-dependent activity (R² >0.98): pharmacodynamic response was attenuated comparing the 'first' vs. 'last' strain of NTHi which persisted in the airway of the same patient for 819 days (EC₅₀ increased >50 times: 0.0821 mg/L vs. 4.23). In the Hollow Fiber Infection Model NTHi viability was maintained throughout simulated Zithromax Z-pak regimens over 10 days.

http://ift.tt/2BjCchH

Increasing antimicrobial resistance in non-typhoidal Salmonella in Australia, 1979 - 2015 [PublishAheadOfPrint]

Australia has high and increasing rates of salmonellosis. To date, the serovar distribution and associated antimicrobial resistance (AMR) patterns of non-typhoidal Salmonella enterica (NTS) in Australia have not been assessed. Such information provides critical knowledge about AMR in the food chain, and informs decisions about public health. We reviewed longitudinal data on NTS in two Australian states over a thirty-seven-year period, between 1979 and 2015, and antimicrobial resistance since 1984. Overall, 17% of isolates were non-susceptible to at least one antimicrobial, 4.9% were non-susceptible to ciprofloxacin, and 0.6% were non-susceptible to cefotaxime. In total, 2.5% of isolates were from invasive infections, with no significant difference in AMR profiles between invasive and non-invasive isolates. Most isolates with clinically relevant AMR profiles were associated with travel, particularly to South East Asia, with multiple 'incursions' of virulent and resistant clones into Australia. Our findings represent the largest longitudinal surveillance system for NTS in Australia and provide valuable public health knowledge on the trends and distribution of AMR in NTS. Ongoing surveillance is critical to identify local emergence of resistant isolates.

http://ift.tt/2iXOGoe

A simple in vitro assay to evaluate the incorporation efficiency of ribonucleotide analog 5' -triphosphates into RNA by human mitochondrial DNA-dependent RNA polymerase [PublishAheadOfPrint]

There is a growing body of evidence suggesting that some ribonucleoside/ribonucleotide analogs may be incorporated into mitochondrial RNA by human mitochondrial DNA-dependent RNA polymerase (POLRMT) and disrupt mitochondrial RNA synthesis. An assessment of incorporation efficiency of a ribonucleotide analog 5' -triphosphate by POLRMT may be used to evaluate potential mitochondrial toxicity of the analog early in the development process. In this report, we provide a simple method to prepare active recombinant POLRMT. A robust in vitro nonradioactive primer extension assay was developed to assay the incorporation efficiency of ribonucleotide analog 5' -triphosphates. Our results showed that many ribonucleotide analogs, including some antiviral compounds currently in various pre-clinical or clinical development stages, can be incorporated into newly synthesized RNA by POLRMT, and that the incorporation of some of them can lead to chain termination. The discrimination values (D values) of ribonucleotide analog 5' -triphosphates over natural ribonucleotide triphosphates (rNTPs) were measured to evaluate the incorporation efficiency of the ribonucleotide analog 5' -triphosphates by POLRMT. Discrimination values of natural rNTPs in the condition of misincorporation by POLRMT were used as a reference to evaluate the potential mitochondrial toxicity of ribonucleotide analogs. We proposed the following criteria for potential mitochondrial toxicity of ribonucleotide analogs based on D values: a safe compound (D > 10⁵); a potentially toxic compound (10⁵ > D > 10⁴); and a toxic compound (D < 10⁴). This report provides a simple screening method that should assist investigators in designing ribonucleoside-based drugs having lower mitochondrial toxicity.

http://ift.tt/2Bh9jm4

Efficacy of novel anti-staphylococcal ectolysin P128 in a rat model of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia [PublishAheadOfPrint]

Staphylococcus aureus (S.aureus) causes systemic infections with high morbidity and mortality and emergence of drug resistance strains are a rapidly growing clinical concerns. Novel therapeutic agents are required to tackle S.aureus infections. P128 is a bacteriophage-derived chimeric ectolysin with potent and rapid bactericidal activity on S. aureus. In the current study, efficacy of P128 was evaluated in a newly-developed rat model of S. aureus bacteremia. Prior to in vivo testing, P128 was shown to be stable in whole blood by incubation in rat blood for up to 6 hrs and testing of its bactericidal activity against MRSA isolate USA 300. Rats succumbed to intravenous challenge with 10⁹ CFU of S. aureus USA300 resulting in 80 to 100% mortality by day 14. Evaluation of the bacterial load in various organs at 96 hours post-infection revealed high bacterial counts in the kidney, and this correlated with the presence of renal abscesses. Treatment of infected animals with P128 either by intravenous bolus administration via tail vein or by one-hour infusion via jugular vein 2 hours post-infection, resulted in dose-dependent survival of rats. P128 treatment also resulted in very few or no abscesses in the kidneys. These data show that P128 is stable in the physiological milieu and that intravenous treatment with P128 is highly effective in rescuing rats from S. aureus bacteremia. P128 can be a novel therapeutic option for treatment of S.aureus systemic infections.

http://ift.tt/2iXOyVM

On the antibacterial and sterilizing effect of benzylpenicillin in tuberculosis [PublishAheadOfPrint]

The modern chemotherapy era started with Fleming's discovery of benzylpenicillin. He demonstrated that benzylpenicillin did not kill Mycobacterium tuberculosis (Mtb). Here, we found that >64 mg/L of static benzylpenicillin concentrations killed 1.16-1.43 log₁₀ CFU/mL below starting inoculum of extracellular and intracellular Mtb over 7 days. When we added the β-lactamase-inhibitor avibactam, benzylpenicillin maximal kill (E_max) of either extracellular log-phase growth Mtb was 6.80±0.45 log₁₀ CFU/mL at an EC₅₀ of 15.11±5.2.32 mg/L, while for intracellular Mtb was 2.42±0.14 log₁₀ CFU/mL at an EC₅₀ of 6.70±0.56 mg/L. The median penicillin (plus avibactam) MIC against South African clinical Mtb strains (80% either multi- or extensively drug-resistant) was 2 mg/L. We mimicked human-like benzylpenicillin and avibactam concentration-time profiles in the hollow fiber model of tuberculosis (HFS-TB). The percentage time above MIC was linked to effect, with an optimal exposure of ≥65%. At optimal exposure in the HFS-TB, the bactericidal activity in log-phase growth Mtb was 1.44 log₁₀ CFU/mL/day, while 3.28 log₁₀ CFU/mL of intracellular Mtb was killed over 3 weeks. In an 8 week HFS-TB study of non-replicating persistent Mtb, penicillin-avibactam alone versus the drug combination of isoniazid, rifampin, and pyrazinamide, both killed >7.0 log₁₀ CFU/mL. Monte Carlo simulations of 10,000 pre-term infants with disseminated disease identified an optimal dose of 10,000 U/kg/hr, while for pregnant women or non-pregnant adults with pulmonary tuberculosis optima dose was 25,000 U/kg/hr, by continuous intravenous infusion. Penicillin-avibactam should be examined for effect in pregnant women and infants with drug-resistant tuberculosis, to replace injectable ototoxic and teratogenic second-line drugs.

http://ift.tt/2Bh9f5O

Comparison of peri-implant clinical and radiographic status around short (6 mm in length) dental implants placed in cigarette-smokers and never-smokers: Six-year follow-up results

Abstract

Background

It is hypothesized that peri-implant clinical and radiographic inflammatory parameters (probing depth [PD], bleeding on probing [BOP] and plaque index [PI]; and radiographic (crestal bone loss [CBL]) are worse among cigarette-smokers (CS) compared with never-smokers (NS) with short implants.

Purpose

The present 6-year follow-up retrospective study compared the peri-implant clinical and radiographic parameters in CS and NS with short dental implants (6 mm in length).

Materials and methods

Fifty-six male individuals were included. These individuals divided into 2 groups as follows: (a) Group-1: 29 self-reported systemically healthy CS with 48 short-implants; and (b) Group-2: 27 self-reported systemically healthy NS with 43 short implants. Peri-implant PD, PI, BOP, and CBL were measured. Group comparisons were done using the Kruskal-Wallis test and sample size was estimated. Level of significance was set at P values < .05.

Results

In groups 1 and 2, the follow-up durations were 6.2 ± 0.1 years and 6.1 ± 0.3 years, respectively. A cigarette smoking history of 8.9 ± 3.6 pack years was reported by individuals in Group-1. At follow-up, scores of peri-implant PD, BOP, PI, and mesial and distal CBL were comparable around short implants in both groups.

Conclusion

Under strict oral hygiene maintenance protocols, short dental implants can remain functionally stable in CS in a manner similar to NS.

http://ift.tt/2zKFJJI

Hepatitis B reactivation and outcomes in persons treated with directly acting antiviral agents against hepatitis C virus: results from ERCHIVES

Summary

Background

Higher risk of hepatitis B reactivation (HBV-r) has been reported in patients with hepatitis C treated with newer directly acting antiviral agents (DAAs).

Aim

To determine the proportion of persons who develop HBV-r and its clinical consequences among DAA treated vs pegylated interferon/ribavirin (PEG/RBV) treated persons.

Methods

We calculated the proportion of persons who developed HBV viral reactivation (HBV-r; new detectable HBV DNA or increase of >1 log₁₀); serum alanine aminotransferase flare (>5 times baseline); all-cause mortality and hepatic decompensation in persons treated with a newer DAA regimen or PEG/RBV. Kaplan-Meier curves were used to demonstrate survival and hepatic decompensation by treatment group and HBV-r.

Results

In 34 632 persons treated with DAA and 23 475 treated with PEG/RBV, HBV-r rate per 1000 person-years was 30.04 (10.41, 49.67) and 25.42 (95% CI 17.23, 33.62) respectively (P = .8). When stratified by SVR or by baseline HBsAg status, HBV-r was not different between groups. Kaplan-Meier survival curves comparing each regimen stratified by presence or absence of HBV-r did not demonstrate a significant difference in incidence of hepatic decompensation over time. For overall survival, there was no difference between PEG/RBV treated persons with or without HBV-r. For DAA treated persons, those with HBV-r had a shortened survival, though the numbers at risk were small.

Conclusions

HBV-r is relatively uncommon after DAA therapy and not higher than among those treated with a PEG/RBV regimen. The small numbers of persons treated with a DAA regimen who do develop HBV-r have a shortened survival compared to those without HBV-r.

http://ift.tt/2iZ06Zf

Sofosbuvir and velpatasvir with or without voxilaprevir in direct-acting antiviral-naïve chronic hepatitis C: patient-reported outcomes from POLARIS 2 and 3

Summary

Background

Chronic hepatitis C infection leads to impairment of patient-reported outcomes (PROs). Treatment with direct-acting antiviral regimens results in short- and long-term improvement of these outcomes.

Aim

To assess PROs in patients treated with a newly developed direct-acting antiviral, a fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) with/without voxilaprevir (VOX).

Methods

The PRO data were collected from participants of POLARIS-2 and POLARIS-3 clinical trials (DAA-naïve, all HCV genotypes). Participants self-administered SF-36v2, FACIT-F, CLDQ-HCV and WPAI:SHP instruments at baseline, during treatment, and in follow-up.

Results

Of 1160 patients, 611 received SOF/VEL/VOX and 549 received SOF/VEL (52.8 ± 11.0 years, 55.9% male, 75.4% treatment-naïve, 33.9% cirrhotic). The sustained viral response at 12 weeks (SVR12) rates were 95%-98%. During treatment, improvements in most PRO scores were significant (all but one P < .01) and ranged from, on average, +2.3 to +15.0 points (on a 0-100 scale) by the end of treatment. These improvements were similar between SOF/VEL/VOX and SOF/VEL arms (all P > .05). After treatment discontinuation, patients treated with both regimens achieved significant and clinically meaningful PRO gains (+2.7 to +16.7 by post-treatment week 12, +3.9 to +20.1 by post-treatment week 24; all but one P < .001). Multivariate analysis showed that depression, anxiety and cirrhosis were the most consistent independent predictors of PRO impairment while no association of PROs with the treatment regimen choice was found (all P > .05).

Conclusions

The pan-genotypic regimens with SOF/VEL with or without VOX not only have excellent efficacy and safety, but also significantly positively impact patients' experience both during treatment and after achieving sustained virologic response in DAA-naïve patients with HCV.

http://ift.tt/2BjFOA3

Towards the Elimination of Hepatitis C in the United States

Abstract

The emergence of effective direct-acting antiviral (DAA) agents has reignited discussion over hepatitis C elimination potential in the United States. Eliminating hepatitis C will require a critical examination regarding technical feasibility, economic considerations, and social/political attention.

Tremendous advancement has been made in recent years with the availability of sensitive diagnostic tests and highly effective DAAs capable of achieving sustained viral response (SVR) in more than 95% of patients. Eliminating hepatitis C requires escalating existing surveillance networks to identify and respond to new epidemics. Basic prevention strategies such as community based outreach and education, testing and counseling, clean syringe and needle exchange programs, safe injection sites, opioid substitution therapies, and mental health services must be scaled up and adapted to target high risk groups.

Although costs of DAAs have raised budget concerns for hepatitis C elimination, studies have shown that eliminating hepatitis C will produce a savings of up to 6.5 billion USD annually along with other intangible benefits such as work productivity and quality of life. Simulation economic models and meta-analyses suggest that all adults should be screened for hepatitis C, but special efforts must focus on high risk populations.

There is growing recognition that social and political factors are at least as important as technical feasibility and economic considerations. Due to lack of promotion and public awareness, HCV elimination efforts continue to receive inadequate funding. Social stigma continues to impede meaningful policy changes. Eliminating hepatitis C from the U.S. is possible but it will require a sustained national commitment and strong political leadership. This article is protected by copyright. All rights reserved.

http://ift.tt/2jr3bAE

Acute Flaccid Myelitis: Etiologic Challenges, Diagnostic and Management Considerations

Abstract

Purpose of review

Purpose of review Acute flaccid myelitis is a polio-like illness defined by the acute onset of flaccid paralysis in the setting spinal MRI demonstrating a longitudinal lesion in the gray matter of the cord. This paper aims to review the current state of knowledge and key clinical points for the diagnosis and management of acute flaccid myelitis.

Recent findings

Recent findings There were clusters of AFM noted in California and Colorado in 2014, with additional cases across the USA that year, and another spike in cases in 2016. Patients have been managed with classic treatments for transverse myelitis, but in general without benefit, although some colleagues have noted anecdotal improvement in individual patients. Our current practice at the Children's Hospital of Philadelphia is to initiate therapy with intravenous immunoglobulin (IVIG) upon recognition of acute flaccid myelitis in hopes of boosting humoral immunity, and to provide an emphasis on rehabilitation services, including physical and occupational therapy. There is some data that suggests a connection to the virus enterovirus D68 (EV D68), but there has been no definitive link. Publications regarding longer-term outcomes in these patients are early in development and, thus far, only provide data for 6 to 12 months from onset.

Summary

Summary AFM is a serious illness with long-term consequences, and we have much to learn. Key areas in need of further investigation involve etiology, host susceptibilities, treatment options, and long-term outcome. Individual clinicians can assist in these efforts by the prompt reporting of cases of AFM to the US Centers for Disease Control and Prevention.

http://ift.tt/2iWYBKS

miR-221/222 cluster expression improves clinical stratification of non-muscle invasive bladder cancer (TaT1) patients' risk for short-term relapse and progression

Abstract

Clinical heterogeneity of bladder cancer prognosis requires the identification of bladder tumors' molecular profile to improve the prediction value of the established and clinically used markers. In the present study, we have analyzed miR-221/222 cluster expression in bladder tumors and its clinical significance for patients' prognosis and disease outcome. The study included 387 tissue specimens. Following extraction, total RNA was polyadenylated at 3΄-end and reversed transcribed. SYBR-Green based qPCR assays were performed for the quantification of miR-221/222 expression. Extensive statistical analysis was completed for the evaluation of miR-221/222 cluster's clinical significance. The expression of miR-221/222 is significantly downregulated in tumors compared to normal urothelium, while ROC curve and logistic regression analysis highlighted cluster's discriminatory ability. However, miR-222 levels were increased in muscle-invasive (T2-T4) compared to superficial tumors (TaT1), and in high compared to low-grade tumors. Kaplan-Meier survival curves and Cox regression analysis revealed the stronger risk of TaT1 patients overexpressing miR-222 for disease short-term relapse and progression following treatment. Moreover, multivariate Cox models highlighted the independent prognostic value of miR-222 overexpression for TaT1 patients' poor prognosis. Finally, the analysis of miR-222 expression improved significantly the positive prediction strength of the clinically used prognostic markers of tumor stage, grade, EORTC risk-stratification and recurrence at the first follow-up cystoscopy for TaT1 patients' outcome, and resulted to higher clinical net benefit following decision curve analysis. In conclusion, the expression of miR-221/222 cluster is deregulated in bladder tumors and miR-222 overexpression results to a superior positive prediction of TaT1 patients' short-term relapse and progression. This article is protected by copyright. All rights reserved.

http://ift.tt/2BidOwL

Histological evaluations and inflammatory responses of different dental implant abutment materials: A human histology pilot study

Abstract

Background

Improvements of soft tissue to the abutment surface results in more stable peri-implant conditions, however, few human histological studies have compared soft tissue responses around different abutment materials.

Purpose

To describe the peri-implant tissue around 3 abutment materials; titanium, zirconia, and gold alloy, over an 8-week healing period.

Materials and Methods

Fifteen edentulous sites were treated with implants. Eight weeks later, peri-implant tissue was harvested and processed using a nonseparation resin embedded technique. The tissue attachment characteristics were assessed at clinical stages using the gingival index (GI) score, surgical stage (surgical score), and histological stage (histological attachment percentage). Additionally, the inflammatory responses were evaluated using inflammatory extent and inflammatory cellularity grades. Nonparametrical statistics were used to describe the GI and surgical scores, and analytical statistics were used to analyze the histological attachment percentages as well as the inflammatory extent and cellularity grades amongst the 3 groups.

Results

There were no statistically significant differences among the groups for GI score (P = .071) and surgical score (P = .262). Titanium and zirconia exhibited nearly similar mean histological attachment percentages while gold alloy had a significantly lower percentage (P = .004). For the inflammatory extent and cellularity grades, the odds of being one grade higher for gold alloy abutment was 5.18 and 17.8 times that of titanium abutment, respectively. However, for the zirconia abutment, the odds were 0.87 and 7.5 times higher than the titanium group.

Conclusions

The tissue around the gold alloy abutments resulted in worse attachment conditions compared with the titanium and zirconia abutments. Inflammation tended to be higher in the tissue around the gold alloy abutments than the titanium and zirconia abutments.

http://ift.tt/2BjdhL0

SHMT2 desuccinylation by SIRT5 drives cancer cell proliferation

The mitochondrial serine hydroxymethyltransferase SHMT2 which catalyzes the rate-limiting step in serine catabolism drives cancer cell proliferation, but how this role is regulated is undefined. Here we report that the sirtuin SIRT5 desuccinylates SHMT2 to increase its activity and drive serine catabolism in tumor cells. SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2 which was crucial for activating its enzymatic activity. Conversely hypersuccinylation of SHMT2 at lysine 280 was sufficient to inhibit its enzymatic activity and downregulate tumor cell growth in vitro and in vivo. Notably, SIRT5 inactivation led to SHMT2 enzymatic downregulation and abrogated cell growth under metabolic stress. Our results reveal that SHMT2 desuccinylation is a pivotal signal in cancer cells to adapt serine metabolic processes for rapid growth, and they highlight SIRT5 as a candidate target for suppressing serine catabolism as a strategy to block tumor growth.

http://ift.tt/2ztVlgu

MYC targeted long non-coding RNA DANCR promotes cancer in part by reducing p21 levels

The MYC oncogene broadly promotes transcription mediated by all nuclear RNA polymerases, thereby acting as a positive modifier of global gene expression. Here we report that MYC stimulates the transcription of DANCR, a long non-coding RNA (lncRNA) that is widely overexpressed in human cancer. We identified DANCR through its overexpression in a transgenic model of MYC-induced lymphoma, but found that it was broadly upregulated in many human cancer cell lines and cancers, including most notably in prostate and ovarian cancers. Mechanistic investigations indicated that DANCR limited the expression of cell cycle inhibitor p21 (CDKN1A), and that the inhibitory effects of DANCR loss on cell proliferation could be partially rescued by p21 silencing. In a xenograft model of human ovarian cancer, a nanoparticle-mediated siRNA strategy to target DANCR in vivo was sufficient to strongly inhibit tumor growth. Our observations expand knowledge of how MYC drives cancer cell proliferation by identifying DANCR as a critical lncRNA widely overexpressed in human cancers.

http://ift.tt/2Ag2bXX

ER alpha binding by transcription factors NFIB and YBX1 enables FGFR2 signalling to modulate estrogen responsiveness in breast cancer

Two opposing clusters of transcription factors (TF) have been associated with the differential risks of estrogen receptor positive or negative breast cancers, but the mechanisms underlying the opposing functions of the two clusters are undefined. In this study, we identified NFIB and YBX1 as novel interactors of the estrogen receptor alpha (ESR1). NFIB and YBX1 are both risk TF associated with progression of ESR1-negative disease. Notably, they both interacted with the ESR1-FOXA1 complex and inhibited the transactivational potential of ESR1. Moreover, signaling through FGFR2, a known risk factor in breast cancer development, augmented these interactions and further repressed ESR1 target gene expression. We therefore show that members of two opposing clusters of risk associated with ESR1 positive and negative breast cancer can physically interact. We postulate that this interaction forms a toggle between two developmental pathways affected by FGFR2 signaling, possibly offering a junction to exploit therapeutically.

http://ift.tt/2zxLarb

Small molecule inhibition of Axl targets tumor immune suppression and enhances chemotherapy in pancreatic cancer

Activation of the receptor tyrosine kinase Axl is associated with poor outcomes in pancreatic cancer (PDA), where it coordinately mediates immune evasion and drug resistance. Here we demonstrate that the selective Axl kinase inhibitor BGB324 targets the tumor-immune interface to blunt the aggressive traits of PDA cells in vitro and enhance gemcitibine efficacy in vivo. Axl signaling stimulates the TBK1-NFκB pathway and innate immune suppression in the tumor microenvironment. In tumor cells, BGB324 treatment drove epithelial differentiation, expression of nucleoside transporters affecting gemcitabine response and an immune stimulatory microenvironment. Our results establish a preclinical mechanistic rationale for the clinical development of Axl inhibitors to improve the treatment of PDA patients.

http://ift.tt/2Ag1BJL

YAP1 and COX2 coordinately regulate urothelial cancer stem-like cells

Overcoming acquired drug resistance remains a core challenge in the clinical management of human cancer, including in urothelial carcinoma of the bladder (UCB). Cancer stem-like cells (CSC) have been implicated in the emergence of drug resistance but mechanisms and intervention points are not completely understood. Here we report that the pro-inflammatory COX2/PGE2 pathway and the YAP1 growth regulatory pathway cooperate to recruit the stem cell factor SOX2 in expanding and sustaining the accumulation of urothelial CSC. Mechanistically, COX2/PGE2 signaling induced promoter methylation of let-7, resulting in its downregulation and subsequent SOX2 upregulation. YAP1 induced SOX2 expression more directly by binding its enhancer region. In UCB clinical specimens, positive correlations in the expression of SOX2, COX2, and YAP1 were observed, with co-expression COX2 and YAP1 particularly commonly observed. Additional investigations suggested that activation of the COX2/PGE2 and YAP1 pathways also promoted acquired resistance to EGFR inhibitors in basal-type UCB. In a mouse xenograft model of UCB, dual inhibition of COX2 and YAP1 elicited a long-lasting therapeutic response by limiting CSC expansion after chemotherapy and EGFR inhibition. Our findings provide a preclinical rationale to target these pathways concurrently with systemic chemotherapy as a strategy to improve the clinical management of UCB.

http://ift.tt/2ztCOk9

Synthetic lethality of PARP inhibitors in combination with MYC blockade is independent of BRCA status in triple negative breast cancer

PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients. Several of those patients exhibit intrinsic/acquired resistance mechanisms that limit efficacy of PARPi monotherapy. Here we show how the efficacy of PARPi in triple-negative breast cancers (TNBC) can be expanded by targeting MYC-induced oncogenic addiction. In BRCA-mutant/sporadic TNBC patients, amplification of the MYC gene is correlated with increased expression of the homologous DNA recombination enzyme RAD51 and tumors overexpressing both genes are associated with worse overall survival. Combining MYC blockade with PARPi yielded synthetic lethality in MYC-driven TNBC cells. Using the cyclin-dependent kinase inhibitor dinaciclib, which downregulates MYC expression, we found that combination with the PARPi niraparib increased DNA damage and downregulated homologous recombination, leading to subsequent downregulation of the epithelial-mesenchymal transition (EMT) and cancer stem-like cell phenotypes. Notably, dinaciclib re-sensitized TBNC cells, which had acquired resistance to niraparib. We found that the synthetic lethal strategy employing dinaciclib and niraparib was also highly efficacious in ovarian, prostate, pancreatic, colon and lung cancer cells. Taken together, our results show how blunting MYC oncogene addiction can leverage cancer cell sensitivity to PARPi, facilitating the clinical use of c-myc as a predictive biomarker for this treatment.

http://ift.tt/2Ag27aF

Perioperative, spatiotemporally coordinated activation of T and NK cells prevents recurrence of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and disseminating cancer resistant to therapy, including checkpoint immunotherapies, and early tumor resection and (neo)adjuvant chemotherapy fails to improve a poor prognosis. In a transgenic mouse model of resectable PDAC, we investigated the coordinated activation of T and NK cells in addition to gemcitabine chemotherapy to prevent tumor recurrence. Only neoadjuvant, but not adjuvant treatment with a PD-1 antagonist effectively supported chemotherapy and suppressed local tumor recurrence and improved survival involving both NK and T cells. Local T cell activation was confirmed by increased tumor infiltration with CD103+CD8+ T cells and neoantigen-specific CD8 T lymphocytes against the marker neoepitope LAMA4-G1254V. To achieve effective prevention of distant metastases in a complementary approach, we blocked the NK cell checkpoint CD96, an inhibitory NK cell receptor that binds CD155, which was abundantly expressed in primary PDAC and metastases of human patients. In gemcitabine-treated mice, neoadjuvant PD-1 blockade followed by adjuvant inhibition of CD96 significantly prevented relapse of PDAC, allowing for long-term survival. In summary, our results show in an aggressively growing transgenic mouse model of PDAC that the coordinated activation of both innate and adaptive immunity can effectively reduce the risk of tumor recurrence after surgery, facilitating long-term remission of this lethal disease.

http://ift.tt/2ib0B5f

miR-139-5p modulates radiotherapy resistance in breast cancer by repressing multiple gene networks of DNA repair and ROS defense

Radiotherapy (RT) is essential to the treatment of most solid tumors and acquired or innate resistance to this therapeutic modality is a major clinical problem. Here we show that miR-139-5p is a potent modulator of radiotherapy response in breast cancer (BC) via its regulation of genes involved in multiple DNA repair and reactive oxygen species defense pathways. Treatment of breast cancer cells with a miR-139-5p mimic strongly synergized with radiation both in vitro and in vivo, resulting in significantly increased oxidative stress, accumulation of unrepaired DNA damage and induction of apoptosis. Several miR-139-5p target genes were also strongly predictive of outcome, specifically in RT-treated patients across multiple independent breast cancer cohorts. These prognostically relevant miR-139-5p target genes were used as companion biomarkers to identify radioresistant BC xenografts highly amenable to sensitization by co-treatment with a miR-139-5p mimetic.

http://ift.tt/2AayWYV

A potent, metabolically stable tubulin inhibitor targets the colchicine binding site and overcomes taxane resistance

Antimitotics that target tubulin are among the most useful chemotherapeutic drugs, but their clinical activity is often limited by the development of multidrug resistance. We recently discovered the novel small molecule DJ101 as a potent and metabolically stable tubulin inhibitor that can circumvent the drug efflux pumps responsible for multidrug resistance of existing tubulin inhibitors. In this study, we determined the mechanism of action of this drug. The basis for its activity was illuminated by solving the crystal structure of DJ101 in complex with tubulin at a resolution of 2.8Å. Investigations of the potency of DJ101 in a panel of human metastatic melanoma cell lines harboring major clinically relevant mutations defined IC50 values of 7-10 nM. In cells, DJ101 disrupted microtubule networks, suppressed anchorage-dependent melanoma colony formation and impaired cancer cell migration. In melanoma-bearing mice, DJ101 administration inhibited tumor growth and reduced lung metastasis in the absence of observable toxicity. DJ101 also completely inhibited tumor growth in a paclitaxel-resistant xenograft mouse model of human prostate cancer (PC-3/TxR), where paclitaxel was minimally effective. Our findings offer preclinical proof of concept for the continued development of DJ101 as a next-generation tubulin inhibitor for cancer therapy.

http://ift.tt/2ibVt0s

Distinct TP63 isoform-driven transcriptional signatures predict tumor progression and clinical outcomes

TP63 is required to maintain stem cell pluripotency and suppresses the metastatic potential of cancer cells through multiple mechanisms. These functions are differentially regulated by individual isoforms, necessitating a deeper understanding of how the distinct transcriptional programs controlled by these isoforms affect cancer progression and outcomes. In this study, we conducted a pan-cancer analysis of The Cancer Genome Atlas (TCGA) to identify transcriptional networks regulated by TAp63 and ΔNp63 using transcriptomes derived from epidermal cells of TAp63-/- and ΔNp63-/- mice. Analysis of 17 cancer developmental and 27 cancer progression signatures revealed a consistent tumor suppressive pattern for TAp63. In contrast, we identified pleiotropic roles for ΔNp63 in tumor development and found that its regulation of Lef1 was crucial for its oncogenic role. ΔNp63 performed a distinctive role as suppressor of tumor progression by cooperating with TAp63 to modulate key biological pathways, principally cell cycle regulation, extra cellular matrix remodeling, epithelial-to-mesenchymal transition, and the enrichment of pluripotent stem cells. Importantly, these TAp63 and ΔNp63 signatures prognosticated progression and survival, even within specific stages, in bladder and renal carcinomas as well as low-grade gliomas. These data describe a novel approach for understanding transcriptional activities of TP63 isoforms across a large number of cancer types, potentially enabling identification of patient subsets most likely to benefit from therapies predicated on manipulating specific TP63 isoforms.

http://ift.tt/2AayRV7

New mechanisms of resistance to MEK inhibitors in melanoma revealed by intravital imaging

Targeted therapeutics that are initially effective in cancer patients nearly invariably engender resistance at some stage, an inherent challenge in the use of any molecular targeted drug in cancer settings. In this study, we evaluated resistance mechanisms arising in metastatic melanoma to MAPK pathway kinase inhibitors, as a strategy to identify candidate strategies to limit risks of resistance. To investigate longitudinal responses, we developed an intravital serial imaging approach that can directly visualize drug response in an inducible RAF-driven, autochthonous murine model of melanoma incorporating a fluorescent reporter allele (tdTomatoLSL). Using this system, we visualized formation and progression of tumors in situ starting from the single cell level longitudinally over time. Reliable reporting of the status of primary murine tumors treated with the selective MEK1/2 inhibitor (MEKi) trametinib illustrated a time-course of initial drug response and persistence followed by the development of drug resistance. We found that tumor cells adjacent to bundled collagen had a preferential persistence in response to MEKi. Unbiased transcriptional and kinome reprogramming analyses from selected treatment time points suggested increased c-Kit and PI3K/AKT pathway activation in resistant tumors, along with enhanced expression of epithelial genes and EMT downregulation signatures with development of MEKi resistance. Similar trends were observed following simultaneous treatment with BRAF and MEK inhibitors aligned to standard of care combination therapy, suggesting these re-programming events were not specific to MEKi alone. Overall, our results illuminate the integration of tumor-stroma dynamics with tissue plasticity in melanoma progression and provide new insights into the basis for drug response, persistence and resistance.

http://ift.tt/2icbjIM

Vitamin C sensitizes melanoma to BET inhibitors

Bromodomain and extra-terminal inhibitors (BETi) are promising cancer therapies, yet prominent side effects of BETi at effective doses have been reported in Phase I clinical trials. Here we screened a panel of small molecules targeting epigenetic modulators against human metastatic melanoma cells. Cells were pretreated with or without ascorbate (vitamin C), which promotes DNA demethylation and subsequently changes the sensitivity to drugs. Top hits were structurally unrelated BETi including JQ1, I-BET151, CPI-203, and BI-2536. Ascorbate enhanced the efficacy of BETi by decreasing acetylation of histone H4, but not H3, while exerting no effect on the expression of BRD proteins. Histone acetyltransferase 1 (HAT1), which catalyzes H4K5ac and H4K12ac, was downregulated by ascorbate mainly via the TET-mediated DNA hydroxymethylation pathway. Loss of H4ac, especially H4K5ac and H4K12ac, disrupted the interaction between BRD4 and H4 by which ascorbate and BETi blocked the binding of BRD4 to acetylated histones. Co-treatment with ascorbate and JQ1 induced apoptosis and inhibited proliferation of cultured melanoma cells. Ascorbate deficiency as modeled in Gulo-/- mice diminished the treatment outcome of JQ1 for melanoma tumorgraft. In contrast, ascorbate supplementation lowered the effective dose of JQ1 needed to successfully inhibit melanoma tumors in mice. Based on our findings, future clinical trials with BETi should consider ascorbate levels in patients. Furthermore, ascorbate supplementation might help reduce the severe side effects that arise from BETi therapy by reducing the dosage necessary for treatment.

http://ift.tt/2AayJVD

Small cell carcinomas of the bladder and lung are characterized by a convergent but distinct pathogenesis

Background Small cell carcinoma of the bladder (SCCB) is a rare and aggressive neuroendocrine tumor with a dismal prognosis and limited treatment options. As SCCB is histologically indistinguishable from small cell lung cancer, a shared pathogenesis and cell of origin has been proposed. The aim of this study is to determine whether SCCBs arise from a pre-existent urothelial carcinoma or share a molecular pathogenesis in common with small cell lung cancer. Results We performed an integrative analysis of 61 SCCB tumors to identify histology- and organ-specific similarities and differences. SCCB has a high somatic mutational burden driven predominantly by an APOBEC-mediated mutational process. TP53, RB1, and TERT promoter mutations were present in nearly all samples. While these events appeared to arise early in all affected tumors and likely reflect an evolutionary branch point that may have driven small cell lineage differentiation, they were unlikely the founding transforming event, as they were often preceded by diverse and less common driver mutations, many of which are common in bladder urothelial cancers but not small cell lung tumors. Most patient tumors (72%) also underwent genome doubling (GD). While arising at different chronological points in the evolution of the disease, GD was often preceded by biallelic mutations in TP53 with retention of two intact copies. Conclusions Our findings indicate that small cell cancers of the bladder and lung have a convergent but distinct pathogenesis with SCCBs arising from a cell of origin shared with urothelial bladder cancer.

http://ift.tt/2zKXgkU

Classifying colorectal cancer by tumor location rather than sidedness highlights a continuum in mutation profiles and Consensus Molecular Subtypes

Purpose: Colorectal cancers (CRCs) are classified as right/left sided based on whether they occur before/after the splenic flexure, with established differences in molecular subtypes and outcomes.  However, it is unclear if this division is optimal and whether precise tumor location provides further information. Experimental Design: In 1,876 patients with CRC we compared mutation prevalence and overall survival (OS) according to side and location. Consensus Molecular Subtype (CMS) was compared in a separate cohort of 608 patients. Results: Mutation prevalence differed by side and location for TP53, KRAS, BRAFV600, PIK3CA, SMAD4, CTNNB1, GNAS, and PTEN. Within left and right sided tumors, there remained substantial variations in mutation rates. For example, within right sided tumors, RAS >mutations decreased from 70% for cecal, to 43% for hepatic flexure location (P=0.0001), while BRAFV600 mutations increased from 10% to 22% between the same locations (P<0.0001). Within left sided tumors, the sigmoid and rectal region had more TP53 mutations (P=0.027), less PIK3CA (P=0.0009), BRAF (P=0.0033), or CTNNB1 mutations (P<0.0001), and less MSI (P<0.0001) than other left sided locations. Despite this, a left/right division preceding the transverse colon maximized prognostic differences by side and transverse colon tumors had K-modes mutation clustering that appeared more left than right sided. CMS profiles showed a decline in CMS1 and CMS3, and rise in CMS2 prevalence moving distally. Conclusions: Current right/left classifications may not fully recapitulate regional variations in tumor biology. Specifically, the sigmoid-rectal region appears unique and the transverse colon is distinct from other right sided locations.

http://ift.tt/2nclZc0

Honokiol Radiosensitizes Squamous Cell Carcinoma of the Head and Neck by Downregulation of Survivin

Purpose: Previous studies revealed diverging results regarding the role of survivin in squamous cell carcinoma of the head and neck (SCCHN).This study aimed to evaluate the clinical significance of survivin expression in SCCHN; the function of survivin in DNA damage repair following ionizing radiationtherapy (RT) in SCCHN cells; and the potential of honokiol to enhance RT through downregulation of survivin. Experimental Design: Expression of survivin in SCCHN patient primary tumor tissues (n=100) was analyzed and correlated with clinical parameters. SCCHN cell lines were used to evaluate the function of survivin and the effects of honokiol on survivin expression in vitro and in vivo. Results: Overexpression of survivin was significantly associated with lymph nodes metastatic status (p=0.025), worse overall survival (OS) and disease free survival (DFS) in patients receiving RT (n=65, OS: p=0.024, DFS: p=0.006) and in all patients with SCCHN (n=100, OS: p=0.002, DFS: p=0.003). In SCCHN cells, depletion of survivin led to increased DNA damage and cell death following RT, whereas overexpression of survivin increased clonogenic survival. RT induced nuclear accumulation of survivin and its molecular interaction with -H2AX and DNA-PKCs. Survivin specifically bound to DNA DSB sites induced by I-SceI endonuclease. Honokiol (which downregulates survivin expression) in combination with RT significantly augmented cytotoxicity in SCCHN cells with acquired radioresistance and inhibited growth in SCCHN xenograft tumors. Conclusions: Survivin is a negative prognostic factor and is involved in DNA damage repair induced by RT. Targeting survivin using honokiol in combination with RT may provide novel therapeutic opportunities.

http://ift.tt/2zKX2dy