Radiographic and clinical outcomes of rooted, platform-switched, microthreaded implants with a sandblasted, large-grid, and acid-etched surface: A 5-year prospective study

Abstract

Background

There is no data available on the long-term outcomes of a rooted, platform-switched, microthreaded implant with a sandblasted, large-grid, and acid-etched surface.

Purpose

This prospective, longitudinal study evaluated the clinical and radiographic outcomes of rooted, platform-switched, microthreaded and sandblasted, large-grid, and acid-etched (SLA) surface implants for 5 years.

Materials and Methods

Sixty implants were placed in sixty patients with partially edentulous maxillae or mandibles. The permanent prostheses were inserted 2–4 months after implant placement. Clinical and radiographic examinations were performed at follow-up visits scheduled postoperation, prosthesis installation, 1 year, and 5 years after surgery, to assess implant survival and success rates, biological and mechanical complications, and marginal bone loss.

Results

After 5 years' follow-up, four patients withdrawn from the study, and 56 implants achieved a 100% survival rate and 98.2% success rate. Three prosthetic complications occurred, resulting in a success rate for prostheses of 94.6%. The incidence of peri-implant mucositis was 9.1% and no peri-implantitis was diagnosed. The average marginal bone loss at the mesial aspect was 0.46 ± 0.27 mm after 1 year and 0.48 ± 0.27 mm after 5 years. The average marginal bone loss at the distal aspect was 0.46 ± 0.32 mm after 1 year and 0.50 ± 0.35 mm after 5 years.

Conclusion

After 5 years of loading, the rooted, platform-switched, microthreaded, and SLA surface implants showed high survival and success rates, steady crestal bone levels, and excellent long-term clinical outcomes in the soft tissue. Overloading may be related to the marginal bone loss around implants, but the surgical protocol, different sites, and jaw position did not correlate with crestal bone loss.

http://ift.tt/2zBLoOi

PARP inhibitors: Clinical utility and possibilities of overcoming resistance.

Related Articles

PARP inhibitors: Clinical utility and possibilities of overcoming resistance.

Gynecol Oncol. 2017 Oct 13;:

Authors: Bitler BG, Watson ZL, Wheeler LJ, Behbakht K

Abstract
PARP inhibitors represent a major breakthrough in ovarian cancer care. Almost half of all ovarian cancers have deficiencies in the homologous recombination (HR) DNA repair pathway, namely BRCA1/2 mutations. Given the limited therapeutic options for recurrent ovarian cancer patients there has been a significant effort to develop novel therapies to exploit DNA repair deficiencies. In 2005 and 2006, inhibiting PARP enzymes was first observed to be highly effective against cancers with HR deficiencies. PARP inhibitors are being utilized in the clinic to manage recurrent ovarian cancers that display defects in the HR repair pathway. However, PARP inhibitors also show significant clinical benefit in patients without HR deficiencies. There are currently three FDA-approved PARP inhibitors for recurrent ovarian cancer and an additional two PARP inhibitors being evaluated in late stage clinical trials. Given the expanding clinical use of PARP inhibitors and the high likelihood of acquired resistance, there is a significant need for clinical strategies to manage PARP inhibitor resistant disease. This review will examine PARP inhibitors in the context of: indications and toxicities, novel biomarkers to predict response, targeted-therapy resistance, and potential approaches to manage resistant disease.

PMID: 29037806 [PubMed - as supplied by publisher]

http://ift.tt/2l2k2Oe

Reappraisal of systemic venous chemoreceptors: might they explain the matching of breathing to metabolic rate in humans?

New Findings

• What is the topic of this review?

  One of the major unanswered questions in physiology is that of how breathing matches metabolic rate. Venous chemoreceptors seem to have been dismissed since the 1960s.

• What advances does it highlight?

  New evidence shows that their apparent dismissal needs reappraisal.

  • The paper on which this depends has more than one interpretation, and another paper obtained the opposite result.
  • Previous search ignored all locations between skeletal muscle and the right heart.
  • Oxygen sensors other than the arterial chemoreceptors do exist. Heymans and colleagues originally demonstrated some residual breathing response to hypoxia in sino-aortically denervated animals. Similar results occur in humans.

One of the major unanswered questions in physiology is that of how breathing matches metabolic rate. The existence in humans of venous chemoreceptors that might control breathing seems to have been dismissed since the 1960s. New evidence has emerged showing that this apparent dismissal needs reappraisal. Firstly, the paper in humans on which this depends has more than one interpretation. Moreover, a previous paper obtained the opposite result and is not cited. Secondly, previous search for venous chemoreceptors failed to examine all venous locations between skeletal muscle and the right heart and lungs. Thirdly, oxygen sensors other than the arterial chemoreceptors do exist. Heymans himself originally demonstrated some residual breathing response to hypoxia in sino-aortically denervated animals. Others confirm a residual breathing response to hypoxia in mammals, including humans. There is now considerable interest in the importance of afferent feedback in controlling the cardiovascular and respiratory systems. Moreover, it is now clear that arterial, aortic and central chemoreceptors have no role in explaining how breathing matches metabolic rate. These together provide a timely reminder that venous chemoreceptors remain ideal candidates still to be considered as metabolic rate sensors to explain matching in humans. Firstly, this is because venous and values do change appropriately in proportion to metabolic rate, so a metabolic rate signal sufficient to drive breathing might already exist. Secondly, chemoreceptor-like anatomical structures are present in the systemic venous system but remain unexplored. Finally, no extant experimental evidence precludes their existence.

http://ift.tt/2hRURZK

Resident-performed laser peripheral iridotomy in primary angle closure, primary angle closure suspects, and primary angle closure glaucoma

http://ift.tt/2xTTox7

Metachronous solitary plasmacytoma

Solitary plasmacytoma is a rare disorder comprising 5%–10% of all plasma cell neoplasms. Progression to multiple myeloma is the most common pattern of relapse. Appearance of new lesions without any systemic disease is the most unusual pattern of relapse seen in <2% cases. We present a case of a 46-year-old female who presented with features of third and seventh cranial nerve palsy, diagnosed with solitary plasmacytoma, with no evidence of any systemic disease. As per standard recommendations, the patient received radiotherapy to the local site. The patient developed relapse twice, at three sites, during the follow-up period. Investigations revealed no evidence of any systemic disease. In view of repeat relapses, the patient was started on immune modulatory agent. Two and half years after the last radiotherapy, the patient is symptom free with no evidence of any new lesion.

http://ift.tt/2l3zDgf

Acute-onset diplopia in a case of nephrotic syndrome

Description

A 12-year-old boy was evaluated in our emergency services for complaints of diplopia and mild generalised headache since past 4 days. The patient was a known case of frequently relapsing idiopathic nephrotic syndrome and was currently in remission since 5 days. He was normal and oriented on general physical and systemic examination. Urine microscopy had revealed only traces of protein on repeated evaluation, and serum albumin was 2.2 g/dL on presentation. Visual acuity was 6/6 in both eyes, and the pupillary reflexes were brisk. The ocular motility examination revealed an esotropia of 20 prism dioptres (figure 1A) along with limitation of the abduction movements in both eyes (figure 1B,C). However, right eye showed a greater limitation compared with left eye. Anterior segment of both the eyes were normal, but the fundus examination revealed bilateral severe established optic disc oedema (figure 2A,B). The...

http://ift.tt/2xTIcQP

A case of autosplenectomy associated with T-cell checkpoint inhibitor treatment

Description

A 77-year-old Caucasian man presented to the oncology service with de novo v-raf murine sarcoma viral oncogene homolog B (BRAF), wild-type metastatic melanoma and widespread disease involving; subcutaneous fat, lymph nodes, bone and spleen with no history of autoimmunity. At diagnosis, the spleen was measured within normal limits on CT. In November 2013, he commenced treatment on a phase-III randomised double-blinded clinical trial (CA209-067) and received combination checkpoint inhibitor therapy with ipilimumab and nivolumab.

Radiological mixed response was observed after three months, with a partial response in all target lesions (RECIST V.1.1 criteria) but an increase in the size of the non-target splenic metastasis consistent with pseudoprogression. In conjunction, splenic enlargement was demonstrated (figure 1).

Figure 1

Subsequent restaging coronal abdominopelvic CT demonstrating an increased splenic length of 11.8 cm.

After seven months of immunotherapy, he achieved a complete radiological response to treatment with an...

http://ift.tt/2l3mofw

Learning from errors: unnecessary intensive care unit admissions

An elderly man was transferred to our emergency department with reported ventricular tachycardia requiring intravenous amiodarone and intensive care unit admission. Device interrogation, the following day, revealed only frequent premature ventricular contractions and non-sustained ventricular tachycardia in a patient with a known history of these conditions. The patient underwent unnecessary invasive monitoring after being emergently transferred to our facility and admitted to the intensive care unit. Fortunately, our patient did not suffer any unwarranted side effects from intravenous amiodarone. This case reports on some negative consequences of inappropriate intensive care unit admissions and how they could have been avoided.

http://ift.tt/2l3ad2n

Community-acquired Pseudomonas aeruginosa meningitis

Gram-negative bacilli such as Pseudomonas aeruginosa are a rare cause of meningitis. Patients developing P. aeruginosa meningitis most commonly have a history of neurosurgical procedures. We report a patient who presented with community-acquired chronic meningitis secondary to P. aeruginosa, related to surgery for otosclerosis 5 years previously.

http://ift.tt/2xSduaR

Result of Health Illiteracy and Cultural Stigma: Fourniers Gangrene, a Urological Emergency

A 63-year-old Caucasian man presents to his regional hospital 8 days postinsertion of beads in his urethra, causing Fournier's gangrene of the penis and delayed surgical management of his gangrene. The reasons for his delay are cultural stigma associated with sexual practices and health illiteracy.

http://ift.tt/2l3mkwi

Anaesthesia and orphan disease: airway and anaesthetic management in Huntingtons disease

We present a case that highlights the issues surrounding the delivery of a safe general anaesthetic to a patient with Huntington's disease (HD) and bulbar dysfunction. In the case of a 46-year-old patient undergoing laparoscopic percutaneous endoscopic gastrostomy tube insertion, we discuss the rationale behind our chosen method and anaesthetic agents as well as airway issues specific to HD. In a patient whose condition would not allow for an awake fibreoptic intubation, we opted for a modified rapid sequence induction. Special considerations were made with regard to muscle relaxation given the complications associated with inadequate paralysis and reversal in patients with HD. The technique we describe may also apply to other patient categories, such as patients with movement disorders, bulbar dysfunction and dementia.

http://ift.tt/2xTJcV2

Rare presentation of an old bug

We highlight a rare presentation of Legionella infection in a 77-year-old woman with a clinical diagnosis of giant cell arteritis 2 months prior to presentation. She was started on 60 mg prednisone that was tapered to 10 mg after 4 weeks following her diagnosis. She presented with a 1-month progressive dyspnoea in the absence of any other symptoms. Her exposure history was significant only for a recent trip to Florida where she stayed at a hotel. Initial laboratory workup was significant for hyponatraemia (127 mmol/L). Workup including bronchoalveolar lavage (BAL) and induced sputum for gram stain, acid fast stain and bacterial culture were negative for Pneumocystis jirovecii pneumonia and other opportunistic infectious agents. However, BAL was positive for Legionella pneumophila via PCR that was confirmed by a positive urinary Legionella antigen. The patient received treatment with levofloxacin that led to full resolution of her symptoms.

http://ift.tt/2l1em6Z

Management challenges of late presentation Dacron patch infection after carotid endarterectomy

An 83-year-old man presented 4 years after right carotid endarterectomy (CEA) with an infection of his prosthetic Dacron patch. Initial scans (CT angiogram and whole body labelled white cell scan) were clear with no infection or collection noted. Systemically, the patient presented well with no recorded fevers. With an occluded left internal carotid artery and severely stenosed vertebral arteries, surgery presented a high risk of major stroke due to the lack collateral supply and this was discussed extensively. The patient subsequently declined surgical management, and he was monitored closely on an outpatient basis. He presented again a year later with ongoing haemoserous ooze from the CEA site. Subsequently a two-stage procedure was performed, where initially a stent was inserted, followed by patch excision and debridement. A muscle flap was then mobilised over the opening. This new approach to carotid patch infections should gain traction over time as a safer alternative for high-risk patients.

http://ift.tt/2xSf5xr

Unusual cause of saddle nose

Description

A 53-year-old female presented with a 2-week history of shortness of breath, cough and fever. Over the past 6 months, she reported painful tongue ulcers and pain in her nose, accompanied with nasal crusting and yellowish discharge. She had a history of pulmonary coccidioidomycosis, diagnosed 10 years ago, and she was treated with antifungal regimen. Physical examination revealed rhonchi bilaterally, multiple shallow ulcerative lesions on her tongue and a saddle nose deformity (figure 1A). CT of the chest demonstrated extensive ground-glass opacities with areas of nodular consolidation. Given her symptoms and history of coccidioidomycosis, nasal cavity biopsy was performed that revealed focal ulceration, non-specific inflammation with many cocci spherules, confirmed by Grocott's methenamine silver stain (figure 1B). Cultures from the lesions and the sputum grew Coccidioides immitis. Treatment with fluconazole 400 mg daily was initiated, and after several days her symptoms improved. 

http://ift.tt/2l1SA3e

Gentamicin-vancomycin-colistin local antibiotherapy in a cement spacer in a 54-year-old haemophilic patient with relapsing plurimicrobial severe prosthetic joint infection

Description

A 54-year-old patient with haemophilia and hepatitis C virus infection experienced acute left prosthetic joint infection due to Klebsiella pneumoniae and Staphylococcus aureus following unipolar exchange in September 2015. As the outcome was not favourable with bloody discharge despite haemophilic factor substitution, a new local debridement was performed in May 2016 and multidrug-resistant Enterobacter asburiae (only susceptible to imipenem, colistin, amikacin and fosfomycin) and Corynebacterium striatum (only susceptible to vancomycin, rifampin and linezolid) grew in cultures. As explantation was considered too risky due to the potential bleeding, systemic intravenous treatment was proposed with imipenem (3 g/day), vancomycin (2.5 g/day) and fosfomycin (12 g/day). After 3 months of therapy, the bloody discharge persisted. One month after discontinuation of antibiotics, the patient presented a large 'bourgeon charnu' with impressive bloody discharge (figure 1A). X-ray revealed trochanter osteolysis, without prosthesis loosening (figure 1B). Prosthesis explantation was performed, and a...

http://ift.tt/2xTezPN

Primary hepatic hemangioendothelioma in a patient with Budd-Chiari syndrome

A 36-year-old woman was diagnosed with compensated cirrhosis of liver secondary to Budd-Chiari syndrome (BCS) and had undergone stenting of a thrombosed left hepatic vein. Eight months later, she presented with jaundice and right upper quadrant pain. CT revealed multiple focal lesions in the liver, which on biopsy proved to be hepatic hemangioendothelioma (HHE). Her liver disease and ascites progressively increased. Four months later, magnetic resonance cholangiopancreatography showed an advanced stage of HHE with infiltration of the common bile duct and vascular invasion with a blocked stent, with metastasis to the spleen and dorsolumbar vertebrae. We believe this is the first reported case of an HHE developing in the background of BCS.

http://ift.tt/2l3mbsK

Re-correction osteotomy with osteophyte graft for correction loss with non-union after high tibial osteotomy

A 68-year-old man with right knee varus osteoarthritis was treated by lateral closed-wedge high tibial osteotomy. A correction loss with non-union occurred 6 months after surgery and a re-correction osteotomy was performed. Removing the proximal screws of the lateral plate, a medial opening-wedge re-osteotomy was performed. Arthroscopically harvested osteophytes were used to fill the gap after opening. An additional medial locking plate was installed on the medial side. Finally, the proximal lateral screws were reinserted and locked again. Mature trabecular continuity was obtained in the gap by 6 months, and there was no varus deformity 4 years after re-correction. Re-correction osteotomy could be a viable treatment when lateral compartment osteoarthritis has not progressed and good range of motion still exists. Osteophyte grafting may be an effective option not only to avoid iliac bone grafting but also to promote bone healing in re-osteotomy.

http://ift.tt/2l3m6oW

Honeycomb and necklace signs in liver abscesses secondary to melioidosis

Melioidosis is endemic in Southeast Asia and tropical Australia with varying clinical features from benign skin lesions to fatal septicaemia. Imaging plays an important role in evaluation of the melioid liver abscesses. A 45-year-old man with underlying diabetes presented with fever and lethargy for 2 weeks and abdominal pain for 2 days. His liver was enlarged on examination. Blood investigations revealed mild leucocytosis and raised liver enzymes. Ultrasound showed multiple multiloculated hypoechoic lesions throughout the liver and spleen. CT of abdomen confirmed that some liver lesions were made up of asymmetric locules of varying sizes (honeycomb sign), while others had hypodense centre with small symmetric peripheral locules in radial fashion (necklace sign). Blood culture was positive for Burkholderia pseudomallei. He was subsequently treated with ceftazidime for a month followed by oral trimethoprim–sulfamethoxazole for 3 months. Follow-up CT of abdomen a month after diagnosis and treatment showed resolving hepatic and splenic lesions.

http://ift.tt/2xV0v8e

Vancomycin-associated drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: masquerading under the guise of sepsis

A patient presented with what appeared to be severe urosepsis. After admission and antibiotic administration, a newly developed rash and subsequent facial swelling appeared to be a reaction to penicillin class antibiotics. However, despite changing class of therapy with continued antimicrobial coverage, end organ damage continued, the rash worsened and facial oedema developed. Drug reaction with eosinophilia and systemic symptoms was ultimately diagnosed and was consistent with clinical and histopathological findings, as well as meeting all criteria for scoring systems. The patient was started on intravenous methylprednisolone 125 mg per 8 hours with rapid improvement of rash, swelling and end organ damage. Initial challenge to decrease dose failed, but the patient was ultimately able to be discharged on an extended taper.

http://ift.tt/2l3Hw5u

Memory of World War II with loud atypical friction rub due to pulmonary asbestosis

Description

An 87-year-old healthy woman was admitted to our hospital with progressive dyspnoea on effort since the preceding 6 months. She had a history of total gastrectomy, performed 5 years earlier. She was a non-smoker and worked as a business manager.

She did not abuse drugs. During World War II, when she was 15 years old, she worked for a year in a factory manufacturing the brake pads of fighter planes using copious amounts of asbestos. Physical examination revealed the presence of a 'hard and high-pitched knocking sound during the early inspiratory phase', in the right middle to lower lung fields, anteriorly (online ).

A chest radiograph showed massive calcifications in both lungs, including at the level of the diaphragm (figure 1A). Thoracic CT confirmed that these calcifications corresponded to the deposition of massive pleural plaques (figure 1B, C), especially in the visceral pleura (figure...

http://ift.tt/2xSSnFw

Single-incision laparoscopic cholecystectomy for gallbladder torsion: A case report and literature review

Abstract

We present a case of preoperatively diagnosed gallbladder torsion (GT) that was successfully treated by single-incision laparoscopic cholecystectomy. An 80-year-old woman presented with sudden pain and a palpable mass in the right upper quadrant. Contrast-enhanced CT revealed ischemic changes, a swollen gallbladder with a V-shaped distortion of the extrahepatic ducts, and the gallbladder in an abnormal anatomical position; clinical findings indicated GT. We performed single-incision laparoscopic cholecystectomy and intraoperatively found that the floating gallbladder was twisted counterclockwise by 180° around the cystic duct. After an uneventful postoperative course, the patient was discharged on postoperative day 7. Laparoscopic cholecystectomy for a GT was first performed in 1994, and since then, 28 cases, including ours, have been treated laparoscopically. Laparoscopic cholecystectomy for GT could be the standard treatment for this condition, and single-incision laparoscopic cholecystectomy may be a good surgical option for patients with GT because of its anatomical characteristics.

http://ift.tt/2yDZH7d

Laparoscopic transabdominal preperitoneal repair for strangulated inguinal hernia

Abstract

Introduction

Laparoscopic transabdominal preperitoneal repair (TAPP) is widely accepted in elective inguinal hernioplasty. However, given the scarcity of data, the feasibility and safety of TAPP in strangulated hernia cases have not yet been determined.

Methods

We retrospectively evaluated the data from a consecutive series of 33 patients who had undergone surgery for acute strangulated inguinal hernia associated with suspected visceral ischemic damage by either TAPP (TAPP group, n = 11) or conventional open hernioplasty via the anterior approach (anterior group, n = 22).

Results

The TAPP group had a significant longer surgical duration than the anterior group (147 vs 84 min) and relatively less blood loss. Incision and enlargement of the hernial orifice, which enables easy reduction of the strangulated organ, was performed in the last 7 of 11 cases in the TAPP group. The morbidity was lower in the TAPP group, but the difference was not statistically significant (18% vs 23%). The TAPP group had a significantly shorter postoperative hospital stay than the anterior group (7 vs 10 days).

Conclusion

For surgeons with sufficient knowledge of the anatomy and expertise in reducing the strangulated organ, TAPP for strangulated inguinal hernia is at least comparable to open hernioplasty via the anterior approach in short-term outcomes.

http://ift.tt/2gvW3Wh

Clinicopathologic implications of CD8 + /Foxp3 + ratio and miR-574-3p/PD-L1 axis in spinal chordoma patients

Abstract

Currently, little is known about the interactions between microRNAs (miRNAs) and the PD-1/PD-L1 signaling pathway in chordoma, and data discussing the role of the immune milieu in chordoma prognosis are limited. We aimed to analyze the relationship between PD-L1, miR-574-3p, microenvironmental tumor-infiltrating lymphocytes (TILs) and clinicopathological features of spinal chordoma patients. PD-L1 expression and TILs (including Foxp3⁺, CD8⁺, PD-1⁺ and PD-L1⁺) were assessed by immunohistochemistry in tumor specimens of 54 spinal chordoma patients. MiRNAs microarray and bioinformatical analysis were used to identify miRNAs potentially regulating PD-L1 expression, which were further validated by quantitative RT-PCR. miR-574-3p was identified to potentially regulate PD-L1 expression in chordoma, which inversely correlated with PD-L1. Positive PD-L1 expression on tumor cells was associated with advanced stages (P = 0.041) and TILs infiltration (P = 0.005), whereas decreased miR-574-3p level correlated with higher muscle invasion (P = 0.012), more severe tumor necrosis (P = 0.022) and poor patient survival. Importantly, a patient subgroup with PD-L1⁺/miR-574-3p^low chordoma phenotype was significantly associated with worse local recurrence-free survival (LRFS) (P = 0.026). PD-1⁺ TILs density was associated with surrounding muscle invasion (P = 0.014), and independently portended poor LRFS (P = 0.040), while PD-L1⁺ TILs showed tendencies of less aggressive clinical outcomes. Multivariate analysis of OS only found CD8⁺/Foxp3⁺ ratio to be independent prognostic factor (P = 0.022). These findings may be useful to stratify patients into prognostic groups and provide a rationale for the use of checkpoint blockade therapy, possibly by administering miR-574-3p mimics, in spinal chordoma.

http://ift.tt/2zC5tEm

New evidence for association of recessive IARS gene mutations with hepatopathy, hypotonia, intellectual disability and growth retardation

http://ift.tt/2gosIJA

Clinicopathologic implications of CD8 + /Foxp3 + ratio and miR-574-3p/PD-L1 axis in spinal chordoma patients

Abstract

Currently, little is known about the interactions between microRNAs (miRNAs) and the PD-1/PD-L1 signaling pathway in chordoma, and data discussing the role of the immune milieu in chordoma prognosis are limited. We aimed to analyze the relationship between PD-L1, miR-574-3p, microenvironmental tumor-infiltrating lymphocytes (TILs) and clinicopathological features of spinal chordoma patients. PD-L1 expression and TILs (including Foxp3⁺, CD8⁺, PD-1⁺ and PD-L1⁺) were assessed by immunohistochemistry in tumor specimens of 54 spinal chordoma patients. MiRNAs microarray and bioinformatical analysis were used to identify miRNAs potentially regulating PD-L1 expression, which were further validated by quantitative RT-PCR. miR-574-3p was identified to potentially regulate PD-L1 expression in chordoma, which inversely correlated with PD-L1. Positive PD-L1 expression on tumor cells was associated with advanced stages (P = 0.041) and TILs infiltration (P = 0.005), whereas decreased miR-574-3p level correlated with higher muscle invasion (P = 0.012), more severe tumor necrosis (P = 0.022) and poor patient survival. Importantly, a patient subgroup with PD-L1⁺/miR-574-3p^low chordoma phenotype was significantly associated with worse local recurrence-free survival (LRFS) (P = 0.026). PD-1⁺ TILs density was associated with surrounding muscle invasion (P = 0.014), and independently portended poor LRFS (P = 0.040), while PD-L1⁺ TILs showed tendencies of less aggressive clinical outcomes. Multivariate analysis of OS only found CD8⁺/Foxp3⁺ ratio to be independent prognostic factor (P = 0.022). These findings may be useful to stratify patients into prognostic groups and provide a rationale for the use of checkpoint blockade therapy, possibly by administering miR-574-3p mimics, in spinal chordoma.

http://ift.tt/2zC5tEm

Symbol Grounding Without Direct Experience: Do Words Inherit Sensorimotor Activation From Purely Linguistic Context?

Abstract

Theories of embodied cognition assume that concepts are grounded in non-linguistic, sensorimotor experience. In support of this assumption, previous studies have shown that upwards response movements are faster than downwards movements after participants have been presented with words whose referents are typically located in the upper vertical space (and vice versa for downwards responses). This is taken as evidence that processing these words reactivates sensorimotor experiential traces. This congruency effect was also found for novel words, after participants learned these words as labels for novel objects that they encountered either in their upper or lower visual field. While this indicates that direct experience with a word's referent is sufficient to evoke said congruency effects, the present study investigates whether this direct experience is also a necessary condition. To this end, we conducted five experiments in which participants learned novel words from purely linguistic input: Novel words were presented in pairs with real up- or down-words (Experiment 1); they were presented in natural sentences where they replaced these real words (Experiment 2); they were presented as new labels for these real words (Experiment 3); and they were presented as labels for novel combined concepts based on these real words (Experiment 4 and 5). In all five experiments, we did not find any congruency effects elicited by the novel words; however, participants were always able to make correct explicit judgements about the vertical dimension associated to the novel words. These results suggest that direct experience is necessary for reactivating experiential traces, but this reactivation is not a necessary condition for understanding (in the sense of storing and accessing) the corresponding aspects of word meaning.

http://ift.tt/2yBg6J4

Real Objects Can Impede Conditional Reasoning but Augmented Objects Do Not

Abstract

In this study, Knauff and Johnson-Laird's (2002) visual impedance hypothesis (i.e., mental representations with irrelevant visual detail can impede reasoning) is applied to the domain of external representations and diagrammatic reasoning. We show that the use of real objects and augmented real (AR) objects can control human interpretation and reasoning about conditionals. As participants made inferences (e.g., an invalid one from "if P then Q" to "P"), they also moved objects corresponding to premises. Participants who moved real objects made more invalid inferences than those who moved AR objects and those who did not manipulate objects (there was no significant difference between the last two groups). Our results showed that real objects impeded conditional reasoning, but AR objects did not. These findings are explained by the fact that real objects may over-specify a single state that exists, while AR objects suggest multiple possibilities.

http://ift.tt/2xSmwjl

Semantic Information and the Syntax of Propositional Attitude Verbs

Abstract

Propositional attitude verbs, such as think and want, have long held interest for both theoretical linguists and language acquisitionists because their syntactic, semantic, and pragmatic properties display complex interactions that have proven difficult to fully capture from either perspective. This paper explores the granularity with which these verbs' semantic and pragmatic properties are recoverable from their syntactic distributions, using three behavioral experiments aimed at explicitly quantifying the relationship between these two sets of properties. Experiment 1 gathers a measure of 30 propositional attitude verbs' syntactic distributions using an acceptability judgment task. Experiments 2a and 2b gather measures of semantic similarity between those same verbs using a generalized semantic discrimination (triad or "odd man out") task and an ordinal (Likert) scale task, respectively. Two kinds of analyses are conducted on the data from these experiments. The first compares both the acceptability judgments and the semantic similarity judgments to previous classifications derived from the syntax and semantics literature. The second kind compares the acceptability judgments to the semantic similarity judgments directly. Through these comparisons, we show that there is quite fine-grained information about propositional attitude verbs' semantics carried in their syntactic distributions—whether one considers the sorts of discrete qualitative classifications that linguists traditionally work with or the sorts of continuous quantitative classifications that can be derived experimentally.

http://ift.tt/2yBaI8G

Mitochondrial ADP/ATP Carrier in Dodecylphosphocholine Binds Cardiolipins with Non-native Affinity

Biophysical investigation of membrane proteins generally requires their extraction from native sources using detergents, a step that can lead, possibly irreversibly, to protein denaturation. The propensity of dodecylphosphocholine (DPC), a detergent widely utilized in NMR studies of membrane proteins, to distort their structure has been the subject of much controversy. It has been recently proposed that the binding specificity of the yeast mitochondrial ADP/ATP carrier (yAAC3) toward cardiolipins is preserved in DPC, thereby suggesting that DPC is a suitable environment in which to study membrane proteins.

http://ift.tt/2yVctPq

Molecular Basis of Overdominance at a Flower Color Locus

Single-gene overdominance is one of the major mechanisms proposed to explain heterosis (i.e., hybrid vigor), the phenomenon that hybrid offspring between two inbred lines or varieties show superior phenotypes to both parents. Although sporadic examples of single-gene overdominance have been reported over the decades, the molecular nature of this phenomenon remains poorly understood and it is unclear whether any generalizable principle underlies the various cases. Through bulk segregant analysis, chemical profiling, and transgenic experiments, we show that loss-of-function alleles of the FLAVONE SYNTHASE (FNS) gene cause overdominance in anthocyanin-based flower color intensity in the monkeyflower species Mimulus lewisii. FNS negatively affects flower color intensity by competing with the anthocyanin biosynthetic enzymes for the same substrates, yet positively affects flower color intensity by producing flavones, the colorless co-pigments required for anthocyanin stabilization, leading to enhanced pigmentation in the heterozyote (FNS/fns) relative to both homozygotes (FNS/FNS and fns/fns). We suggest that this type of antagonistic pleiotropy (i.e., alleles with opposing effects on different components of the phenotypic output) might be a general principle underlying single-gene overdominance.

http://ift.tt/2xa2Esu

Soluble CD163 in intracerebral hemorrhage: biomarker for perihematomal edema

Abstract

Objective

Patients with intracerebral hemorrhage (ICH) may elaborate varying degrees of perihematomal edema (PHE), requiring closer monitoring and a higher intensity of treatment. Here, we explore whether the soluble form of CD163, a scavenger receptor responsible for hemoglobin sequestration, can serve as a prognostic biomarker of PHE development and poor outcome after ICH.

Methods

Our study cohort was comprised of 51 primary age- and sex-matched ICH patients with moderate-sized, hypertensive deep hemorrhages. Patients were part of a prospective ICH registry cataloguing admission data along with functional outcomes. We measured sCD163 levels in serial serum and cerebrospinal fluid (CSF) samples obtained at prespecified timepoints. Descriptive statistics, including a generalized estimating equation for longitudinal data, were used to analyze sCD163 in relation to ICH outcomes.

Results

Acute serum sCD163 (<48 h postictus) was significantly elevated in ICH patients compared to both acute neurological event controls (P = <0.001) and healthy controls (P = 0.003). As predicted, acute serum sCD163 levels were significantly associated with both hematoma volume expansion (P = 0.009) and PHE expansion (P = 0.002). Further examination determined that patients with high PHE expansion had poorer modified Rankin Scale scores at discharge (P = 0.024), and circulating sCD163 levels were found to be significantly lower in patients with high-level PHE expansion.

Interpretation

Acute sCD163 levels may be a useful biomarker for the acute identification of patients at risk for hematoma expansion, perihematomal edema expansion and poorer short-term outcomes.

http://ift.tt/2yBq7Ez

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Abstract

Objective

To evaluate sex differences and the relative effect of G2019S LRRK2 mutations in Parkinson's disease (PD).

Methods

530 LRRK2 PD carriers and 759 noncarrier PD (idiopathic, IPD) evaluated as part of the Fox Foundation (MJFF) Consortium were included. All participants completed a study visit including information on clinical features, treatment, examination, and motor and nonmotor questionnaires. Clinical features were compared between men and women separately for IPD and LRRK2 PD; and features were compared between IPD and LRRK2 PD separately for men and women.

Results

Among IPD: men had higher levodopa equivalency dose (LED), worse activities of daily living and motoric severity but lower complications of therapy (UPDRS-IV). IPD women had higher olfaction and thermoregulatory scores and were more likely to report family history of PD. Among LRRK2 PD: Male predominance was not observed among G2019S LRRK2 cases. Women had worse UPDRS-IV but better olfaction. Among same sex: LRRK2 men and women had better olfaction than IPD counterparts. LRRK2 men demonstrated lower motor and higher cognitive, RBD and thermoregulation scores than IPD men and LRRK2 women had greater UDPRS-IV and rates of dyskinesia.

Interpretation

There were clinical differences between sexes with a more severe phenotype in IPD men and more complications of therapy in women. The more severe male phenotype was moderated by LRRK2, with LRRK2 men and women showing less diversity of phenotype. Our study supports that both genetics and sex drive phenotype, and thus trials in LRRK2 and IPD should consider gender stratification in design or analysis.

http://ift.tt/2xaTuM7

Mitochondrial ADP/ATP Carrier in Dodecylphosphocholine Binds Cardiolipins with Non-native Affinity

Biophysical investigation of membrane proteins generally requires their extraction from native sources using detergents, a step that can lead, possibly irreversibly, to protein denaturation. The propensity of dodecylphosphocholine (DPC), a detergent widely utilized in NMR studies of membrane proteins, to distort their structure has been the subject of much controversy. It has been recently proposed that the binding specificity of the yeast mitochondrial ADP/ATP carrier (yAAC3) toward cardiolipins is preserved in DPC, thereby suggesting that DPC is a suitable environment in which to study membrane proteins.

http://ift.tt/2yVctPq

Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM

Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it. Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance. Results: We observed that mesenchymal EGFR mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. De-repression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance "free" cellular BIM levels both led to re-sensitization of mesenchymal EGFR mutant cancers to EGFR inhibitors. This relationship between EMT and loss of BIM is not restricted to EGFR mutant cancers as it was also observed in KRAS mutant lung cancers and large datasets including different cancer subtypes. Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies.

http://ift.tt/2yvkrhO

Liquid Biopsies Using Plasma Exosomal Nucleic Acids and Plasma Cell-Free DNA compared with Clinical Outcomes of Patients with Advanced Cancers

Purpose: Blood-based liquid biopsies offer easy access to genomic material for molecular diagnostics in cancer. Commonly used cell-free DNA (cfDNA) originates from dying cells. Exosomal nucleic acids (exoNA) originate from living cells, which can better reflect underlying cancer biology. Experimental Design: Next-generation sequencing (NGS) was used to test exosomal nucleic acids (exoNA), and droplet digital PCR (ddPCR) and BEAMing PCR were used to test cfDNA for BRAF V600, KRAS G12/G13, and EGFR exon19del/L858R mutations in 43 patients with progressing advanced cancers. Results were compared with clinical testing of archival tumor tissue and clinical outcomes. Results: Forty-one patients had BRAF, KRAS, or EGFR mutations in tumor tissue. These mutations were detected by NGS in 95% of plasma exoNA samples, by ddPCR in 92% of cfDNA samples, and by BEAMing in 97% cfDNA samples. NGS of exoNA did not detect any mutations not present in tumor, whereas ddPCR and BEAMing detected 1 and 2 such mutations, respectively. Compared with patients with high exoNA mutation allelic frequency (MAF), patients with low MAF had longer median survival (11.8 vs. 5.9 months; P=0.006) and time to treatment failure (7.4 vs. 2.2 months; P=0.009). A low amount of exoNA was associated with partial response and stable disease ≥6 months P=0.006). Conclusions: NGS of plasma exoNA for common BRAF, KRAS, and EGFR mutations has high sensitivity compared with clinical testing of archival tumor and testing of plasma cfDNA. Low exoNA MAF is an independent prognostic factor for longer survival.

http://ift.tt/2gmUGFz

A multicenter phase I study evaluating dual PI3K and BRAF inhibition with PX-866 and vemurafenib in patients with advanced BRAF V600 mutant solid tumors

Purpose: The objectives of the study were to evaluate the safety of daily oral PX-866 in combination with twice daily vemurafenib and to identify potential predictive biomarkers for this novel combination. Experimental Design: We conducted a phase I, open-label, dose escalation study in patients with advanced BRAF V600 mutant solid tumors. PX-866 was administered on a continuous schedule in combination with vemurafenib. Patients underwent a baseline and on-treatment biopsy after 1-week of PX-866 monotherapy for biomarker assessment. Results: 24 patients were enrolled. The most common treatment-related adverse events were gastrointestinal side effects. One dose limiting toxicity (DLT) of grade 3 rash and one DLT of grade 3 pancreatitis were observed in cohort 2 (PX-866 6mg daily; vemurafenib 960mg twice daily) and cohort 3 (PX-866 8mg daily; vemurafenib 960mg twice daily), respectively. Of 23 response evaluable patients, 7 had confirmed partial responses (PRs), 10 had stable disease and 6 had disease progression. Decreases in intra-tumoral pAKT expression were observed following treatment with PX-866. Patients who achieved PRs had higher rates of PTEN loss by immunohistochemistry (80% vs 58%) and pathogenic PTEN mutations and/or deletions (57% vs 25%). Two patients with durable PRs had an increase in intra-tumoral CD8 T-cell infiltration following treatment with PX-866. Conclusions: PX-866 was well tolerated at its maximal tolerated single-agent dose when given in combination with a modified dose of vemurafenib (720mg twice daily). Response to treatment appeared to be associated with PTEN loss and treatment with PX-866 seemed to increase CD8 T-cell infiltration in some patients.

http://ift.tt/2yvkoTa

TLR4-mediated inflammation promotes KSHV-induced cellular transformation and tumorigenesis by activating the STAT3 pathway

Toll-like receptors (TLR) are conserved immune sensors mediating antimicrobial and antitumoral responses, but recent evidence implicates them in promoting carcinogenesis in certain cancers. Kaposi's sarcoma (KS) is caused by infection of Kaposi's sarcoma-associated herpesvirus (KSHV) and is characterized by uncontrolled neoangiogenesis and inflammation. Here we show that TLR4 is upregulated in KSHV-infected spindle tumor cells in human KS lesions. In a model of KSHV-induced cellular transformation, KSHV upregulated expression of TLR4, its adaptor MyD88, and coreceptors CD14 and MD2. KSHV induction of TLR4 was mediated by multiple viral microRNAs. Importantly, the TLR4 pathway was activated constitutively in KSHV-transformed cells resulting in chronic induction of IL-6, IL-1β and IL-18. Accordingly, IL-6 mediated constitutive activation of the STAT3 pathway, an essential event for uncontrolled cellular proliferation and transformation. TLR4 stimulation with lipopolysaccharides or live bacteria enhanced tumorigenesis while TLR4 antagonist CLI095 inhibited it. These results highlight an essential role of the TLR4 pathway and chronic inflammation in KSHV-induced tumorigenesis, which helps explain why HIV-infected patients, who frequently suffer from opportunistic bacterial infections and metabolic complications, frequently develop KS.

http://ift.tt/2gmT66B

Understanding personal risk of oropharyngeal cancer: risk-groups for oncogenic oral HPV infection and oropharyngeal cancer

Abstract

Background

Incidence of human papillomavirus (HPV)-related oropharyngeal cancer is increasing. There is interest in identifying healthy individuals most at risk for development of oropharyngeal cancer to inform screening strategies.

Patients and methods

All data are from 2009 to 2014, including 13 089 people ages 20–69 in the National Health and Nutrition Examination Survey (NHANES), oropharyngeal cancer cases from the Surveillance, Epidemiology, and End Results (SEER 18) registries (representing ∼28% of the US population), and oropharyngeal cancer mortality from National Center for Health Statistics (NCHS). Primary study outcomes are (i) prevalence of oncogenic HPV DNA in an oral rinse and gargle sample, and (ii) incident oropharyngeal squamous cell cancer.

Results

Oncogenic oral HPV DNA is detected in 3.5% of all adults age 20–69 years; however, the lifetime risk of oropharyngeal cancer is low (37 per 10 000). Among men 50–59 years old, 8.1% have an oncogenic oral HPV infection, 2.1% have an oral HPV16 infection, yet only 0.7% will 'ever' develop oropharyngeal cancer in their lifetime. Oncogenic oral HPV prevalence was higher in men than women, and increased with number of lifetime oral sexual partners and tobacco use. Men who currently smoked and had ≥5 lifetime oral sexual partners had 'elevated risk' (prevalence = 14.9%). Men with only one of these risk factors (i.e. either smoked and had 2–4 partners or did not smoke and had ≥5 partners) had 'medium risk' (7.3%). Regardless of what other risk factors participants had, oncogenic oral HPV prevalence was 'low' among those with only ≤1 lifetime oral sexual partner (women = 0.7% and men = 1.7%).

Conclusions

Screening based upon oncogenic oral HPV detection would be challenging. Most groups have low oncogenic oral HPV prevalence. In addition to the large numbers of individuals who would need to be screened to identify prevalent oncogenic oral HPV, the lifetime risk of developing oropharyngeal caner among those with infection remains low.

http://ift.tt/2iqvn9J

Biomarker-guided stratification of autoimmune patients for biologic therapy

Sabine Ivison | Christine des Rosiers | Sylvie Lesage | John D Rioux | Megan K Levings

http://ift.tt/2guf5Mz

Comparison of Young Patients with Gastric Cancer in the United States and China

Abstract

Background

This study aimed to compare the clinicopathologic characteristics and stage-specific prognosis of young patients with gastric cancer (GC) after curative resection (R0) in the United States and China.

Methods

Data were collected on young patients (age ≤40 years) undergoing R0 resection at one U.S. (n = 79) and one Chinese (n = 257) institution. Patient, surgical, and pathologic variables and stage-specific survival rates were compared. Factors associated with 5-year disease-specific survival (DSS) were determined via multivariate analysis.

Results

Tumor location was most often proximal in U.S. patients and distal in Chinese patients. The Chinese patients had more advanced-stage tumors, with a greater number of positive lymph nodes identified. Preoperative chemotherapy was administered more often in the United States. The 5-year overall survival (p = 0.07) and DSS (p = 0.07) did not differ statistically between the U.S. and Chinese cohorts. Among the patients with early GC receiving surgery alone, DSS did not differ significantly between the two cohorts (p = 0.44). Among the patients with advanced GC, DSS was comparable between the U.S. patients receiving preoperative chemotherapy plus surgery and the Chinese patients receiving surgery plus postoperative chemotherapy (p = 0.85). Lauren classification, depth of invasion, number of metastatic lymph nodes, and type of gastrectomy, but not country, were independent predictors of DSS.

Conclusions

Tumor features and therapeutic strategies among young patients with GC differ between the United States and China. Survival is comparable between young patients with advanced GC receiving preoperative chemotherapy plus surgery in the United States and those receiving surgery plus postoperative chemotherapy in China, suggesting that the outcomes for young patients with GC are stage dependent but not country specific.

http://ift.tt/2yDC8eH

Eligibility of Metastatic Pancreatic Cancer Patients for First-Line Palliative Intent nab-Paclitaxel Plus Gemcitabine Versus FOLFIRINOX

Objectives: The PRODIGE and MPACT trials showed superiority of FOLFIRINOX and nab-paclitaxel plus gemcitabine (NG) over gemcitabine alone, respectively. However, both had strict inclusion criteria. We sought to determine the characteristics of patients with metastatic pancreatic cancer (MPC) which inform the appropriateness of first-line chemotherapy FOLFIRINOX and NG in routine practice. Materials and Methods: Patients with MPC who initiated palliative chemotherapy with gemcitabine from 2000 to 2011 at the British Columbia Cancer Agency were identified. Clinicopathologic variables and outcomes were retrospectively collected and compared among groups. Eligibility criteria for each regimen were in accordance with the respective pivotal phase III trials. Results: A total of 473 patients were included: 25% of the patients were eligible for FOLFIRINOX versus 45% for NG. Main reasons for FOLFIRINOX ineligibility were Eastern Cooperative Oncology Group (ECOG) performance status (PS)≥2 (56.5%), age older than 75 years (19.0%), and bilirubin>1.5× upper limit of normal (18.6%), whereas those for NG ineligibility were bilirubin > upper limit of normal (24.5%), ECOG PS≥3 (14.6%), and cardiac dysfunction (13.8%). Univariate analyses revealed that FOLFIRINOX and NG-eligible patients had longer median overall survival than their respective ineligible group (8.6 vs. 4.7 mo, P

http://ift.tt/2x8HH0Z

Locoregional and Overall Recurrence After Neaodjuvant Endocrine Therapy Versus Chemotherapy in Postmenopausal Women With Estrogen Receptor+ HER2− Breast Cancer

Purpose: We report clinical outcomes in patients treated with neoadjuvant endocrine therapy (NET) versus neoadjuvant cytotoxic chemotherapy (NCT) in a cohort of postmenopausal women with ER+, HER2− breast cancer. Materials and Methods: We retrospectively reviewed 140 patients treated between May 1998 and September 2010 and collected patient, disease, and treatment characteristics, response to neoadjuvant therapy, and clinical outcome. Results: The median age was 59.5 years. Stage group: stage I 2.2%, stage II 26.8%, stage III 71%, the median tumor size 6 cm (range, 1.5 to 19 cm). Fifty-seven (40.7%) received NET and 83 (59.3%) NCT. One patient (1.8%) in the NET group and 7 (8.4%) in the NCT group had a pathologic complete response (P=0.142). The median follow-up was 48.1 months. Five-year cumulative incidence of locoregional recurrence (LRR) among the entire cohort was 4.1% (95% confidence interval [CI]: 1.5, 8.9), and any recurrence 25.3% (95% CI: 17.6, 33.6). There was no difference in cumulative incidence of LRR or overall recurrence between NET and NCT. On multivariate analysis adjusting for receipt of chemotherapy, presenting stage, and positive lymph nodes, the use of adjuvant radiation therapy was associated with decreased risk of LRR (hazard ratio [HR]=0.24, P=0.035), and ypN2 status with higher risk of LRR (HR=4.91, P=0.032). When the same multivariate model was fitted for any recurrence outcome, only ypN2 status was a significant predictor of overall recurrence (HR=3.02, P=0.005). Conclusions: We have demonstrated equivalent locoregional and overall outcomes in patients receiving NET versus NCT in a cohort of postmenopausal women with locally advanced ER+HER2−tumors.

http://ift.tt/2xaadiK

Alcohol Abuse Decreases Pelvic Control and Survival in Cervical Cancer: An Opportunity of Lifestyle Intervention for Outcome Improvement

Purpose: We examined the incidence and the effect of alcohol abuse on pelvic control (PC), disease-free survival (DFS), and overall survival (OS) in locally advanced cervical cancer patients undergoing definitive radiation therapy (RT). Methods: Between 2007 and 2013, 95 patients treated with RT were reviewed, and the tumor characteristics, the RT dose, the treatment time, chemotherapy, and the number of cycles were recorded. The association between alcohol abuse and DFS, OS, and the duration of PC was analyzed using multivariable Cox proportional hazards models. Results: Of the 95 patients with an average age of 54.8 years (range, 27 to 91 y), 30% were FIGO stage 1B1, 1B2, 2A, 52% stage 2B, 3A; and 18% stage 3B; 86% of the patients were treated with weekly cisplatin chemotherapy. Alcohol history showed that 10 (10.5%) patients met the CDC criteria for heavy alcohol use. With a mean follow-up time of 2 years, 85 patients (88.5%) achieved PC and 86 patients (90.5%) were free of distant metastasis. A total of 82 patients (86.3%) were alive at the last follow-up. When controlling for the total treatment time, excessive alcohol abuse was significantly associated with a decrease in DFS (P=0.005; hazard ratio [HR], 6.19; 95% confidence interval [CI]: 1.73, 22.18), OS (P=0.001; HR, 6.68; 95% CI: 2.10, 21.26), and PC (P=0.029; HR, 3.10; 95% CI: 1.13, 8.56) on univariable analysis. On multivariable analysis, excessive alcohol abuse was significantly associated with a decrease in DFS (P=0.005; HR, 10.57; 95% CI: 2.07, 53.93) and OS (P=0.001; HR, 10.80; 95% CI: 2.57, 45.40). Conclusions: In this small hypothesis-generating series of patients with heavy alcohol use, the data support the association that heavy alcohol use increases the risk of cancer recurrence and mortality. Additional research is required to better define the patient- and treatment-related factors that may be targeted for intervention.

http://ift.tt/2xaDvO7

Definitive Chemoradiation With Full-dose Gemcitabine for Unresectable Pancreatic Cancer: Efficacy of Involved-Field Radiotherapy

Objectives: Definitive chemoradiotherapy for unresectable pancreatic cancer has traditionally involved 5-fluorouracil-based chemotherapy. Our institution has a long history of combining gemcitabine and radiotherapy (RT), and performed a retrospective review of all patients treated in this manner. Materials and Methods: We reviewed the records of 180 patients treated from 1999 to 2012. Mean RT dose was 40.9 Gy in 2.2-Gy fractions, and targeted only radiographically apparent disease. Ninety-six percent of patients received full-dose gemcitabine-based chemotherapy with RT. Kaplan-Meier was used to analyze time-to-event endpoints, and Cox regression models were used to assess significant prognostic variables. Results: Eighty-nine percent of patients completed RT without a toxicity-related treatment break. Median follow-up was 10.2 months. Twenty-nine percent of patients had a radiographic decrease in primary tumor size following treatment. Median overall survival was 11.8 months, time to distant metastasis (TDM) was 6.7 months, and time to local recurrence (TLR) was 8.3 months. On multivariate analysis, male sex, lower performance status, and higher posttreatment CA 19-9 level predicted for worse overall survival. Posttreatment, CA 19-9 was also associated with TDM and TLR, and radiographic tumor response was associated with better TLR. Conclusion: Definitive chemoradiation using full-dose gemcitabine is well tolerated and achieves survival outcomes comparable to reported trials in the literature.

http://ift.tt/2x9rngi

Stage IIIC Endometrial Cancer: Relapse and Survival Outcomes in Women Treated With Pelvic or Extended Field Para-Aortic Nodal Radiation Therapy

Purpose: The optimal radiation (RT) volume for node-positive endometrial cancer is controversial. This study evaluates clinical outcomes in patients with stage IIIC, N1 endometrial cancer who received RT to the pelvis (PV RT) or pelvis plus para-aortic nodes (PV-PAN RT). Methods: Overall, there were 89 women with stage IIIC endometrial cancer. Of these, 57 women had N1-only disease, forming the study cohort. Clinicopathologic characteristics, recurrence rates, endometrial cancer–specific survival (ECSS), and overall survival (OS) were examined among patients treated with pelvic RT (n=23) compared with pelvic plus para-aortic RT (n=34). Multivariable analysis of ECSS and OS was performed using Cox regression modeling. Results: Median follow-up was 5.1 years. Adjuvant chemotherapy was used in 51/57 (89%) of N1 cases. Women with N1 disease who received PV-PAN RT compared with PV RT experienced lower recurrence (26% vs. 52%, P=0.06) and higher survival rates (5 y ECSS 81.5% vs. 47.0%, P=0.04 and OS 79.1% vs. 47.0%, P=0.01). On multivariable analysis, RT volume was not significantly associated with OS, whereas chemotherapy was associated with improved ECSS and OS. Conclusions: RT conferred excellent local control, whereas chemotherapy was associated with improved survival in women with N1 endometrial cancer. Distant relapse remains the most common site of recurrence despite chemotherapy.

http://ift.tt/2xaDrhl

Seven-Year Outcomes Following Accelerated Partial Breast Irradiation Stratified by ASTRO Consensus Groupings

Objectives: Limited long-term data exist regarding outcomes for patients treated with accelerated partial breast irradiation (APBI), particularly, when stratified by American Society for Radiation Oncology (ASTRO) Consensus Statement (CS) risk groups. The purpose of this analysis is to present 5- and 7-year outcomes following APBI based on CS groupings. Materials and Methods: A total of 690 patients with early-stage breast cancer underwent APBI from 1993 to 2012, receiving interstitial brachytherapy (n=195), balloon-based brachytherapy (n=290), or 3-dimensional conformal radiotherapy (n=205) at a single institution. Patients were stratified into suitable, cautionary, and unsuitable groups with 5-year outcomes analyzed. Seven-year outcomes were analyzed for a subset with follow-up of ≥2 years (n=625). Results: Median follow-up was 6.7 years (range, 0.1 to 20.1 y). Patients assigned to cautionary and unsuitable categories were more likely to have high-grade tumors (21% to 25% vs. 9%, P=0.001), receive chemotherapy (15% to 38% vs. 6%, P

http://ift.tt/2xaDoSH

Improving Survival in Patients Treated for a Lung Cancer Using Self-Evaluated Symptoms Reported Through a Web Application

Objectives: We retrospectively compared survivals in patients with a lung cancer history and followed by the so-called sentinel Web-application that allows early detection of relapse and early palliative care initiation versus a conventional follow-up in our center. Methods: The survival in 98 consecutive patients with lung cancer was assessed. The first part of them (the control arm) was retrospectively recruited between March 2011 and August 2012. The second half of them (the experimental arm) was prospectively recruited between August 2012 and December 2013 to weekly fill a form of 11 self-assessed symptoms, then processed by the "sentinel" Web-application. Data were sent to this sentinel application in real-time between planned visits. An email alert was sent to the oncologist when self-scored symptoms matched some predefined criteria. Follow-up visit and imaging were then organized after a phone call for confirming the suspect symptoms. In the control arm (49 patients), a common follow-up was applied (visit and imaging every 2 to 6 mo according to stage of tumor and kind of treatment). Results: Median follow-up duration was 12.3 months in the experimental arm and 16.7 months in the control arm (P=0.27). Survival was significantly better in the sentinel arm than in the control arm (P=0.0014). Median survival was 16.7 months in the control arm and 22.4 months in the experimental arm. One-year survival was 86.6% in the experimental arm and 59.1% in the control arm. Conclusions: Survival may be improved by early detection of relapse and early palliative care initiation by using sentinel-like Web-application.

http://ift.tt/2xaDn15

Factors Associated With Guideline-recommended KRAS Testing in Colorectal Cancer Patients: A Population-based Study

Objectives: Response to epidermal growth factor receptor inhibitors is poorer among stage IV colorectal cancer (CRC) patients with KRAS mutations; thus KRAS testing is recommended before treatment. KRAS testing was collected by Surveillance, Epidemiology, and End Results (SEER) registries for 2010 CRC cases, and our goal was to provide the first population-based estimates of testing in the United States. Methods: SEER CRC cases diagnosed in 2010 were evaluated (n=30,351). χ2 tests and logistic regression were conducted to determine patient characteristics associated with KRAS testing, stratified by stages I-III versus stage IV. Log-rank tests were used to examine survival by testing status. Results: KRAS testing among stage IV cases ranged from 39% in New Mexico to 15% in Louisiana. In the model, younger age, being married, living in a metropolitan area, and having primary site surgery were associated with greater odds of receiving KRAS testing. Those who received testing had significantly better survival than those who did not (P

http://ift.tt/2xaDjOT

Treatment Toxicity in Elderly Patients With Advanced Non–Small Cell Lung Cancer

Objectives: Toxicity is a main concern limiting the use of chemotherapy and radiotherapy (RT) for elderly patients with non–small cell lung cancer (NSCLC). The objective of this study was to assess the rates of treatment-related toxicity among elderly stage IIIB and IV NSCLC patients. Materials and Methods: We used the Surveillance, Epidemiology, and End Results registry linked to Medicare records to identify 2596 stage IIIB and 14,803 stage IV NSCLC patients aged 70 years and above, diagnosed in 2000 or later. We compared rates of toxicity requiring hospitalization according to treatment (chemotherapy, RT, or chemoradiation [CRT]) in unadjusted and adjusted models controlling for selection bias using propensity scores. Results: Among stage IIIB patients, rates of any severe toxicity were 10.1%, 23.8%, 30.4%, and 39.2% for patients who received no treatment, RT, chemotherapy alone, and CRT, respectively. In stage IV patients, rates of any severe toxicity were 31.5% versus 13.5% among those treated with and without chemotherapy, respectively. In stage IIIB patients treated with CRT, the most common toxicities was esophagitis (odds ratio, 48.5; 95% confidence interval, 6.7-350.5). Among stage IV patients treated with chemotherapy, the risk of toxicity was highest for neutropenia (odds ratio, 8.4; 95% confidence interval, 6.1-11.5). Conclusions: Toxicity was relatively common among stage IIIB patients with up to a 6-fold increase in elderly individuals treated with CRT and a 4-fold increase in toxicities among stage IV patients. This information should be helpful to guide discussions about the risk-benefit ratio of chemotherapy and RT in elderly patients with advanced NSCLC.

http://ift.tt/2xa0ngY

Oncologic Outcome of ypT1-2N0 Rectal Cancer After Neoadjuvant Chemoradiotherapy Compared With pT1-2N0 Rectal Cancer

Objective: To investigate the oncologic outcome of ypT1-2N0 mid and lower rectal cancer after chemoradiotherapy (CRT) compared with pT1-2N0 rectal cancer. Methods: We compared the oncologic outcome of patients with mid and lower rectal cancer who underwent preoperative CRT and who did not, between February 2005 and August 2012. Results: Compared with patients who did not receive preoperative CRT, patients who received preoperative CRT did not have significantly different clinicopathologic features except clinical stage and distal resection margin. The 5-year disease-free survival (DFS) rates were lower in patients who received preoperative CRT than those who did not (84.4% vs. 95.5%, P=0.029). Preoperative CRT was a prognostic factor affecting 5-year DFS in patients with pathologically proven stage T1N0 mid and lower rectal cancer (HR, 11.157; 95% CI, 1.735-71.762; P=0.011) Conclusions: ypT2N0 rectal cancer after neoadjuvant CRT showed shorter DFS compared with pT2N0 rectal cancer.

http://ift.tt/2xaD1HN

Dose-Volume Predictors of Esophagitis After Thoracic Stereotactic Body Radiation Therapy

Objectives: Esophageal toxicity has become a major concern as stereotactic hypofractionated radiation therapy is increasingly utilized for central pulmonary tumors. Our purpose was to define esophageal dosimetric parameters that predict potentially dose-limiting toxicities. Materials and Methods: In total, 157 patients with a planning target volume ≤5 cm from the esophagus were selected from an institutional database. Toxicity was scored with the CTCAE v4.0. Esophageal Dmax and Dv (dose D in Gy covering volume v in mL) in 0.5 mL increments were collected. Corresponding biologically effective dose (BED) was calculated for α/β=10,3 (BED10, BED3). Normal tissue complication probability was computed with conventionally fractionated radiotherapy parameters and equivalent dose in 2 Gy per fraction (EQD2). Dosimetric predictors were identified with multivariate logistic regression with a manual forward stepwise selection technique. Results: The grade≥2 esophagitis rate was 5.7%. BED10 to 1.5 mL was the best predictor of esophagitis. BED10 to 0.5, 1.0, 2.0, 3.0, and 3.5 mL were also predictive but less strong. Results were similar when BED3 and physical dose were examined. Tumor-esophageal distance correlated with esophagitis (10.5% risk of≥grade 2 events with distance≤3.9 cm vs. 1.3% when>3.9 cm, P=0.016). BED10 to 1.5 mL correlated well with EQD2 normal tissue complication probability estimates. Conclusions: BED to 1.5 mL was the strongest predictor of grade≥2 esophagitis (independent of α/β ratio) with a 10.6% toxicity risk when BED10>21.1 Gy (14.3 Gy in 3 fractions, 16.0 Gy in 5). The overall rate of severe toxicity is low, suggesting that higher doses may be tolerable.

http://ift.tt/2x9Xvkf

A Model to Predict the Feasibility of Concurrent Chemoradiotherapy With Temozolomide in Glioblastoma Multiforme Patients Over Age 65

Objectives: It is controversial whether concurrent chemoradiotherapy (CRT) with temozolomide is feasible and beneficial in elderly patients with glioblastoma. Materials and Methods: Retrospective analysis of 74 elderly glioblastoma patients (65 y and above) treated with concurrent CRT with temozolomide. Factors influencing prognosis and feasibility of CRT were investigated. Results: The median overall survival was 11.3 months. Univariate analysis showed a significant difference in median overall survival for cumulative dose of concurrent temozolomide (optimal cutoff, 2655 mg/m2; 13.9 mo for >2655 mg/m2 vs. 4.9 mo for ≤2655 mg/m2; P=0.0216, adjusted for multiple testing). Furthermore, cumulative dose of concurrent temozolomide >2655 mg/m2 was a significant independent prognostic parameter in multivariate analysis (hazard ratio, 0.33; P=0.002). Hematotoxicity was the most common cause of treatment interruption or discontinuation in patients with an insufficient cumulative temozolomide dose. Prognostic factors for successful performance of CRT with a cumulative dose of concurrent temozolomide >2655 mg/m2 were female sex (odds ratio [OR], 0.174; P=0.006), age (OR, 0.826 per year; P=0.017), and pretreatment platelet count (OR, 1.013 per 1000 platelets/µL; P=0.001). For easy clinical application of the model an online calculator was developed, which is available at http://www.OldTMZ.com . Conclusions: The probability of successful performance of concurrent CRT with temozolomide can be estimated based on the patient's age, sex, and pretreatment platelet count using the model developed in this study. Thus, a subgroup of elderly glioblastoma patients suitable for chemoradiation with temozolomide can be identified.

http://ift.tt/2x9mkg2

Exposure-survival analyses of pazopanib in renal cell carcinoma and soft tissue sarcoma patients: opportunities for dose optimization

Abstract

Background

Pazopanib is an angiogenesis inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Post hoc analysis of a clinical trial demonstrated a relationship between pazopanib trough concentrations (C_min) and treatment efficacy. The aim of this study was to explore the pharmacokinetics and exposure-survival relationships of pazopanib in a real-world patient cohort.

Patients and methods

Renal cell cancer and soft tissue sarcoma patients who had at least one pazopanib plasma concentration available were included. Using calculated C_min values and a threshold of > 20 mg/L, univariate and multivariate exposure-survival analyses were performed.

Results

Sixty-one patients were included, of which 16.4% were underexposed (mean C_min < 20 mg/L) using the 800 mg fixed-dosed schedule. In univariate analysis C_min > 20 mg/L was related to longer progression free survival in renal cell cancer patients (34.1 vs. 12.5 weeks, n = 35, p = 0.027) and the overall population (25.0 vs. 8.8 weeks, n = 61, p = 0.012), but not in the sarcoma subgroup (18.7 vs. 8.8 weeks, n = 26, p = 0.142). In multivariate analysis C_min > 20 mg/L was associated with hazard ratios of 0.25 (p = 0.021) in renal cancer, 0.12 (p = 0.011) in sarcoma and 0.38 (p = 0.017) in a pooled analysis.

Conclusion

This study confirms that pazopanib C_min > 20 mg/L relates to better progression free survival in renal cancer and points towards a similar trend in sarcoma patients. C_min monitoring of pazopanib can help identify patients with low C_min for whom individualized treatment at a higher dose may be appropriate.

http://ift.tt/2hQR5Qs

Changes in cerebellar functional connectivity and autonomic regulation in cancer patients treated with the Neuro Emotional Technique for traumatic stress symptoms

Abstract

Purpose

A growing number of research studies have implicated the cerebellum in emotional processing and regulation, especially with regard to negative emotional memories. However, there currently are no studies showing functional changes in the cerebellum as a result of treatment for traumatic stress symptoms. The Neuro Emotional Technique (NET) is an intervention designed to help improve symptoms related to traumatic stress using an integrative approach that combines emotional, cognitive, and motor processing, with a particular focus on autonomic nervous system regulation. In this study, we evaluated whether the NET intervention alters functional connectivity in the brain of patients with traumatic stress symptoms associated with a cancer-related event. We hypothesized that the NET intervention would reduce emotional and autonomic reactivity and that this would correlate with connectivity changes between the cerebellum and limbic structures as well as the brain stem.

Methods

We enrolled patients with a prior cancer diagnosis who experienced distressing cancer-related memories associated with traumatic stress symptoms of at least 6 months in duration. Participants were randomized to either the NET intervention or a waitlist control. To evaluate the primary outcome of neurophysiological effects, all participants received resting-state functional blood oxygen level-dependent (BOLD) magnetic resonance imaging (rs-fMRI) before and after the NET intervention. In addition, autonomic reactivity was measured using heart rate response to the traumatic stimulus. Pre/post comparisons were performed between the NET and control groups.

Results

The results demonstrated significant changes in the NET group, as compared to the control group, in the functional connectivity between the cerebellum (including the vermis) and the amygdala, parahippocampus, and brain stem. Likewise, participants receiving the NET intervention had significant reductions in autonomic reactivity based on heart rate response to the traumatic stimulus compared to the control group.

Conclusions

This study is an initial step towards establishing a neurological signature of treatment effect for the NET intervention. Specifically, functional connectivity between the cerebellum and the amygdala and prefrontal cortex appear to be associated with a reduction in autonomic reactivity in response to distressing cancer-related memories.

Implications for cancer survivors

This study contributes to the understanding of possible mechanisms by which interventions like NET may help reduce emotional distress in cancer patients who suffer from traumatic stress symptoms.

http://ift.tt/2io54kL

Negative genic switch of HER-2 in the primary tumor instead of the synchronous metastatic nodal lesions after neoadjuvant chemotherapy in a patient with primary HER2-positive breast cancer

Abstract

Background

A few retrospective studies have indicated that neoadjuvant chemotherapy (NAC) in breast cancer may change biomarker profiles of the primary tumor. Little is known about the status of HER-2 gene of the synchronous nodal metastases when that of the residual tumor undergoes negative conversion in a neoadjuvant setting.

Case presentation

We describe a female patient with left breast cancer (T2N2M0) who underwent negative conversion of HER-2 in the primary tumor instead of the synchronous nodal lesions after NAC. Core needle biopsy showed invasive ductal carcinoma with HER2 immunohistochemistry (IHC) (2+) and amplified HER-2 gene determined by fluorescence in situ hybridization (FISH). Then, the patient underwent 4 cycles of anthracycline- and taxane-based NAC and subsequent left modified radical mastectomy. Postoperative pathology showed invasive ductal carcinoma involving 4 of 12 surgically excised axillary lymph nodes with HER2 IHC (1+) and FISH negative (HER2 gene not amplified) in the residual tumor of the breast specimen. Due to the negative genic switch of HER2 after NAC, the patient rejected to accept trastuzumab. Under the patient's consent, the synchronous nodal lesions were further investigated and showed HER2 IHC(−) but FISH positive (HER-2 gene amplified). Therefore, the patient agreed to accept adjuvant trastuzumab treatment every 3 weeks for 1 year.

Conclusions

We propose further assessment of HER2 gene in the synchronous nodal metastases, especially when negative genic switch of HER-2 occurs in the primary tumor after NAC in order to tailor the systemic regimens for breast cancer patients.

http://ift.tt/2gTdq01

PTEN expression is upregulated by a RNA-binding protein RBM38 via enhancing its mRNA stability in breast cancer

Abstract

Background

PTEN (phosphatase and tensin homolog gene on chromosome 10), a well-characterized tumor suppressor, is a key regulator of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway involved in cell survival, metastasis and cell renewal. PTEN expression is closely related to the phenotype, prognosis and drug selection in breast cancer. It is mainly regulated by transcriptional and post-transcriptional modifications. RNA binding motif protein 38 (RBM38), an RNA-binding protein (RBP) and a target of P53 family, plays a crucial role in the regulation of cellular processing, especially in post-transcription regulation and gene transcription. In this study, we investigated a new post-transcription regulation mechanism of PTEN expression by RBM38 in breast cancer.

Methods

Immunohistochemistry, lentivirus transfections, Western blotting analysis, qRT-PCR and ELISA were used to conduct the relation between RBM38 and PTEN. RNA immunoprecipitation, RNA electrophoretic mobility shift and dual-luciferase reporter assays were employed to identify the direct binding sites of RBM38 with PTEN transcript. Colony formation assay was conducted to confirm the function of PTEN in RBM38-induced growth suppression.

Results

PTEN expression was positively associated with the expression of RBM38 in breast cancer tissues and breast cancer cells. Moreover, RBM38 stabilized PTEN transcript to enhance PTEN expression via binding to multiple AU/U- rich elements (AREs) in 3′-untranslated region (3′-UTR) of PTEN transcript. Additionally, specific inhibitors of PTEN activity and small interfering (siRNA) of PTEN expression inhibited RBM38-mediated suppression of proliferation, which implied that RBM38 acted as a tumor suppressor partly by enhancing PTEN expression.

Conclusion

The present study revealed a new PTEN regulating mechanism that PTEN was positively regulated by RBM38 via stabilizing its transcript stability, which in turn alleviated RBM38-mediated growth suppression.

http://ift.tt/2xRGJFX

Five-fraction SBRT for ultra-central NSCLC in-field recurrences following high-dose conventional radiation

Abstract

Purpose/objective

Local treatment options for patients with in-field non-small cell lung cancer (NSCLC) recurrence following conventionally fractionated external beam radiation therapy (CF-EBRT) are limited. Stereotactic body radiation therapy (SBRT) is a promising modality to achieve reasonable local control, although toxicity remains a concern.

Materials/methods

Patients previously treated with high-dose CF-EBRT (≥59.4 Gy, ≤3 Gy/fraction) for non-metastatic NSCLC who underwent salvage SBRT for localized ultra-central in-field recurrence were included in this analysis. Ultra-central recurrences were defined as those abutting the trachea, mainstem bronchus, or esophagus and included both parenchymal and nodal recurrences. The Kaplan-Meier method was used to estimate local control and overall survival. Durable local control was defined as ≥12 months. Toxicity was scored per the CTC-AE v4.0.

Results

Twenty patients were treated with five-fraction robotic SBRT for ultra-central in-field recurrence following CF-EBRT. Fifty percent of recurrences were adenocarcinoma, while 35% of tumors were classified as squamous cell carcinoma. The median interval between the end of CF-EBRT and SBRT was 23.3 months (range: 2.6 – 93.6 months). The median CF-EBRT dose was 63 Gy (range: 59.4 – 75 Gy), the median SBRT dose was 35 Gy (range: 25 – 45 Gy), and the median total equivalent dose in 2 Gy fractions (EQD2) was 116 Gy (range: 91.3 – 136.7 Gy). At a median follow-up of 12 months for all patients and 37.5 months in surviving patients, the majority of patients (90%) have died. High-dose SBRT was associated with improved local control (p < .01), and the one-year overall survival and local control were 77.8% and 66.7% respectively in this sub-group. No late esophageal toxicity was noted, although a patient who received an SBRT dose of 45 Gy (total EQD2: 129.7 Gy) experienced grade 5 hemoptysis 35 months following treatment.

Conclusions

Although the overall prognosis for patients with in-field ultra-central NSCLC recurrences following CF-EBRT remains grim, five-fraction SBRT was well tolerated with an acceptable toxicity profile. Dose escalation above 35 Gy may offer improved local control, however caution is warranted when treating high-risk recurrences with aggressive regimens.

http://ift.tt/2gTt2R7

Stereotactic body radiation therapy (SBRT) for definitive treatment and as a bridge to liver transplantation in early stage inoperable Hepatocellular carcinoma

Abstract

Background and Purpose

Stereotactic body radiotherapy (SBRT) is an emerging modality for definitive treatment of Hepatocellular carcinoma (HCC).

Materials and Methods

This retrospective study included all early stage HCC patients who were not candidates for primary resection and/or local therapy, treated with SBRT between 11/2011 and 1/2016.

Results

Twenty-three patients were included. The median age was 62 years; 70% males; 30% females; 70% viral hepatitis carriers; 100% cirrhotic; 13 Child Pugh [CP]-A and 10 [CP]-B. The median tumor volume was 12.7cm³ (range, 2.2–53.6 cm³). Treatment was well tolerated. With the exception of one patient who developed RILD, no other patient had significant changes in 12 weeks of laboratory follow-up. SBRT was a bridge to transplantation in 16 patients and 11 were transplanted.. No surgical difficulties or complications were reported following SBRT, and none of the transplanted patients had local progression before transplantation. The median prescribed dose to the tumor was 54Gy (range, 30-54Gy), the median dose to the uninvolved liver was 6.0Gy(range, 1.6–12.6Gy). With a median follow-up time of 12 months, the median overall-survival for the 11 transplanted patients was not reached (range, 2.0–53.7+ months) and was 23 months for the 12 non-transplanted patients. The median progression-free survival for the transplanted patients was not reached (54+ months) and was 14.0 months for the non-transplanted patients. There was no SBRT-related mortality. Liver explant post SBRT revealed pathological complete response in 3(27.3%), pathological partial response in 6(54.5%), and pathological stable disease in 2(18.2%) tumors.

Conclusions

SBRT is safe and effective and can be used as a bridge to transplantation without comprising the surgical procedure.

http://ift.tt/2ip5reB

Dopamine D 1 receptor activation maintains motor coordination and balance in rats

Abstract

Dopamine (DA) modulates motor coordination, and its depletion, as in Parkinson's disease, produces motor impairment. The basal ganglia, cerebellum and cerebral cortex are interconnected, have functional roles in motor coordination, and possess dopamine D₁ receptors (D₁Rs), which are expressed at a particularly high density in the basal ganglia. In this study, we examined whether the activation of D₁Rs modulates motor coordination and balance in the rat using a beam-walking test that has previously been used to detect motor coordination deficits. The systemic administration of the D₁R agonist SKF-38393 at 2, 3, or 4 mg/kg did not alter the beam-walking scores, but the subsequent administration of the D₁R antagonist SCH-23390 at 1 mg/kg did produce deficits in motor coordination, which were reversed by the full agonist SKF-82958. The co-administration of SKF-38393 and SCH-23390 did not alter the beam-walking scores compared with the control group, but significantly prevented the increase in beam-walking scores induced by SCH-23390. The effect of the D₁R agonist to prevent and reverse the effect of the D₁R antagonist in beam-walking scores is an indicator that the function of D₁Rs is necessary to maintain motor coordination and balance in rats. Our results support that D₁Rs mediate the SCH-23390-induced deficit in motor coordination.

http://ift.tt/2yDcdUn

Accumulation of dysfunctional SOD1 protein in Parkinson’s disease is not associated with mutations in the SOD1 gene

http://ift.tt/2gv7ayF

Impact of Targeted Therapy on the Quality of End-of-Life Care for Patients with Non-Small-Cell Lung Cancer: A population-based study in Taiwan

Targeted therapies with epidermal growth factor receptor tyrosine kinase inhibitors have been widely used in the treatment of advanced non-small cell lung cancer (NSCLC). However, little research has focused on the use of targeted therapies at the end-of-life (EOL).

http://ift.tt/2yAP0Qo

Causes of hospital admissions in Domus: a randomized controlled trial of specialized palliative cancer care at home

Avoidable hospital admissions are important negative indicators of quality of end-of-life care. Specialized palliative care (SPC) may support patients in remaining at home. Therefore, the purpose of this study was to investigate if SPC at home could prevent hospital admissions in patients with incurable cancer.

http://ift.tt/2x9FDpG

A nationwide survey about palliative sedation involving Japanese palliative care specialists: Intentions and key factors used to determine sedation as proportionally appropriate

Although there has long been debate about physicians' intentions and what physicians consider to be proportionally appropriate when performing palliative sedation, few large studies have been performed.

http://ift.tt/2yzJ5LL

Epigenetic mediated zinc finger protein 671 downregulation promotes cell proliferation and tumorigenicity in nasopharyngeal carcinoma by inhibiting cell cycle arrest

Abstract

Background

Epigenetic abnormalities play important roles in nasopharyngeal cancer (NPC), however, the epigenetic changes associated with abnormal cell proliferation remain unclear.

Methods

We detected epigenetic change of ZNF671 in NPC tissues and cell lines by bisulfite pyrosequencing. We evaluated zinc finger protein 671 (ZNF671) expression in NPC cell lines and clinical tissues using real-time PCR and western blotting. Then, we established NPC cell lines that stably overexpressed ZNF671 and knocked down ZNF671 expression to explore its function in NPC in vitro and in vivo. Additionally, we investigated the potential mechanism of ZNF671 by identifying the mitotic spindle and G2/M checkpoint pathways pathway downstream genes using gene set enrichment analysis, flow cytometry and western blotting.

Results

ZNF671 was hypermethylated in NPC tissues and cell lines. The mRNA and protein expression of ZNF671 was down-regulated in NPC tissues and cell lines and the mRNA expression could be upregulated after the demethylation agent 5-aza-2′-deoxycytidine treatment. Overexpression of ZNF671 suppressed NPC cell proliferation and colony formation in vitro; silencing ZNF671 using a siRNA had the opposite effects. Additionally, overexpression of ZNF671 reduced the tumorigenicity of NPC cells in xenograft model in vivo. The mechanism study determined that overexpressing ZNF671 induced S phase arrest in NPC cells by upregulating p21 and downregulating cyclin D1 and c-myc.

Conclusions

Epigenetic mediated zinc finger protein 671 downregulation promotes cell proliferation and enhances tumorigenicity by inhibiting cell cycle arrest in NPC, which may represent a novel potential therapeutic target.

http://ift.tt/2xSOcth

Upregulation of DARS2 by HBV promotes hepatocarcinogenesis through the miR-30e-5p/MAPK/NFAT5 pathway

Abstract

Background

Infection with the hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma (HCC). The osmoregulatory transcription factor nuclear factor of activated T-cells 5 (NFAT5) has been shown to play an important role in the development of many types of human cancers. The role of NFAT5 in HBV-associated HCC has never previously been investigated.

Methods

We compared expression profiles of NFAT5, DARS2 and miR-30e-5p in HCC samples, adjacent nontumor tissues and different hepatoma cell lines by quantitative real-time polymerase chain reaction and /or Western blot. Clinical data of HCC patients for up to 80 months were analyzed. The regulatory mechanisms upstream and convergent downstream pathways of NFAT5 in HBV-associated HCC were investigated by ChIP-seq, MSP, luciferase report assay and bioinformation anaylsis.

Results

We first found that higher levels of NFAT5 expression predict a good prognosis, suggesting that NFAT5 is a potential tumor-suppressing gene, and verified that NFAT5 promotes hepatoma cell apoptosis and inhibits cell growth in vitro. Second, our results showed that HBV could suppress NFAT5 expression by inducing hypermethylation of the AP1-binding site in the NFAT5 promoter in hepatoma cells. In addition, HBV also inhibited NFAT5 through miR-30e-5p targeted MAP4K4, and miR-30e-5p in turn inhibited HBV replication. Finally, we demonstrated that NFAT5 suppressed DARS2 by directly binding to its promoter. DARS2 was identified as an HCC oncogene that promotes HCC cell cycle progression and inhibits HCC cell apoptosis.

Conclusion

HBV suppresses NFAT5 through the miR-30e-5p/mitogen-activated protein kinase (MAPK) signaling pathway upstream of NFAT5 and inhibits the NFAT5 to enhance HCC tumorigenesis via the downstream target genes of DARS2.

http://ift.tt/2l1QFvs

Clinical impact of endoscopic ultrasonography on the management of neuroendocrine tumors: lights and shadows

The incidence of gastroenteropancreatic neuroendocrine neoplasms has increased in the recent decades.An extensive bibliographical search was performed in PubMed to identify guidelines and primary literature (retrospective and prospective studies, systematic reviews, case series) published mostly between year 1997 and June 2017, using both medical subject heading (MeSH) terms and free-language keywords about the accuracy and diagnostic and therapeutic role of endoscopic ultrasound in the context of gastro-entero-pancreatic neuroendocrine neoplasms.

http://ift.tt/2zAYFXo

Histological Features of Ileitis Differentiating Pediatric Crohn Disease From Ulcerative Colitis with Backwash Ileitis

Pediatric ileocolonic Crohn disease (CD) may be difficult to distinguish from ulcerative colitis (UC) with backwash ileitis (BWI). The primary aim of the study was to determine the probability of CD in children with a confluent colitis and ileitis when newly diagnosed with inflammatory bowel disease (IBD).

http://ift.tt/2zmn8yP

Histone deacetylase inhibitor BG45-mediated HO-1 expression induces apoptosis of multiple myeloma cells by the JAK2/STAT3 pathway.

Multiple myeloma (MM) is a hematological malignancy that is characterized by the clonal expansion of plasma cells in the bone marrow. Histone deacetylases (HDACs) represent a new type of molecular targeted therapy for different types of cancers and promising targets for myeloma therapy. We showed that HDAC3 mRNA and protein levels of CD138+ mononuclear cells from MM patients were higher than those in healthy donors. Therefore, we investigated the effects of a novel class I HDAC inhibitor BG45 on MM cells in vitro. BG45 downmodulated heme oxygenase 1 (HO-1) when class I HDACs decreased in MM cells. HO-1 is a target for the treatment of MM. Moreover, BG45 induced hyperacetylation of histone H3 and inhibited the growth, especially the apoptosis of MM cell lines. Treatment with BG45 induced apoptosis by downregulating bcl-2 and Bcl-xl, upregulating Bax and other antiapoptotic proteins and activating poly(ADP-ribose)polymerase, and decreasing protein levels of p-JAK2 and p-STAT3. These effects were partly blocked by HO-1. Correspondingly, BG45 led to an accumulation in the G0/G1 phase, accompanied by decreased levels of CDK4 and phospho-retinoblastoma protein, an increased level of p21, and a moderately reduced level of CDK2. Clinical use of single agents was limited because of toxic side effects and drug resistance. However, combining BG45 with lenalidomide exerted synergistic effects. In conclusion, we verified the potent antimyeloma activity of this novel HDAC inhibitor and that the combination of BG45 and lenalidomide is a new method for MM treatment. Thus, BG45 may be applicable to the treatment of MM and other hematological malignancies. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2x8mO65

Diffusion-Weighted MRI Stroke Volume Following Recanalization Treatment is Threshold-Dependent

Abstract

Purpose

Infarct lesion segmentation has been problematic as there are a wide range of relative and absolute diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) thresholds that have been used for this purpose. We examined differences of stroke lesion volume and evolution evaluated by magnetic resonance imaging (MRI) during the immediate post-treatment phase (<5 h) and at 24 h.

Methods

In this study 33 acute ischemic stroke patients were imaged with MRI <5 h and 24 h post-reperfusion treatment. Lesion volumes were segmented on ADC maps and average DWI using literature cited absolute ADC and relative DWI thresholds. The segmented lesion volumes within both time points were compared and the absolute change in lesion volume (infarct growth) between the two time points was calculated and compared using Bland-Altman analysis.

Results

Lesion volumes differed significantly when different relative DWI or absolute ADC thresholds were used (p < 0.05), which held true for baseline as well as follow-up lesions. The median absolute changes in lesion volume from baseline to follow-up for ADC thresholds of 550 × 10⁻⁶ mm²/s, 600 × 10⁻⁶ mm²/s, 630 × 10⁻⁶ mm²/s and 650 × 10⁻⁶ mm²/s were 3.5 ml, 4.2 ml, 4.5 ml, and 6.5 ml, respectively (p < 0.05). Likewise, the median absolute changes in lesion volume from baseline to follow-up for DWI thresholds, k = 0.85, 1.28, 1.64, 1.96, and 2.7 were 10.1 ml, 7.3 ml, 5.7 ml, 5.4 ml and 4.2 ml, respectively (p < 0.05).

Conclusion

Absolute lesion volumes and changes in lesion volumes (infarct growth) measured after recanalization treatment were dependent on absolute ADC and relative DWI thresholds, which may have clinical significance. Standardization of techniques for measuring DWI lesion volumes requires immediate attention.

http://ift.tt/2yuqcfw

Optimal dosing and delivery of PTH and its analogues for osteoporosis and hypoparathyroidism – translating the pharmacology.

Abstract

In primary hyperparathyroidism (PHPT), bone loss results from the resorptive effects of excess parathyroid hormone (PTH). Under physiological conditions, PTH has actions that are more targeted to homeostasis and to bone accrual. The predominant action of PTH, either catabolic, anabolic, or homeostatic, can be understood in molecular and pharmacokinetic terms. When administered intermittently, PTH increases bone mass, but when present continuously and in excess (e.g., PHPT), bone loss ensues. This dual effect of PTH depends not only on the dosing regimen, continuous or intermittent, but also on how the PTH molecule interacts with various states of its receptor (PTH/PTHrP receptor) influencing downstream signaling pathways differentially. Altering the amino-terminal end of PTH or PTHrP could emphasize the state of the receptor that is linked to an osteoanabolic outcome. This concept led to the development of a PTHrP analogue that interacts preferentially with the transiently linked state of the receptor emphasizing an osteoanabolic effect. On the other hand, designing PTH or PTHrP analogues with prolonged state of binding to the receptor would be expected to be linked to a homeostatic action associated with the tonic secretory state of the parathyroid glands that's advantageous in treating hypoparathyroidism. Ideally, further development of a drug delivery system that mimics the physiological tonic, circadian, and pulsatile profile of PTH would be optimal. This review discusses basic, translational and clinical studies that may well lead to newer approaches to the treatment of osteoporosis as well as to different PTH molecules that could become more advantageous in treating hypoparathyroidism.

http://ift.tt/2yCi1xf

Telotristat ethyl: proof of principle and the first oral agent in the management of well-differentiated metastatic neuroendocrine tumor and carcinoid syndrome diarrhea

Abstract

Introduction

Metastatic neuroendocrine tumors (NETs) are associated with carcinoid syndrome that is typically characterized by diarrhea, cutaneous flushing and bronchospasm. Treatment with somatostatin analogues (SSA) improves the symptom burden but a significant proportion of patients stop responding to SSA therapy eventually. Novel agents with the potential to effectively control the symptoms are urgently needed.

Methods

This article reviews an in-depth analysis of the phase I-III clinical trials determining the clinical rationale for the use of tryptophan hydroxylase inhibitor, telotristat ethyl in patients with well-differentiated metastatic NETs and uncontrolled carcinoid syndrome.

Discussion

Telotristat ethyl has already been approved for the treatment of inadequately controlled carcinoid syndrome symptoms in metastatic NET patients on SSA therapy. Results from multiple phase I–III clinical studies of telotristat ethyl therapy have reported a significant decrease in the daily bowel movement frequency, increase in quality of life and the subsequent decrease in annual health costs related to carcinoid syndrome symptoms in NET patients.

Future directions

The associated decrease in urinary 5-hydroxyindoleacetic acid (u5-HIAA) provides evidence that telotristat ethyl effectively decreases serotonin production, and therefore, offers a rationale to investigate this agent to mitigate serotonin-mediated complications in this patient population, especially cardiac valvular disease or mesenteric fibrosis.

http://ift.tt/2gRPdHh

Treatment-related sinusoidal obstruction syndrome in children with de novo acute lymphoblastic leukemia during intensification

Abstract

Purpose

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, has been described following treatment of acute lymphoblastic leukemia (ALL) with the anti-metabolite 6-thioguanine (6-TG). Previous studies incorporating daily 6-TG into maintenance chemotherapy demonstrated a high incidence of SOS, typically presenting after prolonged exposures to 6-TG. 6-TG continues to be used as a single, 14-day burst during intensification; however, SOS associated with brief courses of 6-TG is poorly described. We aim to describe this rare though clinically significant phenomenon.

Methods

Children with 6-TG-related SOS were retrospectively identified from 680 de novo patients with ALL at Texas Children's Cancer Center over 8 years. Clinical characteristics and outcomes are described.

Results

Ten (1.5%) patients were identified with SOS. No predominant sex, ethnicity, or race was noted. SOS was diagnosed 16.5 (6–42) days from starting 6-TG. Isolated thrombocytopenia (IT) was noted in 9/10 patients and presented a median of 5 days prior to SOS. Refractoriness to platelet transfusions was noted in 8/10 patients, presenting a median of 2 days prior to SOS. Most patients were otherwise clinically stable outpatients upon presenting with IT or transfusion refractoriness. Fever was noted in 7/10 patients at diagnosis and 6/10 had documented or suspected infection within 14 days of SOS. Two patients died, while eight fully recovered. Intermediate thiopurine methyltransferase genotype was noted in 5/8 patients with data available.

Conclusion

SOS following short courses of 6-TG in DI is clinically distinct from SOS following prolonged courses of 6-TG in maintenance, particularly in its early presentation and outcomes.

http://ift.tt/2imtUS1

Isolation and Cultivation of Adult Rat Cardiomyocytes

Here, we present a protocol for the isolation and cultivation of adult rat ventricular cardiomyocytes (ARVC). Isolated ARVC can be used for short and long-term cultivation. The isolation and cultivation of ARVC can play a key role in developing new treatment regimens for cardiac diseases.

http://ift.tt/2gS4Z4W

What EMS leaders, educators can learn from continuing education data

LAS VEGAS — More than 8.7 million continuing education completion records revealed that nationally certified EMS providers complete more CE than state only certified providers, hundreds of thousands of courses are completed after a provider's certification has expired and virtual instructor led training represents only one percent of EMT and paramedic refresher course. The data behind these ...

http://ift.tt/2zBkUg3