Epileptiform abnormalities predict delayed cerebral ischemia in subarachnoid hemorrhage.

OBJECTIVE: To identify whether abnormal neural activity, in the form of epileptiform discharges and rhythmic or periodic activity, which we term here ictal-interictal continuum abnormalities (IICAs), are associated with delayed cerebral ischemia (DCI). METHODS: Retrospective analysis of continuous electroencephalography (cEEG) reports and medical records from 124 patients with moderate to severe grade subarachnoid hemorrhage (SAH). We identified daily occurrence of seizures and IICAs. Using survival analysis methods, we estimated the cumulative probability of IICA onset time for patients with and without delayed cerebral ischemia (DCI). RESULTS: Our data suggest the presence of IICAs indeed increases the risk of developing DCI, especially when they begin several days after the onset of SAH. We found that all IICA types except generalized rhythmic delta activity occur more commonly in patients who develop DCI. In particular, IICAs that begin later in hospitalization correlate with increased risk of DCI. CONCLUSIONS: IICAs represent a new marker for identifying early patients at increased risk for DCI. Moreover, IICAs might contribute mechanistically to DCI and therefore represent a new potential target for intervention to prevent secondary cerebral injury following SAH. SIGNIFICANCE: These findings imply that IICAs may be a novel marker for predicting those at higher risk for DCI development.

Utility of clinical high-depth next generation sequencing for somatic variant detection in the PIK3CA-related overgrowth spectrum.

Next-generation sequencing (NGS) has revolutionized the approach of studying sequence variation, and has been well described in the clinical laboratory setting for the detection of constitutional alterations, as well as somatic tumor-associated variants. It is increasingly recognized that post-zygotic somatic alteration can be associated with congenital phenotypic abnormalities. Variation within the PI3K/AKT/mTOR pathway, including PIK3CA, has been described in somatic overgrowth syndromes and vascular malformations. Detection of PIK3CA somatic alteration is challenging because of low variant allele frequency (VAF) along with the need to assay involved tissue, thus necessitating a highly sensitive methodology. Here we describe the utility of target hybrid capture coupled with NGS for the identification of somatic variation in the PIK3CA-related overgrowth spectrum (PROS) among 14 patients submitted for clinical testing. Assay detection of low allelic fraction variation is coverage dependent with >90% sensitivity at 400× unique read depth for VAF of 10%, and approaching 100% at 1000×. Average read depth among the patient dataset across PIK3CA coding regions was 788.4. The diagnostic yield among this cohort was 71%, including the detection of two PIK3CA alterations novel in the setting of PROS. This report expands the mutational scope and phenotypic attributes of PROS disorders.

Bacterial virulence factor inhibits caspase-4/11 activation in intestinal epithelial cells.

The human pathogen enteropathogenic Escherichia coli (EPEC), as well as the mouse pathogen Citrobacter rodentium, colonize the gut mucosa via attaching and effacing lesion formation and cause diarrheal diseases. EPEC and C. rodentium type III secretion system (T3SS) effectors repress innate immune responses and infiltration of immune cells. Inflammatory caspases such as caspase-1 and caspase-4/11 are crucial mediators of host defense and inflammation in the gut via their ability to process cytokines such as interleukin (IL)-1ß and IL-18. Here we report that the effector NleF binds the catalytic domain of caspase-4 and inhibits its proteolytic activity. Following infection of intestinal epithelial cells (IECs) EPEC inhibited caspase-4 and IL-18 processing in an NleF-dependent manner. Depletion of caspase-4 in IECs prevented the secretion of mature IL-18 in response to infection with EPECΔnleF. NleF-dependent inhibition of caspase-11 in colons of mice prevented IL-18 secretion and neutrophil influx at early stages of C. rodentium infection. Neither wild-type C. rodentium nor C. rodentiumΔnleF triggered neutrophil infiltration or IL-18 secretion in Cas11 or Casp1/11-deficient mice. Thus, IECs have a key role in modulating early innate immune responses in the gut via a caspase-4/11-IL-18 axis, which is targeted by virulence factors encoded by enteric pathogens.

Early Liver Transplantation for Severe Alcoholic Hepatitis in the United States--A Single-Center Experience.

Early liver transplantation (LT) in European centers reportedly improved survival in patients with severe alcoholic hepatitis (AH) not responding to medical therapy. Our aim was to determine if a strategy of early LT for severe AH could be applied successfully in the United States. We reviewed 111 patients with severe AH at our center from January 2012 to January 2015. The primary end point was mortality at 6 months or early LT, with a secondary end point of alcohol relapse after LT. Survival was compared between those receiving early LT and matched patients who did not. Using a process similar to the European trial, 94 patients with severe AH not responding to medical therapy were evaluated for early LT. Overall, 9 (9.6%) candidates with favorable psychosocial profiles underwent early LT, comprising 3% of all adult LT during the study period. The 6-month survival rate was higher among those receiving early LT compared with matched controls (89% vs 11%, p<0.001). Eight recipients are alive at a median of 735 days with 1 alcohol relapse. Early LT for severe AH can achieve excellent clinical outcomes with low impact on the donor pool and low rates of alcohol relapse in highly selected patients in the United States.

Suppression of epithelial-mesenchymal transition and apoptotic pathways by miR-294/302 family synergistically blocks let-7-induced silencing of self-renewal in embryonic stem cells.

The embryonic stem cell (ESC)-enriched miR-294/302 family and the somatic cell-enriched let-7 family stabilizes the self-renewing and differentiated cell fates, respectively. The mechanisms underlying these processes remain unknown. Here we show that among many pathways regulated by miR-294/302, the combinatorial suppression of epithelial-mesenchymal transition (EMT) and apoptotic pathways is sufficient in maintaining the self-renewal of ESCs. The silencing of ESC self-renewal by let-7 was accompanied by the upregulation of several EMT regulators and the induction of apoptosis. The ectopic activation of either EMT or apoptotic program is sufficient in silencing ESC self-renewal. However, only combined but not separate suppression of the two programs inhibited the silencing of ESC self-renewal by let-7 and several other differentiation-inducing miRNAs. These findings demonstrate that combined repression of the EMT and apoptotic pathways by miR-294/302 imposes a synergistic barrier to the silencing of ESC self-renewal, supporting a model whereby miRNAs regulate complicated cellular processes through synergistic repression of multiple targets or pathways.

Insights into the pathophysiology of catch-up compared with non-catch-up growth in children born small for gestational age: an integrated analysis of metabolic and transcriptomic data.

Small for gestational age (SGA) children exhibiting catch-up (CU) growth have a greater risk of cardiometabolic diseases in later life compared with non-catch-up (NCU) SGA children. The aim of this study was to establish differences in metabolism and gene expression profiles between CU and NCU at age 4-9 years. CU children (n=22) had greater height, weight and body mass index standard deviation scores along with insulin-like growth factor-I (IGF-I) and fasting glucose levels but lower adiponectin values than NCU children (n=11; all P<0.05). Metabolic profiling demonstrated a fourfold decrease of urine myo-inositol in CU compared with NCU (P<0.05). There were 1558 genes differentially expressed in peripheral blood mononuclear cells between the groups (P<0.05). Integrated analysis of data identified myo-inositol related to gene clusters associated with an increase in insulin, growth factor and IGF-I signalling in CU children (P<0.05). Metabolic and transcriptomic profiles in CU SGA children showed changes that may relate to cardiometabolic risk.

Nimotuzumab provides survival benefit to patients with inoperable advanced squamous cell carcinoma of the head and neck: a randomized, open-label, phase IIb, 5-year study in Indian patients.

OBJECTIVE: Overexpression of epidermal growth factor receptor (EGFR) in many cancers makes it an attractive therapeutic target. This study evaluated the clinical utility of nimotuzumab, a monoclonal anti-EGFR antibody, used concurrently with radiotherapy (RT) and chemoradiotherapy (CRT) in squamous cell carcinoma of the head and neck (SCCHN). METHODS: This open-label study randomized 92 treatment-naïve patients (1:1) with advanced SCCHN into chemoradiation (CRT ± nimotuzumab) or radiation (RT ± nimotuzumab) group by investigator's discretion; these were further randomized into CRT + nimotuzumab or CRT and RT + nimotuzumab or RT groups, respectively. Treatment included 6 cycles each of cisplatin (50 mg/week), nimotuzumab (200 mg/week), and RT (total dose, 60-66 Gy). Response (tumor size reduction) was assessed at Month 6 post-treatment and survival, at Month 60. RESULTS: Forty and 36 patients in the chemoradiation and radiation groups, respectively (intent-to-treat population) were evaluated. Overall response at Month 6 post-treatment was 100% with CRT + nimotuzumab, 70% with CRT, 76% with RT + nimotuzumab, and 37% with RT. At Month 60, overall survival was 57% with CRT + nimotuzumab, 26% with CRT (P = 0.03), 39% with RT + nimotuzumab, and 26% with RT (P > 0.05). Median overall survival was not reached for CRT + nimotuzumab; it was 21.94 months for CRT (P = 0.0078), 14.36 months for RT + nimotuzumab, and 12.78 months for RT (P = 0.45). Risk of death was 64% lower with CRT + nimotuzumab than with CRT (95%CI: 0.37, 1.56), and 24% lower with RT + nimotuzumab than with RT (95%CI: 0.16, 0.79). Thus nimotuzumab was safe and well tolerated with few mild to moderate self-limiting adverse events. CONCLUSION: Concurrent use of nimotuzumab with CRT/RT is safe and provides long-term survival benefit.

The impact of endovascular lower-limb revascularisation on the aortic augmentation index in patients with peripheral arterial disease.

OBJECTIVES: The aortic augmentation index (AIx), a marker of arterial stiffness, and peripheral arterial disease (PAD) are associated with an increased cardiovascular risk. In claudicants, the effect of balloon angioplasty (percutaneous transluminal angioplasty, PTA) on AIx has not been determined so far. METHODS: Measurements of the ankle-brachial pressure index (ABI) and AIx were performed before and 3 months after PTA and compared to age- and sex-matched PAD patients under best medical treatment. RESULTS: The data of 61 patients (44% female, mean age 68 years) who underwent lower-limb PTA was compared to 48 conservatively treated patients (38% female, mean age 68 years). ABI significantly improved after PTA from 0.73 ± 0.02 to 0.85 ± 0.03 (p = 0.001), but remained unchanged in the control group (0.85 ± 0.23 and 0.80 ± 0.21; p = 0.16). Revascularisation was associated with a significant reduction of AIx from 31.5 ± 1.1% to 28.8 ± 1.1% after 3 months (p = 0.01). In the conservatively treated group, AIx did not change during follow-up (29.9 ± 1.1% to 29.9 ± 1.1%; p = 0.83). CONCLUSION: Lower-limb revascularisation in PAD Rutherford stage II-III is associated with an improvement of markers for arterial stiffness.

Limited economic evidence of carotid artery stenosis diagnosis and treatment: a systematic review.

UNLABELLED: The objective of this article is to assess the availability and validity of economic evaluations of carotid artery stenosis (CS) diagnosis and treatment. DESIGN: Systematic review of economic evaluations of the diagnosis and treatment of CS. METHODS: Systematic review of full economic evaluations published in Medline and Google Scholar up until 28 February 2012. Based on economic checklists (Evers and Philips), the identified studies were classified as high, medium, or low quality. RESULTS: Twenty-three evaluations were identified. The study quality ranged from 26% to 84% of all achievable points (Evers). Seven studies were of high, eight of medium and eight of low quality. No comparison was made between carotid angioplasty and stenting (CAS) and best medical treatment (BMT). For subjects with severe stenosis, comparisons of carotid endarterectomy (CEA) and BMT were also missing. Three of five studies dealing with pre-operative imaging found that duplex Doppler ultrasound (US) was cost-effective compared with carotid angiogram (AG). CONCLUSIONS: There is a huge lack of high-quality studies and of studies that confirm published results. Also, for a given study quality, the most cost-effective treatment strategy is still unknown in some cases ('CAS' vs. 'BMT', 'US combined with magnetic resonance angiography supplemented with AG' vs. 'US combined with computer tomography angiography').

Tracheal resection for thyroid cancer.

INTRODUCTION: Thyroid cancers infiltrating the upper aerodigestive tract are not uncommon. The management of these cases can be demanding, with a high level of surgical skill required to achieve adequate primary resection and reconstruction. MATERIALS AND METHODS: This study was a single institution series of seven patients, managed over two years, who underwent tracheal resection for advanced thyroid cancer. All patients were older than 45 years (range, 45-65 years) and were predominantly male (six of seven). All patients presented to us with a swelling in the neck. Fine needle aspiration cytology detected thyroid cancer in all patients. None of the patients required a tracheostomy prior to surgery; however, they all had varying levels of airway compromise. One patient had lung metastasis at presentation. In all patients, the airway was successfully secured with fibre-optic assisted intubation prior to surgery. All patients underwent a total thyroidectomy with tracheal resection and anastomosis. Montgomery's suprahyoid release was utilised to achieve adequate laryngeal drop. None of the patients required a tracheostomy in the post-operative period. All patients received adjuvant therapy with either radioiodine ablation and/or radiotherapy. CONCLUSION: Tracheal resection and primary reconstruction is a feasible surgical procedure for patients with thyroid cancer infiltrating the upper aerodigestive tract, with good clinical outcomes. However, the morbidity of the procedure mandates careful case selection, airway management and meticulous surgical technique.

Prevalence of high-risk human papillomavirus genotypes in retinoblastoma.

BACKGROUND: The human papillomavirus (HPV) is an important aetiological agent in cancer but its involvement in retinoblastomas (RBs) is controversial. METHODS: 64 formalin-fixed paraffin-embedded tissue blocks and 19 fresh-frozen specimens were subjected to multiplex PCR using PGMY09/11 primers, HPV genotyping, non-isotopic in situ hybridisation and immunohistochemistry for pRb and p16(INK4a). RESULTS: 24% of RBs contained HPV DNA. 90% of HPV genotypes were of high-risk (HR) type and 10% were of intermediate-risk (IR) type. HR HPVs 45, 59, 68 and 52 were detected for the first time, as were IR HPVs 82 and 73. There was only one HPV 18-positive case. Interestingly, no low-risk genotypes were identified. Nine formalin-fixed paraffin-embedded HPV-positive cases showed nuclear HPV positivity by non-isotopic in situ hybridisation. Immunohistochemistry did not show pRb expression in 67% of cases. 34% expressed nuclear p16(INK4a), of which 20 cases were also positive for HPV by multiplex PCR. A statistically significant association between HPV and pRb expression status was observed (p=0.0001).The association of HPV with p16(INK4a) expression was also statistically significant (p=0.0001). CONCLUSIONS: While the presence of HPV in a subset of RB was demonstrated, its role in carcinogenesis needs further elucidation.

Clinical applications of imaging biomarkers. Part 3. The neuro-oncologist's perspective.

Radiation therapy is an important treatment modality in the management of brain tumours. Imaging biomarkers continue to be a focus of active investigation and there is increasing evidence of the utility of biomarkers in refining the overall management plan. This article briefly reviews the literature and outlines the possible clinical applications of imaging biomarkers in neuro-oncology.

Serum C peptide level and renal function in diabetes mellitus.

C peptide is an active peptide hormone with potentially important physiological effects. C peptide has the capacity to diminish glomerular hyperfiltration and reduce urinary albumin excretion in both experimental and human type 1 diabetes. The present study is aimed at correlating the serum C peptide level with that of renal clearance, urinary albumin excretion and duration of diabetes. This is a prospective cross sectional study. Patients with diagnosis of type 2 diabetes mellitus were evaluated for their baseline clinical and laboratory profile. Both males and females above the age of 18 years were included in the study. The laboratory investigations include fasting serum C peptide, HbA(1C), serum creatinine, blood urea nitrogen, urine albumin and creatinine. Creatinine clearance was calculated using modification of diet in renal disease formula from serum creatinine value. A total of 168 patients were included in the study, among them 90 were females (53.57%) and 78 males (46.43%). Mean age of the patients was 57.64 years. Pearson correlation test showed negative correlation of serum C peptide level with creatinine clearance, though statistically not significant. Negative correlation was also seen between serum C peptide, and urine albumin, urine albumin creatinine ratio, HbA(1C) and duration of diabetes. Mean urine albumin was higher in patients with subnormal C peptide level. Duration of disease was more in patients with lower serum C peptide level. The study has shown weak association of serum C peptide level with microalbuminuria and creatinine clearance. Risk of albuminuria is more in patients with low serum C peptide level.

Evaluation of extensions of sinonasal mass lesions by computerized tomography scan.

INTRODUCTION: Cross-sectional imaging has had a significant impact on the management of the sinonasal malignancy. Staging of these lesions has been closely monitored by dependence on computerized tomography (CT) scan and now in small proportion with MRI. The objective of the study was to evaluate the reliability of CT scan in assessing the extensions of the sinonasal mass lesions and their impact on tumor staging. MATERIALS AND METHODS: All cases of sinonasal lesions were reviewed retrospectively from June 2001 to May 2006 (five years) at KMIO, Bangalore. Only those cases that had CT scan reports and Histopatholgy Examination (HPE) reports were included in the study. All the cases, which were subjected to radiotherapy prior to surgery, were excluded from the study. There were a total of 38 cases with slight male preponderance. Tumor staging was done according to the sixth edition of TNM classification of malignant tumors. Two observers evaluated all the cases (Blinded Study) and sensitivity, specificity, positive predictive value, negative predictive value and predictive accuracy were estimated. RESULTS: The relation between the CT scan findings and HPE reports was high. Though false positivity was noted more in the ethmoid sinuses, significant impact on tumor staging was noted with false positivity of the nasopharynx. Also, false positivity was noted with orbital wall/content extensions, resulting in unnecessary exenterations of the orbit. However, CT scan reliably predicted infratemporal fossa extension in the absence of trismus. False negativity was noted more often in soft palate, indicating the need of using MRI for delineation of tumor extension. Thus, we conclude that judicious use of CT scan in all cases and MRI in selected cases will translate into better tumor-free resections and improves survival.

Intradiploic frontal bone aneurysmal bone cyst in a child: a case report.

This report presents the imaging appearances of an uncommon case of intradiploic frontal bone aneurysmal bone cyst (ABC) in a 10-year-old girl. ABCs are rare in the calvarium. The radiological and aetiopathological differences between the more commonly occurring ABCs of the long bones and vertebrae, and their rarer counterparts in the calvarium and facial bones, have been discussed. Unique also to this case is the reconstruction performed using the outer table of the bone flap after excising the tumour.