Low-Grade, Multiple, Ta Non-muscle-Invasive Bladder Tumors: Tumor Recurrence and Worsening Progression

Abstract

Nearly half of newly diagnosed cases of bladder cancer are low grade, noninvasive, and papillary tumors. The standard treatment for non-muscle-invasive bladder cancer (NMIBC) has been transurethral resection of the bladder tumor (TUR-BT) with or without adjuvant intravesical instillation (IVI) of chemotherapy or Bacillus Calmette-Guerin (BCG) therapy. NMIBC is known to be associated with high rates of recurrence and risk of progression. In this study, we have retrospectively analyzed the clinical outcome of initially diagnosed multiple low-grade Ta tumors, with a special focus on tumor recurrence and worsening progression (WP) pattern. We retrospectively reviewed 42 patients with primary, multiple, low-grade Ta bladder cancer. We defined WP as confirmed high-grade Ta, all T1 or Tis/concomitant CIS of bladder recurrence, upper urinary tract recurrence (UTR), or progression to equal to or more than T2. The associations between clinico-pathological factors and tumor recurrence as well as WP pattern were analyzed. Tumor recurrence and WP occurred in 23 (54.76%) and 8 (19.04%) patients during follow-up (median follow-up: 57.38 months), respectively. WP to high grade/stage was seen in 8 patients. Multivariate analysis demonstrated that use of tobacco (p < 0.0001) and absence of IVI (p < 0.0001) were significant risk factors for tumor recurrence. The 5-year recurrence-free survival rate for non-tobacco users (74.0%) was significantly higher than that for tobacco users (42.5%, p = 0.0001), and also higher for patients receiving intravesical instillation (84.2 vs. 30.0% without IVI, p = 0.0001). Recurrence is common in patients with low-grade, Ta bladder cancer, especially in the setting of multiplicity. Recurrences occurred in 54.76% of patients and WP occurred in 19.04% of patients. Use of tobacco and non-use of IVI were strongly associated with high recurrence rate.

http://ift.tt/2njwQyy

Evidence for encephalopsin immunoreactivity in interneurones and striosomes of the monkey striatum

Abstract

In this study, we examined the cellular distribution of encephalopsin (opsin 3; OPN3) expression in the striatum of non-human primates. In addition, because of our long standing interest in Parkinson's disease and neuroprotection, we examined whether parkinsonian (MPTP; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) insult and/or photobiomodulation (670 nm) had any impact on encephalopsin expression in this key area of the basal ganglia. Striatal sections of control naïve monkeys, together with those that were either MPTP- and/or photobiomodulation-treated were processed for immunohistochemistry. Our results revealed two populations of striatal interneurones that expressed encephalopsin, one of which was the giant, choline acetyltransferase-containing, cholinergic interneurones. The other population had smaller somata and was not cholinergic. Neither cell group expressed the calcium-binding protein, parvalbumin. There was also rich encephalopsin expression in a set of terminals forming striosome-like patches across the striatum. Finally, we found that neither parkinsonian (MPTP) insult nor photobiomodulation had any effect on encephalopsin expression in the striatum. In summary, our results revealed an extensive network of encephalopsin containing structures throughout the striatum, indicating that external light is in a position to influence a range of striatal activities at both the interneurone and striosome level.

http://ift.tt/2FpBQrN

Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies—the German Cancer Consortium approach

Abstract

Adoptive transfer of T cells genetically modified by TCRs or CARs represents a highly attractive novel therapeutic strategy to treat malignant diseases. Various approaches for the development of such gene therapy medicinal products (GTMPs) have been initiated by scientists in recent years. To date, however, the number of clinical trials commenced in Germany and Europe is still low. Several hurdles may contribute to the delay in clinical translation of these therapeutic innovations including the significant complexity of manufacture and non-clinical testing of these novel medicinal products, the limited knowledge about the intricate regulatory requirements of the academic developers as well as limitations of funds for clinical testing. A suitable good manufacturing practice (GMP) environment is a key prerequisite and platform for the development, validation, and manufacture of such cell-based therapies, but may also represent a bottleneck for clinical translation. The German Cancer Consortium (DKTK) and the Paul-Ehrlich-Institut (PEI) have initiated joint efforts of researchers and regulators to facilitate and advance early phase, academia-driven clinical trials. Starting with a workshop held in 2016, stakeholders from academia and regulatory authorities in Germany have entered into continuing discussions on a diversity of scientific, manufacturing, and regulatory aspects, as well as the benefits and risks of clinical application of CAR/TCR-based cell therapies. This review summarizes the current state of discussions of this cooperative approach providing a basis for further policy-making and suitable modification of processes.

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The PDGF pathway in breast cancer is linked to tumour aggressiveness, triple-negative subtype and early recurrence

Abstract

Purpose

The platelet-derived growth factor (PDGF) signalling pathway is often dysregulated in cancer and PDGF-receptor expression has been linked to unfavourable prognostic factors in breast cancer (e.g. ER negativity, high Ki67 and high grade). This study aimed to evaluate the expression of PDGFRα, PDGFRβ and ligand PDGF-CC in breast cancer in relation to molecular subtypes and prognosis.

Methods

Protein expression of tumour and/or stromal cell PDGFRα, PDGFRβ and PDGF-CC was evaluated in primary tumours (N = 489), synchronous lymph node metastases (N = 135) and asynchronous recurrences (N = 39) using immunohistochemistry in a prospectively maintained cohort of primary breast cancer patients included during 1999–2003. Distant recurrence-free interval (DRFi) was the primary end-point.

Results

High expression of all investigated PDGF family members correlated to increasing Nottingham histopathological grade and high Ki67. Tumour cells displayed high expression of PDGFRα in 20%, and PDGF-CC in 21% of primary tumours, which correlated with the triple-negative subtype (TNBC). Patients with high PDGF-CC had inferior prognosis (P = 0.04) in terms of 5-year DRFi, whereas PDGFRα was up-regulated in lymph node metastasis and recurrences compared to primary tumours. High primary tumour PDGFRα was associated with increased risk of central nervous system (CNS) recurrence.

Conclusions

High PDGFRα and PDGF-CC expression were linked to breast cancer with an aggressive biological phenotype, e.g. the TNBC subtype, and high PDGF-CC increased the risk of 5-year distant recurrence. Tumour cell PDGFRα was significantly up-regulated in lymph node metastases and asynchronous recurrences. Our findings support an active role of the PDGF signalling pathway in tumour progression.

http://ift.tt/2GqU1P5

Subchronic toxicity, immunoregulation and anti-breast tumor effect of Nordamnacantal, an anthraquinone extracted from the stems of Morinda citrifolia L

Morinda citrifolia L. that was reported with immunomodulating and cytotoxic effects has been traditionally used to treat multiple illnesses including cancer. An anthraquinone derived from fruits of Morinda citrif...

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What to do about the Canadian residency matching process? [Letters]

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Disrespect within medicine for family doctors affects medical students and patients [News]

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Intergenerational abortion tendency between mothers and teenage daughters: a population-based cohort study [Research]

BACKGROUND:

A teenage woman's sexual health practices may be influenced by her mother's experience. We evaluated whether there is an intergenerational tendency for induced abortion between mothers and their teenage daughters.

METHODS:

We conducted a retrospective population-based cohort study involving daughters born in Ontario between 1992 and 1999. We evaluated the daughters' data for induced abortions between age 12 years and their 20th birthday. We assessed each mother's history of induced abortion for the period from 4 years before her daughter's birth to 12 years after (i.e., when her daughter turned 12 years of age). We used Cox proportional hazard models to estimate a daughter's risk of having an induced abortion in relation to the mother's history of the same procedure. We adjusted hazard ratios (HRs) for maternal age and world region of origin, mental or physical health problems in the daughter, mother– daughter cohabitation, neighbourhood-level rate of teen induced abortion, rural or urban residence, and income quintile.

RESULTS:

A total of 431 623 daughters were included in the analysis. The cumulative probability of teen induced abortion was 10.1% (95% confidence interval [CI] 9.8%–10.4%) among daughters whose mother had an induced abortion, and 4.2% (95% CI 4.1%–4.3%) among daughters whose mother had no induced abortion, for an adjusted HR of 1.94 (95% CI 1.86–2.01). The adjusted HR of a teenaged daughter having an induced abortion in relation to number of maternal induced abortions was 1.77 (95% CI 1.69–1.85) with 1 maternal abortion, 2.04 (95% CI 1.91–2.18) with 2 maternal abortions, 2.39 (95% CI 2.19–2.62) with 3 maternal abortions and 2.54 (95% CI 2.33–2.77) with 4 or more maternal abortions, relative to none.

INTERPRETATION:

We found that the risk of teen induced abortion was higher among daughters whose mother had had an induced abortion. Future research should explore the mechanisms for intergenerational induced abortion.

http://ift.tt/2Ehaox3

AI opens new frontier for suicide prevention [News]

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Diagnosis and management of congenital diaphragmatic hernia: a clinical practice guideline [Guideline]

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Care for people with hepatitis C in provincial and territorial prisons [Commentary]

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Dog bites [Practice]

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Unmatched Canadian medical graduates [Letters]

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Eye complications from self-injury in a child [Practice]

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Surgical fires: nightmarish "never events" persist [News]

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Late night decisions [Humanities]

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Newborns exposed to opioids need mothers more than NICU, say pediatricians [News]

http://ift.tt/2DKxhIf

Development and assessment of the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-16)

Summary

Objective

The aim of this study was to develop and validate a brief version of the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE). A secondary aim was to compare the results described in previously published studies using the QOLCE-55 with those obtained using the new brief version.

Methods

Data come from 373 children involved in the Health-related Quality of Life in Children with Epilepsy Study, a multicenter prospective cohort study. Item response theory (IRT) methods were used to assess dimensionality and item properties and to guide the selection of items. Replication of results using the brief measure was conducted with multiple regression, multinomial regression, and latent mixture modeling techniques.

Results

IRT methods identified a bi-factor graded response model that best fits the data. Thirty-nine items were removed, resulting in a 16-item QOLCE (QOLCE-16) with an equal number of items in all 4 domains of functioning (Cognitive, Emotional, Social, and Physical). Model fit was excellent: Comparative Fit Index = 0.99; Tucker-Lewis Index = 0.99; root mean square error of approximation = 0.052 (90% confidence interval [CI] 0.041-0.064); weighted root mean square = 0.76. Results that were reported previously using the QOLCE-55 and QOLCE-76 were comparable to those generated using the QOLCE-16.

Significance

The QOLCE-16 is a multidimensional measure of health-related quality of life (HRQoL) with good psychometric properties and a short-estimated completion time. It is notable that the items were calibrated using multidimensional IRT methods to create a measure that conforms to conventional definitions of HRQoL. The QOLCE-16 is an appropriate measure for both clinicians and researchers wanting to record HRQoL information in children with epilepsy.

http://ift.tt/2nfSpQw

Delayed myelination and neurodevelopment in male seizure-prone versus seizure-resistant rats

Summary

Objective

Aberrant myelination and developmental delay have been reported in epilepsy. However, it is unclear whether these are linked to intrinsic mechanisms that support a predisposition toward seizures and the development of epilepsy. Thus, we compared rates of myelination and neurodevelopment in male rats selectively bred for enhanced susceptibility to kindling epileptogenesis (FAST) with male rats bred for resistance (SLOW).

Methods

Myelin-specific gene expression was compared in the brainstem, cerebellum, and cerebral hemisphere of FAST and SLOW rats on postnatal days (PNDs) 5, 11, 17, 23, and 90 to determine strain-specific myelination rates. Myelin protein levels were also compared at PNDs 5 and 23 in the brainstem. Relative rates of neurodevelopment were evaluated between PNDs 5 and 21 using physical growth landmarks and neuromotor tests including righting reflex, cliff avoidance, negative geotaxis, and locomotor activity.

Results

Myelin-specific mRNA expression was significantly down-regulated in FAST rats on PNDs 5 and 11 in all 3 brain structures, indicating relatively delayed myelination. Likewise, corresponding protein levels were significantly lower in FAST brainstem on PND 5. Developmental delay was evident in the FAST strain such that only 9% of FAST pups, compared to 81% of SLOW, had open eyes by PND 13, locomotor activity was significantly reduced between PNDs 12 and 16, and neuromotor task acquisition was delayed between PNDs 5 and 10.

Significance

Relative delays in myelination and neurodevelopment co-occurred in the seizure-prone FAST strain in the absence of seizures. These findings suggest these symptoms are not seizure-induced and may be mechanistically linked to an underlying pathophysiology supporting a predisposition toward developing epilepsy.

http://ift.tt/2BAIOb2

PCDH19-related epilepsy is associated with a broad neurodevelopmental spectrum

Summary

Objective

To characterize the features associated with PCDH19-related epilepsy, also known as "female-limited epilepsy."

Methods

We analyzed data from participants enrolled in the PCDH19 Registry, focusing on the seizure-related, developmental, neurobehavioral, and sleep-related features. We evaluated variants for pathogenicity based on previous reports, population databases, and in silico predictions, and included individuals with pathogenic or potentially pathogenic variants. We performed a retrospective analysis of medical records and administered a targeted questionnaire to characterize current or past features in probands and genotype-positive family members.

Results

We included 38 individuals with pathogenic or potentially pathogenic variants in PCDH19: 21 de novo, 5 maternally inherited, 7 paternally inherited, and 5 unknown. All 38 had epilepsy; seizure burden varied, but typical features of clustering of seizures and association with fever were present. Thirty individuals had intellectual disability (ID), with a wide range of severity reported; notably, 8/38 (22%) had average intellect. Behavioral and sleep dysregulation were prominent, in 29/38 (76%) and 20/38 (53%), respectively. Autistic features were present in 22/38 (58%), of whom 12 had a formal diagnosis of autism spectrum disorder. We had additional data from 5 genotype-positive mothers, all with average intellect and 3 with epilepsy, and from 1 genotype-positive father.

Significance

Our series represents a robust cohort with carefully curated PCDH19 variants. We observed seizures as a core feature with a range of seizure types and severity. Whereas the majority of individuals had ID, we highlight the possibility of average intellect in the setting of PCDH19-related epilepsy. We also note the high prevalence and severity of neurobehavioral phenotypes associated with likely pathogenic variants in PCDH19. Sleep dysregulation was also a major area of concern. Our data emphasize the importance of appropriate referrals for formal neuropsychological evaluations as well as the need for formal prospective studies to characterize the PCDH19-related neurodevelopmental syndrome in children and their genotype-positive parents.

http://ift.tt/2nkGZKi

Developmental pharmacogenetics of CYP2C19 in neonates and young infants: omeprazole as a probe drug

Abstract

Background

Although substantial progress has been made in understanding of ontogeny of drug metabolism, there is still a gap of knowledge in developmental pharmacogenetics in neonates. We hypothesized that both age and pharmacogenetics might explain the developmental pattern of CYP2C19. We conducted a population pharmacokinetic-pharmacogenetic study to quantify the developmental pharmacogenetics of CYP2C19 in neonates and young infants using omeprazole as a probe drug.

Methods

Pharmacokinetic samples were collected from 51 Caucasian neonates and young infants, who were receiving omeprazole treatment. Population pharmacokinetic-pharmacogenetic analysis of omeprazole and its metabolites was performed using NONMEM.

Results

Data fitted a one-compartment parent and metabolite model with first-order absorption and elimination. CYP2C19 and CYP3A4 are predominantly involved in the metabolism of omeprazole despite their relatively low activities compared to adults. The clearance of omeprazole converted to 5-hydroxy-omeprazole (CL_OMZ-M1) increases with postnatal age. In CYP2C19 poor and intermediate metabolizer, model-predicted CL_OMZ-M1 are 12.5% (5%-95% percentile: 3%-14.9%) and 44.9% (5%-95% percentile: 29.9%-72.6%) of the value in extensive/ultrarapid metabolizer, respectively. Model-predicted absorption rate constant (Ka) of omeprazole is 6.93 (5%-95% percentile: 3.01-14.61) times higher in ABCB1 homozygous mutant patients, 1.86 (5%-95% percentile: 0.86-3.47) times higher in ABCB1 heterozygous patients than that in ABCB1 homozygous wild-type patients.

Conclusions

Developmental pharmacogenetics of CYP2C19 was quantitatively described in neonates and young infants using omeprazole as a probe drug. Our findings emphasize the importance of semi-physiological developmental pharmacokinetic modeling approach when evaluating developmental pharmacogenetics of drugs with multiple routes of biotransformation.

http://ift.tt/2rLSxM7

Exposure-response characterisation of tofacitinib efficacy in moderate to severe ulcerative colitis: results from a dose-ranging phase 2 trial

SUMMARY

BACKGROUND AND AIMS

Tofacitinib is an oral, small molecule JAK inhibitor being investigated for UC. In a phase 2 dose-ranging study, tofacitinib demonstrated efficacy vs placebo as UC induction therapy. In this post-hoc analysis, we aimed to compare tofacitinib dose and plasma concentration as predictors of efficacy and identify covariates that determined efficacy in patients with UC.

METHODS

One- and two-compartment pharmacokinetic models, with first-order absorption and elimination, were evaluated to describe plasma tofacitinib concentration-time data at baseline and week 8. Relationships between tofacitinib exposure (dose, C_av,ss and C_trough,ss) and week 8 efficacy endpoints were characterised using logistic regression analysis. Baseline disease, demographics, prior and concurrent UC treatment were evaluated as covariates.

RESULTS

Plasma tofacitinib concentrations increased proportionately with dose and estimated oral clearance, and C_av,ss values were not significantly different between baseline and week 8. Dose, C_av,ss and C_trough,ss performed similarly as predictors of efficacy based on statistical criteria for model fit and comparison of model predictions for each endpoint. Individual C_av,ss values were similar between clinical remitters and non-remitters at predicted efficacious doses (10 and 15 mg twice daily [b.d.]). Baseline Mayo score was a significant determinant of efficacy. Predicted differences from placebo in clinical remission at 10 mg b.d. for patients with baseline Mayo score >8 and ≤8 were 39% (95% CI: 7–70) and 21% (-2–50), respectively.

CONCLUSIONS

Exposure-response characterisation demonstrated the potential of tofacitinib 10 and 15 mg b.d. as induction therapy for UC without monitoring of plasma drug concentrations for dose optimisation.

http://ift.tt/2Gptcea

The global switch from trivalent oral polio vaccine (tOPV) to bivalent oral polio vaccine (bOPV): facts, experiences and lessons learned from the south-south zone; Nigeria, April 2016

The globally synchronized switch from trivalent Oral Polio Vaccine (tOPV) to bivalent Oral Polio Vaccine (bOPV) took place in Nigeria on April 18th 2016. The country is divided into six geopolitical zones. Thi...

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Case report: a fatal case of disseminated adenovirus infection in a non-transplant adult haematology patient

We report a fatal case of disseminated adenovirus infection in a non-transplant haematology adult patient with chronic lymphocytic leukaemia who had completed combination chemoimmunotherapy a few months before...

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Adverse effects of anti-epileptics in trigeminal neuralgiform pain

Background

Side effects of anti-epileptic drugs (AEDs) have not been adequately documented in trigeminal neuralgia and its variants. The aim of this observational cross-sectional study was to compare the A-B Neuropsychological Assessment Schedule (ABNAS), which measures cognitive side effects to the Adverse Events Profile (AEP), which looks at a broader range of side effects, and to investigate drug/dosage relationships with questionnaire scores to help determine a point at which a drug change would be indicated.

Methods

One hundred five patients were recruited from a facial pain clinic, over a 10-month period. Self-complete questionnaire scores were compared between patients using different AEDs.

Results

A-B Neuropsychological Assessment Schedule score correlated well with AEP indicating that cognitive side effects were a significant burden. Toxic range on the ABNAS was estimated to occur when scores were >43/72 (95% CI: 37.4-48.6). Polytherapy is weakly associated with the higher scores. Oxcarbazepine dosage was found to linearly correlate with AEP and ABNAS scores, better than carbamazepine dosage. Memory alteration was least common with lamotrigine and oxcarbazepine, and there was less association between fatigues with oxcarbazepine/pregabalin.

Conclusion

Anti-epileptic drugs have significant side effects. The ABNAS questionnaire is a useful tool along with the AEP to recognize and monitor AEDs' side effects and to help to adjust medications to optimal dosage.

http://ift.tt/2BybSQt

Diagnostic Value of Circulating Free DNA Integrity and Global Methylation Status in Gall Bladder Carcinoma

Abstract

The current study investigates the role of circulating free DNA (cfDNA) as a liquid biopsy in diagnosis gall bladder carcinoma (GBC) utilizing levels of long DNA fragments (ALU247) derived from tumor necrosis, short apoptotic fragments (ALU115) denoting total cfDNA and cfDNA integrity denoting ratio of ALU247 and ALU115. The global methylation status of cfDNA was also estimated with the hypothesis that these parameters provide a diagnostic distinction between cancer and non-cancer subjects, with higher or altered values favoring presence of malignancy. Study group included 60 cases of GBC and 36 controls including diseased controls (cholecystitis) and healthy subjects. Median levels of ALU115, ALU247 and cfDNA integrity were significantly different in GBC at 1790.88, 673.75, 0.4718 vs. controls at 840.73, 165.03, 0.1989 ng/ml respectively. Global DNA methylation was not significantly different between GBC at 0.679% and controls at 0.695%. The sensitivity and specificity of ALU 247 in discriminating GBC from controls was highest with a sensitivity, specificity and diagnostic accuracy of 80.0%, 86.1% and 82.2% respectively. Global DNA methylation showed lowest sensitivity of 55.0% and specificity of 50.0%. Clinico-pathological parameters showing significant association with cfDNA integrity, on ROC curve analysis, showed significant diagnostic discrimination of the tumor stage, lymphovascular invasion, disease stage and grade histology. This is a first time analysis of ALU115, ALU247 and cfDNA integrity in the diagnosis of GBC and confirms that the combination of ALU247 and cfDNA integrity provides good sensitivity, specificity and diagnostic accuracy in discriminating GBC from controls as well correlates with aggressive disease parameters.

http://ift.tt/2DIhAkM

177 Lu-PSMA-617 radioligand therapy in mCRPC: ready for phase III trial?

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Dosimetric parameters predicting contralateral liver hypertrophy after unilobar radioembolization of hepatocellular carcinoma

Abstract

Purpose

This study aimed at identifying prior therapy dosimetric parameters using ^99mTc-labeled macro-aggregates of albumin (MAA) that are associated with contralateral hepatic hypertrophy occurring after unilobar radioembolization of hepatocellular carcinoma (HCC) performed with ⁹⁰Y–loaded glass microspheres.

Methods

The dosimetry data of 73 HCC patients were collected prior to the treatment with ⁹⁰Y–loaded microspheres for unilateral disease. The injected liver dose (ILD), the tumor dose (TD) and healthy injected liver dose (HILD) were calculated based on MAA quantification. Following treatment, the maximal hypertrophy (MHT) of an untreated lobe was calculated.

Results

Mean MHT was 35.4 ± 40.4%. When using continuous variables, the MHT was not correlated with any tested variable, i.e., injected activity, ILD, HILD or TD except with a percentage of future remnant liver (FRL) following the ⁹⁰Y–microspheres injection  (r = −0.56). MHT ≥ 10% was significantly more frequent for patients with HILD ≥ 88 Gy, (52% of the cases), i.e., in 92.2% versus 65.7% for HILD < 88 Gy (p = 0.032). MHT ≥ 10% was also significantly more frequent for patients with a TD ≥ 205 Gy and a tumor volume (VT) ≥ 100 cm³ in patients with initial FRL < 50%. MHT ≥10% was seen in 83.9% for patients with either an HILD ≥ 88 Gy or a TD ≥ 205 Gy for tumors larger than 100cm³ (85% of the cases), versus only 54.5% (p = 0.0265) for patients with none of those parameters. MHT ≥10% was also associated with FRL and the Child-Pugh score. Using multivariate analysis, the Child-Pugh score (p < 0.0001), FRL (p = 0.0023) and HILD (p = 0.0029) were still significantly associated with MHT ≥10%.

Conclusion

This study demonstrates for the first time that HILD is significantly associated with liver hypertrophy. There is also an impact of high tumor doses in large lesions in one subgroup of patients. Larger prospective studies evaluating the MAA dosimetric parameters have to be conducted to confirm these promising results.

http://ift.tt/2rIGkrz

Reply to ‘Single high dose versus repeated bone-targeted radionuclide therapy’

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Incidental identification of osteoid osteoma by 68 Ga-PSMA PET/CT

http://ift.tt/2rQM2Ib

Is the whole larger than the sum of the parts? Integrated PET/MRI as a tool for response prediction

http://ift.tt/2GpNfJI

FDG PET/CT radiomics for predicting the outcome of locally advanced rectal cancer

Abstract

Purpose

The aim of this study was to investigate the prognostic value of baseline ¹⁸F-FDG PET/CT textural analysis in locally-advanced rectal cancer (LARC).

Methods

Eighty-six patients with LARC underwent ¹⁸F-FDG PET/CT before treatment. Maximum and mean standard uptake values (SUVmax and SUVmean), metabolic tumoral volume (MTV), total lesion glycolysis (TLG), histogram-intensity features, as well as 11 local and regional textural features, were evaluated. The relationships of clinical, pathological and PET-derived metabolic parameters with disease-specific survival (DSS), disease-free survival (DFS) and overall survival (OS) were assessed by Cox regression analysis. Logistic regression was used to predict the pathological response by the Dworak tumor regression grade (TRG) in the 66 patients treated with neoadjuvant chemoradiotherapy (nCRT).

Results

The median follow-up of patients was 41 months. Seventeen patients (19.7%) had recurrent disease and 18 (20.9 %) died, either due to cancer progression (n = 10) or from another cause while in complete remission (n = 8). DSS was 95% at 1 year, 93% at 2 years and 87% at 4 years. Weight loss, surgery and the texture parameter coarseness were significantly associated with DSS in multivariate analyses. DFS was 94 % at 1 year, 86 % at 2 years and 79 % at 4 years. From a multivariate standpoint, tumoral differentiation and the texture parameters homogeneity and coarseness were significantly associated with DFS. OS was 93% at 1 year, 87% at 2 years and 79% after 4 years. cT, surgery, SUVmean, dissimilarity and contrast from the neighborhood intensity-difference matrix (contrast_NGTDM) were significantly and independently associated with OS. Finally, RAS-mutational status (KRAS and NRAS mutations) and TLG were significant predictors of pathological response to nCRT (TRG 3-4).

Conclusion

Textural analysis of baseline ¹⁸F-FDG PET/CT provides strong independent predictors of survival in patients with LARC, with better predictive power than intensity- and volume-based parameters. The utility of such features, especially coarseness, should be confirmed by larger clinical studies before considering their potential integration into decisional algorithms aimed at personalized medicine.

http://ift.tt/2GpBQt2

Head to head comparison of [ 18 F] AV-1451 and [ 18 F] THK5351 for tau imaging in Alzheimer’s disease and frontotemporal dementia

Abstract

Purpose

Tau accumulation is a core pathologic change in various neurodegenerative diseases including Alzheimer's disease and frontotemporal lobar degeneration-tau. Recently, tau positron emission tomography tracers such as [¹⁸F] AV-1451 and [¹⁸F] THK5351 have been developed to detect tau deposition in vivo. In the present study, we performed a head to head comparison of these two tracers in Alzheimer's disease and frontotemporal dementia cases and aimed to investigate which tracers are better suited to image tau in these disorders.

Methods

A cross-sectional study was conducted using a hospital-based sample at a tertiary referral center. We recruited eight participants (two Alzheimer's disease, four frontotemporal dementia and two normal controls) who underwent magnetic resonance image, amyloid positron emission tomography with [¹⁸F]-Florbetaben and tau positron emission tomography with both THK5351 and AV-1451. To measure regional AV1451 and THK5351 uptakes, we used the standardized uptake value ratios by dividing mean activity in target volume of interest by mean activity in the cerebellar hemispheric gray matter.

Results

Although THK5351 and AV-1451 uptakes were highly correlated, cortical uptake of AV-1451 was more striking in Alzheimer's disease, while cortical uptake of THK5351 was more prominent in frontotemporal dementia. THK5351 showed higher off-target binding than AV-1451 in the white matter, midbrain, thalamus, and basal ganglia.

Conclusions

AV-1451 is more sensitive and specific to Alzheimer's disease type tau and shows lower off-target binding, while THK5351 may mirror non-specific neurodegeneration.

http://ift.tt/2rGoIwq

Striking lack of visualization of striatum on 18 F-FDG brain PET in chorea-acanthocytosis

http://ift.tt/2GnpNwq

18 F–fluorodeoxyglucose uptake of hepatocellular carcinoma as a prognostic predictor in patients with sorafenib treatment

Abstract

Purpose

Sorafenib, an oral multikinase inhibitor, is a recommended treatment option available for patients with Barcelona Clinic Liver Cancer (BCLC)-C stage hepatocellular carcinoma (HCC). This study aimed to evaluate the performance of ¹⁸F–fluorodeoxyglucose positron emission tomography (¹⁸F–FDG PET) for predicting tumour progression during sorafenib treatment.

Methods

We formed a retrospective cohort comprising patients treated with sorafenib for at least 30 days and undergoing ¹⁸F–FDG PET/CT within 1 month before treatment. For statistical analyses, the tumour-to-liver standardised uptake value (SUV) ratio (TLR) of the most hypermetabolic lesion was measured.

Results

Among a total of 35 patients, two obtained partial remission, and 11 showed stable disease after the first response evaluation. Patients with a TLR ≥ 2.9 (n = 17) had a median overall survival (OS) of 3.7 months after sorafenib treatment, whereas patients with a TLR < 2.9 (n = 18) had median OS of 12.2 months (P < 0.001), although the disease control rate was not significantly different between the two groups. Pretreatment TLR ≥ 2.9 (hazard ratio [HR] = 6.318, P = 0.002) and Child-Pugh class B (HR = 4.316, P = 0.044) were poor prognostic factors for OS, and a TLR ≥ 2.9 (HR = 2.911, P = 0.024) was the only poor prognostic factor for progression-free survival in a multivariate analysis.

Conclusion

Pretreatment tumour metabolic activity assessed by ¹⁸F–FDG PET is an independent prognostic factor for survival in patients with BCLC-C stage HCC receiving sorafenib monotherapy, although it may not predict tumour response to the treatment.

http://ift.tt/2rKuBJc

Absolute number of new lesions on 18 F-FDG PET/CT is more predictive of clinical response than SUV changes in metastatic melanoma patients receiving ipilimumab

Abstract

Purpose

Evaluation of response to immunotherapy is a matter of debate. The aim of the present study was to evaluate the response of metastatic melanoma to treatment with ipilimumab by means of ¹⁸F-FDG PET/CT, using the patients' clinical response as reference.

Methods

The final cohort included in the analyses consisted of 41 patients with metastatic melanoma who underwent ¹⁸F-FDG PET/CT before and after administration of ipilimumab. After determination of the best clinical response, the PET/CT scans were reviewed and a separate independent analysis was performed, based on the number and functional size of newly emerged ¹⁸F-FDG-avid lesions, as well as on the SUV changes after therapy.

Results

The median observation time of the patients after therapy was 21.4 months (range 6.3–41.9 months). Based on their clinical response, patients were dichotomized into those with clinical benefit (CB) and those without CB (No-CB). The CB group (31 patients) included those with stable disease, partial remission and complete remission, and the No-CB group (10 patients) included those with progressive disease. The application of a threshold of four newly emerged ¹⁸F-FDG-avid lesions on the posttherapy PET/CT scan led to a sensitivity (correctly predicting CB) of 84% and a specificity (correctly predicting No-CB) of 100%. This cut-off was lower for lesions with larger functional diameters (three new lesions larger than 1.0 cm and two new lesions larger than 1.5 cm). SUV changes after therapy did not correlate with clinical response. Based on these findings, we developed criteria for predicting clinical response to immunotherapy by means of ¹⁸F-FDG PET/CT (PET Response Evaluation Criteria for Immunotherapy, PERCIMT).

Conclusion

Our results show that a cut-off of four newly emerged ¹⁸F-FDG-avid lesions on posttherapy PET/CT gives a reliable indication of treatment failure in patients under ipilimumab treatment. Moreover, the functional size of the new lesions plays an important role in predicting the clinical response. Validation of these results in larger cohorts of patients is warranted.

http://ift.tt/2Gr0qKm

Visualization of multiple organ amyloid involvement in systemic amyloidosis using 11 C-PiB PET imaging

Abstract

Purpose

To investigate the utility of Pittsburgh compound B (PiB) positron emission tomography (PET) imaging for evaluating whole-body amyloid involvement in patients with systemic amyloidosis.

Methods

Whole-body ¹¹C-PiB PET was performed in seven patients with systemic immunoglobulin light-chain (AL) amyloidosis, seven patients with hereditary transthyretin (ATTRm) amyloidosis, one asymptomatic TTR mutation carrier and three healthy controls. The correlations between clinical organ involvement, radiological ¹¹C-PiB uptake and histopathological findings were analysed for each organ.

Results

Organ involvement on ¹¹C-PiB PET imaging showed good correlations with the clinical findings for the heart and stomach. Abnormal tracer uptake was also observed in the spleen, lachrymal gland, submandibular gland, sublingual gland, lymph node, brain, scalp, extraocular muscles, nasal mucosa, pharynx, tongue and nuchal muscles, most of which were asymptomatic. Physiological tracer uptake was universally observed in the urinary tract (kidney, renal pelvis, ureter and bladder) and enterohepatic circulatory system (liver, gallbladder, bile duct and small intestine) in all participants. Most of the patients and one healthy control subject showed asymptomatic tracer uptake in the lung and parotid gland. The peripheral nervous system did not show any tracer uptake even in patients with apparent peripheral neuropathy. Histological amyloid deposition was confirmed in biopsied myocardium and gastric mucosa where abnormal ¹¹C-PiB retention was observed.

Conclusions

¹¹C-PiB PET imaging can be used clinically in the systemic evaluation of amyloid distribution in patients with AL and ATTRm amyloidosis. Quantitative analysis of ¹¹C-PiB PET images may be useful in therapy evaluation and will reveal whether amyloid clearance is correlated with clinical response.

http://ift.tt/2rLgPWH

Third-line treatment and 177 Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review

Abstract

Aims

There is a controversy as to the relative efficacy of ¹⁷⁷Lu prostate specific membrane antigen (PSMA) radioligand therapy (RLT) and third-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of our systematic review was to elucidate whether ¹⁷⁷Lu-PSMA RLT and third-line treatment have similar effects and adverse effects (PROSPERO ID CRD42017067743).

Methods

The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Searches in Pubmed and Embase selected articles up to September 2017. A search in ClinicalTrials.gov indicated ongoing studies. The meta-analysis used the random-effects model.

Results

Twelve studies including 669 patients reported ¹⁷⁷Lu-PSMA RLT. Overall, 43% of the patients had a maximum decline of PSA of ≥50% following treatment with ¹⁷⁷Lu-PSMA RLT. The treatment with ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA for imaging and therapy (I&T) had mainly transient adverse effects. Sixteen studies including 1338 patients reported third-line treatment. Overall, 21% of the patients had a best decline of PSA of ≥50% following third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects caused discontinuation of treatment for 10% to 23% of the patients. ¹⁷⁷Lu-PSMA RLT gave a best PSA decline ≥50% more often than third-line treatment (mean 44% versus 22%, p = 0.0002, t test). ¹⁷⁷Lu-PSMA RLT gave objective remission more often than third-line treatment (overall 31 of 109 patients versus 43 of 275 patients, p = 0.004, χ² test). Median survival was longer after ¹⁷⁷Lu-PSMA RLT than after third-line treatment, but the difference was not statistically significant (mean 14 months versus 12 months, p = 0.32, t test). Adverse effects caused discontinuation of treatment more often for third-line treatment than for ¹⁷⁷Lu-PSMA RLT (22 of 66 patients versus 0 of 469 patients, p < 0.001, χ² test).

Conclusions

As for patients with mCRPC, treatment with ¹⁷⁷Lu-PSMA-617 RTL and ¹⁷⁷Lu-PSMA I&T gave better effects and caused fewer adverse effects than third-line treatment.

http://ift.tt/2DLvk2b

Founder of EJNM passed away

http://ift.tt/2GoYLVq

EANM/EARL FDG-PET/CT accreditation - summary results from the first 200 accredited imaging systems

Abstract

Purpose

From 2010 until July 2016, the EANM Research Ltd. (EARL) FDG-PET/CT accreditation program has collected over 2500 phantom datasets from approximately 200 systems and 150 imaging sites worldwide. The objective of this study is to report the findings and impact of the accreditation program on the participating PET/CT systems.

Methods

To obtain and maintain EARL accredited status, sites were required to complete and submit two phantom scans - calibration quality control (CalQC), using a uniform cylindrical phantom and image quality control (IQQC), using a NEMA NU2–2007 body phantom. Average volumetric SUV bias and SUV recovery coefficients (RC) were calculated and the data evaluated on the basis of quality control (QC) type, approval status, PET/CT system manufacturer and submission order.

Results

SUV bias in 5% (n = 96) of all CalQC submissions (n = 1816) exceeded 10%. After corrective actions following EARL feedback, sites achieved 100% compliance within EARL specifications. 30% (n = 1381) of SUVmean and 23% (n = 1095) of SUVmax sphere recoveries from IQQC submissions failed to meet EARL accreditation criteria while after accreditation, failure rate decreased to 12% (n = 360) and 9% (n = 254), respectively. Most systems demonstrated longitudinal SUV bias reproducibility within ±5%, while RC values remained stable and generally within ±10% for the four largest and ±20% for the two smallest spheres.

Conclusions

Regardless of manufacturer or model, all investigated systems are able to comply with the EARL specifications. Within the EARL accreditation program, gross PET/CT calibration errors are successfully identified and longitudinal variability in PET/CT performances reduced. The program demonstrates that a harmonising accreditation procedure is feasible and achievable.

http://ift.tt/2rFVjCs

Prospective evaluation of 18 F-FACBC PET/CT and PET/MRI versus multiparametric MRI in intermediate- to high-risk prostate cancer patients (FLUCIPRO trial)

Abstract

Purpose

The purpose of this study was to evaluate ¹⁸F-FACBC PET/CT, PET/MRI, and multiparametric MRI (mpMRI) in detection of primary prostate cancer (PCa).

Methods

Twenty-six men with histologically confirmed PCa underwent PET/CT immediately after injection of 369 ± 10 MBq ¹⁸F-FACBC (fluciclovine) followed by PET/MRI started 55 ± 7 min from injection. Maximum standardized uptake values (SUV_max) were measured for both hybrid PET acquisitions. A separate mpMRI was acquired within a week of the PET scans. Logan plots were used to calculate volume of distribution (V_T). The presence of PCa was estimated in 12 regions with radical prostatectomy findings as ground truth. For each imaging modality, area under the curve (AUC) for detection of PCa was determined to predict diagnostic performance. The clinical trial registration number is NCT02002455.

Results

In the visual analysis, 164/312 (53%) regions contained PCa, and 41 tumor foci were identified. PET/CT demonstrated the highest sensitivity at 87% while its specificity was low at 56%. The AUC of both PET/MRI and mpMRI significantly (p < 0.01) outperformed that of PET/CT while no differences were detected between PET/MRI and mpMRI. SUV_max and V_T of Gleason score (GS) >3 + 4 tumors were significantly (p < 0.05) higher than those for GS 3 + 3 and benign hyperplasia. A total of 442 lymph nodes were evaluable for staging, and PET/CT and PET/MRI demonstrated true-positive findings in only 1/7 patients with metastatic lymph nodes.

Conclusions

Quantitative ¹⁸F-FACBC imaging significantly correlated with GS but failed to outperform MRI in lesion detection. ¹⁸F-FACBC may assist in targeted biopsies in the setting of hybrid imaging with MRI.

http://ift.tt/2GoyUNF

Metastatic Renal Cell Cancer—Systemic Therapy

Abstract

Management of metastatic renal cell carcinoma (mRCC) has evolved considerably in the past 10 years due to better understanding of tumor biology. This development has changed mRCC to a chronic progressive disease with several lines of treatment options. The introduction of several new targeted therapies including immunotherapy has improved median overall survival of approximately 1 year to >2 years in mRCC.

http://ift.tt/2nis6cd

Regiospecific Analysis of Fatty Acids and Calculation of Triglyceride Molecular Species in Marine Fish Oils

The regiospecific distribution of fatty acids (FAs) and composition of triglyceride (TAG) molecular species of fishes were analyzed and calculated by pancreatic lipase (PL) hydrolysis and Visual Basic (VB) program. DHA was preferentially located at sn-2 position in TAG molecule, whereas EPA was almost equally distributed in each position of glycerol backbone. DOP, DPP, EPP, PoPP, PPO, and PPP were the predominant TAG species. MPP in anchovy, DDP, DOP, DPP in tuna, and EOO and OOO in salmon were the characteristic TAG molecules, which were meaningful to differentiate marine fish oils. Furthermore, the data management, according to TCN and ECN, was firstly applied to classify the TAG molecular species. The ECN42, ECN46, and ECN48 groups were rich in TAGs. The lower ECN values, compared to the higher TCN values, indicated that the most abundant TAGs exhibited a higher unsaturated degree. Therefore, our study not only offered a simple and feasible approach for the analysis of TAG composition but also firstly summarized the information by data management within ECN and TCN.

http://ift.tt/2njQ3zR

Desflurane Attenuates Ventilator-Induced Lung Injury in Rats with Acute Respiratory Distress Syndrome

Ventilator-induced lung injury aggravates the existing lung injury. This study investigated the effect of desflurane on VILI in a rat model of acute respiratory distress syndrome. Forty-eight rats were randomized into a sham (S) group, control (C) group, lipopolysaccharide/ventilation (LV) group, lipopolysaccharide/ventilation/desflurane (LVD) group, or lipopolysaccharide/low ventilation with and without desflurane (LLV and LLVD) groups. Rats in the S group received anesthesia only. Rats in the LV and LVD groups received lipopolysaccharide and were ventilated with a high tidal volume. Rats in LLV and LLVD groups were treated as the LV and LVD groups and ventilated with a low tidal volume. PaO2/FiO2, lung wet-to-dry weight ratios, concentrations of inflammatory factors in serum and BALF, histopathologic analysis of lung tissue, and levels of nuclear factor- (NF-) κB protein in lung tissue were investigated. PaO2/FiO2 was significantly increased by desflurane. Total cell count, macrophages, and neutrophils in BALF and proinflammatory factors in BALF and serum were significantly decreased by desflurane, while IL-10 was increased. The histopathological changes and levels of NF-κB protein in lung tissue were decreased by desflurane. The results indicated that desflurane ameliorated VILI in a rat model of acute respiratory distress syndrome.

http://ift.tt/2nhVDmf

Handling and Treatment of Male European Eels (Anguilla anguilla)for Hormonal Maturation and Sperm Cryopreservation

Protocols for European eel maturation and sperm cryopreservation have been improved over the last years. This article describes the best protocol available using human chorionic gonadotropin (hCG) for inducing maturation and methanol as cryoprotectant.

http://ift.tt/2DJIHfu

The Pathophysiological Mechanisms and the Quest for Biomarkers in Psoriasis, a Stress-Related Skin Disease

Psoriasis is a physically, emotionally, and socially invalidating multifactorial disorder, with a significant impact on the patients' quality of life. Stress is one of the leading triggers for psoriasis and has been associated with disease onset and subsequent flare-ups, while the flare-ups by themselves often lead to psychological discomfort. The treatment of psoriasis is individualized, depending on the patients' measurable severity of illness, as well as the impact the skin condition has on patients' quality of life, as assessed by standardized questionnaires. The clinical scales used nowadays for measuring the severity of psoriasis are characterized by low reproducibility and high variability between examiners. Hence, there is a real need to identify objectively measurable biomarkers to standardize the assessment of the severity of psoriasis. We aim to review the pathophysiological mechanisms involved in psoriasis, focusing on the most critical advances in psoriasis biomarker discovery, pointing out those biomarkers which have also been studied in other stress-related conditions, thus emphasizing the relationship between psoriasis and stress.

http://ift.tt/2nm0i75

DNA Staining Method Based on Formazan Precipitation Induced by Blue Light Exposure

This method allows selective staining and quantification of DNA in gels by soaking the gel in a SYBR Green I/Nitro Blue Tetrazolium solution and then exposing it to sunlight or a blue light source. This produces a visible precipitate and requires almost no equipment, making it ideal for field use.

http://ift.tt/2DIsoiK

A Paired Bead and Magnet Array for Molding Microwells with Variable Concave Geometries

This manuscript introduces a robust method of fabricating concave microwells without the need for complex high-cost facilities. Using magnetic force, steel beads, and a through-hole array, several hundred microwells were formed in a 3 cm x 3 cm polydimethylsiloxane (PDMS) substrate.

http://ift.tt/2Bz0Hap

Recurrent Syncope, a Clue in Amyloid Cardiomyopathy

Infiltrative cardiomyopathies include a variety of disorders that lead to myocardial thickening resulting in a constellation of clinical manifestations and eventually heart failure that could be the first clue to reach the diagnosis. Among the more described infiltrative diseases of the heart is amyloid cardiomyopathy. The disease usually presents with subtle, nonspecific symptoms. Herein, we illustrate a case of recurrent syncope as the initial presenting symptom for systemic amyloid with polyneuropathy and cardiomyopathy as a cause of syncope. The article illustrates the role of advanced cardiac imaging in the diagnosis of the disease with a focused literature review. We also highlight the role of early, shared decision-making between patient, family, and medical team in the management of cardiac amyloidosis.

http://ift.tt/2rJUsRz

Inconsistencies in the drawing and interpretation of smiley faces: an observational study

Pre-prepared smiley face symbols are used widely to gather information on, for example, satisfaction with services or health and well-being. We investigated how women and men of different ages respond when ask...

http://ift.tt/2GmprGi

Prediction of opioid dose in cancer pain patients using genetic profiling: not yet an option with support vector machine learning

Use of opioids for pain management has increased over the past decade; however, inadequate analgesic response is common. Genetic variability may be related to opioid efficacy, but due to the many possible comb...

http://ift.tt/2rO9sxL

Implementing measurement based care in community mental health: a description of tailored and standardized methods

Although tailored implementation methods are touted as superior to standardized, few researchers have directly compared the two and little guidance regarding the specific details of each method exist. Our stud...

http://ift.tt/2GlPTA5

Blood Collection and Cell-Free DNA Isolation Methods Influence the Sensitivity of Liquid Biopsy Analysis for Colorectal Cancer Detection

Abstract

During colorectal cancer (CRC) development tumor-derived cell-free DNA (cfDNA) can be released into the bloodstream. Many different cfDNA isolation methods and specific blood collection tubes preventing the release of genomic DNA and stabilizing cfDNA with preservative reagents became available. These factors may affect greatly on the further liquid biopsy analyses. Our aim was to test different blood collection tubes and cfDNA isolation methods to determine whether these factors influence the cfDNA amount and the promoter methylation of four previously described hypermethylated biomarkers. Three manual isolation methods (High Pure Viral Nucleic Acid Large Volume Kit; Epi proColon 2.0 Kit; Quick-cfDNA™ Serum & Plasma Kit) and automated sample preparation systems (InviGenius and InviGenius PLUS) were examined. Furthermore, K3EDTA Vacuette tubes and Streck Cell-Free DNA BCT® tubes were compared. After cfDNA isolation and bisulfite conversion of samples, the methylation level of SFRP1, SFRP2, SDC2, and PRIMA1 were defined with MethyLight assays. We have ascertained that there are differences between the cfDNA amounts depending on the isolation methods. Higher cfDNA yield was observed using InviGenius system than column-based manual isolation method; however, InviGenius PLUS has produced lower cfDNA amounts. No remarkable variance could be found between K3EDTA and Streck tubes; slightly higher cfDNA quantity was detected in 60% of plasma samples using Streck tubes. In point of methylation level and frequency, manual column-based isolation produced more consistent results. Automated cfDNA extraction systems are easy-to-use and high-throughput; however, further improvements in the isolation protocols might lead to the increase of the sensitivity of further methylation analysis.

http://ift.tt/2DDS0NP

Nephrotic Syndrome: Genetics, Mechanism, and Therapies

http://ift.tt/2nillq2

Biodegradable Alginate-Chitosan Hollow Nanospheres for Codelivery of Doxorubicin and Paclitaxel for the Effect of Human Lung Cancer A549 Cells

A biodegradable alginate coated chitosan hollow nanosphere (ACHN) was prepared by a hard template method and used for codelivery of doxorubicin (DOX) and paclitaxel (PTX) to investigate the effect on human lung cancer A549 cells. PTX was loaded into the nanometer hollow structure of ACHN through adsorption method. DOX was coated on surface of ACHN through electrostatic interaction. Drug release studies exhibited a sustained-release effect. According to X-ray diffraction patterns (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR) analysis, DOX structure in the loading samples (DOX-PTX-ACHN) was of amorphous state while PTX was microcrystalline. Cytotoxicity experiments showed ACHN was nontoxic as carrier material and the combination of DOX and PTX in DOX-PTX-ACHN exhibited a good inhibiting effect on cell proliferation. Cell uptake experiments demonstrated that DOX-PTX-ACHN accumulated in the cytoplasm. Degradation experiments illustrated that ACHN was a biodegradable material. In summary, these results clearly indicate that ACHN can be utilized as a potential biomaterial to transport multiple drugs to be used in combination therapy.

http://ift.tt/2nixxqJ

Epstein–Barr virus strain heterogeneity impairs human T-cell immunity

Abstract

The Epstein–Barr virus (EBV) establishes lifelong infections in > 90% of the human population. Although contained as asymptomatic infection by the immune system in most individuals, EBV is associated with the pathogenesis of approximately 1.5% of all cancers in humans. Some of these EBV-associated tumors have been successfully treated by the infusion of virus-specific T-cell lines. Recent sequence analyses of a large number of viral isolates suggested that distinct EBV strains have evolved in different parts of the world. Here, we assessed the impact of such sequence variations on EBV-specific T-cell immunity. With the exceptions of EBNA2 and the EBNA3 family of proteins, an overall low protein sequence disparity of about 1% was noted between Asian viral isolates, including the newly characterized M81 strain, and the prototypic EBV type 1 and type 2 strains. However, when T-cell epitopes including their flanking regions were compared, a substantial proportion was found to be polymorphic in different EBV strains. Importantly, CD4+ and CD8+ T-cell clones specific for viral epitopes from one strain often showed diminished recognition of the corresponding epitopes in other strains. In addition, T-cell recognition of a conserved epitope was affected by amino acid exchanges within the epitope flanking region. Moreover, the CD8+ T-cell response against polymorphic epitopes varied between donors and often ignored antigen variants. These results demonstrate that viral strain heterogeneity may impair antiviral T-cell immunity and suggest that immunotherapeutic approaches against EBV should preferably target broad sets of conserved epitopes including their flanking regions.

http://ift.tt/2DG2SuG

Lymphovascular invasion after neoadjuvant chemotherapy is strongly associated with poor prognosis in breast carcinoma

Abstract

Purpose

Few studies evaluated the prognostic value of the presence of lymphovascular invasion (LVI) after neoadjuvant chemotherapy (NAC) for breast cancer (BC).

Methods

The association between LVI and survival was evaluated in a cohort of BC patients treated by NAC between 2002 and 2011. Five post-NAC prognostic scores (ypAJCC, RCB, CPS, CPS + EG and Neo-Bioscore) were evaluated and compared with or without the addition of LVI.

Results

Out of 1033 tumors, LVI was present on surgical specimens in 29.2% and absent in 70.8% of the cases. Post-NAC LVI was associated with impaired disease-free survival (DFS) (HR 2.54; 95% CI 1.96–3.31; P < 0.001), and the magnitude of this effect depended on BC subtype (P_interaction = 0.003), (luminal BC: HR 1.83; P = 0.003; triple negative BC: HR 3.73; P < 0.001; HER2-positive BC: HR 6.21; P < 0.001). Post-NAC LVI was an independent predictor of local relapse, distant metastasis, and overall survival; and increased the accuracy of all five post-NAC prognostic scoring systems.

Conclusions

Post-NAC LVI is a strong independent prognostic factor that: (i) should be systematically reported in pathology reports; (ii) should be used as stratification factor after NAC to propose inclusion in second-line trials or adjuvant treatment; (iii) should be included in post-NAC scoring systems.

http://ift.tt/2EhgHAY

A high-risk 70-gene signature is not associated with the detection of tumor cell dissemination to the bone marrow

Abstract

Purpose

The 70-gene signature (70-GS) is a prognostic tool, grouping patients in risk groups to assess their need for adjuvant chemotherapy. Tumor cell dissemination to the bone marrow is a marker of minimal residual disease and associated with impaired survival. In this study, we aimed to evaluate whether 70-GS is associated with the presence of disseminated tumor cells (DTCs) in the bone marrow of patients with early breast cancer.

Methods

In patients with hormone receptor-positive HER2-negative early breast cancer, the 70-GS was obtained and the presence of DTCs was immunohistochemically evaluated using cytokeratin staining with the A45-B/B3 antibody.

Results

149 patients were included into the analysis. 40 (27%) had a high-risk 70-GS and 35 (23%) had detectable DTCs in their bone marrow. 9 (22%) of the 40 patients with high-risk 70-GS and 26 (24%) of the 109 patients with a low-risk 70-GS were positive for DTCs (p = 0.863).

Conclusions

As both 70-GS and DTC detection are known prognostic factors but do not seem to correlate, a follow-up on a larger cohort is warranted to evaluate if a combination of the two is able to better stratify the relapse risk in early breast cancer patients.

http://ift.tt/2DGNmhU

Morbidity of local therapy for locally advanced metastatic breast cancer: an analysis of the Surveillance, Epidemiology, and End Results (SEER)–Medicare Registry

Abstract

Purpose

Limited data exist to guide the management of in-breast tumors that can produce physical and emotional discomfort in the setting of metastatic disease. We evaluated the morbidity of local therapy (LT) among patients with locally advanced metastatic breast cancer.

Methods

Patients with de novo T4M1 breast cancer diagnosed between 2005 and 2011 were identified from the SEER–Medicare database. We assessed receipt of care for loco-regional morbidity before and after LT.

Results

Among 3660 patients with T4M1 disease, 1558 (43%) underwent LT [surgery (19%), radiation (15%), both (9%)]. Before LT, few patients were reported to have loco-regional morbidity (7.9% vs. 6.7% for no LT, P = 0.17). Following LT, patients were reported to have more loco-regional morbidity than patients who did not have LT (22.6% vs. 7.9%). More patients without baseline loco-regional morbidity were reported to have received care for loco-regional morbidity documented after LT compared to baseline loco-regional morbidity reported in patients without LT (19.9% vs. 6.3%, P < 0.001).

Conclusions

The need to address loco-regional morbidity is relatively infrequent among patients with T4M1 disease who do not undergo LT. Receipt of care for loco-regional morbidity was higher following LT. For patients without existing loco-regional morbidity, risks of LT may outweigh potential benefits.

http://ift.tt/2Eimvds

Decoding auditory spatial and emotional information encoding using multivariate versus univariate techniques

Abstract

Emotion can have diverse effects on behaviour and perception, modulating function in some circumstances, and sometimes having little effect. Recently, it was identified that part of the heterogeneity of emotional effects could be due to a dissociable representation of emotion in dual pathway models of sensory processing. Our previous fMRI experiment using traditional univariate analyses showed that emotion modulated processing in the auditory 'what' but not 'where' processing pathway. The current study aims to further investigate this dissociation using a more recently emerging multi-voxel pattern analysis searchlight approach. While undergoing fMRI, participants localized sounds of varying emotional content. A searchlight multi-voxel pattern analysis was conducted to identify activity patterns predictive of sound location and/or emotion. Relative to the prior univariate analysis, MVPA indicated larger overlapping spatial and emotional representations of sound within early secondary regions associated with auditory localization. However, consistent with the univariate analysis, these two dimensions were increasingly segregated in late secondary and tertiary regions of the auditory processing streams. These results, while complimentary to our original univariate analyses, highlight the utility of multiple analytic approaches for neuroimaging, particularly for neural processes with known representations dependent on population coding.

http://ift.tt/2Fn7SEQ

Clinical Significance and Biological Role of HuR in Head and Neck Carcinomas

Background. Hu-antigen R (HuR) is a posttranscriptional regulator of several target mRNAs, implicated in carcinogenesis. This review aims to present the current evidence regarding the biological role and potential clinical significance of HuR in head and neck carcinomas. Methods. The existing literature concerning HuR expression and function in head and neck carcinomas is critically presented and summarised. Results. HuR is expressed in the majority of the examined samples, showing higher cytoplasmic levels in malignant or premalignant cases. Moreover, HuR modulates several genes implicated in biological processes important for malignant transformation, growth, and invasiveness. HuR seems to be an adverse prognosticator in patients with OSCCs, whereas a correlation with a more aggressive phenotype is reported in several types of carcinomas. Conclusions. A consistent role of HuR in the carcinogenesis and progression of head and neck carcinomas is suggested; nevertheless, further studies are warranted to expand the present information.

http://ift.tt/2DIXefh

Central Nervous System Involvement in Peripheral T Cell Lymphoma

Abstract

Purpose of Review

Central nervous system (CNS) involvement in peripheral T cell lymphoma (PTCL) is a difficult condition to treat, both as a primary and a secondary disease.

Recent Findings

Primary CNS lymphoma (PCNSL) in PTCL is very rare, making up only 2% of all PCNSLs. The incidence of CNS relapse is generally 2–6% in all cases of PTCL, but the risk may vary by histologic subtype, and extranodal involvement > 1 has been consistently found to be a risk factor for CNS relapse.

Summary

Currently, there is no consensus about indications for CNS prophylactic treatment. A high-dose systemic methotrexate-based regimen is the most commonly used treatment, with or without consolidation with high-dose chemotherapy with autologous stem cell transplantation for both primary and secondary CNS involvement. This approach, however, is generally toxic for older patients. New therapeutic approaches against PTCL are therefore needed.

http://ift.tt/2njIPv6

Isolation and Characterization of Two New Antimicrobial Acids from Quercus incana (Bluejack Oak)

Two new compounds were purified from ethyl acetate fraction of Quercus incana. The structure of these compounds is mainly established by using advanced spectroscopic technique such as UV, IR, one-dimensional (ID) and two-dimensional (2D) NMR techniques, and EI mass. The structural formula was deduced to be 4-hydroxydecanoic acid and 4-hydroxy-3-(hydroxymethyl) pentanoic acid . Both isolated compounds were tested for their antimicrobial potential and showed promising antifungal activity against Aspergillus niger and Aspergillus flavus.

http://ift.tt/2DIXDOP

Association between Insulin-Like Growth Factor-1 and Uric Acid in Chinese Children and Adolescents with Idiopathic Short Stature: A Cross-Sectional Study

Objective. The aim of this study was to examine the relationship between insulin-like growth factor-1 (IGF-1) and serum uric acid (UA) in Chinese children and adolescents with idiopathic short stature (ISS). Methods. A cross-sectional study of 91 Chinese children and adolescents with ISS was performed. Anthropometric measurements and biochemical parameters were tested. The standard deviation score of IGF-1 (IGF-1 SDS) was calculated. Results. A univariate analysis displayed a significant positive correlation between IGF-1 SDS and UA (). In multivariate piecewise linear regression, the levels of IGF-1 SDS increased with the elevation of UA when UA was between 168 μmol/L and 301 μmol/L (β 0.010, 95% CI 0.004–0.017; ). The levels of IGF-1 SDS decreased with the elevation of UA when UA was either less than 168 μmol/L (β  −0.055, 95% CI −0.081–−0.028; ) or more than 301 μmol/L (β  −0.005, 95% CI −0.013–0.002; ). Conclusions. This study demonstrated a nonlinear relationship between IGF-1 and UA levels in Chinese children and adolescents with ISS. This finding suggests that either high or low levels of UA may have an adverse effect on IGF-1, whereas appropriate UA levels have a beneficial effect.

http://ift.tt/2Fn3aal

Eosinophils from Physiology to Disease: A Comprehensive Review

Despite being the second least represented granulocyte subpopulation in the circulating blood, eosinophils are receiving a growing interest from the scientific community, due to their complex pathophysiological role in a broad range of local and systemic inflammatory diseases as well as in cancer and thrombosis. Eosinophils are crucial for the control of parasitic infections, but increasing evidence suggests that they are also involved in vital defensive tasks against bacterial and viral pathogens including HIV. On the other side of the coin, eosinophil potential to provide a strong defensive response against invading microbes through the release of a large array of compounds can prove toxic to the host tissues and dysregulate haemostasis. Increasing knowledge of eosinophil biological behaviour is leading to major changes in established paradigms for the classification and diagnosis of several allergic and autoimmune diseases and has paved the way to a "golden age" of eosinophil-targeted agents. In this review, we provide a comprehensive update on the pathophysiological role of eosinophils in host defence, inflammation, and cancer and discuss potential clinical implications in light of recent therapeutic advances.

http://ift.tt/2DVx7Rs