A systematic review of treating recurrent head and neck cancer: a reintroduction of brachytherapy with or without surgery.

Purpose: To review brachytherapy use in recurrent head and neck carcinoma (RHNC) with focus on its efficacy and complication rates. Material and methods: A literature search of PubMed, Ovid, Google Scholar, and Scopus was conducted from 1990 to 2017. Publications describing treatment of RHNC with brachytherapy with or without surgery were included. The focus of this review is on oncologic outcomes and the safety of brachytherapy in the recurrent setting. Results: Thirty studies involving RHNC treatment with brachytherapy were reviewed. Brachytherapy as adjunctive treatment to surgical resection appears to be associated with an improved local regional control and overall survival, when compared with the published rates for re-irradiation utilizing external beam radiotherapy (RT) or brachytherapy alone. Safety data remains variable with different isotopes and dose rates with implantable brachytherapy demonstrating a tolerable side effect profile. Conclusions: Although surgery remains a mainstay treatment for RHNC, intraoperative interstitial brachytherapy delivery as adjunctive therapy may improve the treatment outcome and may be associated with fewer complication rates as compared to reirradiation using external beam radiotherapy. Further investigations are required to elucidate the role of brachytherapy for RHNC

DNA methylation profiles correlated to striped bass sperm fertility

Striped bass (Morone saxatilis) spermatozoa are used to fertilize in vitro the eggs of white bass (M. chrysops) to produce the preferred hybrid for the striped bass aquaculture industry. Currently, only one source of domestic striped bass juveniles is available to growers that is not obtained from wild-caught parents and is thus devoid of any genetic improvement in phenotypic traits of importance to aquaculture. Sperm epigenetic modification has been predicted to be associated with fertility, which could switch genes on and off without changing the DNA sequence itself. DNA methylation is one of the most common epigenetic modification types and changes in sperm epigenetics can be correlated to sub-fertility or infertility in male striped bass. The objective of this study was to find the differentially methylated regions (DMRs) between high-fertility and sub-fertility male striped bass, which could potentially regulate the fertility performance. In our present study, we performed DNA methylation analysis of high-fertility and sub-fertility striped bass spermatozoa through MBD-Seq methods. A total of 171 DMRs were discovered in striped bass sperm correlated to fertility. Based on the annotation of these DMRs, we conducted a functional classification analysis and two important groups of genes including the WDR3/UTP12 and GPCR families, were discovered to be related to fertility performance of striped bass. Proteins from the WDR3/UTP12 family are involved in forming the sperm flagella apparatus in vertebrates and GPCRs are involved in hormonal signaling and regulation of tissue development, proliferation and differentiation. Our results contribute insights into understanding the mechanism of fertility in striped bass, which will provide powerful tools to maximize reproductive efficiencies and to identify those males with superior gametes for this important aquaculture species.https://doi.org/10.1186/s12864-018-4548-

Cohort study of the impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis

Background and Aims: All oral direct-acting antivirals (DAAs) effectively treat chronic hepatitis C virus (HCV) infection, but the benefits in advanced liver disease are unclear. We compared outcomes in treated and untreated patients with decompensated cirrhosis. Methods: Patients with HCV and decompensated cirrhosis or at risk of irreversible disease were treated in an Expanded Access Programme (EAP) in 2014. Treatment, by clinician choice, was with sofosbuvir, ledipasvir or daclatasvir, with or without ribavirin. For functional outcome comparison, untreated patients with HCV and decompensated cirrhosis who were registered on a database 6 months before treatment was available were retrospectively studied. Primary endpoint was sustained virological response 12 weeks post antiviral treatment (treated cohort) and the secondary endpoint (both cohorts) was adverse outcomes (worsening in MELD score or serious adverse event) within 6 months. Results: 467 patients received treatment (409 decompensated cirrhosis). Viral clearance was achieved in 381 patients (81.6%) – 209 from 231 (90.5%) with genotype 1 and 132 from 192 (68.8%) with genotype 3. MELD scores improved in treated patients (mean change -0.85) but worsened in untreated patients (mean + 0.75) (p65 or with low (<135 mmol/L) baseline serum sodium concentrations were least likely to benefit from therapy. Conclusions: All oral DAAs effectively cured HCV in patients with advanced liver disease. Viral clearance was associated with improvement in liver function within 6 months compared to untreated patients. The longer term impact of HCV treatment in patients with decompensated cirrhosis remains to be determined

Outcomes in patients with gunshot wounds to the brain.

Introduction:Gunshot wounds to the brain (GSWB) confer high lethality and uncertain recovery. It is unclear which patients benefit from aggressive resuscitation, and furthermore whether patients with GSWB undergoing cardiopulmonary resuscitation (CPR) have potential for survival or organ donation. Therefore, we sought to determine the rates of survival and organ donation, as well as identify factors associated with both outcomes in patients with GSWB undergoing CPR. Methods:We performed a retrospective, multicenter study at 25 US trauma centers including dates between June 1, 2011 and December 31, 2017. Patients were included if they suffered isolated GSWB and required CPR at a referring hospital, in the field, or in the trauma resuscitation room. Patients were excluded for significant torso or extremity injuries, or if pregnant. Binomial regression models were used to determine predictors of survival/organ donation. Results:825 patients met study criteria; the majority were male (87.6%) with a mean age of 36.5 years. Most (67%) underwent CPR in the field and 2.1% (n=17) survived to discharge. Of the non-survivors, 17.5% (n=141) were considered eligible donors, with a donation rate of 58.9% (n=83) in this group. Regression models found several predictors of survival. Hormone replacement was predictive of both survival and organ donation. Conclusion:We found that GSWB requiring CPR during trauma resuscitation was associated with a 2.1% survival rate and overall organ donation rate of 10.3%. Several factors appear to be favorably associated with survival, although predictions are uncertain due to the low number of survivors in this patient population. Hormone replacement was predictive of both survival and organ donation. These results are a starting point for determining appropriate treatment algorithms for this devastating clinical condition. Level of evidence:Level II

Coronaridine congeners attenuate fentanyl seeking during prolonged abstinence

Background: The prevalence of opioid use disorder (OUD) has reached epidemic proportions with a record-breaking number of overdose deaths. Over 70% of the record-breaking number of overdose deaths are caused by synthetic opioids, including fentanyl. Fentanyl is commonly administered intravenously or by inhalation (smoking/vaping), which results in rapid drug bioavailability in the brain. There is a current need to identify a novel pharmacologic therapy to treat OUD, and there is increasing evidence to support the use of novel compounds referred to as coronaridine congeners to treat OUD and other psychiatric illnesses. In preclinical models, coronaridine congeners have been shown to decrease self-administration of drugs of abuse and induce antidepressant and anxiolytic effects. Here we used a preclinical fentanyl vapor self-administration model and fast-scan cyclic voltammetry (FSCV) to study the anti-addictive effects of two coronaridine congeners, 18-methoxycoronaridine (18-MC) and catharanthine (Cath).Methods: C57BL/6J mice were trained to self-administer vaporized fentanyl (5 mg/mL) or vehicle in airtight operant chambers. Mice self-administered vapor for 1 hour per day for 10 days (sessions were conducted for 5 consecutive days, followed by 2 days off). Chambers were equipped with two nosepokes, one active and one inactive. A successful response in the active nosepoke resulted in a vapor delivery that coincided with the presentation of a cue light, followed by a 1-minute timeout period. Mice learned to self-administer vapor with 3-second vapor deliveries for the first 3 days of training, which was then reduced to 1.5-second vapor deliveries the remaining 7 days. After training, mice were returned to their home cages for a forced abstinence period. Cue-induced drug seeking tests were conducted on abstinence days (AD) 20 and 25. During cue-induced seeking tests, successful responses in the active nosepoke resulted in presentation of the drug-associated cue, but no vapor was delivered (i.e. extinction conditions). Cue-induced drug seeking tests were conducted using a crossover design where half of subjects received coronaridine treatment (18-MC or Cath), while the other half received vehicle (ddH2O), on AD20. On AD25, subjects received the opposite treatment compared to AD20. Mice were injected (i.p.) with either vehicle or coronaridine treatment 1 hour before seeking tests. To examine the molecular mechanism of coronaridine congeners, FSCV was conducted on dopaminergic pre-synaptic terminals in the nucleus accumbens (NAc) neurons to measure dopamine (DA) release in the presence of 18-MC and Cath with or without nicotinic acetylcholine receptor antagonists.Results: We found that both 18-MC and Cath significantly reduced fentanylseeking during prolonged abstinence with no effect on mice that had previously self-administered vehicle. Furthermore, FSCV revealed that 18-MC and Cath significantly reduced DA release onto NAc neurons.Conclusion: In this study, we report that both 18-MC and Cath decrease fentanyl seeking during prolonged abstinence. DA release is important for opioid-related behaviors, and we found that 18-MC and Cath reduce DA release in the NAc, a mechanism that may underlie the effect of coronaridine congeners on fentanyl seeking. Together, these results provide evidence that coronaridine congeners may be promising novel compounds for the pharmacotherapeutic treatment of OUD

A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients

Background The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required. Methods Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM). Results A total of 43 hemophilia A patients (FVIII Conclusion We concluded that the existing rFVIII-Fc population PK model is valid for patients >= 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients >= 5 years

Toward optimal implementation of cancer prevention and control programs in public health: A study protocol on mis-implementation

Abstract Background Much of the cancer burden in the USA is preventable, through application of existing knowledge. State-level funders and public health practitioners are in ideal positions to affect programs and policies related to cancer control. Mis-implementation refers to ending effective programs and policies prematurely or continuing ineffective ones. Greater attention to mis-implementation should lead to use of effective interventions and more efficient expenditure of resources, which in the long term, will lead to more positive cancer outcomes. Methods This is a three-phase study that takes a comprehensive approach, leading to the elucidation of tactics for addressing mis-implementation. Phase 1: We assess the extent to which mis-implementation is occurring among state cancer control programs in public health. This initial phase will involve a survey of 800 practitioners representing all states. The programs represented will span the full continuum of cancer control, from primary prevention to survivorship. Phase 2: Using data from phase 1 to identify organizations in which mis-implementation is particularly high or low, the team will conduct eight comparative case studies to get a richer understanding of mis-implementation and to understand contextual differences. These case studies will highlight lessons learned about mis-implementation and identify hypothesized drivers. Phase 3: Agent-based modeling will be used to identify dynamic interactions between individual capacity, organizational capacity, use of evidence, funding, and external factors driving mis-implementation. The team will then translate and disseminate findings from phases 1 to 3 to practitioners and practice-related stakeholders to support the reduction of mis-implementation. Discussion This study is innovative and significant because it will (1) be the first to refine and further develop reliable and valid measures of mis-implementation of public health programs; (2) bring together a strong, transdisciplinary team with significant expertise in practice-based research; (3) use agent-based modeling to address cancer control implementation; and (4) use a participatory, evidence-based, stakeholder-driven approach that will identify key leverage points for addressing mis-implementation among state public health programs. This research is expected to provide replicable computational simulation models that can identify leverage points and public health system dynamics to reduce mis-implementation in cancer control and may be of interest to other health areas

Psilocybin desynchronizes the human brain

A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trial

Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect.

PD-1 blockade represents a promising treatment in patients with head and neck squamous cell carcinoma (HNSCC). We analyzed results of a neoadjuvant randomized window-of-opportunity trial of nivolumab plus/minus tadalafil to investigate whether immunotherapy-mediated treatment effects vary by site of involvement (primary tumor, lymph nodes) and determine how radiographic tumor shrinkage correlates with pathologic treatment effect. Patients and Methods: Forty-four patients enrolled in trial NCT03238365 were treated with nivolumab 240 mg intravenously on days 1 and 15 with or without oral tadalafil, as determined by random assignment, followed by surgery on day 31. Radiographic volumetric response (RVR) was defined as percent change in tumor volume from pretreatment to posttreatment CT scan. Responders were defined as those with a 10% reduction in the volume of the primary tumor or lymph nodes (LN). Pathologic treatment effect (PTE) was defined as the area showing fibrosis or lymphohistiocytic inflammation divided by total tumor area. Results: Sixteen of 32 patients (50%) with pathologic evidence of LN involvement exhibited discordant PTE between primary sites and LN. In four patients with widely discordant adjacent LN, increased PTE was associated with increased infiltration of tumor CD8+ T cells and CD163+ macrophages, whereas stromal regulatory T cells were associated with low nodal PTE. RVR correlated with PTE at both primary tumor (slope = 0.55, p \u3c 0.001) and in LN (slope = 0.62, p \u3c 0.05). 89% (16/18) of radiographic non-responders with T1-T3 primary sites had no (n = 7) or minimal PTE (n = 9), whereas 15/17 (88%) of radiographic responders had moderate (n = 12) or complete (n = 3) PTE. Conclusion: Nivolumab often induces discordant treatment effects between primary tumor sites and metastatic lymph nodes within subjects. This treatment discordance was also demonstrated in adjacent lymph nodes, which may correlate with local immune cell makeup. Finally, although these data were generated by a relatively small population size, our data support the use of early radiographic response to assess immunotherapy treatment effect in HNSCC

Human PTCHD3 nulls: rare copy number and sequence variants suggest a non-essential gene

<p>Abstract</p> <p>Background</p> <p>Copy number variations (CNVs) can contribute to variable degrees of fitness and/or disease predisposition. Recent studies show that at least 1% of any given genome is copy number variable when compared to the human reference sequence assembly. Homozygous deletions (or CNV nulls) that are found in the normal population are of particular interest because they may serve to define non-essential genes in human biology.</p> <p>Results</p> <p>In a genomic screen investigating CNV in Autism Spectrum Disorders (ASDs) we detected a heterozygous deletion on chromosome 10p12.1, spanning the Patched-domain containing 3 (<it>PTCHD3</it>) gene, at a frequency of ~1.4% (6/427). This finding seemed interesting, given recent discoveries on the role of another Patched-domain containing gene (<it>PTCHD1</it>) in ASD. Screening of another 177 ASD probands yielded two additional heterozygous deletions bringing the frequency to 1.3% (8/604). The deletion was found at a frequency of ~0.73% (27/3,695) in combined control population from North America and Northern Europe predominately of European ancestry. Screening of the human genome diversity panel (HGDP-CEPH) covering worldwide populations yielded deletions in 7/1,043 unrelated individuals and those detected were confined to individuals of European/Mediterranean/Middle Eastern ancestry. Breakpoint mapping yielded an identical 102,624 bp deletion in all cases and controls tested, suggesting a common ancestral event. Interestingly, this CNV occurs at a break of synteny between humans and mouse. Considering all data, however, no significant association of these rare <it>PTCHD3 </it>deletions with ASD was observed. Notwithstanding, our RNA expression studies detected <it>PTCHD3 </it>in several tissues, and a novel shorter isoform for <it>PTCHD3 </it>was characterized. Expression in transfected COS-7 cells showed <it>PTCHD3 </it>isoforms colocalize with calnexin in the endoplasmic reticulum. The presence of a patched (Ptc) domain suggested a role for <it>PTCHD3 </it>in various biological processes mediated through the Hedgehog (Hh) signaling pathway. However, further investigation yielded one individual harboring a homozygous deletion (<it>PTCHD3 </it>null) without ASD or any other overt abnormal phenotype. Exon sequencing of <it>PTCHD3 </it>in other individuals with deletions revealed compound point mutations also resulting in a null state.</p> <p>Conclusion</p> <p>Our data suggests that <it>PTCHD3 </it>may be a non-essential gene in some humans and characterization of this novel CNV at 10p12.1 will facilitate population and disease studies.</p