Search

An analysis of health behavior of terminally ill individuals is offered. Additional information on changes in behavioral motivations of the terminally ill is included.

The fully human monoclonal antibody patritumab blocks HER3 activation, a resistance mechanism to cetuximab, induced by heregulin (HRG). A phase Ib study in recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) demonstrated tolerability and tumour response of patritumab + cetuximab + platinum. This was a randomised, double-blind, phase II study of patritumab + cetuximab with platinum-based therapy for first-line treatment of R/M SCCHN (Clinicaltrials.gov identifier: NCT02633800). Patients aged ≥18 years received patritumab or placebo, both combined with cetuximab + cisplatin or carboplatin. Co-primary end-points were progression-free survival (PFS) in the intent-to-treat (ITT) and the high-expression HRG (HRG high) populations. Eighty-seven patients (n = 43 in the patritumab group; n = 44 in placebo group) enrolled. A median (range) of 6.5 (1–24) patritumab cycles were completed. Median PFS was similar between the patritumab group and placebo group in the ITT population (5.6 versus 5.5 months; hazard ratio [HR] 0.99 [95% confidence interval [CI], 0.6–1.7]; P = 0.96) and HRG-high subgroup (n = 51; 5.6 versus 5.6 months; HR 0.93 [95% CI, 0.5–1.8]; P = 0.82). Median overall survival in the ITT population was also similar (10.0 versus 12.7 months; HR 1.3 [95% CI, 0.69–2.29]; P = 0.46). All patients experienced ≥1 treatment-emergent adverse event (TEAE). Grade ≥III TEAEs were more frequent in the patritumab than the placebo group (84.1% versus 60.5%). The most common grade ≥III patritumab-related TEAE in the patritumab group (20.5% overall) was rash (6.8%). Patritumab + cetuximab + platinum was tolerable but not superior to cetuximab + platinum. • Patritumab has potential to block HER3 activation, a cetuximab-resistance mechanism. • This trial examined cetuximab ± patritumab (+platinum) in first-line recurrent and/or metastatic squamous cell carcinoma of the head and neck. • Outcomes in terms of median progression-free survival and overall survival were similar between arms. • Grade ≥III treatment-emergent adverse events were more frequent with patritumab. • Patritumab/cetuximab/platinum was tolerable but not superior to cetuximab/platinum. [ABSTRACT FROM AUTHOR]

Objectives: Ayurveda claims to be effective in the treatment of psychosomatic disorders by means of lifestyle and nutritional counseling.Design: In a randomized controlled study mothers with burnout were randomized into two groups: Ayurvedic nutritional counseling (according to tradition), and conventional nutritional counseling (following the recommendations of a family doctor). Patients received five counseling sessions over twelve weeks.Main Outcome Measures: Outcomes included levels of burnout, quality of life, sleep, stress, depression/anxiety, and spirituality at three and six months. It also included a qualitative evaluation of the communication processes.Results: We randomized thirty four patients; twenty three participants were included in the per protocol analysis. No significant differences were observed between the groups. However, significant and clinically relevant intra-group mean changes for the primary outcome burnout, and secondary outcomes sleep, stress, depression and mental health were only found in the Ayurveda group. The qualitative part of the study identified different conversational styles and counseling techniques between the two study groups. In conventional consultations questions tended to be category bound, while counseling-advice was predominantly admonitory. The Ayurvedic practitioner used open-ended interrogative forms, devices for displaying understanding, and positive re-evaluation more frequently, leading to an overall less asymmetrical interaction.Conclusions: We found positive effects for both groups, which however were more pronounced in the Ayurvedic group. The conversational and counseling techniques in the Ayurvedic group offered more opportunities for problem description by patients as well as patient-centered practice and resource-oriented recommendations by the physician.Trial Registration: NCT01797887. [ABSTRACT FROM AUTHOR]

Exhaust CO 2 , NaCl and H 2 O can be converted to Na 2 CO 3 and HCl by the MgCl 2 /MgO modified ammonia soda process at a maximum temperature of 525 °C. Such a temperature is easily reached by solar troughs. Subsequently this process stores thermal solar energy as chemical energy and concomitantly CO 2 can be removed from the environment. The process has been investigated theoretically and experimentally to further enhance its solar efficiency. It is shown theoretically that Mg-compounds are unique for this process and that the MgCl 2 /MgO modification is optimal. Experiments demonstrate that by splitting the main reaction of this process into two steps the solar efficiency can be enhanced to 21.5% and very highly concentrated HCl aq can be obtained. The yield of the main chemical reaction exceeds 95% at 525 °C. Suggestions are given for an improved thermal solar trough system to perform the main chemical reaction. [ABSTRACT FROM AUTHOR]

Abstract: The conventional Solvay ammonia soda process is a net producer of CO2 and produces large quantities of ecologically doubtful side products. Therefore a possible solution for this problem was investigated. Theoretical and experimental data are given which show the feasibility of a modified ammonia soda process which delivers Na2CO3 and HCl by using exhaust CO2, NaCl and H2O. This modified ammonia soda process would not produce the byproduct CaCl2 as in the conventional Solvay ammonia soda process, would be completely recyclable and could be driven by solar thermal energy. Low maximum reaction temperatures of T ≤ 800 K and an estimated achievable solar efficiency of 10% show that this cycle is not only environmentally friendly but also energetically interesting. Kinetic constants of the main reactions are given which are similar to the ones in the conventional process. The principle of a simple solar thermo-chemical reactor is described. Preliminary economical considerations show that this new process might even be competitive when driven by solar thermal energy instead of using fossil fuels. If this novel process would be implemented worldwide approximately up to 3 × 107 tonne of CO2 could be omitted annually compared with the conventional Solvay ammonia soda process. This would correspond to 0.15% of the annual release of all anthropogenically produced CO2. [Copyright &y& Elsevier]

This study examined the effectiveness of a Swedish parent management training (PMT) intervention for parents of children aged 3 to 10 within the context of regular social service. Self-referred parents of 159 children (aged 3 to 10) with conduct problems were randomly assigned to either 11 practitioner-assisted group sessions (PMT-P), or a single instructional workshop followed by self-administra- tion of the training material (PMT-S), or a waitlist control group. Intent-to-treat analyses showed that both PMT-P and PMT-S improved parent competence and reduced child conduct problems compared to the waitlist at posttest. Both training conditions showed further significant improvements at the 6-month follow-up. In direct comparison, PMT-P was superior to PMT-S on measures of child conduct problems at both posttest and follow-up. Improvement in child conduct was mediated by improvement in parent competencies and homework fidelity. The findings in this study have implications for large-scale dissemination of parent management training through different means of delivery. [ABSTRACT FROM AUTHOR]

Abstract: Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma typically associated with smoking. The incidence of the disease has reduced in recent years in Western Europe as smoking habits have changed . SCLC in never smokers is rare and aetiology unclear. Young''s syndrome is another rare condition, characterized by chronic sinopulmonary infection and obstructive azoospermia. The pathobiology of this is also poorly understood. Here we describe a case of both Young syndrome and SCLC in a never smoker, and raise the possibility of a common aetiology underpinned by aberrant hedgehog signalling. [Copyright &y& Elsevier]

The thermodynamic data of the system SnO2/SnO/Sn in the absence and presence of CH4 and C are calculated as a function of temperature. The direct dissociation of SnOx without any reducing substances needs temperatures T>2000 K at 1 bar. In the presence of CH4 or C, SnOx can be reduced at T<1250 K. The production of H2 from Sn, SnO and H2O is investigated. A real overall solar yield ηreal is defined which compares the output of real fuel cells, fed by solar-produced chemicals, with the total solar input necessary to produce these chemicals. ηreal is then used to find the most promising thermochemical reaction of the system SnO2/SnO/Sn+C/CH4. The optimal reaction is SnO2+2CH4↔Sn+2CO+4H2, proceeding at 980 K (ΔrG=−60 kJ), which is followed by Sn+2H2O↔SnO2+2H2. CO and H2 are then fed to fuel cells producing electricity with ηreal=0.23. The amount of solar upgrading of the fossil fuels CH4 and C is given. A combination of solar reactor, heat recovery device and a following reactor to produce H2 is proposed. The dimension, volume and mass flow of the solar reactor are calculated and the amount of simultaneously produced electricity is given. [Copyright &y& Elsevier]

To evaluate if an internet-delivered parent training program is noninferior to its group-delivered counterpart in reducing child disruptive behavior problems (DBP). This noninferiority randomized clinical trial enrolled families seeking treatment in primary care in Stockholm, Sweden, for DBP in a child 3-11 years of age. Participants were randomized to internet-delivered (iComet) or group-delivered (gComet) parent training. The primary outcome was parent-rated DBP. Assessments were made at baseline and 3, 6, and 12 months. Secondary outcomes included child and parent behaviors and well-being and treatment satisfaction. The noninferiority analysis was determined by a one-sided 95% CI of the mean difference between gComet and iComet using multilevel modeling. This trial included 161 children (mean age 8.0); 102 (63%) were boys. In both intention-to-treat and per-protocol analyses, iComet was noninferior to gComet. There were small differences in between-group effect sizes (d = −0.02 to 0.13) on the primary outcome with the upper limit of the one-sided 95% CI below the noninferiority margin at 3-, 6-, and 12-month follow-up. Parents were more satisfied with gComet (d = 0.49, 95% CI [0.26, 0.71]). At 3-month follow-up, there were also significant differences in treatment effect on attention-deficit/hyperactivity disorder symptoms (d = 0.34, 95% CI [0.07, 0.61]) and parenting behavior (d = 0.41, 95% CI [0.17, 0.65]) favoring gComet. At 12-month follow-up, there were no differences in any outcomes. Internet-delivered parent training was noninferior to group-delivered parent training in reducing child DBP. The results were maintained at 12-month follow-up. This study supports internet-delivered parent training being used as an alternative to group-delivered parent training in clinical settings. Randomized Controlled Trial of Comet via the Internet or in Group Format; https://www.clinicaltrials.gov/ ; NCT03465384. [ABSTRACT FROM AUTHOR]

Most patients with small-cell lung cancer (SCLC) present with extensive-stage (ES) disease and have a poor prognosis despite achieving high initial response rates to platinum-based doublet chemotherapy. This study evaluated whether adding hydroxychloroquine (HCQ) to chemotherapy could improve outcomes. This was a randomised multicentre phase II trial. Eligible patients had untreated ES-SCLC, a performance status 0–2 and measurable disease. Patients were randomly assigned (1:1 ratio) to HCQ (400 mg orally twice daily) plus carboplatin-gemcitabine or carboplatin–etoposide alone. Chemotherapy was administered for up to six cycles, with HCQ given concurrently and then as single agent for up to 30 months. Primary endpoint was PFS, aiming for a hazard ratio (HR) of 0.70. 72 patients were randomised (36 HCQ+chemotherapy and 36 chemotherapy alone). Median HCQ treatment duration was 4.4 months. HCQ did not improve PFS (HR 1·12 95 %CI 0·69–1.84; p = 0·64), with a median of 5.7 months (HCQ+chemotherapy) versus 6.2 months (chemotherapy). The corresponding median OS were 8.9 and 10.2 months (HR 0.83, 95 %CI 0.48–1.45, p = 0.52). Fewer patients in the HCQ arm completed four cycles of chemotherapy due to adverse events (64 % vs. 81 %). Grade ≥ 3 adverse events were higher in the HCQ+chemotherapy arm (83.3 % vs. 27.8 %), primarily anaemia, neutropenia, and thrombocytopenia, partly due to the initially higher gemcitabine dose used Combining HCQ with platinum doublet chemotherapy did not improve PFS or OS outcomes for ES-SCLC, resulting in more patients stopping chemotherapy due to increased adverse events. When considered alongside other randomised studies of HCQ in cancer, the evidence collectively indicates a limited role for HCQ as a therapeutic option. • Study 15 is the 1st & only randomised trial to examine an autophagy inhibitor in SCLC. • Combining HCQ with 1st-line platinum chemotherapy did not improve PFS or OS. • HCQ patients had more grade 3-4 adverse events & fewer completed 4 treatment cycles. • Evidence indicates HCQ has a limited role as an anti-cancer agent in various cancers. • Ongoing autophagy trials should monitor efficacy closely and stop early if futile. [ABSTRACT FROM AUTHOR]

• Metastatic non-sentinel lymph nodes identified in 15.8 % of SNB positive patients. • Presence of metastatic non-sentinel nodes further reduces survival in SNB + patients. • Lymph node ratio & tumour depth are associated with risk of non-sentinel nodes. • Additional positive non-sentinel lymph nodes are usually in adjacent neck levels. • De-escalation of treatment may be possible in certain sentinel node positive cases. [ABSTRACT FROM AUTHOR]

Inter-cycle delays to chemotherapy are often required to manage drug toxicity. The impact of delays on mortality is poorly characterised. This retrospective cohort study examined the association of treatment delay with all-cause mortality in early-stage breast cancer. This real-world analytical study included adult women with stage 2 or 3 breast cancer receiving first-line (neo-)adjuvant chemotherapy between 01/01/2014 and 31/12/2015 in England. Inter-cycle delays > 7 days during the treatment period were calculated, and the association of treatment delay with 5-year all-cause mortality was investigated. Survival was compared between patients experiencing treatment delay and those completing treatment to schedule using landmark methodology and Kaplan-Meier (KM) estimator. Cox proportional hazards regression was used to investigate the impact of delay on survival, using inverse probability of treatment weighting to adjust for confounding variables. 8567 patients were included. 17 % (1448) experienced inter-cycle delay > 7 days during the treatment period. 1120 (13 %) women had died at the end of the 5-year follow up period. Median follow-up time was 5.5 years. Survival probability was significantly lower in patients experiencing treatment delay by KM estimator analysis (p < 0.0001). Cox proportional hazards regression demonstrated a significant positive association between delay and 5-year all-cause mortality (HR 1.33 95 % CI 1.12–1.61, p < 0.001). This is the largest study of its kind demonstrating an association between treatment delay and all-cause mortality. These findings support interventions to improve toxicity management allowing completion of chemotherapy to schedule where patients experience treatment delay due to treatment-related toxicity or hospital capacity pressures. • Delays between chemotherapy cycles were evaluated in women with early breast cancer. • 1448 (17 %) women of 8567 were delayed > 7 days during six cycles of chemotherapy. • Delays were associated with reduced 5-year survival (HR 1.33, 95 % CI 1.12, 1.61). • Relative dose intensity was significantly reduced by delay (82 %) vs no delay (94 %). • Completing chemotherapy to schedule should be prioritised to maximise treatment benefit. [ABSTRACT FROM AUTHOR]

Background: Treatment options for malignant pleural mesothelioma are scarce. Tazemetostat, a selective oral enhancer of zeste homolog 2 (EZH2) inhibitor, has shown antitumour activity in several haematological cancers and solid tumours. We aimed to evaluate the anti-tumour activity and safety of tazemetostat in patients with measurable relapsed or refractory malignant pleural mesothelioma.Methods: We conducted an open-label, single-arm phase 2 study at 16 hospitals in France, the UK, and the USA. Eligible patients were aged 18 years or older with malignant pleural mesothelioma of any histology that was relapsed or refractory after treatment with at least one pemetrexed-containing regimen, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a life expectancy of greater than 3 months. In part 1 of the study, participants received oral tazemetostat 800 mg once on day 1 and then twice daily from day 2 onwards. In part 2, participants received oral tazemetostat 800 mg twice daily starting on day 1 of cycle 1, using a two-stage Green-Dahlberg design. Tazemetostat was administered in 21-day cycles for approximately 17 cycles. The primary endpoint of part 1 was the pharmacokinetics of tazemetostat and its metabolite at day 15 after administration of 800 mg tazemetostat, as measured by maximum serum concentration (Cmax), time to Cmax (Tmax), area under the concentration-time curve (AUC) to day 15 (AUC0-t), area under the curve from time 0 extrapolated to infinity (AUC0-∞), and the half-life (t1/2) of tazemetostat, assessed in all patients enrolled in part 1. The primary endpoint of part 2 was the disease control rate (the proportion of patients with a complete response, partial response, or stable disease) at week 12 in patients with malignant pleural mesothelioma per protocol with BAP1 inactivation determined by immunohistochemistry. The safety population included all the patients who had at least one post-dose safety assessment. This trial is now complete and is registered with ClinicalTrials.gov, NCT02860286.Findings: Between July 29, 2016, and June 2, 2017, 74 patients were enrolled (13 in part 1 and 61 in part 2) and received tazemetostat, 73 (99%) of whom had BAP1-inactivated tumours. In part 1, following repeat dosing of tazemetostat at steady state, on day 15 of cycle 1, the mean Cmax was 829 ng/mL (coefficient of variation 56·3%), median Tmax was 2 h (range 1-4), mean AUC0-twas 3310 h·ng/mL (coefficient of variation 50·4%), mean AUC0-∞ was 3180 h·ng/mL (46·6%), and the geometric mean t1/2 was 3·1 h (13·9%). After a median follow-up of 35·9 weeks (IQR 20·6-85·9), the disease control rate in part 2 in patients with BAP1-inactivated malignant pleural mesothelioma was 54% (95% CI 42-67; 33 of 61 patients) at week 12. No patients had a confirmed complete response. Two patients had a confirmed partial response: one had an ongoing partial response with a duration of 18 weeks and the other had a duration of 42 weeks. The most common grade 3-4 treatment-emergent adverse events were hyperglycaemia (five [7%] patients), hyponatraemia (five [7%]), and anaemia (four [5%]); serious adverse events were reported in 25 (34%) of 74 patients. Five (7%) of 74 patients died while on study; no treatment-related deaths occurred.Interpretation: Further refinement of biomarkers for tazemetostat activity in malignant pleural mesothelioma beyond BAP1 inactivation could help identify a subset of tumours that are most likely to derive prolonged benefit or shrinkage from this therapy.Funding: Epizyme. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The current study evaluated the efficacy of an Internet-based parent-training program for children with conduct problems. Dose–response ratio and costs for the program were also considered. Method: Parents of 104 children (aged 3–12 years) were randomly allocated to either parent training or a waitlist control condition. Diagnostic assessment was conducted at baseline and parent ratings of child externalizing behaviors and parent strategies were completed before and after treatment and at 6-month follow-up. Results: At post-treatment assessment, children whose parent(s) had received the intervention showed a greater reduction in conduct problems compared to the waitlist children. Between group intent-to-treat effect sizes (Cohen’s d) on the Eyberg Intensity and Problem scales were .42 and .72, respectively (study completers .66 and 1.08). In addition, parents in the intervention group reported less use of harsh and inconsistent discipline after the treatment, as well as more positive praise. Effects on behavior problems were maintained at 6-month follow-up. Conclusions: The results support the efficacy of parent training, administered through Internet, with outcomes comparable to many of the group-based parent training programs. The efficacy, low cost, and higher accessibility make this intervention a fitting part in a stepped-care model. [Copyright &y& Elsevier]

Background: Tisotumab vedotin is a first-in-human antibody-drug conjugate directed against tissue factor, which is expressed across multiple solid tumour types and is associated with poor clinical outcomes. We aimed to establish the safety, tolerability, pharmacokinetic profile, and antitumour activity of tisotumab vedotin in a mixed population of patients with locally advanced or metastatic (or both) solid tumours known to express tissue factor.Methods: InnovaTV 201 is a phase 1-2, open-label, dose-escalation and dose-expansion study done at 21 centres in the USA and Europe. Patients (aged ≥18 years) had relapsed, advanced, or metastatic cancer of the ovary, cervix, endometrium, bladder, prostate, oesophagus, squamous cell carcinoma of the head and neck or non-small-cell lung cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and had relapsed after or were not eligible to receive the available standard of care. No specific tissue factor expression level was required for inclusion. In the dose-escalation phase, patients were treated with tisotumab vedotin between 0·3 and 2·2 mg/kg intravenously once every 3 weeks in a traditional 3 + 3 design. In the dose-expansion phase, patients were treated at the recommended phase 2 dose. The primary endpoint was the incidence of adverse events, including serious adverse events, infusion-related, treatment-related and those of grade 3 or worse, and study drug-related adverse events, analysed in all patients who received at least one dose of tisotumab vedotin (full analysis population). This trial is registered with ClinicalTrials.gov, number NCT02001623, and is closed to new participants with follow-up ongoing.Findings: Between Dec 9, 2013, and May 18, 2015, 27 eligible patients were enrolled to the dose-escalation phase. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were seen at the 2·2 mg/kg dose; therefore, 2·0 mg/kg of tisotumab vedotin intravenously once every 3 weeks was established as the recommended phase 2 dose. Between Oct 8, 2015, and April 26, 2018, 147 eligible patients were enrolled to the dose-expansion phase. The most common (in ≥20% of patients) treatment-emergent adverse events of any grade were epistaxis (102 [69%] of 147 patients), fatigue (82 [56%]), nausea (77 [52%]), alopecia (64 [44%]), conjunctivitis (63 [43%]), decreased appetite (53 [36%]), constipation (52 [35%]), diarrhoea (44 [30%]), vomiting (42 [29%]), peripheral neuropathy (33 [22%]), dry eye (32 [22%]), and abdominal pain (30 [20%]). The most common adverse events of grade 3 or worse were fatigue (14 [10%] of 147 patients), anaemia (eight [5%]), abdominal pain (six [4%]), hypokalaemia (six [4%]), conjunctivitis (five [3%]), hyponatraemia (five [3%]), and vomiting (five [3%]). 67 (46%) of 147 patients had a treatment-emergent serious adverse event. 39 (27%) of 147 patients had a treatment-emergent serious adverse event related to the study drug. Infusion-related reactions occurred in 17 (12%) of 147 patients. Across tumour types, the confirmed proportion of patients who achieved an objective response was 15·6% (95% CI 10·2-22·5; 23 of 147 patients). There were nine deaths across all study phases (three in the dose-escalation phase and six in the dose-expansion phase); only one case of pneumonia in the dose-expansion phase was considered possibly related to study treatment.Interpretations: Tisotumab vedotin has a manageable safety profile with encouraging preliminary antitumour activity across multiple tumour types in heavily pretreated patients. Continued evaluation of tisotumab vedotin is warranted in solid tumours.Funding: Genmab A/S. [ABSTRACT FROM AUTHOR]

Parent training is an effective treatment for disruptive behavior problems in children. However, as there is limited access to traditional face-to-face treatment, other delivery formats have been evaluated. This study aims to evaluate possible predictors and moderators of outcome, completion and engagement in parent training when delivered in group or through the internet. A recent randomized controlled non-inferiority trial (N = 161) demonstrated equal effectiveness of the parent training program Comet when delivered in group (gComet) and through the internet (iComet). Demographic, clinical and theory-driven variables were studied to find predictors and moderators of treatment effect, completion and engagement. Linear mixed effects models were used to determine predictors and moderators of change in disruptive behavior from baseline to the 3- and 12-month follow-up. Most variables did not have significant predictive or moderating effects. However, there were some variables that predicted or moderated outcomes that may have implications for practice (e.g., comorbid emotional problems, preferred treatment format, and ADHD). This trial can contribute to guiding clinical work with children with disruptive behavior and results indicate that parent training in both treatment formats can be offered regardless of a range of demographic and clinical factors. Taking patients' treatment preferences into account can increase treatment completion. • Predictors and moderators of group-versus internet-based parent-training were evaluated. • Most demographic and clinical variables did neither predict nor moderate treatment effect. • Treatment preference predicted treatment completion; no variables moderated completion. • Comorbid emotional problems predicted larger treatment effects and more so in the group format of the intervention. [ABSTRACT FROM AUTHOR]

Objectives: p16INK4A (p16) is the most widely used clinical biomarker for Human Papillomavirus (HPV) in head and neck squamous cell cancer (HNSCC). HPV is a favourable prognostic marker in HNSCC and is used for patient stratification. While p16 is a relatively accurate marker for HPV within the oropharynx, recent reports suggest it may be unsuitable for use in other HNSCC subsites, where a smaller proportion of tumors are HPV-driven.Materials and Methods: We integrated reverse phase protein array (RPPA) data for p16 with HPV status based on detection of viral transcripts by RNA-seq in a set of 210 HNSCCs profiled by The Cancer Genome Atlas project. Samples were queried for alterations in CDKN2A, and other pathway genes to investigate possible drivers of p16 expression.Results: While p16 levels as measured by RPPA were significantly different by HPV status, there were multiple HPV (-) samples with similar expression levels of p16 to HPV (+) samples, particularly at non-oropharyngeal subsites. In many cases, p16 overexpression in HPV (-) tumors could not be explained by mutation or amplification of CDKN2A or by RB1 mutation. Instead, we observed enrichment for inactivating mutations in the histone H3 lysine 36 methyltransferase, NSD1 in HPV (-)/p16-high tumors.Conclusions: RPPA data suggest high p16 protein expression in many HPV (-) non-oropharyngeal HNSCCs, limiting its potential utility as an HPV biomarker outside of the oropharynx. HPV-independent overexpression of wild-type p16 in non-oropharyngeal HNSCC may be linked to global deregulation of chromatin state by inactivating mutations in NSD1. [ABSTRACT FROM AUTHOR]

Millions of children are victims of child abuse world-wide. Consequences include long-term health impacts and large societal costs. Parent training is promising to prevent abuse, but challenges with motivation and attrition must be overcome to reach parents in need. To assess the effectiveness and acceptability of Safer Kids, a cognitive behavioral therapy-based parenting program delivered immediately after a report of child abuse. Safer Kids is used within the Child Welfare Services (CWS) in Sweden but has never been evaluated in an RCT. In total, 112 families with children 2–12 years referred to the Swedish CWS for physical or emotional child abuse participated. Families were randomized to Safer Kids or intervention as usual (IAU). Data from parents, children and CWS were analyzed with multilevel and survival analyses. Primary outcomes were parent-rated child abuse potential and re-reports of abuse. Secondary outcomes were child abuse risk factors and treatment satisfaction. Data 4 and 7 months from baseline were available for 96 % of the families. All except one family (98 %) who started Safer Kids completed the program. Both groups improved from baseline to follow-ups on most effectiveness outcomes. The changes were not statistically different between groups. Parents and social workers were more satisfied with Safer Kids than IAU. Short manualized parenting programs can be a way to reach parents reported for child abuse with support. Safer Kids is a viable option to the CWS's standard interventions, as it was equally effective and slightly better accepted than IAU. • Safer Kids is a brief parenting program delivered after a report of child abuse. • Safer Kids was compared to intervention as usual within the Child Welfare Services. • Both groups improved from baseline to follow ups. • Parents and social workers were more satisfied with Safer Kids. • Safer Kids is a viable option to standard interventions. [ABSTRACT FROM AUTHOR]

The aim of this work is to compare Bayesian Inference for nonlinear models with commonly used traditional non-linear regression (NR) algorithms for estimating tracer kinetics in Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI). The algorithms are compared in terms of accuracy, and reproducibility under different initialization settings. Further it is investigated how a more robust estimation of tracer kinetics affects cancer diagnosis. The derived tracer kinetics from the Bayesian algorithm were validated against traditional NR algorithms (i.e. Levenberg-Marquardt, simplex) in terms of accuracy on a digital DCE phantom and in terms of goodness-of-fit (Kolmogorov-Smirnov test) on ROI-based concentration time courses from two different patient cohorts. The first cohort consisted of 76 men, 20 of whom had significant peripheral zone prostate cancer (any cancer-core-length (CCL) with Gleason > 3 + 3 or any-grade with CCL > = 4 mm) following transperineal template prostate mapping biopsy. The second cohort consisted of 9 healthy volunteers and 24 patients with head and neck squamous cell carcinoma. The diagnostic ability of the derived tracer kinetics was assessed with receiver operating characteristic area under curve (ROC AUC) analysis. The Bayesian algorithm accurately recovered the ground-truth tracer kinetics for the digital DCE phantom consistently improving the Structural Similarity Index (SSIM) across the 50 different initializations compared to NR. For optimized initialization, Bayesian did not improve significantly the fitting accuracy on both patient cohorts, and it only significantly improved the v e ROC AUC on the HN population from ROC AUC = 0.56 for the simplex to ROC AUC = 0.76. For both cohorts, the values and the diagnostic ability of tracer kinetic parameters estimated with the Bayesian algorithm weren’t affected by their initialization. To conclude, the Bayesian algorithm led to a more accurate and reproducible quantification of tracer kinetic parameters in DCE-MRI, improving their ROC-AUC and decreasing their dependence on initialization settings. [ABSTRACT FROM AUTHOR]

Background: Photochemical internalisation, a novel minimally invasive treatment, has shown promising preclinical results in enhancing and site-directing the effect of anticancer drugs by illumination, which initiates localised chemotherapy release. We assessed the safety and tolerability of a newly developed photosensitiser, disulfonated tetraphenyl chlorin (TPCS2a), in mediating photochemical internalisation of bleomycin in patients with advanced and recurrent solid malignancies.Methods: In this phase 1, dose-escalation, first-in-man trial, we recruited patients (aged ≥18 to <85 years) with local recurrent, advanced, or metastatic cutaneous or subcutaneous malignancies who were clinically assessed as eligible for bleomycin chemotherapy from a single centre in the UK. Patients were given TPCS2a on day 0 by slow intravenous injection, followed by a fixed dose of 15 000 IU/m(2) bleomycin by intravenous infusion on day 4. After 3 h, the surface of the target tumour was illuminated with 652 nm laser light (fixed at 60 J/cm(2)). The TPCS2a starting dose was 0·25 mg/kg and was then escalated in successive dose cohorts of three patients (0·5, 1·0, and 1·5 mg/kg). The primary endpoints were safety and tolerability of TPCS2a; other co-primary endpoints were dose-limiting toxicity and maximum tolerated dose. The primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00993512, and has been completed.Findings: Between Oct 3, 2009, and Jan 14, 2014, we recruited 22 patients into the trial. 12 patients completed the 3-month follow-up period. Adverse events related to photochemical internalisation were either local, resulting from the local inflammatory process, or systemic, mostly as a result of the skin-photosensitising effect of TPCS2a. The most common grade 3 or worse adverse events were unexpected higher transient pain response (grade 3) localised to the treatment site recorded in nine patients, and respiratory failure (grade 4) noted in two patients. One dose-limiting toxicity was reported in the 1·0 mg/kg cohort (skin photosensitivity [grade 2]). Dose-limiting toxicities were reported in two of three patients at a TPCS2a dose of 1·5 mg/kg (skin photosensitivity [grade 3] and wound infection [grade 3]); thus, the maximum tolerated dose of TPCS2a was 1·0 mg/kg. Administration of TPCS2a was found to be safe and tolerable by all patients. No deaths related to photochemical internalisation treatment occurred.Interpretation: TPCS2a-mediated photochemical internalisation of bleomycin is safe and tolerable. We identified TPCS2a 0·25 mg/kg as the recommended treatment dose for future trials.Funding: PCI Biotech. [ABSTRACT FROM AUTHOR]

Summary: Background: Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. Methods: In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov, NCT00749502. Findings: Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8–46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% [95% CI 19–64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7–93]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. Interpretation: A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. Funding: Merck Sharp and Dohme. [ABSTRACT FROM AUTHOR]

Child abuse is a world-wide problem causing long-term suffering for children and large costs to society. Parent-training programs have been shown to reduce harsh parenting but more research on parenting programs specifically addressing child abuse is needed. This study aimed at assessing the feasibility, implementation, and preliminary effectiveness of Safer Kids (SK); a structured parent-training program delivered immediately after parents are reported for child abuse. Caregivers were eligible if they had been reported for child abuse to the Swedish social services and their child was 3–12 years old. Families were allocated to SK or intervention as usual (IAU) through a quasi-experimental design. Multilevel analyses and a Cox Proportional Hazard Model were used to assess between-group differences in risk factors for abuse and further child welfare reports. In total, 67 families participated. SK was successfully implemented as an early-start intervention and most families completed the intervention. All agencies continued working with SK two years after the study, indicating sustainability of implementation. SK was more effective than IAU in reducing further child welfare reports up to 18 months from baseline. However, analyses of parent and child rated risk factors of re-abuse (abuse potential, wellbeing, and parent-child relationships) indicate none to small differences between conditions. SK can be successfully implemented within the social services and may be effective in reducing occurrence of further child welfare reports. The effects of SK need to be further evaluated in a randomized controlled trial. • Research on child abuse interventions is highly needed. • Safer Kids is a parenting program delivered quickly after a report of child abuse. • The intervention was successfully implemented within the social services. • Safer Kids -parents were reported again to a lower extent than control group families. • The effects of Safer Kids need to be further evaluated in larger trials. [ABSTRACT FROM AUTHOR]