Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022.

BACKGROUND: Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. CONCLUSIONS: We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.

Cutaneous sequelae of a national health crisis: Obesity and the skin.

Background: The global obesity pandemic has far-reaching health consequences and has become a major global health challenge. The worldwide prevalence of obesity nearly doubled between 1980 and 2008 and based on the latest estimates in the European Union, obesity affects up to 30% of adults. As a consequence of this rising prevalence of obesity, there has been an increase in the frequency of certain disease of the skin. Objectives: We review the cutaneous sequelae of obesity, firstly describing the physiological consequences of increased adiposity in the skin and secondly examining the dermatoses associated with obesity.

Could isotretinoin flare hidradenitis suppurativa? A case series.

We report eight cases of patients with severe acne who were treated with isotretinoin and developed painful nodules in the axillae and groin, consistent with hidradenitis suppurativa (HS). The pathogenesis of HS is still not completely understood; recent research from a study in 2011 of biopsies from HS lesions showed a reduction or absence of sebaceous glands compared with normal skin in patients with HS, with the report suggesting that this contributes to the pathogenesis of the disease. Interestingly, the main effect of isotretinoin is to decrease the size and action of sebaceous glands, so hypothetically, as isotretinoin acts by reducing the sebaceous glands further it could potentially aggravate HS. Our experience has instilled caution in our prescribing of isotretinoin, and we question patients, particularly those with acne conglobata, about symptoms of HS prior to and during treatment.

Stochastic partial differential fluid equations as a diffusive limit of deterministic Lagrangian multi-time dynamics.

In Holm (Holm 2015 Proc. R. Soc. A471, 20140963. (doi:10.1098/rspa.2014.0963)), stochastic fluid equations were derived by employing a variational principle with an assumed stochastic Lagrangian particle dynamics. Here we show that the same stochastic Lagrangian dynamics naturally arises in a multi-scale decomposition of the deterministic Lagrangian flow map into a slow large-scale mean and a rapidly fluctuating small-scale map. We employ homogenization theory to derive effective slow stochastic particle dynamics for the resolved mean part, thereby obtaining stochastic fluid partial equations in the Eulerian formulation. To justify the application of rigorous homogenization theory, we assume mildly chaotic fast small-scale dynamics, as well as a centring condition. The latter requires that the mean of the fluctuating deviations is small, when pulled back to the mean flow.

Quality of information about maxillofacial trauma on the Internet.

Patients increasingly search the Internet for information about health and potential treatments, but the content and accuracy of some websites are questionable. To evaluate the quality of information on maxillofacial trauma, we searched for the terms "jaw fracture" and "cheekbone fracture" on Google, Yahoo, and Bing. We assessed the first 10 results of each search and excluded duplicates or those that were unrelated. We then used the DISCERN tool and the JAMA (Journal of the American Medical Association) benchmarks to assess those that remained. Of the original 60 found, 38 were excluded (29 duplicates, 9 unrelated). The mean (range) DISCERN score for each search was 38.5 (27-57) for jaw fracture and 41.9 (26-61) for cheekbone fracture. No website achieved an excellent score (more than 63), and over three-quarters were categorised as poor (27-38) or fair (39-50). None met all the JAMA benchmarks, but most adhered to at least two. The standard of online information on maxillofacial trauma varies, but is generally of poor quality. Patients should therefore be advised to be cautious of online sources and should be directed towards higher-quality websites.

Medical students' understanding of oral and maxillofacial surgery: an Irish perspective.

Oral and Maxillofacial Surgery (OMFS) remains an enigmatic specialty in Irish medicine and many students are unaware of its scope and the unique career pathway involved. We completed a multicentre cross-sectional study to identify their ability to identify the requirements for entry to specialty training year 3 (ST3) in OMFS, to assess their awareness of OMFS surgeons, and their general awareness of, and exposure to, the specialty. Data were collected through an electronic questionnaire. Participants were asked to select the most suitable surgical specialty to treat a number of common conditions in the head and neck, and to choose the requirements they deemed essential for specialist training. Knowledge was measured by the number of correct responses. A total of 443 medical students participated (University College Cork (UCC) n=328, 74%; Royal College of Surgeons in Ireland (RCSI) n=113, 26%). A total of 318/374 (85%) had had no previous experience of OMFS, 38/374 (10%) had had theoretical teaching only, and 18/374 (5%) had had clinical experience. A total of 212/329 (64%) wished for greater exposure as a student, but only 34/329 (9%) would consider a career in the specialty. The median (IQR) number of correct responses for OMFS procedures was 3.0/10 (2.0), with women, direct entrants, and RCSI students scoring highest. Only 11/367 (3%) could identify the minimum entry requirements for a post of specialist registrar. This study has identified a potential gap in the undergraduate curriculum. Although medical students are rarely taught about OMFS, they show an interest in learning more.

Young children with cerebral palsy: families self-reported equipment needs and out-of-pocket expenditure.

BACKGROUND: Costs to families raising a child with cerebral palsy and complex needs are direct and indirect. This study investigated the self-reported real-life costs, equipment needs, and associated characteristics of children who had the highest equipment and care needs. METHOD: The purposive sample (n = 29) were families with a child with cerebral palsy: gross motor function levels 5 (n = 20), level 4 (n = 5), level 3 (n = 4); complex communication needs (n = 21); medical needs (n = 14); hearing impairment (n = 5) and visual impairment (n = 9). Participants completed a specifically designed survey that included the Assistance to Participate Scale. Equipment and technology purchases were recorded in the areas of positioning, mobility, transport, home modifications, communication, splinting and orthoses, self-care, technology, communication devices, medical, adapted toys/leisure items and privately hired babysitters/carers. Descriptive and inferential statistics were used to analyse the data. RESULTS: Families had purchased up to 25 items within the areas described. The highest median number of items were recorded for positioning (15 items), mobility devices (9 items) and adapted toys/leisure items (9 items). Median costs were highest for home modifications (AUD$23000), transport (AUD$15000), splints and orthoses (AUD$3145), paid carers (AUD$3080), equipment for toileting/dressing/bathing (AUD$2900) and technical/medical items ($2380). Children who needed more parental assistance to participate in play and recreation also required significantly more equipment overall for positioning, communication, self-care and toys/leisure. CONCLUSIONS: The equipment needs of young children with complex disability are extensive and out-of-pocket expenses and parental time to support participation in play/recreation excessive. Substantial financial support to offset costs are crucial to better support families in this life situation.

Functional conservation of nucleosome formation selectively biases presumably neutral molecular variation in yeast genomes.

One prominent pattern of mutational frequency, long appreciated in comparative genomics, is the bias of purine/pyrimidine conserving substitutions (transitions) over purine/pyrimidine altering substitutions (transversions). Traditionally, this transitional bias has been thought to be driven by the underlying rates of DNA mutation and/or repair. However, recent sequencing studies of mutation accumulation lines in model organisms demonstrate that substitutions generally do not accumulate at rates that would indicate a transitional bias. These observations have called into question a very basic assumption of molecular evolution; that naturally occurring patterns of molecular variation in noncoding regions accurately reflect the underlying processes of randomly accumulating neutral mutation in nuclear genomes. Here, in Saccharomyces yeasts, we report a very strong inverse association (r = -0.951, P < 0.004) between the genome-wide frequency of substitutions and their average energetic effect on nucleosome formation, as predicted by a structurally based energy model of DNA deformation around the nucleosome core. We find that transitions occurring at sites positioned nearest the nucleosome surface, which are believed to function most importantly in nucleosome formation, alter the deformation energy of DNA to the nucleosome core by only a fraction of the energy changes typical of most transversions. When we examined the same substitutions set against random background sequences as well as an existing study reporting substitutions arising in mutation accumulation lines of Saccharomyces cerevisiae, we failed to find a similar relationship. These results support the idea that natural selection acting to functionally conserve chromatin organization may contribute significantly to genome-wide transitional bias, even in noncoding regions. Because nucleosome core structure is highly conserved across eukaryotes, our observations may also help to further explain locally elevated transition bias at CpG islands, which are known to destabilize nucleosomes at vertebrate promoters.

The use of zolpidem in the treatment of progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a debilitating progressive neurodegenerative disorder for which there is no proven pharmacological treatment. Zolpidem immediate release formulation has been reported to show short-term improvements in motor function and voluntary saccadic eye movements, but the benefits were not sustained. A 61-year-old man with a 4-year history of PSP was observed over 6 months to have sustained improvement in motor function, pseudobulbar symptoms and ocular motility 2 months after commencing zolpidem controlled release (CR) formulation. He was admitted to hospital and a detailed neurological and functional assessment recorded on video after withdrawal of zolpidem CR, and again following re-introduction of the medication. Within 1 hour of administration of 25mg zolpidem CR the patient had a dramatic improvement in fine motor skills, dexterity, speed and fluidity of movement, facial and vocal expression, oropharyngeal coordination and function and pursuit, and voluntary saccadic eye movements. These improvements were observed for 4 hours to 5 hours post-dose and were reproducible on subsequent withdrawal and re-challenging. We found that zolpidem CR, a gamma aminobutryic acid (GABA)ergic agonist of the benzodiazepine type 1 receptor, caused sustained improvement in motor and ocular symptoms in a patient with PSP over 6 months. Further studies are needed to determine the potential roles of GABA neurotransmission in PSP.