Citations

Abstract BRCA1 and BRCA2 (BRCA) testing is uninformative in approximately 80% of families with clinical features of inherited susceptibility to breast cancer. Early identification of the individuals at risk in BRCAx families may lead to enhanced screening and prevention strategies, and potentially improved overall survival as has been seen for carriers of BRCA1/2 mutations. A proportion of these families are likely explained by mutations in other high penetrance and moderate penetrance breast cancer susceptibility genes. Although multi-gene panels are now commercially available for clinical testing, only limited information is available on the spectrum of mutations in breast cancer susceptibility genes in specific subgroups of high-risk breast cancer patients. We performed whole exome sequencing in 278 BRCA1/2 negative individuals with high-risk familial breast cancer, defined as a proband and at least two first or second degree relatives with breast cancer. Samples included 232 individuals from 97 families and 49 unrelated individuals, for a total of 146 independent cases. Data were analyzed for identification of all variants in 18 known high and moderate penetrance breast cancer susceptibility genes, in addition to BRCA1 and BRCA2. Two of the 97 families and one of the 49 singletons (2% of independent cases) were found to have deleterious mutations in high penetrance genes, namely TP53 (2) and CDH1 (1). In addition, nine of 146 independent cases (6%) were found to have deleterious mutations in the other predisposition genes. Mutations in ATM and CHEK2 accounted for seven of the ten moderate penetrance mutations identified; additionally one family had a mutation in BLM, one in MRE11A, and one in PALB2. Furthermore, 15 of 146 independent cases (10%) were found to have variants of unknown significance (VUS) in one of eight genes. There were no deleterious mutations or VUS in eight of the 18 genes. Our data show that significant genetic heterogeneity exists in BRCAx families. Large-scale collaborative efforts will be required to attain sufficient power to understand how to appropriately apply these results clinically in cancer risk evaluation. Citation Format: Kara N. Maxwell, Lucia Guidugli, Kasmintan Schrader, Steven Hart, Vijai Joseph, Tinu Thomas, Xianshu Wang, Bradley Wubbenhorst, Robert Klein, Susan M. Domchek, Csilla Szabo, Susan Neuhausen, Jeffrey Weitzel, Katherine L. Nathanson, Kenneth Offit, Fergus Couch. High and moderate penetrance germline mutations in a number of genes are responsible for a small proportion of familial breast cancer risk in BRCAx families. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1291. doi:10.1158/1538-7445.AM2014-1291

OBJECT Resection can sometimes offer the best chance of meaningful seizure reduction in children with medically intractable epilepsy. However, when surgery fails to achieve the desired outcome, reoperation may be an option. The authors sought to investigate outcomes following resective reoperation in pediatric patients with refractory epilepsy, excluding tumoral epilepsies. Differences in preoperative workup between surgeries are analyzed to identify factors influencing outcomes and complications in this complex group. METHODS Medical records were reviewed for all pediatric patients undergoing a repeat resective surgery for refractory epilepsy at the authors' institution between 2005 and 2012. Tumor and vascular etiologies were excluded. Preoperative evaluation and outcomes were analyzed for each surgery and compared. RESULTS Ten patients met all inclusion criteria. The median age at seizure onset was 4.5 months. Preoperative MRI revealed no lesion in 30%. Nonspecific gliosis and cortical dysplasia were the most common pathologies. The majority of preoperative workups included MRI, video-electroencephalography (EEG), and SISCOM. Intracranial EEG was performed for 60% for the first presurgical evaluation and 70% for the second evaluation. The goal of surgery was palliative in 4 patients with widespread cortical dysplasia. The final Engel outcome was Class I in 50%. The rate of favorable outcome (Engel Class I–II) was 70%. The complication rate for the initial surgery was 10%. However, the rate increased to 50% with the second surgery, and 3 of these 5 complications were pseudomeningoceles requiring shunt placement (2 of the 3 patients underwent hemispherotomy). CONCLUSIONS Resective reoperation for pediatric refractory epilepsy has a high rate of favorable outcome and should be considered in appropriate candidates, even as a palliative measure. Intracranial EEG monitoring should be considered on initial workup in cases where the results of imaging or EEG studies are ambiguous or conflicting. Epilepsy secondary to cortical dysplasia, especially if the dysplasia is not seen clearly on MRI, can be difficult to cure surgically. Therefore, in these cases, as large a resection as can be safely accomplished should be done, particularly when the goal is palliative. The rate of complications, particularly pseudomeningocele ultimately requiring shunt placement, is much higher following reoperation, and patients should be counseled accordingly.

Abstract Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4–5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation. Clin Cancer Res; 21(12); 2722–9. ©2015 AACR. See related article by Paoletti et al., p. 2771

Summary Objective To prospectively evaluate the etiology of new‐onset infantile spasms and evaluate the yield of genetic and metabolic investigations in those without obvious cause after initial clinical evaluation and magnetic resonance imaging ( MRI ). Methods Twenty‐one U.S. pediatric epilepsy centers prospectively enrolled infants with newly diagnosed West syndrome in a central database. Etiology and investigations performed within 3 months of diagnosis were documented. Results From June 2012 to June 2014, a total of 251 infants were enrolled (53% male). A cause was identified in 161 (64.4%) of 250 cases (genetic,14.4%; genetic‐structural, 10.0%; structural‐congenital, 10.8%; structural‐acquired, 22.4%; metabolic, 4.8%; and infectious, 2.0%). An obvious cause was found after initial clinical assessment (history and physical examination) and/or MRI in 138 of 161, whereas further genetic and metabolic studies were revealing in another 23 cases. Of 112 subjects without an obvious cause after initial evaluation and MRI , 81 (72.3%) had undergone genetic testing, which showed a causal abnormality in 23.5% and a variant of unknown significance in 14.8%. Although metabolic studies were done in the majority (serum, 79.5%; urine, 69.6%; and cerebrospinal fluid [ CSF ], 38.4%), these revealed an etiology in only five cases (4.5%). No correlation was found between type of health insurance (public vs. private) and either genetic or metabolic testing. Significance Clinical evaluation and MRI provide a specific diagnosis in 55% of children presenting with West syndrome. We propose that a cost‐effective workup for those without obvious cause after initial clinical evaluation and MRI includes an array comparative genomic hybridization ( aCGH ) followed by an epilepsy gene panel if the microarray is not definitive, serum lactate, serum amino acids, and urine organic acids.

Objectives The objective of this study was to evaluate the problem of multiple chronic conditions and polypharmacy in patients with fibromyalgia. Design Retrospective medical record review. Setting Olmsted County, Minnesota. Participants 1111 adults with fibromyalgia. Primary and secondary outcome measures Number and type of chronic medical and psychiatric conditions, medication use. Results Medical record review demonstrated that greater than 50% of the sample had seven or more chronic conditions. Chronic joint pain/degenerative arthritis was the most frequent comorbidity (88.7%), followed by depression (75.1%), migraines/chronic headaches (62.4%) and anxiety (56.5%). Approximately, 40% of patients were taking three or more medications for symptoms of fibromyalgia. Sleep aids were the most commonly prescribed medications in our sample (33.3%) followed by selective serotonin reuptake inhibitors (28.7%), opioids (22.4%) and serotonin norepinephrine reuptake inhibitors (21.0%). Conclusions The results of our study highlight the problem of multiple chronic conditions and high prevalence of polypharmacy in fibromyalgia. Clinicians who care for patients with fibromyalgia should take into consideration the presence of multiple chronic conditions when recommending medications.

This article experiments with the dialogic epistolary form as a non-traditional representation of ethnographic research on the topic of breastmilk donation. The epistolary genre was chosen because its structure, purpose, and history embodies the key findings of this research, for example, the gulf between milk donors and recipients and the curiosity held by each for the other. The article argues that the dialogic epistolary form provides a more engaging, expansive, and expressive account of the researcher’s role in the ethnographic research process than that offered by traditional academic genres. The article presents research findings in the epistolary form, which provides an accessible and novel presentation of research by inviting readers to occupy the position of both the milk donor and the donor milk recipient. The letters can be used as a resource by health professionals and communities involved in human milk donation or the use of donor milk. The letters are accompanied by an exegesis which offers ethnographers an account of the epistolary genre as a non-traditional form of research representation.

SummarySixty‐four transplant‐eligible patients with newly diagnosed multiple myeloma (NDMM) received carfilzomib (days 1, 2, 8, 9, 15, 16), 300 mg/m2 cyclophosphamide (days 1, 8, 15), 100 mg thalidomide (days 1–28) and 40 mg dexamethasone (days 1, 8, 15, 22) in 28‐day cycles (CYKLONE regimen). Carfilzomib was dose‐escalated to 15/20, 20/27, 20/36 and 20/45 mg/m2 to determine the maximum tolerated dose (MTD), which was 20/36 mg/m2. Regardless of attribution, common Grade 3 or higher adverse events were lymphopenia (38%), neutropenia (23%) and anaemia (20%). All peripheral neuropathy (31%) was Grade 1 and considered most likely to be thalidomide‐related. Common cardiac or pulmonary events of any grade in ≥5% of patients included dyspnoea (20%) and cough (6%). Overall (N = 64), 91% of patients achieved a best response of partial response or better across all cycles of treatment, including five patients with complete responses. At the MTD (n = 29), 59% of patients achieved a very good partial response or better after four cycles (primary end point). Stem cell collection was successful in all patients in whom it was attempted (n = 42). Progression‐free survival and overall survival at 24 months was 76% and 96%, respectively (median follow‐up of 17·5 months). CYKLONE appears highly efficacious in NDMM patients, with manageable toxicities.

Aims and ObjectivesThis paper explores patients' perspectives on infection prevention and control.BackgroundHealthcare‐associated infections are the most frequent adverse event experienced by patients. Reduction strategies have predominantly addressed front‐line clinicians' practices; patients' roles have been less explored.DesignVideo‐reflexive ethnography.MethodsFieldwork undertaken at a large metropolitan hospital in Australia involved 300 hours of ethnographic observations, including 11 hours of video footage. This paper focuses on eight occasions, where video footage was shown back to patients in one‐on‐one reflexive sessions.FindingsViewing and discussing video footage of clinical care enabled patients to become articulate about infection risks, and to identify their own roles in reducing transmission. Barriers to detailed understandings of preventative practices and their roles included lack of conversation between patients and clinicians about infection prevention and control, and being ignored or contradicted when challenging perceived suboptimal practice. It became evident that to compensate for clinicians' lack of engagement around infection control, participants had developed a range of strategies, of variable effectiveness, to protect themselves and others. Finally, the reflexive process engendered closer scrutiny and a more critical attitude to infection control that increased patients' sense of agency.ConclusionThis study found that patients actively contribute to their own safety. Their success, however, depends on the quality of patient–provider relationships and conversations. Rather than treating patients as passive recipients of infection control practices, clinicians can support and engage with patients' contributions towards achieving safer care.Relevance to clinical practiceThis study suggests that if clinicians seek to reduce infection rates, they must start to consider patients as active contributors to infection control. Clinicians can engage patients in conversations about practices and pay attention to patient feedback about infection risk. This will broaden clinicians' understandings of infection control risks and behaviours, and assist them to support appropriate patient self‐care behaviour.

Abstract Purpose: To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors. Experimental Design: Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation. Results: Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4–5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration–time profile for PF-05212384 (half-life, 30–37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies. Conclusions: These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies. Clin Cancer Res; 21(8); 1888–95. ©2015 AACR.