Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

BACKGROUND: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. PATIENTS AND METHODS: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. ELIGIBILITY CRITERIA: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. RESULTS: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10-4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. CONCLUSIONS: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Interventions for cancer-related fatigue: a scoping review.

Cancer-related fatigue (CRF) is common and can be distressing for some survivors. There is increasing interest in measuring levels of CRF, highlighting its impact on quality of life. This review describes the nature and scope of evidence relating to interventions for CRF. Scoping review methodology was used to identify studies, extract data, collate and summarise results. Data were collated according to cancer tumour streams, stage of illness and the types of trial interventions. A total of 447 trials and 37 systematic reviews met the inclusion criteria. Nine papers reported longitudinal results. Populations studied were predominantly of mixed cancer diagnoses and breast cancer. The most frequent interventions were exercise, pharmacological, psycho-education and mind-body interventions. Fatigue was identified as a primary outcome measure (OM) in 58% of studies, with 58 different fatigue measures reported. Emerging evidence exists for the effectiveness of fatigue interventions for some cancer types. More research on interventions with participants with the same cancer type and illness phase is needed. Measurement of severity and impact of CRF using fewer, robust OMs will permit comparisons across studies.

The Clinical Utility of Next Generation Sequencing Results in a Community-Based Hereditary Cancer Risk Program.

Since the 2013 Supreme Court ruling on BRCA1/BRCA2 patenting, hereditary cancer gene panels now include BRCA1 and BRCA2, making these panels an option for first-tier testing. However, questions remain about the clinical utility and implications of these panels for medical management with inclusion of genes of unknown to moderate penetrance. To better understand how use of these panels affected our practice, we reviewed patients who underwent testing in our clinic from July 1, 2013 through May 23, 2014. Indications for testing included personal and/or family history of breast and/or ovarian cancer. A total of 136 patients underwent panel testing via a single commercial laboratory; 12 (8.8 %) patients were positive for a pathogenic or likely pathogenic mutation (four BRCA2 mutations, two TP53 mutations, one CDH1 mutation, two ATM mutations, and one patient each with a CHEK2, NBN, or PALB2 mutation). Of these positive patients, 100 % met the National Comprehensive Cancer Network (NCCN) guidelines for Hereditary Breast and Ovarian Cancer genetic testing (2.2014). Mutations in seven of twelve (58 %) patients led to changes in medical management; three of seven (43 %) had a non-BRCA1 or BRCA2 gene mutation. Our findings suggest that there is clinical utility of panels that include genes of unknown to moderate penetrance.

Recessive mutations in the cancer gene Ataxia Telangiectasia Mutated (ATM), at a locus previously associated with metformin response, cause dysglycaemia and insulin resistance.

AIM: To investigate glucose and insulin metabolism in participants with ataxia telangiectasia in the absence of a diagnosis of diabetes. METHODS: A standard oral glucose tolerance test was performed in participants with ataxia telangiectasia (n = 10) and in a control cohort (n = 10). Serial glucose and insulin measurements were taken to permit cohort comparisons of glucose-insulin homeostasis and indices of insulin secretion and sensitivity. RESULTS: During the oral glucose tolerance test, the 2-h glucose (6.75 vs 4.93 mmol/l; P = 0.029), insulin concentrations (285.6 vs 148.5 pmol/l; P = 0.043), incremental area under the curve for glucose (314 vs 161 mmol/l/min; P = 0.036) and incremental area under the curve for insulin (37,720 vs 18,080 pmol/l/min; P = 0.03) were higher in participants with ataxia telangiectasia than in the controls. There were no significant differences between groups in fasting glucose, insulin concentrations or insulinogenic index measurement (0.94 vs 0.95; P = 0.95). The Matsuda index, reflecting whole-body insulin sensitivity, was lower in participants with ataxia telangiectasia (5.96 vs 11.03; P = 0.019) than in control subjects. CONCLUSIONS: Mutations in Ataxia Telangiectasia Mutated (ATM) that cause ataxia telangiectasia are associated with elevated glycaemia and low insulin sensitivity in participants without diabetes. This indicates a role of ATM in glucose and insulin metabolic pathways.

Interventional oncology for liver and lung metastases from colorectal cancer: The current state of the art.

Interventional oncology is developing rapidly as a result of advances in imaging and medical devices. Although the treatments offered are recent and not yet fully validated in the guidelines, they allow non-invasive curative treatments to be offered to a growing number of patients. When it is used in a highly selected patients with less than three metastases under 2-3cm in size, percutaneous tumor ablation offers local efficacy similar to excision surgery with considerable sparing of the parenchyma, both for lung and liver metastases. Hepatic intra-arterial therapies (chemotherapy, radioembolization, and chemoembolization) are now "salvage" methods after chemotherapy has failed and are being assessed in earlier lines of treatment.

Survey of patient satisfaction after Doppler-guided transanal hemorrhoidal dearterialization performed in ambulatory settings.

BACKGROUND: Transanal hemorrhoidal dearterialization (THD) is a recently developed procedure to minimize postoperative pain from hemorrhoidectomy. This technique utilizes Doppler signals to aid ligation of hemorrhoidal arteries followed by mucopexy of redundant mucosa if needed. The aim of the present study was to assess patient satisfaction after THD. METHODS: This is a retrospective cohort study of patients who underwent THD at three different sites from April 2007 through October 2010. All procedures were performed in ambulatory settings according to protocol. Telephone surveys were conducted after a minimum of 1-month follow-up to assess patients' satisfaction on a scale of 1-10. Patients were asked whether the procedure had alleviated their symptoms. Patients were asked to recall duration of pain and time from surgery to return to work. RESULTS: Between April 2007 and October 2010, 216 patients with grade III-IV hemorrhoids underwent THD. There were 165 males and 61 females. Average age was 52.2 ± 14.2 years. All patients were discharged the same day after meeting ambulatory surgery center discharge criteria. Postoperative difficulty urinating occurred in 37 (17 %) patients, and six of them required temporary urinary catheterization. Transitory postoperative bleeding was reported by 38 (18 %) patients. Transitory incontinence to stool and flatus occurred in 18 (9 %) and 16 patients (8 %), respectively. Pelvic muscle spasms occurred in 21 (10 %) patients. Median follow-up was 23 months (range 1-42 months) with 143 (66 %) having at least 9 months between procedure and interview. Mean patient satisfaction was 8.5 ± 0.7 (on a scale of 1-10 with 10 being the best), and 91.5 % of patients felt the procedure had "helped" them. Average number of days with discomfort was 6.7 ± 2.1. Patients returned to work after an average of 10.3 ± 3.2 days. Our study is limited by lack of long-term follow-up and by retrospective complication assessment. CONCLUSIONS: Patient satisfaction with THD performed in ambulatory settings is high. Our data support performance of this procedure in an ambulatory setting.

A framework for rehabilitation for cancer survivors.

This paper introduces a theoretical framework that recognises the rehabilitation needs of people who have cancer and offers a multi-tiered model to meet these needs. Various models for providing survivorship care have been previously proposed, giving rise to multiple possible delivery systems. Existing cancer rehabilitation frameworks recognise different phases of illness, goals of care and the need for services at all stages of illness. The 'Stained Glass Cancer Rehabilitation Framework' incorporates survivor needs and rehabilitation modalities, arranged in a practical hierarchy and builds on earlier models. A broad view of rehabilitation services considers complexity, temporal and geographic factors. Recognition that needs emerge over time demands a routine long-term approach to screening for physical, functional and psychosocial rehabilitation needs by medical and other health professionals. New methods of care delivery and coordination from specialist to primary care settings are needed, long after treatment is completed. Service delivery infrastructure supported by funding reform and training of rehabilitation professionals in delivering appropriate interventions for cancer survivors is essential, together with more research into cancer rehabilitation interventions, functional outcomes and their delivery.

Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs.

AIMS/HYPOTHESIS: Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes. METHODS: Using a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999-2008. RESULTS: There were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28; p = 3 × 10(-5)), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%). CONCLUSIONS/INTERPRETATION: Hip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.

Common nonsynonymous substitutions in SLCO1B1 predispose to statin intolerance in routinely treated individuals with type 2 diabetes: a go-DARTS study.

SLCO1B1 gene variants are associated with severe statin-induced myopathy. We examined whether these variants are also associated with general statin intolerance in a large population of patients with type 2 diabetes receiving statins as part of routine clinical care. A total of 4,196 individuals were genotyped for rs4149056 (Val174Ala) and rs2306283 (Asp130Asn). Intolerance was defined by serum biochemistry and also by discontinuation, switching, or reduction in dose of the prescribed statin drug. Ala174 was associated with higher intolerance (odds ratio = 2.05, P = 0.043), whereas Asp130 was associated with lower intolerance (odds ratio = 0.71, P = 0.026). Ala174 was associated with a lower low-density lipoprotein cholesterol (LDLc) response to statins (P = 0.01) whereas 130D was associated with a greater LDLc response to statins (P = 0.048), as previously reported; however, this association was no longer present when data for statin-intolerant individuals were removed from the analysis. This study suggests that common genetic variants selected for an extreme phenotype of statin-induced myopathy also predispose to more common milder statin intolerance and may, for this reason, impact lipid-lowering efficacy.

Increased all-cause and cardiovascular mortality in monogenic diabetes as a result of mutations in the HNF1A gene.

AIMS: To investigate all-cause and cardiovascular mortality in subjects with diabetes caused by a mutation in the hepatocyte nuclear factor 1alpha gene (HNF1A). METHODS: We identified 39 British families with HNF1A mutations. Consenting individuals were asked details of age and cause of death of parents and siblings. Copies of death certificates were requested from the family or were obtained via the Offices for National Statistics. RESULTS: Data were collated on 241 control subjects and 153 mutation carriers. Of those who died, 66% of mutation carriers died from a cardiovascular-related illness compared with 43% of control subjects (P = 0.02). Family members with HNF1A mutations died at a younger age than familial control subjects [all-cause hazard ratio, adjusting for sex and smoking status: 1.9 (95% confidence interval 1.2, 2.9, P = 0.006; cardiovascular hazard ratio: 2.3, confidence interval 1.3, 4.2, P = 0.006)]. CONCLUSIONS: We have shown that individuals known to have diabetes caused by a mutation in the HNF1A gene have an increased risk of cardiovascular mortality compared with their unaffected family members. As with other forms of diabetes, consideration should be given to early statin therapy despite a seemingly protective lipid profile.

Adenosine A1 receptor, a target and regulator of estrogen receptoralpha action, mediates the proliferative effects of estradiol in breast cancer.

Estrogen receptor-alpha (ERalpha) and its ligand estradiol (E2) has critical roles in breast cancer growth and are key therapeutic targets. In this study, we report a novel dual role of the adenosine A1 receptor (Adora1) as an E2/ERalpha target and a regulator of ERalpha transcriptional activity. In ERalpha-positive breast cancer cells, E2 upregulated Adora1 messenger RNA (mRNA) and protein levels, an effect that was reversed by the E2 antagonist ICI 182 780. Small interference RNA ablation of Adora1 in ERalpha-positive cells reduced basal and E2-dependent proliferation, whereas Adora1 over-expression in an ERalpha-negative cell line induced proliferation. The selective Adora1 antagonist, DPCPX, reduced proliferation, establishing Adora1 as a mediator of E2/ERalpha-dependent breast cancer growth. Intriguingly, Adora1 ablation decreased both mRNA and protein levels of ERalpha and, consequently, estrogen-responsive element-dependent ERalpha transcriptional activity. Moreover, Adora1 ablation decreased binding activity of ERalpha to the promoter of its target gene TFF1 and led to reduced TFF1 promoter activity and mRNA levels, suggesting that Adora1 is required for full transcriptional activity of ERalpha on E2 stimulation. Taken together, we showed a short feed-forward loop involving E2, ERalpha and Adora1 that favors breast cancer growth. These data suggest that Adora1 may represent an important target for therapeutic intervention in hormone-dependent breast cancer.

Development of a nurse-led skin camouflage clinic.

This article outlines the development of an outpatient skin camouflage service and summarises findings from an audit of the service after one year, which resulted in the clinic expanding to a monthly all-day session.

Early and late morbidity after vasectomy: a comparison of chronic scrotal pain at 1 and 10 years.

OBJECTIVE: To evaluate the incidence and timing of the onset of chronic scrotal pain after vasectomy in two populations at 1 and 10 years after surgery. PATIENTS AND METHODS: In a retrospective questionnaire-based study two groups of men were compared; 460 who had a vasectomy in 1991-92 (group A) and another 460 who had a vasectomy in 2000-1 (group B; 10 and 1 year after surgery, respectively). Data were collected on immediate complications, and the incidence and nature of chronic scrotal pain. Pain severity was graded using a visual analogue score (VAS). Patients were also asked if they regretted having a vasectomy because of pain. RESULTS: In all, 182 and 220 replies were received from patients in group A and B, respectively. Early complications included haematoma in five (2%) and two (0.9%) patients, respectively, and wound infection in 24 (13%) and 17 (7.7%). Eight patients who had scrotal pain even before vasectomy were excluded from the analysis (two in group A and six in group B). In group A, 25 of 180 (13.8%) had a new onset of scrotal pain of some nature, with eight (4.3%) having a VAS of > 5; one patient had an epididymectomy for this. Three of the 25 regretted having a vasectomy because of pain. In group B, 36 of 214 (16.8%) reported persistent scrotal pain, with 13 (5.9%) having a VAS of > 5. Six of the 36 regretted having a vasectomy because of the pain. The incidence of scrotal pain was not significantly different between the groups (P = 0.48, Fisher's exact test). CONCLUSION: Chronic scrotal pain after vasectomy is more common than previously described, affecting almost one in seven patients. All patients undergoing vasectomy must receive appropriate preoperative counselling about this. The incidence of this complication does not appear to increase with time.

Partner's influence on patient preference for treatment in early prostate cancer.

OBJECTIVE: To determine the partner's influence on the patient's choice of treatment for early prostate cancer, and whether partner characteristics and biases predict the preference. PATIENTS, SUBJECTS AND METHODS: Questionnaires for partners to complete retrospectively were sent to consecutive patients recruited in a study comparing treatment options for early prostate cancer. The partners' perceptions about prostate cancer were explored and the partners asked to comment on the suitability of each treatment option. Partners recorded their influence on the patient's choice using a 10-point visual linear analogue scale. RESULTS: Questionnaires were sent to 116 eligible patients and 82 were returned for analysis (mean partner age 63 years). When asked to recall the treatment options initially discussed, all partners recalled radiotherapy (EBRT), all but one radical prostatectomy (RP), 51% brachytherapy, but only 29% watchful waiting (WW); 41% of partners stated RP as their chosen option, 37% EBRT, 12% brachytherapy and 10% no clear favourite. None preferred WW. Employment and education status were not significant predictors of partners' preference but retired partners and those aged > 65 years were 3 times more likely to prefer EBRT than were their employed and younger counterparts, respectively. The partners' mean (median, SD) self-assessed influence factor was 4.8 (5, 3.4). Of the partners, 88% reported active involvement throughout the process, identifying information-gathering and emotional support as their primary roles. Most deliberately chose not to influence the patient's final decision. CONCLUSION: Partner preference is influenced by pre-existing conceptions about cancer and its treatment. While undoubtedly influential throughout the decision-making process, partners deliberately left the final decision to the patient.

Effect of oral administration of excessive iron in adult ponies.

OBJECTIVE: To evaluate the potential of excess dietary iron to cause hepatic lesions similar to those described in horses with suspected iron toxicosis or hemochromatosis. DESIGN: Prospective study. ANIMALS: 6 adult male ponies. PROCEDURE: 4 ponies received 50 mg of iron/kg (22.7 mg/lb) of body weight each day by oral administration of ferrous sulfate, which contained 20% elemental iron; 2 ponies received only the carrier (applesauce). Complete blood counts, serum biochemical analyses, and hepatic tissue biopsies were performed, and serum iron concentrations were measured. Blood and tissue samples were obtained at days 0 and 2, and at the end of weeks 1, 3, 6, and 8 after administration of iron was initiated. Treatment was discontinued after 8 weeks, and hepatic iron concentrations were measured at 28 weeks. RESULTS: Hepatic iron concentrations, serum iron concentrations, percentage saturation of transferrin, and serum ferritin concentrations were increased, compared with baseline and control concentrations, by week 8. Adverse clinical signs or histologic lesions in the liver were not detected in any ponies. At 28 weeks, hepatic iron concentrations had decreased. CONCLUSIONS AND CLINICAL RELEVANCE: Histologic lesions were not seen in the hepatic biopsy specimens obtained from the ponies treated with ferrous sulfate. It was concluded that it would be unlikely for iron toxicosis to develop in adult ponies or horses during a period of < 8 weeks when food or water contained increased amounts of iron. It is suspected that previous reports of hepatopathies in animals with hemosiderin accumulation may represent a primary hepatopathy with secondary hemosiderin accumulation, especially if the only source of iron is via oral consumption.

IL-2 induces the association of IL-2Rbeta, lyn, and MAP kinase ERK-1 in human neutrophils.

IL-2, first identified as a T cell growth factor, has been proven to activate many cell types including polymorphonuclear neutrophils (PMN3). However, the mechanisms involved in PMN activation, especially the signaling pathways used by the IL-2R, are currently unknown. Here we demonstrate that IL-2 has the ability to induce protein tyrosine kinases in human PMN, and we provide the first evidence that lyn kinase is activated and physically associated with MAP kinase/ERK1. Co-immunoprecipitation experiments with anti-IL-2Rbeta and Western blotting with anti-p53/56lym revealed that lyn protein was present in IL-2R precipitates and that the association of lyn with IL-2Rbeta was markedly elevated by IL-2 stimulation. Furthermore the activity of lyn kinase, evaluated by an in vitro kinase assay with enolase as a substrate, increased following IL-2 stimulation. Another important finding was that, upon IL-2 activation, MAPK/ERK1 was also phosphorylated in PMN. A direct association between lyn and ERK1 was initially demonstrated by co-immunoprecipitation/Western blotting and then definitively proven by the use of a GST-ERK1 fusion protein. We showed that ERK1 binds lyn only in IL-2 stimulated PMN, but not in unstimulated PMN. These results suggest that IL-2 can promote the association of lyn protein tyrosine kinase with IL-2Rbeta as well as the direct binding of MAPK/ERK1 to lyn. The signaling pathway utilized by human PMN in response to IL-2 may thus involve the association of lyn with IL-2Rbeta and the activation process also triggers the recruitment and activation of a specific ERK.

Cyclical etidronate: its effect on bone density in patients with acute spinal cord injury.

OBJECTIVE: To compare the effects of a 30-week trial of cyclical etidronate therapy (starting within 6 weeks of spinal cord injury [SCI] and conventional rehabilitation without etidronate treatment on the bone density of the lumbar spine and lower extremities of SCI patients. DESIGN: Prospective, randomized control trial. SETTING: Tertiary care, inpatient rehabilitation center. PATIENTS: Acute SCI, within 6 weeks of injury. Thirteen SCI subjects were recruited; 6 were assigned randomly to receive etidronate and 7 to receive conventional treatment. INTERVENTION: Etidronate, 800 mg orally, once per day for 2 weeks of 15 weeks, repeated once. MAIN OUTCOME MEASURES: Dual X-ray absorptiometry of the spine, hip, distal femur, and proximal tibia measured at baseline, 6 months, and 12 months. RESULTS: A significant interaction between etidronate treatment and ambulatory status over time was observed in the bone density of the patients after SCI (p = .0003). The patients who became ambulatory and received etidronate treatment had a preservation of bone density as compared to all other patients who showed a loss of bone density over time. The loss of bone density occurred in the leg bones, not the spine. Cyclical etidronate treatment was tolerated well without adverse or side effects. CONCLUSION: Cyclical etidronate is a feasible treatment and may prevent osteoporosis associated with SCI in patients who eventually walk.