Risk of colorectal cancer associated with BRCA1 and/or BRCA2 mutation carriers: systematic review and meta-analysis.

BACKGROUND: Carriers of the BRCA1 and/or BRCA2 mutation incur a lifetime risk of up to 85 per cent for breast cancer, and between 20 and 40 per cent for ovarian cancer. Efforts to estimate the lifetime risk of developing colorectal cancer for BRCA mutation carriers have produced conflicting results. Consequently, there are no formal guidelines regarding the need for bowel screening for individuals with BRCA1 and/or BRCA2 mutations. This systematic review and meta-analysis determined the risk of colorectal cancer associated with BRCA carrier mutations. METHODS: The primary outcome was incidence of colorectal cancer in BRCA mutation carriers. Secondary outcomes were the incidence in BRCA1 and BRCA2 carriers, Ashkenazi Jews, and age- and sex-matched cohorts. RESULTS: Eleven studies were included in the review, with an overall population of 14 252 and 4831 colorectal cancers identified. Nine studies were included in the meta-analysis. There was no increase in colorectal cancer among patients carrying a BRCA mutation (odds ratio 1·03, 95 per cent c.i. 0·80 to 1·32; P = 0·82). After adjustment for Ashkenazi heritage, and age and sex estimates, there was no increased odds of developing colorectal cancer (with no heterogeneity, I2  = 0 per cent). CONCLUSION: BRCA1 and/or BRCA2 mutation carriers are not at a higher risk of colorectal cancer.

ANTECEDENTES: Las portadoras de la mutación BRCA1 y/o BRCA2 presentan un riesgo a lo largo de la vida de hasta un 85% para presentar un cáncer de mama y entre 20-40% para el cáncer de ovario. Los esfuerzos para estimar el riesgo de desarrollar cáncer colorrectal (colorectal cancer, CCR) a lo largo de la vida en portadoras de mutaciones BRCA han dado resultados contradictorios. En consecuencia, no existen pautas formales con respecto a la necesidad de realizar el cribado de CRC en personas portadoras de mutaciones BRCA1 y/o BRCA2. Esta revisión sistemática y metaanálisis analiza el riesgo de CRC asociado en pacientes portadoras de mutaciones BRCA. MÉTODOS: Se incluyeron nueve estudios en el metaanálisis. La población general del estudio fue de 18.839 pacientes, con 4.978 con CRC identificado. La variable principal fue la incidencia de cáncer colorrectal en portadoras de mutaciones BRCA. Las variables secundarias incluyeron el análisis de la incidencia de subgrupos en BRCA 1, BRCA 2, etnia judía Ashkenazi y cohortes emparejadas por edad y sexo. RESULTADOS: No hubo un aumento de CRC en pacientes con una mutación BRCA (razón de oportunidades, odds ratio, OR 1,03; i.c. del 95% 0,80-1,32; P = 0,82). Cuando se ajustó de acuerdo con la ascendencia Ashkenazi y las estimaciones de edad y sexo, no hubo mayores probabilidades de desarrollar cáncer colorrectal (sin heterogeneidad en los estudios (I2 = 0)). CONCLUSIÓN: Este metaanálisis concluye que el riesgo de cáncer colorrectal no fue significativamente mayor en las portadoras de mutaciones BRCA1 y/o BRCA2. Sin embargo, se requiere más evidencia antes de no recomendar la colonoscopia de cribado a las portadoras de la mutación BRCA1/2. Las pruebas de inmunoquímica fecal pueden ser una alternativa apropiada en esta población.

The Efficacy of Prophylactic Negative Pressure Wound Therapy for Closed Incisions in Breast Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Negative pressure wound therapy (NPWT) is a promising advance in the management of closed surgical incisions. NPWT application induces several effects locally within the wound including reduced lateral tension and improving lymphatic drainage. As a result, NPWT may improve wound healing and reduce surgical site complications. We aim to evaluate the efficacy of prophylactic application of NPWT in preventing surgical site complications for closed incisions in breast surgery. METHODS: This systematic review was reported according to PRISMA guidelines. The protocol was published in PROSPERO (CRD42018114625). Medline, Embase, CINAHL and Cochrane Library databases were searched for studies which compare the efficacy of NPWT versus non-NPWT dressings for closed incisions in breast surgery. Specific outcomes of interest were total wound complications, surgical site infection (SSI), seroma, haematoma, wound dehiscence and necrosis. RESULTS: Seven studies (1500 breast incisions in 904 patients) met the inclusion criteria. NPWT was associated with a significantly lower rate of total wound complications [odds ratio (OR) 0.36; 95% CI 0.19-069; P = 0.002], SSI (OR 0.45; 95% CI 0.24-0.86; P = 0.015), seroma (OR 0.28; 95% CI 0.13-0.59; P = 0.001), wound dehiscence (OR 0.49; 95% CI 0.32-0.72; P < 0.001) and wound necrosis (OR 0.38; 95% CI 0.19-0.78; P = 0.008). There was no significant difference in haematoma rate (OR 0.8; 95% CI 0.19-3.2; P = 0.75). Statistically significant heterogeneity existed for total wound complications, but no other outcomes. CONCLUSION: Compared with conventional non-NPWT dressings, prophylactic application of NPWT is associated with significantly fewer surgical site complications including SSI, seroma, wound dehiscence and wound necrosis for closed breast incisions.

Health literacy and the perception of risk in a breast cancer family history clinic.

BACKGROUND: Informed consent is an essential component of medical practice, and especially so in procedural based specialties which entail varying degrees of risk. Breast cancer is one of the most common cancers in women, and as such is the focus of extensive research and significant media attention. Despite this, considerable misperception exists regarding the risk of developing breast cancer. AIMS: This study aims to examine the accuracy of risk perception of women attending a breast cancer family history clinic, and to explore the relationship between risk perception accuracy and health literacy. METHODS: A cross-sectional study of women attending a breast cancer family history clinic (n = 86) was carried out, consisting of a patient survey and a validated health literacy assessment. Patients' perception of personal and population breast cancer risk was compared to actual risk as calculated by a validated risk assessment tool. RESULTS: Significant discordance between real and perceived risks was observed. The majority (83.7%) of women overestimated their personal lifetime risk of developing breast cancer, as well as that of other women of the same age (89.5%). Health literacy was considered potentially inadequate in 37.2% of patients; there was a correlation between low health literacy and increased risk perception inaccuracy across both personal ten-year (rs = 0.224, p = 0.039) and general ten-year population estimations. (rs = 0.267, p = 0.013). CONCLUSION: Inaccuracy in risk perception is highly prevalent in women attending a breast cancer family history clinic. Health literacy inadequacy is significantly associated with this inaccuracy.

Association of imaging abnormalities of the subcallosal septal area with Alzheimer's disease and mild cognitive impairment.

AIM: To evaluate the use the distance between the adjacent septal nuclei as a surrogate marker of septal area atrophy seen in Alzheimer's disease (AD). MATERIALS & METHODS: Interseptal distance (ISD) was measured, blind to clinical details, in 250 patients who underwent computed tomography (CT) of the brain at University Hospital of Wales. Clinical details including memory problem history were retrieved. An ISD cut-off value that discriminated those with and without memory symptoms was sought. ISD measurements were also made in 20 AD patients. To test both the method and the defined cut-off, measurements were then made in an independent cohort of 21 mild cognitive impairment (MCI) patients and 45 age-matched healthy controls, in a randomised and blinded fashion. RESULTS: ISD measurement was achieved in all patients. In 28 patients with memory symptoms, the mean ISD was 5.9 mm compared with 2.3 mm in those without overt symptoms (p=0.001). The optimum ISD cut-off value was 4 mm (sensitivity 85.7% and specificity 85.8%). All AD patients had an ISD of >4 mm (mean ISD= 6.1 mm). The mean ISD for MCI patients was 3.84 mm compared with 2.18 mm in age-matched healthy controls (p=0.001). Using a 4 mm cut-off correctly categorised 10 mild cognitive impairment patients (47.6%) and 38 healthy controls (84.4%). CONCLUSION: ISD is a simple and reliable surrogate measurement for septal area atrophy, applicable to CT and magnetic resonance imaging (MRI). It can be used to help select patients for further investigation.

Decoupling of structural and functional brain connectivity in older adults with white matter hyperintensities.

Age-related impairments in the default network (DN) have been related to disruptions in connecting white matter tracts. We hypothesized that the local correlation between DN structural and functional connectivity is negatively affected in the presence of global white matter injury. In 125 clinically normal older adults, we tested whether the relationship between structural connectivity (via diffusion imaging tractography) and functional connectivity (via resting-state functional MRI) of the posterior cingulate cortex (PCC) and medial prefrontal frontal cortex (MPFC) of the DN was altered in the presence of white matter hyperintensities (WMH). A significant correlation was observed between microstructural properties of the cingulum bundle and MPFC-PCC functional connectivity in individuals with low WMH load, but not with high WMH load. No correlation was observed between PCC-MPFC functional connectivity and microstructure of the inferior longitudinal fasciculus, a tract not passing through the PCC or MPFC. Decoupling of connectivity, measured as the absolute difference between structural and functional connectivity, in the high WMH group was related to poorer executive functioning and memory performance. These results suggest that such decoupling may reflect reorganization of functional networks in response to global white matter pathology and may provide an early marker of clinically relevant network alterations.

Neonatal Genetic Variation in Steroid Metabolism and Key Respiratory Function Genes and Perinatal Outcomes in Single and Multiple Courses of Corticosteroids.

OBJECTIVE: The aim of the study is to evaluate the association of steroid metabolism and respiratory gene polymorphisms in neonates exposed to antenatal corticosteroids (ACS) with respiratory outcomes, small for gestational age (SGA), and response to repeat ACS. STUDY DESIGN: This candidate gene study is a secondary analysis of women enrolled in a randomized controlled trial of single versus weekly courses of ACS. Nineteen single nucleotide polymorphisms (SNPs) in 13 steroid metabolism and respiratory function genes were evaluated. DNA was extracted from placenta or fetal cord serum and analyzed with TaqMan genotyping. Each SNP was evaluated for association via logistic regression with respiratory distress syndrome (RDS), continuous positive airway pressure (CPAP)/ventilator use (CPV), and SGA. RESULTS: CRHBP, CRH, and CRHR1 minor alleles were associated with an increased risk of SGA. HSD11B1 and SCNN1B minor alleles were associated with an increased likelihood of RDS. Carriage of minor alleles in SerpinA6 was associated with an increased risk of CPV. CRH and CRHR1 minor alleles were associated with a decreased likelihood of CPV. CONCLUSION: Steroid metabolism and respiratory gene SNPs are associated with respiratory outcomes and SGA in patients exposed to ACS. Risks for respiratory outcomes are affected by minor allele carriage as well as by treatment with multiple ACS.

Safety and pharmacokinetics of nelfinavir during the second and third trimesters of pregnancy and postpartum.

PURPOSE: Evaluate the safety, tolerability, and pharmacokinetics (PK) of nelfinavir during pregnancy and postpartum in HIV-infected women. METHODS: Phase IV, non-randomized, open-label study of nelfinavir 625 mg tablets (1250 mg) in combination with lamivudine/zidovudine twice daily. Primary endpoint was treatment-related or possibly treatment-related gastrointestinal or hepatic adverse events (AEs). Selected maternal and infant outcomes were recorded. Frequent plasma samples were collected for PK studies during the 2nd and 3rd trimesters, and 6 weeks postpartum, to analyze total and free nelfinavir and M8 concentrations. RESULTS: Sixteen HIV+ pregnant women were enrolled. Six mild treatment-related AEs and 3 serious AEs occurred; 1 serious AE (elevated AST) met the primary endpoint. Compared with 6 weeks postpartum, levels of total nelfinavir were reduced by 44% and 46%, total M8 by 82% and 83%, free nelfinavir by 48% and 39%, and free M8 by 83% and 79% in the 2nd and 3rd trimesters, respectively. At 6 weeks postpartum, 75% and 50% of subjects maintained HIV-1 RNA levels <400 and <50 copies/mL, respectively. All pregnancies resulted in live births without transmission in 15 infants. CONCLUSIONS: Nelfinavir in combination with lamivudine/zidovudine was generally well tolerated. Total and free nelfinavir and M8 exposure were reduced in late pregnancy.

Molecular confirmation of primary monophasic synovial sarcoma of the mandible: diagnosis and management.

Synovial sarcoma (SS) is a rare, high-grade, soft tissue malignancy that originates from pluripotent mesenchymal stem cells. Knox introduced the term 'synovial sarcoma', noting its histological similarity to synovial tissue. SS is seen most frequently in young and middle-aged adults with an equal sex distribution. Symptoms are non-specific and relate to the local effect of the mass. Currently, we know of no specific guidelines for the management of SS in the head and neck. We report a case of primary monophasic SS of the mandible in a 59-year-old male, and outline our diagnostic approach and management.

Airway Epithelial Cells Drive Airway Smooth Muscle Cell Phenotype Switching to the Proliferative and Pro-inflammatory Phenotype.

The increased mass of airway smooth muscle (ASM) in the airways of asthmatic patients may contribute to the pathology of this disease by increasing the capacity for airway narrowing. Evidence for the airway epithelium as a participant in ASM remodeling is accruing. To investigate mechanisms by which airway epithelial cells induce ASM cell (ASMC) proliferation, we have employed a co-culture model to explore markers of ASMC proliferative phenotype. Co-culture with epithelial cells led to incorporation of bromodeoxyuridine into ASMCs, indicating augmented proliferation and an associated increase in mRNA of the pro-proliferative co-transcription factor Elk1. Although the mitogen heparin-binding epidermal growth factor (HB-EGF) was augmented in the co-culture supernatant, the ASMC epidermal growth factor receptor (EGFR), an effector of HB-EGF induced proliferation, did not mediate epithelial-induced proliferation. The co-culture increased the expression of ASMC mRNA for the pro-inflammatory cytokines IL-6 and IL-8 as well as the pro-proliferative microRNA miR-210. The transcriptional repressor Max-binding protein (Mnt), a putative target of miR-210, was transcriptionally repressed in co-cultured ASMCs. Together, these data indicate that the airway epithelium-induced proliferative phenotype of ASMCs is not driven by EGFR signaling, but rather may be dependent on miR210 targeting of tumor suppressor Mnt.

Antiretroviral therapy during pregnancy and the risk of an adverse outcome.

BACKGROUND: Some studies suggest that combination antiretroviral therapy in pregnant women with human immunodeficiency virus type 1 (HIV-1) infection increases the risk of premature birth and other adverse outcomes of pregnancy. METHODS: We studied pregnant women with HIV-1 infection who were enrolled in seven clinical studies and delivered their infants from 1990 through 1998. The cohort comprised 2123 women who received antiretroviral therapy during pregnancy (monotherapy in 1590, combination therapy without protease inhibitors in 396, and combination therapy with protease inhibitors in 137) and 1143 women who did not receive antiretroviral therapy. RESULTS: After standardization for the CD4+ cell count and use or nonuse of tobacco, alcohol, and illicit drugs, the rate of premature delivery (<37 weeks of gestation) was similar among the women who received antiretroviral therapy and those who did not (16 percent and 17 percent, respectively); the rate of low birth weight (<2500 g) was 16 percent among the infants born to both groups; and the rate of very low birth weight (<1500 g) was 2 percent for the group that received antiretroviral therapy and 1 percent for the group that did not. The rates of low Apgar scores (<7) and stillbirth were also similar or the same in the two groups. After adjustment for multiple risk factors, combination antiretroviral therapy was not associated with an increased risk of premature delivery as compared with monotherapy (odds ratio, 1.08; 95 percent confidence interval, 0.71 to 1.62) or delivery of an infant with low birth weight (odds ratio, 1.03; 95 percent confidence interval, 0.64 to 1.63). Seven of the women who received combination therapy with protease inhibitors (5 percent) had infants with very low birth weight, as compared with nine women who received combination therapy without protease inhibitors (2 percent) (adjusted odds ratio, 3.56; 95 percent confidence interval, 1.04 to 12.19). CONCLUSIONS: As compared with no antiretroviral therapy or monotherapy, combination therapy for HIV-1 infection in pregnant women is not associated with increased rates of premature delivery or with low birth weight, low Apgar scores, or stillbirth in their infants. The association between combination therapy with protease inhibitors and an increased risk of very low birth weight requires confirmation.

The effect of multiple reexcisions on the risk of local recurrence after breast conserving surgery.

BACKGROUND: Guidelines for breast conserving surgery (BCS) advise mastectomy if negative margins cannot be obtained after reasonable surgical attempts. This study examined the effect of multiple reexcisions on local recurrence (LR) and identified factors predictive of the need for multiple reexcisions. METHODS: 2,770 patients undergoing BCS over 25 years were analyzed; 137 patients (group A) with two or more reexcisions, 1514 patients with one reexcision (group B), and 1119 patients who had no reexcision (group C). The median follow-up was 73 months. RESULTS: The five and ten-year actuarial LR rates for groups A, B, and C were 5.5%, 1.9%, 2.5%, and 10%, 5.7%, and 5.6%, respectively. The number of reexcisions did not predict for LR on multivariate analysis. Women <40 years underwent reexcision more frequently than other age groups. Patients with tumors detected by palpation alone made up 14% of the reexcision group versus 8% of the no reexcision group (p < 0.001). Patients with ductal carcinoma in situ and lobular carcinoma were more likely to require reexcision than those with ductal carcinoma. On multivariate analysis, younger age, detection by physical exam only, lobular histology, smaller tumor size, and the presence of extensive intraductal component (EIC) were highly significant predictors of the need for reexcision. CONCLUSIONS: Multiple reexcisions do not impact on LR rates if negative margins are ultimately obtained. Conversion to mastectomy based solely on the number of excisions performed is not indicated. Subsets of patients more likely to require reexcision, who may be candidates for a larger initial resection, can be identified.

Cervical length and the risk of spontaneous labor at term.

OBJECTIVE: To investigate the relationship between cervical length (CL) at 37 to 40 weeks and delivery within 7 days and delivery by 41 weeks. STUDY DESIGN: We performed transvaginal ultrasound to measure CL in women with singleton gestations at 37 to 40 weeks. We then used a receiver operating characteristic curve (ROC) to assess the relationship between CL and delivery within 7 days and delivery by 41 weeks. RESULT: For the 120 women included in the analysis, the mean CL (+/-s.d.) was 25.3+/-9.8 mm. The logistic regression model to predict each of the outcomes includes gestational age at ultrasound (GA-US) and CL. Neither birthweight, nor parity seems to affect the probability of delivery within 7 days. The ROC curve was used to assess the probability of spontaneous labor within 7 days at each CL measurement. The likelihood ratio of delivery within 7 days when CL is < or = 10 mm is 12. CONCLUSION: CL measurement at 37-40 weeks is an independent predictor of delivery within 7 days and delivery by 41 weeks regardless of GA-US. This information can be utilized when counseling patients regarding the management of term pregnancies.

Sentinel lymph node biopsy in elderly irish patients with malignant melanoma.

In patients with malignant melanoma, Breslow depth increases with age. However, studies suggest that the frequency of sentinel lymph node metastases in malignant melanoma decreases with age. We investigated whether this applied to the cohort of patients undergoing sentinel lymph node biopsy (SLNB) in our institution. In a prospectively accrued database we identified 149 patients undergoing SLNB from 1997 to 2005. Tumour thickness as measured by Breslow depth was assessed in stratified age groups. We assessed the relationship between SLNB positivity and age using the Chi-square for trend. We directly examined the relationship between SLNB positivity in patients aged less than 65 and aged 65 years of age and over. Disease-free and overall survival in patients aged less than 65 and aged 65 years of age and over were also assessed. Comparing the age groups, there was no significant difference identified in Breslow depth (<65 years, median Breslow > or = 1.2 mm (range 0.2-9.7); > or =65 years, median Breslow > or = 1.4 mm (range 0.12-8.5); p > or = 0.06, Mann-Whitney U). Chi-square for trend identified no significant relationship between SLNB positivity and age. We found n=120 patients <65 had SLNB, of which 26 (21.7%) were positive. In patients =65, n=29 had SLNB of which 3 (10.3%) were positive. These differences were not statistically significant (Fisher's exact test, p > or = 0.2). There was no difference in disease-free or overall survival between patients aged <65 or > or =65 who had SLNB (median follow-up 37.5 months (range 5-70); disease-free survival, p > 0.08; overall survival, p > or = 0.3, Logrank test). We did not find that elderly patients with malignant melanoma had a demonstrable difference in tumour thickness when compared to younger patients. In those patients who underwent SLNB there was no significant difference in node positivity between the age groups. Disease-free and overall survival were not significantly different between the age groups. Further study and longer follow-up will help establish the relationship between age and SLNB positivity.

Sentinel lymph node biopsy: is it possible to reduce false negative rates by excluding patients with nodular melanoma?

OBJECTIVE: The aim of this study was to review the outcome of sentinel lymph node biopsy (SLNB) in patients with melanoma and to delineate whether patients with nodular melanoma are more likely to develop nodal recurrence despite negative SLNB. METHODS: Consecutive patients with cutaneous melanoma undergoing SLNB were identified from a departmental database between 1997 and 2005. Factors including demographic data, site, histological subtype, depth and outcome were examined. RESULTS: Of 131 patients, 103 were node negative and eligible for study. The median age was 53 (16-82) years with 46 patients being male (45%) and 57 female (55%). Primary melanoma sites included lower limb (49; 48%), upper limb (29; 28%), head (12; 11%), trunk (7; 7%) and back (6; 6%). The median Breslow thickness was 2mm. Superficial spreading accounted for 43% of melanoma with nodular accounting for 42%. Median follow-up was 40 (3-90) months. Of 20 relapses, seven recurred in the same nodal basin, three were satellite recurrences, one recurred with both satellite and nodal lesions simultaneously, and nine experienced haematogenous spread. Of the eight patients who developed recurrence in the same nodal basin, four were of nodular histological subtype (p=NS). All of the three patients with satellite lesions had nodular melanoma histologically (p=0.02). When nodal and satellite recurrences were combined, eight of 11 were histologically nodular (p=0.01). CONCLUSIONS: This study indicates that lymphatic recurrence occurs more often in SLNB negative patients with nodular melanoma. Further evaluation of the inclusion criteria for sentinel node biopsy is warranted.

Application of the Ottawa Knee Rules in assessing acute knee injuries.

The Ottawa Knee Rules (OKR) were established to identify which adults with acute knee injuries require knee x-rays as part of their assessment. This study evaluates the compliance of non-consultant hospital doctors (NCHDs), working in an Irish Emergency Dept., with these guidelines and assesses the impact of raising the profile of these rules on their implementation. Emergency Dept. (ED) notes of all adults who presented with an acute knee injury in a 3-month period were analysed retrospectively and compliance with the OKR was assessed. ED NCHDs were then educated on the details and value of these guidelines. In the subsequent three months, the improvement in compliance with the OKR was audited. In the initial audit, according to the Ottawa criteria, 65.5% of all x-rays of acute knee injuries were performed unnecessarily. In the second audit, performed after increasing awareness of the OKR, this figure had dropped to 39.1%. The NCHDs involved in this project cited 'patient expectation' for an x-ray as the primary reason why full compliance was not achieved. This study highlights a lack of awareness of and compliance with the OKR in the assessment of acute knee injuries in adults. It shows how the implementation of simple measures, which raised the profile of the OKR among ED staff, significantly improved compliance with the rules, thus cutting patient waiting times and cutting hospital costs. Futhermore, this study revealed that patients, when injured, expect to get x-rayed and ofter doctors comply with these expectations even if no indication exists.

Endocrine therapy adherence: a cross-sectional study of factors affecting adherence and discontinuation of therapy.

BACKGROUND/AIMS: Adjuvant endocrine therapy for at least 5 years improves oncological outcomes in oestrogen receptor-positive breast cancer. Adherence rates to prescribed endocrine therapy are low and the search for modifiable causes of this continues. The aim of this study was to assess adherence rates in an Irish cohort of breast cancer patients prescribed adjuvant endocrine therapy and to assess modifiable factors associated with suboptimal adherence. METHODS: A cross-sectional anonymous survey was performed on 261 patients currently prescribed endocrine therapy. Data were collected regarding demographics, treatment, social and emotional factors and medication side effects. Each patient completed a medication adherence score and provided information about discontinuation of therapy and reasons for same. RESULTS: Only 67.8 % of patients assessed demonstrated complete medication adherence on the medication adherence scale. Twenty-nine patients (10.9 %) permanently stopped taking their prescribed endocrine therapy. Suboptimal adherence was more likely in younger patients (p < 0.001), those in employment (p = 0.005), those who experienced side effects (p = 0.006), those who perceived themselves to have low levels of emotional support (p < 0.001) and those who use the internet to read about their illness (p = 0.003). CONCLUSIONS: Endocrine therapy adherence is suboptimal in almost one-third of patients in our cohort. Appropriate assessment and management of side effects and negative emotions, combined with direction of patients to accurate internet sources of information, could help improve endocrine therapy adherence in women with early-stage breast cancer.

Faster Cancer Treatment: Using timestamp data to improve patient journeys.

This paper presents a case study of research conducted to improve the delivery of treatment to high priority cancer patients. The authors present a modelling framework that uses time-stamp data collected by the North Shore Hospital IT systems as "business as usual", to describe the patient journey through the cancer-care process. A simulation process is developed that uses this data to estimate the service's performance under current operating practices, and enables "what-if" analysis to identify where changes to current practice can most effectively be applied, ensuring the investment of additional resource can be targeted at the steps of the patient pathway where it can result in the greatest improvement. The process is illustrated using the Breast Cancer stream as a case-study, for the initial study period (July 2013 to June 2014), with a follow-up analysis presented briefly for the 3 months from July to the end of September 2014.

When pathological and radiological correlation is achieved, excision of fibroadenoma with lobular neoplasia on core biopsy is not warranted.

BACKGROUND: The diagnosis and management of lobular neoplasia (LN) including lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH) remains controversial. Current management options after a core needle biopsy (CNB) with lobular neoplasia (LN) incorporating both ALH and LCIS include excision biopsy or careful clinical and radiologic follow up. METHODS: A retrospective analysis of the surgical database at Cork University Hospital was performed to identify all core needle biopsies from January 1st 2010 to 31st December 2013 with a diagnosis of FA who subsequently underwent surgical excision biopsy. All cases with associated LN including ALH and classical LCIS were selected. We excluded cases with coexistent ductal carcinoma in situ (DCIS), invasive carcinoma, LN associated with necrosis, pleomorphic lobular carcinoma in situ (PLCIS) or lesions which would require excision in their own right (papilloma, radial scar, atypical ductal hyperplasia (ADH) or flat epithelial atypia (FEA)). Cases in which the radiologic targeted mass was discordant with a diagnosis of FA were also excluded. RESULTS: 2878 consecutive CNB with a diagnosis of FA were identified. 25 cases had a diagnosis of concomitant ALH or classical LCIS. Our study cohort consisted of 21 women with a mean age 53 years (age range 41-70 years). The core biopsy diagnosis was of LCIS and FA in 16 cases and ALH and FA in 5 cases. On excision biopsy, a FA was confirmed in all 21 cases. In addition to the FA, residual LCIS was present in 14 cases with residual ALH in 2 cases. One of the twenty-one cases (4.8%) was upgraded to invasive ductal carcinoma on excision.

Insulin action during pregnancy. Studies with the euglycemic clamp technique.

To assess the mechanisms responsible for the insulin resistance associated with both normal human pregnancy and gestational-onset diabetes, we have measured exogenous glucose disposal using sequential insulin infusions with the euglycemic glucose clamp technique and erythrocyte insulin binding. Three groups of women were studied: nonpregnant women with normal glucose tolerance (N = 7, mean age 32.9 +/- 2.1 yr), pregnant women with normal glucose tolerance (N = 5, mean age 24.8 +/- 3.5 yr), and pregnant women with gestational-onset diabetes (N = 5, mean age 34.6 +/- 2.6 yr). Despite normal plasma glucose levels obtained during a 100-g oral glucose tolerance test, plasma insulin levels were significantly elevated in the pregnant women compared with the nonpregnant control subjects, suggesting a state of insulin resistance. Insulin binding to erythrocytes was similar in all three groups (maximum specific binding being 5.0 +/- 0.6%, 5.5 +/- 1.1%, and 6.0 +/- 0.7% in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively). In vivo peripheral insulin action was measured using the euglycemic glucose clamp technique during an insulin infusion of 40 mU/m2 X min, with blood glucose clamped at a concentration of 75 mg/dl using a variable glucose infusion. Glucose infusion rates were 213 +/- 11 mg/m2 X min, 143 +/- 23 mg/m2 X min, and 57 +/- 18 mg/m2 X min in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively. This demonstrates that pregnant subjects display a state of insulin resistance, and that this appears to be more marked in gestational-onset diabetic subjects. To further define the possible mechanism of insulin resistance during pregnancy, the insulin infusion rate was increased to 240 mU/m2 X min and further euglycemic clamp measurements performed. Glucose infusion rates were 372 +/- 11 mg/m2 X min, 270 +/- 31 mg/m2 X min, and 157 +/- 26 mg/m2 X min, in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively. This demonstrates a shift to the right of the dose-response curve of insulin action and suggests that the insulin resistance of pregnancy may include a decrease in presumed "maximum" insulin responsivity. In four subjects, studies were repeated in the postpartum period, and these demonstrated that the insulin resistance of pregnancy is ameliorated shortly after delivery. These studies suggest that the insulin resistance of pregnancy results from a target cell defect in insulin action beyond the initial step of insulin binding to cellular receptors, a postreceptor (or postbinding) defect in insulin action.

Algorithms for adjustment of insulin dosage by patients who monitor blood glucose.

Patient self-monitoring of blood glucose is a useful adjuvant to diabetes therapy that facilitates improved glycemic control when used as part of an intensive diabetes management program that includes careful balancing of food intake, energy expenditure, and insulin dosage. This paper describes an approach by which patient-determined blood glucose measurements may be used to attain and maintain glycemic control. The patient is provided with a set of algorithms by which minor adjustments in a therapeutic routine may be made to achieve the desired control.