Induction of p53 up-regulated modulator of apoptosis messenger RNA by chemotherapeutic treatment of locally advanced breast cancer.

PURPOSE: In biopsies of patients with locally advanced breast cancer, we investigated the in vivo changes of the gene expression pattern induced by chemotherapy to find genes that are potentially responsible for the efficacy of the drug. EXPERIMENTAL DESIGN: Early cellular responses to chemotherapy-induced damage, both in vivo and in vitro, were investigated by analyzing chemotherapy-induced changes in gene expression profiles. Core biopsies were taken from nine patients with locally advanced breast cancer, before and at 6 hours after initiation of doxorubicin-based chemotherapy. Both samples were cohybridized on the same microarray containing 18,000 cDNA spots. RESULTS: The analysis revealed marked differences in gene expression profile between treated and untreated samples. The gene which was most frequently found to be differentially expressed was p53 up-regulated modulator of apoptosis (PUMA). This gene was up-regulated in eight of nine patients with an average factor of 1.80 (range, 1.36-2.73). In vitro MCF-7 breast cancer cells exposed to clinically achievable doxorubicin concentrations for 6 hours revealed marked induction of PUMA mRNA, as well. CONCLUSIONS: This is the first report describing PUMA mRNA to be up-regulated as a response to chemotherapy in patients. Because PUMA is a known member of the family of BH3-only proapoptotic proteins, this finding suggests PUMA's potential importance for the response to anticancer drugs.     

Large cleaved and immunoblastic lymphoma may represent two distinct clinicopathologic entities within the group of diffuse large B-cell lymphomas.

PURPOSE: The reliability of immunohistochemistry for subdividing diffuse large B-cell lymphomas (DLBCL) into germinal center B-cell-like (GCB) and non-GCB prognostic subgroups is debated. In this study we evaluated the prognostic significance of such subgrouping on a series of 153 DLBCL patients. Furthermore, we investigated whether both subgroups could comprise clinicopathologic entities recognized by their morphology and characterized by a distinct phenotype, specific genetic abnormalities, and clinical characteristics. PATIENTS AND METHODS: All samples from patients were reviewed and morphologically subdivided into large cleaved, immunoblastic, and not otherwise specified DLBCL. GCB and non-GCB immunohistochemical profiles were established. The presence of chromosomal translocations involving BCL2, BCL6, and MYC and/or rearrangements of these genes was investigated. RESULTS: Subdividing DLBCL with either a GCB or non-GCB immunophenotypic profile was not of prognostic significance. Nevertheless, CD10 expression was a predictor of favorable outcome, whereas high bcl-2 expression and BCL6 rearrangement were adverse predictors of disease-free survival. Interestingly, large cleaved DLBCL was clearly associated with a GCB immunophenotypic profile, CD10 expression, BCL2 rearrangement, age younger than 60 years, and low to low/intermediate International Prognostic Index risk, but was not of prognostic significance. In contrast, immunoblastic morphology was associated with a non-GCB profile and was a significant predictor of unfavorable DFS. CONCLUSION: Subdividing DLBCL into subgroups based on their immunohistochemical profile was not of prognostic significance. Nevertheless, it allowed the additional characterization of two lymphoma subgroups previously recognized in the Working Formulation. Both correspond to two distinct clinicopathologic entities within the DLBCL.     

Disclosure and health-seeking behaviour following intimate partner violence before and during pregnancy in Flanders, Belgium: a survey surveillance study

OBJECTIVES: The objectives were to estimate the prevalence of physical and sexual intimate partner violence (IPV) among a regional sample of the general obstetric population as the lifetime prevalence, as the 1-year period prevalence before pregnancy, and as the prevalence during the index pregnancy; to assess the rates of disclosure and help-seeking behaviour with IPV; and to determine the acceptability of screening for IPV. STUDY DESIGN: A multi-centred survey surveillance study was carried out among pregnant women attending five large hospitals in the province of East Flanders, Belgium as a regional probability sample of the general obstetric population. Data were collected through an anonymous, written questionnaire that included the Abuse Assessment Screen and additional questions on the circumstances of the most recent episode of physical or sexual violence, on disclosure and help-seeking behaviour, on reporting assault to the police, and on the acceptability of routine screening for IPV. RESULTS: The sampling frame consisted of 1362 women who received the questionnaire at the antenatal service during a 2-month study period, of which 537 (mean age 29.4 years, S.D. 4.09) returned the envelope (response rate 39.4%). The lifetime prevalence of IPV was estimated to be 10.1% (95% CI 7.7-13.0%) and the period prevalence of IPV during pregnancy and/or in the year preceding pregnancy 3.4% (95% CI 2.1-5.4%). There was a significant difference in the reported lifetime prevalence of IPV between women attending with a partner and those who came to the prenatal visit unattended by their partner in particular (6.8% versus 13.9%, p=0.010). Overall, only 19.2% (23 out of 120) and as few as 6.6% (4 out of 61) of the victims of physical and sexual abuse respectively sought medical care by consulting a general practitioner, gynaecologist, or an emergency department. Routine screening for IPV by a general practitioner or gynaecologist was found to be largely acceptable. CONCLUSIONS: In our highly medicalised society, women experiencing partner violence rarely disclose abuse to the widely available health care services, unless they are directly asked about it, which appears an acceptable practice. Hence, there is a definite need to improve women's awareness regarding abuse and their help-seeking behaviour at a public health level.     

Clinician perspectives on clinical decision support systems in lung cancer: Implications for shared decision‐making

BackgroundLung cancer treatment decisions are typically made among clinical experts in a multidisciplinary tumour board (MTB) based on clinical data and guidelines. The rise of artificial intelligence and cultural shifts towards patient autonomy are changing the nature of clinical decision‐making towards personalized treatments. This can be supported by clinical decision support systems (CDSSs) that generate personalized treatment information as a basis for shared decision‐making (SDM). Little is known about lung cancer patients'' treatment decisions and the potential for SDM supported by CDSSs. The aim of this study is to understand to what extent SDM is done in current practice and what clinicians need to improve it.ObjectiveTo explore (1) the extent to which patient preferences are taken into consideration in non‐small‐cell lung cancer (NSCLC) treatment decisions; (2) clinician perspectives on using CDSSs to support SDM.DesignMixed methods study consisting of a retrospective cohort study on patient deviation from MTB advice and reasons for deviation, qualitative interviews with lung cancer specialists and observations of MTB discussions and patient consultations.Setting and ParticipantsNSCLC patients (N = 257) treated at a single radiotherapy clinic and nine lung cancer specialists from six Dutch clinics.ResultsWe found a 10.9% (n = 28) deviation rate from MTB advice; 50% (n = 14) were due to patient preference, of which 85.7% (n = 12) chose a less intensive treatment than MTB advice. Current MTB recommendations are based on clinician experience, guidelines and patients'' performance status. Most specialists (n = 7) were receptive towards CDSSs but cited barriers, such as lack of trust, lack of validation studies and time. CDSSs were considered valuable during MTB discussions rather than in consultations.ConclusionLung cancer decisions are heavily influenced by clinical guidelines and experience, yet many patients prefer less intensive treatments. CDSSs can support SDM by presenting the harms and benefits of different treatment options rather than giving single treatment advice. External validation of CDSSs should be prioritized.Patient or Public ContributionThis study did not involve patients or the public explicitly; however, the study design was informed by prior interviews with volunteers of a cancer patient advocacy group. The study objectives and data collection were supported by Dutch health care insurer CZ for a project titled ‘My Best Treatment’ that improves patient‐centeredness and the lung cancer patient pathway in the Netherlands.     

Reimagining care for young adults living with type 1 diabetes

Young adults living with type 1 diabetes often struggle to achieve what clinicians consider to be optimal levels of metabolic control. Despite the impact that this can have on a young person''s future risk of complications, there are relatively few studies reporting new ways of organizing or delivering care to this cohort. In this article, we explore some of the reasons why young adult diabetes care is challenging, and describe approaches to “re‐imagining” how care might be improved. The work is informed by the ‘Making Care Fit’ collaborative and by a program of research, entitled D1 Now, involving co‐design of a complex person‐centered intervention with young adults.     

Adjuvant capecitabine-containing chemotherapy benefit and homologous recombination deficiency in early-stage triple-negative breast cancer patients

Background The addition of adjuvant capecitabine to standard chemotherapy of early-stage triple-negative breast cancer (TNBC) patients has improved survival in a few randomised trials and in meta-analyses. However, many patients did not benefit. We evaluated the BRCA1-like DNA copy number signature, indicative of homologous recombination deficiency, as a predictive biomarker for capecitabine benefit in the TNBC subgroup of the FinXX trial.Methods Early-stage TNBC patients were randomised between adjuvant capecitabine-containing (TX + CEX: capecitabine-docetaxel, followed by cyclophosphamide-epirubicin-capecitabine) and conventional chemotherapy (T + CEF: docetaxel, followed by cyclophosphamide-epirubicin-fluorouracil). Tumour BRCA1-like status was determined on low-coverage, whole genome next-generation sequencing data using an established DNA comparative genomic hybridisation algorithm.Results For 129/202 (63.9%) patients the BRCA1-like status could be determined, mostly due to lack of tissue. During a median follow-up of 10.7 years, 35 recurrences and 32 deaths occurred. Addition of capecitabine appears to improve recurrence-free survival more among 61 (47.3%) patients with non-BRCA1-like tumours (HR 0.23, 95% CI 0.08–0.70) compared to 68 (52.7%) patients with BRCA1-like tumours (HR 0.66, 95% CI 0.24–1.81) (P-interaction = 0.17).Conclusion Based on our data, patients with non-BRCA1-like TNBC appear to benefit from the addition of capecitabine to adjuvant chemotherapy. Patients with BRCA1-like TNBC may also benefit. Additional research is needed to define the subgroup within BRCA1-like TNBC patients who may not benefit from adjuvant capecitabine.Subject terms: Breast cancer, Translational research, Predictive markers, Breast cancer     

Addressing Sexuality as Standard Care in People with an Upper Limb Deficiency: Taboo or Necessary Topic?

The purpose of this paper is to analyze whether professionals who work with people with an upper limb deficiency (ULD) received questions about sexuality from their patients and whether they addressed sexuality themselves, and to analyze their knowledge and comfort level, approach and attitudes towards sexuality. An online questionnaire, including questions on self-perceived sexological competence and the Knowledge, Comfort, Approach and Attitudes towards Sexuality Scale (KCAASS) was used to asses these aspects. One out of three professionals had received a question about sexuality from their patients. Nearly one out of five professionals had addressed sexuality themselves. Professionals who received a question about sexuality from patients or addressed this issue themselves had significantly higher scores on self-perceived knowledge about sexuality and on self-perceived conversation skills compared to professionals who did not. The scores on the KCAASS Knowledge and Comfort of professionals who received a question about sexuality or addressed the issue of sexuality were significantly higher than those of professionals who did not. Sexuality is thus only scantly discussed by professionals working with patients with an ULD. Professionals indicated they do not feel confident nor comfortable enough to address this issue. They also experience a lack of appropriate knowledge to address sexuality with patients. Professionals reported a need for courses and training on both knowledge and conversation skills concerning sexuality. In addition, a protocol and necessary facilities need to be provided for the team working with people with an ULD in order to be able to address sexuality systematically.