The prognostic significance of the aberrant extremes of p53 immunophenotypes in breast cancer

Aims: The utility of p53 as a prognostic assay has been elusive. The aims of this study were to describe a novel, reproducible scoring system and assess the relationship between differential p53 immunohistochemistry (IHC) expression patterns, TP53 mutation status and patient outcomes in breast cancer.

Methods and Results: Tissue microarrays were used to study p53 IHC expression patterns: expression was defined as extreme positive (EP), extreme negative (EN), and non-extreme (NE; intermediate patterns). Overall survival (OS) was used to define patient outcome. A representative subgroup (n = 30) showing the various p53 immunophenotypes was analysed for TP53 hotspot mutation status (exons 4-9). Extreme expression of any type occurred in 176 of 288 (61%) cases. As compared with NE expression, EP expression was significantly associated (P = 0.039) with poorer OS. In addition, as compared with NE expression, EN expression was associated (P = 0.059) with poorer OS. Combining cases showing either EP or EN expression better predicted OS than either pattern alone (P = 0.028). This combination immunophenotype was significant in univariate but not multivariate analysis. In subgroup analysis, six substitution exon mutations were detected, all corresponding to extreme IHC phenotypes. Five missense mutations corresponded to EP staining, and the nonsense mutation corresponded to EN staining. No mutations were detected in the NE group.

Conclusions: Patients with extreme p53 IHC expression have a worse OS than those with NE expression. Accounting for EN as well as EP expression improves the prognostic impact. Extreme expression positively correlates with nodal stage and histological grade, and negatively with hormone receptor status. Extreme expression may relate to specific mutational status.

Psychosocial aspects in cardiac rehabilitation: From theory to practice. A position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation of the European Society of Cardiology

A large body of empirical research shows that psychosocial risk factors (PSRFs) such as low socio-economic status, social isolation, stress, type-D personality, depression and anxiety increase the risk of incident coronary heart disease (CHD) and also contribute to poorer health-related quality of life (HRQoL) and prognosis in patients with established CHD. PSRFs may also act as barriers to lifestyle changes and treatment adherence and may moderate the effects of cardiac rehabilitation (CR). Furthermore, there appears to be a bidirectional interaction between PSRFs and the cardiovascular system. Stress, anxiety and depression affect the cardiovascular system through immune, neuroendocrine and behavioural pathways. In turn, CHD and its associated treatments may lead to distress in patients, including anxiety and depression. In clinical practice, PSRFs can be assessed with single-item screening questions, standardised questionnaires, or structured clinical interviews. Psychotherapy and medication can be considered to alleviate any PSRF-related symptoms and to enhance HRQoL, but the evidence for a definite beneficial effect on cardiac endpoints is inconclusive. A multimodal behavioural intervention, integrating counselling for PSRFs and coping with illness should be included within comprehensive CR. Patients with clinically significant symptoms of distress should be referred for psychological counselling or psychologically focused interventions and/or psychopharmacological treatment. To conclude, the success of CR may critically depend on the interdependence of the body and mind and this interaction needs to be reflected through the assessment and management of PSRFs in line with robust scientific evidence, by trained staff, integrated within the core CR team.

Preserving arteriovenous fistula outcomes during surgical training

PURPOSE: Arteriovenous fistulae (AVFs) are the preferred option for vascular access, as they are associated with lower mortality in hemodialysis patients than in those patients with arteriovenous grafts (AVGs) or central venous catheters (CVCs). We sought to assess whether vascular access outcomes for surgical trainees are comparable to fully trained surgeons.

METHODS: A prospectively collected database of patients was created and information recorded regarding patient demographics, past medical history, preoperative investigations, grade of operating surgeon, type of AVF formed, primary AVF function, cumulative AVF survival and functional patency.

RESULTS: One hundred and sixty-two patients were identified as having had vascular access procedures during the 6 month study period and 143 were included in the final analysis. Secondary AVF patency was established in 123 (86%) of these AVFs and 89 (62.2%) were used for dialysis. There was no significant difference in survival of AVFs according to training status of surgeon (log rank x2 0.506 p=0.477) or type of AVF (log rank x2 0.341 p=0.559). Patency rates of successful AVFs at 1 and 2 years were 60.9% and 47.9%, respectively.

CONCLUSION: We have demonstrated in this prospective study that there are no significant differences in outcomes of primary AVFs formed by fully trained surgeons versus surgical trainees. Creation of a primary AVF represents an excellent training platform for intermediate stage surgeons across general and vascular surgical specialties.

A role of autophagy in PTP4A3-driven cancer progression

Autophagy, a "self-eating" cellular process, has dual roles in promoting and suppressing tumor growth, depending on cellular context. PTP4A3/PRL-3, a plasma membrane and endosomal phosphatase, promotes multiple oncogenic processes including cell proliferation, invasion, and cancer metastasis. In this study, we demonstrate that PTP4A3 accumulates in autophagosomes upon inhibition of autophagic degradation. Expression of PTP4A3 enhances PIK3C3-BECN1-dependent autophagosome formation and accelerates LC3-I to LC3-II conversion in an ATG5-dependent manner. PTP4A3 overexpression also enhances the degradation of SQSTM1, a key autophagy substrate. These functions of PTP4A3 are dependent on its catalytic activity and prenylation-dependent membrane association. These results suggest that PTP4A3 functions to promote canonical autophagy flux. Unexpectedly, following autophagy activation, PTP4A3 serves as a novel autophagic substrate, thereby establishing a negative feedback-loop that may be required to fine-tune autophagy activity. Functionally, PTP4A3 utilizes the autophagy pathway to promote cell growth, concomitant with the activation of AKT. Clinically, from the largest ovarian cancer data set (GSE 9899, n = 285) available in GEO, high levels of expression of both PTP4A3 and autophagy genes significantly predict poor prognosis of ovarian cancer patients. These studies reveal a critical role of autophagy in PTP4A3-driven cancer progression, suggesting that autophagy could be a potential Achilles heel to block PTP4A3-mediated tumor progression in stratified patients with high expression of both PTP4A3 and autophagy genes.

Prosthodontic care for elderly patients

For older patients, clinicians should consider maintaining teeth and using functionally-orientated treatment strategies as an alternative to removable prostheses. When the remaining dentition has a poor prognosis, key teeth should be preserved as overdenture abutments and a gradual transition to edentulousness planned. Where complete dentures are provided, these can be retained using dental implants to overcome many of the problems associated with conventional replacement dentures.

CLINICAL RELEVANCE: The elderly population of today is better informed and more demanding of oral healthcare providers than previous generations. Clinicians should be aware of all the prosthodontic treatment options available for older patients.

Pre-operative fasting for intravenous conscious sedation used in dental treatment: are conclusions based on relative risk management or evidence?

Intravenous sedation is a widely used pharmacological method of patient management commonly used in dental surgery for the treatment of anxious patients. Variety exists in fasting regimes between different centres offering dental sedation, with some advocating starvation in line with general anaesthesia protocols and others not enforcing starvation at all. The currently available guidelines on fasting protocols are ambiguous and open to interpretation partly because they are based on expert opinion rather than evidence-based research. This article reviews the available evidence on the subject of pre-operative fasting and discusses current guidelines.

Periodontal Manifestations of Chronic Atypical Neutrophilic Dermatosis With Lipodystrophy and Elevated Temperature (CANDLE) Syndrome in an 11 Year Old Patient

Introduction: Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) is an auto inflammatory syndrome caused by an autosomal recessive gene mutation. This very rare syndrome has been reported in only 14 patients worldwide. A number of clinical signs have been reported including joint contractures, muscle atrophy, microcytic anaemia, and panniculitis-induced childhood lipodystrophy. Further symptoms include recurrent fevers, purpuric skin lesions, periorbital erythema and failure to thrive. This is the first reported case of periodontal manifestations associated with CANDLE syndrome. 
Case Presentation: An 11 year old boy was referred to Cork University Dental School and Hospital with evidence of severe periodontal destruction. The patient’s medical condition was managed in Great Ormond Street Children’s Hospital, London. The patient’s dental management included initial treatment to remove teeth of hopeless prognosis followed by prosthodontic rehabilitation using removable partial dentures. This was followed by further non-surgical periodontal treatment and maintenance. In the long term, the potential definitive restorative options, including dental implants, will be evaluated in discussion with the patient’s medical team.
Conclusion: Periodontitis as a manifestation of systemic disease is one of seven categories of periodontitis as defined by the American Academy of Periodontology 1999 classification system. A number of systemic diseases have been associated with advanced periodontal destruction including Diabetes Mellitus, Leukaemia and Papillon-Lefevre Syndrome. In the case described, treatment necessitated a multidisciplinary approach with input from medical and dental specialities for a young patient with severe periodontal destruction associated with CANDLE syndrome.

Presentation of a plasmablastic lymphoma in a human immunodeficiency virus-positive patient after administration of an inferior alveolar dental block

Human immunodeficiency virus (HIV) is a serious worldwide healthcare problem with implications for all healthcare workers. The reported oral manifestations of the disease are numerous and have been categorised according to the strength of their association with HIV infection. Oral non-Hodgkin's lymphoma is strongly associated with HIV infection, and an increased incidence of such neoplasms is widely reported. This case report details the presentation of a rare subcategory of plasmablastic lymphoma in an HIV-positive patient after administration of an inferior alveolar dental block to facilitate extraction of mandibular teeth. This highly aggressive neoplasm is a large B-cell lymphoma with a predilection for the oral cavity. Unfortunately, the prognosis for such a tumour is poor as detailed in this case.

Barriers to Goals of Care Discussions With Seriously Ill Hospitalized Patients and Their Families: A Multicenter Survey of Clinicians

Importance: Seriously ill hospitalized patients have identified communication and decision making about goals of care as high priorities for quality improvement in end-of-life care. Interventions to improve care are more likely to succeed if tailored to existing barriers.

Objective: To determine, from the perspective of hospital-based clinicians, (1) barriers impeding communication and decision making about goals of care with seriously ill hospitalized patients and their families and (2) their own willingness and the acceptability for other clinicians to engage in this process.

Design, Setting, and Participants: Multicenter survey of medical teaching units of nurses, internal medicine residents, and staff physicians from participating units at 13 university-based hospitals from 5 Canadian provinces.

Main Outcomes and Measures: Importance of 21 barriers to goals of care discussions rated on a 7-point scale (1 = extremely unimportant; 7 = extremely important).

Results: Between September 2012 and March 2013, questionnaires were returned by 1256 of 1617 eligible clinicians, for an overall response rate of 77.7% (512 of 646 nurses [79.3%], 484 of 634 residents [76.3%], 260 of 337 staff physicians [77.2%]). The following family member-related and patient-related factors were consistently identified by all 3 clinician groups as the most important barriers to goals of care discussions: family members' or patients' difficulty accepting a poor prognosis (mean [SD] score, 5.8 [1.2] and 5.6 [1.3], respectively), family members' or patients' difficulty understanding the limitations and complications of life-sustaining treatments (5.8 [1.2] for both groups), disagreement among family members about goals of care (5.8 [1.2]), and patients' incapacity to make goals of care decisions (5.6 [1.2]). Clinicians perceived their own skills and system factors as less important barriers. Participants viewed it as acceptable for all clinician groups to engage in goals of care discussions-including a role for advance practice nurses, nurses, and social workers to initiate goals of care discussions and be a decision coach.

Conclusions and Relevance: Hospital-based clinicians perceive family member-related and patient-related factors as the most important barriers to goals of care discussions. All health care professionals were viewed as playing important roles in addressing goals of care. These findings can inform the design of future interventions to improve communication and decision making about goals of care.

RAS testing of colorectal carcinoma—a guidance document from the Association of Clinical Pathologists Molecular Pathology and Diagnostics Group

Analysis of colorectal carcinoma (CRC) tissue for KRAS codon 12 or 13 mutations to guide use of anti-epidermal growth factor receptor (EGFR) therapy is now considered mandatory in the UK. The scope of this practice has been recently extended because of data indicating that NRAS mutations and additional KRAS mutations also predict for poor response to anti-EGFR therapy. The following document provides guidance on RAS (i.e., KRAS and NRAS) testing of CRC tissue in the setting of personalised medicine within the UK and particularly within the NHS. This guidance covers issues related to case selection, preanalytical aspects, analysis and interpretation of such RAS testing.

miR-433 overexpression attenuates the spindle assembly checkpoint response to paclitaxel

Paclitaxel is a microtubule inhibitory chemotherapeutic drug that is increasingly used for the treatment of solid tumours. In vitro studies have demonstrated that attenuating the spindle assemble checkpoint (SAC) alters the post-mitotic responses to paclitaxel. Furthermore, the aberrant expression of a number of the SAC proteins, MAD2, BUBR1, and Aurora A kinase, are associated with poor patient prognosis. We have identified a microRNA, miR-433, that regulates the expression of MAD2. Overexpression of miR-433 in Hela cells induced downregulation of MAD2 mRNA and protein expression. We have also shown that Hela cells overexpressing miR-433 and treated with paclitaxel are no longer capable of cyclin B stabilisation, and thus have lost the ability to activate the SAC in response to paclitaxel. In addition, cell viability assays showed that Hela cells overexpressing miR-433 and treated with paclitaxel have an attenuated response to paclitaxel compared with microRNA scrambled controls. We have characterised the levels of miR-433, MAD2 gene expression and MAD2 protein levels in a cohort of ovarian cancer cell lines. Cell viability assays on this cohort revealed that responsiveness to paclitaxel is associated with high MAD2 protein expression and lower miR-433 expression. We hypothesise that the expression of miR-433 when deregulated in cancer leads to altered MAD2 expression and a compromised SAC, a key feature underlying drug resistance to paclitaxel. In a pilot study of paired human breast tumour and normal breast tissue samples we have shown that expression levels of miR-433 are elevated in cancer tissue. Targeting this microRNA in cancer may improve the efficacy of paclitaxel in treating breast cancer and ovarian cancer.

Prognostic significance of minichromosome maintenance proteins in breast cancer

A role for the minichromosome maintenance (MCM) proteins in cancer initiation and progression is slowly emerging. Functioning as a complex to ensure a single chromosomal replication per cell cycle, the six family members have been implicated in several neoplastic disease states, including breast cancer. Our study aim to investigate the prognostic significance of these proteins in breast cancer. We studied the expression of MCMs in various datasets and the associations of the expression with clinicopathological parameters. When considered alone, high level MCM4 overexpression was only weakly associated with shorter survival in the combined breast cancer patient cohort (n = 1441, Hazard Ratio = 1.31; 95% Confidence Interval = 1.11-1.55; p = 0.001). On the other hand, when we studied all six components of the MCM complex, we found that overexpression of all MCMs was strongly associated with shorter survival in the same cohort (n = 1441, Hazard Ratio = 1.75; 95% Confidence Interval = 1.31-2.34; p <0.001), suggesting these MCM proteins may cooperate to promote breast cancer progression. Indeed, their expressions were significantly correlated with each other in these cohorts. In addition, we found that increasing number of overexpressed MCMs was associated with negative ER status as well as treatment response. Together, our findings are reproducible in seven independent breast cancer cohorts, with 1441 patients, and suggest that MCM profiling could potentially be used to predict response to treatment and prognosis in breast cancer patients.