Simulation as an effective means of preparing trainees for active participation in MDT meetings.

Introduction: Cancer multi-disciplinary team (MDT) meetings are an important component of consultant workload, however previous literature has suggested trainees are not satisfied with their current curriculum in preparing for MDT working. Methods: This educational pilot assessed whether multi-speciality simulated scenarios with pre-defined learning objectives, could prepare specialist registrars for interacting within an MDT. Participants completed pre- and post-questionnaires assessing a number of areas including: current experience of training, confidence presenting patients and whether the course would alter future practice. Results: Trainee confidence increased significantly from a mean of 5 to 7 (mean to nearest whole number, p < 0.01). Trainees rated the session highly for utility and altering their future practice (mean scores of 9 for both respectively, out of 10). Conclusion: Simulation has shown success in other multidisciplinary teaching, however to our knowledge there are no cancer specific training programmes. Our results highlight a potential gap in UK specialist training, and suggest simulation may be beneficial in preparing trainees to present in MDT meetings.

Correlation between BAP1 Localization, Driver Mutations, and Patient Survival in Uveal Melanoma.

Uveal melanoma (UM) is an uncommon but highly aggressive ocular malignancy. Poor overall survival is associated with deleterious BAP1 alterations, which frequently occur with monosomy 3 (LOH3) and a characteristic gene expression profile. Tumor DNA from a cohort of 100 UM patients from Moorfields Biobank (UK) that had undergone enucleation were sequenced for known UM driver genes (BAP1, SF3B1, EIF1AX, GNAQ, and GNA11). Immunohistochemical staining of BAP1 and interphase FISH for chromosomes 3 and 8 was performed, and cellular localization of BAP1 was correlated with BAP1 mutations. Wildtype (WT) BAP1 staining was characterized by nBAP1 expression with <10% cytoplasmic BAP1 (cBAP1). Tumors exhibited heterogeneity with respect to BAP1 staining with different percentages of nBAP1 loss: ≥25% loss of nuclear BAP1 (nBAP1) was superior to chr8q and LOH3 as a prognostic indicator. Of the successfully sequenced UMs, 38% harbored oncogenic mutations in GNA11 and 48% harbored mutations in GNAQ at residues 209 or 183. Of the secondary drivers, 39% of mutations were in BAP1, 11% were in EIF1AX, and 20% were in the SF3B1 R625 hotspot. Most tumors with SF3B1 or EIF1AX mutations retained nuclear BAP1 (nBAP1). The majority of tumor samples with likely pathogenic BAP1 mutations, regardless of mutation class, displayed ≥25% loss of nBAP1. This included all tumors with truncating mutations and 80% of tumors with missense mutations. In addition, 60% of tumors with truncating mutations and 82% of tumors with missense mutations expressed >10% cBAP1.

Sensitive screening of single nucleotide polymorphisms in cell free DNA for diagnosis of gestational tumours.

Tumours expressing human chorionic gonadotropin (hCG), the majority of which are difficult to biopsy due to their vascularity, have disparate prognoses depending on their origin. As optimal management relies on accurate diagnosis, we aimed to develop a sensitive cell free DNA (cfDNA) assay to non-invasively distinguish between cases of gestational and non-gestational origin. Deep error-corrected Illumina sequencing of 195 common single nucleotide polymorphisms (SNPs) in cfDNA and matched genomic DNA from 36 patients with hCG-secreting tumours (serum hCG 5 to 3,042,881 IU/L) and 7 controls with normal hCG levels (≤4 IU/L) was performed. cfDNA from confirmed gestational tumours with hCG levels ranging from 1497 to 700,855 IU/L had multiple (n ≥ 12) 'non-host' alleles (i.e. alleles of paternal origin). In such cases the non-host fraction of cfDNA ranged from 0.3 to 40.4% and correlated with serum hCG levels. At lower hCG levels the ability to detect non-host cfDNA was variable, with the detection limit dependent on the type of causative pregnancy. Patients with non-gestational tumours were identifiable by the absence of non-host cfDNA, with copy number alterations detectable in the majority of cases. Following validation in a larger cohort, our sensitive assay will enable clinicians to better inform patients, for whom biopsy is inappropriate, of their prognosis and provide optimum management.

An Association of Cancer Physicians' strategy for improving services and outcomes for cancer patients.

The Association of Cancer Physicians in the United Kingdom has developed a strategy to improve outcomes for cancer patients and identified the goals and commitments of the Association and its members.

Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer.

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37-1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10-0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46-2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC.

Evaluation of the red cell distribution width as a biomarker of early mortality in hepatocellular carcinoma.

BACKGROUND: The red cell distribution width is a biomarker of early mortality across various disease states. AIM: To verify whether it may refine estimates of survival in hepatocellular carcinoma. METHODS: The red cell distribution width measured at diagnosis was analyzed in relationship to mortality by any cause both in a retrospective training cohort (N=208), and in an independent prospectively collected validation cohort (N=106) of patients with hepatocellular carcinoma. Based on Cox proportional hazards modelling, a prognostic index was validated. RESULTS: In the training and the validation cohort, median survival time was respectively 1026 and 868 days in patients with red cell distribution width ≤14.6%, vs. 282 and 340 days in patients with red cell distribution width >14.6%; the corresponding hazard ratios were 0.43 (95% CI: 0.31-0.60), p<0.0001 and 0.28 (95% CI: 0.17-0.47), p<0.0001. At multivariate analysis, the red cell distribution width remained an independent predictor of survival (p<0.001) in a Cox model including other widely accepted prognostic factors. Applying to the validation dataset the prognostic index derived from the training dataset, the ability of the model to discriminate the survival probabilities of patients was confirmed (Harrell's C=0.769). CONCLUSIONS: The red cell distribution width is a novel, reproducible, prospectively validated predictor of survival in patients with hepatocellular carcinoma.

Transformation of oncology inpatients: effects on length of stay and patient satisfaction.

The oncology department at Imperial College Healthcare Trust ranked last in the National Cancer Patient Experience Survey in 2011/12 and 2012/13. Length of stay (LOS) was above national average. General Medical Council surveys of junior doctors highlighted significant issues with lack of senior review, education and working hours. Inpatient surveys echoed this with poor patient experience, and major complaints exposed lack of joint nursing and medical care. Restructuring the inpatient care pathway began in 2012 and centred around four target areas: 1) introduction of a ward based consultant; 2) defined admission criteria; 3) development of a cancer assessment unit; and 4) designated elective beds. Restructuring had a rapid effect on the service: total admissions per month declined from 246 in March 2013 to 183 in May 2014 and median LOS fell from 4.3 to 2 days over the same period (p<0.001). Complaints and serious incidents also fell and junior doctor satisfaction improved.

Multicenter experience of nonpegylated liposomal doxorubicin use in the management of metastatic breast cancer.

BACKGROUND: This study aimed to investigate the use of nonpegylated liposomal doxorubicin (NPLD) in the management of metastatic breast cancer (MBC) within routine UK clinical practice and to assess its efficacy and tolerability. PATIENTS AND METHODS: All patients that received NPLD for MBC at 5 institutions were identified. Clinicopathologic details, echocardiographic data, and toxicities were documented. Response to treatment, outcome, cardiotoxicity, and safety were assessed. RESULTS: 63 patients (median age at NPLD therapy, 53.5 years) who had received NPLD were identified; 18 (29%) were anthracycline-naïve, and 42 (67%) were anthracycline-pretreated (median cumulative dose of epirubicin, 450 mg/m(2)). In 3 cases, prior treatment history was not available. NPLD was most frequently (16 [25%] of 63 patients) administered as first-line chemotherapy (median, third-line; range, 1-9), although it was given later in anthracycline-pretreated patients (median, fourth-line; range, 1-9). Overall, 14 (29%) of 49 evaluable patients achieved an objective response, which increased to 10 (71%) of 14 when NPLD was given first-line (anthracycline-naïve, 8 [100%] of 8; anthracycline-pretreated, 2 [50%] of 4; adjuvant treatment unknown, 2). Median progression-free survival was 7 months (first-line, 18 months, vs. ≥ second-line, 6 months; P = .0066), and median overall survival was 10 months (first-line, 18 months, vs. ≥ second-line, 10 months; P = .0971). Toxicities tended to be grade 1 or 2. Three patients had cardiotoxicity (left ventricular ejection fraction < 50% or a fall of ≥ 10% from baseline), which resolved during treatment. CONCLUSION: NPLD was used in both anthracycline-naïve patients and those with prior exposure. There is evidence of clinical activity in those with prior exposure to anthracyclines, with a low incidence of cardiotoxicity.

Breast cancer: current and future endocrine therapies.

Endocrine therapy forms a central modality in the treatment of estrogen receptor positive breast cancer. The routine use of 5 years of adjuvant tamoxifen has improved survival rates for early breast cancer, and more recently has evolved in the postmenopausal setting to include aromatase inhibitors. The optimal duration of adjuvant endocrine therapy remains an active area of clinical study with recent data supporting 10 years rather than 5 years of adjuvant tamoxifen. However, endocrine therapy is limited by the development of resistance, this can occur by a number of possible mechanisms and numerous studies have been performed which combine endocrine therapy with agents that modulate these mechanisms with the aim of preventing or delaying the emergence of resistance. Recent trial data regarding the combination of the mammalian target of rapamycin (mTOR) inhibitor, everolimus with endocrine therapy have resulted in a redefinition of the clinical treatment pathway in the metastatic setting. This review details the current endocrine therapy utilized in both early and advanced disease, as well as exploring potential new targets which modulate pathways of resistance, as well as agents which aim to modulate adrenal derived steroidogenic hormones.

Revisiting the role of systemic therapies in patients with metastatic melanoma to the CNS.

The CNS is a common site of metastasis in patients with malignant melanoma. Locoregional control either with surgery or radiotherapy is first-line treatment for patients with brain metastasis should they be suitable candidates. For those patients who are not and those who progress after previous treatment, there is an unmet clinical need for effective systemic therapies. Systemic cytotoxics, such as temozolamide and fotemustine, have only modest activity, resulting in a median progression-free survival ranging from 1-2 months, in patients with metastatic melanoma to the brain. Newer systemic treatments such as vemurafenib and ipilimumab have been approved for the treatment of melanoma, but evidence regarding their activity in brain metastases is inconclusive due to the limited access of patients to clinical trials. This is now being revised and more data are emerging supporting the inclusion of patients with brain metastasis in trials. In this review, the authors present data regarding the efficacy of systemically administered therapies in patients with metastatic melanoma to the brain.

Role of fulvestrant in the management of postmenopausal breast cancer.

Fulvestrant is a form of endocrine therapy used in the treatment of postmenopausal breast cancer. It has a unique mechanism of action in that it causes the degradation of estrogen receptor and therefore has been labeled a selective estrogen receptor downregulator. Unlike the selective estrogen receptor modulator tamoxifen, it has no agonistic properties and is therefore a pure anti-estrogen. Given its low level of bioavailability and presystemic metabolism, it has been formulated as an intramuscular injection. A number of dosing regimens have been utilized - these include a dose of 250 mg monthly ('approved dose'), an initial 500 mg followed by 250 mg on days 14 and 28, and thereafter 250 mg every 28 days ('loading dose'), or 500 mg on days 0, 14 and 28, and thereafter every 28 days ('high dose'). This article will review its unique mode of action and preclinical data, as well as clinical data for different dosing regimens and data for its combination with aromatase inhibitors. Fulvestrant is a well-tolerated drug and its toxicities will also be reviewed. The optimal position of fulvestrant in sequential endocrine therapy has yet to be defined.

Irosustat: a first-generation steroid sulfatase inhibitor in breast cancer.

Endocrine therapy is a key modality in the management of breast cancer, with current options for postmenopausal women including tamoxifen, aromatase inhibitors and fulvestrant. Unfortunately, in spite of these advances, many women still relapse or progress on endocrine therapy. Given that resistance (de novo or acquired resistance) is a major limiting factor in the use of endocrine therapy, additional endocrine therapies with novel methods of action are required. Steroid sulfatase, which is responsible for the conversion of estrone sulfate to estrone, as well as dehydroepiandrosterone sulfate to dehydroepiandrosterone, has been implicated in endocrine resistance. In this article, we summarize the preclinical and clinical data to support the potential role of steroid sulfatase in breast cancer, as well as the current data on the first available steroid sulfatase inhibitor named irosustat (STX64; 667 Coumate; BN83495), and discuss its potential clinical development.

Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats.

BACKGROUND: Neuroapoptosis is induced by the administration of anesthetic agents to the young. As alpha2 adrenoceptor signaling plays a trophic role during development and is neuroprotective in several settings of neuronal injury, the authors investigated whether dexmedetomidine could provide functional protection against isoflurane-induced injury. METHODS: Isoflurane-induced injury was provoked in organotypic hippocampal slice cultures in vitro or in vivo in postnatal day 7 rats by a 6-h exposure to 0.75% isoflurane with or without dexmedetomidine. In vivo, the alpha2 adrenoceptor antagonist atipamezole was used to identify if dexmedetomidine neuroprotection involved alpha2 adrenoceptor activation. The gamma-amino-butyric-acid type A antagonist, gabazine, was also added to the organotypic hippocampal slice cultures in the presence of isoflurane. Apoptosis was assessed using cleaved caspase-3 immunohistochemistry. Cognitive function was assessed in vivo on postnatal day 40 using fear conditioning. RESULTS: In vivo dexmedetomidine dose-dependently prevented isoflurane-induced injury in the hippocampus, thalamus, and cortex; this neuroprotection was attenuated by treatment with atipamezole. Although anesthetic treatment did not affect the acquisition of short-term memory, isoflurane did induce long-term memory impairment. This neurocognitive deficit was prevented by administration of dexmedetomidine, which also inhibited isoflurane-induced caspase-3 expression in organotypic hippocampal slice cultures in vitro; however, gabazine did not modify this neuroapoptosis. CONCLUSION: Dexmedetomidine attenuates isoflurane-induced injury in the developing brain, providing neurocognitive protection. Isoflurane-induced injury in vitro appears to be independent of activation of the gamma-amino-butyric-acid type A receptor. If isoflurane-induced neuroapoptosis proves to be a clinical problem, administration of dexmedetomidine may be an important adjunct to prevent isoflurane-induced neurotoxicity.

Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain.

BACKGROUND: Anesthetics, including isoflurane and nitrous oxide, an antagonist of the N-methyl-D-aspartate subtype of the glutamate receptor, have been demonstrated to induce apoptotic neurodegeneration when administered during neurodevelopment. Xenon, also an N-methyl-D-aspartate antagonist, not only lacks the characteristic toxicity produced by other N-methyl-D-aspartate antagonists, but also attenuates the neurotoxicity produced by this class of agent. Therefore, the current study sought to investigate xenon's putative protective properties against anesthetic-induced neuronal apoptosis. METHOD: Separate cohorts (n = 5 or 6 per group) of 7-day-old rats were randomly assigned and exposed to eight gas mixtures: air, 75% nitrous oxide, 75% xenon, 0.75% isoflurane, 0.75% isoflurane plus 35% or 75% nitrous oxide, 0.75% isoflurane plus 30% or 60% xenon for 6 h. Rats were killed, and cortical and hippocampal apoptosis was assessed using caspase-3 immunostaining. In separate cohorts, cortices were isolated for immunoblotting of caspase 3, caspase 8, caspase 9, and cytochrome c. Organotypic hippocampal slices of postnatal mice pups were derived and cultured for 24 h before similar gas exposures, as above, and subsequently processed for caspase-3 immunostaining. RESULTS: In vivo administration of isoflurane enhances neuronal apoptosis. When combined with isoflurane, nitrous oxide significantly increases whereas xenon significantly reduces apoptosis to a value no different from that of controls. In vitro studies corroborate the ability of xenon to attenuate isoflurane-induced apoptosis. Isoflurane enhanced expression of indicators of the intrinsic and common apoptotic pathways; this enhancement was increased by nitrous oxide but attenuated by xenon. CONCLUSIONS: The current study demonstrates that xenon prevents isoflurane-induced neonatal neuronal apoptosis.