Expert UK consensus on the definition of high risk of recurrence in HER2-negative early breast cancer: A modified Delphi panel.

BACKGROUND: There is currently no standardised definition for patients at high risk of recurrence of human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC; stages 1-3) after surgery. This modified Delphi panel aimed to establish expert UK consensus on this definition, separately considering hormone receptor (HR)-positive and triple-negative (TN) patients. METHODS: Over three consecutive rounds, results were collected from 29, 24 and 22 UK senior breast cancer oncologists and surgeons, respectively. The first round aimed to determine key risk factors in each patient subgroup; subsequent rounds aimed to establish appropriate risk thresholds. Consensus was pre-defined as ≥70% of respondents. RESULTS: Expert consensus was achieved on need to assess age, tumour size, tumour grade, number of positive lymph nodes, inflammatory breast cancer and risk prediction tools in all HER2-negative patients. There was additional agreement on use of tumour profiling tests and biomarkers in HR-positive patients, and pathologic complete response (pCR) status in TN patients. Thresholds for high recurrence risk were subsequently agreed. In HR-positive patients, these included age <35 years, tumour size >5 cm (as independent risk factors); tumour grade 3 (independently and combined with other high-risk factors); number of positive nodes ≥4 (independently) and ≥1 (combined). For TN patients, the following thresholds reached consensus, both independently and in combination with other factors: tumour size >2 cm, tumour grade 3, number of positive nodes ≥1. CONCLUSIONS: The results may be a valuable reference point to guide recurrence risk assessment and decision-making after surgery in the HER2-negative eBC population.

Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial.

BACKGROUND: The ARTemis trial previously reported that addition of neoadjuvant bevacizumab (Bev) to docetaxel (D) followed by fluorouracil, epirubicin and cyclophosphamide (D-FEC) in HER2 negative breast cancer improved the pathological complete response (pCR) rate. We present disease-free survival (DFS) and overall survival (OS) with central pathology review. PATIENTS AND METHODS: Patients were randomized to 3 cycles of D followed by 3 cycles of FEC (D-FEC), ±4 cycles of Bev (Bev + D-FEC). DFS and OS were analyzed by treatment and by central pathology reviewed pCR and Residual Cancer Burden (RCB) class. RESULTS: A total of 800 patients were randomized [median follow-up 3.5 years (IQR 3.2-4.4)]. DFS and OS were similar across treatment arms [DFS hazard ratio (HR)=1.18 (95% CI 0.89-1.57), P = 0.25; OS HR = 1.26 (95% CI 0.90-1.76), P = 0.19). Both local pathology report review and central histopathology review confirmed a significant improvement in DFS and OS for patients who achieved a pCR [DFS HR = 0.38 (95% CI 0.23-0.63), P < 0.001; OS HR = 0.43 (95% CI 0.24-0.75), P = 0.003]. However, significant heterogeneity was observed (P = 0.02); larger improvements in DFS were obtained with a pCR achieved with D-FEC than a pCR achieved with Bev + D-FEC. As RCB class increased, significantly worse DFS and OS was observed (P for trend <0.0001), which effect was most marked in the ER negative group. CONCLUSIONS: The addition of short course neoadjuvant Bev to standard chemotherapy did not demonstrate a DFS or OS benefit. Achieving a pCR with D-FEC is associated with improved DFS and OS but not when pCR is achieved with Bev + D-FEC. At the present time therefore, Bev is not recommended in early breast cancer. CLINICALTRIALS.GOV NUMBER: NCT01093235.

Understanding of BRCA VUS genetic results by breast cancer specialists.

BACKGROUND: Mainstreaming genetic medicine, increased media coverage and clinical trials for BRCA mutation carriers are leading oncologists into more patient discussions about BRCA genetic testing. BRCA variants of uncertain significance (VUS) occur in 10-20% of tests. VUS detection introduces additional uncertainty for patient and potentially clinician. We aimed to explore the ability of breast cancer specialists (BCS) in the UK to correctly respond to a VUS report. METHODS: A survey sent to 800 UK BCS collected demographics data, VUS general knowledge and interpretation and communication based on two genetics reports. A separate survey of UK clinical geneticists collected demographics data, laboratory reporting practice and methods used to clarify VUS pathogenicity including classification systems. RESULTS: Of the 155 BCS (22.5%) who completed the survey, 12% reported no genetics training. Ninety five percent referred patients for BRCA genetic tests, 71% felt unsure about the clinical implications of the test reports presented here. A VUS report from a patient with a positive family history was interpreted and theoretically communicated correctly by 94% but when presented with a different VUS report with no management guidance and negative family history, 39% did not know how to communicate this result to the patient. Geneticists reported multiple VUS classification systems; the most commonly used was word-based in 32%. CONCLUSIONS: A consistent and standardised format to report particularly VUS results across all diagnostic laboratories plus additional training of UK BCS will be necessary for effective mainstreaming of BRCA testing to the oncology clinic.

Overview of anterior and posterior crossbites in children.

Crossbites are a prevalent condition in children. They represent a challenge to the clinician in both diagnosis and treatment planning. Crossbites may be dental or skeletal in etiology. A thorough clinical assessment and accurate records are necessary. Treatment modalities will vary according to the specific diagnosis.

Volatile anesthetics and NMDA receptors. Enflurane inhibition of glutamate-stimulated [3H]MK-801 binding and reversal by glycine.

The influence of enflurane, a volatile general anesthetic, on [3H]MK-801 binding to a site in the ion channel of the N-methyl-D-aspartate (NMDA) receptor was determined in membranes from rat cerebral cortex. Enflurane disrupted glutamate stimulation of [3H]MK-801 (1 nM) binding with an IC50 of 0.4 mM. This inhibition was associated with a decrease in receptor affinity with no change in the number of [3H]MK-801 binding sites. Basal [3H]MK-801 binding measured in the absence of glutamate was not affected by enflurane. In contrast, [3H]CGS-19775 binding to the glutamate recognition site on the NMDA receptor was only weakly inhibited by enflurane (e.g., less than 20% inhibition of 5 nM [3H]CGS binding by 1.2 mM enflurane). Glycine, a positive allosteric NMDA receptor modulator, markedly attenuated the inhibition of glutamate-stimulated [3H]MK-801 binding by enflurane, with an EC50 of approximately 0.8 microM. Thus, enflurane selectively inhibits glutamate activation of the NMDA receptors, and an allosteric modulator attenuates this action. These effects could reflect anesthetic action at the glycine binding site or at another, undefined site which influences activation of the ion channel. These findings raise the possibility that inhibition of transmission at NMDA receptors contributes to the development of the anesthetic state.

The effect of dental amalgam restorations on blood mercury levels.

Mercury levels in blood and in mouth air before and after chewing were measured in 47 persons with and 14 persons without dental amalgam restorations. Questionnaires relating to exogenous sources of mercury exposure were administered to both groups. Differences in the mouth air mercury levels before and after chewing were statistically significant in the group with amalgams, but not in the group without amalgams. Analysis of the data from the questionnaires indicated that little or no exogenous exposure to mercury occurred among the two groups. Blood mercury concentrations were positively correlated with the number and surface area of amalgam restorations and were significantly lower in the group without dental amalgams.