Safety of aromatase inhibitors in the adjuvant setting

The third-generation aromatase inhibitors (AIs) letrozole, anastrozole, and exemestane are replacing tamoxifen as adjuvant therapy in most postmenopausal women with early breast cancer. Although AIs have demonstrated superior efficacy and better overall safety compared with tamoxifen in randomized controlled trials, they may not provide the cardioprotective effects of tamoxifen, and bone loss may be a concern with their long-term adjuvant use. Patients require regular bone mineral density monitoring, and prophylactic bisphosphonates are being evaluated to determine whether they may protect long-term bone health. AIs decrease the risks of thromboembolic and cerebrovascular events compared with tamoxifen, and the overall rate of cardiovascular events in patients treated with AIs is within the range seen in age-matched, non-breast-cancer populations. AIs are also associated with a lower incidence of endometrial cancer and fewer vaginal bleeding/discharge events than tamoxifen. Compared with tamoxifen, the incidence of hot flashes is lower with anastrozole and letrozole but may be higher with exemestane. Generally, adverse events with AIs are predictable and manageable, whereas tamoxifen may be associated with life-threatening events in a minority of patients. Overall, the benefits of AIs over tamoxifen are achieved without compromising overall quality of life

Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

Genetics of disease, diagnosis and treatmen

Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials

Background Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. Methods We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). Findings Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5–14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21·4% for NACT versus 15·9% for adjuvant chemotherapy (5·5% increase [95% CI 2·4–8·6]; rate ratio 1·37 [95% CI 1·17–1·61]; p=0·0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38·2% for NACT vs 38·0% for adjuvant chemotherapy; rate ratio 1·02 [95% CI 0·92–1·14]; p=0·66), breast cancer mortality (34·4% vs 33·7%; 1·06 [0·95–1·18]; p=0·31), or death from any cause (40·9% vs 41·2%; 1·04 [0·94–1·15]; p=0·45). Interpretation Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered—eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy

The Influence of the 'Travels of Marco Polo' on Jacobo Gastaldi's Maps of Asia

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Increased expression of Ki-67 in mantle cell lymphoma is associated with de-regulation of several cell cycle regulatory components, as identified by global gene expression analysis

Background and Objectives. Mantle cell lymphoma (MCL) is an aggressive disease. Patients with this malignancy have a median survival of 3 years. To better understand disease progression, which is characterized by increased proliferation, we analyzed the gene expression of MCL with different proliferative indices, as determined by immunohistochemical staining for Ki-67. Furthermore, primary and relapsed tumors were compared to identify the possible growth advantages possessed by cells which persist after therapy and which might evolve into a tumor relapse. Design and Methods. Twenty-one samples of MCL were analyzed, using the Affymetrix U95Av2 chip, containing probes for approximately 12,000 transcripts. Samples with a high versus low fraction of Ki-67(+) cells were compared as were relapsed versus primary tumors. Immunohistochemistry was used to confirm the expression of some gene products. Results. A distinct genetic signature, consisting of 32 genes, was found when comparing Ki-67(high) with Ki-67(low) MCL. The signature consisted of genes involved in cellular processes, such as mitotic spindle formation, gene transcription and cell cycle regulation, e.g. components of the p53 and retinoblastoma protein (pRb) pathways. Of note, cyclin D1, the hallmark of MCL, as well as Ki-67 were up-regulated in the samples with a high proliferative index. Comparing primary vs. relapsed tumors, 26 individual genes were found, several involved in cell adhesion. Furthermore, increased expression of transferrin receptor was found in the relapsed tumors. Interpretation and Conclusions. A genetic signature distinguishing Ki-67(high) MCL from Ki-67(low) was established. The generated signature was used to assign new MCL samples to the high proliferative group, validating the association between these genes and proliferation in MCL