Effect of Electroacupuncture on Hyperalgesia and Vasoactive Neurotransmitters in a Rat Model of Conscious Recurrent Migraine.

Migraine onset is associated with the abnormal release of vasoactive neurotransmitters from perivascular nerves, and these neurotransmitters are involved in the pathophysiology of migraine. Hyperalgesia is a key feature of migraine, and accumulating evidence indicates that electroacupuncture (EA) at the single acupuncture point (Fengchi [GB20]) is effective in ameliorating hyperalgesia. In clinical practice, multiple acupuncture points are widely used, especially GB20 and Yanglingquan (GB34). However, the role played by vasoactive neurotransmitters in acupuncture antihyperalgesic effect at the single or multiple acupuncture points remains unknown. We aimed to determine whether EA would exert its antihyperalgesic effects by modulating vasoactive neurotransmitter release from the perivascular nerves. Furthermore, we examined whether targeting multiple acupuncture points would be more effective than targeting a single point in reducing hyperalgesia. The mechanical and thermal hyperalgesia were evaluated by measuring the facial and hind-paw mechanical withdrawal thresholds, tail-flick and hot-plate latencies. Plasma concentrations of vasoactive neurotransmitters were determined using rat-specific ELISA kits from jugular vein, including calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), pituitary adenylate cyclase-activating polypeptide (PACAP), nitric oxide (NO), and endothelin-1 (ET-1). The result suggested that EA significantly ameliorated the mechanical and thermal hyperalgesia, reduced c-Fos levels in the trigeminal ganglion, and attenuated plasma and dural levels of vasoactive neurotransmitters, especially in the multiple acupuncture points group (GB20+GB34). In conclusion, EA exerts antihyperalgesic effect in a rat model of conscious recurrent migraine, possibly via modulation of the vasoactive neurotransmitters. Furthermore, targeting multiple acupuncture points is more effective than targeting a single point in reducing hyperalgesia.

Endocrine therapy or chemotherapy as first-line therapy in hormone receptor-positive HER2-negative metastatic breast cancer patients.

BACKGROUND: For hormone receptor-positive (HR+) human epidermal growth factor receptor 2 (HER2-) negative metastatic breast cancer (MBC), international guidelines recommend endocrine therapy as first-line treatment, except in case of 'visceral crisis'. In the latter case, chemotherapy is preferred. Few studies have compared these two strategies. We used the Epidemiological Strategy and Medical Economics (ESME) programme, UNICANCER, a large national observational database (NCT03275311), to address this question. METHODS: All patients who initiated treatment for a newly diagnosed HR+ HER2-negative MBC between January 2008 and December 2014 in any of the 18 French Comprehensive Cancer Centers participating to ESME were selected. Patients should be aromatase inhibitor (AI)-sensitive (no previous AI or relapse occurring more than 1 year after last adjuvant AI). Objectives of the study were evaluation of progression-free and overall survival (OS) according to the type of first-line treatment adjusted on main prognostic factors using a propensity score. RESULTS: Six thousand two hundred sixty-five patients were selected: 2733 (43.6%) received endocrine therapy alone, while 3532 (56.4%) received chemotherapy as first-line therapy. Among the latter, 2073 (58.7%) received maintenance endocrine therapy. Median OS was 60.78 months (95% confidence interval [CI], 57.16-64.09) and 49.64 months (95% CI, 47.31-51.64; p < 0.0001) for patients receiving endocrine therapy alone and chemotherapy ± maintenance endocrine therapy, respectively. However, this difference was not significant after adjusting on the propensity score (hazard ratio: 0.943, 95% CI 0.863-1.030, p = 0.19). CONCLUSION: In this large retrospective cohort of patients with AI-sensitive metastatic luminal BC, OS was similar, whether first-line treatment was chemotherapy or endocrine therapy. In agreement with international guidelines, endocrine therapy should be the first choice for first-line systemic treatment for MBC in the absence of visceral crisis.

Multitarget botanical pharmacotherapy in major depression: a toxic brain hypothesis.

A significant number of patients with major depression do not respond optimally to current antidepressant drugs. As depression is likely to be a heterogeneous disorder, it is possible that existing neurotransmitter-based antidepressant drugs do not fully address other pathologies that may exist in certain cases. Biological pathologies related to depression that have been proposed and studied extensively include inflammation and immunology, hypercortisolemia, oxidative stress, and impaired angiogenesis. Such pathologies may induce neurodegeneration, which in turn causes cognitive impairment, a symptom increasingly being recognized in depression. A neurotoxic brain hypothesis unifying all these factors may explain the heterogeneity of depression as well as cognitive decline and antidepressant drug resistance in some patients. Compared with neurotransmitter-based antidepressant drugs, many botanical compounds in traditional medicine used for the treatment of depression and its related symptoms have been discovered to be anti-inflammatory, immunoregulatory, anti-infection, antioxidative, and proangiogenic. Some botanical compounds also exert actions on neurotransmission. This multitarget nature of botanical medicine may act through the amelioration of the neurotoxic brain environment in some patients resistant to neurotransmitter-based antidepressant drugs. A multitarget multidimensional approach may be a reasonable solution for patients resistant to neurotransmitter-based antidepressant drugs.

Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study.

BACKGROUND: Neoadjuvant trials conducted using a double HER2 blockade with lapatinib and trastuzumab, combined with different paclitaxel-containing chemotherapy regimens, have shown high pathological complete response (pCR) rates, but at the cost of important toxicity. We hypothesised that this toxicity might be due to a specific interaction between paclitaxel and lapatinib. This trial assesses the toxicity and activity of the combination of docetaxel with lapatinib and trastuzumab. PATIENTS AND METHODS: Patients with stage IIA to IIIC HER2-positive breast cancer received six cycles of chemotherapy (three cycles of docetaxel followed by three cycles of fluorouracil, epirubicin, cyclophosphamide). They were randomised 1 : 1 : 1 to receive during the first three cycles either lapatinib (1000 mg orally daily), trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), or trastuzumab + lapatinib at the same dose. The primary end point was pCR rate defined as ypT0/is. Secondary end points included safety and toxicity. pCR rate defined as ypT0/is ypN0 was assessed as an exploratory analysis. In June 2012, arm A was closed for futility based on the results from other studies. RESULTS: From October 2010 to January 2013, 128 patients were included in 14 centres. The percentage of the 122 assessable patients with pCR in the breast, and pCR in the breast and nodes, was numerically highest in the lapatinib + trastuzumab group (60% and 56%, respectively), intermediate in the trastuzumab group (52% and 52%), and lowest in the lapatinib group (46% and 36%). Frequency (%) of the most common grade 3-4 toxicities in the lapatinib /trastuzumab/lapatinib + trastuzumab arms were: febrile neutropenia 23/15/10, diarrhoea 9/2/18, infection (other) 9/4/8, and hepatic toxicity 0/2/8. CONCLUSIONS: This study demonstrates a numerically modest pCR rate increase with double anti-HER2 blockade plus chemotherapy, but suggests that the use of docetaxel rather than paclitaxel may not reduce toxicity. CLINICALTRIALSGOV: NCT00450892.

High rate of extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer.

BACKGROUND: A dose-dense strategy has been considered to improve results of adjuvant chemotherapy for breast cancer. This randomised phase II trial investigated the feasibility of this approach with sequential anthracyclines and taxanes-based chemotherapy. METHODS: Patients with high-risk node-positive breast cancer were treated with three cycles of fluorouracil 500 mg m(-2), epirubicin 100 mg m(-2), cyclophosphamide 500 mg m(-2) (FEC 100) followed by three cycles of docetaxel 100 mg m(-2) delivered at 2-weekly intervals supported by primary prophylaxis with filgrastim. All patients were randomised to either uninterrupted treatment (arm A) or to have a 2-week additional period of rest between the FEC and docetaxel (arm B). The primary endpoint was the rate of success of chemotherapy delivery. Using a two-stage Fleming design, 120 patients were required with one interim analysis. RESULTS: In March 2005, enrolment was stopped into arm A after the observation of severe skin toxicities. Following the planned interim analysis, the study was closed because of the high rate of grade 3/4 skin toxicities in both arms (arm A: 32.4% and arm B: 18.9%). CONCLUSION: Sequential dose-dense FEC 100 followed by docetaxel 100 mg m(-2) is not feasible. Feasibility still depends largely on several factors including the choice of drugs, dosage and sequence of administration.

Clinical and pathological response to primary chemotherapy in operable breast cancer.

Neoadjuvant chemotherapy is used to improve patients' survival in locally-advanced and inflammatory breast cancer and to increase conservative surgical procedures in bulky tumours. Pathological complete responses are unusual. The aim of this pilot study was to assess the clinical and pathological response rates and to evaluate toxicity with a new protocol of primary chemotherapy in 50 high-risk breast cancer patients. All tumours were > 3 cm and had at least one other adverse prognostic factor: lymph node involvement (32 N1, 6 N2), SBR grade III (20), aneuploidy (29), negative hormonal receptors (19). Patients were treated by 3-week cycles of THP-doxorubicin 20 mg/m2 D1 to 3, vinorelbine 25 mg/m2 D1 and 4, cyclophosphamide 300 mg/m2 and 5-fluorouracil 400 mg/m2 D1 to 4 (TNCF). 38 patients received G-CSF or GM-CSF support. After 4-6 cycles, all underwent surgery (39 conservative, 11 modified radical). Tumour response was assessed clinically, by mammography and echography and on pathological specimens. An objective clinical response was observed for 43 patients: 26 complete (51%) and 18 partial (37%). After pathological review, 11 patients (22%) were devoid of any tumour cells, 4 others (8%) had only in situ carcinoma. From 253 evaluated cycles, grade III-IV toxicity occurred, 81% with neutropenia, 25% with anaemia, and 20% with thrombocytopenia. All patients recovered. This regimen induced a severe but not life-threatening haematological toxicity and resulted in a high pathological response rate (30%).

Long-term prognostic and predictive factors in 107 stage II/III breast cancer patients treated with anthracycline-based neoadjuvant chemotherapy.

The heterogeneity of therapeutic modalities and eligibility criteria and the lack of long-term follow-up in most reports of neoadjuvant chemotherapy for breast cancer preclude us from drawing conclusions about its value in clinically relevant patient subgroups. The present study aims to identify predictive and prognostic factors in 107 non-inflammatory stage II/III breast cancer patients treated between November 1980 and October 1991 with an anthracycline-based induction regimen before locoregional surgery. Preoperative chemotherapy comprised 3-6 cycles of doxorubicin (pirarubicin after 1986), vindesine, cyclophosphamide and 5-fluorouracil. Type of subsequent surgery and adjuvant treatment were decided individually. In analysis of outcome, univariate comparisons of end points were made using the log-rank test, and significant (P < or = 0.05) pre- and post-therapeutic factors were incorporated in a Cox multivariate analysis. With a median follow-up of 81 months (range 32-164+ months), the median disease-free survival (DFS) is 90.5 months while median overall survival has not yet been reached. Cytoprognostic grade and histopathological response in both the primary and lymph nodes were independent covariates associated with locoregional relapse with or without DFS and overall survival. Eleven patients with pathological complete response remain free of disease with a 68-month median follow-up, while the 18 with residual microscopic disease on the specimen showed a 60% cumulative incidence of locoregional recurrence. Despite encouraging response rates based on clinical or radiological evaluation (87% or 70%), neither method showed any significant correlation with pathological response and failed to contribute prognostic information on patients' outcome. Pathological evaluation of antitumoral activity of primary chemotherapy remains a major source of prognostic information and might be used to select patients in need of additional adjuvant treatment.