Hypericum perforatum treatment: effect on behaviour and neurogenesis in a chronic stress model in mice

<p>Abstract</p> <p>Background</p> <p>Extracts of <it>Hypericum perforatum </it>(St. John's wort) have been traditionally recommended for a wide range of medical conditions, in particular mild-to-moderate depression. The present study was designed to investigate the effect of Hypericum perforatum treatment in a mouse model of anxiety/depressive-like behavior, induced by chronic corticosterone administration.</p> <p>Methods</p> <p>CD1 mice were submitted to 7 weeks corticosterone administration and then behavioral tests as Open Field (OF), Novelty-Suppressed Feeding (NSF), Forced Swim Test (FST) were performed. Cell proliferation in hippocampal dentate gyrus (DG) was investigated by both 5-bromo-2'-deoxyuridine (BrdU) and doublecortin (DCX) immunohistochemistry techniques and stereological procedure was used to quantify labeled cells. Golgi-impregnation method was used to evaluate changes in dendritic spines in DG. Hypericum perforatum (30 mg/Kg) has been administered for 3 weeks and then neural development in the adult hippocampus and behavioral changes have been examined.</p> <p>Results</p> <p>The anxiety/depressive-like state due to chronic corticosterone treatment was reversed by exogenous administration of Hypericum perforatum; the proliferation of progenitor cells in mice hippocampus was significantly reduced under chronic corticosterone treatment, whereas a long term treatment with Hypericum perforatum prevented the corticosterone-induced decrease in hippocampal cell proliferation. Corticosterone-treated mice exhibited a reduced spine density that was ameliorated by Hypericum perforatum administration.</p> <p>Conclusion</p> <p>These results provide evidence of morphological adaptations occurring in mature hippocampal neurons that might underlie resilient responses to chronic stress and contribute to the therapeutic effects of chronic Hypericum perforatum treatment.</p

A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients

The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin in combination with infusional 5-fluorouracil (5-FU) and folinic acid (FA) administered every 2 weeks (FOLFOX-4 regimen) in patients with advanced gastric cancer (AGC). A total of 61 previously untreated AGC patients were treated with oxaliplatin 85 mg m−2 on day 1, FA 200 mg m−2 as a 2 h infusion followed by bolus 5-FU 400 mg m−2 and a 22 h infusion of 5-FU 600 mg m−2, repeated for 2 consecutive days every 2 weeks. All patients were assessable for toxicity and response to treatment. Four (7%) complete responses and 19 partial responses were observed (overall response rate, 38%). Stable disease was observed in 22 (36%) patients, with progressive disease in the other six (10%) patients. Median time to progression (TTP) and median overall survival (OS) were 7.1 and 11.2 months, respectively. National Cancer Institute Common Toxicity Criteria grade 3 and 4 haematologic toxicities were neutropenia, anaemia and thrombocytopenia in 36, 10 and 5% of the patients, respectively. Grade 3 peripheral neuropathy was recorded in three (5%) patients. FOLFOX-4 is an active and well-tolerated chemotherapy. Response rate (RR), TTP and OS were comparable with those of other oxaliplatin-based regimens, suggesting a role for this combination in gastric cancer

Purinergic signalling and immune cells

This review article provides a historical perspective on the role of purinergic signalling in the regulation of various subsets of immune cells from early discoveries to current understanding. It is now recognised that adenosine 5'-triphosphate (ATP) and other nucleotides are released from cells following stress or injury. They can act on virtually all subsets of immune cells through a spectrum of P2X ligand-gated ion channels and G protein-coupled P2Y receptors. Furthermore, ATP is rapidly degraded into adenosine by ectonucleotidases such as CD39 and CD73, and adenosine exerts additional regulatory effects through its own receptors. The resulting effect ranges from stimulation to tolerance depending on the amount and time courses of nucleotides released, and the balance between ATP and adenosine. This review identifies the various receptors involved in the different subsets of immune cells and their effects on the function of these cells

20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years

The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment

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

CD4-8- T-cells increase in MRL/lpr mice treated with thymic factors

The in vivo effect of thymic factors on immature lymphocytes was analysed in MRL/lpr mice. This strain carries a genetic defect that causes during their life cycle a block of T-cell differentiation and abnormal proliferation of CD4(-)8(-) (double-negative, DN) T-lymphocytes. In vivo administration of four preparations of thymic factors, thymopentin (TP-1), thymopoietin (TP-5), thymolymphotropin (TLT), and thymomodulin (TMD) into young (2-month-old) MRL/lpr mice induced a significant increase of DN T-cells both in the thymus and in the peripheral lymph nodes, with a concomitant decrease of double-positive (DP) T-cells in the thymus and of single-positive (SP) T-cells in the lymph nodes. The level of DNA fragmentation measured as propidium iodide fluorescence was increased in the thymus population of young mice and in the lymph node population of old mice treated with TLT. SCID mice transplanted with lymph node cells from MRL/lpr donors (MRL-->SCID) developed graft versus host (GVH) reaction due to the activation of MRL CD8(+) alloreactive T-cells. This model was used to analyse the effect of TMD/TLT in vivo on MRL cell proliferation and expansion; in fact, spleen cells from MRL-->SCID mice after treatment with TMD/TLT showed an increased cell proliferation, and an expansion of DN T-cells with a concomitant decrease of SP cells (both CD4(+) and CD8(+) cells). Decreased SP cell numbers in this context could explain why TMD/TLT treatment of SCID mice engrafted with MRL cells increased their survival compared to untreated MRL-->SCID mice

Abstract P6-14-01: The effect trial: A randomized phase II trial evaluating two different doses of weekly (W) NAB-paclitaxel (NP) as first-line chemotherapy in older breast cancer (BC) patients (pts)

Abstract Background: W taxanes (T) are commonly used in the treatment of older BC pts, with neurotoxicity (NTX) and fatigue being dose-limiting toxicities with a possible negative impact on function. No prospective data exists on the safety and efficacy of W NP in this population. NP might be of particular value in older pts, due to no need for premedication with steroids and shorter time to recovery from neurotoxicity than conventional T, resulting in a reduced risk of exacerbation of comorbidities such as hypertension and diabetes, and possibly of functional decline (FD). Methods: Pts aged ≥ 65 years (y) with Her-2 negative or Her-2 positive (+), but contraindicated to anti-Her-2 therapy, advanced BC were randomized to receive NP as first-line chemotherapy at either 100 (Arm A) or 125 mg/m2 (Arm B), days 1, 8, 15 q 28. The primary end-point was event-free survival (EFS). An event was either disease progression (PD), death, or FD - defined as a decrease of at least 1 point from baseline values of activities of daily living (ADL) or instrumental ADL (IADL), deemed by the investigator as treatment-related and confirmed at the subsequent cycle. Secondary endpoints included progression-free survival (PFS), response rate (RR) in pts with measurable disease, and incidence of adverse events (AEs). Results: From January 2013 to September 2016, 160 pts were randomized in 15 Italian centres; all but 2 who never started NP were eligible for final analysis. Pts median age was 72y (range 65-84) in Arm A and 73y (range 65-88) in Arm B. Median ECOG performance status was 0 (range 0-2). Baseline IADL impairment was reported in 20 pts (25%) in both arms. &amp;gt;80% pts had ER+ tumors; 2 pts had HER2+ disease. Visceral disease was present in 71% (Arm A) and 70% (Arm B) of pts. Prior exposure to T in the neo/adjuvant setting was 14% (Arm A) and 13% (Arm B). Median number of delivered cycles of NP was 6 (range 1-28 in Arm A, and 1-22 in Arm B), with 3 pts still on treatment. Dose reductions were similarly reported (72% of pts Arm A, 78% of pts Arm B). At a median follow-up of 21 months (mos) (Interquartile range 14-28.4) 140 events were observed. Arm A/Arm B: PD n=53(67%)/n=52(66%); FD n=13(15%)/n=14(18%), death n=3(4%)n=5(6%). Outcomes data are reported in the following table: Outcomes Arm AArm BMedian EFS, mos (90% CI)6.2 (5.5-8.4)6.4 (5.8-7.7)Median PFS, mos (95% CI)8.3 (5.9-10.5)8.8 (7.4-10.3)RR (95% CI)37% (25-50)42% (30-54) Fatigue (Arm A: grade (G)2 29%, G3 11%; Arm B: G2 46%, G3 5%) and NTX (Arm A: G2 15%, G3 4%; Arm B: G2 28%, G3 8%) were the most frequently reported AEs. No G4 AEs were reported with the exception of neutropenia (1 pt in arm A) and leucopenia (3 pts in Arm A, 1 pt in arm B). 1 G5 (sepsis) was recorded in Arm B. NTX was reported as the reason for treatment discontinuation in 21 pts (13%) of whom 16 (21%) in arm B. Conclusion: Looking at classical study endpoints (PFS, RR), both doses of NP are active in older pts. However, 17% of pts had to stop treatment due to FD, assessed according to predefined criteria. Due to similar efficacy and reduced NTX, W NP 100 is the suggested dose to be used in older pts with advanced BC. Citation Format: Biganzoli L, Berardi R, Pedersini R, Minisini AM, Caremoli ER, Spazzapan S, Lima JS, Baldari D, Orlando L, Magnolfi E, Pistelli M, Brunello A, Zafarana E, Bernardo A, Leo S, Colleoni M, Donati S, De Placido S, Parolin V, Vitale S, Di Leo A, Puglisi F, Boni L, Cinieri S. The effect trial: A randomized phase II trial evaluating two different doses of weekly (W) NAB-paclitaxel (NP) as first-line chemotherapy in older breast cancer (BC) patients (pts) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-14-01.</jats:p

Abstract S5-06: Epirubicin and cyclophosphamide (EC) followed by paclitaxel (T) versus fluorouracil, epirubicin and cyclophosphamide (FEC) followed by T, all given every 3 weeks or 2 weeks, in node-positive early breast cancer (BC) patients (pts). Final results of the gruppo Italiano mammella (GIM)-2 randomized phase III study

Abstract Background. Using a 2 × 2 factorial design, we compared the efficacy of two different schedules of chemotherapy (CT), dose-dense (DD) every 2 weeks versus standard duration every 3 weeks and the role of Fluorouracil (F) in addition to EC, in the adjuvant treatment of node positive BC pts. Patients and Methods. Node positive early BC pts younger than 70 years were eligible and randomly assigned to one of the following treatment arms: ARM A (4 courses of EC [90/600 mg/m2, on day 1, q 21] followed by 4 courses of T [175 mg/m2 on day 1, q 21]); ARM B (4 courses of FEC [600/90/600 mg/m2, on day 1, q 21] followed by 4 courses of T [175 mg/m2 on day 1, q 21]); ARM C (4 courses of EC [90/600 mg/m2, on day 1, q 14] followed by 4 courses of T [175 mg/m2 on day 1, q 14]); ARM D (4 courses of FEC [600/90/600 mg/m2, on day 1, q 14] followed by 4 courses of T [175 mg/m2 on day 1, q 14]). Pts enrolled in the DD arms (ARM C and D) received subcutaneous pegfilgrastim (6 mg) 24 hours after CT. HER2-positive pts enrolled after April 2006 received trastuzumab for 1 year at the end of CT. The primary study endpoint was disease free survival (DFS). Secondary endpoints included overall survival (OS) and toxicity. All analyses were conducted according to the intention-to-treat principle. Results. From April 2003 to July 2006, 2091 pts were enrolled (545 in ARM A, 544 in ARM B, 502 in ARM C, 500 in ARM D). The planned number of CT cycles was completed in 89% of pts in the DD group and in 88.1% of pts in the standard duration group. Pts treated with DD CT (ARM C + ARM D) experienced more frequently anemia (all grades: 67.2% vs 49.5%, p &amp;lt; .0001; G3-G4: 0.2% vs 1.4%, p = .004) and bone pain (53.5% vs 39.2%, p &amp;lt; .0001). Neutropenia occurred more frequently in standard duration arms (ARM A + ARM B): 66.7% vs 28.0%, p = &amp;lt; .0001. At a median follow up of 7.0 years, multivariate analysis, showed that DD treatments (ARM C + ARM D vs ARM A + ARM B) improved the primary endpoint, DFS (hazard ratio [HR] = 0.78; 95% CI 0.66-0.94; p = .007), and OS (HR = 0.68; 95% CI 0.52-0.87; p = .002). Conversely, the addition of F to EC did not improve clinical outcomes: the HR for DFS and OS (ARM A + ARM C vs ARM B + ARM D) were respectively 0.98 (95% CI 0.83-1.17; p = .85) and 0.93 (95% CI 0.73-1.19; p = .578). Subgroup analyses revealed that the benefits associated with DD CT were independent of hormone receptor status: in hormone receptor positive the HRs for DFS and OS were 0.80 (0.65-0.98) and 0.69 (0.51-0.93) respectively; in hormone receptor negative the HRs for DFS and OS were 0.67 (0.47-0.95) and 0.57 (0.36-0.92) respectively (p for interaction for DFS: 0.339; p for interaction for OS: 0.495). Pathological tumor size, nodal status (1-3 vs ≥ 4 positive nodes), histological grade and hormone receptor status were independently associate with DFS and OS. Conclusions. DD CT as adjuvant treatment in node positive BC pts, improves DFS and OS significantly. Conversely, the addition of F to EC does not improve clinical outcomes. (ClinicalTrials.gov number, NCT00433420). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-06.</jats:p