Influence of advanced age on the blastocyst development rate and pregnancy rate in assisted reproductive technology

Objective: To evaluate the percentage of blastocysts developing, the pregnancy rate, the implantation rate, and the abortion rate in women >40 years of age using a cell-free culture system for the development of viable human blastocysts.

Design: Retrospective clinical study.

Setting: Private IVF units.

Patient(s): Two hundred ninety-three cycles in patients undergoing IVF treatment for infertility. Sixty-two cycles were in patients ≥40 years of age, and 231 cycles were in patients <40 years of age.

Intervention(s): Pronucleate oocytes obtained from IVF were cultured in vitro for 5–6 days. One to four embryos were transferred.

Main Outcome Measure(s): Blastocyst development rate, pregnancy rate, implantation rate, and abortion rate.

Result(s): From 293 cycles, 3,115 pronucleate oocytes were cultured, producing 1,175 blastocysts. In the women >40 years of age, the blastocyst development rate was 22.2%, and in the younger group, the rate was 40.5%. The pregnancy rate and implantation rate in the ≥40-year age group were 21.1% and 8.9%, respectively; corresponding rates in the younger group were 44.6% and 19.9%. The abortion rate was increased for the ≥40-year age group (25% versus 13.3%).

Conclusion(s): Success rates for the development of viable human blastocysts, pregnancy, and implantation decline significantly in women ≥40 years old.     

Optical imaging of apoptosis as a biomarker of tumor response to chemotherapy

A rapid and accurate assessment of the antitumor efficacy of new therapeutic drugs could speed up drug discovery and improve clinical decision making. Based on the hypothesis that most effective antitumor agents induce apoptosis, we developed a near-infrared fluorescent (NIRF) annexin V to be used for optical sensing of tumor environments. To demonstrate probe specificity, we developed both an active (i.e., apoptosis-recognizing) and an inactive form of annexin V with very similar properties (to account for nonspecific tumor accumulation), and tested the agents in nude mice each bearing a cyclophosphamide (CPA) chemosensitive (LLC) and a chemoresistant LLC (CR-LLC). After injection with active annexin V, the tumor-annexin V ratio (TAR; tumor NIRF/background NIRF) for untreated mice was 1.22+/-0.34 for LLC and 1.43+/-0.53 for CR-LLC (n=4). The LLC of CPA-treated mice had significant elevations of TAR (2.56+/-0.29, P=.001, n=4), but only a moderate increase was obtained for the CR-LLC (TAR=1.89+/-0.19, P=.183). The in vivo measurements correlated well with terminal deoxyribosyl transferase-mediated dUTP nick end labeling indexes. When inactive Cy-annexin V was used, with or without CPA treatment and in both CCL and CR-CCL tumors, tumor NIRF values ranged from 0.91 to 1.17 (i.e., tumor were equal to background). We conclude that active Cy-annexin V and surface reflectance fluorescence imaging provide a nonradioactive, semiquantitative method of determining chemosensitivity in LLC xenografts. The method maybe used to image pharmacologic responses in other animal models and, potentially, may permit the clinical imaging of apoptosis with noninvasive or minimally invasive instrumentation.     

Significant clinical benefit of first-line palliative chemotherapy in advanced soft-tissue sarcoma: retrospective analysis and identification of prognostic factors in 488 patients

BACKGROUND: The efficacy of palliative chemotherapy was investigated in a large group of patients with advanced soft-tissue sarcomas (STS) treated on routine palliative protocols. METHODS: Patients with STS who had first-line chemotherapy for advanced and/or metastatic disease between 1991 and 2005 were identified from the Royal Marsden Hospital's sarcoma database. Patients with Ewing sarcoma, rhabdomyosarcoma, desmoplastic small round cell tumor, and gastrointestinal stromal tumors were excluded from the study. RESULTS: In all, 488 patients (242 male, 246 female) fulfilled the study criteria. The median age was 49 years and the majority (83%) received chemotherapy for metastatic disease. The most common histologic subtypes were leiomyosarcoma (35%) synovial sarcoma (13%), liposarcoma (10%), and malignant fibrous histiocytoma (10%). In all, 61% received single-agent chemotherapy, usually doxorubicin. An objective response was reported in 33% of patients (53% in those with synovial sarcoma); 22% had stable disease and 45% derived 'clinical benefit' (objective responses + stable disease for >or= 6 months). Median duration of response was 9 months and median posttreatment overall survival (OS) was 12 months. In multivariate analysis, age <40 years, liposarcoma, and synovial histology were found to be positive, and bone involvement to be negative, independent prognostic factors. Patients treated with combination chemotherapy experienced longer OS than those treated with a single agent. CONCLUSIONS: Palliative chemotherapy may be beneficial in approximately half of patients with advanced STS. Synovial sarcoma and liposarcoma subtypes have a better prognosis. However, the overall poor outcome of these patients indicates the need to continue the search for more effective agents.     

Natural and vaccine-induced immunity against Haemophilus influenzae type b in patients with beta-thalassemia

Natural and vaccine-induced immunity and immunological memory to Haemophilus influenzae type b (Hib) were evaluated in adolescents and adults with beta-thalassemia. At baseline 10/23 (43%) unvaccinated patients had naturally acquired anticapsular antibodies >0.15 microg/ml, the threshold of protection, compared to 9/10 (90%) aged-matched controls. Hib-conjugate vaccine (PRP-T) induced protective immune responses in all subjects and there were no differences in geometric mean concentrations at 1 month (GMC) between patients and controls (69.04 versus 40.5, respectively). Vaccine-induced immunological memory was assessed in 12 subjects with beta-thalassemia who had been vaccinated against Hib in the past. All subjects had retained PRP>1 microg/ml at baseline; PRP-T revaccination induced anamnestic responses which were similar, in terms of post vaccination antibody concentration (P=0.54) and avidity (P=0.08), with primary responses given by previously unvaccinated patients. A single dose of PRP-T induces adequate and long-lasting immunity and should be given in all unvaccinated adolescents and adults with beta-thalassemia.     

Memory encoding in hippocampal ensembles is negatively influenced by cannabinoid CB1 receptors

It has previously been demonstrated that the detrimental effect on the performance of a delayed nonmatch to sample (DNMS) memory task by exogenously administered cannabinoid (CB1) receptor agonist, WIN 55212-2 (WIN), is reversed by the receptor antagonist rimonabant. In addition, rimonabant administered alone elevates DNMS performance, presumably through the suppression of negative modulation by released endocannabinoids during normal task performance. Other investigations have shown that rimonabant enhances encoding of DNMS task-relevant information on a trial-by-trial, delay-dependent basis. In this study, these reciprocal pharmacological actions were completely characterized by long-term, chronic intrahippocampal infusion of both agents (WIN and rimonabant) in successive 2-week intervals. Such long-term exposure allowed extraction and confirmation of task-related firing patterns, in which rimonabant reversed the effects of CB1 agonists. This information was then utilized to artificially impose the facilitatory effects of rimonabant and to reverse the effects of WIN on DNMS performance, by delivering multichannel electrical stimulation in the same firing patterns to the same hippocampal regions. Direct comparison of normal and WIN-injected subjects, in which rimonabant injections and ensemble firing facilitated performance, verified reversal of the modulation of hippocampal memory processes by CB1 receptor agonists, including released endocannabinoids.     

An unusual case of colonic mass

Colonic metastasis due to pancreatic adenocarcinoma is extremely rare. Although it is rare, colonic metastasis should be included in the differential diagnosis of colonic mass.     

The insulin-like growth factor-I receptor inhibitor figitumumab (CP-751,871) in combination with docetaxel in patients with advanced solid tumours: results of a phase Ib dose-escalation, open-label study

Background:

This phase Ib trial assessed safety, tolerability, and maximum tolerated dose (MTD) of figitumumab (CP-751,871), a fully human monoclonal antibody targeting the insulin-like growth factor type 1 receptor (IGF-IR), in combination with docetaxel.

Methods:

Patients with advanced solid tumours were treated with escalating dose levels of figitumumab plus 75 mg m^–2 docetaxel every 21 days. Safety, efficacy, pharmacokinetics (PKs), and biomarker responses were evaluated.

Results:

In 46 patients, no dose-limiting toxicities were attributable to the treatment combination. Grade 3 and 4 toxicities included neutropaenia (n=28), febrile neutropaenia (n=11), fatigue (n=10), leukopaenia (n=7), diarrhoea (n=5), hyperglycaemia, lymphopaenia, cellulitis, DVT, and pain (all n=1). The MTD was not reached. Four partial responses were observed; 12 patients had disease stabilisation of ⩾6 months. Pharmacokinetic and biomarker analyses showed a dose-dependent increase in plasma exposure, and complete sIGF-IR downregulation at doses of ⩾3 mg kg^–1. Pharmacokinetics of docetaxel in combination was similar to when given alone. Out of 18 castration-resistant prostate cancer patients, 10 (56%) had ⩾5 circulating tumour cells (CTCs) per 7.5 ml of blood at baseline: 6 out of 10 (60%) had a decline from ⩾5 to <5 CTCs and 9 out of 10 (90%) had a ⩾30% decline in CTCs after therapy.

Conclusions:

Figitumumab and docetaxel in combination are well tolerated. Further evaluation is warranted.