A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma.

BACKGROUND: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry. RESULTS: Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P < 0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P < 0.001) and activated CD86+CD27+ memory B cells (P < 0.001), as an immunopharmacodynamic marker of CD40 activation. CONCLUSIONS: CP-870,893 with cisplatin and pemetrexed is safe and tolerable at 0.15 mg/kg, although most patients experience CRS. While objective response rates are similar to chemotherapy alone, three patients achieved long-term survival. AUSTRALIA NEW ZEALAND CLINICAL TRIALS REGISTRY NUMBER: ACTRN12609000294257.

Suspected serotonin syndrome in a patient being treated with methylene blue for ifosfamide encephalopathy.

Methylene blue has been used not only as a diagnostic agent, but also as an agent in the treatment of ifosfamide-induced encephalopathy (IIE) for several years. Recently, several cases of suspected serotonin syndrome have been reported in patients who received methylene blue in combination with serotonin active agents. Rodent models have revealed that methylene blue is a potent, reversible inhibitor of monoamine oxidase A. It is well known that serotonin active drugs, in combination with monoamine oxidase inhibitors can produce profound serotonin syndrome. To date, cases of serotonin syndrome, which resulted from concurrent methylene blue and serotonin active agents, have been published in the anesthesia literature. We report the first known case of serotonin syndrome in a patient receiving methylene blue for IIE.

The effect of transcervical uterine manipulations on establishment of uterine infection in mares under the influence of progesterone.

Four pony mares were used in a cross-over study to investigate the effect of different treatments on experimentally-induced endometritis. The mares were treated with progesterone to facilitate establishment of uterine infections. They received an intrauterine infusion of Streptococcus zooepidemicus 5 days after the start of progesterone therapy. Five days later, they were treated by intrauterine infusions of 2 g ampicillin in 50 ml sterile water or by sterile water without antibiotic for 3 consecutive days. Prior to infusion of Strep. zooepidemicus, no bacteria were cultured from the uteri of the mares. However, 5 days after infusion of Strep. zooepidemicus and prior to antibiotic therapy, mixed bacterial growths were cultured from endometrial swabbings. After antibiotic therapy, ampicillin-resistant organisms were cultured from endometrial swabbings. Two other progesterone-treated mares received an intrauterine infusion of sterile phosphate buffered saline instead of bacteria. Mixed bacterial cultures were recovered 5 days later from the endometrial swabbings of these mares. It was concluded that the high circulating concentrations of progesterone were probably responsible for the treatment failure and that in clinical situations, therapy involving transcervical manipulations should not be administered when mares are in diestrus.

Measurement by ELISA of equine alpha-1-proteinase inhibitor in uterine flushings from mares.

An enzyme linked immunosorbent assay (ELISA) was developed and used to estimate the concentrations of the serine proteinase inhibitor, alpha-1 proteinase inhibitor (API), in uterine flushings recovered from mares at different stages of the oestrous cycle and before and after the induction of experimental endometritis. There was a significant increase in the concentrations of API and albumin relative to total protein in flushings recovered during oestrus compared with dioestrus but no difference was observed in the concentrations of these proteins relative to total protein before and after the induction of endometritis. A regression analysis revealed a significant correlation between the concentrations of albumin and API in the flushings examined, suggesting that the API was derived entirely from serum and was not produced locally in the uterus.

Characteristics of cyclicity in maiden thoroughbred mares in the United Kingdom.

The characteristics of the cyclicity of 12 maiden thoroughbred mares kept in two groups were studied over a total of 58 cycles. On average, oestrus lasted 5.3 days and in 60 per cent of the cycles ovulation occurred in the last two days of oestrus. Oestrus and ovulation tended to be synchronised in each group of mares. The mean diameter of single-ovulating preovulatory follicles on the day before ovulation was 41.5 mm and during the seven days before ovulation they grew 2.5 mm/day. More than one follicle ovulated in 19 (33 per cent) of the cycles (seven double ovulations and 12 dioestrous ovulations). All the oestrous mares and 25 per cent of the mares with dioestrous ovulations had uterine oedema on the day before ovulation.

Haemoglobinuria due to Clostridium perfringens type A mastitis in a ewe.

A 2-year-old Suffolk gimmer presented with clinical signs of haemoglobinuria, jaundice, anaemia and acute mastitis. Clinical investigation and bacteriological examination of milk samples revealed Clostridium perfringens type A to be the causal agent.

Huntington disease in Maryland: clinical aspects of racial variation.

In a Maryland survey of Huntington disease, the prevalence in blacks was unexpectedly high and equal to that in whites. Age at onset was earlier in blacks, and their clinical features, at all ages at onset, were similar to those seen in juvenile-onset Huntington disease. Blacks had more severe bradykinesia and abnormalities of eye movement and less frequent psychiatric disorder, particularly depression.