Cisplatin plus cytosine arabinoside in adults with malignant gliomas

Summary A combination of cisplatin and cytosine arabinoside was used to treat 21 patients with glioblastomas and 5 patients with recurrent grade 11 gliomas. Cisplatin 60–100 mg/m² was given I.V. in 250 ml 0.45% saline and preceded by 500 ml dextrose 5% in 0.45% saline. Mannitol 50 g was given I.V. concurrently with the cisplatin. Cytosine arabinoside 500–1000 mg/m² was given by rapid I.V. infusion immediately after the cisplatin. Of 25 evaluable patients, 10 (40%) experienced objective tumor shrinkage on CT scan, and 6 (24%) stabilized. There were 2 complete remissions. Patients who had had no prior treatment had a higher response rate (58%) than those previously treated (23%). Myelosuppression occurred in some patients 2–3 weeks after treatment. Gastrointestinal toxicity (vomiting and diarrhea) was dose-limiting. Two patients had possible neurological toxicity. Recommended doses for further studies are cisplatin 90 mg/m² and cytosine arabinoside 900 mg/m².     

Histopathologic quantification of viable tumor versus treatment effect in surgically resected recurrent glioblastoma

Journal of Neuro-Oncology - The prognostic impact of the histopathologic features of recurrent glioblastoma surgical specimens is unknown. We sought to determine whether key histopathologic...     

A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer

Background

This phase I, four-arm, open-label study (NCT01347866) evaluated the PI3K/mTOR inhibitors PF-04691502 (arms A, B) and gedatolisib (PF-05212384; arms C, D) in combination with the MEK inhibitor PD-0325901 (arm A, D) or irinotecan (arm B, C) in patients with advanced solid tumors.

Objectives

Primary endpoint was dose-limiting toxicity with each combination. Secondary endpoints included safety, pharmacokinetics and preliminary antitumor activity.

Patients and Methods

Dose escalation followed a 3 + 3 design in arm C and a zone-based design in arm D.

Results

The PF-04691502 combination arms were closed prematurely due to low tolerability, and the maximum tolerated doses (MTDs) were not determined for either arm. The MTD for the combination of gedatolisib with irinotecan 180 mg/m² was estimated to be 110 mg weekly and for the combination with PD-0325901 was not reached at the highest dose evaluated (gedatolisib 154 mg weekly). Plasma concentrations of gedatolisib were generally similar across dose groups in arm C (with irinotecan) and arm D (with PD-0325901). Frequent dose delays or dose reductions were required for both combinations, potentially preventing sustained therapeutic drug concentrations. Gedatolisib plus irinotecan produced a response rate of ~5% and clinical benefit in 16% of patients with advanced colorectal cancer (progression-free survival, 2.8 months). Preliminary evidence of clinical activity was observed with gedatolisib plus PD-0325901 in patients with ovarian cancer (three partial responses, n = 5) or endometrial cancer (one partial response, n = 1) and KRAS mutations.

Conclusions

Further evaluations of gedatolisib are warranted in patients with advanced solid malignancies.

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Application of intracytoplasmic sperm injection in assisted reproductive technologies

Intracytoplasmic sperm injection (ICSI) entails the mechanical insertion of a chosen spermatozoon directly into the cytoplasm of an oocyte. Due to the consistent fertilization and pregnancy outcome, ICSI is routinely used to treat azoospermic patients where spermatozoa are retrieved by epididymal aspiration or testicular biopsy. Since male subfertility has been associated with a higher incidence of genomic defects, ranging from numerical chromosomal abnormalities to Yq microdeletions, concerns have been raised as to the risk of transmitting genetic defects to the offspring. Screening for such defects can provide invaluable information for appropriate counselling prior to ICSI treatment. In order to address these concerns, a follow-up of the children born after ICSI treatment was conducted.     

Association of markers of tumor aggressivity and cognition in women with breast cancer before adjuvant treatment: The Thinking and Living with Cancer Study

Breast Cancer Research and Treatment - Tumor features associated with aggressive cancers may affect cognition prior to systemic therapy. We evaluated associations of cognition prior to adjuvant...     

Enhanced human nail drug delivery: nail inner drug content assayed by new unique method.

The purpose of this study was to develop an assay method of the human inner nail plate and to compare nail drug penetration by a penetrating enhancing formulation (the test carrier formulation). The test carrier and saline formulations were tested using radiolabeled urea, ketoconazole, and salicylic acid. After twice dosing daily for 7 days on human nail plates, the under inner section of the nail plate was assayed for absorbed drug content using a unique drilling/removal system. Results show that the weight-normalized radioactivity contents of three chemicals in the inner intermediate nail plate center in the carrier formulation were two fold higher than those from saline (p < 0.05). Total radioactivity recovery of dosed [(14)C]-salicylic acid was 89 +/- 2% in the carrier formulation and 88 +/- 5% in saline. In saline formulation, salicylic acid showed greater binding to the outer nail, making it less bioavailable for the inner nail area. This didn't occur with carrier formulation. In conclusion, topical treatment of nail diseases such as onychomycosis is not yet sufficiently effective, likely because of minimal drug penetration into the inner nail plate where the disease perpetuates. The assay system has the unique characteristic of being able to assay the inner part of the nail where the disease resides.