Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB-IVA mycosis fungoides/Sézary syndrome.

BACKGROUND: Quisinostat is a hydroxamate, second-generation, orally available pan-histone deacetylase inhibitor. OBJECTIVES: To evaluate the efficacy and safety of oral quisinostat in patients with previously treated cutaneous T-cell lymphoma (CTCL). METHODS: Patients received quisinostat 8 mg or 12 mg on days 1, 3 and 5 of each week in 21-day treatment cycles. Primary efficacy end point was cutaneous response rate (RR) based on the modified Severity Weighted Assessment Tool (mSWAT). Secondary end points included global RR, duration of response (DOR) in skin, progression-free survival (PFS), pruritus relief, safety and pharmacodynamic markers. RESULTS: Eight of 26 (25 evaluable) patients achieved ≥ 50% reduction in mSWAT score at least once, with confirmed cutaneous response in six (RR 24%). There was a low global RR of 8%. DOR in skin ranged from 2·8 to 6·9 months. Median PFS was 5·1 months. Pruritus relief was more frequent in cutaneous responders (67%) than nonresponders (32%). Serial tumour biopsies revealed an increase in acetylated tubulin, indicating a target effect of histone deacetylase 6. Twenty-one of 26 (81%) patients were withdrawn from the study before or at clinical cut-off; five (19%) continued to receive treatment with quisinostat. The most common drug-related adverse events were nausea, diarrhoea, asthenia, hypertension, thrombocytopenia and vomiting. Grade 3 drug-related adverse events included hypertension, lethargy, pruritus, chills, hyperkalaemia and pyrexia. CONCLUSIONS: Quisinostat 12 mg three times weekly is active in the treatment of patients with relapsed or refractory CTCL, with an acceptable safety profile. Combination therapy with other drugs active in CTCL may be appropriate.

Phase I and pharmacological study of the broad-spectrum tyrosine kinase inhibitor JNJ-26483327 in patients with advanced solid tumours.

BACKGROUND: JNJ-26483327 is an oral, potent, multi-targeted tyrosine kinase inhibitor, inhibiting kinases of epidermal growth factor receptor (EGFR)-1, -2 and -4, rearranged during transfection (RET) receptor, vascular endothelial growth factor receptor (VEGFR)-3 and Src family (Lyn, Fyn, Yes) at low nanomolar concentrations. This phase I, accelerated titration study assessed maximum tolerated dose, safety, pharmacokinetics and pharmacodynamic effects of JNJ-26483327. METHODS: Nineteen patients with advanced cancers received JNJ-26483327 continuous twice daily (BID) in escalating dose cohorts ranging from 100 to 2100 mg. Pharmacodynamic effects were assessed in paired skin biopsies and blood. RESULTS: JNJ-26483327 was well tolerated in doses up to 1500 mg BID, with target-inhibition-related toxicity such as diarrhoea and skin rash, and other common reported toxicities being nausea, vomiting, anorexia and fatigue. At 2100 mg, two episodes of dose-limiting toxicity were observed, consisting of grade 3 anorexia and a combination of grade 3 anorexia and fatigue, respectively. Pharmacokinetics were dose proportional up to 1500 mg in which plasma levels were obtained showing anti-tumour activity in xenograft mouse models. Pharmacodynamic analysis did not show a substantial effect on expression of Ki-67, p27(kip1), phosphorylated mitogen-activated protein kinase, phosphorylated Akt and EGFR, and serum levels of sVEGFR-2, VEGF-C and VEGF-D remained unchanged. Stable disease was noted in six patients (32%). CONCLUSION: JNJ-26483327 is well tolerated and shows a predictable pharmacokinetic profile; the recommended dose for further studies is 1500 mg BID.

[Interactions of carboplatin, cisplatin, and ionizing radiation on a human cell line of ovarian cancer]. / Interactions entre le carboplatine, le cisplatine et les rayonnements ionisants dans une lignée cellulaire humaine de cancer ovarien.

AIM OF THE STUDY: Cisplatin (CDDP) and radiotherapy are frequently used concomitantly in the treatment of various malignant conditions. Because of its toxicity, cisplatin tends to be replaced by carboplatin (CBDCA) in several indications. Available data regarding the combined effects of cisplatin and carboplatin with ionising radiation are contradictory. MATERIALS AND METHODS: Various concentrations of cisplatin and carboplatin and various timing of association with radiation have been tested in vitro in a human ovarian cancer cell line. The parental cell line (AOvC-0) and a cisplatin-resistant stable subline (AOvC-CDDP/0) (De Pooter et al., Canc Res, 1991) were exposed to carboplatin (2.5, 5 and 10 M) and to CDDP (1, 2.5 and 5 M), 16 h and 4 h before and 4 h and 16 h after irradiation, respectively. Cell survival was evaluated by a classical clonogenic assay. RESULTS: Exposure of AOvC-0 to 5 M CBDCA and of AOvC-CDDP/0 to 10 M CBDCA, before or shortly after radiation exposure, increased cell lethality in a clear supra-additive way, with the highest DEF in the shoulder region of the survival curve and at radiation doses relevant to clinical radiotherapy. In the sensitive cell line, 5 M carboplatin resulted in an additional lethality equivalent to 4.5 Gy; in the resistant cells, 10 M carboplatin was equivalent to 3.6 Gy. Replacing carboplatin by cisplatin in an identical set-up demonstrated exclusively simple additivity (DEF = 1). CONCLUSION: These data suggest that carboplatin and cisplatin delivered at equitoxic doses interact with radiation in a different way and that, in the present set-up, only carboplatin enhanced the effects of radiation. Carboplatin might consequently be a better candidate than cisplatin in some concomitant combinations with radiotherapy.

Prognostic value of bcl-2 expression in invasive breast cancer.

Expression of the bcl-2 proto-oncogene was studied immunohistochemically in 251 invasive ductal breast carcinomas (median follow-up time 91 months, range 24-186 months) and the results were correlated with clinicopathological data and prognostic variables. Sixty-three (25%) tumours were scored bcl-2 negative and 188 (75%) tumours were bcl-2 positive. No relationship could be observed between bcl-2 status and tumour grade, pTNM staging or menopausal status. A strong positive relationship was demonstrated between bcl-2 immunoreactivity and oestrogen receptor status (P < 0.001) and progesterone receptor status (P < 0.001). No prognostic value was demonstrated for bcl-2 expression on disease-free survival and overall survival in axillary node-negative breast cancer patients. However, in axillary node-positive breast cancer patients multivariate analysis demonstrated absence of bcl-2 expression to be independently related to shortened disease-free survival (P = 0.003) and shortened overall survival (P < 0.001). Our results suggest a potential important role for bcl-2 expression as a modulator of response to adjuvant therapy in breast cancer.

Fetal fibronectin detection for prediction of preterm birth in low risk women.

OBJECTIVE: To evaluate the clinical value of cervical fetal fibronectin detection by a quantitative enzyme-linked immunosorbent assay (ELISA) (PTDcheck, Adeza Biomedical, Sunnyvale, California, USA) as a screening tool for the prediction of preterm contractions and preterm delivery in an unselected population of pregnant women globally considered to be at low risk for preterm delivery (n = 133). DESIGN: A prospective study in which cervical fetal fibronectin samples were collected at two-week intervals between 26 and 36 weeks of gestation. SETTING: A regional training hospital. SUBJECTS: One hundred and thirty-three singleton pregnancies presenting consecutively at an antenatal clinic. MAIN OUTCOME MEASURE: Occurrence of preterm contractions and preterm delivery (delivery at < 37 weeks of gestation). RESULTS: Twenty-four (18%) patients were considered positive for the presence of fetal fibronectin. Overall 15 patients (11%) developed preterm contractions and, despite therapeutic intervention, 10 patients (8%) were delivered preterm. As a predictor for preterm contractions, cervical fetal fibronectin detection had a sensitivity of 47%, a specificity of 86%, a positive predictive value of 29% and a negative predictive value of 93%. As a predictor for preterm delivery, cervical fetal fibronectin detection had a sensitivity of 60%, a specificity of 85% a positive predictive value of 25% and a negative predictive value of 96%. CONCLUSIONS: Cervical fetal fibronectin determinations at a two-week sampling frequency for prediction of preterm birth in a general obstetric population at low risk for preterm birth has limited clinical value as a routinely performed screening procedure.

Immunohistochemical study of topoisomerase II-alpha expression in primary ductal carcinoma of the breast.

AIMS: To study the patterns of expression of topoisomerase II-alpha in primary invasive ductal breast carcinomas; to correlate this expression with clinicopathological data and prognosis. METHODS: Cryostat sections from 63 primary invasive ductal breast carcinomas were stained immunohistochemically for topoisomerase II-alpha. Nuclear immunoreactivity was quantified by counting at least 500 cells in different random fields and results were expressed as per cent of cells staining positively for topoisomerase II-alpha. RESULTS: Topoisomerase II-alpha nuclear immunoreactivity (median 14% of nuclei; range 2-62%) was detected in all tumours with highly variable intertumour and intratumour nuclear reactivity. Higher levels of topoisomerase II-alpha expression were strongly related to higher tumour grade, larger tumour size, nodal status, and the presence of distant metastases at diagnosis. No correlation was found with menopausal status, steroid hormone receptor status, disease free survival, or overall survival. CONCLUSIONS: Expression of topoisomerase II-alpha is related to the presence of poor prognostic factors. Immunohistochemical assessment of topoisomerase II-alpha expression in breast cancer could be potentially useful for tailoring chemotherapy with topoisomerase II inhibitors.

Serum hCG decline following salpingotomy or salpingectomy for extrauterine pregnancy.

Twenty-five women with ectopic pregnancy were surgically treated, fifteen by conservative salpingotomy and ten by radical salpingectomy. All patients showed a clinically normal postoperative course. Serum human chorionic gonadotropin (hCG) levels were determined serially before and after the surgical procedure until non-pregnant values (< 5 mI.U./ml) were reached. Serum hCG decline was compared between patients treated by salpingotomy versus salpingectomy, using calculated hCG half-life times. We observed a significantly slower decline of serum hCG levels during the early phase of hCG disappearance in patients treated by salpingotomy versus patients treated by salpingectomy.

Preliminary results with the use of the ROM-check immunoassay in the early detection of rupture of the amniotic membranes.

The unequivocal presence of amniotic fluid in the vagina is an important clinical sign of rupture of amniotic membranes, entailing impending delivery or risk for chorioamnionitis. Commonly used methods for detection of amniotic fluid in the vagina include pooling, ferning, nitrazine paper, ultrasound measurement of amniotic sac dimensions, dye injection or measurement of prolactin in vaginal secretions. These results are either difficult to interpret or are obtained after an invasive or expensive procedure. Measurement of alphafetoprotein (AFP) in vaginal secretions has also been considered for this application, but has proven unreliable due to its similar concentration in maternal plasma and amniotic fluid in the third trimester of pregnancy. We have evaluated a recently introduced method, the ROM-check Immunoassay (Adeza Biomedical, Sunnyvale, CA, USA) which is based on the detection of a fetal isoform of fibronectin in vaginal secretions when amniotic fluid is present. Our aim was to establish the reliability and clinical efficacy of this test in a number of obstetrical situations with unequivocal or equivocal rupture of the membranes (ROM). We conclude that in cases of unequivocal rupture and/or intactness of membranes, results of the ROM-check Immunoassay correspond well with the clinical findings, whereas in clinically equivocal rupture of the membranes, the test may add proof to the clinical suspicion of ROM but has to be interpreted with caution along with other clinical and non-clinical parameters.

Placebo-controlled trial of high-dose Mesterolone treatment of idiopathic male infertility.

The possible effect of Mesterolone (Schering N.V., Brussels, Belgium) (1 alpha-methyl-5-alpha-androstane-17 beta-ol-3-one) on semen quality and fertility of men with idiopathic oligoasthenospermia and/or teratozoospermia has been evaluated in a double-blind trial. The study included 52 patients who were treated during 12 months with either 150 mg/d of Mesterolone or placebo. The overall pregnancy rate was similar in the Mesterolone-treated cases (26%) and in the placebo control cases (48%), although a significant increase in motility and in the proportion of spermatozoa with normal morphology was recorded in the Mesterolone-treated cases. Because similar semen improvement also occurred in the placebo controls, our findings cast doubt on the possible usefulness of high-dose Mesterolone treatment of idiopathic male infertility.