Formation and antitumor activity of PNU-159682, a major metabolite of nemorubicin in human liver microsomes.

PURPOSE: Nemorubicin (3'-deamino-3'-[2'(S)-methoxy-4'-morpholinyl]doxorubicin; MMDX) is an investigational drug currently in phase II/III clinical testing in hepatocellular carcinoma. A bioactivation product of MMDX, 3'-deamino-3',4'-anhydro-[2'(S)-methoxy-3'(R)-oxy-4'-morpholinyl]doxorubicin (PNU-159682), has been recently identified in an incubate of the drug with NADPH-supplemented rat liver microsomes. The aims of this study were to obtain information about MMDX biotransformation to PNU-159682 in humans, and to explore the antitumor activity of PNU-159682. EXPERIMENTAL DESIGN: Human liver microsomes (HLM) and microsomes from genetically engineered cell lines expressing individual human cytochrome P450s (CYP) were used to study MMDX biotransformation. We also examined the cytotoxicity and antitumor activity of PNU-159682 using a panel of in vitro-cultured human tumor cell lines and tumor-bearing mice, respectively. RESULTS: HLMs converted MMDX to a major metabolite, whose retention time in liquid chromatography and ion fragmentation in tandem mass spectrometry were identical to those of synthetic PNU-159682. In a bank of HLMs from 10 donors, rates of PNU-159682 formation correlated significantly with three distinct CYP3A-mediated activities. Troleandomycin and ketoconazole, both inhibitors of CYP3A, markedly reduced PNU-159682 formation by HLMs; the reaction was also concentration-dependently inhibited by a monoclonal antibody to CYP3A4/5. Of the 10 cDNA-expressed CYPs examined, only CYP3A4 formed PNU-159682. In addition, PNU-159682 was remarkably more cytotoxic than MMDX and doxorubicin in vitro, and was effective in the two in vivo tumor models tested, i.e., disseminated murine L1210 leukemia and MX-1 human mammary carcinoma xenografts. CONCLUSIONS: CYP3A4, the major CYP in human liver, converts MMDX to a more cytotoxic metabolite, PNU-159682, which retains antitumor activity in vivo.     

Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study.

PURPOSE: The long-term survival of children between age 12 and 24 months with stage 4 neuroblastoma and nonamplified MYCN (MYCN-NA) has not been defined previously. PATIENTS AND METHODS: Survival for stage 4 MYCN-NA neuroblastoma patients enrolled onto Children's Cancer Group (CCG) protocols 321P2 (1986 to 1991) and 3891 (1991 to 1996) was analyzed. Treatment consisted of intensive alkylator-based induction chemotherapy with or without autologous bone marrow transplantation (ABMT) with or without 13 cis-retinoic acid. Survival was analyzed by age strata less than 12, 12 to 18, 18 to 24, and more than 24 months at diagnosis. Patients younger than 12 months were treated on the moderate-intensity CCG protocol 3881. RESULTS: Forty-three patients with stage 4 MYCN-NA disease enrolled onto CCG-321P2 (n = 17) or CCG-3891 (n = 26) were between 12 and 24 months of age at diagnosis. After a median follow-up of 94 months (range, 4 to 140 months), the 6-year event-free survival (EFS) for the 12- to 18-month age group was superior to that of the 18- to 24-month age group (74% +/- 8% v 31% +/- 12%; P = .008). The EFS for children older than 24 months with stage 4 MYCN-NA neuroblastoma was 23% +/- 3%, and for children younger than 12 months was 92% +/- 3%. CONCLUSION: Children diagnosed with stage 4 MYCN-NA neuroblastoma in the second year of life form a transitional group between infants and older children in terms of prognosis. Patients between 12 and 18 months of age have significantly better long-term survival than that of older children treated with intensive chemotherapy with or without ABMT. These patients may not benefit from additional intensification of therapy beyond that provided in earlier clinical trials and may even maintain this high survival rate with less intensive therapy.     

Sport activities and exercise as part of routine cancer care in children and adolescents

The burden of morbidities affecting cardiovascular and musculoskeletal systems, metabolism, and psychosocial health in young patients with cancer is high. It is alarming that patients and survivors of childhood cancer are less physically active than their healthy peers, since exercise may improve many of these conditions significantly and is associated with reduction in all‐cause mortality in the general population. Systematic integration of exercise programing into cancer care remains an exception, above all in children. Pediatric oncologists may contribute to a culture shift towards educating patients and stakeholders on the benefit of exercise and sports for children and adolescents with cancer.     

Hexamethylmelamine, methotrexate, 5-fluorouracil as second line chemotherapy after platinum for epithelial ovarian malignancies

Thirty-three patients were treated with HexAF after previous treatment with cyclophosphamide (C), Adriamycin (A), and cisplatin (P). The patients had either progressed on CAP, had persistent disease after CAP, or recurred after a negative second look. Treatment schedule was hexamethylmelamine (Hex) 150 mg po qd days 1-14, methotrexate (A) 40 mg/m2 IV days 1 and 8, and 5-fluorouracil (F) 600 mg/m2 IV days 1 and 8. Courses were repeated every 4 weeks. Thirty-one of 33 patients were evaluable for response. Three of 31 patients had partial responses, 7 of 31 had stable disease, and 21 of 31 progressed. Median survival of the responders (n = 3) was 23 months and the nonresponders (n = 28) was 6 months (p = 0.027). Patients with less than 1 cm disease (n = 12) had a median survival of 20 months, and those with greater than 1 cm (n = 21) had a median survival of 6 months (p = 0.004). Toxicity was mild. Even with a statistically significant survival advantage for HexAF responders, we consider a response rate of less than 10% unacceptable.     

Thyroid cancer in adolescents and young adults

In adolescents and young adults, thyroid cancer accounts for 13% of all invasive neoplasms, being three times more frequent in females, but overdiagnosis and overtreatment are common. There are two therapeutic approaches, one radical and no longer preferred in all instances, and the other conservative. Permanent complications of surgery and metabolic irradiation can affect quality of life and carry an economic burden. The overall survival rate approaches 100% for patients with differentiated thyroid cancer regardless of the extent of treatment. Medullary thyroid carcinoma is a very different entity, occurring most frequently in the context of hereditary tumor susceptibility syndromes.     

Alopecia With Endocrine Therapies in Patients With Cancer

Background.

Whereas the frequency of alopecia to cytotoxic chemotherapies has been well described, the incidence of alopecia during endocrine therapies (i.e., anti-estrogens, aromatase inhibitors) has not been investigated. Endocrine agents are widely used in the treatment and prevention of many solid tumors, principally those of the breast and prostate. Adherence to these therapies is suboptimal, in part because of toxicities. We performed a systematic analysis of the literature to ascertain the incidence and risk for alopecia in patients receiving endocrine therapies.

Methods.

An independent search of citations was conducted using the PubMed database for all literature as of February 2013. Phase II–III studies using the terms “tamoxifen,” “toremifene,” “raloxifene,” “anastrozole,” “letrozole,” “exemestane,” “fulvestrant,” “leuprolide,” “flutamide,” “bicalutamide,” “nilutamide,” “fluoxymesterone,” “estradiol,” “octreotide,” “megestrol,” “medroxyprogesterone acetate,” “enzalutamide,” and “abiraterone” were searched.

Results.

Data from 19,430 patients in 35 clinical trials were available for analysis. Of these, 13,415 patients had received endocrine treatments and 6,015 patients served as controls. The incidence of all-grade alopecia ranged from 0% to 25%, with an overall incidence of 4.4% (95% confidence interval: 3.3%–5.9%). The highest incidence of all-grade alopecia was observed in patients treated with tamoxifen in a phase II trial (25.4%); similarly, the overall incidence of grade 2 alopecia by meta-analysis was highest with tamoxifen (6.4%). The overall relative risk of alopecia in comparison with placebo was 12.88 (p < .001), with selective estrogen receptor modulators having the highest risk.

Conclusion.

Alopecia is a common yet underreported adverse event of endocrine-based cancer therapies. Their long-term use heightens the importance of this condition on patients'' quality of life. These findings are critical for pretherapy counseling, the identification of risk factors, and the development of interventions that could enhance adherence and mitigate this psychosocially difficult event.     

Oral contraceptives and the risk of death from breast cancer

OBJECTIVE: To examine the relationship between the use of oral contraceptives and the risk of death from breast cancer. METHODS: We used interview data from the Cancer and Steroid Hormone Study, linked to cancer registry data from the Surveillance, Epidemiology, and End Results Program, to examine the 15-year survival and prior use of oral contraceptives among 4,292 women aged 20 to 54 years when diagnosed with breast cancer from December 1, 1980, to December 31, 1982. Cox proportional hazard models were used to estimate the relative rate of death from breast cancer by oral contraceptive use. RESULTS: Duration of oral contraceptive use, time since first use, age at first use, and use of specific pill formulations were not associated with survival. For time since last use, the risk of death from breast cancer decreased significantly with increasing time since last use of oral contraceptives, but a consistent gradient effect was not observed. Adjusted hazard ratios ranged from 0.86 to 1.41 and were 1.00 or less for all recency categories except during 13 to 24 months before diagnosis; none was statistically significant. Women who were currently using oral contraceptives had an adjusted hazard ratio of 0.90 (0.68, 1.19). CONCLUSION: Overall, oral contraceptive use had neither a harmful nor a beneficial effect on breast cancer mortality. The differences between pill users and nonusers were slight, and the risk estimates were usually reduced with confidence limits that nearly always included 1.0.     

WAGR syndrome: is the 'R' always justified?

Although mild-to-moderate intellectual disability is usually considered part of WAGR syndrome (Wilms' tumour (WT), Aniridia, Genital abnormalities, and metal Retardation, due to 11p13 deletion) the neuropsychological profile of the syndrome is little reported in the literature. We report about a 12-year-old boy presenting with WAGR syndrome (WT, right complete aniridia, bilateral cryptorchidism, interstitial deletion involving band 11p13) but with no mental retardation. An in-depth clinical evaluation revealed no behavioural or social problems and the child's neuropsychological profile was found to be within the normal range for all abilities and functions investigated (with the exception of an impulsive cognitive style and some difficulties in academic skills). This case underlines the importance of in-depth neuropsychological evaluation that includes not only IQ measurement, but also examination of attention and academic skills, in order to establish the complete phenotypical profile of WAGR patients, rather than labelling them as learning disabled (i.e. mental retardation).     

Pharmacological characterization of release-regulating serotonin autoreceptors in rat cerebellum

The release of [3H]5-hydroxytryptamine ([3H]5-HT) evoked by 15 mM KCl in superfused rat cerebellum synaptosomes was inhibited by 5-HT (pEC30 = 8.73). Methiothepin antagonized 5-HT (pA2 = 9.28); ketanserin, methysergide, cinanserin and spiperone were ineffective. The receptors involved were activated (pEC30 = 8.90) by the 5-HT1 agonist 5-methoxy-3-[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole (RU 24969) X (-)Propranolol shifted to the right (pA2 = 8.05) the dose-response curve of 5-HT. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was ineffective. In conclusion, autoreceptors are present on 5-HT nerve endings in rat cerebellum and appear to belong to the 5-HT1B subtype.