Multiple primary melanoma.

BACKGROUND: Incidence rates of cutaneous malignant melanoma (CMM) have been increasing for decades among Caucasian populations worldwide. Multiple factors identify persons at increased risk of CMM, including those with a family history of melanoma and those with atypical moles. Approximately 6-12% of melanomas are familial and approximately 12% of patients with familial melanoma have multiple primary melanomas. OBJECTIVE: To report a case of a patient with atypical moles and with 17 multiple primary melanomas. To review the literature on multiple primary melanomas as well as to review the genetics and treatment of melanoma. CONCLUSION: Patients with numerous atypical moles and a family or personal history of melanoma are at greatest risk for developing CMM. Patients from this population tend to develop CMM approximately 10 years earlier than the general population and have an increased risk for developing multiple primary melanomas. Since genetic tests capable of detecting individuals with an inherited susceptibility to CMM are not available, it is important to identify those patients with an increased risk and monitor them closely with regular total-body examinations.

Male breast cancer: a review of the literature.

Although breast cancer is uncommon in men, it can cause significant morbidity and mortality. The current review was undertaken to determine whether strategies applied for the evaluation and treatment of breast cancer in females are appropriate in male breast cancer. Male breast cancer has biological differences compared with female breast cancer, including a high prevalence in certain parts of Africa, a higher incidence of oestrogen receptor positivity and more aggressive clinical behaviour. It responds to hormonal manipulation and chemotherapy, but optimal treatment regimens in males are unknown. Male breast cancer remains an uncommon disease. Most of our current knowledge regarding its biology, natural history and treatment strategies has been extrapolated from its female counterpart. Much research is needed to further characterise the molecular biological properties of male breast tumours and their prognostic significance, and to devise treatment strategies, including optimal chemotherapy regimens.

Abnormal response to IL-5 in B-cell chronic lymphocytic leukemia.

In B-cell chronic lymphocytic leukemia, neoplastic B-lymphocytes are arrested in development. Since interleukins are essential for B-cell differentiation, we examined whether B-CLL cells were capable of responding normally to interleukins. Purified B-lymphocytes from B-CLL patients and controls were compared for their ability to proliferate and differentiate after stimulation with MCAT or SAC plus rhIL-2 or rhIL-5. When rhIL-5 was added to MCAT-stimulated cells, 8 of 10 controls showed a substantial increase in IgM production, compared with only 1 of 10 B-CLL patients. Lack of IL-5 responsiveness could provide insight into the arrested B-lymphocyte development of some B-CLL patients.

An autoradiographic study of calcium phosphate ceramic bone implants in turkeys.

Sintered, porous cylinders of beta-tricalcium phosphate ceramic (TCP) and hydroxyapatite (HAP) labeled with 45Ca were implanted into turkey ulnae for up to six months. Histologic examination of ground sections revealed extensive bone remodeling in the defect regions and resorption of both TCP and HAP. Autoradiograms suggest time- and composition-dependent events. Initial release of calcium ions was observed from both ceramics into adjacent new bone. Diffusion of calcium from TCP, but not HAP, extended into original bone at later periods. At six months, however, calcium from HAP was located intracellularly and within channels of distribution in hard tissue, away from the implant site. These data suggest that physical processes dominate initial HAP resorption while biologic (cellular) mechanisms become more significant later.

Osteomyelitis of the wrist in a patient with Hodgkin's disease.

Osteomyelitis of the carpal bones is extremely uncommon. We here report a case of Staphylococcus aureus osteomyelitis involving the wrist in a patient with Hodgkin's disease, and review the existing literature on this subject. The case illustrates the importance of considering pertinent clinical evidence in a patient with disseminated malignancy.

Hodgkin's disease presenting in the skin: case report and review of the literature.

Cutaneous manifestations of Hodgkin's disease are relatively uncommon. We present a case of Hodgkin's disease with widespread skin involvement and review the literature on the subject.

Effects of sodium valproate and oxygen on the craniofacial skeletal pattern in the CD-1 mouse embryo.

Growth retardation is a consistent finding in animal studies on the effect of sodium valproate (NaVP) in the embryo. Apart from fetal weight, the state of ossification in the embryo may be regarded as an indication of growth. The present study was to determine what effect sodium valproate at human therapeutic drug plasma levels had on the craniofacial skeletal pattern in the CD-1 mouse embryo relative to oxygen conditions, drug treatment or the interaction of the two. Two NaVP-filled Alzet osmotic minipumps were implanted subcutaneously on day 5 of gestation for continuous delivery of a total daily dosage of 850 mg/kg for 7 days. During this same time period the dams were also exposed to either normoxic (21% oxygen), hyperoxic (50% oxygen), or hypoxic (12% oxygen) controlled environments. Dams were removed from the oxygen chambers on day 12 and killed on day 18 of gestation. The fetuses were then processed for skeletal evaluation of the craniofacial region. Ossification centers were present in all but six of the skeletal elements studied. The primary ossification delay was in the tympanic bony labyrinth. In addition, there was a decrease in maxillary and mandibular length and cranial base measurements. The greatest toxic effect on the fetus for all skeletal components studied was in the NaVP/hypoxia treated group. This finding suggests that fetal skeletal maturation may be affected by a combination of intrauterine as well as external factors.

Effects of sodium valproate and oxygen on the CD-1 mouse fetus.

This study reports the effects of valproic acid (VA) on the CD-1 mouse fetus when the drug is administered continuously via osmotic minipumps at human therapeutic drug plasma levels. Two VA-filled Alzet osmotic minipumps were implanted subcutaneously on gestation day 5 for continuous exposure of a total daily dosage of 850 mg/kg on gestation days 5-12. Dams were then exposed continuously to either normoxic (21% oxygen), hyperoxic (50% oxygen), or hypoxic (12% oxygen) controlled environments during gestation days 5-12, in order to determine if hyperoxic maternal conditions offered a protective environment for the fetus, and conversely, if hypoxia exacerbated teratogenicity. Dams were sacrificed on gestation day 18, and litter and fetal data were collected. It was determined in separate groups under normoxic conditions that the osmotic minipump system maintained VA plasma levels corresponding to human therapeutic levels. Sodium valproate was found to induce developmental toxicity in the CD-1 mouse fetus at human therapeutic drug plasma levels. Fetal weights were reduced, and the number of resorptions, deaths, and hematomas was increased. While hypoxia exacerbated the toxic effect on the fetus, hyperoxia failed to ameliorate the outcome.

Developmental stage specificity and dose response of secalonic acid D-induced cleft palate and the absence of cytotoxicity in developing mouse palate.

Incidence of cleft palate (CP) in full-term mouse fetuses was evaluated following administration of 25 mg/kg of the mycotoxin, secalonic acid D (SAD), to groups of female mice on each of Days 10, 11, 12, 13, 14, or 15 of pregnancy. Although the highest numerical incidence (45.3%) of cleft palate resulted following SAD exposure on Day 12 of pregnancy, and the response tapered off to 16.9% on Day 10 and 0% on Day 15 of pregnancy, similar responses were produced also following exposures on Days 11 (38.4%) and 13 (39.9%) of pregnancy. Maternal exposure to doses of 0, 15, 20, 25, or 30 mg/kg of SAD, given on Day 12 of pregnancy indicated that although fetuses in the 30-mg/kg group had the highest incidence (51.9%) of CP, the effect was associated with increased resorptions and decreased fetal weights. The 25-mg/kg dose was optimally teratogenic (45.3% cleft palate) and maximally tolerable with neither an increase in resorptions nor a decrease in fetal body weights. Cytotoxicity of the optimally teratogenic dose of SAD (25 mg/kg given ip) on Day 12 of pregnancy was evaluated as a possible mechanism of SAD teratogenicity using indices such as mesenchymal cell density, mitotic index, and the uptake of [3H]thymidine in the developing palatal shelves. No evidence of SAD cytotoxicity was obtained in palatal shelves indicating a possible role for nonlethal cellular effects of SAD in the pathogenesis of CP. These studies also suggest the suitability of the maternal 25-mg/kg dose of SAD to study cellular biochemical effects in the developing embryo without the complicating influence of cytotoxic effects.

Relationship between ossification and body weight of the CD-1 mouse fetus exposed in utero to anticonvulsant drugs.

The anticonvulsant drugs carbamazepine, Na valproate, and phenytoin have been suspected as a cause of human congenital defects. The malformations produced may include cleft lip and/or palate, heart defects, skeletal defects, and low body weights. Since the toxic effects of these anticonvulsant drugs manifest themselves in terms of fetal growth retardation, evaluation of the state of ossification attained in the fetus is important. In the present study, pregnant CD-1 mice received on gestational days 8-16 an oral dose of 375, 563, 938 mg/kg of carbamazepine; or 225, 338, 563 mg/kg of Na valproate; or 50, 75, 125 mg/kg of phenytoin. These groups were compared to two control groups. On day 17, the dams were killed by cervical dislocation and one-third of the live fetuses were weighed and fixed for skeletal examination. Photographs were taken of the fore- and hindlimb skeletons. From these photographs, the length and width measurement of ossified regions of the humerus and femur were determined using a Zeiss Video-Plan Morphometrics Computer. Of the three anticonvulsant drugs studied, the greatest correlation between reduced fetal weights and retarded ossification of the long bones was phenytoin at the 125 mg/kg dosage. Our results also showed that long bone ossification, when compared to the fetal weight, indicated that 59-66% of variability in weight is predictable by bone measurements.

Teratogenic effects of valproate in the CD-1 mouse fetus.

Valproate sodium has been implicated in the production of spina bifida in humans; this article reports an animal model. Teratogenicity of valproate sodium was studied by oral administration of single doses of 225, 340, and 560 mg/kg to pregnant CD-1 mice on days 7 through 12 of gestation. All fetuses were examined on day 17. Treated fetuses demonstrated external malformations and a decrease in weight. The incidence of malformations was greater at the higher dosage levels of 340 mg/kg and 560 mg/kg, with a predominance of exencephaly, open eyelids, and gross skeletal defects. There was a significant increase in the resorption rate of the fetuses in the treated groups. There was also a significant increase in the malformations observed per litter and per live fetus population when compared with controls.

Scanning electron microscope study of tongue development in the CD-1 mouse fetus.

The objective of this study was to examine three dimensionally the embryonic and fetal stages of tongue development with scanning electron microscopy. Time-bred CD-1 mice were sacrificed at quarter-day intervals on days 10-13, and at half-day intervals on days 13.5-16.5 of gestation. Fetal tongues were dissected and fixed in s-collidine buffered 4% glutaraldehyde at pH7.4, and subsequently processed for SEM viewing. Tongue development was initiated on the 11th day by the appearance of the tuberculum impar and the two lateral lingual swellings on arch I. This was followed by the elevation of the hypobranchial eminence, which unites arches III and IV in the ventral midline, and overgrows arch II anteriorly. During the 12th day, remodeling occurred in areas of arches II and III, forming the root of the tongue. A cone-shaped midline swelling, the epiglottis, appeared in the ventral midline of arches III and IV. By the 13th day, the general proportions of the tongue, occupied by the body, root, and epiglottis, were established. The single circumvallate papilla and fungiform papillae were initiated during the early part of the 13th day, followed on the 15th day by differentiation of filiform and foliate papillae and raised nodules of lingual tonsilar tissue. The SEM study documented the temporal and morphological sequence of events during mouse tongue development. The tuberculum impar persisted to the late fetal stages and may therefore contribute largely to the dorsum of the tongue anterior to the circumvallate papilla.

Teratogenic effects of dosage levels and time of administration of carbamazepine, sodium valproate, and diphenylhydantoin on craniofacial development in the CD-1 mouse fetus.

The objective of this investigation was to study the teratogenic effects of dosage levels and time of administration of three anticonvulsant drugs (carbamazepine [CMZ], sodium valproate [NaV], and diphenylhydantoin [DPH]) on craniofacial development in the CD-1 mouse fetus. Pregnant females were intubated on each of days 8-10, 11-13, 14-16, and 8-16 of gestation with the following dose levels for each drug: 375, 563, 938 mg/kg CMZ; 225, 338, 563 mg/kg NaV; 50, 75, 125 mg/kg DPH. Appropriate control groups were maintained for each drug. On gestation day 17, pregnant females were killed and implantation sites were recorded as live, dead, or resorbed. All live fetuses were examined for craniofacial defects. Results of examination of 1,398 fetuses indicated that CMZ, NaV, and DPH were teratogenic and embryotoxic at all dose levels. This study indicated that the observed decrease in mean fetal weight was drug-, dose-, and time-dependent. There was a drug-, dose-, and time-dependent increase observed in the number of dead fetuses, whereas the number of resorbed fetuses was observed to be only time-dependent. The observed frequencies of hydrocephalies, secondary palatal clefts, and submucous palatal clefts were significant for all three factors (drug, dose, and time) whereas the observed frequencies of hematomas and exencephalies were significant only for drug and time. Cleft lips were observed only in the highest dose level of DPH. Uterine horn distribution of defects indicated that fetuses located at the proximal end of the horns were less subject to major defects than those fetuses located at the distal end of the uterine horns. Fetuses with craniofacial hematomas were found in the proximal one-third of the uterine horn, resorbed fetuses, and fetuses with submucous palatal clefts in the middle one-third of the uterine horns and dead fetuses and fetuses with exencephalies, cleft lips, and secondary palatal clefts were localized in the distal one-third of the uterine horns. In comparing the effect of drug, dosage, and time on the development of craniofacial malformations in the CD-1 mouse fetus, CMZ was the least teratogenic and embryotoxic of the three anticonvulsant drugs employed in this study.

Production of human alpha- and beta- interferons by human-rodent hybrids.

Attempts were made to demonstrate human alpha interferon production in virally induced human-rodent cell hybrids. In all hybrids investigated human beta-interferon production was detected when the relevant human chromosomes were retained, but only low levels of human alpha interferon could ever be detected even when human chromosome 9, which contains at least eight alpha-interferon genes, was present in the hybrid. The detection of human alpha interferon was made possible only by the use of specific antisera to human alpha and beta interferon and the sensitive virus yield-inhibition assay. Evidence is presented for independent regulatory mechanisms governing the expression of human alpha and beta interferons in human-rodent hybrids.

Le interferon mRNA from human fibroblasts.

Human F and Le interferon can be clearly distinguished on the basis of different antigenic properties and host range. After inoculation with Newcastle disease virus (NDV), GM-258 fibroblasts produced Le as well as F interferon; in contrast, only F interferon was detectable after stimulation with poly(I) . poly(C). Polyadenylylated mRNA isolated from fibroblasts induced with poly(I) . poly(C) or NDV was injected into Xenopus laevis oocytes and the interferon activities thus produced were analyzed. Only F interferon production was demonstrable in oocytes injected with mRNA from cells induced with poly(I) . poly(C), whereas both F and Le interferons were made in oocytes injected with mRNA from NDV-induced cultures. The time course of accumulation of F and Le interferon mRNAs in NDV-induced cells corresponded to the kinetics of F and Le interferon synthesis in intact cells. The ratio of F and Le interferons made in oocytes was similar to that observed in intact GM-258 cells. F and Le interferon mRNA activities isolated from GM-258 cells could not be separated by sucrose density gradient centrifugation. However, the profile of F mRNA activity was more heterogeneous and its peak sedimented somewhat more slowly than that of Le interferon mRNA. These results suggest that the varying ratios of F and Le interferon synthesis in different cells after different modes of stimulation are determined at the level of mRNA. The induction mechanisms of F and Le interferon mRNA synthesis appear to be closely related but not identical.