Relapsing granulomatous angiitis of the central nervous system in a patient while in remission from Hodgkin lymphoma.

We present a patient with granulomatous angiitis of the central nervous system (GANS) and Hodgkin lymphoma. His GANS resolved with treatment for the lymphoma, but then reactivated six months later in the absence of activate lymphoma. He made a full neurological recovery after treatment with reducing oral prednisolone over one year. This case indicates that prolonged use of steroids may be necessary to treat GANS in this setting and that it can run a course independent of the Hodgkin lymphoma.

Elevated G2 chromosomal radiosensitivity in Irish breast cancer patients: a comparison with other studies.

Previous studies have shown that a significant proportion of breast cancer patients exhibit elevated G2 chromosomal radiosensitivity in contrast to controls (approximately 40%). In this study, the G2 assay was applied to a small number of Irish breast cancer patients who were recorded as sporadic cases and they were compared with a control group to compare and contrast with the previous documented studies. Lymphocyte cultures were set up on whole blood samples and stimulated with phytohaemagglutinin. The cultures were irradiated 74 h later with 0.5 Gy gamma-radiation and cells were arrested in metaphase by treating the cultures with colcemid. The chromosomes were harvested and the aberrations scored per 100 metaphases to assign a G2 score. The assay was first carried out on four donor controls to estimate intra-individual variation and then ten controls for inter-individual variation to measure assay reproducibility. The G2 assay was then applied to 27 breast cancer patients. Good intrinsic assay reproducibility was observed in the coefficient of variation (CV) data in three out of four controls. Intra-individual variation was similar in three out of four of the donors (4.6 - 5.1%) with one donor showing a higher CV compared with the others (22.9%). Inter-individual variation was calculated at 30.5% for all controls. No significant difference was observed between intra- and inter-individual variation using the variance ratio F-test. A G2 radiosensitivity cut-off of 110 aberrations/100 metaphases was calculated from the controls, and from this 70.4% of breast cancer patients and 7.7% of controls were calculated as G2 radiosensitive. This proportion of G2-sensitive breast cancer patients is the highest recorded in studies to date. It is thought that the G2 radiosensitivity assay is a biomarker of breast cancer predisposition genes of low penetrance, suggesting the presence of these genes in the Irish breast cancer patients used in this study who were recorded as sporadic cases. A larger number of Irish patients would be required to consolidate these findings and be representative of the Irish breast cancer population.

Somatic mutations of KIT in familial testicular germ cell tumours.

Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino-acid substitutions in exon 17 and one was a 12 bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with three out of 116 unilateral cases (P=0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes.

Predictive testing for BRCA1 and 2 mutations: a male contribution.

BACKGROUND: Management strategies for women carrying BRCA1 and 2 mutations are becoming clearer and predictive testing for a known family mutation is commonly undertaken. Implications for men are not as clear and they participate less frequently. PATIENTS AND METHODS: Twenty-six men from 10 extended families underwent predictive testing. Their motivation, reaction and outcome were studied. Subjects had appropriate pre- and post-test counselling. Informed consent was obtained before predictive testing for known deleterious mutations. DNA analysis followed standard procedures. RESULTS: Eighteen tested positive and eight negative. Four had adverse psychological reactions and three reneged on their commitments to impart results. The spouse of another man had an adverse psychological reaction to the disclosure of his positive result. Two, already suffering from prostate cancer, were phenocopies and paternal lineage transmission was unexpectedly determined in another. Risk was removed from 33 offspring and confirmed for 56. CONCLUSIONS: Complex themes associated with genetic testing are confirmed and the spectrum extended. Men appear to understand the importance of participating in this process. Methods of avoiding adverse reactions merit further study along with other aspects of the process.

Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial.

OBJECTIVE: To examine long-term safety and efficacy for weight loss of an herbal Ma Huang and Kola nut supplement (90/192 mg/day ephedrine alkaloids/caffeine). DESIGN: Six-month randomized, double-blind placebo controlled trial. SUBJECTS: A total of 167 subjects (body mass index (BMI) 31.8+/-4.1 kg/m(2)) randomized to placebo (n=84) or herbal treatment (n=83) at two outpatient weight control research units. MEASUREMENTS: Primary outcome measurements were changes in blood pressure, heart function and body weight. Secondary variables included body composition and metabolic changes. RESULTS: By last observation carried forward analysis, herbal vs placebo treatment decreased body weight (-5.3+/-5.0 vs. -2.6+/-3.2 kg, P<0.001), body fat (-4.3+/-3.3 vs. -2.7+/-2.8 kg, P=0.020) and LDL-cholesterol (-8+/-20 vs. 0+/-17 mg/dl, P=0.013), and increased HDL-cholesterol (+2.7+/-5.7 vs. -0.3+/-6.7 mg/dl, P=0.004). Herbal treatment produced small changes in blood pressure variables (+3 to -5 mm Hg, P< or =0.05), and increased heart rate (4+/-9 vs. -3+/-9 bpm, P<0.001), but cardiac arrhythmias were not increased (P>0.05). By self-report, dry mouth (P<0.01), heartburn (P<0.05), and insomnia (P<0.01) were increased and diarrhea decreased (P<0.05). Irritability, nausea, chest pain and palpitations did not differ, nor did numbers of subjects who withdrew. CONCLUSIONS: In this 6-month placebo-controlled trial, herbal ephedra/caffeine (90/192 mg/day) promoted body weight and body fat reduction and improved blood lipids without significant adverse events.

The NCI-Ireland consortium: a unique international partnership in cancer care.

The Ireland-Northern Ireland-National Cancer Institute Cancer Consortium was launched in October of 1999, at a conference in Belfast, Northern Ireland, for the development of cancer programs in Ireland and Northern Ireland, where cancer is a significant cause of mortality and morbidity. Cancer services there have undergone major restructuring as a result of several government reports. Specifically, the National Strategy Document for Cancer proposed that cancer treatment services should be centered around primary care services, regional services, and a national coordinating structure where supra-regional centers would deliver specialist surgery, medical and radiation oncology, rehabilitation, and specialist palliative care. Therefore, this was an opportune time to bring the National Cancer Institute (NCI) on board in a determined effort to redevelop and significantly improve services and outcomes for cancer patients throughout the island. During the NCI All Ireland Cancer Consortium, initial major goals were established as follows: A) To share best available technology and enhance clinical research; B) conduct joint clinical research studies involving people from all jurisdictions; C) sponsor formal training exchanges for Irish and American scholars in cancer programs in partner institutions; D) implement the use of teleconferencing, telesynergy, and other information technology capabilities to facilitate education, and E) consolidate the Cancer Registries of Ireland and Northern Ireland and learn more about cancer incidence and trends on the entire island. In the past year, significant advances have been made in all these areas. Plans are already under way for the second NCI All Ireland Cancer Conference which will be held in late 2002 and feature speakers from Ireland, Northern Ireland, the U.S., and other areas. It will be open to all oncologists, researchers, nurses, students, and other health care professionals interested in learning and enhancing cancer care and research.

Hyperhomocysteinemia and transplant coronary artery disease in cardiac transplant recipients.

BACKGROUND: In cardiac transplant recipients, long-term survival may be limited by transplant coronary artery disease (TxCAD). Hyperhomocysteinemia (Hhcy) has been associated with vascular disease and is common in transplant recipients. The objective of this study was to determine the relationship between fasting homocysteine (Hcy) concentrations and TxCAD in a cohort of cardiac transplant recipients. METHODS: Forty-eight patients more than 5 yr after transplant were recruited from a cohort of 72 consecutive patients with in-depth analysis of homocysteine levels from the Cardiac Transplant Clinic. Early morning fasting blood was obtained, and the plasma separated and frozen within 30 min. Hcy concentrations were determined by high-performance liquid chromatography (HPLC) with pulsed integrated amperometry. Coronary angiograms were reviewed in a blinded fashion. TxCAD was diagnosed, using the most recent angiogram, when a >25% lesion was present anywhere in the coronary tree. RESULTS: Forty-eight patients transplanted between 1985 and 1994 were studied. The mean Hcy concentration for the cohort was 23.5+/-5.0 micromol/L, all patients had homocysteine levels above the upper range of normal (5-15 micromol/L). Hcy concentrations were significantly higher in patients with angiographic evidence of TxCAD: 25.0+/-5.9 vs. 21.9+/-3.4 micromol/L, p=0.03. This effect persisted when covariates were taken into account using logistic regression analysis. CONCLUSIONS: Hhcy is associated with TxCAD. Prospective studies are required to confirm this association and to assess the efficacy of Hcy-lowering therapy in this patient population.

Effective progenitor cell mobilization in lymphoproliferative disorders using ifosfamide, epirubicin and etoposide (IEV).

The combination of ifosfamide, epirubicin and etoposide (IEV) is an effective salvage regimen for lymphoproliferative disease. We report our experience with this combination in mobilization of peripheral blood stem cells (PBSC) in patients with relapsed or refractory/high-risk lymphoma. The median time to leukapheresis was 14 days, with 85% of patients commencing PBSC collection in the range of 13-15 days. Mobilization was successful in 26 of 28 patients (93%), who achieved the minimum transplant dose of 2 x 10(6)/kg CD34+ cells in a median of 2 leukaphereses. Overall, the median CD34+ cell yield was 6.94 x 10(6)/kg (range 0.73-27.4). In 15 of 27 patients (54%), the yield was sufficient (> 6 x 10(6)/kg) to permit CD34+ cell selection and/or a second autograft. IEV was given as an inpatient in all cases. Patients were scheduled for discharge after chemotherapy. This was achieved in 71%, with readmission 1 week later for harvest. Therapy was complicated by neutropenic fever in 13 patients and mild nausea. In autografts carried out using IEV-mobilized PBSC (n = 20), the median time to neutrophils > 0.5 x 10(9)/L was 10 days (range 7-13 days), and to platelets > 20 x 10(9)/L was 13 days (range 11-18 days). There was no mobilization- or transplant-related mortality. We conclude that IEV is a safe, predictable and highly effective mobilization regimen in patients with lymphoma.

The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2.

Breast cancers arising in carriers of mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, differ histologically from each other and from breast cancers unselected for a family history. However, a substantial proportion of families with multiple cases of breast cancer is not attributable to these two genes (non-BRCA1/2 families). We have now characterized the pathology of 82 breast cancers from non-BRCA1/2 families. Breast cancers in non-BRCA1/2 families were of lower grade (P = 0.0018), showed fewer mitoses (P < 0.0001), less nuclear pleomorphism (P = 0.0014), less lymphocytic infiltrate (P < 0.0001), a lesser extent of the tumor with a continuous pushing margin (P = 0.004), a lesser extent of the tumor composed of solid sheets of cells (P = 0.0047), less necrosis (P = 0.002), and wereparison with BRCA2 tumors, non-BRCA1/2 tumors were lower grade (P = 0.017) and exhibited less pleomorphism (P = 0.01) and more tubule formation (P = 0.05). In comparison with control breast cancers unselected for a family history of the disease, non-BRCA1/2 tumors were of significantly lower grade (P = 0.001), showed less pleomorphism (P = 0.0002), and had a lower mitotic count (P = 0.003). The results indicate that non-BRCA1/2 breast cancers differ histologically from both BRCA1 and BRCA2 breast cancers and are overall of lower grade. They also suggest that non-BRCA1/2 breast cancers differ from nonfamilial breast cancers, but these differences may be attributable to various types of bias.

Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours.

Testicular germ-cell tumours (TGCT) affect 1 in 500 men and are the most common cancer in males aged 15-40 in Western European populations. The incidence of TGCT has risen dramatically over the last century. Known risk factors for TGCT include a history of undescended testis (UDT), testicular dysgenesis, infertility, previously diagnosed TGCT (ref. 7) and a family history of the disease. Brothers of men with TGCT have an 8-10-fold risk of developing TGCT (refs 8,9), whereas the relative risk to fathers and sons is fourfold (ref. 9). This familial relative risk is much higher than that for most other types of cancer. We have collected samples from 134 families with two or more cases of TGCT, 87 of which are affected sibpairs. A genome-wide linkage search yielded a heterogeneity lod (hlod) score of 2.01 on chromosome Xq27 using all families compatible with X inheritance. We obtained a hlod score of 4.7 from families with at least one bilateral case, corresponding to a genome-wide significance level of P=0.034. The proportion of families with UDT linked to this locus was 73% compared with 26% of families without UDT (P=0.03). Our results provide evidence for a TGCT susceptibility gene on chromosome Xq27 that may also predispose to UDT.

Correlation between total homocysteine and cyclosporine concentrations in cardiac transplant recipients.

Increased circulating total homocysteine (tHcy) has been implicated as an independent risk factor for atherosclerotic disease. In cardiac transplant patients, accelerated coronary atherosclerosis is an important cause of late allograft failure; however, studies of tHcy in this at-risk group are limited. We sampled a cohort of 72 subjects 3.95+/-3.14 (mean +/- SD) years after transplantation and found that all had tHcy concentrations above our upper reference limit (15.0 micromol/L). The mean tHcy in the transplant group (25.4+/-7.1 micromol/L) was significantly greater than in our reference group (9.0+/-4.3 micromol/L; n = 457; P <0.001). We also examined the effect of age, gender, time since transplant, serum folate and cobalamin, total protein, urate, creatinine, albumin, and trough whole blood cyclosporine concentrations. In a multiple linear regression model, only creatinine (mean 144+/-52 micromol/L; P = 0.021) and trough cyclosporine concentrations (191+/-163 microg/L; P = 0.015) were independent positive predictors of tHcy, whereas serum folate (8.35+/-7.43 nmol/L; P = 0.018) and time since transplant (P = 0.049) were significant negative predictors. We conclude that hyperhomocysteinemia is a common characteristic of cardiac transplant recipients. Our analysis suggests that folate and renal glomerular dysfunction are important contributory factors; however, whole blood cyclosporine concentrations may also predict the degree of hyperhomocysteinemia in this population and therefore influence interpretation of any apparent response to treatment.

Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations.

BACKGROUND: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.

Pseudo-Cushing's syndrome in human immunodeficiency virus-infected patients.

To our knowledge, an association between human immunodeficiency virus infection and pseudo-Cushing's syndrome has not previously been described. We describe four HIV-infected patients with pseudo-Cushing's syndrome, characterized by striking dorsocervical and submandibular fat accumulation and central obesity. In each case, cortisol levels were either normal or suppressed adequately with administration of dexamethasone, excluding the diagnosis of true Cushing's syndrome. Immune function and weight improved significantly preceding the development of pseudo-Cushing's syndrome. Three of the four patients were taking a common protease inhibitor at the onset of symptoms, and the fourth reported the exacerbation of his symptoms with the addition of a protease inhibitor. The observed characteristic pattern of fat deposition may be attributable to a specific effect of new antiretroviral therapies or may relate to recovery independent of medication usage. Distinguishing between pseudo-Cushing's syndrome and true Cushing's syndrome is critical for preventing the unnecessary and potentially harmful treatment of such patients. Further research into the mechanisms of this novel phenomenon is needed.