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Biomedical subjects

A Arnold

Publications and source records attributed to A Arnold.

At least 145 records · Page 8Linked to original sources
PubMed1992

Chemotherapy induced amenorrhoea in a randomised trial of adjuvant chemotherapy duration in breast cancer.

We have previously reported the results of a clinical trial in patients with stage II breast cancer which compared a 12 week chemohormonal regimen with a 36 week chemotherapy regimen. Both pre and post menopausal women were entered. The 12 week regimen was inferior both in terms of disease-free survival and overall survival. The effect of chemotherapy on menstrual function was prospectively documented in 95 of 114 premenopausal women at 3 of the 4 participating centres. 67 of the 95 women (70.5%) developed permanent amenorrhoea. There was a statistically significant difference in the rate of induced amenorrhea between the 12 week and the 36 week groups; 23/42 vs. 44/53, respectively (P = 0.003). Recurrence and mortality rates were lower in the patients who became amenorrheic; 38% vs. 57% (P = 0.03) and 18% vs. 32% (P = 0.17), respectively. Similar trends were observed within treatment groups. The effect of induced amenorrhoea on outcome was seen predominantly in patients under 40 years old. These results suggest that the induction of ovarian failure is a potential mechanism for the observed effect of adjuvant chemotherapy in these patients. The difference in the ovarian failure rates between groups may be a possible explanation for the inferiority of the 12 week regimen.

Adult↗
PubMed1992

A pilot study of intensive cyclophosphamide, epirubicin and fluorouracil in patients with axillary node positive or locally advanced breast cancer.

A multicentre pilot study has been conducted to determine an intensive regimen of cyclophosphamide, epirubicin, and fluorouracil which was tolerable and acceptable to patients with node positive breast cancer. Consecutive patients with operable axillary node positive breast cancer (T1-3, N1-2, M0), 266 patients, or locally advanced breast cancer (T4), 22 patients, were treated with cyclophosphamide post-operatively for 14 days and epirubicin and fluorouracil, both intravenously on days 1 and 8. Each cycle was repeated monthly for 6 months. Dosages were increased according to predetermined guidelines. Outcome measures were admission to hospital for febrile neutropenia and change in cardiac function as assessed by radionuclide angiography. The first 46 patients were treated at the doses of cyclophosphamide = 75 mg/m2, epirubicin = 50 mg/m2, fluorouracil = 375 mg/m2 (level 1), then 42 patients at cyclophosphamide = 75 mg/m2, epirubicin = 50 mg/m2 and fluorouracil = 500 mg/m2 (level 2), 69 patients at cyclophosphamide = 75 mg/m2, epirubicin = 60 mg/m2, and fluorouracil = 500 mg/m2 (level 3), and 42 patients at cyclophosphamide = 75 mg/m2, epirubicin = 70 mg/m2, and fluorouracil = 500 mg/m2 with concurrent antibiotics (level 4). The rates of febrile neutropenia were 8.7% (level 1), 7.1% (level 2), 18.8% (level 3), and 31% (level 4), respectively, P = 0.002. Accrual to level 4 was discontinued according to study guidelines and a further 89 patients were recruited at level 3 dosages with antibiotic prophylaxis (level 3a), resulting in a 5.6% rate of febrile neutropenia. The difference in febrile neutropenia rates between levels 3 and 3a was statistically significant. There were no toxic deaths and 2 cases of heart failure. In conclusion, through a careful dose-finding study in patients with operable or locally advanced breast cancer, an intensive epirubicin-containing adjuvant regimen has been established which is presently being compared with standard CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy in a randomised trial. In addition, this study suggests that antibiotic prophylaxis reduces the risk of febrile neutropenia in breast cancer patients receiving intensive chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

The effect of systemic adjuvant chemotherapy on local breast recurrence in node positive breast cancer patients treated by lumpectomy without radiation.

A randomised trial has previously been repeated in which 437 women with node positive breast cancer received either a 12-week chemohormonal regimen consisting of cyclophosphamide, methotrexate, fluorouracil, vincristine, prednisone, adriamycin and tamoxifen or 36 weeks of CMFVP. The present analysis concerns the local recurrence rates for the 122 lumpectomy patients who did not receive breast irradiation. The cumulative rate of local breast recurrence was greater in the 12-week than the 36-week group, P = 0.02. Similarly, in the lumpectomy patients, the cumulative rate of distant recurrence was greater in the 12-week than the 36-week group, P = 0.04. In conclusion, our results suggest that adjuvant chemotherapy impacts on local breast recurrence in a similar manner to other sites in Stage II breast cancer patients treated by lumpectomy without radiation. Despite the use of a conventional 36-week adjuvant chemotherapy regimen, the local breast recurrence rate was substantial.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

The Riyadh Intensive Care Program applied to a mortality analysis of a teaching hospital intensive care unit.

A computerised system of prediction of death using the Riyadh Intensive Care Program was applied retrospectively over a 17-month period to data collected prospectively on 1155 patients admitted to our intensive care unit. Variables which enable organ failure scores to be generated were recorded daily to make these predictions. Consultant medical opinion predicted that outcome was hopeless in 55% (115/209) of the patients who died. The predictive power of the computer demonstrated a sensitivity of 14.8% and a specificity of 99.8%. It is possible that the occurrence of three false predictions of death in the latter part of the series may have been related to a change in our antibiotic policy. We would be unhappy to recommend the general use of a computerised program for prediction of death without careful explanation of its significance and dangers.

Aged↗
PubMed1992

Assignment of the human cyclin D3 gene (CCND3) to chromosome 6p----q13.

The PRAD1/cyclin D1 gene (CCND1), a member of the D-type cyclin gene family, has been implicated as a protooncogene in parathyroid, lymphoid, and mammary tumors. We cloned and mapped another member of this family, the human cyclin D3 gene (CCND3), to chromosome 6p----q13 using human x rodent hybrids. This assignment raises the hypothesis that cyclin D3 may be involved in the pathogenesis of human neoplasms with abnormalities of chromosome 6.

Blotting, Southern↗
PubMed1992

Clonal origins of adrenocorticotropin-secreting pituitary tissue in Cushing's disease.

It is unclear whether Cushing's disease results from a primary pituitary disorder or arises in response to abnormal hypothalamic control of the pituitary gland. Clonal analysis can provide information as to whether neoplastic tissue is derived from a monoclonal proliferation of a genetically altered cell or from a polyclonal expansion of a group of cells affected by a common stimulus. We used X-linked restriction fragment length polymorphisms at the phosphoglycerate kinase, hypoxanthine phosphoribosyltransferase, and DXS255 loci in 11 women with biochemically and pathologically confirmed Cushing's disease to determine the clonal origins of corticotroph adenomas and corticotroph hyperplasia. Tumor tissue from all 10 women with morphologically and immunohistochemically confirmed ACTH-secreting pituitary microadenomas demonstrated a monoclonal pattern. Pathologically confirmed corticotroph hyperplasia in a patient with a CRH-secreting bronchial carcinoid was found to be polyclonal. We conclude that corticotroph microadenomas in Cushing's disease are monoclonal, supporting the theory that a spontaneous somatic mutation is the primary pathogenetic mechanism in this disorder. In addition, the demonstration of polyclonality in corticotroph hyperplasia implies that excess of hypothalamic hormones is an etiologic mechanism in cases of Cushing's syndrome associated with ectopic CRH-secreting tumors.

Adrenocorticotropic Hormone↗
PubMed1992

PRAD1 (cyclin D1): a parathyroid neoplasia gene on 11q13.

Hyperparathyroidism is a central component of multiple endocrine neoplasia type 1 (MEN 1), and both sporadic and familial forms of parathyroid disease may share certain pathogenetic features. We recently identified a gene that is clonally rearranged with the PTH locus in a subset of sporadic parathyroid adenomas. This candidate oncogene, PRAD1 (previously D11S287), appears to contribute to parathyroid tumorigenesis in a fashion analogous to activation of C-MYC or BCL-2 by rearrangement with tissue-specific enhancers of the immunoglobulin genes in B-lymphoid neoplasia. The PRAD1 gene maps to 11q13 and has been linked to the BCL-1 breakpoint locus, although not to the most tightly linked MEN 1 markers, by pulsed field gel electrophoresis. PRAD1 may, in fact, be the long-sought BCL-1 lymphoma oncogene. PRAD1 encodes a novel type of cyclin protein and thus may normally function in controlling the cell cycle, perhaps through direct interaction with cdc2 or a related kinase. PRAD1's possible primary, or more likely secondary, involvement in the pathogenesis of MEN 1-related tumors is unknown and under investigation.

Amino Acid Sequence↗
PubMed1991

PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma.

Rearrangement of the BCL1 (B-cell lymphoma 1) region on chromosome 11q13 appears to be highly characteristic of centrocytic lymphoma and also is found infrequently in other B-cell neoplasms. Rearrangement is thought to deregulate a nearby protooncogene, but transcribed sequences in the immediate vicinity of BCL1 breakpoints had not been identified. PRAD1, previously designated D11S287E, was identified on 11q13 as a chromosomal breakpoint region rearranged with the parathyroid hormone gene in a subset of parathyroid adenomas; this highly conserved putative oncogene, which encodes a novel cyclin, has been linked to BCL1 and implicated also in subsets of breast and squamous cell neoplasms with 11q13 amplification. We report pulsed-field gel electrophoresis data showing BCL1 and PRAD1 to be no more than 130 kilobases apart. PRAD1 mRNA is abundantly expressed in seven of seven centrocytic lymphomas (Kiel classification), in contrast to 13 closely related but noncentrocytic lymphomas. Three of the seven centrocytic lymphomas had detectable BCL1 DNA rearrangement. Also, two unusual cases of CLL with BCL1 rearrangement overexpressed PRAD1, in contrast to five CLL controls. Thus, PRAD1 is an excellent candidate "BCL1 oncogene." Its overexpression may be a key consequence of rearrangement of the BCL1 vicinity in B-cell neoplasms and a unifying pathogenetic feature in centrocytic lymphoma.

Chromosomes, Human, Pair 11↗
PubMed1991

A novel cyclin encoded by a bcl1-linked candidate oncogene.

We have previously identified a candidate oncogene (PRAD1 or D11S287E) on chromosome 11q13 which is clonally rearranged with the parathyroid hormone locus in a subset of benign parathyroid tumours. We now report that a cloned human placental PRAD1 complementary DNA encodes a protein of 295 amino acids with sequence similarities to the cyclins. Cyclins can form a complex with and activate p34cdc2 protein kinase, thereby regulating progress through the cell cycle. PRAD 1 messenger RNA levels vary dramatically across the cell cycle in HeLa cells. Addition of the PRAD1 protein to interphase clam embryo lysates containing inactive p34cdc2 kinase and lacking endogenous cyclins allows it to be isolated using beads bearing p13suc1, a yeast protein that binds cdc2 and related kinases with high affinity and coprecipitates kinase-associated proteins. Addition of PRAD1 also induces phosphorylation of histone H1, a preferred substrate of cdc2. These data suggest that PRAD1 encodes a novel cyclin whose overexpression may play an important part in the development of various tumours with abnormalities in 11q13.

Adenoma↗
PubMed1991

Hypercalcemia with low-normal serum intact PTH: a novel presentation of primary hyperparathyroidism.

The diagnosis of primary hyperparathyroidism has rested on the finding of hypercalcemia coupled with an elevated serum parathyroid hormone (PTH) level. Over 300 consecutive patients with primary hyperparathyroidism have had elevated or high-normal serum PTH levels using a specific immunoradiometric assay. Here we present a patient who proved to have surgically documented primary hyperparathyroidism in whom PTH levels were completely normal in all assays used. In the immunoradiometric assay, his normal result was unprecedentedly low (17 to 28 pg/mL; normal, 10 to 60 pg/mL) for this condition, and in a range consistent with non-PTH-dependent hypercalcemia or familial hypocalciuric hypercalcemia. This rare biochemical presentation of primary hyperparathyroidism should be considered in the differential diagnosis of hypercalcemia.

Humans↗
PubMed1991

Toxic megacolon associated with anticancer chemotherapy.

The majority of gastrointestinal side effects associated with anticancer chemotherapy are relatively mild and self-limiting and can be managed empirically. However, severe side effects, such as necrotizing enterocolitis and ischemic colitis, sometimes do occur after chemotherapy. The authors present a case of toxic megacolon associated with anticancer chemotherapy. This is a relatively uncommon but potentially lethal complication of ulcerative colitis.

Adult↗
PubMed1991

D11S287, a putative oncogene on chromosome 11q13, is amplified and expressed in squamous cell and mammary carcinomas and linked to BCL-1.

Approximately 15 to 20% of primary breast cancers and an even higher proportion of squamous cell carcinomas of the head and neck show amplification of DNA markers on band q13 of human chromosome 11. However, known genes within the amplified region, such as the FGF-related oncogenes INT-2 and HST-1, are very rarely expressed in these tumors. Here we show that another candidate oncogene, designated D11S287, implicated in the pathogenesis of parathyroid adenomas, is also amplified in breast cancers. Significantly, it is consistently coamplified with INT-2 and HST-1 in 36 out of 202 primary tumors, including one case in which the amplified unit did not encompass the translocation breakpoint marker BCL-1. This implies that D11S287 is on the same side of the breakpoint as INT-2, and pulsed-field gel electrophoresis indicates that D11S287 is less than 250 kb from the BCL-1 marker. Since D11S287 RNA was present at elevated levels in a group of tumors and cell lines in which the 11q13 region is amplified, it may be the key oncogene on this amplified unit, and could also be activated by BCL-1 translocations.

Blotting, Southern↗
PubMed1991

Rearrangement and overexpression of D11S287E, a candidate oncogene on chromosome 11q13 in benign parathyroid tumors.

We report the detailed molecular characterization of a human parathyroid adenoma with a clonal parathyroid hormone gene rearrangement. This rearrangement is similar to one we characterized recently in an independent adenoma. In these two, plus a third partially characterized adenoma, one allele of the PTH gene, on 11p15, is rearranged with DNA from the D11S287 region on 11q13. This region contains a transcribed sequence, D11S287E, distinct from known 11q13 oncogenes, that is expressed in all parathyroid tissues examined, but is overexpressed dramatically in all three tumours with PTH gene-D11S287 rearrangements. These findings suggest that overexpression of D11S287E, perhaps driven by the misplaced PTH gene's regulatory elements, contributed to the development of these benign tumors. D11S287E is a new candidate oncogene with potential importance in parathyroid adenomas and perhaps other tumors with 11q13 abnormalities.

Adenoma↗
PubMed1990

Addition of verapamil and tamoxifen to the initial chemotherapy of small cell lung cancer. A phase I/II study.

Based on experimental observations that verapamil and tamoxifen reverse multiple drug resistance, the authors investigated the feasibility of combining both agents with the initial chemotherapy of extensive small cell lung cancer. Overall, in a consecutive series of 58 patients the most important toxicity was myelosuppression, and there was a 24% rate of severe infections. Therapeutic results included 24% complete and 34% partial response rates, median time to disease progression of 32 weeks, and median survival of 46 weeks. In three consecutive cohorts of patients the dose of either tamoxifen or verapamil were escalated by 25% and 33%, respectively. The cohort of patients receiving verapamil 360 mg/day and tamoxifen 100 mg/day (level 2) had slightly more toxicity but also more responses than the other groups. Therefore, the authors recommend that these doses be used in controlled trials to confirm the promising results of their study.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Use of screening phase data to evaluate observer variation of sputum cytodiagnosis as an outcome measure in a chemoprevention trial.

Sputum samples obtained during the screening phase of a chemoprevention trial in heavy smokers were evaluated independently by trained cytotechnologists and classified for degree of cellular atypia according to the method of Saccommano et al. (G. Saccommano et al., Cancer (Phila.), 33: 256-270, 1974). The level of agreement within and between Observers A and B was calculated as the percentage of agreement and, in addition, a statistic was used (kappa) to correct for chance-expected agreement. Between observer agreement on 300 specimens from 130 subjects was 68% (204 of 300) (kappa = 0.58). Of the 96 disagreements, only 17 were of more than one category in the six-category classification. Within observer agreement for both Observers A and B was evaluated on a subset of 60 specimens from 49 subjects examined on two separate occasions by each observer. The percentage of within observer agreement was 80% for Observer A (kappa = 0.73) and 62% for Observer B (kappa = 0.49) (P less than 0.04). Altogether, 71% (25 of 35) of within observer discordant readings were confined to only one category. These data, obtained from the screening phase of the study, will allow us to refine the outcome measure for the trial without introducing bias that could result from knowledge of the actual study results. The failure of conventional cancer treatments to impact significantly on overall cancer mortality has led to an emphasis on prevention. If premalignant changes can be reliably detected at a time when the malignant process is reversible, then it may be feasible to intervene to prevent the occurrence of some cancers. The appropriate selection of subjects for such intervention trials and the subsequent demonstration of the efficacy of chemoprevention strategies are therefore crucial.

Etretinate↗
PubMed1990

Evaluation of the effect of thrombolytic treatment on infarct size and left ventricular function by enzymatic, scintigraphic, and angiographic methods. The European Cooperative Study Group for Recombinant Tissue Type Plasminogen Activator.

In a double-blind trial of the European Cooperative Study Group, 721 patients with acute myocardial infarction of less than 5 hours' duration were given either 100 mg recombinant tissue-type plasminogen activator (rt-PA) intravenously over 3 hours or an equivalent placebo infusion. In a subset of 312 patients, infarct size was assessed by the cumulative myocardial release of alpha-hydroxybutyrate dehydrogenase (HBDH) during the first 72 hours and by planar thallium scintigraphy (index of hypoperfusion) performed 10 to 22 days after the acute event. Left ventricular ejection fraction (LVEF) was determined by contrast and nuclear angiography. The median values of HBDH during the first 72 hours were 20% lower and the median values of thallium-201 28% smaller in the rt-PA group in comparison with controls. A significant but limited improvement of angiographic LVEF (2 absolute percentage points) was also shown in the patients treated with rt-PA. A moderate but statistically significant linear association between both measurements of infarct size and LVEF was found.

Adult↗