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Biomedical subjects

A Arnold

Publications and source records attributed to A Arnold.

At least 163 records · Page 9Linked to original sources
PubMed1990

Clinically nonfunctioning pituitary tumors are monoclonal in origin.

Clinically nonfunctioning pituitary adenomas are benign neoplasms comprising approximately 25-30% of pituitary tumors. Little is known about the pathogenesis of pituitary neoplasia. Clonal analysis allows one to make the important distinction between a polyclonal proliferation in response to a stimulatory factor versus a monoclonal expansion of a genetically aberrant cell. We investigated the clonal origin of pituitary tumors using X-linked restriction fragment length polymorphisms at the phosphoglycerate kinase and hypoxanthine phosphoribosyl-transferase genes. Restriction enzymes were used to distinguish maternal and paternal X-chromosomes, and combined with a methylation-sensitive restriction enzyme to analyze allelic X-inactivation patterns in six pituitary adenomas. All six tumors showed a monoclonal pattern of X-inactivation. These data indicate that nonfunctioning pituitary adenomas are unicellular in origin, a result consistent with the hypothesis that this tumor type is due to somatic mutation.

Adenoma↗
PubMed1990

Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism.

Preproparathyroid hormone (preproPTH) gene mutation has been proposed as a cause of familial isolated hypoparathyroidism (FIH). We cloned the preproPTH alleles of a patient with autosomal dominant FIH and sequenced the coding regions, 5' flanking regions, and splice junctions. The putatively abnormal (based on previous linkage studies) allele differed from the other allele's normal sequence at only one nucleotide. This T to C point mutation changes the codon for position 18 of the 31 amino acid prepro sequence from cysteine to arginine, disrupting the hydrophobic core of the signal sequence. Because the hydrophobic core is required by secreted proteins for efficient translocation across the endoplasmic reticulum, the mutant protein is likely to be inefficiently processed. Indeed, in vitro studies demonstrated dramatically impaired processing of the mutant preproPTH to proPTH. In summary, we observed a point mutation in the signal peptide-encoding region of a preproPTH gene in one FIH kindred and demonstrated a functional defect caused by the mutation. Mutation of the signal sequence constitutes a novel pathophysiologic mechanism in man, and further study may yield important insights both into this form of hormone deficiency and into the role of signal sequences in human physiology.

Amino Acid Sequence↗
PubMed1990

A randomized trial comparing 12 weeks versus 36 weeks of adjuvant chemotherapy in stage II breast cancer.

A randomized trial has been performed in which women with axillary node-positive breast cancer were allocated to either a short intensive 12-week chemohormonal treatment consisting of cyclophosphamide, methotrexate, fluorouracil, vincristine, prednisone, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and tamoxifen (CMFVP plus AT) or 36 weeks of CMFVP. The median follow-up is 37 months. Of the 222 women randomized to the 12-week treatment, 113 (50.9%) have experienced either recurrence or death as compared with 90 patients (41.9%) in the 36-week treatment group. The corresponding 3-year relapse-free survivals are 55% and 64%, respectively, P = .003. Fifty-nine (26.6%) of the patients in the 12-week group have died compared with 46 (21.4%) of the 36-week group. The corresponding 3-year survival rates are 78% and 85%, respectively, P = .04. A Cox regression analysis showed an associated increased risk ratio for recurrence or death of 1.7, P = .003, and for death of 1.8, P = .017 in the 12-week treatment group compared with the 36-week group. Thus, this 12-week regimen of adjuvant chemohormonal therapy is inadequate treatment for women with axillary node-positive breast cancer; possible explanations for this inferiority are its shorter duration and/or a negative interaction of tamoxifen on the chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Genetic abnormalities in sporadic parathyroid adenomas.

We analyzed genomic DNA from 43 sporadic benign parathyroid adenomas for rearrangements of the PTH gene, and for point mutations of the H-ras (codons 12, 13, and 61), N-ras (codons 12, 13, and 61), and K-ras (codons 12 and 13) genes. One of 43 parathyroid adenomas showed a chromosome 11 rearrangement involving both the PTH gene on the short arm of chromosome 11 (at band p15) and a locus on the long arm (11q13). This rearrangement was indistinguishable from one that was previously described in a parathyroid adenoma by Arnold et al., indicating that this may be an important contributor to tumorigenesis in a small subset of patients with parathyroid adenoma. H-ras, K-ras, and N-ras oncogene activation by point mutation at codons 12, 13, or 61, known to occur in many tumors, could not be detected in any parathyroid adenoma.

Adenoma↗
PubMed1990

Giant-cell tumor of the sphenoid bone: case report and review of the literature.

We report the case of a 23-year-old man with a giant-cell tumor of the sphenoid bone. The radiologic manifestations consisted of an expansile mass arising from the sphenoid bone with extension into the cranial cavity and the nasopharynx. The findings with computed tomography and magnetic resonance imaging best reflected respectively the osseous and soft-tissue extent of the disease.

Adult↗
PubMed1989

Etretinate blood levels in monitoring of compliance and contamination in a chemoprevention trial.

We measured serum etretinate to monitor compliance in an ongoing chemoprevention trial in which heavy smokers are randomized to either etretinate or placebo orally for 6 months. Blood is collected for determination of etretinate levels before treatment and then at 2, 4, 8, 16, and 24 weeks after randomization. The monitoring strategy was assessed by interim evaluation. There were 276 posttreatment samples available from 75 randomized subjects of whom 36 received etretinate and 39 placebo. The mean coefficient of variation for the internal standard retinyl acetate in serum was 4.16% for the high-pressure liquid chromatography method used. Among positive samples, the mean etretinate concentration was 25.7 ng/mL (SD, 23.4). Of the 131 samples obtained from subjects randomized to etretinate, 120 or 91.6% had detectable levels compared with 4 of 145 or 2.8% placebo samples. Among the 36 subjects given etretinate, at least one positive test occurred. In 27 of these 36 participants, etretinate was detected in every sample obtained. In the other nine, the absence of drug could be explained by pill counts or a history of discontinuation of treatment for six. Among the 39 subjects given placebo, the four positive samples were from four individuals, all of whom were negative on three other occasions. These data confirm the usefulness of the monitoring system we used and indicate that compliance and/or contamination will not be major problems in this trial.

Chromatography, High Pressure Liquid↗
PubMed1989

Recruitment for an efficacy study in chemoprevention--the Concerned Smoker Study.

Efficacy studies are important for the development of long-term cancer prevention strategies. Recruitment aims for a highly motivated group of participants. The Concerned Smoker Study is aimed at smokers with at least a 15 pack-year history and bronchial atypia on sputum sampling Recruitment has been primarily through use of the media. During the first year of randomization 905 potential participants expressed interest. Of these, 80 were eventually randomized. With over 60 participants having completed the study only one has defaulted and compliance with the study protocol has been high. Participants became aware of the study through the following sources: daily newspaper 36.6%, weekly newspaper 16.2%, television 14.9%, radio 13.8%, community television 1.3%, other sources 13.3%. Over 90% of potential participants who initially express interest in such a chemoprevention project may not ultimately be suitable. The population chosen for such studies may not be very representative of the more general population; however, a high degree of compliance can be obtained which will provide valuable information on treatment efficacy.

Advertising↗
PubMed1989

Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma.

Parathyroid adenomas are common benign neoplasms for which no chromosomal defects have been described. We recently found two parathyroid adenomas bearing clonal restriction fragment abnormalities involving the PTH locus, and now show that in one of these tumors: (a) a DNA rearrangement occurred at the PTH locus; (b) the rearrangement separated the PTH gene's 5' flanking region from its coding exons, conceivably placing a newly adjacent gene under the influence of PTH regulatory elements; (c) the DNA that recombined with PTH normally maps to 11q13, the known chromosomal location of several oncogenes and the gene for multiple endocrine neoplasia type I; and (d) the rearrangement was a reciprocal, conservative recombination of the locus on 11q13 (Human Gene Mapping Library assignment D11S287) with PTH (on 11p15). These data provide molecular cytogenetic evidence for the clonal occurrence of a major chromosome 11 aberrancy in this benign parathyroid tumor. The D11S287 clone could prove useful in genetic linkage analyses, in determining precise 11q13 breakpoints in other neoplasms, and in identifying a gene on chromosome 11 that may participate in parathyroid tumor development.

Adenoma↗
PubMed1989

Clonal loss of one chromosome 11 in a parathyroid adenoma.

Traditional cytogenetic approaches have been unsuccessful in the study of parathyroid adenomas. We now describe one parathyroid adenoma in which a molecular cytogenetic approach revealed clonal loss of one chromosome 11. Restriction fragment length polymorphism analysis of the patient's normal leukocyte DNA demonstrated heterozygosity at four loci (PTH, INT2, APOA1, and ETS1) that span the length of chromosome 11. However, the adenoma DNA showed clonal deletion of one allele, i.e. loss of heterozygosity, at each locus. Use of five nonpolymorphic probes from chromosome 11 was consistent with 50% loss of total chromosome 11 DNA in the adenoma. No tumor-specific loss of heterozygosity was observed when restriction fragment length polymorphisms from five other autosomes (no. 1, 5, 6, 7, and 12) were analyzed, and an X-chromosome probe also showed no tumor DNA loss. We have demonstrated tumor-specific chromosome loss in a parathyroid adenoma; such a lesion has been described only rarely in benign tumors. Our finding adds to the evidence for monoclonality in parathyroid adenomatosis, indicates that only one PTH gene copy is sufficient for hyperparathyroid tumor function, and raises the possibility that a tumor-suppressor gene important in the development of nonfamilial parathyroid neoplasia is located on chromosome 11.

Adenoma↗
PubMed1989

Expression of transcripts encoding a parathyroid hormone-related peptide in abnormal human parathyroid tissues.

A PTH-related peptide (PTHRP) has been identified and its cDNA cloned from human tumors associated with the syndrome of humoral hypercalcemia of malignancy. The human PTHRP gene has been recently isolated and found to be a complex transcriptional unit using multiple promoters and containing alternatively spliced 3' exons which result in three mRNA classes, each class encoding a PTHRP with a unique carboxy-terminus. The PTHRP gene appears to be expressed in a number of normal tissues, and PTHRP transcripts have been previously reported to be overexpressed in a small sample of human parathyroid adenomas. In the present study we surveyed RNA prepared from a total of 60 abnormal human parathyroid glands for PTHRP gene expression using a combination of Northern blotting and RNase protection techniques. Apparent overexpression of PTHRP mRNA was observed in two thirds of parathyroid adenomas, whereas no overexpression was found in 7 examples of sporadic primary hyperplasia, 5 examples of secondary hyperplasia, and 3 examples of parathyroid carcinoma. Apparent overexpression was also observed in 1 of 4 cases of multiple endocrine neoplasia type 1, 1 of 2 examples of multiple endocrine neoplasia type 2, and 1 gland considered to represent tertiary hyperparathyroidism. Northern analysis of poly(A)+ RNA prepared from three representative adenomas using region-specific probes indicated that two putative promoters are used and revealed a pattern of preferential splicing of transcripts to include the most distal 3' exon. These findings suggest that the PTHRP gene is commonly overexpressed in adenomatous parathyroid glands, but not in sporadic primary hyperplasia, that this overexpression does not seem to be dependent on the use of a single specific promoter, and that adenomatous parathyroid cells appear to preferentially use one of several alternative splicing pathways. It is presently not known whether PTHRP is secreted by abnormal parathyroid tissues and, if so, in what form.

Adenoma↗
PubMed1988

Monoclonality and abnormal parathyroid hormone genes in parathyroid adenomas.

Previous work based on the relative tissue content of glucose-6-phosphate dehydrogenase isoenzymes suggested that parathyroid adenomas, like primary hyperplasia, may be multicellular (not clonal) in origin. We have reexamined this issue by using two independent molecular genetic methods. We report tumor-cell-specific restriction-fragment-length alterations involving the parathyroid hormone gene from two human parathyroid adenomas. These abnormal restriction fragments indicate that in each case a clonal proliferation of cells was present and also suggest that DNA alterations involving the parathyroid hormone locus may be important in the tumorigenesis or clonal evolution of some parathyroid adenomas. In addition, we used a restriction-fragment-length polymorphism in an X-linked gene (hypoxanthine phosphoribosyltransferase) to examine the clonality of eight parathyroid adenomas in women. Of these eight adenomas, six had the DNA hybridization pattern of monoclonality, and two had an equivocal pattern. None of five hyperplastic parathyroid glands had a monoclonal pattern. We conclude that some (and perhaps many) single parathyroid adenomas are monoclonal neoplasms. Our observations suggest that there is a fundamental biologic difference between parathyroid adenomas and primary hyperplasia--a difference that could prove useful in distinguishing these entities clinically.

Adenoma↗
PubMed1988

The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer.

Thromboembolic disease has long been recognized as a complication of cancer. Recent reports have suggested that drugs used in the treatment of cancer, including chemotherapeutic agents and hormones, may contribute to this risk, but it has not been possible to separate the effect of these drugs from that of the cancer. We performed a randomized trial comparing 12 weeks of chemohormonal therapy (using cyclophosphamide, methotrexate, fluorouracil, vincristine, prednisone, doxorubicin, and tamoxifen) with 36 weeks of chemotherapy (using cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone) in patients with Stage II breast cancer. Among 205 patients randomly assigned to treatment, there were 14 episodes of thrombosis (6.8 percent). These 14 episodes occurred during 979 patient-months of chemotherapy; by comparison, there were no events during 2413 patient-months without therapy. During the first 12 weeks of the study, five patients in the 12-week group and four patients in the 36-week group had thrombosis. During the subsequent 24 weeks, when only patients in the 36-week group were still receiving chemotherapy, there was no thrombosis in the 12-week group, but there were five additional events in the 36-week group (P = 0.03). These findings suggest that chemotherapy contributes to thrombosis in patients with breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Quality of life in stage II breast cancer: an instrument for clinical trials.

A questionnaire has been developed for use as an outcome measure in clinical trials of adjuvant chemotherapy in women with stage II breast cancer. The selection of items for this Breast Cancer Chemotherapy Questionnaire (BCQ) was based on the problems and experiences felt to be most important by women undergoing adjuvant chemotherapy. The BCQ consists of 30 questions that focus on loss of attractiveness, fatigue, physical symptoms, inconvenience, emotional distress, and feelings of hope and support from others. The BCQ, other instruments that evaluate quality-of-life (Spitzer, Karnofsky, and Rand), and patient and physician global assessments were administered serially to 418 patients taking part in a randomized trial comparing a 12-week regimen and a 36-week regimen of adjuvant chemotherapy. The validity of the BCQ is supported by its correlation with the Rand Emotional (r = .58), Rand Physical (r = .60), and Spitzer (r = .62) questionnaires. The BCQ correlated more strongly with global ratings of both physical and emotional function by the patients and their physicians than the other instruments. A comparison of the quality-of-life outcomes of patients in the two treatment groups in the period beyond 3 months after initiation of treatment, when one group had completed the treatment course and the other was still on treatment, revealed that the BCQ and Karnofsky were the only instruments able to demonstrate differences between the groups (P less than .0001). Hence, the BCQ is a valid and responsive method of assessing treatment-related morbidity in patients receiving adjuvant chemotherapy for stage II breast cancer.

Antineoplastic Agents↗
PubMed1987

Value of percutaneous core needle biopsy in the differential diagnosis of renal transplant dysfunction.

The value of percutaneous core needle biopsy in the differentiation of rejection from other causes of renal allograft dysfunction, and its subsequent effect on patient management were assessed in 64 consecutive biopsies performed on 34 patients in whom the clinical diagnosis was was uncertain. A complete clinical, biochemical and radiographic assessment was made in each patient before biopsy. Only 1 biopsy (1.6 per cent) yielded tissue inadequate for evaluation, while another biopsy caused a renal artery pseudoaneurysm that ruptured and resulted in graft loss. In 27 of these 64 biopsies (42 per cent) the results differed from the pre-biopsy diagnosis and directly affected patient management, particularly the use of steroids. The remaining biopsy specimens were helpful to confirm uncertain clinical impressions, and allowed accurate counseling for patients and family. Biopsies were of special usefulness in separating acute rejection from complications, such as acute tubular necrosis, cytomegalovirus infections, recurrence of original disease, cyclosporin toxicity and acute superimposed-upon chronic rejection. Of 64 biopsies 22 (34.3 per cent) demonstrated the absence of rejection and 8 demonstrated chronic rejection (12.5 per cent), thereby averting the use of steroids in 46.8 per cent of the patients. All patients with evidence of severe small vessel disease and/or antibody-mediated rejection eventually lost the grafts, including 2 with cytomegalovirus glomerulopathy who also suffered such vascular changes. These data highlight the extreme usefulness of needle biopsy in the evaluation and management of renal allograft dysfunction.

Biopsy, Needle↗
PubMed1987

Immunohistologic analysis of human renal allograft dysfunction.

The value of percutaneous core needle biopsy in the immunohistological evaluation of renal allograft dysfunction was studied in 72 consecutive biopsies performed in 42 patients. The phenotypes of infiltrating cells mediating graft destruction were identified with monoclonal antibodies and immunoperoxidase staining techniques. Light microscopy, electron microscopy, and immunofluorescence staining were performed in all biopsies. Biopsies were divided into groups depending on their classification on the basis of standard histologic criteria, i.e., acute tubular necrosis (ATN), acute interstitial rejection, acute vascular rejection, chronic rejection and renal disease in native kidneys (RDNK) of nontransplant patients. Immunohistologic analysis of graft biopsies showed a significant increase in Leu 1 (pan-T cells), (P less than 0.001), Leu 2 (cytotoxic/suppressor cells) (P less than 0.001), and Leu 3 cells (P less than .05) in acute interstitial rejection. The expression of DR antigen was significantly increased in both acute (P less than .025) and chronic (P less than .05) rejection, when compared with the findings in ATN biopsies. Leu M1 (monocytes/activated T cells) and Leu 10 (B cells/macrophages) were significantly increased (P less than 0.05 and P less than .005, respectively) in acute interstitial rejection only. The helper/suppressor ratio of infiltrating cells showed no significant change in any clinopathologic category. There was no correlation between the cell populations infiltrating the graft and those monitored in the peripheral blood. Allograft mononuclear cell infiltrates in cyclosporine (CsA) vs. azathioprine-treated patients revealed significantly fewer Leu 2 (P less than .05) and Leu M1 (P less than .05) cell populations in CsA patients during acute rejection. In 32 of these 72 biopsies (44.4%), the biopsy results provided a direct contraindication to the use of steroids, by allowing differentiation between allograft rejection and other causes of graft dysfunction. A total of 38% of the biopsies yielded a histological diagnosis that contradicted the clinical pre-biopsy diagnosis. All allografts showing evidence of severe small vessel disease and/or antibody-mediated rejection eventually were lost. These data highlight the usefulness of needle biopsy material as a guide to the study of intragraft immune events and to clinical management of recipients.

Acute Kidney Injury↗