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Biomedical subjects

A A Hart

Publications and source records attributed to A A Hart.

At least 73 records · Page 4Linked to original sources
PubMed1997

Influence of diagnostic conization on surgical morbidity and survival in patients undergoing radical hysterectomy for stage IB and IIA cervical carcinoma.

The purpose of this retrospective study was to investigate whether diagnostic conization influenced surgical morbidity of a subsequent radical hysterectomy in patients with early cervical carcinoma. Furthermore, the impact of an irradical conization on nodal metastases and prognosis was analysed. Included were 271 patients with stage IB and IIA cervical carcinoma who underwent an Okabayashi radical hysterectomy between 1982 and 1991. There were 68 patients who underwent conization prior to radical hysterectomy. The conization-radical hysterectomy interval was approximately six weeks. Surgical morbidity in patients with a previous conization was not significantly different from that in patients without a previous conization. Survival was also not significantly different between these groups (95% vs. 91%, p = 0.23). Multivariate analysis showed that an irradical conization was not associated with an increased risk for nodal metastases or a poorer prognosis. We suggest that in early cervical carcinoma, a diagnostic conization does not adversely affect early morbidity of a following radical hysterectomy. An irradical conization does not seem to influence prognosis.

Adult↗
PubMed1996

Different genetic susceptibility to aberrant crypts and colon adenomas in mice.

Aberrant crypt foci (ACFs) are the earliest identifiable epithelial lesions thought to precede the development of a subset of colon tumors. To assess their predictive value to adenoma development, we have tested in mice whether the development of ACFs and adenomas is controlled by the same genes. Therefore we used the CcS/Dem series of recombinant congenic strains, in which the effect of multiple susceptibility genes might be studied separately. We investigated susceptibility to ACFs in nine CcS/Dem strains and their parental strains, BALB/cHeA and STS/A, 4 weeks after s.c. injection of 1,2-dimethylhydrazine (20 mg/kg body weight). For the strains BALB/cHeA, STS/A, and CcS-19, we also examined the number of ACFs 2, 8, and 12 weeks after treatment. Susceptibility to adenomas was measured as the number of adenomas 6 weeks after 26 weekly s.c. injections of 1,2-dimethylhydrazine (15 mg/kg body weight). The nine CcS/Dem strains, the BALB/ cHeA strain, and the STS/A strain exhibited different patterns of susceptibility to ACFs and adenomas, demonstrating that different subsets of susceptibility genes are involved. Therefore, in evaluating the role of ACFs as a predictive marker for adenoma development, genetic factors must be taken into account.

1,2-Dimethylhydrazine↗
PubMed1996

Fine mapping of colon tumor susceptibility (Scc) genes in the mouse, different from the genes known to be somatically mutated in colon cancer.

The predisposition to colon cancer is multigenetically controlled in animals and probably also in humans. We have analyzed the multigenic control of susceptibility to 1,2-dimethylhydrazine-induced colon tumors in mice by using a set of 20 homozygous CcS/Dem recombinant congenic strains, each of which contains a different random subset of approximately 12.5% of genes from the susceptible strain STS/A and 87.5% of genes from the relatively resistant strain BALB/cHeA. Some CcS/Dem strains received the alleles from the susceptible strain STS/A at one or more of the multiple colon tumor susceptibility loci and are susceptible, whereas others are resistant. Linkage analysis shows that these susceptibility genes are different from the mouse homologs of the genes known to be somatically mutated in human colon cancer (KRAS2, TP53, DCC, MCC, APC, MSH2, and probably also MLH1). Different subsets of genes control tumor numbers and size. Two colon cancer susceptibility genes, Scc1 and Scc2, map to mouse chromosome 2. The Scc1 locus has been mapped to a narrow region of 2.4 centimorgans (90% confidence interval).

1,2-Dimethylhydrazine↗
PubMed1996

High resolution density gradient electrophoresis of cellular organelles.

A density gradient electrophoresis apparatus made of Perspex was constructed, with a separation column (7 x 2.2 cm) containing a 0-5% linear Ficoll gradient. The useful separation path is 6 cm. A specially designed gradient mixer is described which fits over the application cone. This cone permits precise gradient and sample introduction as well as undisturbed fractionation after electrophoresis. A bottom circular palladium cathode is separated hydrodynamically but not electrically from the density gradient by a cellophane membrane, merely secured by an O-ring. The top circular platinum anode allows for upward electrophoresis (80-100 min at 10 mA). The markedly higher resolution of subcellular organelles was compared with separations obtained earlier with a small, but much more difficult to fabricate, prototype. Moreover, ease of manipulation was greatly improved. A wide separation distance was obtained between plasma membrane, endoplasmatic reticulum as well as between two populations of lysosomes. Even early, middle, and late endosomes could be separated with high resolution. Soluble isoenzymes could be separated as well and were far away from the vesicle-enclosed enzymes.

Cellulose↗
PubMed1996

Gene interaction and single gene effects in colon tumour susceptibility in mice.

To dissect the multigenic control of colon tumour susceptibility in the mouse we used the set of 20 CcS/Dem (CcS) recombinant congenic (RC) strains. Each CcS strain carries a unique, random subset of approximately 12.5% of the genome of strain STS/A (STS) on the genetic background of BALB/cHeA (BALB/c). Previously, applying a protocol of 26 injections of 1,2-dimethylhydrazine (DMH), we detected two susceptibility loci, Scc1 and Scc2, on chromosome 2 (refs 4, 5). Using a shorter tumour-induction procedure, combining DMH and N-ethyl-N-nitrosourea (ENU) treatment, we demonstrate that BALB/c, STS and most CcS strains are relatively resistant. The strain CcS-19, however, is susceptible, probably due to a combination of BALB/c and STS alleles at several loci. Analysis of 192 (BALB/c x CcS-19) F2 mice revealed, in addition to the Scc1/Scc2 region, three new susceptibility loci: Scc3 on chromosome 1, Scc4 on chromosome 17 and Scc5 on chromosome 18. Scc4 and Scc5 have no apparent individual effect, but show a strong reciprocal interaction. Their BALB/c and STS alleles are not a priori susceptible or resistant but the genotype at one locus determines the effect of the allele at the second locus and vice versa. These findings and the accompanying paper on lung tumour susceptibility show that interlocus interactions are likely to be an important component of tumour susceptibility.

Animals↗
PubMed1996

The reproducibility of the results of transvaginal sonography of the uterus in patients with abnormal uterine bleeding.

Our objectives were to determine the reproducibility, or interobserver agreement, of transvaginal sonographic imaging of the uterus in patients with abnormal uterine bleeding and to identify the effect of observer experience. Transvaginal ultrasound findings of 235 patients with abnormal uterine bleeding were recorded systematically on videotape. Recordings were reviewed by three observers who had different levels of experience, and who were asked to judge the endometrium/uterine cavity and myometrium separately as being normal, abnormal or inconclusive, according to predefined criteria. Reproducibility was expressed by the observed rates of interobserver agreement and by kappa statistics. The differences in agreement between observer pairs were analyzed by means of McNemar's chi 2 test. The observed rates of agreement for the judgement of the endometrium/uterine cavity varied from 0.85 to 0.89, with a kappa value ranging from 0.70 to 0.78 between observers. The judgment of the myometrium resulted in agreement rates of 0.86-0.91 and kappa values of 0.67-0.80. Although the effect of experience was evident, the differences in agreement between observers were not significant (p > 0.01). The reproducibility of the results of transvaginal sonography of the uterus in patients with abnormal uterine bleeding was good. Observations of the endometrium/ uterine cavity with a normal appearance were the most highly reproducible, with the smallest effect of observer experience. This may reduce the need for invasive diagnostic procedures in patients with abnormal uterine bleeding.

Adult↗
PubMed1996

Survival of adult patients with head and neck soft tissue sarcomas.

A retrospective review and survival analysis is presented of 58 adult patients referred between 1963 and 1993 for treatment of a head and neck soft tissue sarcoma. The 5 year overall and disease-free survival was 60% and 52% respectively. Univariate analysis indicated that age, positive margins, bone invasion, distant metastases, single modality treatment, histological grading, sites below the deep fascia and size might be predictors of survival. On multivariate analysis, age, histological grade, distant metastases, site and referral for recurrent disease emerged as prognostic factors known before treatment. By including variables known after treatment, age remained the most important independent prognostic factor followed by the presence of free margins, histological grading and distant metastases at presentation.

Adolescent↗
PubMed1996

Disease-specific survival and locoregional control in tonsillar carcinoma.

In a nationwide survey on oropharyngeal carcinoma in the Netherlands (1986-1990), 380 patients with a tonsillar carcinoma were retrospectively studied. The records of 268 (71%) men and 112 (29%) women with a median age of 59 yr (range 31-91), who had squamous cell carcinoma (272 patients, 98%) or undifferentiated carcinoma (8 patients, 2%) were reviewed with respect to treatment, disease-specific survival and locoregional control. Distribution by stage according to the UICC'92 system was: 27 patients (7%) stage I, 59 (15%) stage II, 99 (26%) stage III, 182 (48%) stage IV and 13 patients (3%) unknown stage. Using a previously reported revised staging system the following distribution was obtained: 118 patients (31%) stage I, 120 (31%) stage II, 67 (18%) stage III, 54 (14%) stage IV and 21 patients (6%) with an unknown stage. Treatment consisted of radiotherapy alone in 231 patients (61%), surgery and radiotherapy in 101 (27%), surgery alone in 30 (8%), chemotherapy in 5 (2%) and 13 patients (3%) did not receive any treatment. At 5-yr the overall survival was 32%, the disease-specific survival 42% and the locoregional control 61%. In patients treated with radiotherapy alone the disease-specific survival was 39%, for surgery and radiotherapy 53% and for surgery alone 83%. The disease-specific survival according to UICC'92 stage was 71% in stage I, 59% in II, 50% in III and 32% in stage IV (P < 0.0001). In the revised staging the survival figures were 63% in stage I, 43% in II, 31% in III and 9% in IV (P < 0.0001). The two staging systems appeared to be comparable in prognostic discrimination; the clinical relevance of the revised stage might, however, be slightly superior to the UICC'92 version. The difference in results after radiotherapy alone and surgery + radiotherapy remained significant, also after adjusting for stage (P < 0.0001).

Carcinoma↗
PubMed1996

Primary non-Hodgkin lymphoma of the stomach: endoscopic pattern and prognosis in low versus high grade malignancy in relation to the MALT concept.

BACKGROUND: Various histological classifications developed for nodal lymphomas failed to be of value in extranodal lymphomas. More recently, gastric lymphoma is considered to represent a distinctive group derived from mucosa associated lymphoid tissue (MALT). AIM: To study the prognostic value of malignancy grading based on the concept that most gastric lymphomas are of MALT origin, the endoscopic as well as clinical characteristics in 114 patients with primary gastric non-Hodgkin's lymphoma were evaluated. RESULTS: In univariate analysis, patients with low grade lymphoma (n = 51) were younger, had less advanced stage, and less frequently bulky disease than those with high grade lymphoma (n = 63). In multivariate analysis weight loss and increased erythrocyte sedimentation rate were significantly less frequent in low grade (45% and 22%) compared with high grade lymphoma (75% and 53%). In low grade lymphoma endoscopic findings were often interpreted as a benign condition (27 of 51), in contrast with high grade lymphoma, where carcinoma was most frequently (37 of 63) suspected. In low grade lymphoma complete remission rate was 92%, and five year survival 75%, In high grade lymphoma results were significantly less favourable (p = 0.0001): complete remission in 68%, and a five year survival of 46%. CONCLUSION: Malignancy grading was strongly correlated with treatment outcome; endoscopically low grade lymphoma was often hard to distinguish from benign conditions, whereas high grade lymphoma often revealed carcinoma-like features.

Adult↗
PubMed1996

Management of cervical metastases in supraglottic cancer.

A retrospective review of patients from 1979 to 1988 was performed to assess the efficacy of neck dissection, prognostic factors, and the philosophy of treatment of the neck in supraglottic cancer. Of the 89 patients available for analysis, 26 were managed by horizontal partial laryngectomy (HPL), 44 by primary radiotherapy (RT), and 19 by total laryngectomy (TL). A total of 41 patients from the group had 63 neck dissections (NDs); 22 had bilateral and 19 unilateral dissections. A correlation of the pN with N staging revealed that when presenting with N2a nodes (> 3 cm), one third had contralateral metastases, and with N2b (multiple), 100% had contralateral metastases. In multivariate analysis of the disease-free interval, age and staging emerged as independent prognostic variables. Although we observed no increased morbidity by dissecting the opposite side, our results did not support routine bilateral neck dissection in NO patients. However, when the nodes are larger than 3 cm, or ipsilateral and multiple, bilateral neck dissection is recommended.

Carcinoma, Squamous Cell↗
PubMed1995

Apoptosis susceptibility genes on mouse chromosome 9 (Rapop2) and chromosome 3 (Rapop3).

The strain distribution pattern of susceptibility to thymocyte apoptosis induced by ionizing radiation in 20 CcS/Dem recombinant congenic (RC) strains derived from the strains BALB/cHeA (susceptible) and STS/A (resistant) indicates that this trait is controlled by several genes. Recently, we mapped a novel apoptosis susceptibility gene Rapop1 (radiation-induced apoptosis 1) to chromosome 16 (N. Mori et al., 1995, Genomics 25: 604-614). In the present study, the analysis of F2 crosses between the resistant RC strain CcS-8 and the susceptible strain BALB/cHeA or the highly susceptible RC strain CsS-10 demonstrated two additional apoptosis susceptibility genes, Rapop2 and Rapop3, located in the proximal region of chromosome 9 and the telomeric region of chromosome 3, respectively. The possible candidate genes for these loci are discussed.

Analysis of Variance↗
PubMed1995

Clinical value of pretreatment serum Cyfra 21-1, tissue polypeptide antigen, and squamous cell carcinoma antigen levels in patients with cervical cancer.

BACKGROUND: The clinical value of pretreatment serum concentrations of cytokeratin 19 fragments, measured by Cyfra 21-1, was compared with tissue polypeptide antigen (TPA) and squamous cell carcinoma antigen (SCC-Ag) in 78 patients with squamous cell cervical cancer. METHODS: Serum levels were compared with tumor stage, size, lymph node status, parametrial involvement, and prognostic data. The clinical performance of the different tests was evaluated by their receiver operating characteristic (ROC) curves. RESULTS: Serum levels of all markers were related significantly to tumor stage and size. Elevated serum levels of these markers were not found to be predictive for the presence of lymph node metastases. In contrast, a positive relation was found between quantitative serum Cyfra 21-1, TPA, and SCC-Ag levels and the presence of either lymph node metastases or parametrial involvement (i.e., extracervical disease). An elevated, i.e. positive, serum Cyfra 21-1 level was related significantly to the presence of extracervical disease (P = 0.020). The clinical performance of each serum marker in predicting lymph node metastases or parametrial involvement appeared to be similar as expressed by their ROC curves. In the univariate analysis, Cyfra 21-1, TPA, and SCC-Ag showed prognostic value with respect to disease free interval and survival. Elevated serum levels were associated with a poor prognosis. However, after adjusting for tumor stage and size, none of these markers remained statistically significant. CONCLUSIONS: Cyfra 21-1 may be of additional value in assessing stage of disease, tumor size, and the presence of extracervical disease in patients with cervical cancer. Determining its value during follow-up warrants further study.

Adult↗
PubMed1995

Insulin-like growth-factor-binding protein 3 is decreased in early-stage operable pre-menopausal breast cancer.

Insulin-like growth factor I (IGF-I) is a potent mitogen for human breast-cancer cells in vitro. In circulation, most of IGF-I is bound to IGF-binding protein 3 (IGFBP-3). This high-affinity binding is thought to have an important limiting effect on the availability of IGF-I for biological activity. To assess the availability of IGF-I for receptor binding, we determined serum levels of IGF-I and IGFBP-3 and IGF-I/IGFBP-3 ratios. In a case-control study, 150 women aged 38 to 75 years presenting with stage-I or -II breast cancer were investigated just prior to surgery (n = 76), or to irradiation one month after surgery (n = 74). The population-based control group consisted of 441 women of the same age having no breast cancer. Women reporting diabetes mellitus or other hormonal abnormalities were excluded. Premenopausal cases showed elevated IGF-I serum concentrations, decreased IGFBP-3 levels and increased IGF-I/IGFBP-3 ratios. The IGF-I/IGFBP-3 ratio was a significant breast-cancer risk factor, also after adjustment for age, family history, height, body-mass index, body-fat distribution, and serum levels of C-peptide. The relative risk was 7.34 for the highest compared with the lowest quintile of IGF-I/IGFBP-3. The presence or absence of tumor had no influence on these results. Increased levels of available IGF-I in the circulation of pre-menopausal women may contribute to the development of breast cancer.

Adult↗
PubMed1995

Eradication of large human B cell tumors in nude mice with unconjugated CD20 monoclonal antibodies and interleukin 2.

Since antibody-dependent cellular cytotoxicity is considered an important mechanism by which mAbs may exert their antitumor effects, it seems likely that these antitumor effects can be enhanced by the activation of the appropriate effector cell populations. We have used nude mice xenografted with human Daudi tumor cells as a model to compare the antilymphoma effects of unconjugated CD19 (CLB-CD19) and CD20 (BCA-B20) mAbs (IgG2a subclass) alone or in combination with recombinant human interleukin 2 (rhIL-2) or recombinant mouse granulocyte-macrophage-colony-stimulating factor (rmGM-CSF). Treatment of established tumors with BCA-B20 or rhIL-2 or rmGM-CSF as a single agent, all resulted in highly significant decreases of tumor growth rates, but did not increase the number of complete regressions. The combination of CLB-CD19 or BCA-B20 mAbs with rhIL-2 or rmGM-CSF resulted in larger decreases of growth rates than either of the agents alone. Complete eradication of large Daudi tumors could be achieved when treatment with BCA-B20 mAbs was combined with rhIL-2, but not with the combination of CLB-CD19 mAbs and rhIL-2 nor with the combination of BCA-B20 mAbs and rmGM-CSF. Cured animals kept for 2-3 months after complete regression of the tumors were still tumor free. Regression of tumors was correlated with the infiltration of lymphocytes as well as macrophages into the tumor. This is the first report to show that unconjugated CD20 mAbs are to be preferred over unconjugated CD19 mAbs, and interleukin 2 over GM-CSF in the combinational treatment of large B cell tumors.

Animals↗
PubMed1995

The importance of correct stage grouping in oncology. Results of a nationwide study of oropharyngeal carcinoma in The Netherlands.

BACKGROUND: In the frame of a nationwide study of oropharyngeal carcinoma in the Netherlands (1986-1990), the current International Union Against Cancer 1992/American Joint Committee on Cancer 1988 staging system was evaluated with respect to patient distribution and prognostic value. METHODS: Data related to epidemiology, treatment and survival from 640 patients referred for primary treatment were analyzed. Staging was first evaluated in a proportional-hazard regression analysis controlled for these data. Next, all possible combinations of T, N, and M were tested in a stepwise backward elimination model until all remaining indicator variables had a P value of less than 0.05. New stages were defined, based on the coefficients of the remaining indicator variables. RESULTS: The revised stages revealed two advantages compared with the UICC 1992/AJCC 1988 version: a more balanced distribution of patients (31% in Stage I, 31% in Stage II, 18% in Stage III, 14% in Stage IV, and 5% unknown in the revised staging system versus 7% in Stage I, 17% in Stage II, 24% in Stage III, 50% in Stage IV, and 2% unknown in the UICC 1992/AJCC 1988 staging system), and an improved prognostic discrimination for the disease specific survival (5-year results in the revised staging were 67% in Stage I, 42% in Stage II, 28% in Stage III, and 11% in Stage IV, versus 68% in Stage I, 64% in Stage II, 44% in Stage III and 27% in Stage IV in UICC 1992/AJCC 1988). CONCLUSION: Improvements in the current staging system in patient distribution in the stages in prognostic discrimination is feasible by regrouping the T, N, and M but without redefining the categories themselves.

Adult↗
PubMed1995

Enhanced antitumor effects of CD20 over CD19 monoclonal antibodies in a nude mouse xenograft model.

We used a nude mouse xenograft tumor model to compare the efficacy of unconjugated CD19 and CD20 mAbs (IgG2a subclass) in mediating antilymphoma effects. Treatment with the CD20 mAbs NKI-B20 and BCA-B20 resulted in a drastic decrease in tumor take rate (P < 0.0001) in comparison to controls, whereas the CD19 mAb CLB-CD19 was ineffective. Tumor growth rates were reduced by both CD19 and CD20 (P < 0.0001). The decrease in growth rate induced by NKI-B20 or BCA-B20 was larger than that induced by CLB-CD19 (P = 0.0022). In vitro experiments showed that NKI-B20 or BCA-B20 are more powerful than CLB-CD19 in mediating lysis by interleukin 2-activated natural killer cells. No difference was observed between different isotypes (IgG1, IgG2a, IgG2b) of the switch variants of NKI-B20 or CLB-CD19. A positive correlation between antigen density and the sensitivity to antibody-dependent cellular cytotoxicity was demonstrated with human lymphoblastoid B cells, JY, transfected with cDNA encoding the human CD19 antigen that expressed high levels of this antigen. These cells are more efficiently killed by natural killer cells when coated with CLB-CD19 mAbs than JY wildtype cells that express 1 log lower levels of the CD19 antigen. Antibody-dependent cellular cytotoxicity experiments with thioglycolate-activated macrophages show a more complex relationship between antigen density, isotype of the mAb, and cytotoxicity. BCA-B20 (IgG2a) and CLB-CD19 (IgG2a) and all isotypes of NKI-B20 mediated strong cytotoxicity, whereas CLB-CD19 isotypes IgG1 and IgG2b were associated with limited cytotoxicity. Proliferation of Daudi cells was inhibited with high concentrations of all isotypes of CLB-CD19, but not with any of the CD20 mAbs. To our knowledge this is the first report showing that the antitumor effects in vivo of unconjugated CD20 mAbs are far superior to those of CD19 mAbs.

Animals↗
PubMed1995

Genetic dissection of susceptibility to radiation-induced apoptosis of thymocytes and mapping of Rapop1, a novel susceptibility gene.

Genetic dissection of susceptibility to radiation-induced apoptosis of thymocytes was performed by counting dead cells in histologically processed thymuses after 0.5 Gy of whole-body X-irradiation, using recombinant congenic (CcS/Dem) strains derived from inbred mouse strains BALB/cHeA (susceptible) and STS/A (resistant). A high (8/20) number of strains with lower dead cell scores than BALB/cHeA among CcS/Dem recombinant congenic strains (RCS), which contain 12.5% of STS/A genome in the genetic background of BALB/cHeA strain, indicates that the difference between BALB/cHeA and STS/A is caused by several genes and that susceptibility probably requires BALB/cHeA alleles at more than one locus. Similar results were obtained with CXS/Hg recombinant inbred (CXS/Hg) strains. Analysis of F2 hybrids between BALB/cHeA and CcS-7, one of the CcS/Dem strains that showed lower dead cell scores than BALB/cHeA, demonstrated that a novel gene (Rapop1, radiation-induced apoptosis 1) controlling susceptibility to radiation-induced apoptosis in the thymus is located in the proximal region of mouse chromosome 16.

Animals↗