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Biomedical subjects

E N Atkinson

Publications and source records attributed to E N Atkinson.

At least 55 records · Page 3Linked to original sources
PubMed1992

Intrinsic resistance to anticancer agents in the murine pancreatic adenocarcinoma PANC02.

PANC02 is a ductal adenocarcinoma of the pancreas that is resistant to every known class of clinically active antitumor agent. To study the mechanism(s) underlying the intrinsic drug resistance of this tumor, a mammary adenocarcinoma (CA-755) that also grows in C57/BL mice and is known to be drug sensitive was used for comparison. PANC02 resistance and CA-755 sensitivity to several antitumor agents and to X-ray therapy was confirmed in mice, and PANC02 also demonstrated relative resistance in tissue culture. Relative to Chinese hamster ovary (CHO) and CA-755 cells, PANC02 did not appear to show a higher rate of mutation to drug resistance in culture as based on the 6-thioguanine resistance marker. Although P-glycoprotein characteristic of the multidrug resistance (MDR) phenomenon could be demonstrated at the mRNA level using a sensitive RNAse protection assay, the level of expression found was several orders of magnitude lower than that observed in phenotypic MDR cell lines. Furthermore, quinidine failed to increase the sensitivity of PANC02 cells to Adriamycin under conditions that clearly potentiated the toxicity of the drug to a CHO cell line exhibiting classic MDR traits. The heterogeneity in the distribution of drugs was inferred as being significantly greater in PANC02 versus CA-755 cells in vivo as based on measurements of within-animal, within-tumor variance in the distribution of the marker compounds inulin and antipyrine. Although it may not be the only mechanism involved, this greater intratumor heterogeneity in drug distribution could theoretically play a major role in the intrinsic drug resistance of PANC02 in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Youth as a prognostic factor in carcinoma of the cervix: a matched analysis.

A matched analysis comparing 250 patients less than 35 years old with squamous cell cancer of the cervix treated between 1971 and 1981 to a randomly selected group matched on treatment who were greater than 35 years old was performed. A chart review that focused on important prognosticators for survival and progression-free interval was performed. The groups were found to be similar for the important prognosticators. Overall survival and progression-free intervals were plotted using Kaplan-Meier curves and demonstrated that for advanced stages, younger patients were less likely to survive and more likely to recur. Cox proportional-hazard analyses were performed, looking at important prognosticators of survival and progression-free interval. Age, stage, positive lymph nodes, and cervical diameter emerged as statistically significant predictors of survival, while stage, positive lymph nodes, and cervical diameter emerged as statistically significant predictors of progression-free interval. The plot of relative hazard by stage of younger versus older patients showed an interaction between age and stage that merits further exploration.

Adolescent↗
PubMed1992

Resection of pulmonary metastases from uterine sarcomas.

Long-term survival following resection of pulmonary metastases has been well documented. Variables that are believed to have an effect on survival are site of primary tumor, number and size of metastases, resectability, laterality of the metastases, doubling time, and disease-free interval. Published information regarding resection of pulmonary metastases in patients with gynecologic primary tumors is limited. We reviewed 45 patients whose pulmonary metastases from uterine sarcomas were resected at Memorial Sloan Kettering Cancer Center between 1960 and 1989. All cases met carefully defined criteria at time of thoracotomy: prior hysterectomy for uterine sarcoma, no extrathoracic tumor, known disease thought to be resectable, histology consistent with uterine sarcoma, and no medical contraindication to thoracotomy. Seventy-one percent had unilateral lesions, fifty-one percent had one lesion, and seventy percent had nodules greater than 2 cm. Thirty-six percent had incomplete resection at thoracotomy. Actuarial 5- and 10-year survival from hysterectomy for uterine sarcoma was 65 and 50%, respectively, with a mean follow-up of 89 months. Five- and ten-year survival from resection of pulmonary metastases was 43 and 35%, respectively, with a mean follow-up of 25 months. Unilateral vs bilateral disease was a significant predictor of survival after pulmonary resection (P = 0.02). Metastases size, number of metastases, disease-free interval, and patient age were not significant. Among this carefully selected group of patients undergoing resection of pulmonary metastases from uterine sarcomas, long-term survival was achieved by a substantial proportion of patients. No single risk factor is sufficiently accurate to exclude an individual patient from consideration for pulmonary resection.

Female↗
PubMed1992

Prognostic factors influencing survival in gastrointestinal leiomyosarcomas. Implications for surgical management and staging.

The appropriate surgical therapeutic options for either localized or more advanced disease in patients with gastrointestinal leiomyosarcomas remain unclear. A staging classification for this disease has not been adopted nor risk factors identifying patients at risk for recurrence defined. To address these issues, this study evaluated the influence of various clinicopathologic variables on overall and disease-free survival. In an univariate analysis of overall survival involving 191 patients, the Cox proportional hazards model identified four factors that were associated with a significantly better outcome: complete resection without tumor rupture (p less than 0.001), localized lesions (p less than 0.001), low grade of tumor (p = 0.02), and tumors smaller than 5 cm (p = 0.03). When interactive effects of these factors were taken into account, however, type of resection of the tumor was selected as the only significant prognostic factor in a multivariate analysis. Complete resection without tumor rupture improved overall survival of patients with localized disease (median, 46 months) as well as those with contiguous organ invasion (median, 36 months) or peritoneal implants (median, 36 months). In contrast, patients with incomplete resections survived for a median of 21 months. Patients with tumor rupture, despite removal of all gross disease, behaved similarly to those with incomplete resections; median survival was only 17 months. For disease-free survival, important determinants selected from a multivariate analysis were tumor rupture (p = 0.002), contiguous organ invasion (p = 0.02) and high tumor grade (p = 0.02). A staging classification incorporating these prognostic factors of significance was evaluated using a TGM system: T1 (less than 5 cm), T2 (greater than or equal to 5 cm), T3 (contiguous organ invasion or peritoneal implants), T4 (tumor rupture); G: G1 (low grade), G2 (high grade); M: M0 (no metastases), M1 (metastases present). The corresponding 5-year overall survivals for stages I, II, III, IVA, and IVB were 75%, 52%, 28%, 12%, and 7%. Disease-free survival at 2 years after surgery was 89%, 57%, and 47% for stages I, II, and III, respectively. In conclusion, surgery remains the primary modality of treatment for patients with gastrointestinal leiomyosarcomas, and complete resection of all disease without tumor rupture, even of locally advanced disease, improves overall and disease-free survival. A staging classification appears feasible and is recommended to determine outcome in patients with leiomyosarcomas arising from the gastrointestinal tract.

Actuarial Analysis↗
PubMed1991

Sequentially administered ethinyl estradiol and medroxyprogesterone acetate in the treatment of refractory epithelial ovarian carcinoma in patients with positive estrogen receptors.

The activity of sequentially administered hormonal therapy was investigated over 25 days in 25 patients with epithelial ovarian carcinoma who had estrogen receptor (ERc)-positive tumors. Patients received ethinyl estradiol (EE) (50 micrograms/d) on days 1 to 7 and medroxyprogesterone acetate (MPA) (400 mg/d) on days 8 to 25. Twenty-three patients completed one or more courses of treatment. There were no complete responses (CR). Four partial responses (PR) with durations of 9, 4, 3, and 1 months were seen. Two incomplete responses with durations of 6 and 4 months were also seen. Six patients had stable disease (SD), and 11 patients had progression. The overall response rate was 17% and may represent a modest improvement in response over those in previously published studies conducted with MPA alone. No significant toxic effects were noticed, and some patients reported an improved sense of well-being. However, two patients experienced depression with this treatment. The mean ERc values in responders, patients with SD, and nonresponders were 70.0, 36.7, and 47.9 fmol/mg cytosolic protein, respectively. Future studies of hormonal therapy in patients with ovarian carcinoma should attempt to identify more reliable indices for determining sensitivity to these agents.

Administration, Oral↗
PubMed1991

Prognostic indicators for invasive carcinoma of the vulva.

Three hundred sixty-five patients with invasive squamous cell carcinoma of the vulva have been treated at M.D. Anderson Cancer Center between 1944 and 1990. We undertook a rigorous review of the medical records, and a Cox proportional hazards model was applied to examine predictors of both failure to survive and recurrence. Significant predictors of both failure to survive and recurrence included tumor size, clinical stage, therapy aim, pelvic or inguinal nodal metastases, and positive margins. We then undertook an analysis of Stage I and II lesions treated with a curative aim to see if there was a difference in survival or in disease-free interval between those patients treated with radical vulvectomy and those treated with radical wide local excision. There was no survival advantage from the radical vulvectomy procedure. We conclude that careful selection may allow us to choose some patients for less radical procedures.

Carcinoma↗
PubMed1990

Endometrioid carcinoma of the ovary: retrospective review of 145 cases.

From 1967 through December 1987, 145 patients with endometrioid carcinoma of the ovary were treated at the University of Texas M. D. Anderson Cancer Center. Thirty-eight patients (26.2%) had stage I disease, 28 (19.3%) stage II, 60 (41.4%) stage III, and 11 (7.6%) stage IV; 8 patients (5.5%) were unstaged. Grade 2 or 3 histology was seen in 119 patients (82.1%). In addition to surgical therapy, 128 patients underwent chemotherapy, including single-agent therapy, noncisplatin combination therapy, and cisplatin-based therapy. No statistically significant improvement in median survival was noted among these three chemotherapy groups for stages II, III, and IV (P = 0.22). A significant improvement in median survival was noted for those patients who achieved a complete clinical response, regardless of type of chemotherapy (96 or more months for single-agent therapy, P = 0.001; 31.5 months for noncisplatin combination therapy, P = 0.016; and 85 months for cisplatin-based therapy, P = 0.0001). Synchronous ovarian and uterine malignancies were seen in 18 patients (12.4%). No difference in survival was seen for patients with endometriosis (P = 0.13) or endometrial cancer (P = 0.09) when compared with those who did not have these histologic findings.

Adenocarcinoma↗
PubMed1990

Survival following locoregional recurrence after breast conservation therapy for cancer.

We postulated that locoregional recurrence after limited surgery and radiotherapy for breast cancer might be associated with an additional survival hazard, similar to that of a second primary tumor with the same extent of local and regional disease. Using this hypothesis we examined the likely resultant effect on survival. Our calculations indicated that no statistically significant survival deficit due to such recurrence would be detectable until a randomized controlled trial comparing breast conservation with mastectomy had monitored more than 10,000 patients for more than 10 years. A simple mathematical model predicted 5-year survival rates in a cohort of patients treated with breast conservation of 75%, compared to 83% in those without locoregional recurrence. From the date of locoregional recurrence, a 61% 5-year survival rate was predicted, compared to 83% if no hazard was associated with locoregional recurrence. These predictions were compared with the actuarial survival rates of 499 patients with unilateral breast cancer, 49 of whom had developed locoregional recurrence. From the date of initial treatment, the 5-year survival rate of those whose disease recurred was 79%, compared to 88% for those without locoregional recurrence (p = 0.19). The actuarial 5-year survival rate from the date of locoregional recurrence was 63%. The similarity between the patient data and the predictions of the mathematical model indicates that locoregional failure after breast conservation therapy may result in reduced survival. The lack of a significant survival deficit in our cohort or in controlled trials comparing breast conservation therapy with mastectomy is compatible to the small size of the overall effect.

Actuarial Analysis↗
PubMed1989

Metastatic potential of human colorectal carcinomas implanted into nude mice: prediction of clinical outcome in patients operated upon for cure.

To determine whether the production of experimental hepatic metastases in athymic nude mice by human colorectal carcinomas (HCC) correlated with the clinical outcome in patients, we harvested colorectal carcinomas from 82 patients, dissociated the tumors with collagenase and DNase, and injected them into groups of nude mice, either in the flank to assess experimental tumorigenicity or into the spleen to produce experimental metastasis in the liver. Growth in mice was then associated with clinicopathological factors and clinical outcome. Growth of HCC in either the flanks or the livers of nude mice was associated with the time to recurrence in a Wilcoxon analysis. Analysis of the outcome data in a Cox proportional hazards model suggested that there was an interaction between tumorigenicity and metastatic potential of HCC in nude mice and serum CEA concentration in the patient and stage of disease. A univariate analysis indicated that both tumorigenicity and metastatic potential of HCC in nude mice were significantly associated with the serum CEA concentration of the patient but not with the other variables of stage of disease, mucin production, local tissue invasion, state of differentiation, or sex. A subset of 57 patients was operated upon for cure and followed prospectively for up to 61 months. Tumorigenicity and, to a lesser extent, experimental metastatic potential were associated with disease recurrence in 23 of these patients. Seventy-eight % of the subset of patients who were operated upon for cure developed liver metastasis as one site of their progressive disease. Thus, the ability of HCC cells isolated from surgical specimens to grow in athymic nude mice correlates with the development of advanced disease in patients.

Adult↗
PubMed1989

Gracilis myocutaneous vaginal reconstruction concurrent with total pelvic exenteration.

The gracilis myocutaneous vaginal reconstruction is commonly performed in patients undergoing a total pelvic exenteration. This retrospective review compares the operative and perioperative morbidity in 107 patients who underwent reconstruction with that in 44 patients who did not have reconstruction. With incorporation of the reconstructive procedure, there were no increases in operating time, blood loss, or length of hospitalization. Before 1980, 65% of patients experienced prolapse of the neovagina; in 25% it was severe. The frequency of prolapse has since been decreased to 16% (6% severe) because of several modifications to the initial technique. Modifications have included using smaller flaps, anchoring the neovagina to the levator and retropubic fascia, and, when necessary for mobilization, ligating the neurovascular pedicle. With these modifications, 66% of patients also remained free of wound breakdown or necrosis. The frequency of severe necrosis has decreased from 24% to 13%. The anatomic result of the vaginal reconstructions appears to have been enhanced by these changes in technique.

Female↗
PubMed1989

Treatment of advanced endometrial adenocarcinoma with cyclic sequential ethinyl estradiol and medroxyprogesterone acetate.

Fifteen patients with recurrent or progressive endometrial adenocarcinoma of moderate to poor histologic differentiation were entered in a phase II trial of sequentially administered oral ethinyl estradiol and medroxyprogesterone acetate. There were no significant clinical responses in 12 patients evaluated for response and four patients experienced thromboembolic complications. This cyclic treatment regimen is considered ineffective for this patient population at the dosages and schedules used.

Adenocarcinoma↗
PubMed1989

Randomized comparison of viral oncolysate plus radiation and radiation alone in uterine cervix carcinoma.

A randomized, controlled study was performed in patients with high-risk, untreated squamous cell carcinoma of the uterine cervix to evaluate the adjunctive use of viral oncolysate (VO) prepared from the SW756 cell line. Seventy-five patients were stratified by tumor volume and randomized to receive radiation therapy (RT) alone or RT plus intradermal immunization with VO. Fifty-one (68%) patients relapsed with a median survival (MS) of 29.1 months and a median progression-free interval (MPFI) of 18.0 months. No differences in MS or median PFI were observed by treatment arm or site of relapse, although a trend toward improved MS and median PFI in patients with small-volume primary lesions was suggested. Serum surface-binding antibody activity (greater than or equal to 1:8) to the SW756 cell line was detected in 14 of 41 unselected patients prior to therapy. Virus hemagglutination inhibitory activity (greater than or equal to 1:8) was detected in 37 of 41 patients before treatment. four-fold increases in titer were observed to the SW756 cell line in 83% and to influenza in 74% of patients tested after immunization. Preirradiation measurements of phytohemagglutinin-induced blastogenesis by the relative proliferation index (RPI) method in 39 patients revealed RPI values less than 0.58 in nine patients, eight of whom relapsed. At 3-6 months after the initiation of irradiation, 32 of 39 patients had values less than 0.58. Patients in the RT group with values less than 0.58 had significantly more relapses than those who received RT plus VO.

Adult↗
PubMed1988

The significance of müllerian inclusions found at second-look laparotomy in patients with epithelial ovarian neoplasms.

When no visible tumor is identified at second-look laparotomy, selected biopsy specimens or cytologic washings may reveal microscopic tumor or benign pathologic atypia. The pathology material from 311 patients with epithelial ovarian carcinoma who had no macroscopic tumor at second-look laparotomy was evaluated for psammoma bodies, müllerian inclusions (benign glandular inclusions), microscopic tumor, and either inflammation or fibrosis. Progression-free intervals and survival rates were influenced by the presence of müllerian inclusions (favorably), tumor or positive cytology (unfavorably), and inflammation or fibrosis (unfavorably). Multivariate analysis (proportional hazards model) demonstrated that both the progression-free interval and survival rates were influenced significantly by the presence of microscopic tumor and tumor grade. Of 51 patients with müllerian inclusions and no microscopic tumor, 23 received additional treatment after second-look laparotomy. No differences were noted in the progression-free interval or survival rates when these patients were compared with the 28 nontreated patients. Of the treated patients, three died from chemotherapy toxicity, whereas there were no chemotherapy-related deaths in the nontreated group. These findings indicate that the presence of müllerian inclusions at second-look laparotomy does not justify treatment, and that further treatment after misinterpretation of these benign pathologic entities may lead to harmful results.

Antineoplastic Agents↗
PubMed1987

Projection from previous studies: a Bayesian and frequentist compromise.

We present methods that use the results of a previous study to predict the outcome of a specified comparative trial in which each subject's outcome is categorized dichotomously (e.g., response or no response). The methods can be generalized to other two-sample cases for which power can be calculated (e.g., exponential survival), and to one-sample cases such as demonstrating a minimal response rate or demonstrating superiority to a historic control. Bayesian methods are used on the results of the preliminary study to obtain a posterior distribution representing the state of knowledge of the parameters of interest. This distribution provides the probability that the experimental regimen is superior to the standard by any particular amount. The probability that a future study will demonstrate the superiority of the experimental treatment is obtained by using the posterior distribution to average the power of the test over the parameter space.

Bayes Theorem↗
PubMed1987

Lack of concordance of growth rates of primary and recurrent breast cancer.

The degree of concordance of growth rates of primary tumors with corresponding recurrences was investigated by using data from 184 patients with breast cancer with measurable recurrences. For conduction of this examination, the detection processes of both the primary tumor and the recurrence were explored. The probability of detection of a recurrence per unit time was found to be nearly proportional to the tumor's diameter. Approximately 60,000 cells initiated the recurrence, and the distribution of doubling times of the recurrences was exponential, with a mean of 2.1 months. The probability of detection of the primary tumor per unit time was approximately proportional to its volume. The distribution of doubling times of primary tumors was nearly exponential; from other evidence, we inferred that the mean doubling time was also close to 2.1 months. Several techniques to measure growth rate agreement between the primary and recurrent tumors within individuals were developed, and all of them yielded the result that the growth rates are nearly unrelated.

Breast Neoplasms↗
PubMed1986

13-cis-retinoic acid in the treatment of oral leukoplakia.

13-cis-Retinoic acid has been reported to be effective in treating oral leukoplakia. We randomly assigned 44 patients with this disease to receive 13-cis-retinoic acid (24 patients) or placebo (20), 1 to 2 mg per kilogram of body weight per day for three months, and followed them for six months. There were major decreases in the size of the lesions in 67 percent (16 patients) of those given the drug and in 10 percent (2 patients) of those given placebo (P = 0.0002); dysplasia was reversed in 54 percent (13 patients) of the drug group and in 10 percent (2 patients) of the placebo group (P = 0.01). The clinical response to the drug correlated with the histologic response in 56 percent (9 of 16) of the patients evaluated. Relapse occurred in 9 of 16 patients two to three months after treatment ended. The toxic effects of the drug were acceptable in all but two patients. Cheilitis, facial erythema, and dryness and peeling of the skin were common; conjunctivitis and hypertriglyceridemia also occurred. All adverse reactions could be reversed by reducing the dose or temporarily discontinuing the drug. We conclude that 13-cis-retinoic acid, even in short-term use, appears to be an effective treatment for oral leukoplakia and has an acceptable level of toxicity.

Aged↗
PubMed1986

Ethinyl estradiol and medroxyprogesterone acetate in patients with epithelial ovarian carcinoma: a phase II study.

Patients with ovarian carcinoma refractory to chemotherapy received a sequential combination of ethinyl estradiol and medroxyprogesterone acetate in two dose regimens. There was no difference in therapeutic activity of the two dose regimens. Of 65 patients, nine (14%) responded to treatment and 13 (20%) had stable disease. Vascular complications occurred in three patients; hemiplegia developed in one of those. Nine patients had significant nausea and vomiting, and one experienced severe depression that required treatment withdrawal. The sequential and combined use of ethinyl estradiol and medroxyprogesterone acetate may provide an alternative treatment for certain patients with ovarian carcinoma that does not respond to optimum chemotherapy. Additional studies are required to determine if synergism exists between this treatment and other modalities of therapy. Further investigation is required into the vascular disorders that complicate therapy to determine whether appropriate preventive measures are possible.

Adult↗