p53-based blood test for p53PIN3 and risk for sporadic ovarian cancer.
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Publications and source records attributed to E N Atkinson.
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The objective of this study was to describe and compare the outcome of patients with recurrent adenocarcinoma versus squamous cell carcinoma of the uterine cervix who have been treated with pelvic exenteration. All patients undergoing pelvic exenteration for cervical adenocarcinoma from 1955 to 1989 were identified and a retrospective review was conducted. For these 35 patients, we identified 70 controls who had exenteration for squamous cell carcinoma and who were matched for node status, year of procedure, and type of procedure. No significant difference was noted between the control group and the adenocarcinoma group for size of recurrent tumor, status of margins, presence of hydronephrosis prior to exenteration, and the time elapsed from initial diagnosis to exenteration. The two groups were compared for survival and recurrence pattern. Median patient age was 47 years (range 22-70). All patients had prior pelvic radiotherapy. Thirty patients had total pelvic exenteration and 5 had anterior exenteration. There were 3 postoperative deaths (8.6%). Median survival was 38 months for the adenocarcinoma patients and 25 months for the squamous patients (P > 0.99). The overall survival between the two sets of patients was very similar (log rank P = 0.86). There were 23 postexenteration recurrences among the adenocarcinomas (22 in which the site is known) and 32 postexenteration recurrences among the squamous patients (30 with known site). For the adenocarcinoma patients, 14 of 22 had a distant recurrence versus 14 of 30 for the squamous patients (P = 0.27). Patients with central recurrence of cervical adenocarcinoma can be successfully treated with pelvic exenteration and have survival rates similar to squamous carcinoma.
Forty-nine women with ductal carcinoma in situ (DCIS) treated with lumpectomy and irradiation were studied retrospectively. The median age was 50 years (range, 29 to 73 years) and the median follow-up time from initiation of therapy was 86 months (range, 17 to 230 months). Twelve patients presented with palpable masses (0.4 to 4 cm), three with breast thickening, and three with nipple discharge. In 31 patients the tumors were detected by mammography. Intraoperatively, excision of lesions was confirmed by specimen x-ray (38 specimens) or gross inspection (five specimens) and was recorded to be complete. No record was available in the other six patients. Margins of excision free of DCIS were microscopically confirmed in 25 specimens. The size of impalpable DCIS lesions recorded in 25 patients ranged from 0.4 to 5.0 cm (mean, 1.5 cm). Using Lagios' classification system, there were 18 classic comedocarcinomas, high nuclear grade (NG) with necrosis; seven cribriform/papillary, high NG with necrosis; 17 cribriform/micropapillary, intermediate NG with or without necrosis; and seven cribriform/micropapillary, low NG without necrosis. In two patients residual malignant calcifications were present on the postoperative mammogram. Disease recurred in the treated breast at the site of incision in five patients at 18 months and 8, 11, and 12 (two patients) years from initial therapy. The rate of local disease recurrence was 2% at 5 years and 6% at 10 years; three recurrences showed invasive ductal carcinoma and two were DCIS. To evaluate risk factors the following characteristics were considered: necrosis, NG, histological type, periductal fibrosis, periductal lymphoid infiltrate, margin status, age, and method of tumor detection. The end points chosen were recurrence and death from any cause (because only one patient died of disease). Although the recurrences were attributed to residual disease in two patients, of the clinical and pathological parameters evaluated, only periductal fibrosis showed a significant relationship with outcome, with a P value < or = .05 by the Wilcoxon test. On the other hand, using the proportional hazards model, necrosis was a significant predictor for recurrence (P = .02), as was the pair fibrosis and tumor detection when taken together (P = .05). Fibrosis significantly associated with high NG, Lagios' histological subtypes I and II, periductal lymphoid infiltrate, and necrosis (P < or = .0006).(ABSTRACT TRUNCATED AT 400 WORDS)
Analogous to breast cancer, the expression of estrogen receptors (ER) by human ovarian cancers is thought to be of prognostic significance. This prospective study was designed to evaluate the ability of immunohistochemistry (IHC) for ER to define prognostic subgroups in this disease and to possible characterize the group of patients that would benefit from ER analysis. The IHC technique for localising ER was published by Press and Green (1984). In IHC the percentage of cells stained was determined as well as the staining intensity that was graded on a 4 step scale. Tissue from the primary focus of 61 ovarian cancers was sampled during surgery and frozen immediately. FIGO Stage 1 disease was observed in 7 patients, stage 2 in 2, stage 3 in 36 and stage 4 in 16 women. Tumours of histological grade 1 were found in 3 cases, grade 2 in 20 and grade 3 in 38 specimen. Serous carcinoma was diagnosed in 43 lesions, mixed cell types in 10, mucinous and endometrioid each in 4. Minimal follow-up was 8 years. Statistical analysis was performed using the Wilcoxon Rank and Log-Rank test of Kaplan Meier curves. The median survival was 10.62 +/- 1.83 years for stage 1, 5.83 +/- 0.39 years for stage 2, 2.38 +/- 0.39 years for stage 3, and 3.71 +/- 0.76 years for stage 4. Tumour stage (p < 0.05), grade (p < 0.05) and cell type (p < 0.01) were predictors of survival. Age was of borderline significance (p = 0.058). The relative amount of stained cells was no predictor of prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)
A pilot study was conducted in patients who had advanced epithelial ovarian carcinoma, and who were refractory to platinum-based chemotherapy, to determine the feasibility and clinical effects of a schedule of intraperitoneal (IP) tumor-infiltrating lymphocytes (TIL) expanded in recombinant interleukin-2 (rIL-2), and low-dose rIL-2 IP. TIL were expanded from solid metastases or malignant effusions in serum-free AIM V medium supplemented with low concentrations (600 IU/ml) or rIL-2 using a four-step method of expansion that included a hollow fiber bioreactor (artificial capillary culture system). Patients received IP TIL suspended in dextrose 5% in sodium chloride 0.2% containing 0.1% human albumin and 6 x 10(5) IU rIL-2 on day 1, followed by 6 x 10(5) IU rIL-2/m2 body surface area, administered daily by bolus IP injection, on days 2-4, 8-11, and 15-18. In the absence of disease progression, two additional 4-day cycles of IP rIL-2 were administered. Patients (n = 3) whose TIL failed to grow in vitro received IP IL-2 alone. Eight patients received rIL-2 expanded TIL (10(10)-10(11) range) plus rIL-2 followed by several cycles of rIL-2 alone. One of these patients was treated twice with TIL plus rIL-2. Expanded TIL were primarily CD3+CD4+TCR alpha beta+ (eight TIL-derived T-cell lines). One TIL-derived T-cell line was comprised mostly of CD3+CD8+TCR alpha beta+ cells. Eleven patients (eight treated with TIL plus rIL-2 and three patients treated with rIL-2 alone) received a total of 38 cycles of rIL-2 without TIL. Grade 3 clinical toxicity (peritonitis) occurred in 1 of 9 cycles of TIL plus rIL-2 and 1 of 38 cycles of rIL-2 alone. Each cycle was 4 days long. Grade 3 anemia occurred in 1 of 9 TIL plus rIL-2 cycles and 3 of 38 cycles of rIL-2 alone. There were no measurable responses; however, four of eight patients treated with IP TIL plus rIL-2 had some indication of clinical activity: ascites regression (two patients), tumor and CA-125 reduction (one patient), and surgically confirmed stable tumor and CA-125 values (one patient). The schedule of IP TIL plus low-dose rIL-2 shows manageable toxicity and is worthy of further evaluation in patients with epithelial ovarian cancer who have less tumor burden.
Studies have shown that argyrophilic nucleolar organizer region-associated proteins (AgNORs) may correlate with DNA ploidy and/or proliferative activity in neoplastic and non-neoplastic conditions. However, studies have estimated only the mean AgNOR counts. Here we used two AgNOR counts, one of which may correlate with DNA ploidy and the other with proliferative activity. The mean AgNOR count (mAgNOR) was defined as the mean number of AgNORs/nucleus in 100 cells and may represent DNA or RNA index. The percentage of nuclei exhibiting 5 or more AgNORs/nucleus (pAgNOR) may reflect proliferative activity. These two AgNOR counts were correlated with results from acridine orange flow cytometry in 50 fine-needle aspirate (FNA) smears of nodal and extranodal sites, including three cases of reactive lymphadenopathy and 47 cases of non-Hodgkin's lymphoma. The mean mAgNOR count in the diploid specimens was 2.03 (+/- 0.74 SD) and 2.62 (+/- 0.73 SD) in the aneuploid tumors (P less than 0.0001). Samples with a low RNA index had mean mAgNOR of 1.80 (+/- 0.41 SD), whereas those with high RNA had a mean mAgNOR of 2.93 (+/- 0.86 SD) (P less than 0.0001). Lesions with low proliferative index, determined by flow cytometry, had a mean pAgNOR of 4%, whereas those with intermediate and high proliferative indices had a mean pAgNOR of 16% (P less than 0.0001). A similar but less significant correlation existed between RI and pAgNOR (P less than 0.005). We conclude that the two AgNOR counting methods may reliably reflect cell kinetics and distinguish ploidy from proliferative activity, making them useful adjuncts to flow cytometry in limited cytology specimens and small biopsy samples.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.