Efficacy of vitamin E, phosphatidyl choline and pyruvate on Abeta neurotoxicity in culture.

Oxidative stress is a pivotal factor in neuronal degeneration including that induced by exposure to amyloid-beta (Abeta). Treatment with antioxidants such as vitamin E can alleviate Abeta neurotoxicity. However, vitamin E was only marginally effective in clinical trials in Alzheimer's disease. Recent studies indicate that treatment with vitamin E (as a-tocopherol), sodium pyruvate and phosphatidyl choline (PC) is more effective than vitamin E alone against neuronal oxidative stress. We demonstrate herein that treatment of cultured murine cortical neurons with these 3 agents is also more effective than vitamin E alone against Abeta neurotoxicity as assayed by generation of reactive oxygen species and increased levels of phospho-isoforms of the microtubule-associated protein tau. These data underscore the potential efficacy of a combinatorial neuroprotective formulation against Abeta neurotoxicity.

Intraoperative radiation therapy in gynecologic cancer: update of the experience at a single institution.

PURPOSE: To update the Mayo Clinic experience with intraoperative radiation therapy (IORT) in patients with gynecologic cancer. METHODS AND MATERIALS: Between January 1983 and June 1991, 39 patients with recurrent or locally advanced gynecologic malignancies received intraoperative radiation therapy with electrons. The anatomical area treated was pelvis (side walls or presacrum) or periaortic nodes or a combination of both. In addition to intraoperative radiation therapy, 28 patients received external beam irradiation (median dose, 45 Gy; range, 0.9 to 65.7 Gy), and 13 received chemotherapy preoperatively. At the time of intraoperative radiation therapy and after maximum debulking operation, 23 patients had microscopic residual disease and 16 had gross residual disease up to 5 cm in thickness. Median follow-up for surviving patients was 43.4 months (range, 27.1 to 125.4 months). RESULTS: The 5-year actuarial local control with or without central control was 67.4%, and the control within the IORT field (central control) was 81%. The risk of distant metastases at 5 years was 52% (82% in patients with gross residual disease and 33% in patients with only microscopic disease postoperatively). Actuarial 5-year overall survival and disease-free survival was 31.5 and 40.5%, respectively. Patients with microscopic disease had 5-year disease-free and overall survival of 55 and 50%, respectively. Grade 3 toxicity was directly associated with IORT in six patients (15%). CONCLUSION: Patients with local, regionally recurrent gynecologic cancer may benefit from maximal surgical debulking and IORT with or without external beam irradiation, especially those with microscopic residual disease.

Prognostic value of p53 and proliferating cell nuclear antigen expression in endometrial carcinoma.

The degree of expression of p53 and proliferating cell nuclear antigen (PCNA) was measured in archival samples from 221 patients managed surgically for endometrial carcinoma between 1979 and 1983. With use of primary antibodies to the p53 protein (DO7) and PCNA (PC10), immunoperoxidase nuclear staining of paraffin-embedded tissue was performed. The computerized CAS200 Image Analysis System was used to determine the percentage of nuclear area stained. There was no evidence to conclude that progression-free survival differed with respect to PCNA expression. In contrast, intense p53 expression (66% or more nuclear area stained) was significantly associated with compromised progression-free survival both in the analysis of all stages (P < 0.001) and in the subset of patients with stage I disease (P < 0.001). Intense expression of p53 was significantly associated with other prognostic indicators, including stage, grade, depth of myometrial invasion, histologic subtype, cytologic findings, DNA ploidy, and HER-2/neu expression. Multivariate analysis identified four independent prognostic factors for progression-free survival in endometrial carcinoma: intense p53 expression, histologic subtype, DNA ploidy status, and HER-2/neu expression. When none of these four independent factors are present, the 4-year progression-free survival is 96%. In contrast, it is 63% when one or more of these factors are present (P < 0.001) and 40% when two or more factors are present (P < 0.001).

Treatment of recurrent adenocarcinoma of the endometrium with pelvic exenteration.

Women with recurrent endometrial carcinoma are usually not considered candidates for pelvic exenteration. To assess the efficacy of this procedure, the records of all patients undergoing pelvic exenteration for adenocarcinoma of the endometrium at four institutions from 1955 through 1988 were reviewed. Of the 31 procedures performed, 7 were for primary therapy and 4 were judged to be palliative in nature and were excluded from analysis. Of the 20 patients with recurrent endometrial cancer who underwent exenteration with curative intent, all had previously received pelvic radiotherapy, 14 as part of their primary treatment and 6 as part of the treatment of recurrent disease. Six of 20 patients also received chemotherapy or hormonal therapy prior to exenteration. The median patient age was 65 years (range 44-79 years). At most recent follow-up, 8 patients were alive and disease free, 2 were alive with disease, 6 had died of disease, and 4 had died of other causes. The median follow-up of living patients is 89 months. Twelve of 20 patients experienced major complications, the most common of which was neovaginal flap necrosis. Of the 20 patients, 1 patient (5%) died in 1963 of surgical complications. The Kaplan-Meier estimate of 5-year disease-free survival is 45%. Pelvic exenteration can produce an acceptable rate of disease-free survival in highly selected patients with local recurrence of endometrial adenocarcinoma who have exhausted other treatment modalities.

Extrapulmonary lymphangioleiomyomatosis and lymphangiomatous cysts in tuberous sclerosis complex.

OBJECTIVE: To describe the clinical manifestations, imaging findings, and histologic features of extrapulmonary lymphangioleiomyomatosis (LAM) in the tuberous sclerosis complex (TSC). DESIGN: We retrospectively reviewed institutional medical records since 1940 to identify patients with TSC and extrapulmonary LAM. MATERIAL AND METHODS: Of 403 patients with TSC, 3 had pulmonary and extrapulmonary LAM and retroperitoneal lymphangiomatous cysts. The clinical, imaging, and histologic features of these three patients were summarized, including analysis of biopsy specimens by conventional histology, immunohistology, radiolabeled ligand-binding assays, and tissue culture. RESULTS: The three young women had characteristic dermatologic findings of TSC and pulmonary LAM. Two patients were of normal intelligence, and one had a recent history of contraceptive use. All three patients had intra-abdominal lymphangiomatous cysts, uterine LAM, and renal angiomyolipomas. Renal and uterine biopsy specimens demonstrated positive immunostaining for melanoma-related antigens and expression of estrogen and progesterone receptors by ligand-binding assay and immunohistology. Cells cultured from LAM tissue of one of the patients exhibited a mitogenic response to estradiol. CONCLUSION: Clinically significant extrapulmonary LAM is a rare manifestation of TSC and may occur in women with this disease who also have pulmonary LAM. The clinical features of these patients confirm the importance of sex steroids in the development of these lesions. Immunohistochemical findings suggest that LAM and angiomyolipomas have a neuroectodermal origin. The development of lymphangiomatous cysts in these patients is probably due to smooth muscle proliferation in lymph vessels, which can result in lymphatic obstruction.

Giant uterine fibromyoma producing secondary polycythemia.

BACKGROUND: Although the association between large uterine fibromyomas and secondary polycythemia has been described previously, the mechanism has not been elucidated definitively. Investigators have measured erythropoietin levels in fibromyomas to determine whether these tumors are causing the polycythemia by erythropoietin overproduction; however, these studies were performed before the availability of recombinant erythropoietin assays. CASE: A 59-year-old woman presented with a 3-year history of polycythemia. Pelvic examination revealed a large lower abdominal mass. Laboratory evaluation revealed a hemoglobin of 20.8 g/dL, red blood cell mass of 3300 mL, oxygen pressure of 58 mmHg with an oxygen saturation of 89%, and erythropoietin level of 18 mU/mL. Cardiac echocardiogram showed no evidence of shunt. Computed tomography scan of the abdomen showed a large mass arising in the pelvis and compressing both ureters. The patient was treated surgically with a total abdominal hysterectomy. Pathology confirmed a uterine leiomyoma weighing 2320 g. Two months post-surgery, the patient was asymptomatic with a hemoglobin of 13.9 g/dL and erythropoietin level less than 4.0 mU/mL. CONCLUSION: This case provides evidence for three of the postulated mechanisms by which uterine fibromyomas may cause polycythemia. First, the patient was hypoxic, suggesting shunting within the tumor. Second, the leiomyoma was compressing the ureters, so the kidneys may have been inappropriately producing excess erythropoietin. Third, the tumor itself may have been producing the erythropoietin. In any case, the erythropoietin level in this patient was inappropriately high, providing useful evidence that her polycythemia was secondary to her fibromyoma.

Stage III papillary serous cystadenocarcinoma of the ovary in a 15-year-old female.

Epithelial ovarian cancer is the most common cause of death due to gynecologic malignancies in adults, but is rare in children and adolescents. The majority of ovarian cancers in children and adolescents are stage I at diagnosis and conservative management with preservation of fertility is often possible. Twenty-nine serous epithelial cancers have been reported in females under age 20, only two of which are known to be advanced stage (both stage III). We present a case of advanced stage papillary serous cystadenocarcinoma in a 15-year-old female treated with bilateral salpingo-oophorectomy and debulking surgery followed by combination chemotherapy.

Pseudomyxoma peritonei. Long-term patient survival with an aggressive regional approach.

OBJECTIVE: The aims of this study were to analyze the natural history of patients with pseudomyxoma peritonei (PMP), evaluate clinical and pathologic variables as prognostic indicators, and review the authors' experience with different treatments. SUMMARY BACKGROUND DATA: PMP is an unusual form of intra-abdominal neoplasm that presents with large amounts of extracellular mucin. Diffuse peritoneal spread occurs in most patients with PMP, and distant metastasis is infrequent. Debulking surgery, radiation therapy (radioisotope and external beam), and chemotherapy (both intraperitoneal and systemic) have all been advocated for optional patient management, but the variability of patients studied, the small patient numbers, and the prolonged course of this disease make the evaluation of results difficult. METHODS: Fifty-six patients were treated for PMP at the Mayo Clinic between 1957 and 1983. The data were collected retrospectively. Univariate (log-rank test) and multivariate (Cox regression model) analyses were performed for disease recurrence and patient survival. RESULTS: Most patients with PMP had carcinomas of the appendix (52%) or ovary (34%). All gross tumor could be removed only in the 34% of patients with limited disease. Although tumor progression occurred in 76% of patients, the 1-, 5-, and 10-year survival rates were 98%, 53%, and 32%, respectively. Adverse predictors of patient survival included weight loss (p = 0.001), abdominal distention (p = 0.004), use of systemic chemotherapy (p = 0.005), diffuse disease (p = 0.038), and invasion of other organs (p = 0.04). Intraperitoneal chemotherapy (p = 0.009) and radioisotopes (p = 0.0043) both were effective in prolonging the recurrence time of symptomatic PMP. CONCLUSIONS: Although PMP is an indolent disease, aggressive surgical debulking followed by intraperitoneal radioisotopes and/or chemotherapy should be considered because of the diffuse peritoneal involvement.

Vulvar cancer with bulky nodal metastasis in a young woman. A case report.

We report a case of vulvar cancer (clinical stage IV, surgical stage III) that occurred in a young woman without identifiable risk factors. The patient underwent radical vulvectomy followed by adjuvant radiotherapy. She remained free of disease two years after diagnosis and treatment. Our case emphasizes the need to biopsy any suspicious vulvar lesions, even those in young patients. Furthermore, histologic evaluation is mandatory prior to ablation of vulvar lesions in any age group.

Deoxyribonucleic acid analysis facilitates the pretreatment identification of high-risk endometrial cancer patients.

OBJECTIVE: Our purpose was to assess the proficiency with which cytometrically determined deoxyribonucleic acid variables from pretreatment curettage specimens identify patients at high risk for extrauterine disease or posttreatment relapse. STUDY DESIGN: Flow cytometrically determined deoxyribonucleic acid ploidy, S-phase fraction, deoxyribonucleic acid index, and proliferative index were assessed in 140 paraffin-embedded curettage specimens containing endometrial carcinoma. RESULTS: Although clinical staging identified only 19% of patients with advanced disease, 46% of surgical stages III and IV were aneuploid, 69% had an S-phase fraction > or = 9%, and 69% had a proliferative index > or = 14%. Documented recurrences and cancer-related deaths correlated with nondiploid patterns (29% of 140, 50% of recurrences, 54% of deaths), S-phase fraction > or = 9% (41% of 140, 67% of recurrences, 75% of deaths), and proliferative index > or = 14% (45% of 140, 73% of recurrences, 79% of deaths). Deoxyribonucleic acid index (< 1.5 vs > 1.5) provided additional stratification of aneuploid tumors (p < 0.01). Multivariate analysis identified the proliferative index as the most cogent independent prognostic factor (p < 0.01). CONCLUSION: Deoxyribonucleic acid ploidy and proliferative activity in pretreatment curettage specimens identified the majority of patients at high risk for extrauterine metastasis and relapses.

Intraoperative radiation therapy in gynecologic cancer: the Mayo Clinic experience.

Nineteen patients with recurrent and two patients with locally advanced gynecologic malignancies received intraoperative radiation therapy (IORT) with electrons at the Mayo Clinic. Fourteen of the patients also received external beam irradiation. Actuarial local control with or without central control at 5 years was 71%, and actuarial control within the IORT field (central control) was 80%. The distant metastases rate at 5 years was 47%. Actuarial 2- and 5-year overall survival was 58 and 33%, respectively, and disease-free survival was 47 and 40%, respectively. Patients with microscopic disease had significantly higher 5-year disease-free and overall survival (70 and 67%, respectively). In summary, IORT in combination with maximum debulking surgery with or without external beam therapy in patients with paraaortic or pelvic sidewall recurrences of gynecologic malignancies appeared to improve long-term local control and survival. The addition of hyperthermia or hypoxic sensitizers may be a consideration to further improve local control in patients with gross residual disease. The high incidence of distant metastasis warrants the search for effective systemic chemotherapy. IORT-related toxicity was acceptable.

Colonic cancer during pregnancy: case report and review of the literature.

Colonic cancer during pregnancy is rare. Herein we describe a case of adenocarcinoma of the transverse colon in a 29-year-old pregnant patient. Early diagnosis is difficult because the initial symptoms of colorectal cancer, such as abdominal pain, nausea and vomiting, constipation, and abdominal distention, are often attributed to a normal pregnancy. Management of colonic cancer during pregnancy depends on gestational age and operability of the tumor. Medical and surgical management considerations are discussed.

HER-2/neu expression: a major prognostic factor in endometrial cancer.

The HER-2/neu oncogene encodes for a specific cell-surface glycoprotein similar to the human growth factor receptor. An analysis of 247 patients with endometrial cancer treated between 1979 and 1983 was performed using an immunoperoxidase technique on paraffin-embedded tissue samples to detect HER-2/neu overexpression. Specimens were graded blindly with regard to HER-2/neu staining intensity. Overexpression of HER-2/neu was identified as strong in 37 patients (15%), mild in 144 (58%), and none in 66 (27%). The 5-year progression-free survival was 56% for the strong, 83% for the mild, and 95% for the nonstaining groups. The strong (P < 0.0001) and the mild (P = 0.028) staining groups were distinct from the nonstaining group in predicting progression-free survival. Likewise, strong overexpression was associated with a poor (51%) overall survival (P < 0.0001). Multivariate analysis revealed that intense overexpression had independent significance in predicting progression-free (P = 0.0003) and overall survival (P < 0.0001). In stage I patients (203), the 5-year progression-free survival was 62% for the strong and 97% for the nonstaining groups (P = 0.0007). This retained independent significance when subjected to multivariate analysis (P = 0.0017). Other significant stage I prognostic factors in multivariate analysis included DNA ploidy, histologic subtype, and histologic grade but not depth of invasion.

Suture entrapment and secondary ureteral obstruction.

During the 6-year period ending in 1988, suture entrapment and secondary postoperative ureteral obstruction occurred in 18 (0.33%) of the 5379 patients who underwent major pelvic operations for benign conditions. Sixteen cases occurred after vaginal surgery and two after abdominal hysterectomy. Placement of the McCall suture or sutures for elevation of a bladder neck caused ureteral entrapment most frequently. Early diagnosis was facilitated by comparison of preoperative and postoperative serum creatinine levels. The mean change in serum creatinine level in patients with unilateral obstruction was an increase of 0.8 mg/dl. Treatment by either antegrade placement of ureteral stents or abdominal exploration with deligation or ureteroneocystotomy was successful in all cases. Retrograde placement of ureteral stents was unsuccessful.

Chylous ascites after whole-abdomen irradiation for gynecologic malignancy.

From November 1981 through December 1987, 207 patients received whole-abdomen irradiation (WAI) for gynecologic malignancies at the Mayo Clinic. In seven (3%) of these patients, chylous ascites subsequently developed; one additional patient with chylous ascites after WAI for a gynecologic malignancy was referred to us from another institution. In these eight patients, irradiation was done either adjuvantly (five patients) or as salvage therapy after chemotherapy failure (three patients). Chylous ascites was confirmed by laboratory analysis in six cases and was presumed based on the clinical course in two cases. Mean cumulative radiation doses were 2,925 and 5,122 cGy to the abdomen and pelvis, respectively, with para-aortic boosts administered in six cases to a mean cumulative dose of approximately 4,200 cGy. The mean time from completion of WAI to development of ascites was 12 months (range, 6 to 18 months). In six patients, therapy was conservative-observation and diuretics. Two other patients required multiple paracenteses for relief of abdominal distention. Parenteral nutrition was given to two patients who had associated radiation enteritis. The ascites resolved in all eight cases at a mean of 18 months (range, 8 to 30 months) after development. At a mean follow-up of 57 months after initial diagnosis and 16 months after resolution of the ascites, seven patients are without evidence of disease and one patient died of recurrent carcinoma. Distinguishing this clinical entity from recurrent carcinoma is important because of its benign course and its resolution with conservative management.

DNA ploidy in endometrial carcinoma: major objective prognostic factor.

Paraffin-embedded tissue samples from 256 patients who received primary treatment (surgical staging, reduction of tumor size, and adjuvant therapy based on surgical and pathologic risk factors) for endometrial carcinoma at the Mayo Clinic between 1979 and 1983 were analyzed by flow cytometry to determine DNA ploidy characteristics. Diploid patterns constituted 78% of the cases, whereas aneuploid and tetraploid patterns accounted for 17% and 5%, respectively. Only 10% of patients with diploid tumors had a relapse in comparison with 39% of those with nondiploid lesions (34% with aneuploid; 58% with tetraploid). Significant differences (P less than 0.001) were noted in estimated 4-year progression-free survivals--88% for patients with diploid and 57% for those with nondiploid tumors. Stage, grade, depth of myometrial invasion, histologic subtype, peritoneal cytology, and DNA ploidy all demonstrated independent prognostic significance (P less than 0.001) in this study population. When subjected to multivariate analysis, however, grade and depth of myometrial penetration failed to retain prognostic significance (P greater than 0.15) and surgical stage was marginally significant (P = 0.05), whereas histologic subtype and DNA ploidy maintained significant predictive powers (P less than 0.001 and P less than 0.01, respectively). We conclude that DNA ploidy is a major objective prognostic factor and therapeutic determinant for endometrial carcinoma.

Evaluation of unfavorable histologic subtypes in endometrial adenocarcinoma.

A retrospective review of 388 patients who presented to the Mayo Clinic for treatment of endometrial carcinoma between 1979 and 1983 was performed and the surgical and pathologic observations were documented. An uncommon histologic subtype was detected in 52 patients (13%): 20 adenosquamous, 14 serous papillary, 11 clear cell, 7 undifferentiated. In contrast to the survival of patients with endometrioid lesions (92%), the overall survival in these patients was only 33%. Each of the individual abnormal histologic subtypes exhibited a survival of less than 50%. At the time of surgical staging, 62% of patients with unfavorable histologic subtypes had extrauterine spread of disease. Despite liberal utilization of postoperative adjuvant therapy in 42 of the 52 patients (81%), only 10% of these patients survived 5 years. Fifty-five percent had a component of recurrence outside of the abdominal/pelvic cavity. Subsequent treatment considerations should incorporate regimens addressing systemic and local tissue control.

Flow cytometric DNA analysis of stage I endometrial carcinoma.

Flow cytometric DNA analysis was performed on 203 paraffin-embedded archival specimens obtained from patients with surgical stage I endometrial carcinoma. Primary therapy for those patients (1979-1983) had been definitive extirpation with adjuvant therapy determined by histologic grade, histologic subtype, myometrial invasion, and peritoneal cytologic findings. Diploid DNA patterns were identified in 171 (84%) specimens and nondiploid characteristics were observed in the remaining 32 (25 DNA aneuploid, 7 DNA tetraploid). Although DNA nondiploid specimens accounted for only 16% of all stage I patients, they accounted for 50% of all relapses. Regardless of treatment or other pathologic features, progression-free 5-year Kaplan-Meier survival estimates were 92 and 63% for patients with DNA diploid and DNA non-diploid patterns, respectively (P less than 0.001). Overall 5-year progression-free survival for patients with grade 1 or 2 lesions was 90%; stratification by DNA diploid and DNA nondiploid patterns revealed progression-free survivals of 94 and 64%, respectively (P less than 0.001). Peritoneal cytologic study was positive in seven patients; none of the five with a DNA diploid pattern had a relapse and both with the DNA nondiploid pattern had relapses. These studies suggest that DNA ploidy status may be an objective prognostic determinant for patients with stage I endometrial carcinoma.

Evaluation of treatment and survival after positive second-look laparotomy.

During the 9-year interval 1977 through 1985, of 250 patients undergoing second-look laparotomy, 116 (46%) were found to have clinically occult ovarian carcinoma. Salvage therapy consisted of external irradiation in 37, intraperitoneal 32P in 12, chemotherapy in 63, and no therapy in 3 or other therapy in 1. Eligible follow-up time ranged from 1 to 9 years. The Kaplan-Meier projected median time-to-progression and survival were 15 and 22.5 months, respectively, with 4-year progression-free and overall survival rates being 21 and 27%, respectively. Survival was independent of the original stage of disease but was significantly influenced by histologic grade and microscopic (55%) versus macroscopic (19%) residual tumor after the laparotomy. Projected 4-year salvage rates in patients with microscopic or residual disease less than or equal to 5 mm was 72, 39, and 19% for intraperitoneal 32P, external irradiation (33/37, whole abdominopelvic), and chemotherapy, respectively. However, multivariable analysis demonstrated that histologic grade and isotope therapy retained independent influence on survival, but no therapeutic advantage for external irradiation over chemotherapy was demonstrable. Furthermore, use of regimens that were identical to, partially altered from, or different from the first-trial agents did not affect chemotherapy salvage rates.