With the use of hybridization in situ, c-myc and c-ras oncogene expression has been identified in the cytotrophoblast of hydatidiform mole and in the malignant trophoblast cell line BeWo. Expression ...was also found in early villous placenta. No expression of these two oncogenes was found in the cytotrophoblast of an 11-week conceptus, nor was it found in term placenta. The significance of these findings is discussed.
We report 54 patients with mixed mullerian tumors of the uterus treated at Yale-New Haven Hospital from 1962 to 1983. Seven had previous pelvic irradiation. Twenty-five neoplasms were homologous and ...29 were heterologous. The mainstay of therapy was surgery and radiation. By FIGO criteria 9 patients had stage IA disease, 31 stage IB, 6 stage II, and 8 patients had clinical extrauterine disease. Ten of forty-six patients (23%) with FIGO stage I and II disease had extrauterine disease found at surgery. No patient with extrauterine disease had prolonged survival. The 2-year disease-free survival with stage IA was 66%, with stage IB surgically confirmed 32%, and for stage II 33%. Surgically advanced disease in clinical stage I and II patients and recurrence were associated more frequently with a heterologous histology (67%). The small uterus with a less than 10-cm cavity had a better prognosis. Among 29 surgically confirmed stage I and II patients, 83% of recurrences appeared within 2 years (mean 16 months +/- 7 months). Patients who received both intracavitary radiation and external beam developed only 17.6% pelvic recurrence but this reduction in local recurrence was not associated with significant improved long-term survival. Six of eight patients treated with cis-platinum, Adriamycin, and dimethyl triazeno imidazole carboximide for persistent disease or for recurrence showed response for 4 to 24 months, none complete. Five patients were treated by radiation, surgery, and adjuvant chemotherapy (4 with Adriamycin-Cytoxan, 1 with Adriamycin-platinum). Four of the five (80%) are disease free from 36 to 60 months. These data and the experience of others support the need for a clinical trial with adjuvant platinum and Adriamycin in this disease.
Pure ovarian dysgerminomas with associated elevation of human chorionic gonadotropin (hCG) are rare, and their optimum management is unclear. We report here a 24-year-old woman with stage III ...dysgerminoma of the ovaries, with bulky intrapelvic disease, paraaortic adenopathy, and elevated pre- and postsurgical serum beta-hCG titers. Following administration of whole abdominal-pelvic and mediastinal irradiation therapy, the patient's adenopathy regressed, her serial beta-hCG titers returned to normal, and she has remained free of disease for the past 30 months. Histopathological studies revealed a pure dysgerminoma with scattered giant cells which were negative for hCG by immunoperoxidase staining. The literature is reviewed with reference to the significance of elevated hCG levels, the presence of giant cells in association with dysgerminoma of the ovary, and therapeutic implications. Serial determinations of beta-hCG titers may prove to be as valuable in the management of these patients as they are in patients with testicular tumors.
: Loss of heterozygosity (LOH) on chromosome 8p in 20 BRCA‐1 mutation positive familial breast/ovarian cancer patients from nine families was examined. Allelic deletions on chromosome 8p were ...identified with at least one marker in 11 of 17 (65%) informative cases. Seven of eight (88%) informative cases showed deletion of chromosome 17q consistent with inactivation of the BRCA‐1 gene. Our data suggests loss of a tumor suppressor gene on chromosome 8p may be a frequent genetic event in the development of familial breast and ovarian cancer.
We examined the relationship of axillary level of lymph node metastases from clinical stage I and II breast cancer to overall survival and disease-free survival rates in 135 patients who underwent ...complete axillary lymph node dissection to determine if anatomic level of axillary involvement (I vs II vs III) is an independent prognostic factor. All patients underwent either modified radical mastectomy or lumpectomy with axillary dissection and whole breast radiotherapy for breast cancer. Median follow-up was 6.9 years. We found no difference in overall survival or disease-free survival between patients whose highest or only level of axillary involvement was level I compared with patients whose highest or only level was II. Although patients whose highest level of nodal involvement was III had significantly worse overall survival and disease-free survival rates than patients whose highest nodal involvement was I or II, when patients were stratified by the total number of positive nodes (one to three vs four or more), there was no difference in overall survival or disease-free survival rates between levels I, II, and III. These findings indicate that the level of axillary involvement for stage II breast cancer is not of independent prognostic significance.
Energy deregulation and abnormalities of tumor cell metabolism are critical issues in our understanding of cancer. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is an aggressive form of RCC ...characterized by germline mutation of the Krebs cycle enzyme, fumarate hydratase (FH), and is known to be highly metastatic and unusually lethal. There is significant utility in establishing preclinical cell and xenograft models for study of disorder of energy metabolism as well as development of new therapeutic approaches targeting of tricarboxylic acid (TCA) cycle deficient human cancers. Here we report the first immortal cell line derived from a patient having aggressive HLRCC-associated recurring kidney cancer, designated as UOK 262. We investigated gene expression, chromosome profiles, efflux bioenergetic analysis, mitochondrial ultrastructure, FH catabolic activity, invasiveness, and optimal glucose requirements for
in vitro
growth. UOK 262 cells have isochromosome 1q i(1)(q10) as recurring chromosome abnormality; demonstrate compromised oxidative phosphorylation and
in vitro
dependence on anaerobic glycolysis consistent with the clinical manifestation of HLRCC. Furthermore the cells display glucose-dependent growth, an elevated rate of lactate efflux, over-expression of the glucose transporter Glut 1 and lactate dehydrogenase (LDH) 5. Mutant FH protein was primarily present in edematous mitochondria, but its catalytic activity was nearly undetectable. UOK 262 xenografts retain the characteristics of HLRCC histopathology. Our findings indicate that the severe compromise of oxidative phosphorylation and rapid glycolytic flux in UOK 262 are an essential feature of this TCA cycle enzyme deficient form of kidney cancer. This tumor model is the embodiment of the “Warburg effect”. UOK 262 provides a unique
in vitro
and
in vivo
preclinical mode to study the bioenergetics of the Warburg effect in human cancer.
Energy deregulation and abnormalities of tumor cell metabolism are critical issues in understanding cancer. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is an aggressive form of RCC ...characterized by germline mutation of the Krebs cycle enzyme fumarate hydratase (FH), and one known to be highly metastatic and unusually lethal. There is considerable utility in establishing preclinical cell and xenograft models for study of disorders of energy metabolism, as well as in development of new therapeutic approaches targeting of tricarboxylic acid (TCA) cycle enzyme-deficient human cancers. Here we describe a new immortalized cell line, UOK 262, derived from a patient having aggressive HLRCC-associated recurring kidney cancer. We investigated gene expression, chromosome profiles, efflux bioenergetic analysis, mitochondrial ultrastructure, FH catabolic activity, invasiveness, and optimal glucose requirements for in vitro growth. UOK 262 cells have an isochromosome 1q recurring chromosome abnormality, i(1)(q10), and exhibit compromised oxidative phosphorylation and in vitro dependence on anaerobic glycolysis consistent with the clinical manifestation of HLRCC. The cells also display glucose-dependent growth, an elevated rate of lactate efflux, and overexpression of the glucose transporter GLUT1 and of lactate dehydrogenase A (LDHA). Mutant FH protein was present primarily in edematous mitochondria, but with catalytic activity nearly undetectable. UOK 262 xenografts retain the characteristics of HLRCC histopathology. Our findings indicate that the severe compromise of oxidative phosphorylation and rapid glycolytic flux in UOK 262 are an essential feature of this TCA cycle enzyme-deficient form of kidney cancer. This tumor model is the embodiment of the Warburg effect. UOK 262 provides a unique in vitro and in vivo preclinical model for studying the bioenergetics of the Warburg effect in human cancer.
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