Biomedical subjects
Publications and source records attributed to M J Casey.
Given the limitations regarding the impact of screening and the uncertainties concerning chemoprevention for women with significant genetic susceptibilities to breast, endometrial and ovarian cancers, recent research and publications on prophylactic surgery for cancer prevention and improved long-term survival for women at hereditary risk have increasing importance.
OBJECTIVE: The literature reports conflicting studies claiming premalignant histological features in benign ovaries from women who may have hereditary predilections for ovarian carcinoma. To test the veracity of these claims, this investigation studied ovaries prophylactically removed from members of hereditary breast ovarian cancer (HBOC) syndrome families who carry BRCA1 and BRCA2 mutations and compared these with the ovaries of mutation-negative women from the same HBOC syndrome kindred. METHODS: Sixty cases of women from HBOC syndrome families who had undergone prophylactic oophorectomies and whose BRCA1 and BRCA2 mutation status had been tested were selected from our database. Thirty had tested positive for BRCA1 mutations, 3 carried BRCA2 mutations, and 27 were negative for both BRCA1 and BRCA2 germline mutations. Histologic material from each case was examined by light microscopy blinded to the mutation status. Histologic features, previously reported to be possible precursor lesions for ovarian cancer, were quantified. Data from BRCA1 and BRCA2 mutation carriers were compared with those from mutation-negative cases in the direct line of genetic inheritance from the same HBOC syndrome families. RESULTS: Statistical analysis found that a more frequent occurrence of ovarian surface micropapillae in 87% of mutation carriers compared with just 55% of mutation-negative cases was the only histologic feature which was significantly different between the two groups (P = 0.39). Cortical clefts tended to be deeper in the ovaries of mutation carriers, but this did not reach significance (P = 0.051). There were no other significant histologic differences between the ovaries removed from mutation carriers and those from noncarriers. CONCLUSIONS: The results of our large and prospectively controlled, blinded study contrast with those reported from smaller, unblinded investigations. Except for the possible biological significance of surface micropapillae on ovaries from BRCA1 and BRCA2 mutation carriers, we found no histologic evidence for a genetically determined ovarian carcinoma precursor lesion.
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A retrospective case control study was performed on a cohort of 244 peritoneal dialysis patients followed over 5 years to determine whether dialysate fill-volume was associated with hernia development. The laboratory and clinical parameters of patients who developed hernias during this time period were compared with those of patients who did not develop hernias. Information on 27 patients who developed hernias was compared with that on 217 patients who did not develop hernias. Dialysate fill-volume was similar between groups (2.2 +/- .3 L for patients with hernias vs. 2.2 +/- .3 L for controls). Three patients with fill-volumes of 1.5 L developed hernias, and no patients with fill-volumes of 3 L developed hernias. Age, duration of time on dialysis, and body surface area were also similar between groups. This investigation could not find a relationship between fill-volume and hernia formation. From this study it would appear that physicians should not hesitate to increase fill-volume based on concerns of hernia development.
Ovarian cancer is a disease that will affect approximately 1% of American women during their lifetime, and contributes to more than 14,000 deaths annually. If not detected early, this disease has a 5-year survival rate of less than 20%. Ovarian cancer develops predominantly from the malignant transformation of a single cell type, the surface epithelium. Although the biological mechanisms of transformation remain unclear, it is probably a multistep process requiring an accumulation of genetic lesions in a number of different gene classes. Several proto-oncogenes, such as AKT2 and Ki-RAS, are activated during ovarian cancer development, with putative oncogene-containing chromosomal regions showing imbalances and DNA amplifications. A number of chromosomal regions are also lost in ovarian tumors, indicating that the inactivation of tumor suppressor genes, such as TP53, may also contribute to cancer development. An important recent advancement in the field of ovarian cancer research is the identification of the breast/ovarian cancer susceptibility genes, BRCA1 and BRCA2. Mutations in these two tumor suppressor genes are responsible for the majority of heritable forms of epithelial ovarian cancers. A second class of genes involved in DNA mismatch repair (MMR) are responsible for most cases of hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC or Lynch II cancer syndrome patients are also at an increased risk for developing ovarian cancer. Individuals in cancer-prone kindreds are currently being screened for germline mutations in BRCA1, BRCA2, and several MMR genes (eg, MSH2, MLH1), and mutant allele carriers counseled for cancer risks. Issues related to counseling and management of women at high risk for developing ovarian cancer are discussed. Although BRCA1, BRCA2, and a number of MMR genes have been identified, many more genes involved in gynecologic malignancies remain to be discovered and the clinical significance of the cancer genes already known is still in its infancy.
IFN-gamma has a direct antitumor effect on many tumor cell lines mediated through the IFN-gammaR. One effect of IFN-gamma is to induce the nuclear transcription factor IFN regulatory factor-1 (IRF-1), which may function as a tumor suppressor. In this study, mouse IRF-1 cDNA under a high constitutive expression promoter was transfected into the highly aggressive, nonimmunogenic MCA 101 murine sarcoma. Clones were obtained by G418 selection and screened for IRF-1 mRNA expression by reverse transcriptase-PCR (RT-PCR). High expression clones had high levels of two MHC class I proteins (H-2Kb and H-2Db) on the cell surface that correlated with increased levels of class I mRNA by RT-PCR. Furthermore, these clones also had increased levels of MHC class II protein (I-Ab), which correlated with increased levels of one subunit of class II mRNA by RT-PCR. IRF-1-expressing clones had markedly diminished cell growth in vitro and decreased anchorage-independent growth in a soft agar assay. These clones also demonstrated markedly prolonged tumor latency and slowed growth in syngeneic C57BL/6 mice. IRF-1 gene-transfected cells had shortened tumor latency and formed faster growing tumors in gamma-irradiated immunodeficient mice compared with results in immunocompetent mice. Mice immunized with IRF-1-transfected cells were protected against subsequent challenge with IRF-1 transfected cells and also demonstrated greater tumor latency and slower tumor growth against subsequent challenge with untransfected cells compared with mice immunized with empty vector-transfected cells. These studies demonstrate a tumor suppressor effect of IRF-1, which acts in vivo through both partial reversion of the malignant phenotype and enhanced immune recognition and may play a role in the antitumor effects of IFN-gamma.
Our first year of experience in the use of PET scanning in the management of nine patients with ovarian cancer leads us to conclude that this promising new technique may be more sensitive than either serum CA-125 determinations or computed tomography for the detection and demonstration of residual or recurrent abdominal and pelvic tumor. Seven of these patients underwent second-look laparotomy which confirmed our impressions from preoperative PET scans in six patients, and the one other scan showed a focus of metabolic uptake coinciding with residual tumor in our retrospective review. The clinical courses of two other patients who did not undergo laparotomy confirmed the impressions gained from PET scans.
The first 115 laparoscopically assisted vaginal hysterectomies (LAVH) done by our faculty surgeons were compared with 220 vaginal hysterectomies (VH) and 194 abdominal hysterectomies (AH) done in our affiliated hospitals over the same period of time. Logistic regression analysis indicates that LAVHs were done for cases that would significantly be more likely selected for AH than for VH (p less than 0.0001). Matched case control studies with 28 LAVH/VH and 34 LAVH/AH pairs and bivariate analyses demonstrated that LAVH can be accomplished with low morbidity, short lengths of stay, and little, if any, increase in operating times compared with VH and AH. The LAVH procedure can be expected to replace many AHs in the future.
Laparoscopic management of ectopic pregnancies is the accepted method of treatment in most centers. This report describes a case of persistent trophoblastic implants to the peritoneum after laparoscopic linear salpingostomy for evacuation of an early ectopic pregnancy. Based on this experience, methods for follow up after such procedures, and recommendations for management of persistent trophoblastic implants are discussed.
Lynch syndrome II was diagnosed when two sisters manifested early-onset synchronous carcinomas of the ovary and endometrium and a third sister was found to have Duke's A carcinoma of the cecum. A detailed cancer family history indicated paternal transmission of the deleterious genotype. The pattern of carcinoma of the colorectum and extracolonic sites throughout the extended family was then found to be consonant with this hereditary cancer-prone disorder. Lynch syndrome II may be exceedingly difficult to diagnose due to an absence of premonitory clinical signs or biomarkers of genotypic susceptibility. Its recognition is therefore dependent on a detailed cancer family history (all anatomic sites), coupled with knowledge of the pattern of the cancer spectrum, distribution, and natural history, as manifested in this hereditary disorder. We describe the decision logic that was involved in the diagnosis of Lynch syndrome II in this family and indicate the important role of the gynecologists in this process.
Patients who underwent laparoscopy-assisted vaginal hysterectomy with or without adnexectomy experienced less fever, required less postoperative analgesia, were able to tolerate a full diet within 24 hours of surgery, and had a faster recovery and shorter hospital stay than patients who had abdominal or traditional vaginal hysterectomy.
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This case report demonstrates the successful localization of metastatic medullary thyroid carcinoma with 99mTc-labeled methoxyisobutylnitrile (MIBI). Disease recurrence was initially localized using 201Tl and by immunoscintigraphy with 111In-labeled anti-carcinoembryonic antigen (anti-CEA) antibody fragments. Scintigraphy with 99mTc-MIBI yielded higher target-to-background ratios than 201Tl or 111In-anti-CEA. Technetium-99m-MIBI may be a useful agent in the localization of recurrent medullary thyroid carcinoma.
A milk fraction containing whey proteins of 10-30 kDa was injected into one mammary gland of lactating goats via the teat canal. This fraction produced a temporary dose-dependent reduction in milk yield in the treated gland; the milk yield of the other gland, which received an equal volume of carrier solution, was not affected. Injection of a second fraction, containing whey proteins of greater than 30 kDa, affected milk secretion only at high doses, and this effect was not wholly specific to the treated gland. The 10-30 kDa fraction and the greater than 30 kDa fraction produced similar transient changes in the concentrations of several ions and lactose in milk of the treated gland, but not in that of the untreated gland. These data indicate that a milk constituent present in the 10-30 kDa whey inhibits milk secretion in a temporary and reversible manner. The results are discussed in relation to regulation of milk secretion through local feedback inhibition.
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A case of endodermal sinus tumor of the ovary associated with hirsutism and increased testosterone production is described. Electron-microscopic examination revealed accumulation of basement membrane-like material and other ultrastructural features consistent with endodermal sinus tumor. Groups of polyhedral cells associated with the tumor were found to contain abundant lipid material. These luteinized stromal cells were evidently responsible for the endocrine manifestations.