Altered autophagy induction by sera from pregnant women with pre-eclampsia: a case-control study.

OBJECTIVE: Mechanisms leading to pre-eclampsia remain incompletely defined. Autophagy is a conserved process necessary for cell survival under adverse conditions. We hypothesised that sera from women with healthy pregnancies and women with pre-eclampsia differed in autophagy induction. DESIGN: A case-control study. SETTING: Weill Cornell Medical College. POPULATION: Twenty-four normotensive pregnant women and 20 women with pre-eclampsia. METHODS: Sera were incubated with peripheral blood mononuclear cells (PBMCs) from female donors. After 48 hours the PBMCs were lysed and the intracellular concentration of p62 was determined by enzyme-linked immunosorbent assay (ELISA). Its concentration is inversely proportional to the extent of autophagy induction. Serum endoglin, interleukin 13 (IL-13), insulin-like growth factor 1 (IGF-1), and transforming growth factor ß1 (TGF-ß1) levels were quantitated by ELISA. MAIN OUTCOME MEASURES: Differences in autophagy induction and serum mediator levels in the two groups. RESULTS: Autophagy induction increased with gestational age in sera from normotensive women (P = 0.0045), but not in women with pre-eclampsia. In the presence of an autophagy inducer, the capacity for autophagy induction decreased with gestational age in sera from women with pre-eclampsia (P = 0.0235), but not from controls. Endoglin concentrations were positively associated with the extent of autophagy induction in controls only (P = 0.0141). There was no association between autophagy and serum IL-13, IGF-1, or TGF-ß1 levels. CONCLUSIONS: Sera from women with pre-eclampsia differ from normotensive women by their inability to induce autophagy as a function of gestational age.

A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group Study.

After hysterectomy, 156 evaluable patients with stage I (limited to the corpus) or stage II (limited to the corpus and cervix) uterine sarcomas were randomly assigned to adjuvant chemotherapy with Adriamycin (Adria Laboratories, Columbus, Ohio) for six months or to no further treatment. Pelvic irradiation (external or intracavitary) was optional before randomization. Of 75 patients receiving Adriamycin, 31 have suffered recurrences compared with 43 of 81 receiving no adjuvant chemotherapy. This difference is not statistically significant. Moreover, there is no difference in progression-free interval or survival. The optional radiotherapy did not influence the outcome although there was a suggestion that vaginal recurrence was decreased by pelvic radiotherapy. The recurrence rates in specific cell types (leiomyosarcoma, homologous mixed mesodermal sarcoma, or heterologous mixed mesodermal sarcoma) were not significantly different although the pattern of recurrence differed, with pulmonary metastases being more common in leiomyosarcoma and extrapulmonary recurrence being more common in mixed mesodermal sarcoma. The outcome with respect to chemotherapy was not altered even after adjusting for maldistribution of cases. Thus, we could not show a benefit for this dose schedule of Adriamycin as adjuvant treatment for uterine sarcomas.

Staging and surgical evaluation of ovarian cancer.

Ovarian carcinoma is the only female genital malignancy surgically staged. Appropriate preoperative roentgenographic, isotopic, and endoscopic studies can help define the spread of disease and the extent of surgery required. At surgery, the common sites of metastases--pelvic and para-aortic lymph nodes, diaphragm, serosal surfaces and omentum--should be examined and biopsied or excised. Total hysterectomy, bilateral salpingo-oophorectomy, and appendectomy should also be performed in patients with epithelial ovarian tumors. Evidence suggests that patients who have had optimal cytoreduction of the tumor (less than 1.5 cm) have a better outcome following chemotherapy. Patients who have no clinical or CT evidence of disease after a full course of chemotherapy should be explored to confirm disease status. Peritoneoscopy can be used as an interval procedure to assess response to treatment.

Plasma prostaglandin levels in radiation-induced enteritis.

Increased prostaglandin synthesis has been implicated as a causative factor in the production of radiation induced enteritis. Seventeen patients selected to begin pelvic irradiation for treatment of gynecological cancer had plasma Prostaglandin E, Prostaglandin F, and 13, 14 dihydro 15 keto PGF2 alpha metabolite determined by radioimmunoassay, prior to initiation of radiotherapy, at weekly intervals during treatment and at six weeks following completion of radiotherapy. A total of 362 prostaglandin determinations were performed. Thirteen patients (76%) developed significant diarrhea consisting of three or more watery bowel movements per day. Nine patients (53%) had intermittent colicky pain and six patients (35%) had nausea and vomiting during treatment. Statistical evaluation revealed no significant elevation of plasma prostaglandins during radiotherapy.

Effect of radiation on prostaglandin production by human bowel in vitro.

The effect of gamma irradiation on the production of prostaglandins by human colon was investigated. Squares of tissue in organ culture dishes were irradiated with 500, 1000, or 2500 rad in single applications. Tissues that were not irradiated served as controls. After treatment the tissues were superfused and prostaglandin concentrations in the effluent fluid were determined. The rates of production of prostaglandins E2 and F2 alpha by irradiated tissues were significantly lower (p less than 0.05) than those of nonirradiated tissues. Neither the release of lactate dehydrogenase nor the rate of production of 13,14-dihydro-15-keto-prostaglandin F2 alpha were increased in the irradiated samples, suggesting that neither decreased cell viability nor increased prostaglandin metabolism accounted for the decreased prostaglandin production rates. We conclude that irradiation of the human colon in vitro results in an acute inhibition of prostaglandin synthesis. The cytoprotective nature of prostaglandins is discussed with regard to the possible pathophysiological significance of these findings.

Para-aortic lymph node irradiation in carcinoma of the cervix after exploratory laparotomy and biopsy-proven positive aortic nodes.

From July 1970 to January 1977, 23 patients with previously untreated cancer of the cervix (CA CX), mostly Stage IIIB, were included in this study. The para-aortic lymph nodes (PALN) were histologically documented to have metastatic disease in all 23 patients. External radiation treatment (RT) was delivered using a Cobalt--60 machine to a spade-shaped field to treat the pelvic cavity and para-aortic area. The majority of the patients received 4000-6000 rad to the pelvic cavity and from 5000-5500 rad to the PALN's by external RT. In addition, intracavitary radium was used in 21 patients. Five patients are alive and free of disease at 115, 110, 90, 73 and 45 months after completion of RT. One survivor had clinical Stage IB, one had Stage IIB, and three had Stage IIIB cervical carcinoma. Two of 15 patients with clinically enlarged and suspicious para-aortic nodes are alive, while 3 of 8 patients with clinically normal appearing nodes survived. Three (60%) of the survivors developed late bowel radiation damage. Eighteen patients died--10 during the first year, 3 during the second year, 2 during the third year, 1 during the fourth year and 2 during the eighth year of the follow-up. Five (27.8%) of the patients who died had developed late bowel radiation damage. Fifteen of the 18 died with disease at an average of 21 months. Three patients died of intercurrent disease. Their average survival was 40 months, double that of patients dying of disease. This report suggests that in cancer of the cervix, radiation therapy can control some PALN metastatic disease, but the risk of complications is rather high. In the absence of better methods of management, this risk of complications is justifiable because the alternative is to leave known disease untreated.

Apoptosis (programmed cell death) in colonic cells: from normal to transformed stage.

We determined apoptosis in whole rat colonic tissue and in isolated colonocytes from the various rat crypt regions in preneoplastic stages up to frank neoplasia following administration of the procarcinogen, dimethylhydrazine (DMH). Apoptotic cells were determined by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL)-method, by evaluating sections stained with hematoxylin and eosin, and caspase-1 immunostaining. Apoptotic cells in whole colonic tissue from untreated rats were confined to the upper crypt while, in DMH-treated rats apoptotic and caspase-1 positive cells were located in the crypt proliferative regions. Numerous apoptotic and caspase-1-positive cells were found in sections from early tumors while in the delayed tumors, apoptotic-positive cells were absent and number of caspase-1-positive cells was negligible. A marked reduction in the apoptotic index along the crypt was observed in isolated transformed colonic cells, this was not the case for caspase-1-positive cells. We conclude that: (i) in colorectal tumors at progressive stage apoptosis is altered, (ii) the mechanistic alteration in apoptosis may be located between caspase-1-protease activity and the fragmentation process of DNA.

Treatment of carcinoma in situ of the vulva with topical 5-fluorouracil.

Topical 5-fluorouracil (5-FU) has been suggested as a simple and effective approach to the treatment of carcinoma in situ of the vulva. In this study, 12 patients with carcinoma in situ of the vulva were evaluated and treated with topical 5-FU. Satisfactory results were obtained in 2. The nonresponders have subsequently undergone surgical therapy. Follow-up to date has been 9 to 96 months (average 38 months). The value of topical 5-FU in the treatment of carcinoma in situ of the vulva seems to be limited. Its use in vulvar neoplasia is discussed.

Disseminated intravascular coagulation in gynecologic cancer.

Disturbances in the blood coagulation mechanism are seen by the obstetrician and gynecologist as rare complications of abruptio placentae, retained dead fetus syndrome, amniotic fluid embolism, toxemia, saline amnioinfusion, and septic abortion. Two cases of disseminated intravascular coagulation complicating gynecologic malignancy are presented. Laboratory studies showed thrombocytopenia, hypofibrinogenemia, and increased fibrin degradation products. Derangements of hemostasis in patients with malignancy are discussed from a clinical viewpoint.

Pigskin xenograft as biologic dressing in radical vulvectomy.

Wound infection and breakdown constitute the most common complication of radical vulvectomy and groin lymphadenectomy. The use of pigskin xenograft as biologic dressing when the skin edges cannot be closed primarily without tension after radical vulvectomy and groin lymphadenectomy is described. This technique allows for clean granulation tissue to develop early (within five to seven days) and seems to accelerate the healing process. Its use has been associated with early ambulation and rapid recovery as well as a shorter postoperative stay.

Intraarterial pelvic infusion chemotherapy in advanced gynecologic cancer.

Fourteen patients with advanced localized gynecologic cancer were treated with 44 courses of intraarterial pelvic infusion chemotherapy. All patients received methotrexate with folinic acid rescue; 9 patients also received vincristine. Tumor regression was observed in 3 of 14 patients (21.4%). In 5 patients there were major complications related to 28 intraarterial catheter placements. Two patients developed leukopenia following chemotherapy. The value of intraarterial infusion chemotherapy in gynecologic cancer is limited. Its use in gynecologic oncology is discussed.

Subarachnoid phenol block for pain relief in gynecologic malignancy.

One hundred and thirty-three subarachnoid phenol blocks were performed in 90 patients with intractable pain secondary to gynecologic cancer at the University of Iowa Hospitals in the period 1961 to 1975. Excellent to moderate pain relief was obtained in 77% of 117 evaluable blocks. Fifty-two percent of the blocks gave relief of over 1 months' duration and 27% over 2 months. Fourteen patients had a second contralateral block and 11 obtained 4 to 8 weeks' relief. Complications were temporary and occurred in 71% of the blocks, the most common being urinary and rectal incontinence. Subarachnoid phenol block is an effective method for relief of intractable pain; its use in gyneclogic oncology is discussed.

Use of the bulbocavernosus muscle (Martius procedure) for repair of radiation-induced rectovaginal fistulas.

Radiation-induced fistulas of the vagina are rare, occurring in only 1 of 3% of patients treated for cancer of the uterine cervix. Primary surgical repair of these fistulas is usually unsuccessful because the defect is a result of devascularization. This type of radiation injury results from endarteritis obliterans, and successful repair requires an accessory blood supply. From 1971 to 1980, the authors performed 14 Martius procedures on 12 patients with radiation-induced rectovaginal fistulas. Eleven patients had successful closure of their fistulas using this procedure, and no operative complications occurred. The Martius procedure is effective for most radiation-induced vaginal fistulas, and the operation is well tolerated by most patients.

Pathology slide review in gynecologic oncology.

OBJECTIVE: To analyze the diagnostic accuracy and alteration in treatment planning from interinstitution (different institution) pathologic consultation. METHODS: We reviewed pathologic reports from 720 referred patients. The diagnosis rendered from a gynecologic pathologist was compared with the original diagnosis. Discrepancies were coded as none, minor, or major. A discrepancy was major if it led to treatment alteration. A discrepancy was minor if it did not lead to treatment alteration. The judgment to declare a discrepancy was made by a gynecologic pathologist, a gynecologist, and three gynecologic oncologists. The review cost was $150 per case. The Cochran-Mantel-Haenszel test evaluated any systematic pattern in discrepancies. RESULTS: Seven hundred twenty specimens consisted of 113 vulvar, 170 uterine, 289 cervical, 105 ovarian, and 43 vaginal tissues. Six hundred one (84%) pathologic diagnoses showed no discrepancy. There were 104 (14%) minor and 15 (2%) major discrepancies. After reviewing 15 major discrepancies, six surgeries were canceled, two surgeries were modified, one adjuvant radiation treatment was added, one chemotherapy treatment was modified, and five adjuvant chemotherapy treatments were cancelled. No systematic error was identified with regard to the sources (tissue origin) or methods of obtaining the specimen (P = .675). The cost of reviewing 720 specimens was $108,000. The cost of identifying each major discrepancy was $7200. CONCLUSION: Reviewing pathology slides before definitive treatment reveals notable discrepancies in diagnoses. The cost of pathology review is globally expensive but has consequential impact on proper treatment planning for the individual patient.

Vicryl mesh in pelvic floor reconstruction.

A new synthetic absorbable mesh made of polyglactin 910 (Vicryl) fiber was used to reconstruct the pelvic floor in seven women undergoing pelvic exenteration. The technique is described. The follow-up ranged from three to 31 months and no patient developed a bowel problem. The material seems to be appropriate for this use, is completely absorbed, and acts as a latticework for the deposition of granulation tissue. The technique can be applied in patients requiring pelvic irradiation following surgery for malignant neoplasms of the gastrointestinal or genitourinary tracts. The small bowel is effectively held out of the pelvis and the radiation field, and is spared the effects of the radiation beam.

Virulence of Streptococcus pneumoniae may be determined independently of capsular polysaccharide.

Mice were inoculated intranasally with Streptococcus pneumoniae isolates of serotype 14 with different genetic backgrounds (14R, 14DW) and a capsular switch of 14R, strain 9VR (serotype 9V). Inoculation of the mice with 14R and 9VR resulted in 60% mortality. All the mice survived 14DW inoculation. No differences in lungs' bacterial loads were found 3 h following inoculation. Bacterial clearance of 5 logs was observed 48 h after inoculation with 14DW versus within 1 log 48 h after inoculation with 14R and 9VR. No significant differences in bacterial size or the capsular amount could be found between 14R and 14DW. We conclude that factor(s) in addition to the capsule, contribute to disease outcome.

Biotechnological applications of image analysis: present and future prospects.

The current and potential biotechnological applications of image analysis and image processing systems are reviewed. Image analysis systems have proven to be highly versatile and efficient tools for assisting academic biotechnological research. It is expected that image analysis systems will allow more rapid and accurate quantification of numerous biotechnological analyses. There is, therefore, much scope for the implementation of image analysis/processing systems in a large variety of industrial and clinical applications.

Initial steps in Streptococcus pneumoniae interaction with and pathogenicity to the host.

Streptococcus pneumoniae (Pnc) is one of the leading pathogens in the world. Attachment to respiratory mucosal and lung surfaces is presumed to be involved in carriage, in disease and in the interaction with macrophages initiating innate immune responses. We hypothesized that bacterial adhesins mediate Pnc adhesion and host cell invasiveness. Initial studies have focused on the purification of cell wall and membrane proteins using fetuin affinity chromatography, SDS PAGE and western blot analysis probed with pooled healthy human sera. Using a Pnc clinical isolate, and a gpt mutant we have detected 10-lectin proteins isolated from the cell wall and adherent to the affinity column and 15 lectins isolated from membrane extracts. The fetuin-captured lectins agglutinated rabbit erythrocytes. 15 proteins in the cell wall and 18 proteins in the membrane that failed to bind to the fetuin column did not agglutinate rabbit erythrocytes. Further purification of the cell wall and membrane fetuin-separated fractions was achieved via anion exchange FPLC, was verified by SDS PAGE. These proteins maintained their agglutinating activity, and were subsequently tested for their ability to interfere with Pnc adhesion and invasion of epithelial cells in culture. Additional biochemical, immunological and molecular techniques are being used in attempt to identify relevant proteins.

Adenoid cystic carcinoma of the vulva with lung metastases. A case report.

The presenting symptoms of adenoid cystic carcinoma of the vulva in a 57-year-old woman were a vulvar mass and pain. The mass was excised locally. The disease recurred in the lung four years later. The patient was treated with several regimens of chemotherapy, without significant effect. She died of pulmonary failure six years after diagnosis.

Naproxen sodium vs. a combination of aspirin, phenacetin, caffeine and codeine phosphate for pain after major gynecologic surgery. A multicenter comparison.

In this multicenter study a nonnarcotic analgesic available for moderate pain, naproxen sodium, 550 mg, was compared to a combination that is used extensively for moderate to severe pain, aspirin, phenacetin, caffeine and codeine phosphate (APC/C) (60 mg of codeine phosphate). Women with pain after major gynecologic surgery reported a similar pattern in pain reduction with the two medications except for a relatively sharper increase in pain intensity between four and six hours after administration of APC/C. A smaller number of patient complaints suggested that naproxen sodium was better tolerated than APC/C.