p53 and Ki-ras gene mutations in epithelial ovarian neoplasms.

In an effort to define the pathogenic relationship between ovarian neoplasms spanning the clinicopathological spectrum from benign to malignant, the incidence of Ki-ras and p53 mutations was determined in 20 ovarian cystadenomas, 20 low malignant potential (LMP) tumors of the ovary, and 23 ovarian carcinomas. Using DNA extracted from paraffin embedded tissue, polymerase chain reaction amplification, designed restriction fragment length polymorphism analysis, and DNA sequencing, 1 cystadenoma (5%), 6 LMP tumors (30%), and 1 ovarian carcinoma (4%) demonstrated an activated Ki-ras gene. All of the Ki-ras mutations identified except one were GGT to GAT transversions at codon 12. One LMP tumor demonstrated a CAA to CAC transversion at codon 61. Using polymerase chain reaction/single strand conformational polymorphism, DNA sequencing, and immunohistochemistry, 11 ovarian carcinomas (48%) demonstrated a p53 mutation. These mutations included 5 missense, 2 nonsense, and 1 frameshift mutation located within exons 6-8 and 3 mutations that were identified only by immunohistochemical staining. No p53 mutations could be identified in cystadenomas or LMP tumors. Clinically, the presence of either a Ki-ras or p53 mutation was associated with advanced stage disease. The pattern of Ki-ras and p53 mutations appears to distinguish LMP tumors from invasive carcinomas and suggests that they may be separate biological entities.

Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience.

Long-term follow-up was obtained on 726 women with advanced ovarian carcinoma (suboptimal stage III and stage IV) who had received primary chemotherapy on two Gynecologic Oncology Group (GOG) protocols between 1976 and 1982. The first study compared melphalan alone versus melphalan plus hexamethylmelamine versus cyclophosphamide plus doxorubicin (CA). The second study evaluated the same CA regimen with or without cisplatin. Eligibility for the two studies was the same. At last contact, 76 patients were alive. In a multivariate analysis, cell type other than clear cell or mucinous, cisplatin-based treatment, good performance status, younger age, lower stage, clinically nonmeasurable disease, smaller residual tumor volume, and absence of ascites were favorable characteristics for overall survival (P less than .05). Second-look laparotomy was negative significantly more often among those with endometrioid tumors; there were no negative second-look laparotomies among those with mucinous or clear cell tumors. There were 30 patients with suboptimal stage III disease who had a negative second-look laparotomy; 18 (60%) have experienced recurrence, and 13 (43%) have died. Although cisplatin treatment was beneficial, new treatments are clearly needed.

Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirus type 16 E7.

Human papillomavirus (HPV) infection has been causally associated with cervical cancer. We tested the effectiveness of an HLA-A*0201-restricted, HPV-16 E7 lipopeptide vaccine in eliciting cellular immune responses in vivo in women with refractory cervical cancer. In a nonrandomized Phase I clinical trial, 12 women expressing the HLA-A2 allele with refractory cervical or vaginal cancer were vaccinated with four E786-93 lipopeptide inoculations at 3-week intervals. HLA-A2 subtyping was also performed, and HPV typing was assessed on tumor specimens. Induction of epitope-specific CD8+ T-lymphocyte (CTL) responses was analyzed using peripheral blood leukapheresis specimens obtained before and after vaccination. CTL specificity was measured by IFN-gamma release assay using HLA-A*0201 matched target cells. Clinical responses were assessed by physical examination and radiographic images. All HLA-A*0201 patients were able to mount a cellular immune response to a control peptide. E786-93-specific CTLs were elicited in 4 of 10 evaluable HLA-A*0201 subjects before vaccination, 5 of 7 evaluable HLA-A*0201 patients after two vaccinations, and 2 of 3 evaluable HLA-A*0201 cultures after all four inoculations. Two of three evaluable patients' CTLs converted from unreactive to reactive after administration of all four inoculations. There were no clinical responses or treatment toxicities. The ability to generate specific cellular immune responses is retained in patients with advanced cervical cancer. Vaccination with a lipidated HPV peptide epitope appears capable of safely augmenting CTL reactivity. Although enhancements of cellular immune responses are needed to achieve therapeutic utility in advanced cervical cancer, this approach might prove useful in treating preinvasive disease.

Alterations in regional myocardial blood flow after nitroprusside and nitroglycerin in patients with and without significant coronary artery disease.

To evaluate vasodilator-induced redistribution of regional myocardial blood flow, intravenous sodium nitroprusside and nitroglycerin were administered in doses producing matched reductions (15%) in mean arterial pressure at constant heart rate. Anterior left ventricular great cardiac vein blood flow (thermodilution) was measured in 14 patients without angiographic anterior collateral supply. Global coronary sinus blood flow remained constant with both nitroprusside and nitroglycerin administration, despite significant reductions in mean arterial pressure. However, nitroglycerin reduced great vein flow by 25 +/- 17% and nitroprusside by 10 +/- 16% (p less than 0.01). Subgroup analysis indicated that the nitroglycerin-nitroprusside regional blood flow differences were more pronounced in patients without significant left anterior descending coronary artery narrowing. Neither vasodilator produced significant differences in arterial-coronary sinus oxygen or lactate contents, calculated myocardial oxygen consumption, left ventricular dP/dt, or electrocardiographic or clinical signs of myocardial ischemia. Despite qualitatively similar hemodynamic effects, comparisons of vasodilator-induced relative reductions in normally supplied anterior left ventricular regional coronary blood flow suggest a mechanism of the reported beneficial effects of nitroglycerin on potentially ischemic myocardial regions.

Antibiotic prophylaxis in vaginal hysterectomy: a review.

Recent experimental studies in laboratory animals have elucidated the pathogenesis of operative site infections and have defined the mechanism by which prophylactic antibiotics enhance host defenses against infection. On the basis of these experimental observations, several investigators have conducted well-designed studies to evaluate the effectiveness of prophylactic antibiotics in reducing the risk of infection associated with vaginal hysterectomy. Without exception, these studies have demonstrated a dramatic decrease in the incidence of pelvic infections when antimicrobial agents are administered for a limited time in the perioperative period. To date, short courses of prophylactic antibiotics have not been shown to create selective pressures for the emergence of drug-resistant organisms or to lead to the development of more serious superinfections.

Cervical carcinoma in pregnancy.

Forty-one cases of invasive carcinoma of the cervix associated with pregnancy that were treated at the Walter Reed Army Medical Center from January 1961 through April 1979 were reviewed. Postpartum patients were included in the study if the diagnosis of cancer was made within 6 months of delivery. Three cases of clinical stage IA disease treated by Wertheim-Taussig hysterectomy had a 5-year survival rate of 100%. There were 22 cases of stage IB disease with a 5-year actuarial survival rate of 90%. Four patients with stage IB were treated by radiotherapy, 17 by Wertheim-Taussig hysterectomy, and 1 by a combination of pelvic irradiation, cesium application, and simple extrafascial total abdominal hysterectomy and bilateral salpingo-oophorectomy for a barrel-shaped cervix. Twelve cases of stage II disease treated by radiotherapy had a 5-year actuarial survival rate of 24%. There were no survivors in 2 cases of stages III and IV disease. The 5-year actuarial survival rate of patients with stage I carcinoma of the cervix associated with pregnancy is not statistically different from that of nonpregnant patients, regardless of the method of treatment.

Diagnostic outpatient aspiration curettage.

Outpatient uterine curettage has proved to be an effective diagnostic tool and could replace the need for many hospital curettages. The materials needed to perform an outpatient curettage are described. The method was evaluated on 300 patients who underwent conventional hospital curettage under anesthesia 24 hours after the outpatient curettage. The outpatient curettage was evaluated for safety, reliability, economy, effectiveness, and patient acceptance. The results of the two methods compared favorably.

Quality assessment and assurance programs in the Gynecologic Oncology Group.

The Gynecologic Oncology Group (GOG), a program of ACOG, is one of 12 cooperative groups conducting clinical trials supported by the National Cancer Institute. Recently, an occurrence of research fraud was found in one of the other cooperative groups. The GOG maintains a quality assessment and assurance program that includes three primary functions: Original source documentation is examined to verify accuracy of treatment modalities, all protocols are regularly scrutinized for consistency and validity, and regular on-site audits are conducted at all institutions. The group endeavors to reassure physicians and their patients that research fraud is not rampant in the cooperative group system and that data published by the cooperative groups are reliable.

Microinvasive carcinoma of the cervix.

The clinical and pathologic features of 51 cases of microinvasive carcinoma of the cervix treated by radical hysterectomy and pelvic lymphadenectomy are presented. Microinvasion was defined as stromal penetration by carcinoma not exceeding a depth of 5 mm from the surface at the point of origin. Patients with confluent patterns and lymphatic invasion were not excluded. Lymphatic invasion was demonstrated in 24% of the patients, but none of the resected lymph nodes from the entire series contained metastatic tumor. Residual invasive disease was present in 9 of 47 patients who underwent conization including 1 in which the residual tumor invaded to 8 mm, although the depth of invasion in the cone biopsy was only 2.5 mm. Factors related to the presence of residual invasive disease included the pattern and extent of invasion and involvement of the cone margin. There were no surgery-related deaths or fistulae in this series; the actuarial survival rate at 5 years was 100%. Simple hysterectomy seems justified if the cone margin is free of tumor since none of these patients has residual disease. In contrast, radical hysterectomy may be indicated if the cone margins are involved in view of high frequency of residual tumor (39%) and the possibility of invasion in the cervix exceeding 5 mm.

Repair of urinary tract fistulas with bulbocavernosus myocutaneous flaps.

Urinary tract fistulas resulting from severe trauma or pelvic irradiation are often associated with extensive tissue loss, scar formation, and fibrosis. Two cases, one with a urethro-vaginal fistula secondary to trauma and one with a vesico-vaginal fistula secondary to irradiation, are presented. In neither case could the bladder, urethra, or vagina be repaired primarily. Using a bulbocavernosus myocutaneous "island" flap, the fistulas were successfully repaired. The anatomy of the graft and the operative procedure are described. This new procedure should be considered in urinary tract fistulas in which there is extensive tissue loss and scarring.

End colostomy using the end-to-end anastomosis instrument.

Gastrointestinal stapling instruments have achieved wide-spread application in intestinal surgery. Reported advantages of stapled bowel procedures compared to classic hand-sutured procedures include reduced tissue trauma, shorter operating time, and improved blood supply to the stapled bowel segment. A technique for creation of an end colostomy using the end-to-end anastomosis stapler (EEA instrument) is described. This technique was used in 11 gynecologic oncology patients who required colostomy. Postoperative stomal function was normal in all cases. No patient developed stomal necrosis, peristomal hematoma, or abscess. No delayed complications have been observed. Colostomy creation with the EEA instrument is a safe, simple and rapid procedure. Possible advantages of the stapled colostomy are enhanced blood flow to the stomal site, reduced incidence of peristomal infection, and improved appliance fit.

Clinical patterns of tumor recurrence after radical hysterectomy in stage IB cervical carcinoma.

We reviewed the cases of 31 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB cervical carcinoma who developed recurrent disease after radical hysterectomy and pelvic lymphadenectomy between 1961 and 1982. The overall incidence of recurrence was 11.3%. Recurrence was significantly more common in patients with adenocarcinoma or adenosquamous carcinoma (17.4%) than in those with pure squamous tumors (9.2%). The median time from operation to recurrence was eight months. The median survival of patients dying of disease was 18 months. Sites of recurrence were categorized as central pelvic in 35% of cases, pelvic sidewall in 39%, and distant in 26%. Patients treated with postoperative pelvic radiotherapy for positive pelvic nodes or surgical margin involvement were more likely to develop distant recurrence. Various therapeutic modalities were used to treat recurrent disease. Twenty-two of 23 patients with central pelvic or sidewall recurrence failed radiation therapy. None of four patients with central recurrence treated by pelvic exenteration survived. No patient treated with chemotherapy survived. Overall survival for patients with recurrence was 3.2%. The dismal prognosis for this group of patients warrants evaluation of alternative treatment modalities.

Calyceal rupture with perirenal urinoma in a patient with cervical carcinoma.

A patient is presented with calyceal rupture and perirenal urinoma formation secondary to distal ureteral obstruction by cervical carcinoma. Preoperative diagnosis was established with computed tomography and renal scan. Surgical placement of an indwelling ureteral stent resolved the urinoma. Causes of perirenal urine extravasation and approaches to diagnosis and management are reviewed.

Endodermal sinus tumor of the infant vagina treated exclusively by chemotherapy.

A 5-month-old Hispanic female, diagnosed as having endodermal sinus tumor of the vagina, was treated with combination chemotherapy in an attempt to preserve pelvic function. An incisional biopsy was performed before starting chemotherapy. After completion of chemotherapy, no residual disease was found at exploratory laparotomy. The patient received no further therapy and is disease-free 45 months later. This case represents successful treatment of a vaginal endodermal sinus tumor without any operative excision.

Cervical carcinoma found incidentally in a uterus removed for benign indications.

Thirty-five patients with invasive cervical carcinoma discovered in a uterus removed for benign indications were evaluated and treated from 1961 through 1983. Although formal staging was not possible, patients with presumed stage IA disease had a 100% five-year survival rate regardless of the addition of adjuvant therapy. All patients with more advanced disease received radiation therapy. Patients with presumed stage IB disease had a corrected five-year survival rate of 78%, and those with presumed stage IIB disease had a corrected five-year survival rate of 67%. No patient in this series was thought to have disease more advanced than a stage IIB equivalent. The hysterectomy alone may have been adequate therapy for patients with presumed stage IA disease. Adjuvant radiation therapy appears to be effective treatment for patients with presumed stage IB or IIB disease.

Intraoperative evaluation of depth of myometrial invasion in stage I endometrial adenocarcinoma.

In patients with stage I endometrial adenocarcinoma, the incidence of pelvic and para-aortic lymph node metastasis is related to the grade of the tumor and the depth of myometrial invasion. Although the grade of the tumor may be predicted preoperatively by endometrial sampling, the depth of myometrial invasion cannot be determined until after the uterus has been removed. Although complications have been attributed to lymph node sampling, failure to perform the procedure in patients at risk for nodal metastasis may result in underdiagnosis of extrauterine disease, leading to inadequate therapy. Gross visual examination of the cut surface of the tumor at the time of hysterectomy accurately determined the depth of myometrial invasion in 135 of 148 prospectively studied patients (91%) (P less than .001). The sensitivity of the test was 0.71, the specificity was 0.96, and the positive predictive value was 0.80. Intraoperative assessment of the depth of myometrial invasion is a simple, inexpensive, and useful technique for selecting those patients with stage I endometrial adenocarcinoma who might benefit from selective para-aortic lymphadenectomy.

Treatment failure in endometrial carcinoma.

Endometrial carcinoma has been regarded as one of the more curable gynecologic malignancies. Clinical stage, grade, and depth of myometrial invasion are well-established prognostic variables. We examined the clinical course of 520 patients with endometrial carcinoma treated at Walter Reed Army Medical Center and the Naval Hospital, Bethesda, Maryland, between January 1, 1960 and December 31, 1982. Life table 5-year survivals for stages Ia, Ib, II, III, and IV were 89, 92, 77, 27, and 0%, respectively. Compared with patients with grade 1 endometrial adenocarcinomas, significant decreases in survival were noted for patients with grade 2 or 3 endometrial, papillary endometrioid, serous papillary, and clear-cell tumors. There were six treatment-related deaths (1.2%). Thirty-eight patients (7.3%) developed recurrent disease, with a median time to recurrence of 15 months and a median survival of 21 months. Two of 11 patients with pelvic recurrence were salvaged by radiotherapy, whereas none of 27 patients with distant failure survived. Sixteen advanced-stage patients (3.1%) with persistent disease had a median survival of 4.5 months. Patients with advanced disease or unfavorable histologic subtypes responded poorly to conventional therapy. Current salvage treatments are largely ineffective. Combined-modality therapy and systemic adjuvant therapy should be prospectively evaluated in high-risk patient subgroups.

The molecular genetics of gyn malignancies.

Gynecologic malignancies, representing 13% of all cancers affecting women, have a major impact on women's health. Cervical, endometrial, and ovarian cancers comprise the majority of these tumors and contribute significant morbidity and mortality to the female population. While cervical and endometrial cancers can be detected early in their development, sadly, many patients present with advanced disease, as do the majority of patients with ovarian cancer. Unfortunately, advanced cases of these malignancies are usually lethal despite modern therapeutic modalities. In order to impact upon these grim statistics, gynecologic researchers have turned to molecular biology in an attempt to elucidate the etiology of these cancers. Recent research describing dominant oncogene and tumor suppressor gene mutations common to these malignancies is providing a basis for the molecular genesis of these cancers. This information should offer new avenues for the development of early detection and chemoprevention, as well as novel treatment strategies.