Chemoprevention of cervical cancer with folic acid: a phase III Southwest Oncology Group Intergroup study.

Several epidemiological reports and experimental investigations have suggested a preventive role for folic acid in the etiology of cervical cancer. The effect of p.o. folic acid supplementation on the natural history of cervical intraepithelial neoplasia (CIN) was evaluated in a multiinstitutional prospective, randomized, double-blind, placebo-controlled trial. Three hundred thirty-one women with biopsy-proven koilocytic atypia, mild CIN, or moderate CIN were randomized to receive oral folic acid (5 mg) or a similar-appearing placebo daily for 6 months following a 1-month run-in placebo period. Colposcopy, Papanicolaou smear, and serum vitamin levels (folate, retinol, alpha-tocopherol, beta-carotene, and retinyl palmitate) were monitored every 3 months. Demographic, medical, dietary, and sexual history data were obtained from personal interviews. The primary end point of the study was improvement in both Papanicolaou smear and colposcopic picture after 3 and 6 months of treatment as compared to the start of treatment. After 6 months of treatment there was no significant difference between the two study groups in the percentage of patients improved. Median serum folate levels in the treatment arm at 3 and 6 months (29.0 and 20.0 micrograms/dl) were significantly higher than those in the placebo arm (7.8 and 7.1 micrograms/dl, respectively). Mean serum levels of retinol, retinyl palmitate, alpha-tocopherol, and beta-carotene did not differ significantly between the two treatment arms. Our data support the conclusion that supplementation with folic acid (5 mg/day) does not enhance the regression of early epithelial abnormalities of the cervix.(ABSTRACT TRUNCATED AT 250 WORDS)

High dose para-aortic lymph node irradiation for gynecologic cancer: technique, toxicity, and results.

A technique for high dose (5600-6100 cGy) extended field irradiation to the para-aortic lymph nodes is described. Fourteen patients have been treated with this technique, of whom 10 have had histologic confirmation of para-aortic node metastases. With follow-up ranging from 11 to 78 months, 7 of 14 patients are alive and clinically cancer-free. Acute effects of extended field treatment on patient weight and circulating blood counts are analyzed, and late treatment morbidity assessed. The findings suggest that such treatment, executed with modern equipment and appropriate technique, is not significantly more hazardous than pelvic irradiation, and can result in a substantial probability of disease-free survival.

Adjuvant postoperative pelvic radiation for carcinoma of the uterine cervix: pattern of cancer recurrence in patients undergoing elective radiation following radical hysterectomy and pelvic lymphadenectomy.

Thirty-seven patients with invasive cervical cancer have been referred to the Department of Radiation Oncology at the University of Washington following radical hysterectomy and pelvic lymphadenectomy. Patients at high-risk for tumor recurrence were selected for adjuvant pelvic irradiation because of adverse risk factors identified on pathological study of the hysterectomy specimen. All patients were treated because of possible residual, microscopic carcinoma. Fourteen patients (38%) developed recurrent cancer, of whom 10 (27%) manifested initial failure within the irradiated volume. Possible explanations for this observation are discussed.

Combined radiotherapy and chemotherapy in the management of local-regionally advanced vulvar cancer.

PURPOSE: To determine, in a retrospective single institutional study, the role of concurrent radiotherapy and chemotherapy in the treatment of local-regionally advanced vulvar cancer. METHODS AND MATERIALS: From 1984 to 1991, 20 patients with locally extensive primary or recurrent carcinoma of the vulva were treated with initial combined radiotherapy and chemotherapy. Seven patients had Federation Internationale de Gynecologie et d'Obstretrique Stage III disease, 10 had Stage IV disease, and three were treated for recurrent disease. None of these patients were considered candidates for primary radical vulvectomy and groin node dissection. Median radiation doses to regions of microscopic disease and gross tumor were 40 Gy (range 30-54 Gy) and 54 Gy (34-70.4 Gy), respectively. All patients received 2 or 3 cycles of 5-Fluorouracil concurrently with radiotherapy. In addition, five patients received Cis-platinum, and one Mitomycin-C. Median at-risk follow-up interval was 37 months. RESULTS: Ten patients had complete resolution of tumor to initial chemoradiotherapy, and eight of these have remained free of tumor relapse. Eight other patients had partial responses, with tumor bulk reduced by > 50%, while the remaining two patients had local-regionally progressive disease. Six of the patients with partial responses had residual tumor successfully resected, although four subsequently recurred. For the entire group of 20 patients, the actuarial 3- and 5-year local control rates were 48% each, and the corresponding disease-specific survival rates were 59% and 49%. There was a suggestion that better local control was obtained in patients who received gross tumor radiation doses > or = 50 Gy. Skin reaction was the major acute toxicity and responded well to conservative management. Long-term sequalae were limited to skin and subcutaneous atrophy. CONCLUSION: These results indicate that initial combined radiotherapy and chemotherapy is effective in the management of advanced vulvar cancer.

Malignant melanoma of the vulva: a case report of distal recurrence in a patient with a superficially invasive primary lesion.

Malignant melanoma of the vulva is a rare but highly lethal disease traditionally treated by radical surgery. Recently, data has been presented suggesting that less aggressive surgical management for superficially invasive lesions results in low levels of local recurrence and metastatic disease. We present a patient with a Clark level II superficial spreading melanoma of the vulva that developed distal recurrence after wide local excision.

Stage I vulvar cancer: criteria for microinvasion.

Thirty-eight women with stage I epidermoid carcinoma of the vulva were studied retrospectively in an attempt to define the criteria for conservative therapy in early invasive vulvar cancer. Among the 38 women, 23 met the 6 criteria established for early invasive carcinoma of the vulva. In those 23 women, there were no nodal metastases. Depth of stromal invasion correlated strongly with the degree of tumor differentiation and the presence of carcinoma in situ (CIS). Stromal invasion less than 3 mm and presence of CIS were predictive of no involvement of the lymph nodes or endothelial-like space.

The morbidity and benefits of concurrent gracilis myocutaneous graft with pelvic exenteration.

This study was undertaken to evaluate the morbidity and potential benefits of concurrent gracilis myocutaneous graft with exenteration. All patients undergoing exenteration from 1962-1986 were reviewed, of whom 24 had concurrent grafts. The mean operative time, blood loss, and hospital stay were not different in patients with versus without grafts. The rate of fistula formation in the hospital was less in the graft group (P = .004) but was not different when compared with contemporary patients only. The total infection rate (wound and pelvic) was decreased in the graft group (P = .04) when graft infections were excluded. The major problem with the graft was significant necrosis of the flap(s) in nine of the 24 patients. There were no life-threatening complications attributed to concurrent placement of gracilis myocutaneous flaps. Experience with the technique is improving the cosmetic and functional outcome of the neovagina formed with the graft. Patients most likely to benefit from this procedure include those requiring immediate reconstruction or those with potentially poor healing due to high-dose pelvic radiation, including intraoperative radiation.

Osteomyelitis pubis after radical gynecologic operations.

The clinical and microbiologic features of five cases of osteomyelitis of the pubis after radical gynecologic and exenterative pelvic surgery are reported. Pain and tenderness over the pubic symphysis and difficulty with ambulation were common features. The interval between surgery and diagnosis ranged from eight to 17 weeks (average, 13.6 weeks). Erythrocyte sedimentation rate and alkaline phosphatase level were often abnormal, and x-rays, bone scan, and gallium scan were useful diagnostic tests. Osteomyelitis of the pubis contributed to an increased hospital stay of 5.6 weeks (mean) for patients undergoing radical vulvectomy and ten to 24 weeks for patients undergoing total pelvic exenteration. Intravenous antibiotic therapy followed by long-term oral administration may provide effective therapy, but the presence of necrotic bone requires surgical excision of necrotic and infected tissue.

Glassy cell carcinoma of the cervix redefined.

Glassy cell carcinoma of the cervix has been classically regarded as a poorly differentiated adenosquamous carcinoma, infrequently diagnosed and associated with a poor outcome regardless of the modality of therapy. The histologic characteristics associated with this lesion are also frequently encountered among undifferentiated large-cell, nonkeratinizing cervical carcinomas. In a review of all undifferentiated large-cell carcinomas of the cervix encountered at the University Hospital in Seattle, Washington, over an eight-year period, 29 cases appeared to display the characteristic histologic criteria described as typical for glassy cell carcinoma. All cases were stage Ib lesions, and 28 were treated by radical hysterectomy. The mean age was ten years younger than that of the usual patient treated at this institution with stage I carcinoma. Fourteen of these patients (45%) have developed recurrent carcinoma, and in all but one, the interval to recurrence was less than eight months. Only two have survived after second-line salvage therapy. The current survival rate among the 29 women is 55%. These observations suggest that the poor prognosis ascribed to the classically defined glassy cell carcinoma also holds true for this extended group of large-cell, undifferentiated cervical cancers that display similar histologic features and pursue a similarly aggressive clinical course.

Supraumbilical upper abdominal midline incision for pelvic surgery in the morbidly obese patient.

An upper abdominal midline incision was used for pelvic surgery in 16 morbidly obese patients (229-401 lb). When this approach is used, a Bookwalter retractor displaces the incision inferiorly and compresses the abdominal wall over the pelvis, and is then secured to the operating-room table. This approach provides adequate exposure of the pelvic organs and avoids an incision in the panniculus with its associated complications. No wound infections, postoperative dehiscences, or other serious postoperative morbidity occurred in these patients.

Oncogene expression: long-term compared with short-term survival in patients with advanced epithelial ovarian cancer.

OBJECTIVE: To determine if oncogene overexpression in patients with advanced epithelial ovarian cancer correlates with survival. METHODS: Twenty-two women with stage III ovarian cancer, observed for a median of 66 (range 48-204) months were compared with 30 with a median survival of 18 (range 2-28) months. Using immunocytochemistry, tumors were immunostained for overexpression of p53, c-erb-B-2, and epidermal growth factor receptor and were evaluated quantitatively for expression of estrogen receptor, progesterone receptor, and Ki-67 antigen, a marker of cellular proliferation. RESULTS: The median age of long-term survivors was 52 (range 30-76) years compared with 55 (range 36-80) years for short-term survivors. Optimal cytoreduction was achieved in 11 of the 22 long-term survivors compared with seven of the 30 short-term survivors, a significant difference (P=.05). The average level of Ki-67 expression was 43% in long-term survivors and 64% in short-term survivors (P=.007). Overexpression of p53 was seen in 54% of long-term survivors and 80% of short-term survivors (P=.05). A combination of Ki-67 level of 50% or greater plus p53 overexpression was seen in 22% of long-term survivors compared with 68% of short-term survivors (P=.005). Epidermal growth factor receptor, c-erb-B-2, estrogen receptor, and progesterone receptor statuses did not differ significantly between the two groups. CONCLUSION: Markers that did not correlate with survival included the hormone receptors, estrogen receptor and progesterone receptor, and the oncogenes, c-erb-B-2 and epidermal growth factor receptor. Long-term survivors with advanced ovarian cancer were more likely to have had an optimal cytoreduction and lower levels of Ki-67 antigen expression and were less likely to overexpress p53 than were short-term survivors.

Umbilical artery Doppler flow velocimetry in intrauterine growth restriction and its relation to perinatal outcome.

OBJECTIVE: The purpose of this retrospective analysis was to compare pregnancy outcomes in growth-restricted fetuses retaining normal umbilical artery Doppler flow and the outcomes of pregnancies with end-diastolic velocity either diminished or severely reduced/absent. METHODS: One hundred pregnant women with growth-restricted fetuses were followed with Doppler velocimetry of the umbilical artery between weeks 28 and 41 of pregnancy. Outcomes were compared for the normal Doppler group (16%), the less-severely abnormal group (77%), and the group with severely reduced or absent end-diastolic velocity waveforms (7%). RESULTS: The diagnosis-to-delivery interval was significantly shorter, and the average birth weight and gestational age at delivery were significantly lower, for fetuses with abnormal Doppler velocimetry (showing diminished or severely reduced/absent end-diastolic velocity) than for those in the normal Doppler group. Fetuses with abnormal Doppler velocimetry also had a significantly higher incidence of oligohydramnios, low-birth weight (<10th percentile), and admission to the Neonatal Intensive Care Unit. There were no perinatal deaths among the normal Doppler patients. CONCLUSIONS: Growth-restricted fetuses with normal umbilical artery velocimetry are at significantly lower risk than those with abnormal velocity waveforms, and immediate delivery of the fetus with diminished end-diastolic flow may be unnecessary. Knowing this relationship may be useful in the clinical management of such pregnancies. Doppler surveillance of growth-restricted fetuses supplemented with cardiotocography, preferably combined with biophysical profile testing, results in a prolonged gestational age and acceptable fetal outcome.

Factors influencing ototoxicity in ovarian cancer patients treated with Cis-platinum based chemotherapy.

Seventy-seven ovarian cancer patients were evaluated for auditory toxicity following low-dose, slow-infusion cisplatin therapy. Twenty patients had baseline normal hearing with conventional audiological assessment of pure tone sensitivity at 250 to 8,000 Hz prior to therapy, along with at least one repeated audiogram before subsequent treatments. Ten of these patients also had serial assessment of ultra-high frequencies (10,000 to 18,000 Hz). Six of the 20 patients (30%) developed pure tone threshold elevations of at least 10 dB in any two frequencies. This hearing loss was predominantly persistent, bilateral, symmetrical, and above the speech range. Hearing loss was categorically mild and not statistically significant, at any specific frequencies. Hearing loses were not progressive with repeated doses of cisplatin. Only one of 20 patients reported tinnitus, and no vestibular toxicity was observed. One patient complained of clinically significant hearing difficulty. The risk of developing hearing loss appeared significant for patients older than 42 years, but failed to correlate statistically with disease stage at diagnosis, cumulative cisplatin dosage, or the presence of other ototoxic drugs (furosemide and IV aminoglycosides). The relationship between nephrotoxicity and ototoxicity in this study was inconclusive.

Enchondromatosis (Ollier's disease) and ovarian juvenile granulosa cell tumor.

An ovarian juvenile granulosa cell tumor in a 15-year-old white girl is reported. The patient had enchondromatosis (Ollier's disease). amd a review of the literature revealed two previous reports linking enchondromatosis with ovarian sex-cord stromal tumors. This heretofore unrecognized association between these two unusual lesions indirectly supports a generalized mesodermal dysplasia in patients with enchondromatosis. It also draws attention to the possible emergence of ovarian neoplasms in addition to the more frequently encountered chondrosarcomas.

Adenocarcinoma of the uterine tube: potential for lymph node metastases.

A clinicopathologic study of 15 cases of primary adenocarcinoma of the uterine tube occurring over a 12-year period is presented. The mean age of the patients was 54.8 years. Predominant symptoms were abnormal bleeding, abnormal vaginal discharge, and pelvic pain. Abnormal vaginal cytology was noted in two instances (13%). A pelvis mass was detected in two thirds of patients. The neoplasm was bilateral in three instances (20%). Lymph nodes were involved in eight cases (53%), and metastatic spread to the para-aortic nodes was present in five (33%). The most common primary treatment was total abdominal hysterectomy and bilateral salpingo-oophorectomy. Various combinations of adjuvant radiation therapy and chemotherapy were also employed. Six patients (40%) are alive without evidence of recurrent cancer. It is concluded that lymphatic spread, especially to the para-aortic nodes, is a major pattern of disseminaton for adenocarcinoma of the uterine tube. The presence of tumor in capillary-like spaces bears a strong relationship to lymph node metastases, and the para-aortic nodes are a frequent site of involvement even when the disease is apparently limited to the tube.

Patterns of recurrence of carcinoma following radical hysterectomy.

One hundred eighty-six radical abdominal hysterectomies are reviewed. Twenty-two instances of clinically recurrent carcinoma following operation were encountered over a 18-year period. In review of these cases it is apparent that patients with adenocarcinoma or adenocystic carcinoma have an increased likelihood of positive lymph node metastases or lymphatic-vascular invasion at the time of surgery. If this occurs, there is an increased probability of recurrent disease. Poor differentiation of the tumor, bulky disease, deep infiltration of tumor, involvement of capillary-like spaces, and lymph node metastases all appear to represent poor prognostic indices in patients operated upon. Patients with adenocarcinoma generally have a longer disease-free interval before recurrence than patients with squamous carcinoma. Postoperative radiation therapy following radical surgery appears to increase significantly the disease-free interval until recurrence and influences the site of recurrent disease but has no demonstrable effect on ultimate survival.

Lymphatic spread in carcinoma of the vulva.

A study of 153 patients with squamous cell carcinoma of the vulva is reviewed. Regional node metastases were present in 20%, and lymphatic spread proved the single most significant prognostic factor in this disease. Recurrent carcinoma developed in 47% of cases with nodal metastases. Lymph node metastases were directly related to stage of disease, tumor differentiation, lesion size, and depth of invasion. Sixty percent of nodal disease was not suspected by clinical examination. No patient developing recurrent disease after identification of positive nodes survived the disease. Surgical staging based only upon size of lesion and presence of nodal metastases appears to offer a clearer prognostic profile than conventional clinical staging. The pattern and frequency of nodal spread suggest that in selected instances modifications of the standard surgical treatment of vulvar cancer may be appropriate.

Expression of c-erb B-2 oncogene product in persistent gestational trophoblastic disease.

OBJECTIVE: Much debate exists on the initiation of chemotherapy for women at risk for persistent gestational trophoblastic disease. This is a result of a lack of early predictors for the development of persistent gestational trophoblastic disease after evacuation of a complete hydatidiform mole, because the only current reliable method of detection and diagnosis lies in persistent or rising postmolar beta-human chorionic gonadotropin values. We used immunocytochemical techniques to retrospectively study the expression of the c-erb B-2 oncogene product in formalin-fixed, paraffin-embedded trophoblastic tissues as a potential indicator of the development of persistent gestational trophoblastic disease. STUDY DESIGN: In this retrospective study 56 trophoblastic tumors were examined by means of immunocytochemical techniques to stain for the oncogene product for evidence of c-erb B-2 expression. Our 56 cases included original tissue from 20 cases of complete mole that progressed to persistent gestational trophoblastic disease, seven cases of choriocarcinoma after term pregnancy or abortion, and 29 cases of hydatidiform mole representing postevacuation, spontaneously regressing disease (including one partial mole). We also studied 11 cases of first-trimester trophoblast and 15 cases of term placenta as additional controls. RESULTS: Our results showed positive immunostaining for c-erb B-2 gene product in one case of persistent gestational trophoblastic disease, with negative staining in all other cases in the study groups and controls. CONCLUSION: Analysis for the significance of c-erb B-2 expression in persistent gestational trophoblastic disease showed that this correlation between c-erb B-2 expression and persistent gestational trophoblastic disease is not significant, suggesting that future efforts should be directed at the involvement of different oncoproteins.