Cisplatin inhibits paclitaxel-induced apoptosis in cisplatin-resistant ovarian cancer cell lines: possible explanation for failure of combination therapy.

Combination chemotherapy using paclitaxel with a platinum-based regimen is currently the standard first-line therapy for ovarian cancer after surgical cytoreduction. Whereas cisplatin-paclitaxel combination chemotherapy has shown significant efficacy over previous drug combinations in ovarian cancer, 20-30% of patients fail to respond to this combination. These patients are deemed cisplatin-paclitaxel resistant, although it is unclear whether the tumors are resistant to one or both drugs. Because the options available to ovarian cancer patients for second-line therapy are limited, and knowing that mechanistic differences exist between cisplatin and paclitaxel, we assessed the efficacy of combination drug therapy on cisplatin-resistant (cisplatinR) ovarian cancer cells. We found that paclitaxel induced apoptosis in cisplatinR cells as well as in the cisplatin-sensitive parental cell lines. In cisplatinR C-13 cells, the concomitant addition of cisplatin blocked paclitaxel-induced apoptosis as determined by DNA fragmentation assays, fluorescence microscopy, and flow cytometry. Paclitaxel-induced multimininucleation was also inhibited when the cells were exposed sequentially to paclitaxel and then cisplatin. Cisplatin did not block paclitaxel-induced stabilization of microtubules or prevent paclitaxel-induced loss of Bcl-2 expression in cisplatinR cells. Conversely, paclitaxel did not inhibit p53 protein accumulation by cisplatin. These results suggest that cisplatin blocks paclitaxel-induced apoptosis at a point downstream of Bcl-2 degradation and independent of microtubule stabilization. Our research shows that cisplatin can inhibit the effectiveness of paclitaxel in cispatinR cell lines. Therefore, the establishment of a clinical protocol to evaluate the efficacy of paclitaxel alone versus another second-line regimen in patients with cisplatin-paclitaxel-resistant ovarian cancer is warranted.

Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker.

Hypoxia in human tumors is associated with poor prognosis, but the molecular mechanisms underlying this association are poorly understood. One possibility is that hypoxia is linked to malignant progression through vascular endothelial growth factor (VEGF) induction and the associated angiogenesis and metastasis. The present clinical study measures hypoxia and VEGF expression on a cell-by-cell basis in human squamous cell carcinomas to test the hypothesis that hypoxia and VEGF protein expression are coupled in human tumors. Eighteen patients with invasive squamous cell carcinoma of the uterine cervix and head and neck have been investigated by a quantitative image analysis of immunostained sections from their tumors. The hypoxia marker pimonidazole was used to measure tumor hypoxia, and a commercially available antibody was used to measure VEGF protein expression. A quantitative immunohistochemical comparison of hypoxia and VEGF protein expression revealed no correlation between the two factors.

Hydroxyurea versus misonidazole with radiation in cervical carcinoma: long-term follow-up of a Gynecologic Oncology Group trial.

PURPOSE: Long-term follow-up data of a randomized trial that compared hydroxyurea and the hypoxic-cell radiosensitizer to misonidazole as adjuncts to standard radiation therapy in locally advanced carcinoma of the cervix are reported. PATIENTS AND METHODS: Three hundred eight women were entered, and all 294 eligible patients are assessable as randomized. Eighty-one percent of patients have been monitored for 5 years or to death. RESULTS: There was an advantage for hydroxyurea in progression-free interval and survival (P = .05 and P = .066, respectively). There was no significant difference in the distribution of sites of failure between the regimens. For the 39% of patients with stages III to IVA disease, the advantage in progression-free interval for hydroxyurea was significant (47.8% v 33.6%). More leukopenia occurred on the hydroxyurea regimen than on the misonidazole regimen. CONCLUSION: In summary, these data provide stronger evidence than our previous analysis that hydroxyurea is superior to misonidazole as an adjunct to radiation therapy. For patients with locally advanced carcinoma of the cervix, hydroxyurea continues to be the adjunct of choice with radiation.

Paclitaxel, an active agent in nonsquamous carcinomas of the uterine cervix: a Gynecologic Oncology Group Study.

PURPOSE: A phase II trial of paclitaxel was initiated in advanced nonsquamous carcinoma of the cervix to determine its activity in patients who had failed standard chemotherapy. PATIENTS AND METHODS: Eligible patients had at least one measurable lesion. The starting dose of paclitaxel was 170 mg/m(2) (135 mg/m(2) for patients with prior pelvic radiation) given as a 24-hour continuous intravenous infusion with courses repeated every 3 weeks. Dose escalation to 200 mg/m(2) and de-escalation to 110 mg/m(2) were allowed based on adverse effects. RESULTS: In this trial, 42 assessable patients were initially entered onto the study, and 13 responses were seen; four patients had a complete response, and nine patients had a partial response. The overall response rate was 31%. The primary and dose-limiting toxicity was neutropenia. CONCLUSION: The response rate to paclitaxel exceeds the rates reported using other single agents in nonsquamous carcinoma of the cervix.

Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study.

PURPOSE: In 1986, a protocol comparing primary radiation therapy (RT) plus hydroxyurea (HU) to irradiation plus fluorouracil (5-FU) and cisplatin (CF) was activated by the Gynecologic Oncology Group (GOG) for the treatment of patients with locally advanced cervical carcinoma. The goals were to determine the superior chemoradiation regimen and to quantitate the relative toxicities. METHODS: All patients had biopsy-proven invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix. Patients underwent standard clinical staging studies and their tumors were found to be International Federation of Gynaecology and Obstetrics stages IIB, III, or IVA. Negative cytologic washings and para-aortic lymph nodes were required for entry. Patients were randomized to receive either standard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU. RESULTS: Of 388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to HU. Adverse effects were predominantly hematologic or gastrointestinal in both regimens. Severe or life-threatening leukopenia was more common in the HU group (24%) than in the CF group (4%). The difference in progression-free survival (PFS) was statistically significant in favor of the CF group (P = .033). The sites of progression in the two treatment groups were not substantially different. Survival was significantly better for the patients randomized to CF (P = .018). CONCLUSION: This study demonstrates that for patients with locally advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU, and with manageable toxicity.

Carcinoma of the cervix: analysis of bladder and rectal radiation dose and complications.

From April 1969 through December 1980, 527 patients with epidermoid carcinoma of the cervix received radical radiation therapy at North Carolina Memorial Hospital (NCMH). The treatment was designed to deliver a combined dose (external beam plus intracavitary) of 7000-8000 cGy to Point A and 5000-6500 cGy to the pelvic lymph nodes depending upon the stage of the disease. The maximum dose to the bladder and to the rectum were calculated from the orthogonal intracavitary placement films with contrast material in these organs. Thirty-three cases of cystitis and fifty-eight cases of proctitis were recorded. The mean bladder dose for the group of patients with cystitis was higher, 6661 +/- 1309 cGy, than that for the patients without cystitis, 6298 +/- 1305 cGy, p = .19. The risk of cystitis increased as a function of bladder dose ranging from 3% for patients receiving less than or equal to 5000 cGy to the bladder to 12% for patients receiving greater than or equal to 8001 cGy to the bladder. A similar correlation was also found for rectal dose and proctitis. The mean rectal dose for the group of patients with proctitis was higher, 6907 +/- 981 cGy, than that for the patients without proctitis, 6381 +/- 1290 cGy, p = .003. The risk of proctitis increased as a function of rectal dose ranging from 2% for patients receiving less than or equal to 5000 cGy to the rectum to 18% for patients receiving greater than or equal to 8001 cGy to the rectum. A study of the severity of the cystitis as a function of bladder dose revealed a relationship between bladder dose and the severity of the complication (Grade I cystitis = 6600 +/- 1318 cGy vs Grade III cystitis = 6856 +/- 853 cGy). A dose-response relationship was found between the rectal dose and the severity of the complication (Grade I proctitis = 6810 +/- 906 cGy vs Grade III proctitis = 6997 +/- 1137 cGy). This relationship was statistically significant, p = .003. While there was no difference in the frequency of cystitis as a function of dose to the whole pelvis, the risk of proctitis did increase with increasing doses of external beam to the whole pelvis. It ranged from 3% for patients who received 2000 cGy or less to the whole pelvis to 14% for patients who received greater than 4000 cGy to the whole pelvis, p = .02.

Invasive carcinoma of the uterine cervix in women age 25 or less.

The incidence of cervix cancer in young women appears to be increasing. However, the influence of young age on prognosis remains unknown. There is almost no information on the prognosis of very young women, age 25 years or less, with invasive cervical carcinoma. From April 1969 to June 1987, 40/2195 (1.8%) patients, age 25 years or less, with invasive carcinoma of the uterine cervix were diagnosed, staged, and treated at our institution. Median age was 24.7 years (range 20.7 to 25.9 years). Distribution by FIGO stage was: Stage IA 7 (18%), Stage IB 23 (58%), Stage II 4 (10%), Stage III 4 (10%), and Stage IVA 2 (4%). Thirty-four (85%) patients had squamous cell carcinoma and six (15%) had adenocarcinoma. Treatment consisted of radical hysterectomy for all Stage IA patients, radical hysterectomy with or without bilateral pelvic node dissection for the 12 early Stage IB patients, and radiation with or without surgery for the remaining 11 Stage IB patients and all Stage II-IVA patients. Median follow-up was 122 months (range 13.2-190.6 months). Five-year disease-free survival rates were: Stage IA 100%; Stage IB 54.8%; and Stage II-IVA 13.7%. Five-year disease-free survival for the Stage IB patients with squamous cell carcinoma age 25 years or less was 64.7%, compared with 83% for women of all ages with Stage IB squamous histology treated at our institution. Seven of 23 Stage IB patients suffered regional recurrence only, one a local recurrence only, one a distant recurrence only, and one a combined recurrence. Seventy-five percent of these patients presented with Stage I disease; however, one-third died from their disease. The major site of failure was in the pelvis only. This, coupled with the low risk of long-term serious complications, suggests that more aggressive pelvic therapy may result in improved disease-free survival.

Carcinoma of the cervix stage IB: results of treatment with radiation therapy.

An analysis has been made of 101 patients treated with radiation therapy for epidermoid carcinoma of the cervix Stage IB (FIGO) from January 1970 through December 1976. The patients were treated with a combination of intracavitary therapy and external beam therapy delivering a total combined dose of 8000 rad to the paracervical areas (Points AR and AL) and 5500 rad to the pelvic lymph nodes (Points IR and IL). The cumulative, disease-free survival at 2, 3 and 5 years was 89%, 87% and 84%. Sixteen failures were recorded in this group of patients, of which 3 were a result of loco-regional disease, 5 loco-regional disease plus distant metastasis and 8 distant metastasis only. The failure rate was greater among the patients who had lesions 4 or more cm in diameter and in patients who received doses of external beam therapy to the whole pelvis of 4000 rad or more. Eighteen patients developed complications; however, one patient had a recto-vaginal and a vesico-vaginal fistula; thus 19 complications were recorded. The complications were divided according to their severity into three groups: Grade I (mild), Grade II (moderate) and Grade III (severe). There were 10 Grade I, 4 Grade II and 5 Grade III complications.

1000 cGy single dose palliation for advanced carcinoma of the cervix or endometrium.

Between January 1980 and the present, 42 patients with symptomatic, incurable gynecologic malignancies were treated at the University of North Carolina with 1000 cGy in a single fraction to the pelvis, repeated once or twice at monthly intervals as necessary. Of patients with adequate follow-up, total cessation of bleeding was seen in 18 of 30 (60%), complete pain relief in 2/9 (22%), and complete tumor eradication in 7/28 (25%). These palliative benefits were permanent in approximately half of the patients. Five serious treatment complications have been documented, four occurred more than 10 months after treatment. We conclude that 1000 cGy single-fraction whole pelvis treatment can be an effective means of palliating advanced gynecologic cancer provided the patient has a life expectancy of less than 1 year. Patients with a longer life expectancy are at risk for both recurrence of symptoms and for treatment related complications.

Multilamellar bodies as potential scattering particles in human age-related nuclear cataracts.

PURPOSE: To characterize within human age-related nuclear cataracts rare spherical objects covered by multiple membranes, termed multilamellar bodies (MLBs). METHODS: Adult human normal, transparent lenses were obtained from eye bank donors and age-related nuclear cataracts were obtained immediately after extracapsular extraction. Each sample was Vibratome sectioned fresh into 200 microm thick sections that were fixed and embedded for light or electron microscopy. Confocal images were recorded from sections stained with the lipid soluble dye, DiI. RESULTS: Light micrograph montages of the equatorial plane containing the fetal and embryonic nuclei were examined. Rare, but distinct, circular 1-3 microm diameter objects were observed consistently in the cataracts. These objects did not appear to be components of the complex intercellular interfaces. Serial sections indicated that the objects were spherical, or contained a spherical component. For about 20,000 fiber cell cross-sections in each lens, the frequency of MLBs was 10 times higher in cataracts than in the normal lens nuclei. Although extensive searching with the electron microscope was necessary, the size, circular profile and multiple layers of thin (5 nm) membranes easily identified the MLBs. Interiors of the MLBs displayed variable textures. Confocal images indicated that the coverings were enriched in lipid compared to the adjacent plasma membranes. The calculated density of the MLBs in the cataractous nuclei was about 3800/mm3, which represents a volume fraction of 0.00003. CONCLUSIONS: Because the MLBs are large compared to the wavelength of light, display interiors with variable staining textures and have lipid-rich coverings, they appear to be ideal candidates for large scattering particles that may contribute to the forward light scattering in nuclear cataracts.

Cervical stenosis following minor gynecologic procedures on DES-exposed women.

The findings associated with diethytlstilbestrol (DES) exposure in utero are expanding rapidly. Structural abnormalities in both the cervix and uterus are well documented; in addition the authors have noted indications of an abnormal healing response in these women. Locally destructive methods such as cryosurgery, cauterization, and excision have resulted in permanent and significant physical damage. Caution is advised in attempting even minor gynecologic procedures on DES-exposed offspring.

In utero exposure to DES. Evaluation and followup of 199 women.

Among 199 women from 12 to 30 years of age who had been exposed to DES in utero, the colposcopic evaluation of the vagina and cervix was considered normal for only 13.6%. The incidence of colposcopically detected lesions was not related to the trimester of DES exposure, the patient's age, use of oral contraceptives, or presenting symptoms. Areas of punctation, mosaic patterns, white epithelium, and keratosis were not considered areas of adenosis. Cervical bands, hoods, cock's combs, etc., were considered as part of the cervix. Under this definition adenosis of the vagina was diagnosed in only 14.1% of the patients. Eight (4.0%) women were found to have cervical intraepithelial neoplasia (CIN), Grade 3 lesions, and an additional 36 (14.1%) women were found to have CIN, Grade 1 lesions based on the light microscopy evaluation of directed biopsies. There were no cases of clear cell adenocarcinoma. It appears that women with in utero DES exposure may be at a higher risk of developing squamous neoplasia compared with non-DES-exposed women.

PIP: In 1972, the Gynecologic Oncology Division of the University of North Carolina started a program which would identify, evaluate and follow-up women with in utero DES (diethylstilbestrol). Visual, bimanual, digital and colposcopic examination were performed on 199 women with suspected DES exposure (mean age, 21.6 years). Depending on severity of findings, patients were followed up at intervals of 6 weeks to 6 months. The terms white "epithelium, mosaic pattern, punctuation, keratosis, cervical eversion, adenosis of vagina, and cock's combs were defined according to the FIGO classfication. 86.4% had abnormal colposcopic examination of vagina and/or cervix; 13.6% had normal colposcopic findings. Lesions of the cervix or vagina did not correlate with the trimester of DES exposure, patient's age, use of oral contraceptives, or symptoms at initial examination. Patients with abnormal colposcopic findings showed that 14.1% had CIN, Grade 1 lesions, and 4.0% had CIN, Grade 3 lesions based on the light microscopy evaluation of directed biopsies. No cases of clear cell adenocarcinoma were observed. The relative risk of developing squamous neoplasia in DES-exposed women was 4.4 to 13.3. Other therapeutic approaches for treating DES-exposed women were partial vaginectomy (Sherman et.al.), CO2 laser (Bellina), multiple punch biopsies (Scott) cryosurgery, and progesterone suppositories (Herbst et.al.). As not all risks associated with intrauterine DES exposure have been clearly defined, DES exposed women should have regular colposcopic examination and vaginal/cervical cytology (depending on the severity of the lesions in the lower vaginal tract).

Giant basal cell carcinoma of the vulva.

A giant basal cell carcinoma of the vulva is reported. The lesion was atypical in its large size and gross morphology, therefore making clinical diagnosis difficult. Diagnosis of this lesion is often delayed because of its varied clinical appearance. The importance of adequate biopsy and careful pathological evaluation of vulvar lesions is stressed. Differentiation from metatypical or basosquamous cell carcinoma is discussed, and proper therapy is reviewed.

Morbidity of lymph node sampling in cancers of the uterine corpus and cervix.

To assess the morbidity of lymph node sampling, medical records were reviewed for all patients with cancers of the uterine corpus and cervix who underwent primary surgical therapy between January 1, 1980 and December 31, 1986. Five hundred fifty-four patients were identified. Of the 292 patients with corpus cancer undergoing total abdominal hysterectomy, lymph node sampling was performed in 65.4%. Operative blood loss, transfusion requirements, and length of hospital stay were not increased significantly (P greater than .05) in women having node sampling. Of the 262 patients with cervical cancer, 72 underwent abdominal hysterectomy, 111 underwent radical hysterectomy, and 79 underwent staging laparotomy, with lymph node sampling performed in 82, 100, and 92% of these groups, respectively. The incidence of perioperative complications in this group was similar to that in the corpus cancer group. Vascular injuries, hematomas, and lymphocysts were more frequent after lymph node sampling. One postoperative death was attributed to complications from node sampling, but there were no other long-term sequelae. The low overall risk associated with lymph node sampling supports its inclusion in the surgical evaluation of gynecologic malignancies.

Introital stenosis requiring pelvic resection and soft tissue reconstruction.

BACKGROUND: Introital stenosis from both bony and soft tissue contracture is an unusual clinical problem not well addressed in the literature. CASE: A woman with a history of pelvic irradiation at age 1 for malignancy presented with severe introital stenosis unresponsive to conservative topical and dilatational therapy. She ultimately required staged bony resection of her infantile pelvis and soft tissue reconstruction to reestablish her introital aperture to an adequate and functional size. CONCLUSION: Introital stenosis from childhood requires a different treatment because development of the pelvis may not have been normal, and bony narrowing may exist in conjunction with soft tissue contracture. A staged multispecialty approach is recommended to treat this interesting variant of introital stenosis.

Radical hysterectomy with or without preoperative radium for stage IB squamous cell carcinoma of the cervix.

A retrospective study of 119 patients ranging from 30 to 69 years of age was undertaken to evaluate the effectiveness of preoperative radium treatment for patients with Stage IB (FIGO 1971) squamous cell carcinoma of the cervix undergoing radical hysterectomy. Results in 61 patients who had radical hysterectomy without preoperative radium treatment were compared to those in 58 patients who had received radium preoperatively. The patients receiving radium systems had an uncorrected 5-year survival rate of 89.7%, while the patients without preoperative radium treatment had a 75.1% 5-year rate of survival. This difference in survival rate was judged to be secondary to the greater incidence of lymphatic invasion and residual tumor in the surgical specimens of the patients who did not receive preoperative radium. The occurrence of significant gastrointestinal and urinary tract complications was identical in the 2 groups.

Stage II carcinoma of the endometrium. An analysis of treatment.

An analysis of 41 patients with histologically documented Stage II adenocarcinoma of the endometrium treated between 1969 and 1974 is presented. The 3-year survival for all patients was 46%. Patients treated with radiation therapy alone (tandem, ovoids, and external radiation therapy) had 29% survival while patients treated with radiation therapy and surgery had a 71% survival. For all patients, survival by grade was 80% (Grade I), 36% (Grade II), and 20% (Grade III). Among those patients with recurrent disease, 40% of cases were in the pelvis while 20% were isolated distal recurrences. Patients with stromal invasion of the cervix had a 30% survival while patients without stromal invasion had a 67% survival. An analysis of these data, along with a review of the literature, reveals that 1) hysterectomy plays a critical role in survival, 2) invasion of the cervical stroma would appear to be a requisite criteria for the establishment of Stage II disease, and 3) aggressive radiation therapy with uterine packings (Heyman capsules) should be attempted in those patients who are not surgical candidates.

Cryosurgical treatment of early cervical intraepithelial neoplasia.

Two hundred forty patients, ages 12 to 54 years, with biopsy-confirmed early cervical intraepithelial neoplasia (CIN I) treated by cryosurgery were reviewed. CIN I has been viewed historically as having high rates of remission or stabilization. The initial cure rate was 89%, with a 97% cure rate after retreatment of failures. All failures were confirmed histologically. The initial cure rates are no better than those for higher grades of CIN. Thus, CIN I should be viewed with the same seriousness as CIN II or CIN III.

Intestinal anastomoses after radiation therapy by surgical stapling instruments.

The use of automated stapling instruments in 17 patients requiring intestinal surgery following irradiation therapy for gynecologic malignancies has been reviewed. Fifteen of these patients also had other medical problems thought to inhibit optimal anastomotic healing: malnutrition, persistent intraabdominal cancer, uremia, hypoalbuminemia, and recent antineoplastic chemotherapy. Although these conditions severely test a method of intestinal anastomosis, no patient had a complication involving the intestinal anastomosis. The use of these stapling instruments reduced both the operating time and the contamination of the peritoneal surfaces by bowel content, thereby improving the postoperative recovery of these patients. The favorable results and the secure anastomoses justify the continued use of stapling instruments in gynecologic oncology patients with prior irradiation therapy.

Steroid receptors in endolymphatic stromal myosis.

Endolymphatic stromal myosis is a neoplasm derived from the endometrial stromal cell. As such it should respond to hormonal manipulation. Reported are positive estrogen and progesterone cytosol receptors in three cases of endolymphatic stromal myosis with disease regression following progestational therapy. Estrogen and progesterone receptor studies are recommended in all cases of endolymphatic stromal myosis. When positive, progestational therapy is appropriate.