Treatment of advanced gynecologic malignancies with intraarterial chemotherapy and accelerated fractionation radiation therapy: a preliminary report

The results of a pilot study employing the administration of intraarterial chemotherapy and accelerated fractionation radiotherapy for advanced gynecologic malignancies are reported. The protocol consisted of three treatment sessions every 3 to 4 weeks. Each session consisted of bilateral or unilateral catheterization of the hypogastric artery with the infusion of cisplatin 100 mg/m2 on Day 1 and 2-deoxy-5-fluorouridine (FUDR) 300 mg/m2 on Day 2. An accelerated fractionation schedule of external-beam radiation was begun on Day 1 consisting of 200 rads twice daily for 4 days (1600 rads per session). Eight patients entered the protocol, and seven completed external-beam radiotherapy. Five completed three intraarterial sessions, and three, two sessions. Five of seven evaluable patients had a complete local response. Local control was sustained fom 6 to 24 months in four patients. Complications included three sensorimotor neuropathies, one clinically insignificant catheter-related thrombosis, and three clinically significant radiation injuries. This multimodality treatment for locally advanced gynecologic tumors appears feasible with modification, and continued work exploring this approach is encouraged.     

Natural killer cell activity in patients with gynecologic malignancies: correlation with histologic grading and stage of disease.

Basal natural killer (NK) cell activity in peripheral blood lymphocytes (PBLs) of 29 patients with gynecologic malignancy and 10 healthy controls was performed using K 562 cell line. A significant decrease of NK cell activity was observed in patients with gynecologic malignancy (p = 0.003). The NK cell activity of patients with poorly differentiated tumor or with stage IV of disease was significantly reduced with respect to patients at any other lower grade or earlier stage. We conclude that in patients with gynecologic malignancies there is a decrease of basal NK cell activity of PBLs, which is more significant in cases of distant tumor dissemination or poorly differentiated tumor (p less than 0.001).     

Atypical presentations of carboplatin hypersensitivity reactions: characterization and management in patients with gynecologic malignancies

OBJECTIVES: Carboplatin skin testing (ST) can help identify patients with platinum hypersensitivity (PH), however, we have encountered patients who do not immediately test positive yet exhibit subtle or delayed allergy symptoms prior to PH. We describe the "atypical platinum reactions" (APH) of 14 patients and our experience with skin testing and desensitization. METHODS: Retrospective chart review was performed on carboplatin-treated patients. Patients with +ST, PH or APH were offered desensitization, and the number of successful additional treatments was recorded. RESULTS: A total of 73 ST were administered to patients receiving their >6th carboplatin cycle. 19 +ST and 10 PH with -ST were identified. 14 APH were identified including delayed +ST conversions and allergy symptoms. The median onset and duration of symptoms after treatment were 6 and 3.5 days respectively. 12 APH patients had ST on their next cycle, seven of which were immediately positive. ST was positive in 36% of those tested, resulting in a negative predictive value of 76%. The median number of carboplatin cycles received prior to ST conversion, PH or APH was eight. 29% of patients with a +ST, PH, or APH had a prior history of systemic allergic reaction to other medications or allergens. Desensitization and dose escalation were successful in 14/20 patients (70%) for an average of 1.9 cycles/patient. CONCLUSIONS: ST will not identify all patients with carboplatin-associated reactions. Careful questioning regarding symptoms in between chemotherapeutic cycles may identify patients who will benefit from desensitization, allowing continuation of treatment and prevention of life-threatening adverse events.     

Serum squamous cell carcinoma antigen levels in patients with invasive squamous vulvar and vaginal cancer: a preliminary report

Pretreatment serum squamous cell carcinoma antigen (SCC) levels were obtained in 12 patients with invasive vulvar and 5 patients with invasive vaginal squamous cancer. Only 4 of 12 (33%) patients with vulvar cancer and 1 of 5 (20%) patients with vaginal cancer, usually those with more advanced disease, had elevated serum SCC levels at the time of diagnosis.     

Serum levels of CA-125 in patients with endometriosis: a preliminary report

Seven out of 8 patients with endometriosis demonstrated levels of CA-125 antigen above 35 U/ml. None of 15 patients with other benign gynecologic diagnoses demonstrated elevated levels. This antigen has been proposed as a tumor marker for epithelial carcinoma and other gynecologic neoplasms. However, it cannot be used to differentiate clinically between cancer and endometriosis.     

Potassium and glucose concentrations in patients treated with oral tocolytic agents: a preliminary report

Fifteen patients referred to the Division of Maternal-Fetal Medicine with the diagnosis of cervical incompetence were placed in a study protocol where prophylactic oral beta mimetic agents were used in an attempt to prevent cervical dilatation between 20 and 36 weeks of gestation. Our study suggest that after the first week of therapy prolonged maternal oral tocolytic therapy has no significant effect on glucose or serum potassium levels and no deleterious effects on the immediate neonatal course.     

Human immunodeficiency virus testing in patients with invasive cervical carcinoma: a prospective trial of the gynecologic oncology group

To determine the frequency of positive human immunodeficiency virus (HIV) serostatus among North American women 50 years of age or younger with invasive cervical cancer and to define their tolerance to treatment. Consenting patients with newly diagnosed invasive cervical cancer, age 50 or younger were tested by enzyme-linked immunosorbent assay. The study design anticipated that approximately 3% of patients would be HIV positive. After the accrual of 913 eligible and evaluable patients, interim analysis revealed that only 9/913 ( approximately 1%) patients were HIV seropositive, indicating that it would not be feasible to achieve the study objective. The study was closed to further accrual. Between 1994 and 1997, the frequency of positive HIV serostatus among North American women with newly diagnosed cervical cancer was quite low. As a consequence, no evaluation of response to treatment or treatment tolerance can be made.     

Combination cisplatin and dichloromethotrexate in patients with advanced or recurrent cervical cancer: a preliminary report

The chemotherapy combination of cisplatin and dichloromethotrexate was administered to 14 patients with measurable cervical cancer. Six (46%) have had a complete response for 6+, 7, 11, 14, 15, and 21 months. Four (30%) have had a partial response for 1, 6, 10, and 11 months. Two patients (15%) have had stable disease for 6 and 11 months. Only one patient failed to respond to this combination. In six of these patients, the measurable mass was located in a previously radiated area. This combination was well tolerated with only three instances of severe toxicity. No irreversible renal dysfunction was seen in any patient.     

Amifostine pretreatment for protection against topotecan-induced hematologic toxicity: results of a multicenter phase III trial in patients with advanced gynecologic malignancies

OBJECTIVE: To determine if amifostine could reduce the hematologic toxicity associated with topotecan. METHODS: Thirty patients with recurrent/refractory gynecologic malignancies were randomized to receive topotecan (TOPO) (1.5 mg/m(2)/day days 1-5) with or without amifostine (AMI/TOPO) (500 mg/m(2)/day days 1-5) every 3 weeks for six cycles. The primary study endpoints were the incidence of grade 3 and 4 neutropenia. RESULTS: Fifteen patients were randomized to each arm for a total of 49 TOPO and 53 AMI/TOPO cycles. Patient characteristics and pretreatment ANC were similar between groups. Topotecan 1.5 mg/m(2)/day days 1-5 was initially administered to seven patients. Five developed neutropenic fevers, one an uncomplicated grade 4 neutropenia, and the other an uncomplicated grade 3 neutropenia. There were two treatment-related deaths due to sepsis (one in each treatment arm). The starting dose was thereafter reduced to 1.25 mg/m(2)/day days 1-5 every 21 days. No treatment related deaths occurred after this dose reduction. The incidence of combined grade 3/4 neutropenia was reduced from 67% (33/49 cycles) to 38% (20/53 cycles) with the addition of amifostine (P = 0.003; OR 0.29; 95% CI 0.12-0.71). CONCLUSIONS: Topotecan at 1.5 mg/m(2)/day days 1-5 in heavily pretreated patients resulted in excessive toxicity not manageable with amifostine. At the reduced topotecan dose (1.25 mg/m(2) x 5 days), pretreatment with amifostine reduced the hematologic toxicity associated with topotecan chemotherapy in women with recurrent/refractory gynecologic malignancies.     

Adriamycin and hydroxyurea as radiopotentiators in the treatment of squamous cell carcinoma of the cervix implanted in nude mice: A preliminary report

A tumor model using human squamous cell carcinoma of the cervix implanted in nude mice was developed. Hydroxyurea and Adriamycin were used as radiopotentiators. A regression delay was observed in tumors treated with radiation therapy alone and radiation therapy and Hydroxyurea. No regression delay was observed when the tumors were treated with radiation therapy and Adriamycin. Six weeks after treatment, 75% of the tumors treated with radiation therapy and Adriamycin were not palpable, while all the tumors were present in the group treated with radiation therapy alone and radiation therapy and Hydroxyurea. No difference in tumor response was noted between the group receiving radiation therapy alone and radiation therapy and Hydroxyurea. This preliminary observation shows obvious interaction between Adriamycin and radiation therapy, suggesting radiopotentiating activity. The tumor model was found useful and practical.     

In vivo expression and antitumor activity of p53 gene transfer with naked plasmid DNA in an ovarian cancer xenograft model in nude mice

INTRODUCTION: Abnormalities in the p53 and p16 tumor suppressor genes are one of the most common occurrences associated with human neoplasia. Consequently, restoration of wild-type p53 or p16 functions is seen as a particularly promising approach for cancer gene therapy. In vitro and in vivo data have demonstrated that virus-mediated p53 gene transfer can induce active cell death and ovarian tumor regression. AIM: To evaluate the efficiency of intratumoral injection of naked DNA in tumor growth inhibition in an ovarian xenograft model. For that purpose, plasmid vectors encoding wild-type p53 (wt-p53) or p16 alone or in combination were used. METHODS: Nude mice were injected subcutaneously with the human ovarian adenocarcinoma cell line SKOV3. Three weeks after xenograft, tumor-bearing mice were injected twice a week with plasmid vectors carrying WT-p53 and/or WT-p16 cDNA. Empty plasmids and saline buffer were used as control. Tumor growth was monitored to evaluate the inhibition potential with p53 and/or p16 restoration. RESULTS: When compared to the control, intratumoral repeated injections of naked plasmid DNA encoding wt-p53 were inhibiting tumor growth. This inhibition was not observed with p16 and no synergy could be obtained between p53 and p16. p53 expression was restored in 84% of mice injected with plasmid encoding wt-p53. p16 expression was restored in 63% of mice injected with plasmid encoding p16. CONCLUSIONS: In this report we demonstrated that: (i) naked DNA represents an efficient gene transfer in the SKOV3 xenograft model; (ii) restoration of wt-p53 gene allows tumor growth inhibition; and (iii) this inhibition could be correlated with p53 expression as seen in 84% of treated mice after repeated naked DNA injections. These results allow us to envisage naked DNA as a therapeutic adjuvant in ovarian cancer treatment, concomitantly with tumor resection and chemotherapy.     

Long-term effects of neovaginal reconstruction with sigmoid loop technique on sexual function and self image in patients with gynecologic malignancies: results of a prospective study

ObjectiveWe evaluated the long-term results of sigmoid vaginoplasty in women with gynecologic malignancies after radical pelvic surgery, with specific focus on safety and effects of the procedure on patients' sexuality and self image.MethodsThis prospective study included women with gynecologic malignancies who underwent partial or complete colpectomy as part of the cancer treatment. In all cases a pedicled sigmoid loop was used for the neovaginal reconstruction. Systematic clinical examination was performed and validated questionnaires about sexuality (Female Sexual Function Index), quality of life (SF-12) and susceptibility to depression (ADSk-15) were answered by all patients at the earliest 6 months after vaginoplasty.ResultsSeven patients with sigmoid vaginoplasty, recruited between 11/2003 and 02/2008, were evaluated in the present analysis. Mean patients age was 48 ± 8.49 years. Mean neovaginal length was 6.4 cm (range: 2–12 cm). The mean Female Sexual Function Index (FSFI)-score of all patients was 16.6 ± 12.6. In the subset of sexually active patients the mean FSFI-score was 22.5 ± 9.4 higher. Regarding early operative morbidity and complications, sigmoid vaginal reconstruction appears to be a safe procedure, though in a long-term assessment 85% of the patients developed a vaginal stenosis with the need for operative bougienage.ConclusionsThe vaginal reconstruction using a sigmoid loop is a safe and well accepted procedure in patients with gynecologic malignancies. However lower sexuality scores seem to be achieved than in non-cancer patients after equivalent vaginoplasty. Cancer-related physical and psychological comorbidity seem to have negative effects on the overall outcome and patient's satisfaction.     

Leydig and Sertoli cell function in normal and oligospermic males: a preliminary report.

Sertoli and Leydig cell function was evaluated in patients with oligospermia. Testicular biopsy specimens were incubated in vitro with follicle-stimulating hormone (FSH) or luteinizing hormone (LH), and the amount of cyclic adenosine 3':5'-monophosphate (cyclic AMP) generated was measured. Cyclic AMP has been shown to be intracellular mediator for the pituitary gonadotropins FSH and LH. The amount generated by the Sertoli cells response to FSH, and by the Leydig cells in response to LH, was contrasted with that in age-matched, normal control subjects. The Leydig cell response was similar in both groups. However, the amount of cyclic AMP generated by the Sertoli cells from oligospermic males was much less when compared with normal control subjects. This finding suggests a possible metabolic abnormality in the Sertoli cells of patients with oligospermia which might, in turn, alter spermatogenesis.     

Optimization of cryocycles by using pinopode detection in patients with multiple implantation failure: preliminary report

The aim of this study was to investigate pinopode formation patterns in patients with a history of multiple IVF failures and to evaluate if their detection with subsequent modification of protocols using frozen-thawed embryos could help to increase the pregnancy and live-birth rates in these patients. The study included 55 women with at least three implantation failures. On-time pinopodes were present in only 12.7% of cases, the rest showed acceleration, delay, arrest or asynchronization of pinopode formation. Patients with anomalies of pinopode development were divided into two subgroups, one of which had the standard protocol and the other a modified protocol, in which the duration of progesterone administration before embryo transfer was changed according to pinopode formation pattern. In nine patients with the modified protocol, with asynchronized and arrested pinopodes, simultaneous transfer of embryos of different ages was fulfilled. The implantation, pregnancy and take-home-baby rates for the modified and standard protocols were 28.0% versus 6.0%, 52.4% versus 12.0% and 47.6% versus 12.0%, respectively. Detection of inappropriately timed pinopode formation with subsequent synchronization of embryonic development and endometrial maturation allowed improvements in the effectiveness of programmes using frozen-thawed embryos in women with multiple implantation failure.     

Abdominal sacral colpopexy in patients with gynecologic cancer: report of 25 cases with long-term follow-up and literature review

OBJECTIVE: The aim of this study was to evaluate abdominal sacral colpopexy performed in conjunction with radical pelvic surgery for gynecologic cancer. METHODS: Over a 9-year period from 1990 to 1999 25 patients with invasive gynecologic cancer and concomitant uterovaginal or vaginal vault prolapse underwent surgery. These patients were compared to a series of 50 patients with no history of gynecologic cancer who underwent abdominal sacral colpopexy during the same period. RESULTS: All surgeries were performed without intraoperative complication. There was one failed vault suspension in each group and no postoperative mesh complications as a result of radical pelvic surgery or postoperative radiation or chemotherapy. CONCLUSION: Abdominal sacral colpopexy may be safely performed along with radical pelvic surgery for gynecologic cancer without an increase in intra- or postoperative morbidity even if patients require chemotherapy or radiation therapy after surgery.     

Cerebrospinal fluid levels of magnesium in patients with preeclampsia after treatment with intravenous magnesium sulfate: a preliminary report

The purpose of this study is twofold: (1) to correlate magnesium levels of serum with those of cerebrospinal fluid in patients with preeclampsia receiving intravenous magnesium sulfate, and (2) to determine whether the magnesium ion crosses the blood-brain barrier in significant amounts after intravenous magnesium sulfate therapy. Of the 21 patients in whom spinal anesthesia was used for delivery, ten patients with preeclampsia with therapeutic serum magnesium levels made up the study group and 11 term nontreated normotensive gravid women served as controls. At the time of spinal anesthesia, a 1 ml aliquot of cerebrospinal fluid was obtained from each patient. The mean cerebrospinal fluid magnesium level for the control group was 2.56 +/- 0.19 mg/dl (range 2.2 to 2.8 mg/dl). For the preeclamptic group who received intravenous magnesium sulfate, the mean cerebrospinal fluid magnesium level was 3.04 +/- 0.12 mg/dl (range 2.9 to 3.2 mg/dl). Although only a small amount of magnesium crosses the blood-brain barrier after intravenous magnesium sulfate treatment, this increment is highly significant (p less than 0.001).