Chemotherapy with cisplatin and paclitaxel in locally advanced cervical cancer: has this regimen still a role as neoadjuvant setting?

AIM: Neoadjuvant chemotherapy represents a promising alternative to concomitant chemo-radiation therapy in locally advanced cervical cancer patients. The aim of this study was the evaluation of pathologic response rates, toxicity and predictors of response in locally advanced cervical cancer patients treated with neoadjuvant cisplatin and paclitaxel followed by radical surgery. METHODS: Fourteen patients with stage IB2 to IIB cervical cancer received three cycles of cisplatin 75 mg/m2 and paclitaxel 175 mg/m2 intravenously every three weeks followed by radical hysterectomy and bilateral pelvic lymphadenectomy. Toxicity, pathologic response and predictors of response were evaluated. RESULTS: Chemotherapy related toxicities we-re as follows: alopecia 100%, asthenia 35.7%; nausea and vomiting 14.3%; paclitaxel hypersensitivity 7.1%, neutropenia 7.1%. Optimal, partial and no pathologic response was achieved in 21.4%, 64.3% and 14.2% of the patients, respectively. Based on lack of pathologic risk factors, 43% of the patients did not receive any adjuvant radiotherapy. Better response rates were obtained in patients with stage IIB, tumor diameter <5 cm, Hb >12 g/dL and SCC antigen <1.5 mg/dL. None of these variables reached statistical significance. CONCLUSION: Neoadjuvant chemotherapy with cisplatin and paclitaxel in locally advanced cervical cancer appeared to be well-tolerated. Even though the TIP regimen has been shown to be more effective than the TP regimen in randomized controlled prospective trial, the TP regimen remains a reasonable alternative in those patients in whom the TIP regimen is considered or shown to be too toxic.

Norethisterone acetate in the treatment of colorectal endometriosis: a pilot study.

BACKGROUND: This pilot study evaluates the efficacy of norethisterone acetate in treating pain and gastrointestinal symptoms of women with colorectal endometriosis. METHODS: This prospective study included 40 women with colorectal endometriosis, who had pain and gastrointestinal symptoms. Patients received norethisterone acetate (2.5 mg/day) for 12 months; in case of breakthrough bleeding, the dose of norethisterone acetate was increased by 2.5 mg/day. The degree of patient satisfaction with treatment (primary end-point) and the changes in symptoms (secondary end-point) were evaluated. Side effects of treatment were recorded. RESULTS: Norethisterone acetate determined a significant improvement in the intensity of chronic pelvic pain, deep dyspareunia, dyschezia. Treatment determined the disappearance of symptoms related to the menstrual cycle (dysmenorrhea, constipation during the menstrual cycle, diarrhoea during the menstrual cycle and cyclical rectal bleeding). The severity of diarrhoea, intestinal cramping and passage of mucus significantly improved during treatment. On the contrary, the administration of norethisterone acetate did not determine a significant effect on constipation, abdominal bloating and feeling of incomplete evacuation after bowel movements. At the completion of treatment, 57% of the patients with diarrhoea or diarrhoea during the menstrual cycle continued the treatment with norethisterone acetate compared with 17% of the patients with constipation or constipation during the menstrual cycle. CONCLUSIONS: In some patients with bowel endometriosis, the administration of norethisterone acetate may determine a relief of pain and gastrointestinal symptoms. This therapy has greater benefits in patients with gastrointestinal symptoms related to the menstrual cycle, diarrhoea and intestinal cramping.

Letrozole combined with norethisterone acetate compared with norethisterone acetate alone in the treatment of pain symptoms caused by endometriosis.

BACKGROUND: The available data on effectiveness of aromatase inhibitors in treating pain symptoms related to endometriosis is limited. We compared the efficacy and tolerability of the aromatase inhibitor letrozole combined with norethisterone acetate versus norethisterone acetate alone in treating pain symptoms. METHODS: This prospective, open-label, non-randomized trial included 82 women with pain symptoms caused by rectovaginal endometriosis. Patients received either a combination of letrozole and norethisterone acetate (group L) or norethisterone acetate alone (group N) for 6 months. Changes in pain symptoms during treatment and in the 12 months of follow-up were evaluated. Side effects of each treatment protocol were recorded. RESULTS: Intensity of chronic pelvic pain and deep dyspareunia significantly decreased during treatment (P < 0.001 versus baseline by 3 months) in both study groups. At both 3- and 6-month assessment, the intensity of chronic pelvic pain (P < 0.001, P = 0.002, respectively) and deep dyspareunia (P < 0.001, P = 0.005, respectively) was significantly lower in group L than group N. At completion of treatment, 63.4% of women in group N were satisfied with treatment compared with 56.1% in group L (P = 0.49). Pain symptoms recurred after the completion of treatment; at 6-month follow-up no difference was observed in the intensity of pain symptoms between the groups. Adverse effects were more frequent in group L than in group N (P = 0.02). CONCLUSIONS: The combination drug regimen was more effective in reducing pain and deep dyspareunia than norethisterone acetate; however, letrozole caused a higher incidence of adverse effects, cost more and did not improve patients' satisfaction or influence recurrence of pain.

Does transvaginal ultrasonography combined with water-contrast in the rectum aid in the diagnosis of rectovaginal endometriosis infiltrating the bowel?

BACKGROUND: The aim of this study was to determine whether adding water-contrast in the rectum during transvaginal ultrasonography (RWC-TVS) improves the diagnosis of rectal infiltration in women with rectovaginal endometriosis. METHODS: This prospective study included 90 women, with suspect rectovaginal endometriosis, who underwent operative laparoscopy. TVS and RWC-TVS were independently performed by different investigators. RWC-TVS was performed by injecting saline solution into the rectal lumen under ultrasonographic control through a 6-mm catheter. Presence of rectovaginal nodules, presence and degree of rectal infiltration, and the largest diameter of the bowel nodules were evaluated. Ultrasonographic results were compared to surgical and histological findings. RESULTS: Although RWC-TVS had higher accuracy than TVS in diagnosing rectovaginal endometriosis, the difference between the two techniques was not statistically significant. RWC-TVS was significantly more accurate than TVS in determining the presence of endometriotic infiltration reaching at least the muscular layer of the rectal wall. The sensitivity of RWC-TVS in identifying rectal lesions was 97%, the specificity 100%, the positive predictive value 100% and the negative predictive value 91.3%. RWC-TVS caused a higher intensity of pain than TVS. CONCLUSIONS: RWC-TVS determines the presence of rectovaginal nodules infiltrating the rectal muscularis propria more accurately than TVS; RWC-TVS could be used when TVS cannot exclude the presence of rectal infiltration.

A new technique for surgical treatment of stress urinary incontinence: the TVT-secur.

AIM: The aim of this pilot study was to evaluate the surgical feasibility of a new device for the treatment of stress urinary incontinence, named tension-free vaginal tape (TVT)-secur. Fifteen patients underwent the TVT-secur procedure. METHODS: The mean operation time was 13 minutes (range, 7-21). There was no intraoperative complication. Duration of surgery was shorter in the second half of cases than in the first eight procedures. RESULTS: The number of technical difficulties experienced by the surgeon was significantly higher in the first 8 procedures than in the following 7 cases; these difficulties included bleeding reducing the identification of anatomical structures, dislocation or removal of the mesh tape during the removal of the inserter, need to repeat the procedure. The cure rate, determined by urodynamic study, was 80% at 3 months follow-up. The cought test was negative in 86.7% of women at 6 months follow-up. CONCLUSION: The implantation of the TVT-secur is simple, safe, and minimally invasive with a short learning curve.

Efficacy on menopausal neurovegetative symptoms and some plasma lipids blood levels of an herbal product containing isoflavones and other plant extracts.

OBJECTIVES: To assess the efficacy of a product containing isoflavones and other plant extracts (BIO) on whole menopausal symptomatology and plasma lipids profile. METHODS: Multicentre, randomized, double blind, placebo controlled clinical investigation on 125 menopausal women randomly assigned to two groups treated for 6 months with placebo or one tablet daily of an herbal product containing 72 mg/dose of isoflavones of different plants origin and other plant extracts (BIO). Primary end-point: Kupperman Menopause Index (KI) variations; secondary end-point: activity on plasma lipids profile and clinical global impression (CGI) on efficacy and tolerability by investigators and patients. The usual parametric test (paired Student t test) was performed to evaluate the significance. In case of non-applicability of parametric tests, the non-parametric Mann-Whitney U test was used. The differences where considered significant at p<0.05 level. RESULTS: At the end of treatment in both groups KI showed a significant decrease (p<0.001). However, in the BIO group the KI reduction was significantly higher (p=0.0265) than in the placebo group after 4 and 6 months of treatment. In the BIO treated patients the LDL cholesterol showed a borderline but not significant reduction compared to placebo (p=0.0608) and triglyceride (TG) a significant (p=0.0151) decrease compared to placebo. The investigator's and patient's CGI on BIO group where superior as compared to placebo. Clinical tolerability was good in booth groups. CONCLUSION: On the basis of positive effects on KI and lipids profile as well as of good clinical tolerability, BIO can be considered one of the possible alternative therapy for conventional HRT.

Hydrothorax following ovarian hyperstimulation for assisted reproduction. Case report and review of the literature.

In case of ovarian hyperstimulation syndrome, the high incidence of dyspnea in relation with ascites and enlarged ovaries should not justify omission of thoracic evaluation. This manuscript reviews the pathogenesis and clinical presentation of hydrothorax following controlled ovarian hyperstimulation. In addition, we describe the case of a 33-year-old woman with a right massive hydrothorax resulting from controlled ovarian hyperstimulation for intracytoplasmic sperm injection.

The risk of premalignant and malignant pathology in endometrial polyps: should every polyp be resected?

AIM: There is no wide consensus in the literature on the clinical significance and management of symptomatic and asymptomatic polyps. Aims of the study are to evaluate frequency of premalignant and malignant histo-pathologic features in endometrial polyps resected hysteroscopically and identify clinical parameters able to predict final histopathologic diagnosis. METHODS: Clinical data and pathologic report of 90 consecutive operative hysteroscopies performed on women with endometrial polyps were collected. Frequency of premalignant and malignant histopathologic features on the polyps were calculated and relation to clinical risk factors analyzed. RESULTS: The frequency of premalignant and malignant histopathologic features in polyps was 6.7% and 2.2% respectively. Owing to the small sample size no statistical analysis to detect clinical risk factor for premalignant or malignant histopathologic features could be performed. CONCLUSION: Frequency of premalignant and malignant histopathologic features in symptomatic and asymptomatic patients is not negligible. Reported clinical risk factors for malignant degeneration of endometrial polypoid lesions are the same as those reported for endometrial cancer and are very common in patients with endometrial polyps. Every endometrial polyp should be resected.

Antiangiogenic therapies in endometriosis.

Oral contraceptives, androgenic agents, progestins and gonadotropin-releasing hormone analogues have all been successfully used in the treatment of endometriosis. However, none of these drugs can eradicate the disease. It is widely accepted that the growth of newly formed blood vessels is essential for the establishment and growth of endometriotic lesions; therefore, inhibition of angiogenesis may offer a new option for treatment of this disorder. In this paper, we reviewed anti-vascular endothelial growth factor agents and other angiostatic drugs (i.e., TNP470, endostatin, anginex, rapamycin) that have been studied in laboratory and animal models of endometriosis. Although preliminary results are interesting, further investigations are required before clinical trials can be planned in humans.

High-dose versus low-dose cisplatin in combination with cyclophosphamide and epidoxorubicin in suboptimal ovarian cancer: a randomized study of the Gruppo Oncologico Nord-Ovest.

PURPOSE: The aim of the study was to compare high-versus low-dose cisplatin in combination with cyclophosphamide and epidoxorubicin as primary chemotherapy for suboptimal stage III and IV ovarian cancer. PATIENTS AND METHODS: One hundred forty-five patients were randomized to receive six courses of cisplatin 50 or 100 mg/m2 plus epidoxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2. The two treatment arms were well balanced; all patients had greater than 2 cm and 37.2% had greater than 5 cm of residual disease; 29.6% had stage IV disease. RESULTS: Patients in the high-dose arm received a double dose-intensity and double total dose of cisplatin. The high-dose regimen induced significantly more episodes of leukopenia (47.8% v 32.8%, P = .05), thrombocytopenia (21.7% v 3.2%, P = .003), anemia (37.6% v 12.5%, P = .002), nephrotoxicity (six v one patient), and neurotoxicity (30.4% v 6.3%, P = .002). There were no significant differences in efficacy in terms of clinical response rate (high-dose 57.5% v low-dose 61.1%), pathologic complete response (CR) (9.6% v 18.1%), median survival times (29 v 24 months), and median progression-free survival (18 v 13 months). CONCLUSION: This study shows that doubling the dose-intensity and total dose of cisplatin in combination with epidoxorubicin and cyclophosphamide has significant toxic effects and does not improve clinical outcome in patients with suboptimal ovarian cancer.

Increased cyclin D1 expression is associated with features of malignancy and disease recurrence in ovarian tumors.

Alterations in the expression of cyclin D1 have been reported frequently in several human cancers, but their significance in the multistep model of carcinogenesis has been scantly described. To define the pattern of cyclin D1 expression in the development of ovarian cancer and clinical outcome, 55 cases of benign ovarian tumors, 12 borderline cases, and 37 ovarian carcinomas (32 primary and 5 recurrent carcinomas) were studied. Analyses were carried out on fresh tumor specimens by Western blotting and reverse transcription-PCR and provided significant superimposable results (P = 0.00001). Cyclin D1 abundance was classed according to the densitometric values as undetectable, detectable, well detectable, and highly detectable. A significant increase (P < 0.000001) in median cyclin D1 values was observed from benign (0.038; range, 0.001-0.705) to borderline (0.226; range, 0.001-0.623) to malignant (0.347; range, 0.027-2.330) to recurrent (0.887; range, 0.309-2.2260) tumors. In addition, higher median cyclin D1 values were reported in serous carcinomas (P = 0.058) and advanced-stage diseases (P = 0.003). Survival analyses carried out in the 32 primary carcinomas showed no significant difference in overall survival between detectable versus well/highly detectable cyclin D1 neoplasms. Conversely, a significant relationship between cyclin D1 expression and progression-free survival was found (P = 0.031). These results may elucidate the function of altered cyclin D1 expression in ovarian tumorigenesis and provide a basis for additional studies on its prognostic role.

Cytological analysis of the distension fluid used during diagnostic office hysteroscopies in patients with suspected endometrial pathology.

OBJECTIVE: Evaluation of the feasibility and usefulness of cytological analysis of the distension fluid used during diagnostic office hysteroscopy in patients with suspected endometrial pathology. METHODS: In 243 consecutive patients undergoing diagnostic hysteroscopy for suspected endometrial pathology a few milliliters of the distension medium used for uterine visualization were collected and sent for cytological analysis. Findings of these "endometrial washings" were compared to visual hysteroscopic impression, endometrial biopsy and uterine histology--when available. RESULTS: Endometrial washings were considered adequate in 227 patients (93.4%). In 12 cases (5.3%) atypical cells were detected: all of these presented either atypical complex hyperplasia or endometrial cancer at the final histological evaluation of the uterus. Four of the 16 (25%) patients diagnosed with endometrial cancer or atypical complex hyperplasia at the final histopathological analysis of the uterus had inadequate washings. No patient with cancer or atypical hyperplasia had negative cytology. CONCLUSIONS: Collection and analysis of the distension fluid is feasible and, when positive, has a remarkable value in the diagnosis of endometrial cancer and its precursors.

Tumour kinetics, response to chemotherapy and survival in primary ovarian cancer.

The analysis of thymidine labelling index (TLI) in relation to clinico-pathological variables and survival was carried out in 111 ovarian cancer patients. The significance of TLI in predicting response to aggressive first line chemotherapy regimens was examined. The overall median TLI value of 1.8% was used as a cut-off to discriminate slowly from highly proliferating cancers. 94 patients entered into two consecutive randomised trials, and were treated with six courses of cisplatin-based chemotherapy with or without doxorubicin. A significantly higher objective response of 60% was reported in the subset of patients with TLI > 1.8% as compared to 35% in patients with TLI < or = 1.8% (P = 0.03). In addition, patients achieving complete response had tumours with median TLI of 3.8% as compared to 2.4% for partial responders, 1.5% for patients with stable disease and 1.7% for those with progressive disease. A significant increase in tumour kinetics was observed in advanced cancers (P = 0.001), more undifferentiated tumours (P = 0.02) and postsurgical residual disease greater than 2 cm (P = 0.04). In univariate analysis, TLI failed to influence significantly clinical outcome: 26 versus 32 months median survival time for patients with high and low tumour TLI, respectively. In the Cox's regression model, the only independent prognostic variables were performance status and amount of residual disease after primary surgery (P = 0.000).

Prediction of survival by thymidine labelling index in patients with resistant ovarian carcinoma.

The relationship between tumour proliferative activity, evaluated by thymidine labelling index (TLI), clinicopathological variables and clinical outcome, was analysed in a series of 64 chemotherapy-resistant, ovarian cancer patients. The median TLI of 4.6% (range 0.01-45.7) was used as the cut-off to discriminate rapidly from slowly proliferating tumours. Univariate analyses showed a significant advantage in survival for patients with TLI less than or equal to 4.6 (P = 0.0004), ECOG performance status less than or equal to 1 (P = 0.0001) and residual disease after primary surgery less than or equal to 2 cm (P = 0.019). Multivariate analysis demonstrated that performance status was the only independent prognostic variable, although TLI was the last covariate removed from the Cox's regression model.

Adjuvant cisplatin-based chemotherapy for stage I and II ovarian cancer: a 7-year experience.

87 patients with high risk of recurrence FIGO stage I and II ovarian carcinoma were treated with adjuvant chemotherapy consisting of cisplatin 50 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1 every 28 days for 6 courses. Toxicity and efficacy of the regimen was evaluated after a median follow-up of 45 months. Treatment-related toxicity was mild and reversible, consisting chiefly of acute WHO grade 2 myelosuppression (10% of patients) and controllable grade 3 emesis (55%). No late toxicity was observed. Actuarial 7-year survival and relapse-free survival (RFS) were 76% and 61%, respectively; a statistically significant difference in outcome was observed for undifferentiated grade tumour (G1 vs. G2 vs. G3: P less than 0.01) but not for FIGO stage disease (stage I vs. stage II). In our opinion, short-term chemotherapy including the most active single agent, i.e. cisplatin, appears a tolerable and effective treatment which deserves further evaluation in large randomised trials.

Application of nonparametric procedure for bioassay data to the evaluation of analgesics in man.

Parametric tests for bioassay data are commonly applied to scores of pain intensity and relief for the assessment of potency ratios of analgesic drugs. It has been demonstrated, however, that scores derived from semiquantitative scales often deviate from normal distribution. In addition, when scores decrease as a consequence of analgesic treatment, the variances may be nonhomogenous. Both parametric and nonparametric procedures have been employed in this study for the evaluation of results of a double-blind multicenter trial of the analgesic effect of indoprofen and ASA (both drugs at three dose levels) and placebo in episiotomy pain. There was a good agreement between potency ratios obtained with the two assays. Peak PID appeared a less efficient means of estimating potency ratio than other measurements such as SPID and TOTPAR. The nonparametric test for quantitative bioassay appears to be a valid statistical procedure for evaluating results of clinical trials, and it does not imply any assumptions as to the type of distribution of the data.

Clinical study of mezlocillin for the treatment and prevention of postoperative obstetric and gynecological infections.

Twenty-one women were given mezlocillin for the treatment or prevention of infections after obstetric and gynecological surgery. Ten women had active infections caused by Escherichia coli, Klebsiella species, Proteus mirabilis, Pseudomonas aeruginosa, or Streptococcus faecalis. They had a 90% rate of recovery after an average of seven days of treatment with 6 to 15 gm/day of mezlocillin. The other 11 women were given mezlocillin prophylactically, 2 gm every 12 hours for seven days. All had good postoperative courses without complications caused by infections. Among both groups only three adverse reactions occurred, two instances of rash and one case of moderate diarrhea. All resolved spontaneously without discontinuation of treatment.

Comparison of mezlocillin and carbenicillin as therapy for various infectious diseases.

The efficacy and safety of mezlocillin, a new broad-spectrum semisynthetic penicillin, were compared with those of carbenicillin in a nonblind, controlled clinical study in 89 adult patients. The infections treated were primarily those of the urinary tract, skin, and gastrointestinal or hepatobiliary tract. Escherichia coli, Proteus mirabilis, Proteus morganii, and Pseudomonas aeruginosa were the causative organisms isolated most frequently. A complete resolution of signs and symptoms was achieved in 78% of the mezlocillin patients and in 71% of the carbenicillin patients. In the mezlocillin group, causative organisms were eliminated in 80% of the courses, and in the carbenicillin group the elimination rate was 86%. Two adverse reactions, rash and diarrhea, were reported in mezlocillin-treated patients; none were reported for the carbenicillin group.

Growth hormone response to clonidine in anovulatory infertile women resistant to clomiphene citrate stimulation.

OBJECTIVE: To evaluate the GH response to the clonidine test in a group of infertile women and to determine their ovulatory response to clomiphene citrate (CC) stimulation. DESIGN: Prospective study. SETTING: Reproductive endocrinology unit. PATIENT(S): Thirty-three anovulatory infertile women (age range, 25-36 years) and 9 healthy controls with normal ovulation. INTERVENTION(S): In the early follicular phase, 0.3 mg of clonidine was administered between 8:30 and 9:00 A.M. and blood samples were collected for 120 minutes thereafter for measurement of serum GH levels. Plasma levels of insulin and glucose were measured after a 75-g glucose load, and CC was given at a dosage of 50-250 mg/d for ovulation-induction. MAIN OUTCOME MEASURE(S): Serum concentrations of GH, insulin-like growth factor I, insulin, and insulin-like growth factor binding protein-1. RESULT(S): On the basis of their ovulatory response to CC, 15 patients were considered nonresponsive (group 1) and 18 patients were considered responsive (group 2). Baseline levels of GH, insulin-like growth factor I, and insulin-like growth factor binding protein-1 were similar in the two groups of patients and the controls. The GH response to clonidine was significantly greater in group 2 and in the controls than in group 1. Concentrations of insulin and glucose after the glucose load were not different among the three groups. CONCLUSION(S): Women who were resistant to CC had a reduced GH response to clonidine. These data suggest that adequate GH secretory capacity is important for CC action.

Role of major histocompatibility complex class I expression and natural killer-like T cells in the genetic control of endometriosis.

OBJECTIVE: To evaluate whether the expression of human leukocyte antigen (HLA) class I on eutopic and ectopic endometrial cells modify the susceptibility to lysis mediated by lymphocytes. DESIGN: Evaluation of T lymphocyte cytotoxic activity and HLA class I expression on endometrial cells. SETTING: Subjects were recruited at laparoscopy. PATIENTS: Patients with endometriosis (n = 7). Healthy women as controls (n = 10). MAIN OUTCOME MEASURES: Human leukocyte antigen class I molecule analysis of endometrial cells was carried out by immunofluorescence and flow cytometry. Phenotyping of T lymphocytes was performed to analyze T-cell subsets. Cytotoxicity was performed to determine cytolytic activity against endometrial cells. RESULTS: In vitro culture of endometrial cells down-regulates the expression of HLA class I molecules and enhances the susceptibility to lysis mediated by natural killer (NK)-like T lymphocytes. Cytolytic T-cell clones, expressing the CD94 antigen, are inhibited by the HLA-B7 allele on endometrial cells. Ectopic endometrial cells modulate the expression of HLA class I molecules. CONCLUSIONS: The resistance to lysis of endometrial cells is related to expression of surface HLA class I molecules, which send a negative signal for lysis mediated by NK-like T lymphocytes. The HLA-B7 allele inhibits the cytotoxic activity, suggesting that the growth of ectopic endometrial cells might be under a genetic control.