Maintenance therapy of patients with recurrent epithelial ovarian carcinoma with the anti-tumor-associated-mucin-1 antibody gatipotuzumab: results from a double-blind, placebo-controlled, randomized, phase II study.

BACKGROUND: Gatipotuzumab is a humanized monoclonal antibody recognizing the carbohydrate-induced epitope of the tumor-associated mucin-1 (TA-MUC1). This study aimed to evaluate the efficacy and safety of switch maintenance therapy with gatipotuzumab in patients with TA-MUC1-positive recurrent ovarian, fallopian tube, or primary high-grade serous peritoneal cancer. PATIENTS AND METHODS: In this double-blind, randomized, placebo-controlled, phase II trial, patients with at least stable disease (SD) following chemotherapy were randomized 2:1 to receive intravenous gatipotuzumab (500 mg followed by 1700 mg 1 week later) or placebo every 3 weeks until tumor progression or unacceptable toxicity occurred. Stratification factors were the number of prior chemotherapy lines (2 versus 3-5), response versus SD after the most recent chemotherapy, and progression-free survival (PFS) <6 versus 6-12 months following the prior therapy. Primary endpoint was PFS according to modified immune-related RECIST 1.1 response criteria. Secondary endpoints were PFS at 6 months, safety, overall response rate, CA-125 progression, overall survival, quality of life, and pharmacokinetics. RESULTS: Overall, 216 patients were randomized to gatipotuzumab (n  = 151) or placebo (n  = 65). Median PFS with gatipotuzumab was 3.5 months as compared with 3.5 months with placebo (hazard ratio 0.96, 95% confidence interval 0.69-1.33, P  = 0.80). No advantage for gatipotuzumab over placebo was seen in the secondary efficacy endpoints or in any stratified subgroups. Gatipotuzumab was well tolerated, with mild to moderate infusion-related reactions being the most common adverse events. CONCLUSIONS: Gatipotuzumab switch maintenance therapy does not improve outcome in TA-MUC1-positive ovarian cancer patients. TRIAL REGISTRATION: ClinicalTrials.govNCT01899599; https://clinicaltrials.gov/ct2/show/NCT01899599.

Fertility of testicular cancer patients after anticancer treatment--experience of 11 years.

Testicular cancer affects men mostly in their reproductive age with a cure rate over 90%. Preserved fertility is one of the main concerns of the survivors. To further elucidate the question of fertility after anticancer treatment for testicular cancer, we performed a survey among patients who underwent sperm cryopreservation procedure in our department. A structured questionnaire was designed to collect data on demography, anticancer treatment, histological type of cancer, family planning intentions and fertility prior to and after treatment. During a period of 11 years 86 men underwent semen cryopreservation before starting chemo-or radiotherapy. Fifty-nine of them consented to participate in the study. The average length of follow up was 4.6 +/- 3.8 years. In case of 11.9% of the patients their banked sperm was used, which led to live birth in 57% of the couples. The partners of 6 patients became pregnant after in vitro fertilization (IVF) resulting in 4 live births and 2 miscarriages. The spontaneous pregnancy rate was 22%. Spontaneous pregnancy occurred in 13 partners resulting in 18 pregnancies followed by 12 live births, 2 artificial abortions and 4 miscarriages. We could not prove any association between preserved fertility and anticancer treatment or the histological type of the cancer. In conclusion, although spontaneous pregnancy rate is remarkably high after anticancer treatment for testicular cancer, the risk of infertility after receiving gonadotoxic treatment cannot be predicted. Cryopreservation is a safe and effective method to preserve fertility in these cases. As a result we strongly recommend discussing the advantages of semen cryopreservation with all patients awaiting treatment for testicular cancer.

Increased titer of anti-beta2-glycoprotein I IgG antibody among factor V Leiden carriers during oral contraceptive use.

The risk of thromboembolism during oral contraceptive (OC) use is increased among factor V Leiden (FVL) carriers compared to women with wild-type genotype of the gene for coagulation factor V (FV). The carrier frequency in the general population is too high for FVL alone to be responsible for the reported association. Additional risk factors may be required to explain the increased risk of thromboembolism of carriers during OC use. We conducted a case-control study to compare the titer of anti-beta2-glycoprotein I immunoglobulin G (IgG) and the frequency of elevated titer of IgG type anti-beta2-glycoprotein I antibody between FVL carriers and individuals with FV wild-type genotype with and without pill use. An asymptomatic population of 313 unrelated nonpregnant women were screened for FVL and for the presence of anti-beta2-glycoprotein I IgG antibody. Sixty-six women were FVL carriers and 247 had normal genotype. One-hundred and thirty-five women used OC at the time of screening and 178 did not. Among FVL carriers, OC pill users had a higher mean anti-beta2-glycoprotein I IgG titer than nonusers (9.2 SGU/mL vs. 4.7 SGU/mL, p = 0.0485). Among women with FV wild-type genotype, there was no significant difference in anti-beta2-glycoprotein I IgG titers between users and nonusers of OCs (6.4 SGU/mL and 6.0 SGU/mL, respectively; p = 0.7010). The odds of an elevated anti-beta2-glycoprotein I IgG titer during OC use in FVL heterozygous women was 2.41 (95% confidence interval: 0.79-7.39) relative to users with-type genotype. FVL may contribute to the development of elevated titer of IgG type anti-beta2-glycoprotein I antibody during OC use. The elevated titer of IgG type anti-beta2-glycoprotein I antibody may select women among FVL carriers during OC use with an increased risk of thromboembolism.

The role of preoperative brachytherapy as an adjunct to surgery and postoperative radiotherapy in the treatment of stage I endometrial carcinoma.

PURPOSE: Between 1978 and 1993, 817 cases of endometrial carcinoma were treated with simple hysterectomy with bilateral salpingo-oophorectomy. Five hundred and twenty-six cases had preoperative brachytherapy (Preo), and 291 cases underwent surgery without preoperative radiotherapy (Nopre). The aim of the study was to compare disease-free survival of the two groups. METHODS AND MATERIALS: Survival comparison of the two groups was controlled for postoperative treatment type, according to stage, histological type, degree of differentiation, depth of myometrial invasion and age. The life-table method was used for survival analysis. Cumulative disease-free survival probabilities were calculated as a function of the proportion of normal remaining life elapsed from the time of diagnosis. RESULTS: Five-year disease-free survival of patients with and without preoperative brachytherapy in stage IA, IB and IC was 93 and 93.6%, 93 and 94%, and 80 and 65%, respectively. In well differentiated tumors and poorly differentiated tumors, there was no difference in disease-free survival between patients with and without preoperative brachytherapy. Patients with moderately differentiated tumor treated with preoperative brachytherapy had significantly better disease-free survival than those without preoperative radiotherapy, however, this was confounded by uneven distribution of invasion depth. CONCLUSION: Preoperative brachytherapy plays a limited role in the treatment of early stage endometrial carcinoma.

Factor V Leiden as a risk factor for miscarriage and reduced fertility.

The Leiden mutation is a recent discovery. It is the main cause of inherited thrombophilia and has been found in 20-60% of deep vein thrombosis cases. More recently it has been found in a significant number of cases of obstetric complications attributable to placental thrombosis. Current patient management practice for dealing with the Leiden mutation is based mainly on information about deep vein thrombosis because there is little information on pregnancy complications. There are no prospective studies examining the risk of developing pregnancy complications for Leiden mutation carriers. The aim of this study is to do that by comparing the frequency of unfavourable pregnancy outcomes among carriers with those among controls. The number of women developing miscarriages, intrauterine deaths, or infertility problems among 128 Leiden mutation carriers was compared with the number among 461 controls. The risk of having at least one miscarriage or infertility problems was 1.5 times greater for Leiden mutation carriers than controls. This result was statistically significant (95% CI 1.2, 2.7). The risk of having at least two miscarriages or infertility problems was 2.5 times greater for Leiden mutation carriers than controls. This was also statistically significant (95% CI 1.2, 5.13).

Stage-related superoxide anion production of granulocytes of gynecologic cancer patients.

OBJECTIVE: To measure superoxide anion production of polymorphonuclear leukocytes (PMNLs) in 58 gynecologic cancer patients and compare to that of healthy controls. METHODS: PMNLs were separated from peripheral blood samples by Ficoll and subsequent Percoll gradient sedimentation. Baseline and phorbol-dibutyrate (100 nmol/l) stimulated superoxide anion production was measured spectrophotometrically as superoxide dismutase inhibitable reduction of ferricytochrome c (50 micromol/l) absorbance. Differences between the mean superoxide anion production of different patient groups and the control group were assessed by Student's t-test. RESULTS: The mean superoxide anion production of PMNLs of healthy controls was 1.855 nM/min/3 x 10(5) cells (SD=0.211 nM/min/3 x 10(5) cells). Superoxide anion production of gynecologic cancer patients and healthy controls varied in a wide range. PMNLs of patients had lower baseline and stimulated activity than those of healthy volunteers. The frequency of a mean superoxide production at least 2 x SD below the control showed a parallel increase with advancing stage. CONCLUSION: Granulocytes of gynecologic cancer patients have reduced capacity and inducibility of superoxide anion production already at an early stage of disease.

Single-cell measurement of superoxide anion and hydrogen peroxide production by human neutrophils with digital imaging fluorescence microscopy.

Besides flow cytometry, fluorescence microscopy combined with computerized image analysis offers an alternative tool for assessing phagocyte oxidant generation at the single-cell level. This technique provides an opportunity for the direct visualization of cells and simultaneous measurement of cellular fluorescence intensity. Thus, we developed a simple method for the quantitative evaluation of intracellular superoxide anion and hydrogen peroxide production with image cytometry by using hydroethidine and dihydrorhodamine 123 dyes, respectively. Human neutrophils stimulated with phorbol dibutyrate and labeled by these fluorogenic substrates showed intense, well recognizable red or green fluorescence. The intensity of signals from individual granulocytes of cytospin preparations were quantitatively measured in digitized images. There was a great heterogeneity in response to the stimulus within the granulocyte population as shown by the integrated fluorescence intensity values. In agreement with the results of parallel flow cytometric experiments, this simple image analysis performed on cells of cytospin preparations was able to detect the defects in the oxidative metabolism of neutrophils from patients with cervix carcinoma. We demonstrated that even minor alterations in superoxide anion/hydrogen peroxide generation can be detected by image cytometry as efficiently as by flow cytometry. This result validates imaging microscopy as an alternative to flow cytometry in such experiments. In addition, the image cytometric technique allows the observation of the kinetics of free radical production in individual cell under adherent conditions. Therefore, we carried out image analysis of the oxidative burst of neutrophils adherent to uncoated glass and fibronectin- and type IV collagen-coated surfaces in response to stimulation with phorbol dibutyrate or N-formyl-methionyl-leucyl-phenylalanine. We elaborated a calibration technique for the quantitative measurement of the ethidium bromide generation mediated by superoxide anion within individual adherent granulocytes. The ethidium bromide production varied between 0.48 and 1.17 amol/cell/min.

[Prevention of thromboembolic side effects of oral contraceptives: methodologic recommendations]. / Orális fogamzásgátlás thromboemboliás szövödményeinek megelözése: módszertani javaslat.

The authors analyse the incidence of thromboembolic complications during combined oral contraception. Among genetic factors predisposing to venous thrombosis and thromboembolic disease, they present, with the help of three case histories, the molecular biology of activated protein-C resistance, the newly discovered and most frequently implicated pathogenetic factor of inherited thrombophilia. Among 350 asymptomatic women requesting prescription for an oral contraceptive they found a 9.1% frequency of heterozygote Leiden-mutation carriers. For the prevention of a rare, however, almost always life-threatening complication the authors recommend activated protein C-resistance analysis to be carried out whenever an oral contraceptive is prescribed for the first time. Positive results will provide life-time aid in avoiding factors which increase the risk of thromboembolic disease. Negative results may help reducing the number of those who, risking an unwanted pregnancy, are hesitant to start on oral contraceptives for their implication in thromboembolic disease.

Contents of childbirth-related fear among couples wishing the partner's presence at delivery.

In order to explore the contents of childbirth-related fears, a survey was carried out among 216 pairs of prospective parents who opted for the presence of the partner at delivery. Each couple took part in a three-class parentcraft course during the third trimester. During the first antenatal class, couples were asked to fill in a questionnaire with inquiries about specific contents of fear they might have in relation to pregnancy, childbirth and relationship with their partner after childbirth. Each item of the questionnaire called for an answer from a five-grade scale of fear such as 'absolutely not', 'slightly', 'quite', 'quite strongly' and 'very much'. Their worries were ranked according to the weighted average of the frequency of positive answers. More than 80% of both men and women had some fears relating to childbirth. Women were most worried about, in order of significance, having a malformed or injured baby, assisted or operative delivery, being lonely in a strange environment, doing something wrong, and facing the uncertainties of how the delivery was going to happen. The wife having severe pain and suffering, operative delivery, fetal birth injuries, helplessness, powerlessness and the wife's death in childbirth were the most significant subjects of men's fears. Eighty per cent of women and 76% of men felt that the presence of the partner at delivery would have no adverse effect on their future personal relationship.

HPV- and node status in cervical cancer long-term results.

OBJECTIVE: To evaluate prognostic significance of HPV-status in cervical cancer and to compare that with the prognostic significance of lymph-node status. METHODS: Cervical cancer biopsy specimens from primaries and, in surgical cases, from pelvic lymph-nodes too were analysed for the presence of human papillomavirus type 16 DNA-sequences using PCR technique. The management of surgical cases with two exceptions included Wertheim's hysterectomy predominantly with preoperative local radiotherapy and also with postoperative local and external beam radiotherapy depending on the histology. Non-surgical cases were treated with combined local and external radiotherapy to pelvic fields. RESULTS: Patients have been followed up for an average of 37 months after treatment ranging between 0 and 102 months. The mean progression-free survival time of surgical and non-surgical cases were 43 and 28 months, respectively. Patients with HPV-16 positive biopsies from the cervical primary had an average progression-free survival of 37 months, the same as those with HPV-16 negative cervical biopsies. Those patients who were found to carry HPV-16 DNA in their surgically removed pelvic lymph-nodes had an average of 27 months progression-free survival. The mean progression-free survival among histologically node-positive and node-negative surgical cases were 23 and 42 months, respectively. The mean progression-free survival time of node-positive cases with HPV-16 positive cervical primary was 7.5 months while that of patients with HPV-16 negative cervical biopsy was 38 months. Among histologically node-negative patients, HPV-16 positive and negative cases had an average progression-free survival time of 38 and 46 months, respectively. CONCLUSIONS: Among those under investigation the most important factors to predict progression-free survival were surgically amenable disease, histologically negative pelvic lymph-nodes and HPV-16 negative cervical biopsies, though this latter one proved significant only among surgical cases.

[Prenatal diagnosis of fetal thrombocytopenia]. / Magzati thrombocytopenia születés elótti diagnózisa.

A case of maternal idiopathic thrombocytopenic purpura complicated by severe fetal thrombocytopenia is reported. Fetal thrombocytopenia was diagnosed by scalp blood-sampling during labour. With discussion of the relevant literature, the authors recommend the use of their method in thrombocytopenic patients in labour. In cases of fetal thrombocytopenia Caesarean section in recommended to prevent trauma and subsequent neonatal haemorrhagic complications.

Analysis of survival in stage Ib and IIa cervical cancer treated with or without preoperative local radiotherapy.

The impact of preoperative local radiotherapy on the survival of cervix carcinoma has been evaluated retrospectively in 324 Stage Ib and IIa cases treated between 1969 and 1986 at the University Department of Obstetrics and Gynaecology of Debrecen, Hungary. One hundred and ninety nine Stage Ib cases had radical hysterectomy, 132 of them following brachytherapy. Among 125 radically operated Stage IIa cases 95 had preoperative local radiotherapy. Stage-respective survival curves of patients treated by radical surgery with or without preoperative local radiotherapy were analysed by the life-table method. The use of preoperative radiotherapy was not reflected in better survival when compared to survival of patients without it. Results suggest that preoperative local radiotherapy has a limited role in the management of patients with Stage Ib and IIa cervix carcinoma.

Clinical and pathological evaluation of large loop diathermy excision of the transformation zone.

In order to make accurate diagnosis and to carry out treatment of cervical preneoplastic disease, large loop diathermy excision of the transformation zone was performed in 98 patients. The colposcopic assessment was indicated by abnormal smear or history of treatment for preneoplastic changes. The entire transformation zone could be excised in one piece in 90% of cases. Histological examination of the specimens confirmed dysplasia in 89% of patients and in 4 cases invasive cervical disease was revealed. The ectocervical and endocervical excision margins were free of dysplastic epithelium in 68% of cases. Compared to traditional cone biopsy, the new method is cheaper and more simple. Loop diathermy excision of the transformation zone can be performed in local anaesthesia as an out-patient procedure and there is no need for postoperative hospitalization. By reducing the number of general anesthesia, the workload in gynaecological theatres and by eliminating the need for postoperative hospital stay the method substantially contributes to the improvement of the hospital budget.

Cervical cancer in young women: a poorer prognosis?

OBJECTIVE: The existence of an aggressive form of cervical carcinoma affecting young women is studied by survival analysis of a large patient population. METHOD: Between 1969 and 1986, 1577 cases of cervical cancer were treated according to well-defined policies at the University Department of Obstetrics and Gynaecology in Debrecen, Hungary. Patients' records were reviewed to obtain data for survival analysis. Kaplan-Meier survival curves were generated for each stage and stratified for age. The log-rank test was used to compare the survival of younger and older patients at each stage. Multivariate analysis was performed to control for stage and treatment type when 5-year survival trends across four different age groups were examined. RESULTS: Comparison of survival of patients under 35 and over 35 years of age, and also those under 40 and over 40 years of age revealed no significant differences. Five-year survival across the < 30, 30-39, 40-49 and > or = 50 years age groups showed no significant trend. No differences in survival were revealed when the comparison was controlled for stage of disease and treatment type. CONCLUSION: Results suggest that cervical carcinoma in young women is not more aggressive than in other age groups.

Potential contribution of human papillomavirus testing to cervical cancer screening.

A prospective study was carried out to assess the clinical value of HPV DNA identification in terms of cases missed by either cytology or combined cytology and colposcopy screening methods, 231 exfoliative cytology specimens and forty-one cervical tissue samples were analysed for the presence of HPV 6, 11, 16 and 18 DNA sequences using filter in situ and Southern blot hybridisation methods, 36% of cytology specimens examined by filter in situ hybridisation method were found to carry HPV DNA sequence. Forty-nine (27%) out of 184 cases without cytological evidence of neoplasia had a positive HPV test. Simultaneous colposcopic examination of these patients showed no abnormality in 17 cases. The relevance of HPV investigations was based on the characteristic HPV prevalence in preneoplastic and normal cervical tissue samples. The results suggest that traditional cervical screening may be improved by simultaneous HPV testing. According to the presented data, only a very small portion of a random patient population can be expected to carry HPVs without cytologic or colposcopic abnormalities.

Clinical significance of amniotic fluid bacteriological cultures taken at caesarean section.

To predict postoperative infection after Caesarean section by bacteriological examination of amniotic fluid samples a prospective analysis was performed on amniotic fluid bacteriological results and infectious morbidity in 266 consecutive Caesarean sections. Culture and sensitivity results were analysed in relation to postoperative febrile complications and their antibiotic treatment. One hundred and twelve samples grew bacteria. There was a significantly higher frequency of postoperative pyrexial complications among those patients with a positive amniotic fluid culture (22.3% vs 14.2%). Eighty per cent of amniotic fluid samples with significant bacterial growth provided useful information when antibiotic treatment had been required. Routine amniotic fluid sampling for bacteriology at Caesarean section is of clinical value in the prediction and management of postoperative pyrexial complications.