Reconstruction of the vulva with sensate gluteal fold flaps.

BACKGROUND AND AIMS: Soft-tissue reconstruction of the vulva following resection of malignancies is challenging. The function of perineal organs should be preserved and the reconstructed area should maintain an acceptable cosmetic appearance. Reconstruction with local flaps is usually sufficient in the primary phase after a radical vulvectomy. Numerous flaps have been designed for vulvar reconstruction usually based on circulation from the internal pudendal artery branches. In this paper we introduce our modification of the gluteal fold V-Y advancement flap as a primary reconstruction after a radical vulvectomy. PATIENTS AND METHODS: Twenty-two patients were operated with a radical vulvectomy because of vulvar malignancies. The operation was primary in eight and secondary in 14 patients. The reconstruction of the vulva was performed in the same operation for each patient. RESULTS: All flaps survived completely. Wound complications were registered in three patients. Late problems with urinary stream were corrected in two patients. A local recurrence of the malignancy was observed in six patients during the follow-up period. CONCLUSIONS: Gluteal fold flap is easy to perform, has a low rate of complications and gives good functional results. Even a large defect can be reconstructed reliably with this method. A gluteal fold V-Y advancement flap is sensate and our modification allows the flap to be transposed with lesser dissection as presented before.

Spontaneous bleeding from the uterine arteries during pregnancy--problems in diagnosis and therapy--bleeding from uterine arteries during pregnancy.

Arterial bleeding, initially negative on MRI, ultrasonography and radiographic angiography, complicated the course of pregnancy with severe and recurrent vaginal and pelvic haemorrhage in the second trimester. Bleeding from the left uterine artery was successfully terminated by angiographic embolisation. No harmful effects on the fetal well-being were recorded after the embolisation. Massive haemorrhage, most probably from the right uterine artery, recurred some days later, and Caesarean section was performed. At postpartal ultrasonography and catheter angiography, massive arterial bleeding from a pseudoaneurysmatic vessel was clearly imaged on the right side of the cervical myometrium and could successfully be treated by radiographic embolisation. Though the primary aetiology of bleeding remains uncertain, it is possible that cervical endometriosis could have been associated with this complication.

Magnetic resonance imaging based volume estimation of ovarian tumours: use of a segmentation and 3D reformation software.

The application of a new segmentation software, Anatomatic in the evaluation of volumetric measurements of ovarian tumours and the new Medimag three-dimensional (3D) software in the evaluation of 3D image representation of ovarian tumours with 1.5 T magnetic resonance imaging (MRI) is described. Our goal was to compare MRI based volumetry with operative findings at laparotomy for six consecutive patients with suspected ovarian tumours. Volumetric analysis and three dimensional image reconstructions of the tumours were obtained. At laparotomy, the tumour sizes were measured in situ, and the volumes were calculated. Using Anatomatic, reproducible tumour volumes were achieved with ease and within a reasonably fast time in patients with ovarian tumours without ascites. Medimag helped achieve realistic 3D representations of the tumours. For the four solitary tumours segmentation based volumetry and laparotomy findings agreed in three cases. In one patient with an oval shaped tumour, the segmented volume was double as compared to that estimated at laparotomy. Of the two patients with multiple tumours, both patients had significant ascites, and volumetry misinterpreted the fluid as tumour cyst fluid and markedly overestimated the tumour size. In conclusion, the MRI based segmentation volumetry and 3D image reconstructions are rapid, and reproducible methods of measuring ovarian tumours in patients without significant ascites.

Cytokine production profiles in the peritoneal fluids of patients with malignant or benign gynecologic tumors.

BACKGROUND: Cytokines play a key role in the regulation of cells of the immune system and also have been implicated in the pathogenesis of malignant diseases. Some cytokines have been shown to have potential in the diagnosis of cancer. METHODS: A total of 111 patients with ovarian, cervical, or endometrial carcinomas or benign ovarian or uterine tumors were enrolled on the study, and the levels of interleukin (IL)-2, IL-4, IL-6, IL-10, interferon (IFN)-gamma, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), and tumor necrosis factor (TNF)-alpha were measured by cytokine specific, enzyme-linked immunoadsorbent assays. In addition, ratios of IL-2, IL-4, and IFN-gamma production were studied to characterize the type of T-cell response that occurred in the peritoneal cavities of the patients. RESULTS: High levels of M-CSF (mean for all patients, 26,050 pg/mL) and G-CSF (mean for all patients, 20,267 pg/mL) were observed in virtually all patients, but no significant differences between the study groups were observed. Similarly, no differences in the levels of IL-2, IL-4, IL-10, IFN-gamma, GM-CSF, or TNF-alpha were found. However, IL-6 levels were significantly higher in patients with ovarian carcinoma (mean +/- standard error of the mean [SEM]: 5572 +/- 1266) or benign tumors (mean +/- SEM: 4474 +/- 2008) than in those with cervical (mean +/- SEM: 1222 +/- 546) or endometrial carcinoma (mean +/- SEM: 1977 +/- 616). A predominantly Th1 type cytokine profile, irrespective of the diagnosis, was observed in patients with gynecologic tumors. CONCLUSIONS: With the exception of IL-6, the cytokine synthesis profiles in the peritoneal fluids of patients with benign and malignant gynecologic tumors were found to be similar. These results suggest that cytokine production in these patients is a result of nonspecific inflammation rather than a specific response against the tumor cells, and that skewing of cytokine synthesis toward either the Th1 or the Th2 phenotype is not the underlying mechanism resulting in the malignant process in women with gynecologic tumors.

The subrenal capsule assay in selecting chemotherapy for ovarian cancer: a prospective randomized trial.

In order to find out whether the response rate and survival in epithelial ovarian cancer can be improved by aid of sensitivity testing with the subrenal capsule assay (SRCA), 196 patients with FIGO Stage II-IV epithelial ovarian cancer were randomized to be treated with either cyclophosphamide-doxorubicin-cisplatin (CAP) or SRCA-guided chemotherapy. The drug combinations tested with the SRCA were (1) cyclophosphamide-doxorubicin-carboplatin (CACAR), (2) CAP, (3) carboquone-methotrexate-tegafur (CQ-MTX-TEG), (4) cisplatin-etoposide-hexamethyl-melamine (P-VP-HXM), and (5) bleomycin-epirubicin-cisplatin (BEP). A total of 132 patients (CAP, 69; SRCA, 63) were eligible for efficacy analysis based on relaparotomy findings. The overall response rate was 59% in the CAP arm and 62% in the SRCA arm. In the SRCA arm, 16 patients were treated with CACAR, 24 with CAP, 10 with CQ-MTX-TEG, 11 with P-VP-HXM, and 2 with BEP. The response rate to CACAR was 63% and to SRCA-CAP was 75%. The number of complete responses was higher when CAP was given as guided by the assay than when given at random (14/24 vs 23/69; P = 0.03, Pearson chi 2). Survival curves as estimated by Kaplan-Meier method gave a median survival of 24 (SE = 4) months to the SRCA arm and 28 (SE = 5) for the CAP arm (P = 0.7; log-rank test). Because no survival benefit was achieved, the SRCA obviously needs further development before it can be routinely recommended in the choice of first-line chemotherapy for patients with ovarian cancer.

Human T helper cell epitopes overlap B cell and putative cytotoxic T cell epitopes in the E2 protein of human papillomavirus type 16.

Activation of T helper cells is a prerequisite for the function of cytotoxic T lymphocytes (CTL) and the maturation of the B cell response. Because epitopes recognized by each of these cells may overlap, we scanned the E2 protein of human papillomavirus (HPV) type 16 to identify the T helper cell epitopes. Four major T helper cell epitopes (mapping between aa:s 11-25, 141-155, 191-205 & 231-245) and adjacent human B cell epitopes were found. The first peptide-defined epitope (RLNV) 11CQDKILTHYENDSTD25 overlapped five putative HLA-I (A1, A2, A0205, A3 & A11) binding motifs (CQDKILTHY, RLNVCQDKI, NVCQDKIL, RLNVCQDK & RLNVCQDK). This epitope is also part of an N-terminal alpha-helix which may form four HLA-II (DR2, DR4, DR7 & DR8) specific agretopes for structures recognizable by the T cell receptor (e.g. KILT). The second epitope 141EEASVTVVEGOVDYY155 (GLYY) overlapped the putative HLA-A1 & HLA-Bw37 binding motifs (VVEGQVDYY/QVDYYGLYY and EEASVTVV), and two HLA-II (DR1 & DR3) specific agretopes. The third and fourth epitopes were not associated with more than one putative CTL epitope each. Only the first epitope shared considerable aa-homology with corresponding regions of other genital HPV types.

Immunohistochemical determination of estrogen and progesterone receptors and DNA flow cytometry in endometrial cancer.

Estrogen and progesterone receptor contents (ER, PR) were assessed by an immunohistochemical method and DNA ploidy and S-phase by flow cytometry in frozen endometrial cancer tissue sections from 39 cases. Comparison of the immunohistochemical and cytosol assays showed 81% and 84% concordance in ER and PR contents, respectively. An aneuploid DNA pattern was identified in 30% and a high S-phase fraction was found in 33% of 36 specimens studied. Negative ER status was associated with aneuploid and high S-phase fraction. A similar association was found between PR status and high S-phase fraction. Combined analysis of immunohistochemical receptor status and DNA flow cytometry in the same sample makes it possible to identify two strong predictive factors in endometrial adenocarcinoma.

DNA ploidy, cell proliferation and steroid hormone receptors in endometrial hyperplasia and early adenocarcinoma.

We determined DNA content, S-phase fraction, and estrogen (ER) und progesterone receptor (PR) levels in 36 stage I endometrial adenocarcinomas and in 22 hyperplastic lesions to obtain information on the genesis and progression of endometrial malignancy. DNA aneuploidy was detected in 12/36 (33%) carcinomas and in none of the hyperplastic lesions. DNA aneuploidy was significantly more common in poorly and moderately differentiated carcinomas than in the well-differentiated ones. Similarly, the highest number of cells in S-phase were found in poorly and moderately differentiated carcinomas, whereas well-differentiated carcinomas and all hyperplasias had an equally small S-phase fraction. Mean ER and PR levels were highest in hyperplastic lesions, especially those with atypical features, whereas carcinomas of all grades had significantly lower values. Thus, it is likely that the loss or decreased expression of steroid receptors is an early event during carcinogenesis in human endometrium, whereas an increase in the cell proliferation rate and the formation of DNA aneuploidy occur later during tumor progression.

Comparison of ondansetron with customary treatment in the prophylaxis of nausea and emesis induced by non-cisplatin containing chemotherapy.

One hundred cancer patients receiving non-cisplatin containing chemotherapy were entered in a prospective study in which the efficacy of ondansetron was compared with standard antiemetic treatments in the prophylaxis of nausea and emesis. During the first 24 h, 77% of patients on ondansetron reported complete control of emesis compared with 56% of those on customary treatments (p = 0.03). However, no statistically significant difference was observed between ondansetron and customary treatments in control of delayed emesis on days 2-5. Nor was any statistically significant difference seen between ondansetron and customary treatments in preventing acute or delayed nausea.

Activities of antioxidant enzymes and lipid peroxidation in endometrial cancer.

Antioxidant enzyme activities and lipid peroxidation were analysed in normal endometrium and endometrial cancer tissues from Finnish and Japanese patients. The catalase and glutathione peroxidase activities of normal endometrium were significantly lower in Finns than in Japanese. Lipid peroxidation was slightly higher in endometrial cancer as compared with normal endometrium both in the Finns and in the Japanese. When cancer tissues were compared with normal endometrium both in Finns and Japanese the activity of superoxide dismutase was significantly lower in cancer tissue than in normal endometrium. In Finns glutathione S-transferase activity was also lower in endometrial cancer tissue than in normal endometrium, and a similar tendency was also found in Japanese. This study suggests that endometrial cancer tissue is associated with an impaired enzymic antioxidant defence system.

Pre- and posttreatment serum antibody responses to HPV 16 E2 and HSV 2 ICP8 proteins in women with cervical carcinoma.

Serum antibodies to early proteins of human papillomavirus type 16 (HPV 16 E2 protein) and herpes simplex virus type 2 (HSV 2 ICP8) can be measured by ELISA. In the serum of 122 newly diagnosed cervical carcinoma patients and age-matched controls, enhanced IgA antibody levels to an HPV-16 E2 protein derived peptide no. 245 indicated a 9.5-fold (95% confidence limits 2.8-57.2) relative risk of cervical carcinoma. No significant risk was found with a corresponding HPV 6 E2 peptide or HSV 2 ICP8. To evaluate the HPV 16 E2 peptide as a possible tumor marker for cervical carcinoma serial postoperative serum samples were tested from 27 women with cervical carcinoma. Antibody responses to the HPV 16 E2 peptide depended on the clinical stage. Stage I and II patients showed decreasing posttreatment IgA and/or IgG antipeptide antibody levels. Stage III and IV patients initially showed decreasing antipeptide antibody levels followed by increasing levels. These patients also showed increasing IgG antibody levels to the HSV 2 ICP8. However, increasing antibody levels to the HPV 16 E2 peptide indicated significantly (P less than 0.05) worse 2-year disease free survival (recurring disease) than did stable or decreasing antibody levels. The results suggest that serum antipeptide antibodies to the HPV 16 E2 peptide no. 245 can be used for the monitoring of cervical carcinoma.

Production of interleukin-1 beta and tumour necrosis factor-alpha in patients with benign or malignant ovarian tumours.

To assess the role of interleukin-1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF alpha) in the physiological host defence mechanisms against malignancies, the production of these cytokines in sera, ascitic and cyst fluids and in the tumour tissues of patients with benign or malignant ovarian tumours was studied. IL-1 beta was found neither in the sera nor in the ascitic fluids of these patients. It was also virtually absent from the cyst fluid samples. However, a mean value of 790 pg IL-1 beta/g tumour was found. Like IL-1 beta, TNF alpha was virtually absent in the serum samples. It was, however, detectable in the ascitic and cyst fluids and tumour tissues. The TNF alpha concentrations were highest in the tumour tissues, with a mean level of 328 pg/g tumour. When comparing the level of IL-1 beta and TNF alpha in patients with benign tumours to that seen in patients with malignant tumours, no differences in production were observed, regardless of the origin of the test samples. Our results indicate the production of IL-1 beta and TNF alpha in patients with ovarian tumours. More importantly, the finding that the production of these cytokines in patients with benign tumours is similar to that in patients with malignant tumours supports the conclusion that the production of these cytokines is more a nonspecific indicator of an inflammatory process than a specific response to a malignant process.

Placebo-controlled study on the efficacy of the pyrimido-pyrimidine derivative RA 233 in ovarian cancer.

This prospective double-blind, multicenter study was aimed at evaluating the clinical efficacy of RA 233 (a derivative of dipyridamole) in ovarian cancer. Following primary surgery, 497 patients with ovarian cancer were treated with combination cytotoxic chemotherapy; those in clinical stage II were also treated with pelvic irradiation. The patients were randomly allocated to receive RA 233 (N = 251) or placebo (N = 246) for 2 years. The groups did not significantly differ from each other in any of the clinical, therapeutic, or histopathological variables evaluated. There were no significant differences between RA 233-treated patients and placebo-treated patients with respect to appearance of new metastases, progressive growth of malignancy, or survival of all patients, in any of the clinical stages of the disease, in radically operated patients or in nonradically operated patients, in different histopathological groups, or in different age groups. Hence, supplementation of carcinoma therapy with long-term administration of the antiplatelet drug RA 233 has no clinical benefit in this malignancy. Using Cox's multifactorial stepwise analysis, this study revealed that the clinical stage of the disease, the extent of surgery, and the histopathology of the tumor, but not the age of the patient or the use of RA 233, were significant and independent predictors of survival. With respect to the histopathology, the poor prognosis of serous and mesonephric carcinomas appeared to be independent of the other prognosis indicators.

Alterations in vitamin D metabolites and minerals in diabetic pregnancy.

Vitamin D metabolites and minerals involved in bone metabolism were studied in 68 control mothers, 14 gestational diabetics and 68 insulin-dependent diabetics during pregnancy and at delivery. 25(OH)D and 1,25(OH)2D concentrations were significantly (p less than 0.001) lower in insulin-dependent diabetics than in the control or gestational diabetic groups. A similar difference was also observed between infants. 24,25(OH)2D, phosphorus and magnesium values were similar in all groups. Corrected calcium values were significantly lower in both mothers (p less than 0.001) and infants (p less than 0.05) in the insulin-dependent group than in the other two groups. Postpartum, 10% of infants of diabetic mothers received calcium therapy. Our results show alterations in vitamin D and mineral metabolism in pregnant insulin-dependent diabetics and their newborn infants and indicate observation during pregnancy and after delivery.

Serum vitamins A and E and carotene in patients with gynecologic cancer.

Serum concentrations of vitamin A (retinol), vitamin E (alpha-tocopherol) and total carotene were measured in 88 women with gynecologic cancer (9 vulvar, 15 cervical, 36 endometrial and 28 ovarian carcinomas) and 31 healthy controls. No significant differences were found in the serum levels of the vitamins and carotene in patients with vulvar, cervical or endometrial cancer compared to the controls. The patients with ovarian cancer had a significantly (P less than 0.01) lower mean serum level of vitamin A than the controls, while carotene and vitamin E level were similar in both groups. The results indicate that vitamin A may have a role in the metabolism of patients with advanced ovarian cancer.

Successful treatment of malignant trophoblastic diseases in a small oncologic unit.

Between 1962 and 1983 a total of 26 patients with malignant trophoblastic disease were diagnosed in northern Finland. The incidence of this disease was 1:21,000 pregnancies. Eight patients had choriocarcinoma and 18 an invasive mole. Clinically, 15 patients belonged to the nonmetastatic and 11 to the metastatic group. Of the latter, 4 patients belonged to the low-and 7 to the high-risk categories. During the first years of the study period, cytotoxic chemotherapy, mostly single-drug therapy, was often complemented with adjunctive surgery and/or irradiation. During recent years, single- or multidrug chemotherapy was supplemented with surgery in only one case with chemotherapy-resistant pulmonary metastases. All 26 patients are alive and disease-free, and after therapy 6 of them have given birth to 1-3 children. Our results suggest that malignant trophoblastic diseases can be successfully treated also in small centers of gynecologic oncology with up-to-date knowledge of the principles of modern cytotoxic chemotherapy.

Vitamin D and mineral metabolism in intrahepatic cholestasis of pregnancy.

Serum concentrations of 25(OH)D, 24,25(OH)2D, 1,25(OH)2D, total protein, calcium, phosphorus, magnesium and alkaline phosphatase were measured in patients with intrahepatic cholestasis of pregnancy and in control subjects at the third trimester of pregnancy and at delivery. 25(OH)D levels of 40.5 +/- 21.5 nmol/l in the patient group were initially significantly (P less than 0.01) higher than the value of 26.3 +/- 9.5 nmol/l in the control group and decreased significantly (P less than 0.01) to 26.0 +/- 16.3 nmol/l at delivery. The levels of active 1,25(OH)2D and inactive 24,25(OH)2D did not alter in either group. Also the concentrations of calcium, phosphorus and magnesium remained unchanged in both groups. No significant differences in fetal vitamin D metabolites were observed between patients and controls, and the other analysed fetal parameters were similar in both groups. Cholestyramine and/or phenobarbital treatment had no influence on vitamin D metabolites. Since levels of 1,25(OH)2D and mineral parameters remained normal and a change in 25(OH)D concentrations was only transient, the clinical role of 25(OH)D variations cannot be substantial.

Serum levels of vitamin D metabolites, calcium, phosphorus, magnesium and alkaline phosphatase in Finnish women throughout pregnancy and in cord serum at delivery.

Serum concentrations of 25(OH)D, 24,25(OH)2D, 1,25(OH)2D, total calcium, protein, phosphorus, magnesium and alkaline phosphatase were measured in two groups of Finnish women throughout pregnancy and in cord serum at delivery. The autumn group delivered in August-September and the spring group in February-March. There was strong seasonal variation in the 25(OH)D concentrations in both groups. Maternal values (mean +/- s.d.) at delivery were 44.3 +/- 20.8 nmol/l in autumn and 26.0 +/- 13.0 nmol/l in spring. Fetal concentrations were 28.8 +/- 14.3 and 18.3 +/- 11.3 nmol/l, respectively. In both mothers and infants low 25(OH)D values were measured in winter. In the autumn group 7 out of 21 mothers (33 per cent) and in the spring group 17 out of 36 mothers (47 per cent) had values below 17 nmol/l, which is the lowest winter reference value recorded in our laboratory. No significant seasonal variation was observed in dihydroxylated vitamin D metabolites, although 24,25(OH)2D values were a little higher in summer than in winter. Concentrations of 1,25(OH)2D tended to rise towards delivery. Corrected calcium, magnesium and phosphorus concentrations did not change during pregnancy. Fetal calcium and phosphorus concentrations were significantly (P less than 0.001) higher than maternal ones. The data indicate that many mothers and infants have poor vitamin D status in the latitude of Finland. Our results support the concept that vitamin D supplementation should be considered in Finland for pregnant women at least in winter.