The steroid metabolome in women with premenstrual dysphoric disorder during GnRH agonist-induced ovarian suppression: effects of estradiol and progesterone addback.

Clinical evidence suggests that symptoms in premenstrual dysphoric disorder (PMDD) reflect abnormal responsivity to ovarian steroids. This differential steroid sensitivity could be underpinned by abnormal processing of the steroid signal. We used a pharmacometabolomics approach in women with prospectively confirmed PMDD (n=15) and controls without menstrual cycle-related affective symptoms (n=15). All were medication-free with normal menstrual cycle lengths. Notably, women with PMDD were required to show hormone sensitivity in an ovarian suppression protocol. Ovarian suppression was induced for 6 months with gonadotropin-releasing hormone (GnRH)-agonist (Lupron); after 3 months all were randomized to 4 weeks of estradiol (E2) or progesterone (P4). After a 2-week washout, a crossover was performed. Liquid chromatography/tandem mass spectrometry measured 49 steroid metabolites in serum. Values were excluded if >40% were below the limit of detectability (n=21). Analyses were performed with Wilcoxon rank-sum tests using false-discovery rate (q<0.2) for multiple comparisons. PMDD and controls had similar basal levels of metabolites during Lupron and P4-derived neurosteroids during Lupron or E2/P4 conditions. Both groups had significant increases in several steroid metabolites compared with the Lupron alone condition after treatment with E2 (that is, estrone-SO4 (q=0.039 and q=0.002, respectively) and estradiol-3-SO4 (q=0.166 and q=0.001, respectively)) and after treatment with P4 (that is, allopregnanolone (q=0.001 for both PMDD and controls), pregnanediol (q=0.077 and q=0.030, respectively) and cortexone (q=0.118 and q=0.157, respectively). Only sulfated steroid metabolites showed significant diagnosis-related differences. During Lupron plus E2 treatment, women with PMDD had a significantly attenuated increase in E2-3-sulfate (q=0.035) compared with control women, and during Lupron plus P4 treatment a decrease in DHEA-sulfate (q=0.07) compared with an increase in controls. Significant effects of E2 addback compared with Lupron were observed in women with PMDD who had significant decreases in DHEA-sulfate (q=0.065) and pregnenolone sulfate (q=0.076), whereas controls had nonsignificant increases (however, these differences did not meet statistical significance for a between diagnosis effect). Alterations of sulfotransferase activity could contribute to the differential steroid sensitivity in PMDD. Importantly, no differences in the formation of P4-derived neurosteroids were observed in this otherwise highly selected sample of women studied under controlled hormone exposures.

Nutritional marginal zinc deficiency disrupts placental 11ß-hydroxysteroid dehydrogenase type 2 modulation.

This paper investigated if marginal zinc nutrition during gestation could affect fetal exposure to glucocorticoids as a consequence of a deregulation of placental 11ßHSD2 expression. Placenta 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) plays a central role as a barrier protecting the fetus from the deleterious effects of excess maternal glucocorticoids. Rats were fed control (25 µg zinc per g diet) or marginal (10 µg zinc per g diet, MZD) zinc diets from day 0 through day 19 (GD19) of gestation. At GD19, corticosterone concentration in plasma, placenta, and amniotic fluid was similar in both groups. However, protein and mRNA levels of placenta 11ßHSD2 were significantly higher (25% and 58%, respectively) in MZD dams than in controls. The main signaling cascades modulating 11ßHSD2 expression were assessed. In MZD placentas the activation of ERK1/2 and of the downstream transcription factor Egr-1 was low, while p38 phosphorylation and SP-1-DNA binding were low compared to the controls. These results point to a central role of ERK1/Egr-1 in the regulation of 11ßHSD2 expression under the conditions of limited zinc availability. In summary, results show that an increase in placenta 11ßHSD2 expression occurs as a consequence of gestational marginal zinc nutrition. This seems to be due to a low tissue zinc-associated deregulation of ERK1/2 rather than to exposure to high maternal glucocorticoid exposure. The deleterious effects on brain development caused by diet-induced marginal zinc deficiency in rats do not seem to be due to fetal exposure to excess glucocorticoids.

Evidence for NQO1 and NQO2 catalyzed reduction of ortho- and para-quinone methides.

NAD(P)H: quinone oxidoreductase (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) catalyze the two-electron reduction of quinones and thereby prevent generation of toxic radicals. Quinone methides (QMs) covalently react with cellular macromolecules to form DNA adducts and/or protein conjugates resulting in toxicity and carcinogenesis. Based on similar structural features of quinones and QMs, it is logical to assume that NQO1 and/or NQO2 could also catalyze the two-electron reduction of QMs. However, hitherto the reduction of QMs, as both endogenous and/or exogenous biological substrates, by either NQO1/NQO2 has never been demonstrated. Here we show for the first time that both NQO1 and NQO2 can catalyze the reduction of electrophilic ortho-/para-QMs. The involvement of the enzyme in the reduction of p-cresol quinone methide (PCQM) and o-cresol quinone methide (OCQM) was demonstrated by reappearance of NQO1/NQO2-FAD peak at 450 nm after addition of the QMs to the assay mixture. Further reduction of methides by NQO1/NQO2 was confirmed by analyzing the assay mixture by tandem mass spectrometry. Preliminary kinetic studies show that NQO2 is faster in reducing QMs than its homolog NQO1, and moreover, ortho-QMs are reduced faster than para-QMs. Enzyme-substrate docking studies showed results consistent with enzyme catalysis. Thus, NQO1/NQO2 can play a significant role in deactivation of QMs.

Monitoring rainwater and seaweed reveals the presence of (131)I in southwest and central British Columbia, Canada following the Fukushima nuclear accident in Japan.

Detailed analysis of (131)I levels in rainwater and in three species of seaweed (Fucus distichus Linnaeus, Macrocystis pyrifera, and Pyropia fallax) collected in southwest British Columbia and Bella Bella, B.C., Canada was performed using gamma-ray spectroscopy following the Fukushima nuclear power plant accident on March 11, 2011. Maximum (131)I activity was found to be 5.8(7) Bq/L in rainwater collected at the campus of Simon Fraser University in Burnaby, B.C. nine days after the accident. Concomitantly, maximum observed activity in the brown seaweed F. distichus Linnaeus was observed to be 130(7) Bq/kg dry weight in samples collected in North Vancouver 11 days following the accident and 67(6) Bq/kg dry weight in samples collected from the Bamfield Marine Sciences Centre on Vancouver Island 17 days following the accident. The (131)I activity in seaweed samples collected in southwest B.C. following the Fukushima accident was an order of magnitude less than what was observed following Chernobyl. Iodine-131 activity in F. distichus Linnaeus remained detectable for 60 days following the accident and was detectable in each seaweed species collected. The Germanium Detector for Elemental Analysis and Radioactivity Studies (GEARS) was modeled using the Geant4 software package and developed as an analytical tool by the Nuclear Science group in the Simon Fraser University Department of Chemistry for the purpose of these measurements.

Radiotherapy alone for invasive vaginal cancer: outcome with intracavitary high dose rate brachytherapy versus conventional low dose rate brachytherapy.

PURPOSE: Our aim was to compare the role of remote afterloaded high-dose-rate brachytherapy (HDRB) with traditional low-dose-rate brachytherapy (LDRB) for patients with invasive primary vaginal carcinoma. METHODS: The study group comprised 190 patients with invasive carcinoma of the vagina. The patients were staged according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. Eighty patients were treated with intracavitary high-dose rate iridium 192 brachytherapy with or without external beam therapy. These patients are compared with a historical group of 110 patients treated with intracavitary low-dose-rate radium 226 or cesium 137 brachytherapy with or without external beam therapy. RESULTS: No significant differences were found for stages, tumor grade or location between the two groups. Crude 5-year survival for all patients was 41% in the former LDRB group, 81% in stage I and 43% in stage II. Overall actuarial 3-year survival and disease-specific survival rates for all patients in the HDRB series were 51% and 66%, respectively. Disease-specific 3-year survival attained 83% in stage I and 66% in stage II. There were no significant differences in local and distant recurrences between the treatment modalities. The comparison of treatments with or without external beam radiation and of complications showed no significant differences between the HDRB and LDRB series. CONCLUSION: With HDRB and its advantages of decreased radiation exposure and patient immobilization and precise positioning, treatment results to be obtained are at least similar to traditional LDRB for primary vaginal cancer.

High-dose versus low-dose rate brachytherapy in definitive radiotherapy of cervical cancer.

BACKGROUND: To retrospectively compare the clinical outcome in cervical cancer patients treated by external irradiation and intracavitary high-dose rate (HDR) brachytherapy with iridium 192 versus low-dose rate (LDR) brachytherapy with radium 226 or caesium 139. METHODS: 450 LDR patients were treated from 1982 to 1986 and compared with 189 HDR patients treated from 1993 to 1999. Cobalt (CO) 60 treatment was replaced in the HDR group by modern megavoltage photon radiotherapy (Linac 25 MV). Brachytherapy was given in either 2 or 3 LDR radium 226 implants for the earlier patient cohort, and 3-6 HDR iridium 192 implants for the latter cohort. The primary endpoint assessed was the 3-year overall survival. RESULTS: The median duration of follow-up was 70 months (range, 2-108 months) in the LDR group and 34 months (range, 4-69 months) in the HDR group. Actuarial overall 3-year survival after conventional LDR brachytherapy was 51.3%, versus 58.2% after HDR brachytherapy. No difference in 3-year survivors was seen in the small groups of stage I (68.3% vs. 84.6%) and stage IV (23.1% vs. 37.5%) patients. In stage II and III and in the overall group there were statistically significantly more 3-year survivors in the HDR group (58.1% vs. 78.9%, p < 0.001 in stage II; 37.3% vs. 53.8%, p < 0.01 in stage III; and 46.7% vs. 67.2%, p < 0.001 in the total group). Retrospectively assessed complication rates in the former LDR group were 3.8% for irreversible side effects, and 13.3% for chronic radiation damage. In the HDR group the actuarial late complication rates for grades 3 and 4 were 2.9% for the bladder, 4.0% for the bowel, and 6.1% for the rectum. CONCLUSION: In our preliminary experience, HDR brachytherapy combined with external beam radiation produced similar and even better survival rates compared with the LDR series. HDR brachytherapy combined with external beam radiation is an efficient method for the treatment of cervical cancer and adverse side effects are comparable.

Radiation therapy in the treatment of endometrial stromal sarcoma.

OBJECTIVE: The efficacy of radiation therapy in the treatment of endometrial stromal sarcoma (ESS) is still not clear. We report our results over an 18-year period in comparison to data from literature concerning adjuvant radiation therapy and other treatment modalities. PATIENTS AND METHODS: During 1981-1998, 21 patients with ESS were treated at General Hospital Vienna. The age of the patients ranged between 44-76 years (median: 65 yr). The 1989 FIGO classification for endometrial carcinoma was used in this study retrospectively. Eleven patients presented in Stage I, 1 in Stage II and 5 in Stage III. Four patients had Stage IV tumors or recurrences. The majority of patients (66.7%) had a Grade 3 tumor. Seventeen patients were treated in a curative intent. Fifteen patients were referred for postoperative radiotherapy after hysterectomy. Thirteen of them received a combined radiotherapy. Two patients were referred for primary radiotherapy. They received a combined radiotherapy. Four patients were referred for radiotherapy with a palliative intent. Twenty patients received external beam therapy (EBT) in daily fractions of 1.6-2.0 Gy up to a total dose of 27-57 Gy to the pelvis. Seventeen patients received brachytherapy. RESULTS: Follow-up was 8 to 170 months (mean: 70.3 months, median: 64 months). Eleven patients are still alive, 10 without tumor and 1 with tumor. Ten patients are dead, 6 due to ESS, 1 due to breast cancer, and 3 due to intercurrent diseases. After adjuvant radiotherapy, 3 patients had tumor recurrences. All had distant metastases, and 1 had local failure additionally. Two patients with primary treatment died due to intercurrent disease without tumor. The overall actuarial survival and the disease-specific survival rates were 63.4% and 80.9% after 5 years and 52.8% and 80.9% after 10 years. The overall local control rate was 93.8% after 5 years. Four patients treated with a palliative intent showed partial response. Three patients died rapidly due to tumor. One patient with a Grade 1 tumor is still alive 12 months after treatment. CONCLUSION: In our experience, surgery and adjuvant radiation therapy are most effective treatments for patients with ESS due to the excellent local control in all stages and the good disease-specific survival in early stages.

Definitive radiotherapy based on HDR brachytherapy with iridium 192 in uterine cervix carcinoma: report on the Vienna University Hospital findings (1993-1997) compared to the preceding period in the context of ICRU 38 recommendations.

UNLABELLED: According to the reports described in the literature, fractionated HDR brachytherapy seems to represent one option for the primary treatment of cervical carcinoma. In order to render such treatment transparent and comparable for those interested in the field, we have attempted to report our recent experience obtained in Vienna from 1993-1997 using the terminology proposed by the ICRU report 38, focusing in particular on dose and volume reporting and a linear-quadratic model. Based on these parameters, a comparison with the preceding period in Vienna (LDR/HDR) has been made, with an attempt to correlate different methods and parameters with outcome. MATERIAL AND METHODS: One hundred and eighty-nine patients (mean age 67 years) were treated with curative intent (stage Ia: 2, Ib: 11, IIa: 11, IIb: 79, IIIa: 19, IIIb: 59, IVa: 5, IVb: 3 patients) using a combination of intracervical high-dose rate (HDR) brachytherapy (ring-tandem applicator) and a box technique for external-beam therapy (EBT: 48.6-50 Gy, linac 25 MV). Small tumors were treated with 5-6 fractions of 7 Gy at point A and 50 Gy EBT (25 Gy in the brachytherapy reference volume) which is isoeffective to 76-86 Gy at point A. Large tumors received 3-4 fractions of 7 Gy after 50 Gy EBT with open fields, which is isoeffective to 82-92 Gy at point A. TRAK varied from mean 1.4 cGy (3 fractions) to 2.8 cGy (6 fractions) at one meter. 3-D treatment planning for brachytherapy was based on conventional X-rays and in 181/189 patients on computed tomography (CT) with the applicator in place. Computer-calculated volumes of the brachytherapy reference isodose (7 Gy/fraction) ranged from 46-155 ccm (mean 87 ccm); the respective mean hwt-volume (height x width x thickness) was 180 ccm. The 60 Gy HWT volumes (25 Gy from EBT) for the irradiation of small tumors ranged from 240 to 407 ccm (mean 337 ccm) and for larger tumors (50 Gy for EBT) from 452 to 785 ccm (mean 607 ccm). The mean dose for brachytherapy was 16.2 Gy (6.2-37.8 Gy) at the ICRU rectum reference point and 14.4 Gy (4.6-35.7 Gy) at the ICRU bladder point. Taking into account the dose for EBT, the mean isoeffective dose at the ICRU rectum reference point was 69.9 Gy (28.4-98.7 Gy). Overall treatment time was six weeks for small tumors and eight weeks for large tumors. RESULTS: After a mean follow-up of 34 months, actuarial pelvic control and disease-specific survival rates at three years were 77.6/68.6% for all patients, 100/77.1% for stage Ib, 100/100% stage IIa, 87.0/78.0% stage IIb, 52.7/52.1% stage IIIa, 69.1/58.6% stage IIIb and 60/53.3% stage IVa. According to the LENT/SOMA score which had been prospectively introduced, the actuarial late complication rate for grades 3 and 4 was 2.9% for the bladder, 4.0% for the bowel, 6.1% for the rectum and 30.6% for the vagina (shortening and obliteration); in total for all grades 23.6, 18.4, 24.2, and 67.6%, respectively. CONCLUSION: In our experience, HDR brachytherapy combined with EBT is an efficient method if sufficient radiation doses and volumes are applied, both with regard to tumor control and adverse side effects. In future, the therapeutic window will be increased by systematic integration of magnetic resonance imaging (MRI) into treatment planning, thus allowing for a highly individualized approach with further adaptation of radiation dose and volume both to the target and to the individual topography of organs at risk.

Accuracy of intraoperative frozen-section diagnosis in stage I endometrial adenocarcinoma.

The purpose of our study was to determine if frozen-section diagnosis accurately identified patients suffering from endometrial adenocarcinoma FIGO stage I for surgical staging consisting of total abdominal hysterectomy, bilateral salpingo-oophorectomy, peritoneal cytology, and complete bilateral pelvic lymphadenectomy in moderately differentiated tumors with myometrial invasion. In all poorly differentiated tumors, and in all tumors with deep myometrial invasion (more than 50%) surgical staging included additional para-aortic lymphadenectomy. We performed a retrospective study including 70 patients. Frozen-section diagnosis of myometrial invasion and tumor grade was compared with permanent-section diagnosis. The accuracy rates were determined, and compared with accuracy rates of frozen-section diagnosis in the literature, and a total accuracy rate for 624 patients suffering from stage I endometrial adenocarcinoma was evaluated. In our patient collective, the overall accuracy rate of frozen-section diagnosis for myometrial invasion and tumor grade was 80 and 84%, respectively. In the five comparable studies, the mean accuracy rate for myometrial invasion and tumor grade was 89 and 84%, respectively. In combination with the five comparable studies our recent study produced an accuracy rate of frozen-section diagnosis for myometrial invasion and tumor grade of 88 and 84% in 624 patients, respectively. Despite an accuracy level of frozen-section diagnosis for myometrial invasion of 80 and 84% for tumor grade in our patient collective, all patients who required surgical staging were accurately identified.

Results of primary and adjuvant radiotherapy in the treatment of mixed Müllerian tumors of the corpus uteri.

OBJECTIVE: The benefit of primary or adjuvant irradiation in the treatment of mixed Müllerian tumors is still not clear. METHODS: During 1981-1997 63 patients were referred for primary (n = 13) or postoperative (n = 50) radiotherapy. Analysis of outcome of primarily and postoperatively irradiated patients was performed separately because of different staging systems. Of 50 patients treated after surgery 29 presented in histopathologic stage I, 4 in stage II, 14 in stage III, and 3 in stage IV. Clinical stage distribution for primary treatment was stage I: n = 9, stage II: n = 1, stage III: n = 3. Forty-four patients in the postoperatively treated group and 6 in the primarily treated group received radiotherapy with a curative intent; external beam therapy was given up to 56 Gy to the pelvis combined with intravaginal or intracavitary brachytherapy. RESULTS: Five-year actuarial overall survival, disease-specific survival, local control, and distant control for 50 patients receiving adjuvant irradiation was 52.9, 57. 5, 83.4, and 70.8%, in stage I: 68.4, 76.1, 95.2, and 81.7%, in stage II: 50.0, 50.0, 75.0, and 66.7%, and in stage III: 31.3, 34.1%, 70.4, and 47.6%, respectively. Four of 13 patients treated with primary irradiation achieved long-term local control. CONCLUSION: These data suggest that adjuvant radiotherapy improves local control and disease specific survival in the treatment of mixed Müllerian tumors compared to data in the literature concerning treatment by surgery alone.

A head-to-head comparison between technetium-99m-tetrofosmin and technetium-99m-MIBI scintigraphy to evaluate suspicious breast lesions.

The aim of this study was to assess the diagnostic value of technetium-99m-tetrofosmin and technetium-99m-MIBI in a head-to-head comparison. Both radiopharmaceuticals are routinely used for detecting breast cancer. In a prospective, open, diagnostic trial, the two radiopharmaceuticals were administered randomly on different days to the same 101 women suffering from 103 breast tumours. Planar images and single photon emission computer tomography (SPET) were performed. After histological examination of the tumours, sensitivity, specificity and positive and negative predictive value were compared. 99mTc-tetrofosmin and 99mTc-MIBI showed low sensitivity in planar images (44% vs 46%, respectively). SPET improved sensitivity (70% vs 69%, respectively). Specificity in planar images was 83% and 87%, and it was even lower using SPET (70% vs 78%, respectively). Positive predictive value in planar images was 76% vs 81%, and it was not changed by SPET. Negative predictive value was low in planar images (54% vs 57%, respectively), but it was improved by using SPET (65% vs 67%, respectively). In conclusion, 99mTc-tetrofosmin and 99mTc-MIBI scintigraphy show similar diagnostic value in assessing suspicious breast lesions.

Treatment of endometrial carcinoma with high-dose-rate brachytherapy alone in medically inoperable stage I patients.

PURPOSE: To review the results of treatment with high-dose-rate brachytherapy alone in 228 patients with stage I endometrial carcinoma who are unfit for surgery. METHODS: All patients received an exclusive radiation therapy by means of high-dose-rate Iridium 192 intracavitary brachytherapy without additional external beam radiation. RESULTS: At 5 years, the overall survival rate was 59.7% and disease specific survival 85.4% at 10 years 30.2% and 75.1%. In clinical stage Ia disease specific survival was 88.6% at 5 years and 82.7% at 10 years, in stage Ib 80.2% and 63.4%, respectively (p<0.02). Disease specific survival was not affected by tumor grade or age. The rates of local control are related to the size of the uterus but not to the tumor grading. Intrauterine recurrence occurred in 17.5% but extrauterine pelvic relapse in only 0.4% of patients. The calculated probability of severe complications was 4.6% at 5 years. CONCLUSION: HDR brachytherapy alone achieves excellent disease specific survival rates in patients with medically inoperable stage I endometrial carcinoma.

Amplification and expression of the c-erbB-2 oncogene in Müllerian-derived genital-tract tumors.

This study focused on 18 uterine corpus tumors and 7 ovarian endometrioid tumors, all of them malignant and Müllerian derived. Differential polymerase chain reaction (DPCR), dot blot hybridization, and immunohistochemical technique were employed to determine c-erbB-2 amplification and expression. Of 25 Müllerian-derived tumors, 17 (68.0%) demonstrated amplified c-erbB-2 (two to eight copies) by DPCR. These 25 samples were reexamined by dot blot and immunohistochemical technique, revealing c-erbB-2 amplification and expression of to be 52.0 and 40.0%, respectively. There seemed to be a slight correlation between the amplification and expression of c-erbB-2 and patient survival. Although c-erbB-2 was frequently present in Müllerian-derived genital-tract tumors, it is uncertain whether this oncogene may serve as their sole prognostic marker. The question remains whether c-erbB-2 alone, or in conjunction with other oncogenes or suppressor genes, accounts for the pathogenesis of Müllerian-derived tumors. However, these results suggest for the first time in the literature that DPCR is a sensitive enough technique for detecting c-erbB-2 amplification in M ullerian-derived tumors.

Results of postoperative radiotherapy in the treatment of sarcoma of the corpus uteri.

BACKGROUND: The role of radiotherapy in the treatment of uterine sarcoma still is not clear. Data from the literature advocating adjuvant radiotherapy most often are based on very small patient groups, whereas larger epidemiologic studies, which appear to show no benefit for the additional radiotherapy, lack information regarding clinical data influencing the choice for adjuvant irradiation. METHODS: During 1981-1992, 72 patients were referred for postoperative radiotherapy. Histologic diagnoses were leiomyosarcoma (LMS) in 30 patients, endometrial stromal sarcoma (ESS) in 11 patients, mixed müllerian tumors (MMT) in 28 patients, and other sarcoma types in 3 patients. The 1988 International Federation of Gynecology and Obstetrics classification for endometrial carcinoma was applied retrospectively. Forty patients presented with Stage I disease, 9 with Stage II, 17 with Stage III, and 6 with Stage IV. External beam therapy was given with a cobalt-60 unit using a rotation technique with 2 separate arcs in daily fractions of 2 gray (Gy), up to a total dose of 56 Gy to the pelvis. Brachytherapy was given to the vaginal vault either with 2 radium applications (median: 1600 milligram-hours to the applicator surface) or, in the majority of cases, with 3 fractions of high dose rate afterloading applications (iridium-192, 10-Curie source) with 7 Gy each to an isodose 7.5 mm from the applicator surface. RESULTS: The 5-year actuarial overall survival, disease specific survival, and local control rates for 72 patients were 52.3%, 58.5%, and 77.9%, respectively; in Stage I patients they were 74.8%, 84.6%, and 94.4%, respectively; in Stage II patients they were 53.3%, 53.3%, and 88.9%, respectively; in Stage III patients they were 15.7%, 17.9%, and 55.5%, respectively; and in Stage IV patients they were 0%, 0%, and 0%, respectively. For LMS, the 5-year actuarial overall survival, disease specific survival, and local control rates were 49.4%, 52.0%, and 76.0%, respectively; for ESS they were 81.8%, 81.8%, and 90.9%, respectively; and for MMT they were 42.3%, 54.9%, and 72.4%, respectively. CONCLUSIONS: These data suggest that adjuvant radiotherapy is an effective treatment for uterine sarcoma with regard to disease specific survival in patients with early stage disease and increases local control, even in patients with advanced stage disease.

[Operation or irradiation of cervix carcinoma?]. / Operation oder Bestrahlung beim Gebärmutterhalskarzinom?

Treatment of early invasive carcinoma of the uterine cervix by radical surgery or radiation continues to engender controversy after many decades of effective therapy. A recently published first prospective randomised trial revealed that stage I and IIa cervical carcinoma can be cured by radical surgery or radiotherapy with an identical 5-year survival (83% in both groups) and a similar recurrence rate (25 vs. 26%). In many points, a prospective Italian study confirms the retrospective results of our previous published studies. Surgery and radiotherapy alone are equally effective but differ in associated complications. Severe morbidity occurred in the Italian study after surgery and radiotherapy alone in 28 and 12%, respectively (p < 0.0004). In our retrospective study, severe complications were found with surgery and adjuvant radiation in 36.4%, with radiotherapy alone in 13.7% (p < 0.001). The usefulness of postoperative radiation is not clear, and patients should not be subjected to both therapies. Optimum candidates for primary radical surgery are women with normal ovarian function and cervical diameters of 4 cm or smaller. Adenocarcinomas of the uterine cervix are better treated with surgery (5-year survival 66 vs. 47%, p < 0.02).

Does T1, N0-1 vulvar cancer treated by vulvectomy but not lymphadenectomy need inguinofemoral radiation?

PURPOSE: The objective of our study was to demonstrate differences in relapse rates, total survival times, and complication rates between inguinofemoral radiation and its absence in cases of invasive vulvar carcinoma without lymph node involvement (FIGO Stages T1, N0-1). METHODS AND MATERIALS: From 1974 to 1990, 135 patients with invasive vulvar carcinoma in Stage T1 without clinical evidence of inguinal lymph node involvement underwent simple vulvectomy performed by hot-knife resection without lymphadenectomy. Although 65 patients (Group 1) received postoperative inguinofemoral radiation therapy, 70 patients (Group 2) did not, and none received local vulva irradiation. RESULTS: The 5-year survival rates were 93.7% in Group 1 and 91.4% in Group 2 (p = NS). Although clitoris involvement was significantly more prevalent in the irradiation group (p = 0.04), inguinal relapse was found less frequently in Group 1 (4.6% or 3 out of 65 patients) than in group 2 (10% or 7 out of 70 patients) (p = 0.32). The complication rates were, 7.7% in Group 1 and 2.9% in Group 2, 2.7% for vaginal stenosis (two patients in each group), 1.5% for inguinal pain (one patient in Group 1), 1.5% for rectovaginal fistula (one patient in Group 1), 1.5% for vulvar infection (one patient in Group 1). CONCLUSION: No statistically significant differences in the relapse rates and survival times were found. Risk factors were equally distributed in both study groups except for clitoris involvement. The 5-year survival rates in both groups were similar to those reported in the literature for radical vulvectomy and inguinal lymph-node dissection (83-96%). Morbidity in our study was low. Although our data showed similar results in both groups, we are not recommending at this time to omit groin radiation in general, but it may be justified in low-risk cases.

Primary treatment of endometrial carcinoma with high-dose-rate brachytherapy: results of 12 years of experience with 280 patients.

PURPOSE: This study aimed to evaluate the efficacy of high-dose-rate brachytherapy (HDRB) in the primary treatment of endometrial carcinoma. The results of 12 years of experience (1981-1992) covering 280 patients (mean age 72 years) and their follow-up over 10 years (mean 55 months) are reported. METHODS AND MATERIALS: Staging was based on clinical examination and fractionated curettage. There were 116 patients in clinical Stage Ia, 119 in Stage Ib, 37 in Stage II, and 8 in Stage III. HDRB was performed four to five times (8.5 Gy) with a one-channel intracavitary applicator and one to two times (7 Gy) with an intravaginal cylinder applicator. Overall and disease-specific survival, local control according to stage and histology, and late side effects were analyzed retrospectively (actuarial method). RESULTS: At 5 years, overall survival, disease-specific survival, and local control were 52.7%, 76.6%, and 75.4% (Stage Ia: 63.9%, 84.9%, and 86.0%; Stage Ib: 47.3%, 73.3%, and 68.8%; and Stage II: 40.2%, 68.6%, and 60.5%) according to histopathologic Grade 1: 65.1%, 83.5%, and 77.7%; for Grade 2: 44.7 %, 75.4%, and 75.8%; and for Grade 3: 37.7%, 63.9%, and 74.1%. Eight patients showed progressive disease, 64 developed recurrence after a median of 13 months (45 of whom had a local recurrence only, and 6 of whom had a local recurrence with distant metastases), 6 developed a lymph node recurrence only, and 7 developed distant metastases only. The calculated probability for developing a Grade III late side effect was 5.2% at 5 years. CONCLUSION: At Stages Ia, Ib, and II in endometrial carcinoma, HDRB is a very effective treatment modality with acceptable local control rates and disease-specific survival for patients who are not fit for surgery. During the time frame of 12 years and in 280 patients the method has proven to have a low risk of acute complications and an acceptable risk of long-term side effects.

[The results of primary HDR-afterloading brachytherapy in corpus carcinoma]. / Ergebnisse der primären HDR-Afterloading-Brachytherapie beim Korpuskarzinom.

PURPOSE: In general the results of radiotherapy are regarded to be inferior compared to those of surgery, when it comes to the treatment of endometrial carcinoma, but some patients are elderly and have multiple medical problems, which make them inoperable. The risk of intracavitary radium therapy, caused by immobilisation, can be reduced by the use of fractionated high-dose-rate afterloading brachytherapy. With this method there are only very few results reported. PATIENTS AND METHODS: Treatment results of HDR brachytherapy (4 to 5 times 8.5 Gy, one-channel applicator, intracavitary and 1 to 2 times 7 Gy intravaginal) at the University Hospital Vienna were analysed retrospectively (actuarial method [Kaplan-Meier]) regarding overall survival and recurrence-free interval according to stage and histology. Over a period from April 1981 until December 1992 325 patients were treated by this technique alone or combined with external beam therapy. Two hundred and eighty patients could be evaluated. Staging based on clinical examination and fractionated curettage. RESULTS: Five-year overall survival was 58.1%, in stage Ia 68.5%, stage Ib 49.9%, stage II 48.7%, according to histopathologic grading 1 68.5%, grade 2 53.2%, grade 3 37.5%. 64 patients developed a recurrence after a median of 13 months, 45 of those a local recurrence only, 6 a local recurrence with distant metastases, 6 a lymph node recurrence only and 7 patients distant metastases only. CONCLUSION: These results are at least comparable to those of intracavitary radium therapy and low-dose-rate afterloading techniques. Better local control rates should be obtained by the Heyman packing method using Norman-Simon applicators based on individualised brachytherapy treatment planning, which optimises dose distribution according to the target volume based on computerised imaging.

-Inguinal irradiation versus no lymph node therapy in small vulvar carcinoma with clinically negative lymph nodes (T1, NO-1)-. / Inguinalbestrahlung versus keine Lymphknotentherapie beim kleinen Vulvakarzinom mit klinisch negativen Lymphknoten (T1, NO-1).

OBJECTIVE: The objective of this retrospective study was to determine if groin radiation was superior to no therapy in patients with small vulvar cancer with not palpable or not suspicious inguinal lymph nodes (T1, N0-N1). METHODS: From 1974 to 1990, 135 patients with invasive T1, NO-1 vulvar cancer underwent radical vulvectomy with hot knife, groin nodes were left in situ. In 65 patients vulvectomy was followed by inguinofemoral irradiation: 70 patients had none. There were more cases with clitoris carcinoma (p < 0.04) in the group with groin irradiation but no other significant difference in prognostic factors was found. RESULTS: The actuarial 5-year survival was 93.7% with groin irradiation versus 92.4% without lymph node therapy. Inguinal relapses occurred in only 4.6% of cases with groin irradiation versus 10% without lymph node treatment (n.s.). CONCLUSIONS: Radiation therapy to the groin seems to reduce groin relapses in early vulvar cancer.