Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)†.

BACKGROUND: The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses. PATIENTS AND METHODS: Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, ß = 0.8) 379 events had to be observed in the bevacizumab arms. RESULTS: With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1-3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups. CONCLUSIONS: Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline-taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients. CLINICAL TRIAL NUMBER: NCT 00567554, www.clinicaltrials.gov.

Chromosomal translocations affecting 12q14-15 but not deletions of the long arm of chromosome 7 associated with a growth advantage of uterine smooth muscle cells.

Cytogenetically, uterine leiomyomata are the best investigated human tumours. The most frequent clonal abnormalities are structural rearrangements involving 12q14-15 and deletions of part of the long arm of chromosome 7. The present study investigated a possible growth advantage conferred by these abnormalities, when compared with myomata having an apparently normal karyotype. A total of 155 myomata were included in the study. All samples were obtained after hysterectomy enabling karyotype analysis of all detectable tumours. Myomata with clonal chromosome abnormalities were significantly larger than those with a normal karyotype (6.8 +/- 5.3 versus 3.4 +/- 2.1 cm; P < 0.001). However, when differentiating between the two main aberrations, this was found to be true for the myomata with 12q14-15 changes affecting the high mobility group protein IC (HMGIC) gene (8.9 +/- 5.6 cm), but not for the group of tumours characterized by deletions of chromosome 7 (3.5 +/- 2.0 cm). The results are compatible with the hypothesis that myomata develop due to an unknown event, whereas the chromosomal abnormalities act as secondary changes, with those affecting the HMGIC gene increasing the growth potential of the corresponding tumours.

HMGIC expressed in a uterine leiomyoma with a deletion of the long arm of chromosome 7 along with a 12q14-15 rearrangement but not in tumors showing del(7) as the sole cytogenetic abnormality.

Cytogenetic studies on uterine leiomyomas have shown that more than 60% of these tumors possess a normal karyotype and that 30% have clonal chromosomal aberrations. The most frequent changes are aberrations involving 12q14-15 and show rearrangements of the long arm of chromosome 7. Recently, we were able to demonstrate that in a variety of mesenchymal tumors showing 12q14-15 aberrations the HMGIC gene is rearranged thus playing a role in tumorigenesis. Here we report the results of HMGIC expression studies by RT-PCR of five uterine leiomyomas with different karyotypes. The RT-PCR studies were performed on two primary tumors showing a 12q14-15 aberration, one of which with an additional del(7) and three tumors with del(7) as the sole aberration. The tumor with the 12q14-15 aberration as the sole alteration and the leiomyoma with 12q14-15 rearrangement plus deletion of the long arm of chromosome 7 were shown to express HMGIC. In contrast, in all three tumors with the del(7) as the sole aberration no expression of HMGIC was noted.

An endometrial polyp with a rearrangement of HMGI-C underlying a complex cytogenetic rearrangement involving chromosomes 2 and 12.

Cytogenetic studies of an endometrial polyp of an 82-year-old patient revealed a karyotype 46,XX,der(2)inv(2)(p25q21)ins(2;12)(p25;q13q14)t(2;12)(q21; q15),der(12)del(12)(q13q14)del(12)(q15). By fluorescence in situ hybridization (FISH) we found the chromosome 12 translocation breakpoint to be mapping within the third intron of the HMGI-C gene also harboring the breakpoints of translocations involving 12q15 seen in uterine leiomyomas, lipomas, pleomorphic adenomas, and pulmonary chondroid hamartomas.

Structural aberrations of chromosome 6 in three uterine smooth muscle tumors.

Clonal karyotypic alterations of chromosome 6 in three uterine smooth muscle tumors are reported. In all cases an apparently identical breakpoint on the short arm of chromosome 6 was found. Two cases displayed the histologic features of cell-rich myomas with severe nuclear atypia but no clear evidence for malignancy. The remaining case was a primary uterine leiomyosarcoma of an 80-year-old patient showing an apparently balanced reciprocal chromosomal translocation, t(1;6)(p32-33;p21.3), as the sole karyotypic abnormality. This type of aberration has not been reported before in leiomyosarcomas. Because of the nuclear atypia in the other myomas with a breakpoint involving the short arm of chromosome 6 we feel that this cytogenetically recognizable but rare subgroup of uterine smooth muscle tumors warrants a careful clinical follow-up.

Rearrangements of the high mobility group protein family genes and the molecular genetic origin of uterine leiomyomas and endometrial polyps.

The results of cytogenetic studies of uterine leiomyomas have revealed that approximately 50% of these tumours are characterized by clonal chromosomal alterations. These karyotypic deviations are dominated by rearrangements involving a particular part of chromosome 12, i.e. region 12q13-15. We recently showed that the multiple aberration region on chromosome 12q15 harbours recurrent breakpoints frequently found in a variety of benign solid tumours. Within this region a gene encoding for a member of the so called high mobility group family proteins (HMG) was mapped. Further investigation revealed that this gene i.e. HMGI-C is often truncated by the chromosomal aberrations and fused to ectopic DNA sequences leading to fusion genes. Therefore, the results suggest a causal relationship between mutations of the HMGI-C gene and the development of uterine leiomyomas. Apparently identical mutations have been found also in endometrial polyps. Furthermore, there is an obvious coincidence between the chromosomal assignment of other members of the HMG family and the breakpoints of other non-random chromosome abnormalities seen in uterine leiomyomas.

Telomere repeat fragment sizes do not limit the growth potential of uterine leiomyomas.

We have compared the length of telomere repeat fragments (TRF's) in 19 uterine leiomyomas from 6 patients with the corresponding myometrium. The advantage of this study of TRF length is that cells from uterine leiymyoma and cells from corresponding myometrium do not contain any considerable proportions of other cells as revealed by analysis of clonality. In all tumor samples a loss of TRF length ranging from 1120 to 4690 bp was noted. There was no correlation between tumor volume or size of tumor population as revealed by histological examination and loss of TRF length. From the obtained TRF length data (an average myometrial TFR length of 13 kb and an average loss of TRF length in myoma cells of 83 bp per cell division) we concluded that TRF length reduction does not limit the growth potential of uterine leiomyomas.

Transabdominal Doppler-sonographic measurements of blood flow differences in the main pelvic arteries during physiological spontaneous ovarian cycles.

The Doppler flow velocity wave forms originating from the common, external and internal iliac arteries of 20 healthy volunteers were recorded in order to find out if the arteries showed characteristic velocity wave forms. Further questions included whether these flow patterns changed during the ovarian cycle and whether differences between both pelvic sides occurred. The measurements were performed at least every 3 days during ovarian cycles by using the transabdominal Duplex method. The recorded signals were quantified using the pulsatility and resistance indices (PI and RI). In addition, follicular development in the ovaries was monitored by transabdominal ultrasound and the concentrations of follicle stimulating hormone, luteinizing hormone, oestradiol and progesterone were analysed in venous blood. Nine of the 20 cycles were classified as physiological with a sufficient luteal phase and at least five cardiac cycles were needed to determine one value. The internal iliac arteries showed lower indices than the other arteries (PI, P < 0.001). In these vessels the PI decreased between the day before and the day after ovulation on both sides (PI, P < 0.02, active side). Two days before the demonstration of the corpus luteum, the side carrying the dominant follicle had a lower RI than the side of the passive ovary (RI, P < 0.02). In the luteal phase, however, the side carrying the corpus luteum showed a higher PI than the opposite side (PI, P = 0.05). No significant cyclic changes in PI and RI respectively were found in the external and common iliac arteries.

Molecular-cytogenetic refinement of the 12q14-->q15 breakpoint region affected in uterine leiomyomas.

Recent molecular and cytogenetic studies on uterine leiomyoma cell lines with aberrations in 12q14-->q15 have shown that the chromosome 12 breakpoints seem to cluster in a 260-kb region designated as ULCR 12 (uterine leiomyoma cluster region of chromosome 12 breakpoints). Here we report the results of fluorescent in situ hybridization (FISH) studies using a molecular probe composed of five different cosmids that cover a 700-kb region encompassing ULCR 12. The FISH studies were performed on primary tumor specimens of uterine leiomyomas. With the exception of one case, our results demonstrated that the cosmid pool bridges the breakpoint region 12q14-->q15 in primary tumors as well. In the remaining case signal was localized distal to the breakpoint, indicating a breakpoint outside the region covered by the cosmid pool or a deletion in the region surrounding the chromosome 12 breakpoint. Individual cosmid probes from the pool were then used to narrow the localization of the breakpoint region in both the primary leiomyomas and established cell lines. The results showed that the breakpoints involving 12q14-->q15 in the primary uterine leiomyomas and derived cell lines are clustered in a single 170-kb breakpoint region within ULCR 12. For three of the cell lines studied, the breakpoint map within a 40-kb segment covered by one cosmid.

[Contrast hysterosalpingography (or HyCoSy)]. / L'hystérosalpingosonographie de contraste (ou HyCoSy).

A new echogenic contrast medium, SHU-454 is a new method for direct imaging of fallopian tube passage in tubal diagnostics using transvaginal B-mode echography. Clinical studies in over 1,600 patients have shown that this product offers a reproducible echogenic contrast, significantly amplifies Doppler signal and is well tolerated. SHU-454 is injected through the cervix into the uterus and fallopian tubes using the same technique as for radiologic hysterosalpingography. This examination is easily performed in 5 to 10 minutes. Results, compared with two conventional methods, hysterosalpingography and chromolaparoscopy, in 115 women show that HyCoSy is a reliable procedure for detecting tubal patency. HyCoSy results totally agree with the results from the conventional methods in case of tubal patency. This technique may be suitable as an easy, quick and low-risk outpatient examination. It does not involve radiation exposure and is unlikely to cause allergic reactions such as those known to occur with iodinated contrast media. Transvaginal HyCoSy can be used to assess tubal patency early in sterility diagnostics, before adnexal or uterine (myoma) surgery or when tubes and uterine appendages cannot be seen during chromolaparoscopy.

[Cytogenetic subtyping of 139 uterine leiomyoma]. / Eine zytogenetische Subtypisierung von 139 Uterus-Leiomyomen.

A cytogenetic study of 139 uterine leiomyomas of 70 patients is presented. 26 of the tumours failed to grow, 87 showed an apparently normal karyotype and 26 tumours were characterised by clonal aberrations. In 5 tumours, a numerical change was the only abnormality, including 2 tumours with a trisomy 12. 5 myomas showed an interstitial deletion of the long arm of chromosome 7. The largest group were 9 tumours with an aberration involving chromosome 12 in the band of 14-15. 2 myomas showed a t(12; 14) as the only abnormality, in 4 tumours very complex rearrangements with up to 12 breakpoints were observed. In the last group 7 myomas with other clonal aberrations involving 11 different chromosomes were found.

The clinical significance of antisperm antibodies in infertile couples.

Sera from 150 women and 162 men with unexplained infertility were examined using a commercial enzyme-linked immunosorbent assay (ELISA) kit for antisperm antibodies. The results were compared to those of the Friberg agglutination test, the post-coital test, the sperm-cervical mucus contact (SCMC) test and the pregnancy rate. We also tested follicular fluids obtained from 38 women who underwent in-vitro fertilization (IVF). These data were compared with those obtained in serum, post-coital test data and with the later development of the oocyte in IVF. Antibodies in follicular fluid were found only in women with antibodies circulating in serum. The correlation coefficient between these was 0.88 (P < 0.001). There was no correlation between antisperm antibodies in serum found with the ELISA test, and with the agglutination test, the post-coital test or the SCMC test. Neither was there any correlation between antibodies in follicular fluid and the post-coital test, the pregnancy rate or successful IVF.

The response of uterine fibroids to GnRH-agonist treatment can be predicted in most cases after one month.

Twenty-seven patients with uterine fibroids were treated for 3 months with the GnRH-agonist goserelin prior to surgical myomectomy. Ovarian function was suppressed reliably in all patients. After three applications, 15 fibroids were reduced in volume by more than 50%, and one complete remission was achieved. Seven patients showed a decrease of 10-50% in volume. However, in 5 cases there was no significant reduction. Analysing the time course of the fibroid reduction, the response can be predicted in most cases as early as four weeks after the first injection. Retrospective statistical analysis showed that a 50% reduction in fibroid size due to GnRH treatment is preceded by a 35% reduction after 4 weeks in 81% of cases, and after 8 weeks in all cases. Only 2 of 12 fibroids, which showed a smaller response (less than 50%) to GnRH therapy, were reduced by more than 35% after 4 and 8 weeks. In most cases it seems to be possible to estimate the individual response to GnRH-application after the first injection, so that it is possible to stop therapy in non-responding patients.

Transvaginal hysterosalpingo-contrast sonography for the assessment of tubal patency with gray scale imaging and additional use of pulsed wave Doppler.

OBJECTIVE: To determine whether the additional use of pulsed wave (PW) Doppler can improve the tubal diagnosis reached with gray scale imaging in doubtful cases. DESIGN: The study is an open, uncontrolled clinical trial of women of childbearing age. SETTING: Clinical environment. PATIENTS: Seventeen female patients (23 to 37 years of age) with diagnosed sterility problems. INTERVENTIONS: The contrast agent SH U 454 was administered transcervically during transvaginal gray scale and PW Doppler sonography. MAIN OUTCOME MEASURES: Hysterosalpingo-contrast sonography by gray scale and by PW Doppler and follow-up chromolaparoscopy (n = 16) or hysterosalpingography (HSG, n = 1) were performed. The diagnostic efficacy of gray scale and PW Doppler were compared with each other and against a conventional control procedure (chromolaparoscopy or HSG). RESULTS: The gray scale findings were confirmed by PW Doppler in 5 cases on one side; confirmed by PW Doppler in 7 cases on both sides; corrected by PW Doppler in 4 cases on one side; and corrected by PW Doppler in 1 case on one side and confirmed on the other side by PW Doppler. In all 17 cases, the tubal findings after PW Doppler were confirmed by chromolaparoscopy or HSG. CONCLUSION: The additional use of PW Doppler in hysterosalpingo-contrast sonography is recommended as a supplement to gray scale imaging (1) in cases of suspected tubal occlusion and (2) in the event of intratubal flow demonstrable only over a short distance.

[Reactions to stress during the normal menstrual cycle]. / Stressreagibilität innerhalb normaler Menstruationszyklen.

In the present study, we questioned, whether the variability of physiological parameters within a menstrual cycle are connected with psychological variables like mood, state of health and positive/negative daily occurrences. We examined 20 women with normal cycles. The definition of a normal cycle was: 28 (+/- 5) days of length, standard weight according to Broca, 3-5 days menstrual bleeding, no oral contraceptive during the last 6 months, no IUP, inconspicuous hormones (no raised prolactin or testosterone levels), gynecologically unremarkable findings. Gynecological and psychological data were gathered daily during one menstrual cycle: hormone levels, vaginal ultrasound for detecting follicle growth, ovulation, corpus luteum and endometrial development. The psychological data on mood, state of health and positive/negative occurrences were recorded in parallel in the form of a diary, in which new entries were made daily. The results showed, that only 6 out of the 20 women had a normal menstrual cycle as defined above. Women with a normal (physiological) cycle, report in their diary: less negative bodily tendencies, more positive everyday situations, but the same amount of negative situations as women with noticeable cycles. Both the normal cycle group and the conspicuous cycle group report more negative body states and more negative moods in the premenstruum than the middle phase. The implications of these results are discussed.

[Sex cord stromal tumor with annular tubules in a sterility patient]. / Keimstrang-Stroma-Tumor mit annulären Tubuli bei einer Sterilitätspatientin.

We report on the case of a 24 year old patient under medical treatment, because of sterility. The diagnosis of a rare sex cord tumour with annular tubules of the ovary before pregnancy, was followed by observation during this time and finally controlled after delivery by a sphenoidal excision from both ovaries. The influence of this disease on fertility and pregnancy and the influence of pregnancy on the tumour with its therapeutical consequences, will be discussed with reference to the current literature. The tumor is no reason for sterility. During pregnancy, an operative intervention may be inevitable. The histological status seems to be unchanged during pregnancy.

Hysterosalpingo-contrast sonography of the uterus and fallopian tubes: results of a clinical trial of a new contrast medium in 120 patients.

The feasibility, diagnostic efficacy, and patient tolerance of a new diagnostic modality, hysterosalpingo-contrast sonography (HyCoSy), were evaluated in a clinical study of 120 patients with suspected infertility. A new echogenic contrast medium for ultrasound was administered transcervically with conventional tools for hysterosalpingography or a balloon catheter. The flow of multiple fractions of the contrast medium through each fallopian tube was observed in real time in appropriate imaging planes by means of a transvaginal probe. All patent tubes were diagnosed correctly with HyCoSy, results comparing well with findings at hysterosalpingography or laparoscopy. With B-mode scanning only, sensitivity was 88% for the right tube and 90% for the left; specificity was 100% for each tube. The supplementary use of Doppler techniques (duplex, color Doppler) provided additional information in special cases of suspected tubal occlusion and led to an improvement in diagnostic accuracy. The contrast agent was well tolerated. HyCoSy demonstrates normal anatomy and tubal patency with high reliability and permits advance selection of patients in whom more invasive diagnostic procedures may be required.

[Transvaginal contrast hysterosalpingo-sonography with the B-image procedure and color-coded duplex sonography for the assessment of fallopian tube patency]. / Transvaginale Hysterosalpingo-Kontrastsonographie (HKSG) im B-Bild-Verfahren und in der farbcodierten Duplexsonographie zur Abklärung der Tubenpassage.

Transvaginal hysterosalpingo-contrast-sonography (HYCOSY), a new method for the direct assessment of tubal patency by means of ultrasonography, was employed in 68 women with infertility problems. In 67 cases, the findings were compared with hysterosal-pinography or chromolaparoscopy, performed either subsequently while the patient was still under the anaesthetic or later. The contrast demonstration of the Fallopian tubes was performed with the B mode procedure in 54 cases (Group 1) and by means of colour-coded duplex sonography in 14 (Group 2). In Group 1, the findings agreed completely in 39 cases, partially in 14 and not at all in one. In Group 2, in which 13 of the 14 cases were compared, the findings were identical in 9 cases and partially in 4. From the point of view of image documentation, the more vivid demonstration of free tubal passage in colour Doppler sonography compared to the simple B mode appears to be an advantage. Further studies are needed to determine whether contrast-perfused but dislocated tubes can be detected more easily and quickly with colour Doppler than in B mode.