[Breast cancer: adjuvant therapy with trastuzumab: herceptin adjuvant (HERA) Trial Study, B-31- and N9831-Study].
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Antibodies, Monoclonal↗
Biomedical subjects
P Mallmann
Publications and source records attributed to P Mallmann.
Strong evidence that the common variant S384F in BRCA2 has no pathogenic relevance in hereditary breast cancer.
INTRODUCTION: Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10). METHODS: For co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated. RESULTS: We identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 x 10-8 in favour of neutrality of the variant. CONCLUSION: Our data provide conclusive evidence that the S384F variant is not a disease causing mutation.
Adult↗
Differential indication for histological evaluation of endometrial fluid in postmenopause.
OBJECTIVES: The endometrium carcinoma is the most frequent malignancy of the female genital tract. Approximately, 10-20% of all patients with an endometrial carcinoma are free of symptoms until the time of diagnosis. The frequent occurrence of an endometrial carcinoma in connection with intrauterine cavity fluid collection (sero- or mucometra) has been discussed controversially in literature. What are the hysteroscopic and histological findings in patients with sonographically determined endometrial fluid in postmenopause, and how should these findings be interpreted? METHODS: 74 patients, in whom endometrial fluid without bleeding disorders had been diagnosed during routine transvaginal sonography, underwent hysteroscopy conducted with a 4.5 mm optics and dilatation and curettage (D&C). The median age of the patients was 68 years with a range of 32 years. RESULTS: The simple thickness of the endometrium, i.e. single layer measured sonographically at the point of maximal thickness, was on average 5.7 mm +/- 3.6 mm (2-15 mm). Hysteroscopically, an endometrium polyp was found in 23 cases (31.1%), endometrium hyperplasia in 12 (16.2%), and an atrophy in 35 cases (47.3%). In four cases (5.4%), an endometrial carcinoma was suspected. The histological results were consistent with the hysteroscopic findings. In all instances, in which the simple endometrial thickness amounted to 3 mm or less, an atrophic endometrium was found. The frequency of intrauterine pathologies increased significantly with a greater thickness of the endometrium. In 80% of patients, a cervical stenosis existed. CONCLUSIONS: Endometrial fluid by itself, without assessment of the endometrium, does not indicate the requirement for additional histological clarification. As diagnostics, the authors suggest especially the endometrial morphology.
Aged↗
DNA integrity and motility of human spermatozoa after standard slow freezing versus cryoprotectant-free vitrification.
BACKGROUND: In contrast to the technique of conventional freezing, the vitrification of spermatozoa requires high cooling rates (720 000 degrees K/min), which could be damaging for spermatozoa. The aim of our study was to compare slowly frozen and vitrified spermatozoa in terms of their post-thaw DNA integrity and motility. METHODS: Semen samples were prepared according to the routine swim-up technique and divided into aliquots for comparison of fresh, conventionally frozen and vitrified spermatozoa from the same ejaculate in the presence or absence of cryoprotectants. Spermatozoa motility and DNA integrity were determined. RESULTS: The motility of spermatozoa conventionally (slowly) frozen with a cryoprotectant was similar to that recorded for spermatozoa vitrified in the absence of cryoprotectant (47 versus 52%). The DNA integrity was unaffected by the cryopreservation method or presence of cryoprotectants. CONCLUSION: The vitrification of human spermatozoa in the absence of conventional cryoprotectants is indeed feasible. The DNA integrity of vitrified sperm is comparable with that shown by standard slow-frozen/thawed spermatozoa, yet the method is quick and simple and does not require special cryobiological equipment.
Cryopreservation↗
PTEN mutations do not cause nuclear beta-catenin accumulation in endometrial carcinomas.
PTEN: and beta-catenin mutations constitute the predominant genetic alterations in endometrioid carcinomas of the endometrium. PTEN encodes a dual-specificity phosphatase with lipid phosphatase and protein tyrosine phosphatase activities that regulate both apoptosis and interactions with the extracellular matrix. Recent studies have associated PTEN mutations with tumorigenesis of prostate carcinoma via the Wnt signaling pathway, leading to nuclear beta-catenin accumulation. To elucidate the potential interaction of PTEN and beta-catenin in endometrial cancer, we performed mutation analyses of the entire PTEN gene and of exon 3 of the beta-catenin gene that is most frequently targeted by mutations. A total of 82 endometrial carcinomas comprising 62 type I endometrioid carcinomas and 20 type II high-grade carcinomas were investigated. In addition in a subset of 22 carcinomas, the intracellular beta-catenin distribution was analyzed by immunohistochemistry. Overall, 20 (24.4%) of 82 tumors revealed mutations in the PTEN gene, and 16 (19.5%) of 82, in the beta-catenin gene. Six tumors (7.3%) showed mutations in both the PTEN and beta-catenin gene. Mutations were mainly detected in endometrioid carcinomas of the endometrium. As expected, a striking nuclear accumulation of beta-catenin could be shown in tumors with beta-catenin mutations. In the vast majority of tumors with PTEN mutations, a regular staining pattern of the cytoplasmic and membranous compartments was found. We therefore conclude that, in contrast to prostate cancer, mutations in the PTEN gene seem not to affect cellular distribution of the beta-catenin protein in endometrial carcinomas.
Carcinoma, Endometrioid↗
Comparison of necrosis in human ovarian tissue after conventional slow freezing or vitrification and transplantation in ovariectomized SCID mice.
This paper examines and compares necrosis in human ovarian tissue after conventional slow freezing or vitrification and ensuing xenotranplantation. Slow cryoconserved or vitrified ovarian tissue samples and fresh controls from nine patients were subcutaneously transplanted into SCID mice. The tissue samples were explanted after 6 weeks and the necrotic areas were examined by staining with Lucifer yellow SV. The size of the necrotic areas in parallel cultivated ovarian tissue samples was compared, as was necrosis in cultivated prostate tumour spheroids where the emergence of necrosis and its pathophysiological correlation have been described. Examinations showed no significant rise in the proportion of necrotic areas after slow cryoconservation/transplantation and in the controls (transplanted fresh tissue, not transplanted fresh tissue, long-term culture). The proportion of necrotic areas in the tumour spheroids was significantly higher than in the ovarian tissue. Vitrification could, after these results, be presented as an alternative to conventional slow cryoconservation.
Adult↗
[Diagnostic value of preoperative contrast-enhanced MR imaging of the breast].
PURPOSE: To evaluate preoperative contrast enhanced MR imaging in clinically, mammographically and/or ultrasonographically established breast cancer. MATERIALS AND METHOD: From September 1998 to August 1999, preoperative contrast-enhanced MR imaging of the breast was performed in 91 patients with lesions highly suggestive of malignancy (BIRADS IV and V) by clinical, mammographic, and/or ultrasonographic criteria. MR imaging findings were postsurgically correlated with other imaging, intraoperative and histopathologic results. RESULTS: Histopathologic analysis revealed 61 (66 %) malignant and 31 (34 %) benign lesions. In 63 (69 %) of the 91 investigated patients, MR mammographies were classified as tumor suspect and in the remaining 28 (31 %) cases as benign. The sensitivity, specificity and accuracy were 90 %, 67 % and 81 % for contrast-enhanced MR imaging. Additional tumor manifestations (multifocal or multicentric disease, contralateral carcinoma) were found by MR imaging alone in 10 patients (11 %). CONCLUSION: Contrast-enhanced MR imaging may reveal unsuspected multifocal, multicentric or contralateral breast carcinoma that changes the surgical therapy if the intention is total tumor removal. The prognostic role of a potentially more radical surgical therapy on the basis of these findings is not clear.
Breast↗
Construction of phage display libraries from reactive lymph nodes of breast carcinoma patients and selection for specifically binding human single chain Fv on cell lines.
The display of recombinant antibody fragments on the surface of filamentous phage mimicks B cells and is therefore a technology ideal to generate antibodies against any potential target antigen in vitro. In order to obtain tumor specific, high-affinity single chain antibody fragments (scFv), it has been speculated that lymph node tissue from cancer patients infiltrated with activated B cells must be a valuable source of antibody V-genes. The aim of this study was to generate a human scFv-phage library from lymph nodes of patients with breast cancer and to develop a stringent depletion and selection protocol in order to isolate specific single chain antibodies recognizing potentially new antigens in breast cancer. The amplification of the V-genes cloned from regional lymph node tissue and their assembly to single chain variable fragments was optimized in terms of library size and diversity. A large set of degenerated primers, annealing to all known V-gene families, was designed and used under optimized PCR conditions. The amplified V-genes were genetically fused in all possible combinations and cloned into a phagemid vector. Depletion and selection on mammary epithelial and primary breast carcinoma cell lines, respectively led to the isolation of a breast cancer cell line specific scFv (BCK-1 scFv) from this patient-derived scFv-phage display library as demonstrated in polyclonal and monoclonal ELISA, using immobilized cell membrane fractions of the indicated cell lines. A new recombinant breast cancer cell line specific antibody based on V-genes derived from reactive B-lymphocyte-infiltrated lymph nodes of patients with breast cancer was isolated via phage display, performing stringent depletion and selection protocols. We believe that this combination of antibody V-gene source and elaborated phage display depletion and selection strategy will be successful for the retrieval of numerous other recombinant, tumor specific antibody fragments.
Amino Acid Sequence↗
Ultra-structure of intracellular lipid vesicles of porcine GV-oocytes after in vitro fertilization and parthenogenetic activation.
The aim of our investigation was to compare the ultrastructure of lipid droplets in porcine pronuclear oocytes obtained after in vitro fertilization (IVF) or parthenogenetic activation (PGA) of Metaphase II (MII) oocytes. The ultrastructure of lipids in the IVF or PGA pronuclear oocytes after vitrification was also studied. There are two kinds of lipid droplets in porcine GV oocytes: 'dark' and homogenous vesicles next to 'grey' vesicles with electron-lucent streaks. After IVF or PGA and following 16-h culture, only the presence of 'grey' vesicles was detected in IVF and PGA oocytes. Ultra-structure of lipid vesicles of PGA and IVF oocytes was similar. The PGA oocytes can be as model of the two pronuclear stage IVF oocytes.
Animals↗
Oncogenic human papillomavirus DNA loads in human immunodeficiency virus-positive women with high-grade cervical lesions are strongly elevated.
Human papillomavirus (HPV) DNA loads of six oncogenic HPV types were measured by real-time PCR in cervical scrapes of human immunodeficiency virus (HIV)-infected and uninfected women. In both groups, HPV loads increased with the grade of cervical disease. HIV infection did not affect HPV loads in low-grade lesions but was associated with significantly higher HPV loads in severe dysplasia; highest loads were found in advanced HIV disease. Our data reflect the aggressive course of HPV infection in HIV-positive women.
Adolescent↗
[Dietary prevention of carcinomas of the breast and prostate: fundamental and practical aspects of the Nutritional Cancer Prevention (NCP) program].
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Alcohol Drinking↗
Weekly carboplatin and docetaxel for locally advanced primary and recurrent cervical cancer: a phase I study.
OBJECTIVE: The aim of this study was to determine the dose-limiting toxicities (DLTs) and maximum tolerated doses (MTDs) of a docetaxel-carboplatin regimen in patients with locally advanced cervical cancer (LACC) or recurrent cervical cancer. The regimen was administered weekly, with a maximum of 12 courses. PATIENTS AND METHODS: Twenty patients were treated with with a total of 145 cycles of weekly carboplatin and docetaxel. The starting dose of docetaxel was 25 mg/m(2) with increments of 5 mg/m(2) until a final dose of 35 mg/m(2) was reached. Dose-escalation of docetaxel was followed by carboplatin at AUC 2, AUC 2.5, and AUC 3, respectively. Defined dose-limiting toxicities were WHO grade (G) 3 hematotoxicity, G4 mucositis, and G2 neurotoxicity. The response status of the patients was assessed using the common ECOG response criteria. RESULTS: Two of four patients developed a DLT at dose level 4. Nonhematological toxicity was generally mild, except for ubiquitous complete alopecia. The MTD was reached at docetaxel 35 mg/m(2) and carboplatin AUC 2 mg/mL.min. The overall response rate was 65% in the entire group of evaluable patients and 77% in patients with primary LACC, with two cases of pathological complete response. CONCLUSION: This dose-dense regimen was well-tolerated and could be administered on an outpatient basis.
Adult↗
Prognostic value of repeated serum CA 125 measurements in first trimester pregnancy.
OBJECTIVE: To assess the diagnostic value of maternal CA 125 in patients with symptomatic first trimester pregnancy and to evaluate the prognostic significance of CA 125 versus beta-hCG in early pregnancies with intact fetal heartbeat, complicated by vaginal bleeding. STUDY DESIGN: Two prospective open-label studies with longitudinal follow-up in the second trial. SETTING: Academic Department of Obstetrics and Gynecology, University of Cologne. PATIENTS: Study 1: 168 patients presenting between gestational weeks 6 and 12 with: extrauterine pregnancy, 29; missed abortion, 50; incomplete spontaneous abortion, 38; imminent abortion, 33; and normal pregnancy (no history of endometriosis or ovarian mass), 18. Study 2: Fifty consecutive patients with vaginal bleeding during gestational weeks 6-12 all of whom having demostrable fetal heartbeat. Eighteen patients finally aborted whereas the remainder had normally continuing pregnancy until term. MAIN OUTCOME MEASURE: Study 1: Single serum determinations of CA 125 and beta-hCG were correlated with the different disorders observed. Study 2: Two sequential measurements of serum CA 125 and beta-hCG performed within a 5-7 days interval were related to the outcome of pregnancy as indicated by changes of the ultrasound presentation, miscarriage, future hospitalization, or delivery. RESULTS: Study 1: Patients with vaginal bleeding generally had higher median CA 125 values (38 IU/ml; range 1.3-540) compared to non-bleeding patients (17.8 IU/ml; range 1.0-157). No statistically significant differences in regard to median serum CA 125 levels between symptomatic and normal pregnancies occurred: normal pregnancy, 25.5 IU/ml (range 3.2-97); ectopic pregnancy, 26 IU/ml (range 1.3-157); missed abortion, 19.1IU/ml (range 1-242); threatened abortion, 48 IU/ml (range 5.2-540); spontaneous abortion, 40 IU/ml (range 5.4-442). Study 2: Initial CA 125 levels did not differ significantly between both groups of patients with 27/32 non-aborters and 13/18 aborters showing concentrations below 65 IU/ml. After 5-7 days, CA 125 in all patients who eventually aborted remained high or increased whereas non-aborters all had constantly low or steeply declining CA 125 measures. beta-hCG increased in all non-aborters but also in 13/18 aborters during the 5-7 day interval. CONCLUSION: Single serum measurements of CA 125 in symptomatic first trimester pregnant patients failed to discriminate spontaneous abortion, ectopic or normal pregnancies. However, sequential determinations of maternal CA 125 measurements appear to be a highly sensitive prognostic marker in patients with viable pregnancy at risk for abortion.
Abortion, Spontaneous↗
Gasless laparoscopy as an option for conservative therapy of adnexal pedical torsion with twin pregnancy.
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Abdomen, Acute↗
[Uterus septus with primary infertility - an operating indication?].
OBJECTIVE: The following retrospective study is intended as a contribution towards determining the necessity of a hysteroscopic metroplasty in patients with primary infertility. - MATERIAL AND METHODS: 21 patients with primary infertility and a septate uterus, who had undergone a hysteroscopic dissection of the septum between 1993 and 2000, were evaluated. With the help of medical records, operation reports, standardised questionnaires as well as telephone contact with the patient's doctor and/or the patient, anamneses, operation as well as postoperative development were recorded. - RESULTS: All dissections of the septum occurred without complication. During follow-up (median 24.0 +/- 23.7 months), 11/21 patients became pregnant (52.4 %). Of these 11 pregnancies, 7 ended (63.3 %) at full-term, 2 (18.2 %) prematurely and one (9.1 %) as a miscarriage. One pregnancy is currently in the 3(rd) trimester. - CONCLUSIONS: The hysteroscopic metroplasty demonstrates a low intra- and postoperative rate of complication. Particularly the indication of a lower rate of miscarriages, possibly of an increase in the pregnancy rates, should, in our opinion, give reason to proceeding with a diagnostic hysteroscopy, especially prior to extensive sterility therapies. Where suspicion exists of a septum > 1.0 cm, this should be corrected by means of an operative hysteroscopy.
Adult↗
Measurement of apoptosis in long-term cultures of human ovarian tissue.
At present, the long-term culture of ovarian tissue is problematic. The aim of this study was to measure apoptosis in long-term cultures of human ovarian tissue. Biopsies of human ovaries were cultured for 6 weeks. Samples were taken weekly for histological investigation. The apoptotic cells were marked with anti-caspase 3. Simultaneous to this experiment, other tissue samples were preincubated for 3 h with 1 micromol staurosporine l(-1), an inducer of apoptosis, and apoptosis was compared among samples. Furthermore, the proportion of lethal cells was determined weekly. After 6 weeks, 99% of the tissue samples showed an intact structure. They expanded in all directions on the floor of the multi-wells to form a monolayer. Apoptotic cells could be marked only sporadically (16.3 +/- 5.9 fluorescence (counts per 3600 microm(2))) after 6 weeks. After preincubation with staurosporine after the same period of culture, the proportion of apoptotic cells was significantly increased compared with that in untreated control samples (66.8 +/- 14.5 versus 16.3 +/- 5.9%, respectively; P < 0.05). Under the same experimental conditions, the proportion of lethal cells was 3.6 +/- 0.9, 3.9 +/- 2.1 and 5.2 +/- 1.5% for weeks 1, 3 and 6, respectively. After preincubation with 1 micromol staurosporine l(-1), the proportion of pyknotic cells after 6 weeks of culture was significantly higher (37.2 +/- 4.4%) than that in control samples (3.95 +/- 2.05%; P < 0.05). No significant increase in apoptosis in cultured human ovarian tissue after 6 weeks was observed compared with control tissues on day 1. These results indicate that under optimal culture conditions it is possible to cultivate human ovarian tissue long term. The influence of long-term culture on hormone synthesis and follicle maturity will be investigated further.
Adult↗
[MRI-controlled preoperative wire marking of uncertain breast lesions].
PURPOSE: Small suspicious breast lesions that are only visible at MR imaging were preoperatively marked with a hook wire under MR-guidance to allow the removal of the lesion with tissue-sparing surgery. METHOD: In all patients the suspicious lesions were marked preoperatively under MR guidance with a hook wire using a commercially available stereotactic device. Interventions were performed with MR guidance on a 1.0 T and on a 1.5 T system. RESULTS: In 19 patients 22 lesions were localized. One lesion was missed and removed in a second procedure. The mean duration for localization was 66 +/- 20 min (range 38-119 min). In two patients two lesions were localized. The mean deviation of the wire tip to the lesion was 2.0 +/- 2.6 mm. In this series, 6 of 22 lesions were malignant. The mean diameter of the lesion was 7.6 +/- 2.6 mm (range 3-14 mm). CONCLUSION: Suspicious breast lesions detectable only in MR imaging can be accurately localized with a hook wire preoperatively under MR control to remove the lesion with a tissue-saving surgery.
Adult↗
Intra-arterial mitoxantrone and paclitaxel in a patient with Stewart-Treves syndrome: selection of chemotherapy by an ex vivo ATP-based chemosensitivity assay.
We report on a 72-year-old patient developing Stewart-Treves syndrome (STS) of the right arm 9 years after curative irradiation for ipsilateral stage III breast cancer. Facing the poor track record of both irradiation and chemotherapy in this highly malignant lymphangiosarcoma, amputation was recommended but refused by the patient. Therefore, limb conserving-therapy using three courses of intra-arterial mitoxantrone (MX) and paclitaxel (PTX) was attempted. This novel chemotherapy protocol was selected by pretherapeutic ex vivo ATP-based chemosensitivity testing of autologous tumor tissue. The patient experienced complete response, which was subsequent histologically confirmed by compartment resection. When developing recurrent STS outside of the perfused area 6 months after primary therapy, the patient was retested and reinduced with three other courses of intraarterial MX/PTX which again produced durable complete remission. This case demonstrates the benefit of indivdualized therapy in this prognostically desperate disease allowing both limb conservation and maintained quality of life.
Adenosine Triphosphate↗