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Biomedical subjects

E F Solomayer

Publications and source records attributed to E F Solomayer.

At least 19 recordsLinked to original sources
PubMed2006

Detection of disseminated tumor cells in patients with gynecological cancers.

OBJECTIVES: The presence of disseminated tumor cells (DTC) in breast cancer patients is associated with poor prognosis. However, there are limited data about the prevalence and prognostic impact of DTC in patients with gynecological tumors. The aim of this study was to evaluate the presence of DTC in the bone marrow (BM) of patients with gynecological cancers and to correlate their presence with established prognostic factors. METHODS: BM aspirates of 201 patients with primary ovarian (n=69), cervical (n=54) and endometrial cancer (n=78), undergoing surgery at the Department of Gynecology and Obstetrics, University Hospital, Tuebingen, Germany between 1/2002 and 01/2006, were included into the study. Cytokeratin (CK)-positive cells were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3. RESULTS: The bone marrow positivity rate was 36% in ovarian, 26% in cervical and 17% in endometrial cancer, respectively. Presence of DTC was significantly correlated with FIGO (International Federation of Gynecology and Obstetrics) tumor stage (p<0.05). The recurrence rate was 14% in patients with CK-positive cells compared to 8% in CK-negative patients (p=0.2). There was no correlation between DTC and other established prognostic factors including nodal status or grading except for cervical cancer. Patients with positive lymph node status were more likely to be bone marrow positive compared to those with negative lymph node status (p<0.05). CONCLUSIONS: Disseminated tumor cells seem to be a general phenomenon in epithelial tumors even though their clinical impact remains to be evaluated. The hypothesis that bone marrow is the homing site of disseminated tumor cells is further supported by these data since gynecological tumors only rarely metastasize to the skeletal system.

Bone Marrow↗
PubMed2005

Methods for isolating circulating epithelial cells and criteria for their classification as carcinoma cells.

Novel assay methods developed for the isolation and characterization of circulating tumor cells (CTC) of epithelial origin offer the potential of markers for the non-invasive gathering of clinical information relevant to the diagnosis, evolution and treatment of carcinoma. Of the numerous techniques currently used to analyze CTC, slide-based assays are perhaps the most common. While traditional combined immunocytochemical/brightfield microscopy systems continue to be the most frequently employed, fluorescence-based analysis is gaining in importance. This is partly because fluorescence microscopy analysis of slide-mounted CTC can provide simultaneously cytogenetic as well as morphologic and multiple phenotypic information. In particular, fluorescence microscopy analysis of slide-mounted CTC can accurately determine genetic changes at the chromosomal level in patients with recurrent disease. More importantly, by identifying genetic aberrations in CTC, it becomes possible to choose those patients most likely to benefit from a given treatment. The potential of this technique has already been demonstrated by employing fluorescence in situ hybridization (FISH) methods to measure expression of the HER2/neu gene in tissue from patients with breast carcinoma for the specific purpose of identifying those patients most likely to respond to Trastuzumab targeted therapy. Here, we review the major methodologies used in the preparation and analysis of the slide-based assays.

Carcinoma↗
PubMed2004

Hemodynamic changes with phenotype reversal during pregnancy in twin-twin transfusion syndrome.

OBJECTIVES: We report an atypical case of twin-twin transfusion syndrome (TTTS) in monochorionic-diamniotic twins with arterio-arterial anastomoses in which the former donor became the recipient during pregnancy. METHODS: Serial sonographic monitoring was performed. RESULTS: There was a phenotype reversal in TTTS concerning growth and amniotic fluid ending at 27 weeks, with the dominance of the former smaller donor. Doppler sonography changed from absent enddiastolic flow of the donor to normal values in both twins. The new recipient showed transient ascites, the now smaller actual donor (former recipient) developed progressive cardiomegaly, hypertrophy of the myocardium and mitral and tricuspid insufficiency at 29 weeks. Doppler sonography in the new donor deteriorated to highly pathologic flow in the venous system, leading to cesarean section. The donor fetus died 12 h after delivery because of myocardial decompensation. The recipient did very well and was discharged 8 weeks later from the neonatology unit. CONCLUSION: This atypical course shows the importance of serial sonographic monitoring in pregnancies with TTTS.

Adult↗
PubMed2001

Enrichment of memory T cells and other profound immunological changes in the bone marrow from untreated breast cancer patients.

Previous studies with animal tumors showed that bone marrow (BM) is a privileged site where potentially lethal tumor cells are controlled in a dormant state by the immune system. Here, we investigated BM of breast cancer patients with respect to tumor cell content, immune activation status and memory T-cell content. BM-derived cells from primary operated breast cancer patients (n = 90) were compared with those from healthy donors (n = 10) and also with cells from respective blood samples. Cytokeratin 19-positive tumor cells were detected by nested polymerase chain reaction. Three-color flow cytometry was used to identify numbers and activation state of T cells, natural killer (NK) cells, monocytes/macrophages and subsets by a panel of monoclonal antibodies (mAbs). The proportion of memory T cells among the CD4 and CD8 T cells was much higher in BM of cancer patients than in healthy donors (p < 0.001). The extent of memory T-cell increase was related to the size of the primary tumor. Patient-derived BM memory CD8 T cells could be shown to contain specific HLA-A2/Her-2/neu(369-377) tetramer binding cells. Patients with disseminated tumor cells in their BM had more memory CD4 T cells and more CD56(+) CD8(+) cells than patients with tumor cell-negative BM. Only some of the immunological changes seen in BM samples of cancer patients were also detectable in peripheral blood samples. Our hypothesis that BM is a special compartment for immunological memory and tumor dormancy is supported by the above findings. The overall results reveal that BM is a valuable additional compartment for immune diagnosis in pathological conditions and possibly for follow-up treatment strategies.

Adult↗
PubMed2001

Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow.

In an analysis of 84 primary-operated breast cancer patients and 11 healthy donors, we found that the bone marrow of most patients contained memory T cells with specificity for tumor-associated antigens. Patients' bone marrow and peripheral blood contained CD8+ T cells that specifically bound HLA/peptide tetramers. In short-term culture with autologous dendritic cells pre-pulsed with tumor lysates, patients' memory T cells from bone marrow (but not peripheral blood) could be specifically reactivated to interferon-gamma-producing and cytotoxic effector cells. A single transfer of restimulated bone-marrow T cells into NOD/SCID mice caused regression of autologous tumor xenotransplants associated with infiltration by human T cells and tumor-cell apoptosis and necrosis. T cells from peripheral blood showed much lower anti-tumor reactivity. Our findings reveal an innate, specific recognition of breast cancer antigens and point to a possible novel cancer therapy using patients' bone-marrow-derived memory T cells.

Amino Acid Sequence↗
PubMed2001

Time independence of the prognostic impact of tumor cell detection in the bone marrow of primary breast cancer patients.

PURPOSE: Tumor cell detection (TCD) in bone marrow is an outstanding prognostic factor in breast cancer. There is only one other study that has investigated more than 300 patients with a median follow-up of more than 5 years (J. L. Mansi et al., Lancet, 354:197-202, 1999). We report data from 727 patients with a median follow-up period of 6.5 years. EXPERIMENTAL DESIGN: In a prospective study, intraoperatively aspirated bone marrow was screened for micrometastatic cancer cells. We used an immunocytological method (monoclonal mucin antibody 2E11; the avidin-biotin complex method). RESULTS: Forty-three percent of the patients were TCD positive. Sixty percent of the patients with distant metastases were tumor cell positive (155 of 258 patients). Forty-nine percent of the patients with positive TCD developed distant metastases (155 of 315 patients). TCD was an independent prognostic factor for clinical outcome after a median follow-up time of 6.5 years. The prognostic impact of TCD and tumor size remains constant with the time, whereas the impact of grading and progesterone receptor on risk seems to decrease with longer follow-up time. CONCLUSIONS: TCD remains an independent prognostic factor The impact of TCD does not change with longer follow-up time. TCD is a reliable prognostic factor and provides important information about the process of metastasis.

Adult↗
PubMed2000

Bisphosphonates and the prevention of metastasis: first evidences from preclinical and clinical studies.

BACKGROUND: Bisphosphonates have been used successfully for many years in the treatment of hypercalcemia and to reduce skeletal-related complications of metastases. In the first years of bisphosphonate use, the efficacy of these substances was thought to lie purely in the inhibition of osteoclasts. However, there is recent evidence to suggest that an antitumor effect also may play a role. As well as having an apoptotic and antiproliferative effect on osteoclasts, bisphosphonates may exert a similar influence on macrophages and tumor cells. METHODS: The current investigation summarizes all results published to date that deal with the potential antitumor properties of the bisphosphonates. On the one hand, these include results from basic research into the action mechanism and preventative models in animals. In addition, the results of initial clinical experience with metastasis prophylaxis with bisphosphonates in breast carcinoma patients are presented and interpreted. RESULTS: Improvements in the survival time of certain subpopulations have been found in many Phase III studies with bisphosphonates to date, both in the setting of metastatic breast carcinoma and in multiple myeloma. Some preclinical studies showed that down-regulation of bone metabolism by bisphosphonates is associated with a lower incidence of bone metastases and destruction in animals, whereas activation is correlated with a higher number of metastases. However, varying results were found in animal experiments with regard to the effect of bisphosphonates on the incidence and growth pattern of nonosseous metastases. The results of three randomized studies in patients with primary breast carcinoma in which patients received 1600 mg clodronate orally have now been evaluated and presented. All three studies arrived at different results. Because the dose was identical in all three studies, the differing results can only be either random or methodologic (inclusion criteria, sample size, etc.). CONCLUSIONS: Overall, the results are very promising but need confirmation in further studies. At the moment, we have more open than answered questions. First, it is unclear whether this type of adjuvant therapy with bisphosphonates should be given continually by the oral route, or whether an intravenous interval therapy could produce the same results. It is also uncertain whether the doses used in a palliative setting are optimal or whether lower doses might also suffice. The optimum period of adjuvant treatment is also subject to debate. What is clear, however, is that confirmation of the initial clinical results will open a new chapter in the treatment of malignant tumors.

Animals↗
PubMed2000

[Micrometastatic cells in the bone marrow of patients with breast carcinoma].

BACKGROUND: The immunocytological detection of disseminated epithelial cells in bone marrow in patients with breast cancer has been performed at many hospitals and institutes since the early 1980s. Despite numerous publications in this field, it has not been possible to standardize the method and establish the ideal antibody, either nationally or internationally. Molecular biological methods using PCR technology could extend the diagnostic spectrum. However, one of the major problems in breast cancer is the lack of a disease-specific marker gene. As a result, immunocytology is still the standard procedure for tumour cell detection. METHODS: The detection of disseminated single cells in bone marrow in primary breast cancer (also known as minimal residual disease) is a new prognostic factor for disease-free and overall survival. This has been demonstrated in three large (N > 300) groups and several small to medium groups (N = 50-300). As a marker of dissemination in a target organ for metastasis this prognostic factor corresponds much more closely to the tendency of breast cancer to early haematogenic spread. Tumour cell detection may predict the course of the disease better than the axillary lymph node status. Bone marrow aspiration and detection of disseminated cells might replace lymph node dissection, at least in those patients with small tumours and no clinical signs of lymph node involvement. This strategy will soon be investigated in appropriate studies. Another possible clinical use might be deciding on whether or not to give adjuvant systemic therapy to node-negative patients. Patients with positive tumour cell detection are at a higher risk of subsequent metastasis, even if the axillary nodes are histologically normal. APPLICATION OF METHODS: The immunohistological or molecular biological detection of tumour cells in axillary lymph nodes might also be very useful, now that is has been shown that a considerable subset of patients determined to be node-negative by means of conventional methods, are positive according to these new techniques. These methods could be a useful supplement to sentinel node biopsy. A further potential use of this method is in monitoring therapy with new treatment modalities such as gene therapy and immunotherapy. Repeated bone marrow aspiration can provide information on the success of therapy in minimal residual disease (cytoreduction). Immunocytochemical investigation of individual cells may be useful in studying the pathogenesis of metastasis, in particular in the skeleton. Phenotyping of cells might allow statements to be made in the metastatic potential of cells and the question of cell dormancy. It remains to be hoped that this aspect of minimal residual disease will be granted more attention in future.

Bone Marrow↗
PubMed2000

Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis.

Although metastasis is a frequent event in breast cancer patients, insight into the clinical course, prognosis and therapy with respect to the site of the first metastases has been poor and contradictory in former investigations. Follow-up data from 648 patients with metastatic breast cancer were statistically analyzed. Patients with bone metastases at first relapse had better overall survival (median 71 vs. 48 months; p < 0.001) and survival after first metastases (median 24 vs 12 months; p < 0.001) than patients with visceral metastases at first relapse. Bone was the site of first metastasis in 46%, and 71% of patients with metastatic breast cancer developed bone metastases. The localization of the second metastatic site was of prognostic relevance in patients with first visceral metastases, but not in patients with first bone metastases. The presence of osseous metastases correlated significantly with estrogen and progesterone receptor positivity, tumor grading I/II and S-phase fraction <5%. The better prognosis of patients with bone metastases is not determined exclusively by hormone receptor status. The disease is significantly more stable in patients with first bone metastases than in those with first visceral metastases.

Abdominal Neoplasms↗
PubMed2000

Treatment of metastatic bone disease in breast cancer: bisphosphonates.

Like other metastases, bone metastases in breast cancer patients are not only a sign of the incurable nature of the underlying disease, but are also associated with specific complications. In particular, bone pain and pathological fractures impair the quality of life of those affected. Any treatment concept must, therefore, place the highest priority on preventing or reducing skeletal complications. There are two treatment options--local and systemic. Local therapy includes radiotherapy as well as surgical and orthopedic measures. The four pillars of systemic treatment are hormone therapy, chemotherapy, antiresorptive therapy with bisphosphonates, and treatment with centrally and/or peripherally acting analgesics. A precondition for successful treatment is close cooperation between medical/clinical oncologists, radiotherapists, surgeons/orthopedists, gynecologists, pain specialists, and endocrinologists (in the presence of a hypercalcemic syndrome). Patients with breast cancer associated solely with osseous metastasis may live for a number of years. It is, therefore, all the more important to start appropriate therapeutic measures early. Bisphosphonates play a particularly valuable role, since their main effect lies in the prevention of skeletal complications. Rather than replacing antineoplastic therapy, this class of substances supplements other treatments. Once started, bisphosphonate therapy should be given for the remainder of the patient's life, even in the event of osseous progression.

Analgesics, Non-Narcotic↗
PubMed1999

Does the measurement of four fetal arteries provide more information than the measurement of just two arteries in prenatal Doppler sonography?

OBJECTIVE: The objective of this study was to evaluate whether the measurement of two or more fetal arteries provides more information and leads to a selection of fetuses at higher risk. DESIGN: In 244 pregnancies Doppler examinations in four fetal arteries (fetal aorta, common carotid artery, middle cerebral artery, umbilical artery) were performed. The evaluation of the results was made by means of a Doppler score for standardization and systematization. The results were divided into four groups (normal, pre-pathological, pathological, highly pathological) and the individual correlations with fetal outcome parameters were investigated. The results from measuring only two fetal arteries (the fetal aorta and middle cerebral artery) were then compared with those from all four arteries. RESULTS: Increasing pathology of the Doppler score correlated with fetal outcome parameters. The results showed that if the Doppler result in the two-vessel measurement was normal (n = 180), pre-pathological (n = 29) or highly pathological (n = 12) then measuring four vessels generally brought no additional information. However, the four-vessel measurement was of advantage in the pathological group (n = 23) because it selected the high-risk fetuses (30.4%), as categorized by outcome. CONCLUSIONS: Differentiating between several degrees of pathology is important for the estimation of fetal risk. In cases of pathological Doppler findings, the measurement of more than two vessels is important in order to select fetuses at increased risk.

Arteries↗
PubMed1999

Serum bone sialoprotein in patients with primary breast cancer is a prognostic marker for subsequent bone metastasis.

Bone sialoprotein (BSP) is a noncoflagenous bone matrix protein that is important for both mineralization and cell-cell interactions. Tissue studies in primary breast cancers have shown that immunohistochemical expression of BSP is associated with a high incidence of bone metastases in the course of the disease. We used a RIA to investigate the importance of serum BSP as a marker for subsequent bone metastases. Between 1994 and 1996, preoperative blood samples were collected from 388 consecutive patients with nonmetastatic breast cancer and from 30 control patients with benign breast disease. Serum BSP concentrations were measured in a blinded fashion by RIA. The cutoff for elevated serum BSP values was 24 ng/ml, ie., two SDs above the normal mean value. Serum BSP was correlated with the risk of metastasis and analyzed with regard to its prognostic value. After a median follow-up period of only 20 months, 28 patients had developed metastases. Fourteen patients had bone metastases only, 9 visceral metastases only, and 5 a combination of osseous and visceral metastases. Of the 19 women with skeletal metastases, 17 had preoperative serum BSP values in excess of 24 ng/ml (median BSP values: 48.3 ng/ml for isolated metastatic bone disease, 30.6 ng/ml for combined metastases), whereas none of the women with visceral metastases only had elevated serum BSP concentrations (median BSP value: 12.3 ng/ml). The median serum BSP value in the control group (benign breast disease) was 8.8 ng/ml serum BSP; levels correlated with the size of the primary tumor, but not with any other prognostic factors. Using a multivariate regression analysis, serum BSP was found to be the most important independent prognostic factor for the development of skeletal metastasis (P < 0.001; relative risk, 94); its specificity was 96.7%, and its sensitivity was 89.5%. Our study shows that patients with preoperatively elevated serum BSP levels are at high risk of subsequent bone metastases in the first years after primary surgery. The mechanism of BSP in the pathogenesis of skeletal metastases is unclear. Because BSP contains an integrin recognition sequence, its expression in tumor cells may facilitate their adhesion to the bone surface. However, it is possible that a proportion of circulation BSP is derived from normal or tumor-induced bone turnover. Breast cancer patients with elevated serum BSP levels may benefit from osteoprotective adjuvant therapy with bisphosphonates.

Adult↗
PubMed1998

Reduction in new metastases in breast cancer with adjuvant clodronate treatment.

BACKGROUND: Bisphosphonates are effective against the increased bone resorption caused by certain diseases because they inhibit the activity of osteoclasts. In patients who have breast cancer and metastatic bone disease, the bisphosphonate clodronate (clodronic acid) reduces the frequency of skeletal complications. Experiments in animals and preliminary clinical observations indicate that early clodronate therapy reduces the incidence of new bony metastases in breast cancer. We investigated the effects of clodronate on the incidence and extent of new metastases in patients with breast cancer. METHODS: Between 1990 and 1995, 302 patients with primary breast cancer and tumor cells in the bone marrow (the presence of which is a risk factor for the development of distant metastases) were randomly assigned to receive clodronate at a dose of 1600 mg per day orally for two years (157 patients) or standard follow-up (145 patients). The median length of observation was 36 months. All patients in both groups received standard surgical treatment and customary hormonal therapy or chemotherapy. RESULTS: Distant metastases were detected in 21 patients in the clodronate group and in 42 patients in the control group (P<0.001). The incidence of both osseous and visceral metastases was significantly lower in the clodronate group than in the control group (P=0.003 for both osseous and visceral metastases). Six patients in the clodronate group died, as did 22 in the control group (P=0.001). The mean number of bony metastases per patient in the clodronate group was roughly half that in the control group (3.1 vs. 6.3). CONCLUSIONS: Clodronate can reduce the incidence and number of new bony and visceral metastases in women with breast cancer who are at high risk for distant metastases.

Adult↗
PubMed1998

Results of iliac crest biopsies taken from 1465 patients with primary breast cancer.

This study was performed to analyze the relevance of iliac crest biopsy in patients with primary breast cancer with regard to metastases of the primary tumor and osteogenic disease. We performed intraoperative bilateral biopsy of the anterior iliac crests in 1465 patients with primary breast cancer. The bone specimens were histologically evaluated with regard to quality of the biopsy, tumor involvement, and osteogenic and hematogenic disease. Accurate and clear evaluation of the iliac crest biopsies was possible in 1365 patients (93%). Osteopenia was diagnosed in 48 patients (3.5%); 24 patients (1.7%) showed histological evidence of tumor involvement of the skeletal system. All these 24 patients received systemic (adjuvant) therapy after surgery. Ten patients had micrometastases, although in 5 of them both the postoperative bone scan and X-rays showed no pathological results. In 10 women with histologically negative bone biopsies, metastases to the bone were diagnosed by bone scan and radiological methods. Random perioperative iliac bone biopsy cannot be recommended in patients with primary breast cancer. Iliac crest biopsy is relevant in certain scenarios (e.g. suspected recurrence, doubtful bone scan).

Aged↗
PubMed1998

Prognostic relevance of cathepsin D detection in micrometastatic cells in the bone marrow of patients with primary breast cancer.

Patients with an elevated level of cathepsin D in breast cancer tissue have an adverse prognosis. This study evaluated the prognostic relevance of cathepsin D detection in disseminated tumour cells in bone marrow. Bone marrow was sampled intraoperatively from both anterior iliac crests in 290 patients with primary breast cancer. Interphase cells were enhanced and stained immunocytologically with two antibodies: BM2, which detects tumour-associated glycoprotein TAG 12, which is typically expressed by almost all breast cancer cells, and the anti-cathepsin D antibody. 67 of 149 BM2-positive women (45%) developed metastatic disease (median follow-up time: 69 months). Of these, 15 were cathepsin D-positive (22%). Patients with cathepsin D-positive cells in bone marrow (n = 26; 9%) had a significantly shorter metastasis-free interval (38 months) compared with women who were cathepsin D-negative (64.5 months). The worst prognosis was seen in patients positive for both markers (30.5 months), followed by those who were cathepsin D-negative and BM2-positive (48 months). The detection of cathepsin D on disseminated tumour cells characterises a subgroup of patients with a poorer prognosis who should undergo more aggressive adjuvant systemic therapy.

Bone Marrow↗
PubMed1998

[Complete remission after salvage chemotherapy in metastatic breast carcinoma after failure of induction cycles of planned high dosage chemotherapy with stem cell support].

We report on a patient with metastatic breast cancer confined to visceral (lung and pleura) site. A high-dose chemotherapy with peripheral progenitor blood cell transplantation was indicated. In contrast to other 24 patients two induction cycle chemotherapies (intensive dosis of Epirubicin/Ifosfamid/GCSF) didn't show any remission of metastases. Therefore a high dose chemotherapy with peripheral progenitor blood cell transplantation was not indicated any more. This patient had lung and pleura metastases and showed a complete remission after the following conventional chemotherapy (Carboplatin/Toxol) persisting more than 7 months. Non-responder after induction therapies have a poor prognosis but salvage therapy may be successful anyway. Mammary neoplasms can be sensible on special chemotherapy drugs only.

Adult↗
PubMed1997

Prognostic relevance of urokinase plasminogen activator detection in micrometastatic cells in the bone marrow of patients with primary breast cancer.

Patients with an elevated level of urokinase plasminogen activator (uPA) in breast cancer tissue have an adverse prognosis. This study evaluated the prognostic relevance of uPA detection in disseminated tumour cells in bone marrow. Bone marrow was sampled intraoperatively from both iliac crests in 280 patients with primary breast cancer. Interphase cells were enhanced and stained immunocytologically with two antibodies: 2E11, which detects TAG 12--a tumour-associated glycoprotein typically expressed by almost all breast cancer cells--and the anti-uPA antibody HD-UK9. Thirty-five of the 2E11-positive women (n = 132, 47%) developed metastatic disease (median follow-up time 44 months). Of these, most were uPA positive (n = 23, 65%) and only 12 were uPA negative. Patients with uPA-positive cells in bone marrow (n = 98, 35%) had a significantly shorter metastasis-free interval (36 months) than women who were uPA negative (44.5 months). The worst prognosis was seen in patients positive for both markers (29.5 months), followed by those who were uPA negative and 2E11 positive (37 months). The detection of uPA on disseminated tumour cells characterizes a subgroup of patients with an even worse prognosis, who should undergo more aggressive adjuvant systemic therapy. For the first time, it was possible to evaluate an important qualitative parameter involved in the process of breast cancer metastases.

Antibodies, Monoclonal↗