Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changing the major histocompatibility complex (MHC) class I phenotype is a pivotal strategy of tumor cells to circumvent an effective immune response and is associated with tumor progression in cancer patients. Epithelial cells in bone marrow have been detected in various tumor types, but the clinical observation that only a portion of the patients with a positive bone marrow status develops solid bone metastasis suggests a certain molecular equipment of the isolated tumor cells as a prerequisite for metastatic formation. In the present study the prognostic impact of the MHC class I phenotype of disseminated epithelial cells in bone marrow was evaluated in a cohort of 30 curatively resected (R0) patients without distant metastases (M0) (designated R0M0) who had minimal residual disease. Immunocytochemical analysis using the alkaline/anti-alkaline immunogold double staining procedure revealed a heterogeneous MHC class I expression profile [monoclonal antibody (mAb) W6/32] of the epithelial cells (mAb CK2). In 16 patients (53.3%) all epithelial cells were human leukocyte antigen (HLA) class I-positive (CK2+//W6/32+ phenotype). Eight patients (26.7%) showed complete loss of the HLA class I molecules (CK2+//W6/32- phenotype) and in 6 patients (20%) partial loss of HLA class I expression was found (CK2+//W6/32+ and - phenotype). CK2+ cells with the HLA class I negative phenotype (CK2+//W6/32- phenotype and CK2+//W6/32+ and - phenotype) were often derived from poorly differentiated (G3) primary breast carcinomas (p = 0.036) and were associated with short survival of the R0M0 patients (follow-up 15-98 months, log rank p = 0.072). These findings support the necessity to develop immmunotherapeutic strategies leading to the restoration of MHC class I positive phenotype.
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PMID:MHC class I negative phenotype of disseminated tumor cells in bone marrow is associated with poor survival in R0M0 breast cancer patients. 1147 61

Soft-tissue sarcomas are characterized by the development of disease recurrence in a distinct subgroup of patients. Despite intense efforts in applying multimodal treatment, the risk of local recurrence or distant metastases remains a considerable threat to patients with soft-tissue sarcoma. This review focuses on the efforts aimed at defining local and systemic tumor extent at the level of minimal residual disease (MRD) tumor cell detection. Examination of MRD in soft-tissue sarcomas has experienced a significant boost from the definition of fusion transcripts resulting from stable chromosomal translocations. The sensitivity and exclusive specificity of the reverse-transcription polymerase chain reaction (RT-PCR) protocols have given insights into tumor cell residues in nearly all body compartments. The accumulated data demonstrates that even after oncologic resections most patients will still harbor a significant tumor burden. Clinical concepts arising out of these new data are under way. One of these concepts is the targeting of the fusion transcript for therapy. However, this approach is still restricted to the experimental setting. The development of clinical applications remains a challenging task, requiring the treatment of as many patients as possible in centers specializing in all of the affected disciplines.
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PMID:Minimal residual disease in soft-tissue sarcomas. 1174 71

The development of novel anti-cancer strategies requires more sensitive and less invasive methods to detect and monitor in vivo minimal residual disease in cancer models. Bone marrow metastases are indirectly detected by radiography as osteolytic and/or osteosclerotic lesions. Marrow micrometastases elude radiographic detection and, therefore, more sensitive methods are needed for their direct identification. Injection of cancer cells into the left cardiac ventricle of mice closely mimics micrometastatic spread. When luciferase-transfected cells are used, whole-body bioluminescent reporter imaging can detect microscopic bone marrow metastases of approximately 0.5 mm(3) volume, a size below the limit in which tumors need to induce angiogenesis for further growth. This sensitivity translates into early detection of intramedullary tumor growth, preceding the appearance of a radiologically evident osteolysis by approximately 2 weeks. Bioluminescent reporter imaging also enables continuous monitoring in the same animal of growth kinetics for each metastatic site and guides end-point analyses specifically to the bones affected by metastatic growth. This model will accelerate the understanding of the molecular events in metastasis and the evaluation of novel therapies aiming at repressing initial stages of metastatic growth.
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PMID:Optical imaging of cancer metastasis to bone marrow: a mouse model of minimal residual disease. 1189 Dec 10

A novel alpha-particle emitting ((213)Bi) plasminogen activator inhibitor type 2 construct, which targets the membrane-bound urokinase plasminogen activator on prostate cancer cells, was prepared and evaluated in vitro and in a xenograft animal model. The PC3 prostate cancer cell line expresses urokinase plasminogen activator which binds to its receptor on the cell membrane; plasminogen activator inhibitor type 2 is bound to urokinase plasminogen activator/urokinase plasminogen activator receptor to form stable complexes. In vitro, the cytotoxicity of (213)Bi-plasminogen activator inhibitor type 2 against prostate cancer cells was tested using the MTS assay and apoptosis was documented using terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick end-labelling (TUNEL) assay. In vivo, antiproliferative effects for tumours and prostate cancer lymph node metastasis were carried out in an athymic nude mouse model with a subcutaneous xenograft of PC3 cells. (213)Bi-plasminogen activator inhibitor type 2 was specifically cytotoxic to PC3 cells in a concentration-dependent fashion, causing the cells to undergo apoptosis. A single local or i.p. injection of (213)Bi-plasminogen activator inhibitor type 2 was able to completely regress the growth of tumours and lymph node metastases 2 days post subcutaneous inoculation, and obvious tumour regression was achieved in the therapy groups compared with control groups with (213)Bi-plasminogen activator inhibitor type 2 when the tumours measured 30-40 mm(3) and 85-100 mm(3). All control animals and one of five (20%) mice treated with 3 mCi kg(-1) (213)Bi-plasminogen activator inhibitor type 2 developed metastases in the lymph nodes while no lymphatic spread of cancer was found in the 6 mCi kg(-1) treated groups at 2 days and 2 weeks post-cell inoculation. These results demonstrate that this novel (213)Bi-plasminogen activator inhibitor type 2 conjugate selectively targets prostate cancer in vitro and in vivo, and could be considered for further development for the therapy of prostate cancer, especially for the control of micro-metastases or in minimal residual disease.
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PMID:213Bi-PAI2 conjugate selectively induces apoptosis in PC3 metastatic prostate cancer cell line and shows anti-cancer activity in a xenograft animal model. 1195 71

Although only less than 10% of women with primary breast cancer have clinicopathologic signs of overt metastases, metastatic relapse occurs in about half of the cases with apparently localized tumors within five years after surgery. In 23% of the patients, bone marrow metastases are detectable at first relapse and this rate even increases in patients with metastatic breast cancer. However, hematogeneous or lymphatic spread of occult tumor cells can arise before diagnosis at an early stage of primary tumor growth and is regularly underestimated by currently available clinical and pathologic staging procedures. We studied cytokeratin-positive (CK+) cells in the bone marrow (BM) and tumor markers in the blood of 128 patients with primary breast cancer in order to obtain an early diagnosis of residual disease. In a second study, we monitored cytokeratin (CK)/17-1A positive cells in the BM and peripheral blood stem cells (PBSC) to evaluate whether dose intensive or high-dose (HD)-chemotherapy can eliminate micrometastases in high-risk breast cancer patients. The overall CK+ rate was 34% (44/128 patients), 29% (15/51) for patients with T1 tumors, 33% (28/84) for N0 patients and 31% (26/82) for patients with G1-2 breast carcinoma. Interestingly, 67% of CK+ patients were only positive in one of the two BM aspirates studied. At least one tumor marker including carcinoembryonic antigen, carbohydrate antigen 15-3 and tissue polypeptide antigen, was increased in 58/128 (45%) patients [21/58 (36%) were CK+ in the BM]. Surprisingly, levels for the extracellular domain of Her-2/neu in serum samples were within the normal range in every patient studied. After a 2-year follow-up, 7/128 patients relapsed (3/7 CK+/TM-; 2/7 CK-/TM+; 2/7 CK-/TM-). We concluded that studying two BM aspirates for CK+ cells by immunocytochemistry in combination with tumor marker determination is useful for identifying patients with a higher risk for relapse. A tumor cell enrichment technique, applied in 70 patients prior to immunocytochemistry using dynabeads directly coupled to an antibody (BerEp4) targeting the 17-1A antigen, did not enhance the detection rate of disseminated tumor cells in this patient group. We monitored CK+/17-1A+ cells in the BM and PBSC and studied Her-2/neu serum levels of patients with locally advanced (n=13, group 1) and metastatic breast cancer (n=30, group 2). CK+ cells were found in the BM of 3/13 (23%) group 1 patients before but not after chemotherapy resulting in an overall survival (OS) of 92% after a median follow-up of 33 months. Contamination of PBSC in 2/9 (22%) patients was not associated with decreased survival. In group 2 patients, the CK+ rate was 60% (18/30 patients) before and 40% (4/10 patients) after therapy with an OS rate of 43% after 29 months. PBSC samples were positive in 7/24 (29%) patients. CK+ BM and PBSC led to a rapid progress and short OS whereas tumor cell free BM and PBSC resulted in a mean OS of 30 months. The antigen 17-1A was detected on most CK+ cells in both patient groups before therapy, on all CK+ PBSC and on CK+ cells in group 2 patients after therapy. Increased Her-2/neu levels were found in group 2 patients before chemotherapy. In conclusion, micrometastatic cells are present in blood and PBSC grafts of high-risk breast cancer patients and can survive even HD-chemotherapy. Immunotherapeutic target antigens on the cell surface of these cells support the idea that a combined chemoimmunotherapy might be successful in eliminating minimal residual disease.
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PMID:A summary of two clinical studies on tumor cell dissemination in primary and metastatic breast cancer: methods, prognostic significance and implication for alternative treatment protocols (Review). 1195

To evaluate the ability of serum c-erbB-2 protein to (1) indicate occult and manifest metastases and (2) reflect response to first-line therapy, serial serum c-erbB-2 measurements were performed in a retrospective series of 52 primary breast cancer patients who had developed metastatic disease during follow-up. The results were compared with CA 15-3. Preoperatively, 31% (16/52) of the primary breast cancer patients had elevated c-erbB-2 concentrations. The CA 15-3 positivity rate was 13% (7/52). After surgery, 10 of the 52 patients showed either stable but highly elevated or rising c-erbB-2 serum levels indicating serum c-erbB-2 producing minimal residual disease. Increasing CA 15-3 concentrations were seen in only three patients. Elevated serum c-erbB-2 levels predicted manifest metastases in 27 and 50% of the patients at 6 and 3 months, respectively, prior to clinical diagnosis. CA 15-3 was less sensitive. Only 16 and 32% of the patients had increased CA 15-3 serum concentrations at 6 and 3 months, respectively, prior to clinical detection. The positivity rates of c-erbB-2 and CA 15-3 were similar when metastases were clinically diagnosed. Elevated c-erbB-2 concentrations were found in 62% (32/52). The sensitivity of CA 15-3 was 56% (29/52). The association between serum profiles and response to first-line therapy was evaluated in detail for 45 patients. Serial c-erbB-2 and CA 15-3 measurements reflected disease course in 24 and 27 patients, respectively. The serum profiles of c-erbB-2 and CA 15-3 were similar in 17 patients. In summary, our results suggest that serial determinations of serum c-erbB-2 are useful to monitor breast cancer patients.
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PMID:Clinical utility of serial serum c-erbB-2 determinations in the follow-up of breast cancer patients. 1224 12

Although surgery remains the mainstay for the treatment of most solid tumors, investigators are seeking complementary therapies to eradicate microscopic disease, which causes tumor relapse even after an apparently complete surgical excision. Although adjuvant chemotherapy has achieved some significant results, the control of minimal residual disease is still a challenge for clinicians. Among novel therapeutic approaches, immunotherapy holds promise. This anticancer strategy aims at triggering a highly specific endogenous killing machine against tumor cells. Recent progress in tumor immunology has improved our understanding of host-immune system interactions. In particular, new technologies have fostered the identification of potentially immunogenic tumor antigens that can be used as suitable targets for immune effector cells. After observing immunotherapy-mediated clinical responses in patients with metastatic disease, investigators have started evaluating this anticancer modality in the adjuvant setting. Here, we review the immunological strategies so far explored in humans and report worldwide results following the clinical application of adjuvant immunotherapy for solid tumors.
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PMID:Adjuvant immunotherapy for solid tumors: from promise to clinical application. 1243 3

Surgery remains the mainstay of treatment for early non-small cell lung cancer (NSCLC) but more than 80% of recurrences occur within 2 years from radical surgery. The pattern of recurrence may differ by histology with more local recurrences seen for patients with squamous cell carcinoma and more distant metastases seen in patients with adenocarcinoma. A number of studies demonstrate that dissemination of cancer cells at levels much below those detected by any current available imaging techniques, including PET scanning also, affect prognosis of patients with clinical early-stage NSCLC. The current clinical evidence does not recommend adjuvant chemotherapy and/or radiotherapy in completely resected stage I-II-IIIA for N1. There are few randomised trials available for analysis of neo-adjuvant chemotherapy involving patients with resectable stage III disease; overall these trials suggest that induction chemotherapy (with or without radiation) improves survival, particularly in those patients who undergo significant downstaging. Heterogeneous study populations limit the ability to define the optimal patient population who would most benefit from this approach. There is no conclusive evidence that neo-adjuvant chemotherapy in early NSCLC is associated with an increased post surgical morbility and mortality. Additional trials are needed. More recently neo-adjuvant chemotherapy has been tested in resectable stage I-II NSCLC and proved to be feasible and better tolerated than adjuvant chemotherapy. Several randomised trials are currently ongoing. In the next future the role of targeted biological therapies as agents acting on minimal residual disease should be explored.
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PMID:Consensus development conference on the medical treatment of non-small cell lung cancer: treatment of the early stages. 1246 40

The cure of a tumor patient with gastrointestinal cancer is dependent on the extension of the primary tumor (TNM-classification) and the option of curative resection (R0-resection) at the time of operation. The additional application of multimodal therapy approaches has lead to an improvement of prognosis in different advanced tumor stages. Nevertheless, despite curative tumor resection about 50% of patients with locally advanced gastrointestinal cancer develop recurrent tumor disease or distant metastases and die tumor-related. A possible explanation is the seed of disseminated tumor cells in blood, bone marrow or lymph nodes pre-, intra- or postoperatively, but also during diagnostic procedures. Several studies have shown in the last years that the presence of minimal residual disease (MRD) influences the course of disease and the patient's prognosis after curative tumor resection. Although several groups have reported the prognostic impact of disseminated tumor cells in the different compartments of bone marrow, lymph nodes and blood, the phenomenon of minimal residual disease is not acknowledged as an established prognostic factor and is not integrated into the classification of the UICC. Therefore, no therapeutic consequences were drawn at present from the detection of disseminated tumor cells in patients with gastrointestinal cancer. A possible explanation are missing multi-center-studies, which confirm the results of the several single-center-studies. Standardization of study designs and methodical procedures and the evidence of reproduction are mandatory in order to value and interpret the multitude of studies and the available data in this field. Only these results will allow to decide if the presence and detection of disseminated tumor cells can alter the tumor staging and individualize or possibly minimize further oncological therapy strategies.
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PMID:[Minimal residual disease in gastrointestinal tumors: tumor detection in bone marrow, blood and lymph nodes]. 1250 60

Ewing family of tumors is a group of highly aggressive neoplasias that occur most commonly in the first two decades of life. These tumors are most frequently localized in bones, less frequently in soft tissues. They usually appear as undifferentiated small round-cell tumors. With current treatment regiments, 5-year disease-free survival rates exceed 60% in patients with a localized disease. Patients with metastatic disease at the time of their first presentation have a poor prognosis. We describe a rare case of visceral primitive neuroectodermal tumor with the involvement of the kidney in a 9-year-old girl. The tumor was studied with immunohistochemistry, cytogenetics, and molecular biology methods. Strong expression of protein MIC(2) by immunochemistry (antibody HBA 71) with subsequent demonstration of a translocation consistent with t(11;22)(q24;q12) using cytogenetic and reverse transcriptase polymerase chain reaction (RT-PCR) confirmed the histopathological diagnosis of peripheral primitive neuroectodermal tumor. We detected minimal residual disease in bone marrow using RT-PCR.
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PMID:Malignant peripheral primitive neuroectodermal tumor of the kidney. 1254 63


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