Genetic and biochemical analysis of Staphylococcus epidermidis biofilm accumulation.
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Agglutination Tests↗
Biomedical subjects
K Kiel
Publications and source records attributed to K Kiel.
Evaluation of the kinetics of the bone marrow tumor load in the course of sequential high-dose therapy assessed by quantitative PCR as a predictive parameter in patients with multiple myeloma.
The aim of this investigation was to examine the possible clinical significance of the kinetics of bone marrow (BM) tumor load during the course of sequential high-dose therapy (HDT) as assessed by quantitative PCR in patients with multiple myeloma. In 20 patients with multiple myeloma (MM) treated with two consecutive cycles of HDT followed by autologous peripheral blood stem cell transplantation (PBSCT), clonotypic cells in the peripheral blood (PB) and BM were quantitated by PCR using allele-specific oligonucleotides (ASO) prior to the first, immediately prior to the second, and after the second HDT. The median proportion of clonotypic cells in the BM was 1.27% before the first HDT (range, 0.03-70%), 0.17% after the first (range, 0.001-22%), and 0.05% after the second HDT (range, 0.00009-1.44%). The median number of circulating clonotypic cells was 65/ml (range, 0.9-10842) prior to HDT, 2.7/ml (range, 0-315) after the first, and 3.5/ml PB (range, 0.7-97) after the second HDT. While the median BM tumor load decreased during the first (P = 0.03) and second (P = 0.044) HDT cycles, only the first cycle resulted in a reduction of clonotypic cells in the PB (P = 0.00078 and P= 1.0, respectively). In seven patients, the BM tumor load did not decrease below the initial level after one or two cycles of HDT. All of these patients developed progressive disease (median, 19 months post first cycle; range, 10-21). Of the remaining 13 patients, only four relapsed (18, 19, 21 and 22 months after the first cycle of HDT), while nine remain in response (median followup, 29 months; range, 18-41) (log-rank test P = 0.0009). Our results indicate that the kinetics of the BM tumor load is a predictive parameter in patients with MM and identifies those patients who could benefit from further therapy including new treatment modalities.
Adult↗
NCCN Practice Guidelines for Colorectal Cancer.
The NCCN Colorectal Cancer Guidelines panel believes that a multidisciplinary approach is necessary for the management of the patient with colorectal cancer. The panel endorses the concept that treatment of patients in a clinical trial has priority over standard or accepted therapy. The recommended surgical procedure for resectable colon cancer is an en bloc resection; laparoscopic surgery should be done only in the context of a clinical trial. For patients with stage III disease, 5-FU-based adjuvant therapy is recommended. A patient who has metastatic disease in the liver or lung should be considered for surgical resection if he or she is a candidate for surgery and if surgery can extend survival. Surgery should be followed by adjuvant chemotherapy. The panel advocates a conservative post-treatment surveillance program for colon and rectal carcinoma patients. Serial CEA determinations are appropriate if the patient is a candidate for aggressive surgical resection, should recurrence be detected. Abdominal and pelvic CT scans should be utilized only when there are clinical indications of possible recurrence. Patients whose disease progresses during 5-FU-based therapy should be treated with irinotecan or encouraged to participate in a phase I or phase II clinical trial.
Colorectal Neoplasms↗
Rehabilitation of breast cancer.
Breast cancer is a complicated disease treated with multimodality therapy. Adult women of any age can develop breast cancer, and most will be cured. Treatment of primary disease is associated with more side effects than the cancer. The process of metastatic cancer to death can be long. The entire family is affected by breast cancer whether early or late. A rehabilitation program must address the physical and psychosocial aspects of breast cancer, both at presentation and at recurrence. For a patient with early breast cancer, lifestyle changes may be important. A primary goal of a rehabilitation program is that each breast cancer patient should become well informed regarding treatment and its consequences (Table 9) in order to continue with her life. Treatment to recover the patient to her former physical and psychosocial state, and therapy for chronic problems from breast cancer or its treatment, requires an approach distinct from that given to other malignancies. Issues regarding survival prevail in any rehabilitation program for both early and late breast cancer.
Breast Neoplasms↗
Analysis of circulating tumor cells in patients with multiple myeloma during the course of high-dose therapy with peripheral blood stem cell transplantation.
In multiple myeloma (MM) circulating CD19+ cells have been considered as myeloma precursors. As these cells are also possibly a reservoir of treatment resistant disease evaluation of the CD19+ cells during the course of high-dose therapy has to be a major concern. We determined the number of tumor cells in the CD19+ as well as CD19- fractions of PB of eight patients with disease sensitive to VA[I]D chemotherapy, of 10 patients who achieved partial or complete remission post-high-dose therapy (HDT) with peripheral blood stem cell transplantation (PBSCT) and of a further seven patients with disease progression post-transplantation. CD19+ cell fractions were obtained by preparative sequential magnetic and fluorescence activated cell sorting with a median purity of 97.1%. In addition, PB samples of seven patients post-transplantation were sorted for CD20+ cells (median purity, 98.7%). The number of tumor cells in the CD19+, the CD19- and the CD20+ fractions were determined using a quantitative CDR3 PCR assay. The number of CD19+ tumor cells in patients in remission post-HDT was similar to those of the patients post-VA[I]D (median, 1.05 vs 0.92 CD19+ tumor cells/ml PB, P = 0.72) providing evidence for the persistence of this tumor cell fraction during the course of HDT. This was in contrast to the CD19- compartment, in which the number of tumor cells was significantly reduced in those patients in remission post-transplantation (median, 53 vs 0 CD19- tumor cells/ml PB; P = 0.006). In patients with progressive disease the number of tumor cells in both cell fractions was significantly higher (CD19+: median, 1.05 vs 21 tumor cells/ml PB, P = 0.05; CD19-: 0 vs 63 tumor cells/ml PB, P = 0.008). While the absolute number of CD19+ cells was reduced in the group of patients after VA[I]D treatment, a polyclonal CD19+ reconstitution had occurred in patients responding to HDT. The tumor cell content in the CD19+ fractions could be confirmed by the results obtained analyzing the CD20+ cell fractions. In conclusion, these results indicate that disease progression after PBSCT in MM is accompanied by an expansion of tumor cells in both the CD19+ and CD19- fractions. Similar numbers of CD19+ clonotypic cells post-HDT suggest that these cells persist and thus, contribute to disease dissemination and relapse.
Adult↗
Clonotypic CD20+ and CD19+ B cells in peripheral blood of patients with multiple myeloma post high-dose therapy and peripheral blood stem cell transplantation.
The number of circulating clonotypic B cells in patients with multiple myeloma (MM) after high-dose therapy (HDT) with peripheral blood stem cell transplantation (PBSCT) was investigated. Peripheral CD19+ B cells have been reported to persist throughout conventional and HDT and might resemble a source of relapse in patients with MM. We assessed the proportion of malignant cells in CD20+ and CD19+ cell fractions of 14 peripheral blood (PB) samples from 12 patients after HDT and PBSCT. Nine samples were obtained from patients in continuous remission, and five patients were in progressive disease or beginning relapse. The CD20+ fractions obtained had a mean purity of 96.8%. The percentages of tumour cells were determined using a quantitative allele-specific oligonucleotide PCR assay based on the method of limiting dilutions. In the group of patients in continuous remission the median number of tumour cells in the CD20+ cell fractions was 1.9/ml (range 0-7.2 tumour cells/ml PB) higher than in the CD20- fractions (median 0; range 0-29 tumour cells/ml PB). Higher tumour cell numbers in both fractions, particularly pronounced in the negative ones, were found in patients with progressive disease or beginning relapse (CD20+: range 3.8-585; median 32 tumour cells/ml PB; CD20-: range 25-25527; median 334 tumour cells/ml PB). Enrichment with the anti-CD19 antibody as a second pan B-cell marker revealed comparable tumour cell numbers. In conclusion, an anti-CD20 antibody treatment could be a promising approach for the eradication of malignant cells in the PB of patients in continuous remission after HDT and PBSCT with low amounts of tumour cells in the B-cell compartment and an almost complete absence of tumour cells in the CD20- fractions.
Adult↗
Decreased numbers of circulating B cells in myeloma patients with reduction after conventional chemotherapy.
Reports of high numbers of circulating monotypic B cells in patients with multiple myeloma (MM) have recently been published. These cells, which were identified by their expression of CD19, were reported to be resistant to conventional chemotherapy and to represent the source of relapse. We examined blood samples from 48 patients before and 53 patients after glucocorticoid containing chemotherapy by dual color flow cytometry. The absolute count of CD19+B cells in patients before treatment (212.6+/-24.8 x 10(6)/l) was decreased compared to normal controls (P = .038). In the post-treatment group, circulating B cells were highly significantly lower than in untreated patients (45.23+/-6.69 x 10(6)/l. P < .001). This reduction was also seen in 26 patients, that were followed during chemotherapy. The cytoplasmic kappa/lambda ratio was within normal range before and after treatment with no difference according to the light chain isotype of the paraprotein. We conclude that circulating B cells are not increased in patients with MM, that the majority of these cells are polyclonal, and that conventional chemotherapy effectively reduces circulating B cells without leading to dominance of resistant monotypic cells.
ADP-ribosyl Cyclase↗
First and second apheresis in patients with multiple myeloma: no differences in tumor load and hematopoietic stem cell yield.
Autologous peripheral blood stem cells (PBSC) are now widely used to support myeloablative therapy in patients with multiple myeloma (MM). The presence of malignant cells in these autografts has been demonstrated. Characteristic kinetics with differential and concomitant mobilization of CD34+ and malignant cells after high-dose (HD) chemotherapy and hematopoietic growth factor administration have been reported. We determined the amounts of tumor cells and PBSC in leukapheresis products (LP) collected on day 1 (LP1) and 2 (LP2) from 16 MM patients harvested after HD chemotherapy and G-CSF. Furthermore, LP from six patients collected on day 5 (LP5) could be examined. The content of clonotypic cells was quantitated by an allele-specific oligonucleotide (ASO)-PCR assay based on limiting dilutions. CD34+ PBSC were determined by flow cytometry. The percentages of malignant cells in the leukapheresis products were in the range of 0% to 0.713% (mean 0.047%). CD34+ cells ranged between 0.06% and 5.4% (mean 1.23%). Comparing LP1 with LP2, no differences in the quantity of tumor cells (mean 0.0538% vs 0.0448%; P = 0.96) and CD34+ cells (mean 1.49% vs 1.33%; P= 0.50) were seen. The calculated number of tumor cells per CD34+ cell did not differ significantly (mean 0.0420 vs 0.0249; P = 0.65). Analyzing LP5 revealed no changes in the number of tumor cells per CD34+ cell (0.0511 vs 0.1044; P = 0.46) indicating a relatively constant ratio of PBSC to tumor cells during the course of PBSC harvesting. These results offer the possibility of combining LP harvested over several days without increasing the tumor load per CD34+ cell.
Adult↗
Leukapheresis products in multiple myeloma: lower tumor load after mobilization with cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) compared with G-CSF alone.
High-dose therapy with autografting of peripheral blood stem cells (PBSCs) has become an accepted treatment modality. However, gene-marking studies in patients with acute myeloid leukemia and neuroblastoma have revealed that malignant cells reinfused along with leukapheresis products (LPs) contribute to relapse. Thus, a reduction in the number of malignant cells in autografts is desirable. We analyzed the percentage of malignant cells and the number of CD34+ PBSCs in LPs mobilized by granulocyte colony-stimulating factor (G-CSF) alone (LP-S) compared with high-dose cyclophosphamide plus G-CSF (LP-CY) in patients with multiple myeloma (MM). A quantitative polymerase chain reaction assay involving CDR3-specific primers based on the method of limiting dilutions was used to determine the tumor loads of LPs. Sixteen LPs from eight patients with MM were analyzed intraindividually in matched pairs. The percentage of malignant cells was lower in LP-CY (p = 0.017; median 0.0067 vs. 0.009%), whereas the number of CD34+ cells was higher (p = 0.012; median 0.3 vs. 0.095%). The calculated number of malignant cells per CD34+ cell was significantly lower in LP-CY as well (p = 0.017). We conclude that mobilization by cyclophosphamide plus G-CSF leads to a lower number of malignant cells per CD34+ cell in LPs compared with G-CSF alone.
Adult↗
Concomitant cisplatin/5-FU infusion and radiotherapy in advanced head and neck cancer: 8-year analysis of results.
BACKGROUND: The purpose of this study was to analyze long-term follow-up of a single institution's experience with a regimen of concomitant cisplatin/fluorouracil (5-FU) infusion and radiation given every other week. This analysis was stimulated by results of a randomized trial showing superiority for this regimen over induction cisplatin/5-FU chemotherapy followed by radiotherapy, especially in regional disease control. METHODS: All patients with stage III/IV disease who were referred by surgeons for nonoperative therapy and had a follow-up of at least 2 years were included. Concomitant chemoradiotherapy was administered days 1-5 of a 2-week treatment cycle, for a total of 7 cycles, with cisplatin 60 mg/m2 day 1, 5-FU 800 mg/m2 given over 24 hours days 1-5, and radiation 2 Gy days 1-5. RESULTS: Seventy-eight patients with stage III (n = 16) or IV (n = 62) were treated and followed for a median of 8 years. Six patients died during treatment, of aspiration pneumonia, sudden death, gastrointestinal bleeding, and stroke. When assessed 6 weeks after the end of treatment, 45 patients (63%) had no clinical evidence of disease, whereas 27 (37%) still had some persistent abnormality. However, 17 of these "partial responders" have not recurred. In all, 24 patients (31%) have recurred or progressed, 13 at the primary site, 5 after 3 years. None of 16 stage III and 24 (39%) of 62 stage IV patients ever progressed. Tongue and glottic larynx did best, with only 1 of 22 patients ever failing (none locally). Supraglottic and oral cavity cancers other than tongue had the worst failure rates. Nineteen patients (24%) died of other causes (DOC), tumor-free. Patients who DOC correlated strongly with T stage (p < .002) but not with N stage or with AJC stage. The 5-year progression-free survival was 60% (confidence interval [CI] = 49% to 72%), and overall survival was 43% (CI = 33% to 56%). CONCLUSIONS: Disease control for this advanced head and neck cancer population was excellent. This regimen was especially effective in advanced tongue and glottic cancers and all stage III disease sites. Advanced supraglottic and hypopharynx cancers are problematic. These, and especially T4 lesions, are associated with high DOC rates, possibly in part related to swallowing malfunction. Nevertheless, the long-term survival without surgical intervention was high with this regimen.
Adult↗
A quantitative PCR assay for the detection of low amounts of malignant cells in multiple myeloma.
BACKGROUND: High-dose chemotherapy (HDT) with autografting of hematopoietic stem cells induces up to 50% of complete remissions in patients with multiple myeloma. Cases of molecular remissions have been reported. However, qualitative assays determine only the absence or presence of a monoclonal population depending on their sensitivity. Therefore reliable and sensitive methods to quantitate tumor loads are necessary. MATERIALS AND METHODS: We have established a quantitative PCR assay (qPCR) with allele-specific primers complementary to hypervariable CDR3 regions. Sample DNA was serially diluted in 0.5 log steps and amplified in 10 replicates. PCR results were analysed by likelihood maximization and chi 2 minimization to calculate the tumor load. RESULTS: Three approaches were taken to validate the qPCR. 1) Single copies of the CDR3 region of U266 cells could be detected. 2) Analysis of a bone marrow sample by FACS for CD 38+2 and kappa/lambda restricted plasma cells and by qPCR yielded results of 1.4 and 2.5% respectively. 3) qPCR results with plasmids carrying CDR3 regions simulating different tumor loads diverged by no more than a factor of 1.6 from the expected values. CONCLUSION: We consider the qPCR to be an accurate method for assessing samples with low amounts of malignant cells.
Base Sequence↗
High-dose chemotherapy, autologous bone marrow or stem cell transplantation and post-transplant consolidation chemotherapy in patients with advanced breast cancer.
This study was designed to determine the complete response (CR) rate, event-free survival (EFS) and overall survival (OS) in patients with metastatic breast cancer treated with an adriamycin-based induction regimen, high-dose chemotherapy consisting of cyclophosphamide and thiotepa with autologous bone marrow or stem cell reinfusion, followed by post-transplant 5-fluorouracil and cisplatin. Forty-eight consecutive patients were enrolled and 35 received two to four cycles of a cytoreductive chemotherapy regimen followed by high-dose chemotherapy which included cyclophosphamide and thiotepa. Thirty-three patients with non-progressive disease received at least one cycle of post-transplant 5-fluorouracil and cisplatin. Fifty percent of patients with evaluable disease responded to induction chemotherapy. Three of the 34 patients (9%) evaluable for response to high-dose chemotherapy achieved CR, eight (24%) achieved partial response (PR), 12 (35%) had stable disease (SD) and 11 (32%) had progressive disease (PD). The median time to neutrophil recovery was 11.5 days (range, 8 to 40 days) post- reinfusion. The median time to platelet independence was 14.5 days (range, 8 to 44 days). The median follow-up is 24.5 months (range, 1 to 96 months). The actuarial probability of EFS for all patients is 17% at 4 years. The EFS for patients receiving all four cycles of post-transplant chemotherapy is 27% at 4 years, compared to 36% at 1 year for patients not receiving any post-transplant chemotherapy. Ten of the 48 patients (21%) are alive, and seven of these (15%) have no evidence of disease. High-dose chemotherapy with autologous bone marrow or peripheral blood-derived stem cell transplantation followed by post-transplant consolidation chemotherapy in patients with metastatic breast cancer results in a proportion of patients without evidence of disease at 4 years.
Adult↗
A rationale for positive selection of peripheral blood stem cells in multiple myeloma: highly purified CD34+ cell fractions of leukapheresis products do not contain malignant cells.
In multiple myeloma (MM), the presence of tumor cells in leukapheresis products (LP) has been demonstrated with highly sensitive molecular biological tools in up to 100% of cases. Therefore methods to reduce the tumor load of LP by CD34+ selection are envisaged. However, there is controversy as to whether the CD34+ cell is already involved in the malignant process. We have established a PCR assay with allele-specific oligonucleotide primers (ASO) complementary to the CDR3-hypervariable region of the immunoglobulin heavy chain gene of each patient's myeloma clone. Using this ASO-PCR, 43 LP of 10 patients with MM eligible for high-dose therapy were assessed for malignant cells. Furthermore, in an experimental setting we have examined 10 CD34+ and four CD19+ fractions obtained from PCR-positive LP by sequential preparative magnetic and fluorescence activated cell sorting (purity >96%) for the presence of the tumor-specific CDR3 region. The majority of LP harbored cells of the myeloma clone (93%), while all CD34+ fractions were PCR-negative. In all CD19+ fractions malignant cells were detected. These results confirm that CD34+ selection can be considered for LP in MM. The sensitivity of the ASO-PCR (up to 10[-5]) enables us further to monitor the efficacy of CD34+ enrichment protocols in the clinical setting.
Adult↗
NCCN Colorectal Cancer Practice Guidelines. The National Comprehensive Cancer Network.
In summary, the committee believes that a multidisciplinary approach is necessary for the management of the patient with colorectal cancer. The committee endorses the concept that treatment of patients on a clinical trial has priority over standard or accepted therapy. The recommended surgical procedure for managing resectable colon cancer is an en bloc resection; laparoscopic surgery should be done only in the context of a clinical trial. For patients with stage III disease, 5-FU-based adjuvant chemotherapy is recommended. A patient who has metastatic disease in the liver or lung should be considered for surgical resection if he or she is a candidate for surgery and if surgery can extend survival. The committee advocates a conservative post-treatment surveillance program for colon and rectal cancer patients. A determination of CEA should be done only if CEA was elevated at baseline and decreased following primary resection. Abdominal and pelvic CT scans should be utilized only when there are clinical indications of possible recurrence. Patients whose disease progresses during 5-FU-based therapy should be considered for treatment with irinotecan or encouraged to participate in a phase I or II clinical trial.
Colonic Neoplasms↗
[The significance of recurrence-inducing events for patients with chronic inflammatory bowel diseases. Results of a prospective longitudinal study over three years].
This study examined whether life event stress under general or more specific conditions (fear of separation, feeling of being under pressure, feeling of being caught between two quarreling parties, separation experiences) contribute to the aggravation of inflammatory bowel disease. Firstly, 51 patients with ulcerative colitis, 57 patients with Crohn's disease, and 60 controls were compared in terms of these variables. In addition, the IBD patients filled out questionnaires regarding life events, the specific psychological conditions mentioned above, and their symptoms several times in the three years after the first measurement. By means of group comparisons and intraindividual correlations between relapse precipitating life events and illness activity, only feelings of being under pressure showed a modest correlation to the disease activity. We conclude that the variables in question have little influence on the beginning of the relapse.
Adaptation, Psychological↗
Combined simultaneous cisplatin/fluorouracil chemotherapy and split course radiation in head and neck cancer.
Fifty-three patients with stage III (eight patients, 15%), stage IV (36 patients, 68%), or recurrent disease (nine patients, 17%) entered a study of simultaneous cisplatin, 60 mg/m2 day 1, fluorouracil (5-FU) infusion, 800 mg/m2 days 1 to 5, and radiation, 2 Gy days 1 to 5, every other week for a total of seven cycles (70 Gy in 13 weeks). Patient acceptance was high, with only two patients (4%) refusing to complete therapy. The median actual dose delivered was 88% of the planned dose for cisplatin, 78% for 5-FU, and 70 Gy for radiation. Weight loss of 10% or more and severe mucositis were the most common side effects (53% and 48% incidence, respectively). All patients were followed at least 1 year (median, 51 months). While the complete response rate (55%) seemed no better than that reported in other series, freedom of progression of regional disease (73%), and the survival of all patients (median, 37 months) were substantially improved. Only 33% of partial responders have failed regionally, while 15% of complete responders have failed regionally (P greater than .10), which indicates that clinical assessment of response was unreliable. Stage, the presence of N3 disease, and delivery of less than the median actual dose received of 5-FU (but not cisplatin) were significantly associated with failure. This regimen is feasible and tolerable in this difficult patient population. It generally requires no special forced feeding techniques. Survival results from this limited institution study appear better than those using sequential multimodality therapies. With such favorable regional control, this approach may offer an alternative in the future to radical surgery and radiation in resectable disease. More definitive evaluation seems warranted.
Actuarial Analysis↗
Intra-operative radiation therapy in the treatment of pelvic malignancies: a preliminary report.
Local control of advanced pelvic malignancies, particularly when complete surgical resection is not feasible, is often impeded by dosage limitations in radiation therapy and the intolerance to radiation of normal tissues. This is a preliminary report on the feasibility of improved local control in pelvic malignancies treated by intra-operative radiation therapy, as a radiation boost, in addition to conventional surgical resection and external beam radiation therapy. Fifteen gynaecological malignancies (five cervix, five uterus, four ovary, and one vulva) from Rush Medical College and the University of Navarre, as well as 36 other pelvic malignancies (32 colorectal, 4 genito-urinary) from Rush Medical College were reviewed. All tumours were advanced or recurrent, and all patients were felt to be at high risk of local failure. IORT was administered at a dose range of 10-26 Gy. Our data suggest that the probability of local control improves when IORT is used for primary and for microscopic disease, when the tumour is at least partially resectable, and when the total dose given in IORT and external beam radiation exceeds 70 Gy.
Brachytherapy↗
Primary hepatocellular carcinoma.
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Adult↗