Biomedical subjects

Jan Tennvall

Publications and source records attributed to Jan Tennvall.

11 recordsLinked to original sources

PubMed2005

Dose-fractionated radioimmunotherapy in non-Hodgkin's lymphoma using DOTA-conjugated, 90Y-radiolabeled, humanized anti-CD22 monoclonal antibody, epratuzumab.

PURPOSE: Fractionated radioimmunotherapy may improve therapeutic outcome by decreasing heterogeneity of the dose delivered to the tumor and by decreasing hematologic toxicity, thereby allowing an increased amount of radionuclide to be administered. Because humanized anti-CD22 epratuzumab can be given repeatedly, a single-center study was conducted to establish the feasibility, safety, optimal dosing, and preliminary efficacy of weekly administrations of 90Y-labeled 1,4,7,10-tetra-azacyclodecane-N,N',N'',N'''-tetraacetic acid-conjugated epratuzumab. EXPERIMENTAL DESIGN: Cohorts of three to six patients with B-cell lymphoma received 185 MBq/m2 [90Y]epratuzumab with unconjugated epratuzumab (total protein dose 1.5 mg/kg) once weekly for two to four infusions, with [(111)In]epratuzumab coadministered at first infusion for scintigraphic imaging and dosimetry. RESULTS: Sixteen patients received treatment without significant infusional reactions. The overall objective response rate was 62% (95% confidence interval, 39-86%) in both indolent (75%) and aggressive disease (50%). Complete responses (CR/CRu) occurred in 25% of patients and were durable (event-free survival, 14-41 months). Two patients receiving four infusions had hematologic dose-limiting toxicity. Serum epratuzumab levels increased with each weekly dose. Of 13 patients with tumor cell CD22 expression determined by flow cytometry, seven of eight with strongly positive results had objective responses, versus one of five with negative or weakly positive results (P = 0.032). CONCLUSIONS: Radioimmunotherapy with weekly 185 MBq/m2 [90Y]epratuzumab achieved a high objective response rate (62%) across lymphoma subtypes, including durable CRs. The findings that three weekly infusions (555 MBq/m2, total dose) can be administered safely with only minor toxicity, that antibody levels increased during treatment weeks, and that therapeutic response predominantly occurs in patients with unequivocal CD22 tumor expression provide guidance for future studies.

Adult↗

PubMed2004

Genetic and expression profiles of squamous cell carcinoma of the head and neck correlate with cisplatin sensitivity and resistance in cell lines and patients.

PURPOSE: The choice of treatment for squamous cell carcinoma of the head and neck (SCCHN) is still primarily based on the tumor-node-metastasis classification. However, it is reasonable to believe that biological profiles of SCCHN may be independently associated with response to therapy. The aim of the present study was to examine genetic changes and gene expression profiles that might correlate with sensitivity to cisplatin [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay] in 10 SCCHN cell lines. EXPERIMENTAL DESIGN: Five cisplatin-sensitive and five cisplatin-resistant cell lines [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay] were studied by comparative genomic hybridization, spectral karyotyping, and cDNA microarray analysis (21,632 sequence-validated human cDNA; confirmation by reverse transcriptase-PCR for selected genes). For the MET proto-oncogene, which showed low expression in the chemosensitive cell lines, we did immunohistochemical staining on SCCHN of 29 patients who received induction chemotherapy. RESULTS: The five cisplatin-resistant cell lines showed significantly more genetic imbalances (regions of loss and amplification) and chromosomal abnormalities by comparative genomic hybridization and spectral karyotyping, respectively, than did the five cisplatin-sensitive cell lines. Microarray studies identified approximately 60 genes that clearly distinguish between the two groups of cell lines. Some of these genes are known to be involved in tumor progression, metastasis, and drug resistance. We identified low expression of c-met (immunohistochemistry) as a predictive factor for complete response in nondiploid tumors (P = 0.026). CONCLUSIONS: We conclude that cisplatin sensitivity and resistance are related to distinctive differences in the genetic and expression profiles in individual SCCHN tumor cell lines and in SCCHN patients. The genes we have identified may serve as potential targets for novel treatment strategies.

Adult↗

PubMed2004

DNA ploidy, S-phase fraction and associations with 2-18F-fluoro-deoxy-2-D-glucose positron emission tomography findings before and during therapy of head and neck squamous cell carcinoma.

OBJECTIVES: The main purpose of this study was to investigate the feasibility of fine needle aspiration (FNA) of neck node metastases in head and neck squamous cell carcinoma (HNSCC) for evaluating changes in DNA ploidy and S-phase fraction (SPF) during cytotoxic treatment. The results of flow cytometric (FCM) and image cytometric (ICM) analyses of ploidy were compared. Secondly, the association of SPF and ploidy with the metabolic rate (MR) of 2-18F-fluoro-deoxy-2-D-glucose (FDG) in positron emission tomography (PET) was studied. MATERIAL AND METHODS: Between 1993 and 1999, 47 patients with locally advanced, non-resectable HNSCC underwent FDG PET prior to (PET1) and early during (PET2) cytotoxic radical treatment. The MR of FDG was calculated separately in primary tumours and lymph node metastases. Immediately after both PET scans, FNA of node metastases was done in 29 patients at PET1 and in 27 at PET2. DNA ploidy was evaluated using FCM and manually using ICM. The SPF was evaluated using FCM only. RESULTS: At PET1 it was possible to evaluate the SPF using FCM in only 13/29 aspirations due to a poor cell yield or large amounts of debris. Ploidy was obtained in 23/29 aspirates using FCM and in 27/29 using ICM. A discordance in ploidy findings was apparent, with more non-diploid clones being detected by ICM than FCM. Eradication of non-diploid clones during therapy was observed in six cases using FCM, of which only one was confirmed by ICM. Neither SPF nor ploidy status showed any strong correlation with the MR of FDG. CONCLUSION: FNA of HNSCC metastases demands a high and qualitatively good cell yield for FCM examinations. ICM is laborious but feasible and offers more accurate detection of non-diploid cell clones. Ploidy and SPF were not strongly associated with FDG metabolism.

Adult↗

PubMed2003

Change in tumor-absorbed dose due to decrease in mass during fractionated radioimmunotherapy in lymphoma patients.

PURPOSE: In radionuclide therapy, cumulated activity and tumor volume/mass are the principal quantities necessary for the calculation of the absorbed dose to the tumor. When treating a fast-responding macroscopic tumor, there may be a decrease in its mass during therapy, and at any given uptake, this will result in an increase in the absorbed dose. The purpose of the present work is to demonstrate the limitations in current internal dosimetry protocols that assume a fixed tumor mass in lymphoma patients, using a fractionated radioimmunotherapy schedule and using a single infusion. EXPERIMENTAL DESIGN: Patients with B-cell lymphoma were treated with (90)Y-labeled epratuzumab (Immunomedics, Inc., Morris Plains, NJ) using a weekly dose-fractionation schedule for 2-4 weeks. They received either 185 MBq/m(2) (5 mCi/m(2)) in each infusion or, if they had a history of high-dose chemotherapy with stem cell rescue, 92.5 MBq/m(2) (2.5 mCi/m(2)) in each infusion. All patients received (111)In-labeled epratuzumab with the first infusion to verify tumor targeting and for dosimetry. The present report is based on three selected patients, in whom repeated assessments of tumor mass were possible. In two patients, (111)In-labeled epratuzumab was also coadministered with one of the subsequent treatments, i.e. during the second and third of two and three scheduled infusions. The tumor volume was determined from computer tomography images obtained before the first infusion and on different times after the infusion. An exponential equation was fitted to the decreasing mass of the tumor and implemented in the calculation of the absorbed dose. For comparison, the absorbed dose to the tumor was also calculated using the tumor volume determined from the baseline pretreatment computer tomography examination. RESULTS: The tumor volume for the patients changed rapidly. For one patient, the pretreatment volume was 19.5 ml, and for another patient, it was 840 ml. For these two patients, the ratio of tumor volume at the beginning of therapy compared with that after 8 days and 14 days of therapy was 0.7 and 0.8, respectively. This rapid decrease in volume and subsequent mass reduction result in an increase of mean absorbed dose to the tumor of as much as a factor of 1.75. CONCLUSIONS: At a given activity uptake, a decrease in tumor mass during therapy will significantly increase the calculated absorbed dose. Taking the change in tumor mass into account when calculating absorbed dose may improve the correlation between the mean absorbed dose to the tumor and the response to the therapy.

Antibodies, Monoclonal↗

PubMed2003

Tumour therapy with radionuclides: assessment of progress and problems.

Radionuclide therapy is a promising modality for treatment of tumours of haematopoietic origin while the success for treatment of solid tumours so far has been limited. The authors consider radionuclide therapy mainly as a method to eradicate disseminated tumour cells and small metastases while bulky tumours and large metastases have to be treated surgically or by external radiation therapy. The promising therapeutic results for haematological tumours give hope that radionuclide therapy will have a breakthrough also for treatment of disseminated cells from solid tumours. New knowledge related to this is continuously emerging since new molecular target structures are being characterised and the knowledge on pharmacokinetics and cellular processing of different types of targeting agents increases. There is also improved understanding of the factors of importance for the choice of appropriate radionuclides with respect to their decay properties and the therapeutic applications. Furthermore, new methods to modify the uptake of radionuclides in tumour cells and normal tissues are emerging. However, we still need improvements regarding dosimetry and treatment planning as well as an increased knowledge about the tolerance doses for normal tissues and the radiobiological effects on tumour cells. This is especially important in targeted radionuclide therapy where the dose rates often are lower than 1Gy/h.

Genomic Instability↗

PubMed2003

Biotinylation, pharmacokinetics, and extracorporeal adsorption of humanized MAb 111In-MN14 using an avidin-affinity column in rats.

UNLABELLED: Extracorporeal adsorption (ECAT) reduces toxicity in radiosensitive organs by removing excess of biotinylated and radiolabeled MAb from unseparated blood in an avidin-agarose column. AIM: To investigate the influence of biotinylation on pharmacokinetics and biodistribution of humanized MAb (111)In-MN14 and to validate the effect of subsequent ECAT on activity reduction in the whole body, in blood, and in various organs after i.v. administration of biotinylated (111)In-hMN14 in rats. METHODS: Humanized MAb MN14 recognizes the carcinoembryonic antigen. Ninety-three rats were used. (111)In-hMN14-DOTA was biotinylated using NHS-biotin or Sulfo-NHS-biotin enabling antibodies to be absorbed on the avidin-agarose column. Eight rats underwent ECAT, which implied that three blood volumes were passed through the column during 2.5 h. Whole body counts and blood activity were monitored. At dissections, organs of interest were removed and measured for activity-content. RESULTS: HPLC showed signs of fragmentation at a low ratio of NHS-biotin/mg of MAb. No fragmentation or aggregation was observed using sulfo-NHS-biotin. When ECAT started at 6 h p.i., whole body and blood activity were reduced by 64% and 98%, respectively. The uptake in organs sensitive to radiation was also reduced, varying between 39% for the liver and 84% for the lungs and bone marrow. CONCLUSIONS: (111)In-hMN14 can be safely biotinylated using sulfo-NHS-biotin without significantly affecting antigenicity and biodistribution of the antibody. ECAT based on avidin-biotin concept effectively removed biotinylated (111)In-hMN14 from blood circulation and reduced activity in radiosensitive organs.

Absorption↗

PubMed2002

Time dependence of the activity concentration ratio of red marrow to blood and implications for red marrow dosimetry.

BACKGROUND: The method for red marrow dosimetry in radioimmunotherapy, in the absence of specific activity uptake in red marrow, is based on the activity measured in the blood or plasma. The activity concentration ratio of red marrow to blood is then assumed to be constant. The aim of the current study was to determine whether this ratio varies with time after injection. METHODS: Measurements were carried out with both animals and patients.Tumor-bearing rats were intravenously injected with iodine-131-, iodine-125-, indium-111-, or rhenium-188-labeled BR96, a chimeric immunoglobulin G1 monoclonal antibody. (All were chelate-labeled, except for iodine-131, which was iodogen-labeled.) Measurements were made of the activity concentration in blood and bone marrow at different points in time after injection, and the ratio of activity concentration in red marrow and blood as a function of time postinjection (RMBLR[t)]) was calculated. For patients treated with iodine-131-labeled monoclonal antibody (LL2, Immunomedics Inc., Morris Plains, NJ; anti-CD22; immunoglobulin G2 isotype of mouse origin), blood samples were drawn and scintillation camera images taken at different times after injection. The red marrow activity concentration in the sacrum was determined by activity quantification from regions of interest. The activity concentration in blood was also measured. The RMBLR(t) was calculated based on these data. RESULTS: For both patients and rats, the RMBLR(t) was increased 72 hours after injection. Furthermore, it was found that the use of a constant RMBLR can lead to an over- or underestimation of the absorbed dose in bone marrow. CONCLUSIONS: These data demonstrate the difficulty in using fixed values of the activity concentration ratio of red marrow to blood for dosimetry.

Animals↗

PubMed2002

Single tumor cell uptake and dosimetry of technetium-99m Fab' or minute anti-CD22 in low-grade B-cell lymphoma.

BACKGROUND: A patient with follicular lymphoma was investigated with 0.5 mg Fab' or minute anti-CD22 labeled with 1100 MBq technetium-99m ((99m)Tc). A computed tomography scan performed a week later revealed regression. This unexpected response prompted an investigation of single cell dosimetry of low-energy electron emitters. METHODS: Another patient with low-grade, unclassifiable B-cell lymphoma with a low expression of CD22 was injected with (99m)Tc anti-CD22. Blood samples were drawn 30 minutes, 4 hours, and 24 hours after injection. Lymphoma cells (CD19+) and T cells (CD3+), which served as control cells, were separated using a flow cytometer. The radioactivity of the two cell populations was measured in an NaI(Tl) well-type detector. The mean uptake per cell and absorbed dose were calculated. The CD22 expression of the patient's cells and of a B-cell lymphoma cell line (Raji) were assessed by flow cytometry for the extrapolation of the absorbed dose from the patient's cells to a cell line with higher CD22 expression. RESULTS: The average number of (99m)Tc atoms per CD19+ and CD3+ cell 4 hours postinjection were 5.4 and 0.054, respectively. Depending on the assumed ratio between antibody and CD22 molecules (1:2 or 1:1), the CD22 expression on the patient's cells and Raji cells varied from 2800 to 5700 and from 37,000 to 74,000 per cell, respectively. The average absorbed dose per cell ranged from 4 x 10(-7) to 0.1 grays (Gy). CONCLUSIONS: It seems feasible to assess the mean single tumor cell uptake of (99m)Tc targeted by Fab' or minute anti-CD22 in a patient's lymphoma using sorted cell populations, thereby allowing single cell dosimetry. Extrapolation of the absorbed dose from (99m)Tc to cells with higher CD22 expression was made and under certain conditions absorbed doses of 0.1 Gy were obtained, indicating the potential relevance of low-energy electron emitters to therapy.

Antigens, CD↗

PubMed2002

FDG PET studies during treatment: prediction of therapy outcome in head and neck squamous cell carcinoma.

BACKGROUND: Positron emission tomography (PET) provides metabolic information of tissues in vivo. The purpose of this study was to assess the value of PET with 2-[(18) F] fluoro-2-deoxy-D-glucose (FDG) in prediction of therapy outcome (tumor response, survival, and locoregional control) in locally advanced HNSCC. METHODS: Between 1993 and 1999 47 patients underwent PET before (PET(1)) and after (PET(2)) 1 to 3 weeks of radical treatment with evaluation of metabolic rate (MR) and standardized uptake value (SUV) of FDG. All patients received radiotherapy, and 10 also received neoadjuvant chemotherapy. Median follow-up time was 3.3 years. RESULTS: Low and high MR FDG at PET(2), with median value as cutoff, was associated with complete remission in 96% and 62% (p =.007), with 5-year overall survival in 72% and 35% (p =.0042) and with local control in 96% and 55% (p =.002), respectively. CONCLUSIONS: FDG PET in the early phase of treatment of HNSCC is associated with tumor response, survival, and local control.

Adult↗

PubMed2002

A population-based study on the first forty-eight breast cancer patients receiving trastuzumab (Herceptin) on a named patient basis in Sweden.

Several studies have presented data on the efficacy and tolerability of trastuzumab within clinical trials. As a minority of patients is included in these trials, we undertook this retrospective study to describe trastuzumab therapy in clinical routine and its tolerability. We reviewed the medical records of the first 48 patients in Sweden who received treatment with trastuzumab on a named patient basis with (n = 29) and without (n = 19) chemotherapy. Forty-six patients had metastatic disease and had failed to respond to several prior regimens before starting antibody treatment. Two patients had locally advanced breast cancer failing on given neoadjuvant therapy. Patients with breast cancers with strong (3+) c-erbB-2 overexpression tended to have an improved survival from start of trastuzumab treatment versus those with a moderate (2+) overexpression (p = 0.09). Adverse events were registered in 22 patients (46%). The most common and acute side effects were fever and chills (7 patients, 15%). The toxicity seemed reasonable but two patients (4%) suffered serious cardiac events, both of them having received previous treatment with antracyclines.

Antibodies, Monoclonal↗

PubMed2002

131I-labelled anti-CD22 MAb (LL2) in patients with B-cell lymphomas failing chemotherapy. Treatment outcome, haematological toxicity and bone marrow absorbed dose estimates.

The experience with radioimmunotherapy in B-cell lymphomas using the rapidly internalizing antibody, anti-CD22 (LL2), is limited. In this study we investigated the efficacy and toxicity of 131I-labelled-LL2 for radioimmunotherapy in patients with B-cell lymphomas that failed one or two cytostatic regimens. Eleven patients were treated with one or repeated cycles of 131I-anti-CD22 antibody, 1330 MBq/m2 (36 mCi/m2). Six of the 11 treated patients demonstrated an objective response, three of them with complete remission. All follicular (3 patients) and transformed lymphomas (2 patients) responded compared to one of four diffuse large B-cell lymphomas. Two out of six responders exhibited event-free survival (EFS), which was comparable with or longer than the EFS following primary anthracycline-containing chemotherapy. Non-haematological toxicity was mild. Haematological toxicity was associated with pretreatment clinical characteristics but not with estimated absorbed bone marrow doses. Objective remission following treatment with 131I-anti-CD22 can be achieved in patients with various subtypes of B-cell lymphomas, failing standard chemotherapy. Follicular or transformed lymphomas seem particularly responsive. Haematological toxicity seems to be dependent on the functional status of the bone marrow before radioimmunotherapy.

Adult↗