| 1. |
- Amini, Rose-Marie, et al.
(författare)
-
A novel B-cell line (U-2932) established from a patient with a diffuse large B-cell lymphoma following Hodgkin lymphoma
- 2002
-
Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 43:11, s. 2179-2189
-
Tidskriftsartikel (refereegranskat)abstract
- Little is known about mechanisms leading to secondary non-Hodgkin lymphomas (NHL) in patients treated for Hodgkin lymphoma (HL). Our aim was to characterise in detail a cell line derived from a diffuse large B-cell lymphoma (DLBCL) that had developed in a patient with relapsing HL. The cell line U-2932 was established from ascites in a patient suffering from DLBCL previously treated for HL with multiple chemotherapy regimens. Characterisation was based on morphology, immunophenotype, Epstein-Barr virus (EBV)-status, IgH gene rearrangement status, tumourigenicity, p53 sequencing, and immunohistochemical expression of p53, BCL-2 and BCL-6. The karyotype was investigated using G-banding, comparative genomic hybridisation (CGH) and spectral karyotype (SKY) analysis. This cell line shows typical morphological features of a DLBCL and grows as colonies in nude mice. It expresses a B-cell phenotype with a somatically hypermutated V(H)4-39 gene and is negative for EBV. The origin of U-2932 was confirmed by demonstrating an identical V(H)4 rearrangement in ascites from the patient. A point mutation of the tumour-suppressor gene p53 was detected in amino acid position 176 and immunohistochemical over-expression of the p53 protein was also demonstrated. U-2932 carries a complex karyotype including high-level amplifications of the chromosomal bands 18q21 and 3q27 and expresses aberrant BCL-2 and BCL-6 immunohistochemically. We were unable to investigate the clonal relationship between the original HL and U-2932. In conclusion, U-2932 is a unique B cell line established from a patient suffering from HL followed by NHL. Overexpression of BCL-2, BCL-6 and p53 may play a role in the tumourigenesis and drug resistance. This cell line may become a useful tool to better understand the mechanisms responsible for development of secondary NHL in patients treated for HL.
|
|
| 2. |
- Mahteme, Haile, et al.
(författare)
-
Heterogeneous activity of cytotoxic drugs in patient samples of peritoneal carcinomatosis
- 2008
-
Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 0748-7983 .- 1532-2157. ; 34:5, s. 547-552
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: To investigate if the pattern of cytotoxic drug sensitivity in vitro in patient samples of peritoneal carcinomatosis (PC) is supportive to the current standardized approach for drug selection for perioperative intraperitoneal chemotherapy (IPC). METHODS: The cytotoxic effect of cisplatin, oxaliplatin, irinotecan, 5-fluorouracil, mitomycin-C, doxorubicin and melphalan was investigated in vitro on tumour cells from 223 patient tumour samples of different PC origins. RESULTS: Considerable differences in cytotoxic drug sensitivity between tumour types of the PC entity and within each tumour type were observed. Cisplatin showed high cross-resistance with oxaliplatin but low cross-resistance with doxorubicin and irinotecan. No cross-resistance was found between irinotecan and doxorubicin. The dose-response relationships for melphalan and irinotecan in individual samples showed great variability. CONCLUSIONS: The activity in vitro of cytotoxic drugs commonly used in IPC for PC is very heterogeneous. Efforts for individualizing drug selection for PC patients undergoing IPC seem justified.
|
|
| 3. |
- Tholander, Bengt, et al.
(författare)
-
Complete response with combined BRAF and MEK inhibition in BRAF mutated advanced low-grade serous ovarian carcinoma.
- 2020
-
Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 125:4, s. 325-329
-
Tidskriftsartikel (refereegranskat)abstract
- More effective treatments are needed for low-grade serous ovarian carcinoma (LGSOC). Our patient, who suffers from metastatic LGSOC, had received all established treatments. Sequencing analysis revealed an activating BRAF mutation. Therefore, combined treatment with BRAF and MEK inhibitors, which is the gold standard in malignant melanoma, was initiated. After eight months of therapy, the response was assessed as complete and the treatment is still, 3.5 years after initiation, of benefit. To our knowledge, no complete response on combined BRAF and MEK inhibitor treatment of low-grade serous ovarian cancer has previously been reported.
|
|
| 4. |
- von Heideman, Anne, 1956-, et al.
(författare)
-
Assessment of Chemotherapeutic Drug Sensitivity in Epithelial Ovarian Cancer Using Primary Cultures of Tumour Cells from Patients
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Sensitivity of epithelial ovarian cancer to chemotherapeutic drugs relevant in treatment of this cancer type was analysed in 125 tumour samples from 112 patients using a short-term primary culture assay based on the concept of total cell kill. Sensitivity was related to histopathological subtypes, treatment status and clinical tumour response. For cisplatin, doxorubicin, 5-FU, cyclophosphamide and topotecan, seropapillary high grade and clear cell ovarian cancer were the most sensitive subtypes and the mucinous tumours the most resistant subtype, whereas endometrioid tumours and the seropapillary low grade/borderline tumours showed intermediate sensitivity. In contrast, docetaxel showed the opposite pattern of activity. Samples from patients previously treated with chemotherapy tended, for the majority of drugs, to be slightly more resistant than samples from treatment naïve patients. The activity of cisplatin correlated strongly with that of the other drugs with the exception of docetaxel, implicating non-cross resistance between these key drugs in ovarian cancer. Tumour samples from two sites in the same patient at the same occasion showed similar and samples taken at different occasions different cisplatin sensitivity, which may implicate tumour clonal selection over time. At group level, samples from patients clinically responding to treatment were more sensitive to most drugs than samples from non-responding patients. At the individual patient level, optimized analyses of drug sensitivity in vitro compared with clinical response showed sensitivities and specificities in the 90 – 100% and 54 – 83% ranges, respectively. In conclusion, ovarian cancer subtypes exhibit different chemotherapeutic drug sensitivity in vitro, which needs consideration in treatment decisions for this disease. Furthermore, in vitro assessment of ovarian cancer tumour cell chemotherapeutic drug sensitivity provides clinically relevant information that could be useful in efforts to optimize treatment in individual patients with this disease.
|
|
| 5. |
- von Heideman, Anne, et al.
(författare)
-
Chemotherapeutic drug sensitivity of primary cultures of epithelial ovarian cancer cells from patients in relation to tumour characteristics and therapeutic outcome
- 2014
-
Ingår i: Acta Oncologica. - : Informa Healthcare. - 0284-186X .- 1651-226X. ; 53:2, s. 242-250
-
Tidskriftsartikel (refereegranskat)abstract
- Background. A number of chemotherapeutic drugs are active in epithelial ovarian cancer (EOC) but so far choice of drugs for treatment is mostly empirically based. Testing of drug activity in tumour cells from patients might provide a rationale for a more individualised approach for drug selection. Material and methods. Sensitivity of EOC to chemotherapeutic drugs was analysed in 125 tumour samples from 112 patients using a short-term primary culture assay based on the concept of total cell kill. Sensitivity was related to tumour histology, treatment status and clinical tumour response. Results. For most EOC standard drugs serous high grade and clear cell EOC were the most sensitive subtypes and the mucinous tumours the most resistant subtype. Docetaxel, however, tended to show the opposite pattern. Samples from previously treated patients tended to be more resistant than those from treatment naive patients. The activity of cisplatin correlated with that of other drugs with the exception of docetaxel. Tumour samples from two sites in the same patient at the same occasion showed similar cisplatin sensitivity in contrast to samples taken at different occasions. Samples from patients responding in the clinic to treatment were more sensitive to most drugs than samples from non-responding patients. At the individual patient level, drug sensitivity in vitro compared with clinical response showed sensitivities and specificities in the 83-100% and 55-83% ranges, respectively. Conclusions. Assessment of EOC tumour cell drug sensitivity in vitro provides clinically relevant and potentially useful information for the optimisation of drug treatment.
|
|
| 6. |
- von Heideman, Anne, 1956-
(författare)
-
Exploring Cancer Drugs In Vitro and In Vivo : With Special Reference to Chemosensitivity Testing and Early Clinical Development
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of this thesis were to investigate the utility of in vitro drug sensitivity testing to optimize the use of cancer chemotherapy and to assess the properties of a new cancer drug in a phase I clinical trial. Tumour cells from patients were analysed with the short-term Fluorometric Microculture Cytotoxicity Assay (FMCA). In samples from a wide spectrum of tumour types, the effect of the drug combination FEC (5Fu-epirubicin-cyclophosphamide) was generally appropriately predicted from the effect of the best component drug. However, of samples intermediately sensitive to the best single drug, 45% converted to sensitive when testing the combination. Thus, combination testing may identify advantageous interactions and improve in vitro test performance. In tumour samples from peritoneal carcinomatosis, significant differences in drug sensitivity between diagnoses were observed, cross-resistance between most drugs was modest or absent, and the concentration-effect relationships for two drugs in individual samples varied considerably. Thus, for optimal selection of drugs for intraperitoneal chemotherapy, differences in drug sensitivity at the diagnosis and individual patient level should be considered. In samples from patients with ovarian carcinoma, drug sensitivity was related to tumour grade, histologic subtype and patient treatment status. In a homogeneous subset of patients, the FMCA predicted individual patient tumour response with high sensitivity and specificity. Thus, if carefully interpreted in the context of important clinical variables, in vitro testing could be of value for individualizing chemotherapy in ovarian cancer. Employing a once weekly dosing schedule in a phase I trial, the mechanistically new and preclinically promising NAD depleting drug CHS 828 produced dose limiting thrombocytopenia and gastrointestinal toxicity without clear evidence of anti-tumour efficacy. It is concluded that in vitro drug sensitivity testing could be a way to optimize the use of chemotherapy and that successful development of new cancer drugs needs improved strategies.
|
|
| 7. |
- von Heideman, Anne, et al.
(författare)
-
Safety and efficacy of NAD depleting cancer drugs : results of a phase I clinical trial of CHS 828 and overview of published data
- 2010
-
Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 65:6, s. 1165-1172
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials. METHODS: A phase I clinical trial of CHS 828 in patients with advanced solid tumours was performed. Published clinical trials on NAD depleting drugs for cancer treatment were summarised for safety and efficacy. RESULTS: Seven patients with previously treated solid tumours received oral administration of CHS 828 in the dose range 20-80 mg once weekly for 3 weeks in 4 weeks cycles. Toxicity was dominated by gastrointestinal symptoms including nausea, vomiting, diarrhoea, constipation, subileus and gastric ulcer. One patient had thrombocytopenia grade 2. There were two cases each of grade 3-4 hyperuricemia and hypokalemia. Safety and efficacy of the NAD depleting drugs CHS 828 and FK866 have been reported from four phase I clinical trials, including a total of 97 patients with previously treated solid tumours. Outstanding toxicity reported was thrombocytopenia and various gastrointestinal symptoms. No objective tumour remission has been observed in the total of 104 patients treated in the above early trials. CONCLUSIONS: Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low.
|
|
