| 1. |
- Bardi, G, et al.
(författare)
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Tumor karyotype predicts clinical outcome in colorectal cancer patients
- 2004
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 22:13, s. 2623-2634
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To investigate the prognostic value of the overall karyotypic features and specific chromosome aberrations in colorectal cancer (CRC). Patients and Methods Cytogenetic features of 150 primary CRCs investigated at the time of surgery were correlated with patient survival by univariate and multivariate analyses, using classical clinicopathologic parameters as covariates. Results In univariate analysis, in addition to tumor grade and clinical stage, structural aberrations as well as rearrangements of chromosomes 8 and 16 were significantly correlated with shorter overall survival. Karyotypic complexity, rearrangements of chromosomes 8 and 16, and loss of chromosome 4 were significantly correlated with shorter disease-free survival. In multivariate analysis, in addition to tumor grade, the type of chromosome aberrations (structural or numerical), ploidy, and loss of chromosome 18 came across as independent prognostic factors in the group of all patients. In the subset of patients with stage I and II carcinomas, none of the clinicopathologic variables could independently predict patient survival, whereas the presence of structural chromosomal aberrations was the only independent predictor of poor prognosis. In the subset of patients with stage III carcinomas, the presence of structural changes of chromosome 8 was a stronger independent predictor of prognosis than was tumor grade. Conclusion Cytogenetic tumor features are valuable predictors of prognosis in CRC patients. The tumor karyotype should therefore be taken into account in the clinical management of patients with this disease, especially for patients having cancers of the early or intermediate stages I, II, and III.
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| 2. |
- Baselga, J, et al.
(författare)
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Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types
- 2002
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 20:21, s. 4292-4302
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. PATIENTS AND METHODS: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. RESULTS: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for >or= 3 months; seven of these patients remained on study drug for >or= 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. CONCLUSION: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.
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| 3. |
- Fletcher, Christopher D.M., et al.
(författare)
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Clinicopathologic re-evaluation of 100 malignant fibrous histiocytomas: prognostic relevance of subclassification
- 2001
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 19:12, s. 3045-3050
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Malignant fibrous histiocytoma (MFH) has been regarded as the most common soft tissue sarcoma (STS) in adults. Yet its true nature and the validity of this diagnostic concept have increasingly been questioned. Available data suggest that most patients with MFH can be subclassified into specific STS types, but the clinical relevance of such categorization has been argued. In a retrospective study, we reclassified 100 tumors of the extremity and trunk wall primarily diagnosed as MFH and analyzed the outcome. PATIENTS AND METHODS: Patients were adults (median age, 70 years; range, 32 to 94 years). The median tumor size was 8 cm (range, 1 to 30 cm), and the thigh was the most common tumor location (n = 31). Median follow-up was 8 years (range, 3 to 16 years). The overall 5-year metastasis-free survival rate was 0.64. The tumors were reanalyzed histologically, immunohistochemically, and, where available, ultrastructurally, and were classified according to strict diagnostic criteria. Patients were staged according to the American Joint Committee on Cancer system, and prognoses were compared among different groups of the reclassified diagnoses, paying special attention to myogenic tumors. RESULTS: In 84 of 100 tumors, a specific line of differentiation was either proved or strongly suggested. The most common diagnoses were myxofibrosarcoma (n = 22) and leiomyosarcoma (n = 20). Overall, 30 tumors could be grouped as some form of myogenic sarcoma. These tumors had a worse prognosis, even within the same American Joint Committee on Cancer stage, and a shorter time to metastasis than nonmyogenic tumors. CONCLUSION: This retrospective study confirms that most so-called MFH can be subclassified by defined criteria; it provides evidence that such classification is clinically important. Specifically, pleomorphic STS showing myogenic differentiation are significantly more aggressive, a finding that allows planning future therapeutic trials.
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| 4. |
- Friberg, Lena E., et al.
(författare)
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Model of Chemotherapy-Induced Myelosuppression With Parameter Consistency Across Drugs
- 2002
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 20:24, s. 4713-4721
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To develop a semimechanistic pharmacokinetic-pharmacodynamic model describing chemotherapy-induced myelosuppression through drug-specific parameters and system-related parameters, which are common to all drugs. PATIENTS AND METHODS: Patient leukocyte and neutrophil data after administration of docetaxel, paclitaxel, and etoposide were used to develop the model, which was also applied to myelosuppression data from 2'-deoxy-2'-methylidenecytidine (DMDC), irinotecan (CPT-11), and vinflunine administrations. The model consisted of a proliferating compartment that was sensitive to drugs, three transit compartments that represented maturation, and a compartment of circulating blood cells. Three system-related parameters were estimated: baseline, mean transit time, and a feedback parameter. Drug concentration-time profiles affected the proliferation of sensitive cells by either an inhibitory linear model or an inhibitory E(max) model. To evaluate the model, system-related parameters were fixed to the same values for all drugs, which were based on the results from the estimations, and only drug-specific parameters were estimated. All modeling was performed using NONMEM software. RESULTS: For all investigated drugs, the model successfully described myelosuppression. Consecutive courses and different schedules of administration were also well characterized. Similar system-related parameter estimates were obtained for the different drugs and also for leukocytes compared with neutrophils. In addition, when system-related parameters were fixed, the model well characterized chemotherapy-induced myelosuppression for the different drugs. CONCLUSION: This model predicted myelosuppression after administration of one of several different chemotherapeutic drugs. In addition, with fixed system-related parameters to proposed values, and only drug-related parameters estimated, myelosuppression can be predicted. We propose that this model can be a useful tool in the development of anticancer drugs and therapies.
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| 5. |
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| 6. |
- Henningsson, Anja, et al.
(författare)
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Mechanism-based pharmacokinetic model for paclitaxel
- 2001
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 19:20, s. 4065-4073
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE To create a model based on known mechanisms of paclitaxel distribution that could describe the pharmacokinetics (PK) of total and unbound plasma concentrations, as well as blood concentrations. In addition, to investigate the relationship between exposure, based on unbound and total concentrations, and neutropenia. PATIENTS AND METHODS Paclitaxel and Cremophor EL (CrEL) concentrations were obtained from 23 female and three male patients (50 courses in total) with different cancer types that received paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) (135 to 225 mg/m(2)) as 3- or 24-hour intravenous infusions. Seven of the patients received combination therapy with doxorubicin or cisplatin. The population PK model was built to fit three types of data simultaneously: unbound, total plasma, and blood concentrations. The area under the curve, threshold, and general models were used to relate neutrophil survival fraction from 19 patients (29 courses in total) to exposure based on unbound and total plasma concentration, respectively. RESULTS The PK model included a linear three-compartment model for unbound concentration, binding directly proportional to CrEL, linear and nonlinear binding to plasma proteins, and linear and nonlinear binding to blood cells. The threshold model best described the PK/pharmacodynamic (PD) relationship for total concentration. No distinction could be made between the models for unbound drug. CONCLUSION Earlier PK models for paclitaxel have been empirical. This study shows that a mechanistic model can be used to describe the nonlinear PK of paclitaxel. There is an indication that the PK/PD relationship is not the same for unbound and total plasma concentrations.
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| 7. |
- Jansson, Agneta, 1973-, et al.
(författare)
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Bax expression decreases significantly from primary tumor to metastasis in colorectal cancer
- 2002
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 20:3, s. 811-816
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Bax is a proapoptotic member of the bcl-2 family. Previous studies about Bax have shown that the expression increases from normal to tumor tissue, but the clinical significance is contradictory. Our aims were to analyze the expression of Bax from normal mucosa to primary tumor and to metastases in colorectal cancer patient. We further investigated whether low Bax expression in the primary tumor or changed expression from normal mucosa to primary tumor and to metastases had biologic and clinical significance.PATIENTS AND METHODS: The study included 135 patients with primary colorectal adenocarcinoma, of whom 31 had metastases in the lymph nodes and 75 had normal mucosa. Immunohistochemistry, DNA sequencing, and microsatellite analysis were used to detect Bax expression, mutations, and microsatellite instability.RESULTS: The protein was observed in 132 of 135 tumors, all normal epithelial cells and metastases. The frequencies of weak expression were greater from well/moderately to poorly differentiated and to mucinous carcinomas. Bax expression was stronger from normal to tumor tissue, but subsequently decreased in metastases. The matched cases with lower expression in the metastases than in the primary tumor showed a more infiltrative growth pattern and more distal metastases.CONCLUSION: The association of Bax expression with tumor differentiation/histologic types and a decreased expression in the metastases, suggests that Bax expression may be involved in tumor differentiation/histologic types and metastatic progression. We also propose the novel notion that changed Bax expression in the metastases compared with the primary tumors might provide information to determine the clinicopathologic characteristics of the tumor.
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| 8. |
- Jordhoy, Marit S., et al.
(författare)
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Quality of life in palliative cancer care: results from a cluster randomized trial
- 2001
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 19:18, s. 3884-3894
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To assess the impact of comprehensive palliative care on patients' quality of life. The intervention was based on cooperation between a palliative medicine unit and the community service and was compared with conventional care. PATIENTS AND METHODS: A cluster randomized trial was carried out, with community health care districts defined as the clusters. Patients from these districts who had malignant disease and survival expectancy between 2 to 9 months were entered onto the trial. The main quality-of-life end points were physical and emotional functioning, pain, and psychologic distress assessed monthly by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) questionnaire and Impact of Event scale (IES). In total, 235 intervention patients and 199 controls were included. RESULTS: During the initial 4 months of follow-up, the compliance was good (72%) and comparable among treatment groups. No significant differences on any of the quality-of-life scores were found. At later assessments and for scores that were made within 3 months before death, there was also no consistent tendency in favor of any treatment group on the main outcomes or other EORTC QLQ-C30 scales/items. CONCLUSION: A general program of palliative care may be important to ensure flexibility and to meet the needs of terminally ill patients. However, to achieve improvements on a group level of the various dimensions of quality of life, specific interventions directed toward specific symptoms or problems may have to be defined, evaluated, and included in the program.
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| 9. |
- Lens, MB, et al.
(författare)
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Effect of pregnancy on survival in women with cutaneous malignant melanoma
- 2004
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 22:21, s. 4369-4375
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Tidskriftsartikel (refereegranskat)abstract
- Purpose An adverse influence of pregnancy on the risk of death in women with cutaneous melanoma was suggested historically by anecdotal reports. Previous studies included small numbers of women observed for short periods. Methods Using data from the Swedish National and Regional Registries, we performed a retrospective cohort study of all Swedish women who were diagnosed with cutaneous melanoma during their reproductive period, from January 1, 1958, to December 31, 1999. The relationship between pregnancy status at the diagnosis of melanoma and overall survival was examined in multivariable proportional-hazards models. Results The cohort comprised 185 women (3.3%) diagnosed with melanoma during pregnancy and 5,348 (96.7%) women of the same childbearing age diagnosed with melanoma while not pregnant. There was no statistically significant difference in overall survival between pregnant and nonpregnant groups (log-rank chi(2)1 [r] = 0.84, P =.361). Pregnancy status at the time of diagnosis of melanoma was not related to survival in a multivariable Cox model in the 2,101 women (hazard ratio for death in the pregnant group was 1.08, 95% Cl, 0.60 to 1.93). In the multivariable analysis, pregnancy status after diagnosis of melanoma was not a significant predictor of survival (hazard ratio for death in women who had pregnancy subsequent to the diagnosis of melanoma was 0.58, 95% Cl, 0.32 to 1.05). Conclusion The survival of pregnant women with melanoma is not worse than the survival of nonpregnant women with melanoma. Pregnancy subsequent to the diagnosis of primary melanoma was not associated with an increased risk of death. (C) 2004 by American Society of Clinical Oncology.
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| 10. |
- Malmström, Per, et al.
(författare)
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S-phase fraction and urokinase plasminogen activator are better markers for distant recurrences than Nottingham Prognostic Index and histologic grade in a prospective study of premenopausal lymph node-negative breast cancer
- 2001
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 19:7, s. 2010-2019
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Histologic grade, Nottingham Prognostic Index (NPI), estrogen receptor (ER) and progesterone receptor (PSR) status, and tumor size have previously been shown to be important prognostic indicators for distant recurrence of breast cancer. The purpose of this study was to compare the prognostic value of these factors with flow cytometric S-phase fraction (SPF), urokinase plasminogen activator (uPA), and plasminogen activator inhibitor type 1 (PAI-1) in premenopausal patients with lymph node-negative breast cancer. Patients and Methods: In 237 consecutive premenopausal patients with lymph node-negative breast cancer and freshly frozen tumor material available, SPF, ER and PgR status, uPA and its inhibitor PAI-1, histologic grade, and NPI were evaluated. Results: SPF was univariately the most powerful prognostic factor for distant recurrence, followed by uPA, histologic grade, PgR, age, ER, NPI, and PAI-l,the latter being nonsignificant. Multivariate analysis revealed that neither NPI nor histologic grade was significant after adjustment for SPF, ct fact that may be explained by the strong association between these factors. uPA was, however, an independent prognostic factor in addition to SPF, NPI, or histologic grade. Conclusion: In this prospective study, SPF and uPA were found to be independent prognostic factors in premenopausal women with lymph node-negative breast cancer. We suggest that SPF, if performed under standardised conditions, can replace histologic grade as a selection instrument for adjuvant medical treatment. The value of the combination of SPF and uPA needs to be confirmed in an independent prospective trial.
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