Apoptotic DNA fragments in serum of patients with muscle invasive bladder cancer: a prognostic entity

Patients with malignancies often possess increased concentrations of cell-free serum DNA. In this study, we investigated serum DNA levels in each 45 patients with bladder cancer (BCA) undergoing radical cystectomy and with benign prostate hyperplasia. A quantitative real-time PCR was used to amplify a 124 bp (PTGS2; mostly apoptotic origin) and a 271 bp (Reprimo; mostly necrotic origin) DNA fragment. Changes in the origin of DNA fragments were specified as the Apoptosis Index (AI, ratio of 124 bp/271 bp fragments). Small and large fragments were increased (p < 0.001 and p = 0.041) in BCA patients. The AI increase suggests that DNA fragmentation was mostly (p < 0.001) caused by apoptosis. High levels of small DNA fragments distinguished between BCA and BPH with high sensitivity (96%) and moderate specificity (62%). DNA levels and the AI were not correlated with clinicopathological parameters. However, an increased AI was correlated with BCA-specific mortality in a multivariate analysis (p = 0.011) indicating that the AI is an independent prognostic factor. Thus, cell-free DNA seems to be a useful prognostic marker in patients with BCA.     

BCL-2, TP53 and BAX protein expression in superficial urothelial bladder carcinoma

Whether TP53, BCL-2 and BAX expressions add independent prognostic information in patients with Ta/T1bladder urothelial carcinoma remains unclear. TP53 overexpression correlated with high tumor grade (p = 0.004), WHO grading categories (0.045), BAX expression (p = 0.043) and pathologic stage (p = 0.05). BCL-2 immunostaining was inverse associated with tumor grade (p = 0.008). Lack of BAX expression was related to reduced patient’s survival (p = 0.028). Mortality was higher in patients with BCL-2+/TP53+ (p = 0.023) or TP53+/BAX− (p = 0.027) phenotype. BAX and pathologic stage were independent predictors of progression-free and overall survival, respectively. Therefore, BAX expression might be relevant in patient’s prognosis.     

Is there a prognostic role of K-ras point mutations in the serum of patients with advanced non-small cell lung cancer?

The purpose of this study was to investigate the prognostic significance of K-ras mutations in circulating DNA in advanced non-small lung cancer (NSCLC) patients. Serum samples were assessed prior to platinum-based chemotherapy start in 67 patients with advanced NSCLC (stage IIIB or IV), treated between April 1999 and June 2002. Patients were not previously treated with chemotherapy. K-ras oncogene mutations at codon 12 were analyzed by genomic amplification and direct sequencing of the patient's DNA present in serum. Pre-treatment serum was available in all 67 patients. Twenty patients (30%) demonstrated K-ras mutations while 47 patients (70%) had wild-type K-ras. Among K-ras mutations, the amino acid glycine was substituted by cystein in 90% and valine in 10%. When patients were grouped according to K-ras genotype, there was no significant difference for any of the baseline patient characteristics. There was a tendency towards a higher response rate for patients with K-ras mutations versus wild-type K-ras in serum, however not statistically significant (p = 0.37). Median progression-free survival was 7.3 months versus 5.5 months in patients with mutations and with wild-type K-ras, respectively (p = 0.23). For median overall survival time, the mutation group was comparable to the wild-type K-ras group with 12.5 and 11.4 months, respectively (p = 0.28). In conclusion, there were no significant differences between the patients with K-ras mutations and those with wild-type genotype with respect to baseline patient characteristics, response rates, progression-free survival, or overall survival.     

Cell transfer regimens in patients with highly advanced surgically unresectable non-small cell lung cancer: significantly improved overall survival in patients with lower levels of serum immunosuppressive acidic protein

Sixty-one non-small cell lung cancer (NSCLC) patients with stage II and III/IV were enrolled and 49 completed immunotherapy. Patients were grouped based on immunosuppressive acidic protein (IAP). All patients received monthly intravenous infusions containing 1 × 10¹⁰ (mean cell number per patient) ex vivo expanded and IFN--treated peripheral blood mononuclear cells. No patients had grade 2 or greater adverse events. The patients with ≤580 μg/ml of serum IAP levels (n = 33) had significantly longer recurrence-free survival than those with >580 μg/ml of serum IAP levels (n = 16). Patients with lower IAP levels are still under immunotherapeutic control after 27 months free of recurrence. The IAP levels may be a prognostic marker for treatment efficacy in NSCLC. This immunotherapeutic regimen was feasible and well tolerated in patients with advanced NSCLC in terms of prolongation of survival.     

Myofibroblasts in stroma of odontogenic cysts and tumors can contribute to variations in the biological behavior of lesions

Stromal myofibroblasts (MF) have the potential to facilitate progression of neoplastic epithelial lesions that could contribute to their biological behavior. To assess immunohistochemically the frequency of stromal MF in different odontogenic cysts and tumors and correlate it to their aggressive biological behavior. The study included cases of dentigerous cyst (DC, n = 7), odontogenic keratocyst—parakeratinized type (OKC-P, n = 8), orthokeratinized type (OKC-O, n = 9), ameloblastic fibroma/fibro-odontoma (AMF/O, n = 11), unicystic ameloblastoma (UAM, n = 6), and solid ameloblastoma (SAM, n = 7). Cases of oral squamous cell carcinoma (SCC, n = 5) served as control. Myofibroblast frequency was assessed as the number of alpha smooth muscle actin (SMA)-positive stromal cells in 10 high-power fields, presented as the mean number of positive cells per field. Counts showed that mean number of positive cells in OKC-P (25.7 ± 11.4) was significantly higher than in DC (8.7 ± 11.6) (p = 0.024) and in SAM (29 ± 7) it was significantly higher than in UAM (14.9 ± 4.9) and AMF/O (5.6 ± 7.5) (p < 0.001). Counts in OKC-P and SAM were not significantly different from SCC (21.3 ± 5.3) (p > 0.05). The high frequency of stromal MF in known aggressive odontogenic lesions, such as OKC-P and SAM, implies that MF can contribute to the biological behavior of these odontogenic lesions. Various pharmacological agents that control stromal MF can be used as an aid to reduce extensive and mutilating surgery in cases of remarkably aggressive odontogenic lesions.     

Plasma MIP-1beta levels and skin toxicity in Japanese non-small cell lung cancer patients treated with the EGFR-targeted tyrosine kinase inhibitor, gefitinib

Gefitinib (Iressa^®) is an orally active, selective EGFR tyrosine kinase inhibitor that blocks signal transduction pathways. Skin toxicity has been reported to be the major toxicity observed in patients treated with the EGFR-targeted tyrosine kinase inhibitors, such as gefitinib and erlotinib. Although the mechanisms underlying the development of the skin toxicity remain to be precisely clarified, immunological mechanisms are considered to be involved. We examined the correlations between the plasma levels of several cytokines and the risk of development of adverse events, especially skin toxicity, induced by the administration of gefitinib as first-line monotherapy in non-small cell lung cancer (NSCLC) patients.

Paired plasma samples were obtained from a total 28 patients of non-small cell lung cancer; the first before the initiation of gefitinib administration (250 mg/day) (24 patients) and the second 2 or 4 weeks after the initiation of treatment (23 patients). The plasma concentrations of 17 major cytokines were measured using a bead-based multiplex assay. The median concentrations of eight of these cytokines before the start of treatment ranged from 0.06 (IL-5) to 58.26 (MIP-1β) (μg/ml). The concentrations of the remaining nine cytokines were under the detectable limit (<0.01 μg/ml) in more than 50% of the samples. Comparisons of the levels before and after treatment showed no significant differences for any of the cytokines measured.

The MIP-1β levels were significantly lower in the patients with skin toxicity (16/24) as compared with those in the patients not showing any skin toxicity (59.1 ± 10.5 versus 119.0 ± 36.8; p = 0.042 by the two-sample t-test). The K-Nearest Neighbor Prediction (K = 3) showed the classification rate to be 75% for the prediction sets containing MIP-1β, IL-4 and IL-8. There were no significant associations between the levels of any of the cytokines measured and any other parameters, including the tumor response to the drug. In conclusion, the plasma MIP-1β level may be a useful predictor of the development of skin toxicity in patients receiving gefitinib treatment.     

Regulatory polymorphisms of multidrug resistance 1 (MDR1) gene are associated with the development of childhood acute lymphoblastic leukemia

The aim of this study is to determine whether the polymorphisms of the MDR1 gene are associated with the development of childhood acute lymphoblastic leukemia (ALL).

The MDR1 gene polymorphisms, −2352 G > A, −934A > G, −692T > C (5′ regulatory region) and 3435C > T (exon 26), were examined in 157 ALL patients and 96 healthy children. The amounts of MDR1 mRNA were quantified in 54 healthy individuals using normal peripheral blood mononuclear cells to evaluate the effect of each polymorphism on the gene expression.

The frequency of the G/G genotype of the −2352 G > A was significantly higher in ALL than in controls (74/109 versus 52/96, p = 0.04). The frequency of the T/T genotype of the 3435C > T was also significantly higher in ALL (29/118 versus 10/96, p = 0.006). In a haplotype analysis using the 5′ regulatory sites, the frequency of a certain haplotype was higher in ALL than in controls (59/90 versus 42/88, p = 0.048). When the −2352G > A was examined in different age groups, patients aged six or older were found to have the G/G genotype more frequently than the controls (42/51 versus 52/96, p = 0.0014), while no difference was observed in the younger age group. The amounts of MDR1 mRNA were significantly higher in either G/G or G/A genotype of the −2352 G > A than in A/A genotype (p = 0.04).

The present study suggests that the genetic background of MDR1 may be associated with the development of childhood ALL, possibly due to a quantitative change in the MDR1 gene resulting from genetic polymorphisms.     

Expression of TCL-1 as a potential prognostic factor for treatment outcome in B-cell chronic lymphocytic leukemia

TCL-1 expression is variable in CLL, and no study has examined its association with treatment response. We measured TCL-1 protein in CLL cells from 51 patients who then received pentostatin, cyclophosphamide, and rituximab. TCL-1 expression did not correlate with any pre-treatment characteristics. Lower TCL-1 levels were associated with higher probability of attaining flow cytometry-negative status post-treatment (52% versus 17%, p = 0.046). Trends toward improved complete remission rate (49% versus 19%, p = 0.064) and progression-free survival (medians: 33 versus 20 months, p = 0.199) were noted with lower TCL-1 expression. These data suggest TCL-1 expression may help predict treatment outcome in CLL patients following chemoimmunotherapy, and examination in larger studies is warranted.     

MTHFR polymorphisms' influence on outcome and toxicity in acute lymphoblastic leukemia patients

Recently the influence of polymorphisms of different genes involved in metabolism of chemoterapic agents have been studied especially in childhood acute lymphoblastic leukemia (ALL). We evaluated the influence of C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) polymorphisms on time to relapse and survival and on methotrexate (MTX) toxicity in 82 ALL adult patients.

Relapse free survival and event free survival between homozygous wild-type and variant patients in both polymorphisms were not significantly different. However, we observed an association between 677TT variant and survival in a subset of ALL patients homogenously treated with MTX-based maintenance (p = 0.02). In the same subgroup we confirmed the role of 677TT variant on toxicity during MTX treatment (p = 0.003).     

Stromal myofibroblasts and malignant transformation in a 4NQO rat tongue carcinogenesis model

This study assesses the correlation of changes in the density of stromal myofibroblasts to propagation of histopathologic alterations and proliferative activity of the epithelium in a rat 4NQO-induced tongue rat carcinogenesis model.Forty-three male Wistar rats were administered 0.001% 4NQO in drinking water for: 0 (n = 7, control), 7 (n = 4), 8 (n = 8), 14 (n = 6), 22 (n = 9), and 28 (n = 9) weeks, after which they were euthanized. Tongue sections were divided equally into anterior, middle and posterior thirds. Each third was given a histopathologic score (hematoxylin and eosin), ranging from normal, hyperplasia/hyperkeratosis, and escalating degrees of dysplasia to carcinoma, and analyzed by the point-counting method for density of epithelium-associated stromal myofibroblasts (SMA) and of proliferating epithelial cells (PCNA). Histopathologic changes significantly increased in severity (carcinoma) with duration of 4NQO administration (p < 0.001) in the posterior third of the tongue. The density of stromal myofibroblasts and proliferating epithelial cells was significantly higher in the posterior third of the tongue at 28 weeks compared to the other time points and locations (p < 0.001, p = 0.01, respectively). Significant correlations were found between occurrence of carcinoma and the increase in density of stromal myofibroblasts (p < 0.001) and of proliferating epithelial cells (p = 0.001) in the posterior third of the tongue. Increased density of stromal myofibroblasts was distinctively associated with the development of carcinoma but not with pre-malignant changes. Defining the mechanism of evolvement of carcinoma-associated stromal myofibroblasts is expected to further broaden our knowledge on the micro-environmental events occurring during the malignant transformation.     

小细胞肺癌化疗前后血清VEGF和b-FGF的变化及临床意义

  目的  探讨化疗前后小细胞肺癌(SCLC)患者血清血管内皮生长因子(VEGF)和碱性成纤维细胞生长因子(b-FGF)水平的变化及临床意义。  方法  用酶联免疫吸附法测定34例SCLC患者化疗前后VEGF和b-FGF的浓度变化, 并与34例健康志愿者做对照。  结果  化疗前肺癌组VEGF及b-FGF水平均明显高于健康对照组, 差异有统计学意义(P < 0.001);化疗后有效组VEGF及b-FGF水平明显低于化疗前, 差异有统计学意义(P < 0.001);肺癌组VEGF和b-FGF水平无显著相关性; 相关性分析表明VEGF浓度的升高仅与化疗疗效和NSE升高相关(P < 0.05), b-FGF的升高与各项病理特征均无显著相关性(P > 0.05);Kaplan-Meier生存分析证实VEGF和b-FGF低浓度组的平均生存期均明显长于高浓度组(P < 0.05)。  结论   SCLC患者血清VEGF和b-FGF浓度与生存明显相关, 可以作为SCLC患者生存的预后因子。此外, 化疗前后血清VEGF和b-FGF浓度变化可以作为预测SCLC患者化疗疗效的指标。      

Correlation of angiogenesis with 18F-FMT and 18F-FDG uptake in non-small cell lung cancer

L-[3-¹⁸F]-α-methyltyrosine (¹⁸F-FMT) is an amino-acid tracer for positron-emission tomography (PET). We have conducted a clinicopathologic study to elucidate the correlation of angiogenesis with ¹⁸F-FMT and 2-[¹⁸F]-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) uptake in patients with non-small cell lung cancer (NSCLC). Thirty-seven NSCLC patients were enrolled in this study, and two PET studies with ¹⁸F-FMT and ¹⁸F-FDG were performed. Uptake of PET tracers was evaluated with standardized uptake value. Vascular endothelial growth factor (VEGF), CD31, CD34, L-type amino acid transporter 1 (LAT1) and Ki-67 labeling index of the resected tumors were analyzed by immunohistochemical staining, and correlated with the clinicopathologic variables and the uptake of PET tracers. The median VEGF rate was 45% (range, 10–78%). High expression was seen in 30 patients (81%, 30/37). VEGF expression was statistically associated with progressively growing microvessel count. VEGF showed a correlation with LAT1 expression ( P  = 0.04) and Ki-67 labeling index ( P  = 0.01). However, it showed no correlation with age, gender, disease stage, tumor size, and histology. Microvessel density (MVD) showed no correlation with any parameters. ¹⁸F-FMT and ¹⁸F-FDG uptake correlated significantly with VEGF ( P  < 0.0001, P  = 0.026, respectively), whereas the correlation of ¹⁸F-FMT and VEGF was more meaningful. The present study demonstrated that the metabolic activity of primary tumors as evaluated by PET study with ¹⁸F-FMT and ¹⁸F-FDG is related to tumor angiogenesis and the proliferative activity in NSCLC. ( Cancer Sci 2009; 100: 753–758)     

Serum vascular endothelial growth factor (VEGF) levels correlate with tumor VEGF and p53 overexpression in endocrine positive primary breast cancer

Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, associated with unfavorable clinical characteristics in breast cancer. The aim of this study was to evaluate different angiogenic markers in endocrine-positive breast cancer patients. The authors analyzed serum and tumor samples from 71 patients with endocrine-positive operable primary breast cancer to determine the expression and the possible relationship between circulating serum VEGF levels, tumor VEGF expression, microvessel density (MVD), and other immunohistochemical parameters. Basal VEGF serum levels were significantly higher in breast cancer patients than in healthy controls. A significant correlation was observed between basal VEGF serum concentrations, microvessel density (p = 0.01) and p53 status (p = 0.004). Intratumoral VEGF expression was significantly associated with neoplastic embolization (p = 0.041) and circulating VEGF levels (p = 0.047). The results confirm that in primary endocrine-positive breast cancer serum VEGF levels are elevated and show a positive relationship with tumor VEGF and p53 overexpression.     

ErbB2 and fatty acid synthase (FAS) expression in 102 squamous cell carcinomas of the tongue: correlation with clinical outcomes

The oncoprotein ErbB2 (HER-2/neu) is a tyrosine kinase cell surface receptor overexpressed in several human malignancies, including oral squamous cell carcinoma (OSCC). ErbB2 was recently shown to regulate the expression of fatty acid synthase (FAS), a multifunctional enzyme complex responsible for the de novo biosynthesis of saturated fatty acids. Here we evaluated the relationship between the immunohistochemical expression of ErbB2, FAS, and Ki-67 with the clinicopathologic characteristics of tongue squamous cell carcinoma (SCC). One hundred and two patients with tongue SCC treated from 1990 to 1995 were studied. Clinical and treatment data were obtained from the medical records and histopathological features revised. Paraffin-embedded tissues were submitted to standard immunohistochemical reactions for ErbB2, FAS and Ki-67. A strong positive correlation between ErbB2 labeling at the cell membrane and FAS expression was found in the tongue SCC samples (p < 0.0001). The intracytoplasmatic expression of ErbB2 as well as Ki-67 nuclear staining were significantly associated with a high risk of recurrence by predicting both disease free survival (log-rank test, p = 0.0096 and p = 0.0047, respectively) and overall survival (log-rank test, p = 0.0029 and p = 0.0001, respectively). Taken together, our results suggest that the immunolocalization of ErbB2 at the cell surface of malignant oral keratinocytes is linked to FAS expression whereas the intracytoplasmatic ErbB2 or Ki-67 staining predict high risk of recurrence of tongue SCC.     

Placenta growth factor not vascular endothelial growth factor A or C can predict the early recurrence after radical resection of hepatocellular carcinoma

The purpose of this study was to evaluate the relationship between the expression of PlGF in tumor tissue and clinical outcomes in HCC patients. Tumor PlGF and vascular endothelial growth factor (VEGF)-A and VEGF-C mRNA were analyzed. Results demonstrated that patients with PlGF expression levels higher than median tended to have early recurrence compared to patients with PlGF expression lower than median (P = .031). In patients with AJCC stage II–III disease, this difference was even more significant (P = .002). In contrast, VEGF-A and VEGF-C could not predict early recurrence-free survival. Since PlGF expression correlated with early recurrence of HCC, PlGF may be an important prognostic indicator in HCC.     

非小细胞肺癌患者血清VEGF表达水平及其临床意义

目的：检测非小细胞肺癌（NSCLC）患者血清血管内皮生长因子（vascula rendothelial growth factor,VEGF）的表达水平,探讨其临床意义。方法：应用酶联免疫吸附法（ELISA）检测114例NSCLC和87例健康对照组血清中VEGF水平,计算VEGF的灵敏度和特异度,阳性预测值和阴性预测值,分析患者治疗前血清VEGF水平对其近期疗效的影响以及VEGF与CYFRA21-1和CEA联合检测的临床意义。结果：（1）NSCLC组血清VEGF平均水平为203.70ng/L,对照组为76.21ng/L,两组差别有统计学意义（P〈0.001）。有负荷组患者血清VEGF水平高于无负荷组（P〈0.001）。（2）VEGF以200.6ng/L为医学参考值上限,VEGF对NSCLC诊断的灵敏度为69.7%,特异度为96.4%;有负荷组患者灵敏度可达到81.9%,而无负荷组仅为33.7%,其差别有统计学意义（P〈0.01）。（3）NSCLC患者随着血清VEGF平均水平的升高,其疗效逐渐降低（P〈0.05）。3种肿瘤标记物联合分析显示,随着患者血清肿瘤标记物阳性数目的增多,无效患者的比例呈上升趋势,当患者血清肿瘤标记物阳性数目达到3种时,约87.5%的患者治疗无效。（4）血清VEGF水平与肿瘤大小、分化程度及临床分期密切相关（P〈0.01）,与患者的年龄无关（P〉0.05）。结论：VEGF在NSCLC的发生、生长和转移过程中起着极其重要的作用,有可能成为一种新的肿瘤标记物用于NSCLC的辅助诊断或检测指标。     

VEGF, TNF-alpha and 8-isoprostane levels in exhaled breath condensate and serum of patients with lung cancer

The aim of the present study was to evaluate the levels of VEGF, 8-isoprostane and TNF-alpha in EBC and serum of patients with primary lung cancer prior to the initiation of any treatment, in order to evaluate their possible diagnostic role. Furthermore, associations between VEGF, 8-isoprostane and TNF-alpha levels in EBC and serum with clinicopathologic factors were investigated. We enrolled 30 patients with lung cancer (mean age 65.2+/-10.5 years) and 15 age and gender-matched healthy smokers as controls. Serum and EBC were collected before any treatment. TNF-alpha, VEGF and 8-isoprostane levels in EBC and serum were analyzed by an immunoenzymatic method (ELISA). A statistically significant difference was observed between lung cancer patients and the control group regarding the values of TNF-alpha, both in EBC (52.9+/-5.0 pg/ml vs. 19.4+/-3.9 pg/ml, p<0.0001) and serum (44.5+/-6.3 pg/ml vs. 22.2+/-4.3 pg/ml, p=0.035). Moreover, EBC VEGF levels were higher in patients with T3-T4 tumor stage compared to T1-T2 (9.3+/-2.8 pg/ml vs. 2.3+/-0.7pg/ml, p=0.047). A statistically significant correlation was also observed between serum and EBC values of VEGF (r=0.52, p=0.019). In addition, serum levels of VEGF were higher in lung cancer patients than in controls (369.3+/-55.1 pg/ml vs. 180.5+/-14.7 pg/ml, p=0.046). VEGF serum levels were also found higher in patients with advanced stage of disease (IIIB-IV) and distant nodal metastasis (N2-N3). No differences were observed in 8-isoprostane in EBC between lung cancer patients and controls. In contrast, serum 8-isoprostane levels were higher in lung cancer patients compared to controls (24.9+/-3.6 pg/ml vs. 12.9+/-1.6 pg/ml, p=0.027) and were higher in patients with advanced disease. All three biomarkers presented acceptable reproducibility in the EBC on two consecutive days. In conclusion, we have shown that TNF-alpha, VEGF and 8-isoprostane are elevated in the serum of lung cancer patients and increased serum VEGF and 8-isoprostane levels are related to advanced disease. In EBC, increased TNF-alpha levels were observed in lung cancer patients, whereas increased VEGF levels were observed in advanced T-stage. Further longitudinal studies are warranted for the evaluation of the prognostic role of these biomarkers in lung cancer.     

Vascular Endothelial Growth Factor Levels in Relation to Oxidative Damage and Antioxidant Status in Patients with Breast Cancer

Purpose

Oxidative stress and angiogenesis are important elements in the pathogenesis of inflammatory diseases and cancer. Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic cytokines and is up-regulated by conditions associated with the generation of free radicals and reactive oxygen intermediates. In this study, we investigated the association between oxidative stress and serum VEGF status in patients with breast cancer.

Methods

Forty patients with breast carcinoma, of which 21 were stage II and 19 were stage III, along with 40 age- and gender-matched healthy controls were enrolled. Oxidative stress, total antioxidant status, and VEGF levels in serum were evaluated by spectrophotometric procedures. Malondialdehyde (MDA) levels were measured and antioxidant status was assessed by measuring total antioxidant status (TAS) to assess oxidative damage.

Results

VEGF and MDA levels were significantly higher in patients with breast cancer than those of controls (p<0.005). Total antioxidant level decreased significantly in patients compared to that in controls. MDA, TAS, and VEGF levels were also analyzed based on menopausal status and different clinical disease stages. MDA and TAS level significantly different in the postmenopausal group than the premenopausal group, whereas VEGF level remained unchanged.

Conclusion

Increased VEGF level and its positive correlation with oxidative stress level and decreased antioxidant status suggest a link between oxidative stress and malignant transformation.     

Imatinib for hepatocellular cancer--focus on pharmacokinetic/pharmacodynamic modelling and liver function

The effects of imatinib are partly mediated by the inhibition of platelet-derived growth factor (PDGF), which is highly expressed in the liver. In this phase-I/II trial pharmacokinetic parameters of imatinib given for hepatocellular cancer were similiar to those previously derived from CML patients. The AUC of N-desmethyl-imatinib depended on liver function; the metabolism of imatinib was otherwise comparable to other populations. During short-termed imatinib treatment (4 weeks, 400 mg/d), plasma PDGF significantly decreased. The AUC of N-desmethyl-imatinib could best be attributed to the pharmacodynamic effect of PDGF inhibition (r = −0.679 [95% CI: −0.917 to −0.0868], p = 0.031).     

Influence of low-dose daily cisplatin on the distant metastasis-free survival of patients with locally advanced nonmetastatic head and neck cancer treated with radiation therapy

We investigated the impact of low dose daily cisplatin on distant metastasis-free survival (DMFS) in locally advanced head and neck cancer treated with hyperfractionated radiotherapy (77 Gy in 70 fractions in 35 treatment days). In locally controlled tumors cisplatin led to better DMFS (p = 0.0272); Cisplatin may have acted independently of micrometastasis in locally advanced H&N cancer.