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.     

Serum vascular endothelial growth factor is related to systemic oxidative stress in patients with lung cancer

Vascular endothelial growth factor (VEGF) is known to play crucial role in tumour angiogenesis. It is demonstrated that VEGF can be up-regulated by oxidative stress. The aim of this study was to determine the serum VEGF levels and oxidative stress in patients with primary lung cancer and to investigate their association with clinicopathologic factors.

We measured serum VEGF levels and oxidative stress in 63 patients (age 63.02 ± 1.12 S.E.M.) with primary lung cancer before any treatment (39 NSCLC and 24 SCLC; 6 patients stage I, 3 stage II, 25 stage III and 29 stage IV) and 25 normal subjects. The serum VEGF levels were measured with enzyme linked immunosorbent assay. Serum oxidative stress levels were detected by a commercially available assay (D-ROMs test, Diacron, Grossetto, Italy).

The levels of oxidative stress in patients were higher than those in normal subjects (555.3 ± 30.35 UCarr vs. 360.1 ± 17.46 UCarr). Additionally, a significant difference was found in serum VEGF levels between lung cancer patients and healthy control subjects (428.1 ± 38.42 pg/ml vs. 298.8 ± 19.89 pg/ml, respectively, p = 0.040). Interestingly, serum oxidative stress presented a significant correlation with serum VEGF levels in patients with lung cancer (r = 0.542, p = 0.002). Serum VEGF levels were significantly associated with the clinical staging (N-stage) of the patients (p = 0.023), performance status (p = 0.004) and age (p = 0.004).

In conclusion, oxidative stress and VEGF are significantly increased in patients with primary lung cancer. The correlation between them might implicate new aspects of the mechanisms controlling tumour angiogenesis and may present clinical interest in the future. Further studies are warranted to evaluate the role of oxidative stress and VEGF as possible biomarkers for the diagnosis and follow-up of patients with lung cancer.     

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.     

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.     

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.     

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.     

Prediction of lymph node metastasis using the combined criteria of helical CT and mRNA expression profiling for non-small cell lung cancer

To improve the diagnostic accuracy of nodal metastasis, we suggest new criteria for the prediction of nodal metastasis with combining CT and mRNA expression profiling. Gene signatures related to nodal metastasis were selected from a microarray using extracted mRNA of 112 patients who underwent surgical resection for non-small cell lung cancer. Included patients were randomized into two groups; the training set (n = 79) and the test set (n = 33). On the basis of the gene signatures, the chest CTs of the training set of patients were re-analyzed and we set up hypothetical criteria for nodal diagnosis. Thirty-one genes were selected from the mRNA expression profiling to separate the LN-metastasis prediction (+) and LN-metastasis prediction (−) groups. On the basis of these signatures, the criteria of lymph node was adjusted (1) in cases of ‘LN-metastasis prediction (+)’, mediastinal nodes greater than a 5 mm in short axis diameter and detectable hilar nodes were considered as metastatic, and (2) in cases of ‘LN-metastasis prediction (−), the conventional size criterion was applied for both mediastinal and hilar lymphadenopathies, except for enlarged nodes along with obstructive pneumonia. The sensitivity and accuracy for the nodal diagnosis were improved from 31% to 85% and 58% to 86%, respectively (p < 0.05) by using the combined criteria of CT and the microarray results in the test set as compared to those of CT alone. Prediction of lymph node metastasis using combination of gene signatures and chest CT is superior to the CT-only diagnosis.     

The serum bone morphogenetic protein-2 level in non-small-cell lung cancer patients

Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily, and some studies demonstrated that BMPs enhance tumorigenesis and metastasis. The purpose of this study was to identify whether BMP-2 levels are elevated in the serum of non-small-cell lung cancer (NSCLC) patients and are associated with the stage and overall survival. Blood samples from 150 patients with NSCLC were analyzed. Also, 69 healthy volunteers were tested as control group. In NSCLC patients, whole blood was obtained before beginning any treatment modalities, and serum BMP-2 levels were quantified by commercially available ELISA kit. The NSCLC group demonstrated a significantly higher level of serum BMP-2 than the control group. (The median levels were 25.50 pg/ml for the control group and 72.23 pg/ml for the NSCLC group, P < 0.001). The median serum BMP-2 level in the advanced stage group (stage IIIb or IV) was significantly more elevated than that of the localized stage group (stage I, II, IIIa) (75.66 pg/ml and 44.36 pg/ml, P = 0.006). Patients with multiple metastatic sites (≥5) showed significantly higher level of serum BMP-2 than the patients with less than 5 metastatic sites. (79.39 pg/ml vs. 59.70 pg/ml, P = 0.013), and the median serum BMP-2 level from the patients with multiple metastatic organs (≥3) was significantly higher than that from the patients with single or two metastatic organs (<2) (89.39 pg/ml vs. 66.90 pg/ml, P = 0.001). Moreover, the patients with relatively lower BMP-2 level (≤70 pg/ml) had longer median overall survival than the patients with higher BMP-2 level (>70 pg/ml). (525 days vs. 260 days). One-year survival rate for the patients with lower BMP-2 level was also higher than that for the patients with higher BMP-2 level. (59.6% versus 40.2%, P = 0.034). The serum BMP-2 level is positively correlated with the stage and metastatic burden and maybe a probable predictor of survival in the NSCLC patients.     

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.     

Malignant pleural effusion of multiple myeloma: prognostic factors and outcome

Malignant pleural effusion (MPE) in multiple myeloma (MM) is rare. Approximately 80 cases have been reported. To delineate optimal treatment and prognostic variables in these patients, we reviewed 11 MM patients with MPE. MPE developed at median of 12 months from diagnosis of MM. All the patients had high-risk disease based on complex karyotypic abnormalities including deletions of chromosome-13 (n = 9), elevated beta-2 microglobulin (B2M) (n = 9), high C-reactive protein (CRP) (n = 8), high plasma cell labeling index (n = 5) or high LDH (n = 5). A significant increase in B2M, LDH, and CRP was observed at the onset of MPE. The initial diagnosis of MPE was based on positive cytology (n = 9), pleural fluid cIg/DNA (n = 9) or pleural fluid cytogenetics (n = 4). Pleural tissue infiltration was found on pleural biopsy and autopsy in one patient each. Systemic chemotherapy comprising dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) (n = 7) and pleurodesis (n = 7) were effective in resolving MPE but survival was short. High dose chemotherapy with peripheral blood stem cell support for MPE in six patients conferred no clear survival advantage. These patients died at median of four months from onset of MPE. Patients with bone marrow complex karyotypic abnormalities including deletion-13 (n = 9) had a shorter (median-18 months) overall survival compared to patients with normal cytogenetics (median-38 months). MPE in patients with MM is often associated with high-risk disease including deletion 13 chromosomal abnormality and heralds a poor prognosis despite aggressive local and systemic 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.     

晚期非小细胞肺癌患者血清CA125水平的预后价值

目的　通过检测晚期非小细胞肺癌 (NSCLC)患者血清CA12 5 ,以判断血清CA12 5水平对患者预后的影响。方法　 6 6例晚期NSCLC患者 ,接受 2～ 4周期化疗 ,其中 17例辅助放疗。所有患者在治疗前抽血测血清CA12 5。结果　 2 4例患者血清CA12 5水平升高 ,占 36 4%。CA12 5升高患者的 1年生存率为 12 5 % ,2年生存率为 0 ,与CA12 5正常患者的生存率差异有显著性 (P <0 0 5 )。Cox模型多因素分析表明 ,患者的预后与CA12 5水平 (P =0 0 0 0 )和疗效 (P =0 0 46 )有关。结论　血清CA12 5水平升高的晚期NSCLC患者生存期缩短 ,预后差 ,可以将血清CA12 5水平作为判断晚期NSCLC患者预后的一个独立指标。     

Serum immunosuppressive acidic protein as a potent prognostic factor for patients with metastatic renal cell carcinoma

BACKGROUND: Estimation of survival probability of individual patients with metastatic renal cell carcinoma was difficult owing to diverse prognostic factors. We analyzed serum immunosuppressive acidic protein (IAP) levels and the cutoff value, then tested its validity for assessing patients' prognoses. METHODS: Serum IAP was measured longitudinally in 84 patients with metastatic disease. Before therapy, cutoff levels of IAP were tested every 20 microg/ml between 600 and 1200 microg/ml. The prognostic importance of IAP and its cutoff level was estimated. RESULTS: The cutoff level of IAP was set at 800 microg/ml for 40 patients who had metastatic disease with the primary tumor in situ and for 44 patients with recurrent disease. IAP was found to be a significant prognostic factor for both patient groups. CONCLUSIONS: Serum IAP is an important prognostic factor for patients with metastatic renal cell carcinoma. Stratification of patients according to prognosis is feasible using the cutoff level.     

调强放疗联合化疗对晚期非小细胞肺癌血清三种因子表达变化的队列研究

目的 探究调强放疗联合化疗对晚期非小细胞肺癌(NSCLC)患者血清细胞增殖抗原(PCNA)、肿瘤特异性生长因子(TSGF)、可溶性E-钙黏蛋白(SE-CAD)表达变化及与预后的关系。方法 选取2016-2018年南京医科大学附属淮安第一医院收治的晚期NSCLC患者 84例(ⅢA、ⅢB、Ⅳ期分别为29、30、25例),均给予调强放疗联合化疗。检测对比不同TNM分期、治疗前后血清PCNA、TSGF、SE-CAD水平,并比较不同疗效患者血清PCNA、TSGF、SE-CAD水平。采用Logistic法分析血清PCNA、TSGF、SE-CAD水平与疗效关系。Kaplan-Meier法生存分析。结果 Ⅳ期患者疗前血清PCNA、TSGF、SE-CAD水平高于 ⅢB和 ⅢA期[(584.11±60.25) pg/ml∶(531.06±51.37) pg/ml和(477.54±46.49) pg/ml、(96.13±7.54) U/ml∶(88.52±5.91) U/ml和(82.41±5.0) U/ml、(3.02±0.26) ng/ml∶(2.87±0.22) ng/ml和(2.71±0.15) ng/ml,均 P<0.05],ⅢB期高于 ⅢA期(均 P<0.05)。疗后血清PCNA、TSGF、SE-CAD水平低于疗前水平[(396.11±50.23) pg/ml∶(528.37±75.09) pg/ml、(74.81±4.72) U/ml∶(88.68±6.13) U/ml、(1.92±0.24) ng/ml∶(2.86±0.31) ng/ml,均 P<0.05]。疗后18个月生存患者PCNA、TSGF、SE-CAD水平低于死亡患者[(332.51±54.32) pg/ml∶(444.92±60.07) pg/ml、(70.59±6.20) U/ml∶(78.05±8.44) U/ml、(1.71±0.24) ng/ml∶(2.08±0.27) ng/ml,均 P<0.05]。血清PCNA、TSGF、SE-CAD水平与预后显著相关(均 P<0.05)。84例NSCLC患者疗后客观缓解率为29%(24/84)。疗后血清血清PCNA、TSGF、SE-CAD高表达组生存曲线低于低表达组(均 P<0.05)。结论 血清PCNA、TSGF、SE-CAD水平在晚期NSCLC患者中呈高表达,与临床分期、预后密切相关,且有助于预测生存状况。     

Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571)

Isolated central nervous system (CNS) relapse occurred in 5 out of 24 patients (20.8%) with chronic myeloid leukemia (CML) lymphoid blast crisis (2), Philadelphia (Ph) chromosome positive acute lymphoblastic leukemia (ALL) (2) or CML with biphenotypic markers (1) treated on imatinib mesylate (IM) protocols at our institution. CNS relapse occurred despite peripheral blood (5) and bone marrow (3) complete responses. Median time to CNS relapse was day 32 (range 23 to 100). This observation raised the possibility that IM may not penetrate into the CNS. Simultaneous plasma and cerebral spinal fluid (CSF) IM levels were determined in four subsequent patients by liquid chromatography and mass spectrophotometric assay. Levels of IM were found to be approximately two logs lower in CSF than in plasma (0.044 μg/ml (0.088 ± 0.029 μM) vs 3.27 μg/ml (6.54 ± 0.93 μM)). CSF levels were substantially below the concentration required for inhibition of BCR-ABL and killing of cell lines in vitro. These results suggest that IM may not penetrate the intact blood/brain barrier and its implications are discussed.     

Serum 20S proteasome is elevated in patients with renal cell carcinoma and associated with poor prognosis

Background:

To date, no reliable serum marker for clear cell renal cell carcinoma (CCRCC) is available. The aim of this study was to evaluate the putative significance of circulating 20S proteasome levels.

Methods:

Preoperative 20S proteasome serum levels were determined in 113 CCRCC patients and 15 healthy controls by a sandwich enzyme-linked immunosorbent assay. Associations with CCRCC, pathological variables, disease-specific survival (DSS), and response to sunitinib were evaluated.

Results:

Median 20S proteasome levels were higher in CCRCC patients than in healthy controls (4.66 vs 1.52 μg ml⁻¹, P<0.0001). The area under the receiver operating characteristics curve curve was 87.1%. The 20S proteasome levels were associated with symptoms (P=0.0008), distant metastases (P=0.0011), grade (P=0.0247), and necrosis (P=0.0462). The 20S proteasome levels were identified as a prognostic factor for DSS in both univariable (hazards ratio 1.21, P<0.001) and multivariable (hazards ratio 1.17, P=0.0015) survival analysis. In patients responding to sunitinib, 20S proteasome levels were lower than in patients with stable disease and progressive disease.

Conclusion:

This study demonstrates for the first time that increased 20S proteasome levels are associated with CCRCC, advanced disease, and poor prognosis. Routine use of this marker may allow better diagnosis, risk stratification, risk-adjusted follow-up, and identification of patients with a greater likelihood of response to targeted therapy.     

Elevated serum level of sialylated glycoprotein KL-6 predicts a poor prognosis in patients with non-small cell lung cancer treated with gefitinib

PURPOSE: The factors affecting survival after gefitinib treatment in patients with non-small cell lung cancer (NSCLC) remain to be fully elucidated, although epidermal growth factor receptor (EGFR) mutation is a substantial prognostic factor. KL-6 has been studied as a useful indicator for interstitial lung diseases; however, it was first discovered as a lung cancer-related antigen. The aim of this study was to investigate the prognostic value of the serum KL-6 levels in advanced NSCLC patients treated with gefitinib and thus determine its association with the EGFR mutation status. PATIENTS AND METHODS: Between September 2002 and September 2005, 41 patients with NSCLC were treated with gefitinib after having their serum KL-6 levels measured at Okayama University Hospital. EGFR mutations were analyzed by direct sequence methods. RESULTS: The serum KL-6 levels ranged from 199 to 9080U/ml (median, 550U/ml), and 54% of 41 patients showed a level higher than the cut-off level of 500U/ml. The median progression-free survival (PFS) time and the median overall survival (OS) time were 4.7 months and 13.9 months, respectively. Multivariate analyses revealed that the elevated KL-6 level was an independent adverse prognostic factor for PFS (hazard ratio: 2.278, p=0.040) as well as OS (hazard ratio: 4.858, p=0.002) in NSCLC patients treated with gefitinib. The EGFR mutation status was analyzed in 22 patients (54%). Among those with wild-type EGFR, the patients with high serum KL-6 levels also had a worse survival than those within normal serum KL-6 levels (6.5 months versus 13.3 months, p=0.0194). CONCLUSION: Our data suggest that NSCLC patients with high serum KL-6 levels tended to have a poor clinical outcome when treated with gefitinib.     

Phase I and pharmacokinetic study of preirradiation chemotherapy with BCNU, cisplatin, etoposide, and accelerated radiation therapy in patients with high-grade glioma

Purpose: We conducted a Phase I study of bischloroethylnitrosourea (BCNU), cisplatin, and oral etoposide administered prior to and during accelerated hyperfractionated radiation therapy in newly diagnosed high-grade glioma. Pharmacokinetic studies of oral etoposide were also done.

Methods and Materials: Patients started chemotherapy after surgery but prior to definitive radiation therapy (160 cGy twice daily × 15 days; 4800 cGy total). Initial chemotherapy consisted of BCNU 40 mg/m² days 1–3, cisplatin 30 mg/m² days 1–3 and 29–31, and etoposide 50 mg orally days 1–14 and 29–42, repeated in 8 weeks concurrent with radiation therapy. BCNU 200 mg/m² every 8 weeks × 4 cycles was given after radiation therapy.

Results: Sixteen patients, 5 with grade 3 anaplastic astrocytoma and 11 with glioblastoma were studied. Grade 3–4 leukopenia (38%) and thrombocytopenia (31%) were dose-limiting. Other toxicities were anorexia (81%), nausea (94%), emesis (56%), alopecia (88%), and ototoxicity (38%). The maximum tolerated dose was BCNU 40 mg/m² days 1–3, cisplatin 20 mg/m² days 1–3 and 29–31, and oral etoposide 50 mg days 1–21 and 29–49 prior to radiation therapy and repeated in 8 weeks with the start of radiation therapy followed by BCNU 200 mg/m² every 8 weeks for 4 cycles. Median time to progression and survival were 13 and 14 months respectively. Responses occurred in 2 of 9 (22%) patients with evaluable disease. In pharmacokinetic studies, all patients achieved plasma concentrations of >0.1 μg/ml etoposide (the in vitro radiosensitizing threshold), following a 50 mg oral dose. The mean ± SD 2 hr and 6 hr plasma concentrations were 0.92 ± 0.43 μg/ml and 0.36 ± 0.12 μg/ml, respectively. Estimated duration of exposure to >0.1 μg/ml etoposide was 10–17 hr.

Conclusions: Preirradiation chemotherapy with BCNU, cisplatin, and oral etoposide with accelerated hyperfractionated radiation therapy in high-grade gliomas is feasible and merits further investigation. Sustained radiosensitizing concentrations can be achieved with low oral doses of etoposide.     

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.     

Remission induction using alemtuzumab can permit chemotherapy-refractory chronic lymphocytic leukemia (CLL) patients to undergo allogeneic stem cell transplantation

The outcome of allogeneic stem cell transplantation depends upon the disease status before transplantation. Patients with refractory disease are at high risk for relapse. To improve the curative potential of the transplant procedure, we treated 3 chemotherapy-refractory CLL patients with alemtuzumab before allogeneic stem cell transplantation. Prior to therapy, all patients suffered from B-symptoms, and had massive adenopathy, splenomegaly, thrombocytopenia, and anemia; two patients had hepatomegaly. Alemtuzumab greatly reduced tumor mass in blood and bone marrow, B-symptoms resolved, and organomegaly improved. Two patients became blood product independent. All patients proceeded to transplantation after conditioning with TBI 2 Gy (n = 1) or Treosulfan (n = 2) in combination with Fludarabine either from an HLA-matched sibling (n = 2) or from an HLA-matched unrelated donor (n = 1). All patients engrafted, and are alive and well. Two patients reached complete remission (CR); one patient attained stable partial remission (PR). These heavily pre-treated refractory patients gained substantial clinical benefit from alemtuzumab, and received successful allografts.