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.     

Gefitinib-induced autologous antitumor immunity

Aim:   We previously reported that thromboxane (TX) B2, p-selectin, and the cytokine that is regulated on activation, normal T expressed and secreted (RANTES) were elevated in patients with non-small cell lung cancer (NSCLC) treated with gefitinib. It is reported that macrophages are activated by platelets. We hypothesized that macrophages were activated in patients medicated with gefitinib, and we measured their plasma macrophage inflammatory protein (MIP)-1 beta.
Methods:   Patients with NSCLC not curable by surgery were entered in the study and received gefitinib at a dose of 250 mg/day over a period of two weeks. Blood samples were drawn before and after administration and MIP-1 beta was measured by enzyme-linked immunosorbent assay.
Results:   A total of 28 patients, 42–82-years of age (median, 67); 16 men and 12 women, were the subjects of the study: 21 had adenocarcinomas and seven squamous cancers. Partial response to gefitinib occurred in 11 patients, 12 had stable disease and five had progressive disease. The mean serum level of MIP-1 beta in the 28 evaluable patients increased significantly after gefitinib medication for 1 and 2 weeks from a baseline of 101 ± 19 pg/mL to 139 ± 25 pg/mL at one week ( P  < 0.05) and 131 ± 29 pg/mL at 2 weeks ( P  < 0.05).
Conclusion:   Immunological markers related to activated platelets including MIP-1 beta as well as thromboxane A2 p-selectin and RANTES, are elevated in patients undergoing therapy with gefitinib. We speculate that gefitinib has a potential autologous immunological anti-tumor activity.     

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.     

Does p16ink4a expression increase with the number of cell doublings in normal and malignant lymphocytes?

p16^ink4a is known to be a major inhibitor of cyclin-dependent kinases of G1-phase. Its accumulation is associated with replicative senescence. We analyzed to what extent the number of cell doublings may participate to p16^ink4a expression in normal and malignant lymphocytes.

p16^ink4a expression, not found in normal quiescent B or T-lymphocytes, was observed after stimulation of B-lymphocytes (72 h) and T-lymphocytes (2 weeks) before the occurrence of replicative senescence markers such as senescence-associated-β-galactosidase activity. Afterwards, in lymphocyte long-term cultures, the increase in p16^ink4a followed the expression of features of cell ageing.

In acute lymphoblastic leukemia, the analysis of the individual differences between peripheral blood and blood compartments (34 cases) showed a decrease in cell proliferation (p < 0.005), in telomerase activity (p < 0.0005), and in hTERT expression (p < 0.04), associated with an increase of p16^ink4a (p < 0.035) in blood leukemic cells.

These results support the hypothesis that (i) an increase in p16^ink4a expression in normal lymphocytes is linked, in part, to the number of cell doublings before the occurrence of replicative senescence and (ii) this process is maintained in leukemic cell populations of numerous patients.     

In Vivo Accumulation of Etoposide in Peripheral Leukemic Cells in Patients Treated for Acute Myeloblastic Leukemia; Relation to Plasma Concentrations and Protein Binding

Since etoposide interacts with the nuclear enzyme topoisomerase II, the drug concentrations in the malignant cells during chemotherapy may have clinical correlates. Plasma protein binding of etoposide is extensive (94%) and alterations of the non-proteinbound fraction affect pharmacokinetic behavior of the drug. The pharmacokinetics of etoposide was therefore studied in plasma, total and non-proteinbound concentrations, and in leukemic cells isolated from peripheral blood samples from 22 patients after the first dose of the induction treatment for acute myelocytic leukemia. Fourteen patients received 100 mg/m² and eight patients 200 mg/ m² as a 1 h infusion. The mean area under the concentration versus time curve AUC_(0-x) in plasma was at the lower dose level 78.4 ± 29.1 (mean ± S.D.) μg/ml x h and 201.0 ± 56.5 μg/ml x h at the higher dose level. The fraction of non-proteinbound etoposide in plasma was 5.2 ± 3.4 and 5.4 ± 2.1% in the two treatment groups. AUC_(0-16h) in leukemic cells was 8.4 ± 8.7 and 22.4 ± 12.1 μ/ml x h at the two dose levels, respectively. The cellular etoposide concentration was 12.1 ± 7.9 and 14.7 ± 5.1% of the plasma concentration at the end of the infusion. The interpatient variability in cellular drug levels was considerable and exceeded the variability in plasma concentrations. Cellular accumulation of etoposide could be important for treatment outcome.     

Stereotactic body radiation therapy and intensity modulated radiation therapy induce different plasmatic cytokine changes in non-small cell lung cancer patients: a pilot study

Purpose

To assess kinetics of plasmatic cytokines during radiation therapy (RT) for locally advanced and early-stage non-small cell lung cancer (NSCLC).

Methods

This prospective study was conducted on 15 early-stage NSCLC underwent to extreme hypofractionated regimen (52 Gy in 8 fractions) with stereotactic body RT (SBRT), and 13 locally advanced NSCLC underwent to radical moderated hypofractionated regimen (60 Gy in 25 fractions) with intensity modulated RT (IMRT). For patients undergoing SBRT, peripheral blood samples were collected on the first day of SBRT (TFd), the last day (TLd) and 45 days (T45d) after the end of SBRT. For patients undergoing IMRT, blood samples were collected at: TFd, 2 weeks (T2w), 4 weeks (T4w), TLd, and T45d. The following cytokines were measured: IL-1, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17A, EGF, FGF-2, INF-γ, MIP-1α, MIP-1β, TGF-α, TNF-α, and VEGF. Cytokine levels measured in different RT time and compared.

Results

No difference in baseline levels of cytokines was documented between patient radiation approaches (except for MIP-1α). For SBRT patients, a mean reduction of IL-10 and IL-17 plasma level was documented between TLd and TFd, respectively (p < 0.05). For IMRT patients, a statistically significant (p < 0.05) mean plasma level reduction was documented between T4w and TFd for all the following cytokines: IL-1, IL-1ra, IL-2, IL-12, FGF-2, MIP-1α, MIP-1β, TGF-α, TNF-α, VEGF.

Conclusions

SBRT and IMRT induce different plasmatic cytokine changes in NSCLC patients, supporting hypothesis that RT regimes of dose schedules and techniques have different impacts on the host immune response.

     

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.     

Prospective study evaluating the plasma concentrations of twenty-six cytokines and response to morphine treatment in cancer patients

Cytokine signaling is involved in pain and opioid-receptor signaling. In this prospective study, we studied the plasma cytokine levels in order to identify candidate biomarkers for predicting resistance to morphine treatment in a cohort of opioid-treatment-na?ve cancer patients. We analyzed pain rating and the plasma concentrations of 26 cytokines at baseline and after morphine treatment using a multiplex immunoassay system for the following cytokines: eotaxin, colony stimulating factor, granulocyte (G-CSF), colony stimulating factor granulocyte-macrophage (GM-CSF), interferon α2 (IFN-α2), IFN-γ, interleukin 1α (IL-1α), IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IP-10, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, tumor necrosis factor-α (TNF-α) and TNF-β. No correlation was observed between the clinical characteristics and the numerical rating scale for pain at baseline or among patients who developed resistance to morphine treatment. Interestingly, the plasma concentration of MIP-1α significantly decreased during morphine treatment (day 8 vs. baseline, p=0.03). Regarding the baseline plasma cytokine concentrations, none of the cytokine levels were correlated with the numerical rating scale for pain at baseline; however, the baseline plasma concentrations of eotaxin, IL-8, IL-12 (p40), IL-12 (p70), MIP-1α and MIP-1β were significantly lower in patients who required a high dose of morphine or who developed resistance to morphine treatment. In conclusion, this is the first report revealing that the plasma concentrations of several cytokines were significantly modulated during treatment and were correlated with treatment outcome of morphine. Our results suggest that plasma cytokine levels may be promising biomarkers for morphine treatment and that they warrant further study.     

Plasma transforming growth factor β1 as a predictor of radiation pneumonitis

Purpose: To investigate prospectively the utility of plasma transforming growth factor β1 (TGFβ1) as a marker for the development of symptomatic radiation pneumonitis.

Materials and Methods: Seventy-three patients with lung cancer treated with curative intent are reported herein. Plasma TGFβ1 samples were obtained before, weekly during, and at each follow-up after radiation therapy (RT). TGFβ1 was extracted using an acid/ethanol method. An enzyme-linked immunosorbent assay was used to quantify plasma TGFβ1 concentrations. The TGFβ1 level at the end of RT was considered “normal” if it was both ≤ 7.5 ng/ml and less than the pretreatment value. All patients were followed for at least 6 months, unless symptomatic pneumonitis developed sooner. Pneumonitis was defined by National Cancer Institute (NCI) common toxicity criteria.

Results: Fifteen of the 73 patients (21%) developed symptomatic pneumonitis and the remaining 58 (79%) did not. A normal plasma TGFβ1 by the end of RT, as defined above, was more common in patients who did not develop pneumonitis. A return of the plasma TGFβ1 to normal accurately identified patients who would not develop pneumonitis with both a sensitivity and positive predictive value of 90%.

Conclusion: Plasma TGFβ1 levels appear to be a useful means to identify patients at low risk for the development of pneumonitis from thoracic RT. Thus, monitoring of plasma TGFβ1 levels may identify candidates for dose escalation studies in the treatment of lung cancer.     

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.     

Modified functional neck dissection: a useful technique for oral cancers

Among 60 patients with oral squamous cell carcinoma, 30 were treated by the modified functional neck dissection (preserve 8 functional tissues), 30 were treated by functional neck dissection (preserve 3 functional tissues). The recurrent rate of cervical lymph node and the sense of skin were assessed. The recurrence rates in cervical nodes was 6.67% and 10%, respectively (p > 0.05) in patients who accepted modified functional neck dissection and functional neck dissection. The sensation in skin in patients who accepted modified functional neck dissection was better than those who accepted functional neck dissection (p < 0.01). Modified functional neck dissection is helpful to decrease postoperative complications, without increasing recurrent rates of cervical lymph node.     

Interleukin 1 receptor antagonist gene polymorphism and risk of lung cancer: a possible interaction with polymorphisms in the interleukin 1 beta gene

Tobacco smoking is the main risk factor for lung cancer. Only 10–15% of smokers develop lung cancer, suggesting that genetic factors are of importance in determining individual susceptibility to the disease. Several studies in recent years indicate that chronic inflammation is a cofactor in lung carcinogenesis. We have previously reported an association of interleukin 1 beta gene (IL1B) polymorphisms with lung cancer risk. Interleukin-1 receptor antagonist (IL-1Ra) has been implicated in carcinogenesis of different cancer types. IL-1Ra binds competitively to the same membrane receptor as interleukin-1β (IL-1β) and thereby acts as an antagonist to the pro-inflammatory actions of IL-1β. The aim of the study was to examine whether a common VNTR polymorphism in the interleukin 1 receptor antagonist gene (IL1RN) is associated with lung cancer risk. Due to the tight relationship between IL1RN and IL1B, we also explored the possibility of an interaction between the two genes. The study population comprised of 340 non-small cell lung cancer cases and 412 healthy controls of Norwegian origin. Our results indicate that individuals homozygous for the IL1RN*1 allele and carrying the IL1B–31T allele had increased risk of non-small cell lung cancer (odds ratio C/T 3.08; 1.10–8.62 and T/T 5.87; 2.15–16.05). Furthermore, IL1RN*1 carriers had nearly two-fold higher levels of bulky/hydrophobic DNA adducts in the lung. Our findings support the significance of IL1 gene cluster polymorphisms and risk of lung cancer.     

Laparoscopic surgery for colorectal cancer is not associated with an increase in the circulating levels of several inflammation-related factors

It has been hypothesized that inflammatory response triggered by surgery might induce the release of molecules that could promote proliferation, invasion and metastasis of surviving cancer cells. To test this hypothesis, the levels of multiple inflammation-related circulating factors were analyzed in patients undergoing surgery for colorectal cancer. A Luminex xMAP system was used to simultaneously assess levels of IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, FGF, eotaxin, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α and VEGF in 20 colorectal cancer patients and 10 age-matched non-neoplastic patients. In cancer patients analyses were performed at baseline (before surgery) and at different time points (up to 30 days) following laparoscopic surgery. Significantly higher levels of IL-1β, IL-7, IL-8, G-CSF, IFN-γ and TNF-α were detected in colorectal cancer patients compared to controls at baseline. In colorectal cancer patients, circulating levels decreased progressively following surgery and after day 30 post-surgery were no longer different from controls. These findings suggest that expression levels of several cytokines are higher in colorectal cancer patients compared to control subjects and no significant increase in several inflammation-related circulating factors is observed following laparoscopic surgery for cancer. Confirmation and validation in a different and larger cohort of patients are warranted.     

Blood classical monocytes phenotype is not altered in primary non-small cell lung cancer

AIM: To evaluate the M1 and M2 monocyte phenotype in patients with non-small cell lung cancer (NSCLC) compared to controls. Also, to examine the expression of Th1 and Th2 cytokines in plasma of NSCLC vs controls.METHODS: Freshly prepared peripheral blood mononuclear cells samples were obtained from patients with NSCLC (lung adenocarcinoma and squamous cell lung carcinoma) and from non-cancer controls. Flow cytometry was performed to investigate M1 and M2 phenotypes in peripheral monocytes (classical monocytes CD14+, CD45+ and CD16-) using conventional surface markers. Th1 and Th2 cytokine production was also analysed in the plasma using cytometric bead array technique.RESULTS: There were no significant difference in expression of M1 (HLA-DR) and/or M2 markers (CD163 and CD36) markers on classical monocytes in patients with NSCLC compared to non-cancer controls. Expression of CD11b, CD11c, CD71 and CD44 was also shown to be similar in patients with NSCLC compared to non-cancer controls. Th1 and Th2 cytokines [interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12 (p70), tumor necrosis factor (TNF)-α, TNF-β, and interferon-γ] analysis revealed no significant difference between patients with NSCLC and non-cancer controls.CONCLUSION: This study shows no alteration in peripheral monocyte phenotype in circulating classical monocytes in patients with NSCLC compared to non-cancer controls. No difference in Th1 and Th2 cytokine levels were noted in the plasma of these patients.     

吉非替尼治疗化疗失败的晚期非小细胞肺癌临床观察

目的:评价吉非替尼治疗化疗失败的晚期非小细胞肺癌(NSCLC)的疗效及不良反应。方法:对68例化疗失败的经病理或细胞学证实的晚期NSCLC患者给予吉非替尼250mg,qd,口服,至病情进展或出现不可耐受的不良反应。结果:68例患者中,CR 1例,PR 20例,SD 23例,PD 24例。有效率30.88%(21/68),疾病控制率为64.71%(44/68);全组中位疾病进展时间(TTP)为5.2个月,中位生存时间为9.3个月,1年生存率为52.94%(36/68)。与药物相关的不良反应主要为Ⅰ、Ⅱ度皮疹和腹泻,皮疹发生率为26.47%(18/68),腹泻发生率为19.12%(13/68),多在用药后1周内出现,症状轻不需特殊处理。1例出现Ⅰ度转氨酶升高。结论:吉非替尼治疗化疗失败的晚期非小细胞肺癌安全有效,不良反应轻微,患者耐受性和依从性良好。     

Phase 1 Trial of Recombinant Human Interleukin-1β (rhIL-1β), Carboplatin, and Etoposide in Patients with Solid Cancers: Southwest Oncology Group Study 8940

Recombinant human interleukin-1β (rhIL-1β) was evaluated in a phase 1 Clinical Trial in which patients with metastatic or unresectable solid tumors received carboplatin and etoposide in cycle 1 and carboplatin, etoposide, and rhIL-1β in cycle 2. Recombinant hIL-1β was given intravenously for 5 days in one of three schedules: (1) immediately postchemotherapy, (2) delayed for 5 days after chemotherapy, or (3) concurrently with chemotherapy. Four dose levels of rhIL-1β were evaluated: 20, 50, 100, and 200 ng/kg. The doses of carboplatin and etoposide were not changed between cycle 1 and cycle 2 so that the effect ofrhlL-1β on chemotherapy-induced hematotoxicity was evaluated; 54 patients were entered on study and 42 patients received at least two cycles of therapy and were thus evaluablefor rhIL-1β toxicity and for the effect ofrhIL-1β on hematotoxicity of carboplatin andetoposide. The major toxicities of rhIL-1β were chills, rigors, headache, fatigue, and hypotension. The maximum tolerated dose of rhIL-1β was not determined since the toxicities at all dose levels were similar. However, only 3/8 patients at the 200 ng/kg level received all 5 IL-1β infusions. We compared the effect of rhIL-1β on hematotoxicity of carboplatin/etoposide by comparing peripheral blood count parameters between cycles 1 and 2: rhIL-1β given postchemotherapy significantly increased absolute neutrophil count (AND) nadirs and improved neutrophil recovery times regardless ofrhIL-1β dose level. Platelet count parameters were also improved when rhIL-1β was given postchemotherapy although these changes did not reach statistical significance. Thus, IL-1β exhibited extensive hematological effects but the usefulness of this agent in clinical practice will be limited by extensive toxicity at all tested dose levels.     

肺癌患者血清中21种细胞因子的表达水平及其临床意义

目的:检测肺癌患者血清中21种细胞因子[干扰素诱导的T细胞趋化因子(IFN-inducible T cellαchemoattractant,ITAC)、GM-CSF、Fractalkine、IFN-γ、IL-10、巨噬细胞炎性蛋白-3α(macrophage inflammatory protein-3α,MIP-3α)]、IL-12(p70)、IL-13、IL-17A、IL-1β、IL-2、IL-4、IL-21 、IL-23、IL-5、IL-6、IL-7、IL-8、MIP-1α、MIP-1β和TNF-α的表达情况并分析其意义.方法:收集2015年3月至6月的山西省肿瘤医院40例肺癌患者;采用液相芯片技术检测30名健康人和40例初诊肺癌患者治疗前血清中21种细胞因子的表达水平,分析其与肺癌临床特征之间的关系及表达存在明显差异细胞因子间的相关性.结果:肺癌患者血清中11种细胞因子[(GM-CSF、Fractalkine、IFN-γ、MIP-3α、IL-12 (p70)、IL-1β、IL-2、IL-6、IL-7、IL-8、TNF-α]的表达水平明显升高(P＜0.05或P＜0.01),肺癌患者非转移组与转移组血清中21种细胞因子的表达水平比较无明显差异(P＞0.05),肺腺癌(adenocarcinoma,AC)组血清IFN-γ与MIP-1β水平明显高于鳞癌(squamous cell carcinoma,SCC)组(均P＜0.05),肺SCC组血清ITAC表达水平明显高于小细胞肺癌(small cell lung cancer,SCLC)组(P＜0.05).高表达的11种细胞因子在两组间表达的相关性不同.结论:肺癌患者血清中IL-6、IL-8等11种细胞因子表达升高,可能参与了肺癌发生发展,这些高表达的细胞因子或许可用于肺癌的辅助诊断,并为肺癌治疗提供新的靶标.     

Phase I trial of fixed dose rate infusion gemcitabine with gefitinib in patients with pancreatic carcinoma

Purpose: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of gemcitabine using a fixed dose rate infusion (FDRI) in combination with gefitinib in patients (pts) with pancreatic adenocarcinoma (PCa). Patients and methods: Patients with advanced PCa were given gemcitabine at the FDRI of 10 mg/m²/min IV on Days 1, 8, and 15 of a 28-day cycle. Dose levels of 1000, 1200, and 1500 mg/m² were evaluated. Oral gefitinib 250 mg was given daily. DLTs were defined as 2 instances of Grade 3 hematologic or 4 nonhematologic or any Grade 4 hematologic toxicity. At least 4 patients were treated at each dose level. Dose escalation occurred in the absence of DLTs. Results: Five women and 8 men were enrolled. Median age was 59 and performance status 1. All had metastatic disease. Four patients received prior adjuvant chemoradiation for PCa, and one chemotherapy for lung cancer. Median cycles were 4 per patient. The MTD was 1,200 mg/m². Toxicity was predominantly hematologic. At 1,500 mg/m², 1 patient had Grade 4 granulocytopenia and 3 patients Grade 3 granulocytopenia. Overall, 8 patients (60 percent) developed Grade 1 or 2 acneiform rashes. One patient had Grade 3 vomiting; no significant diarrhea or liver toxicity was seen. There were no objective responses seen. Median time to progression and overall survival were 4.57 months and 7.13 months, respectively. Conclusion: Combining FDRI gemcitabine with gefitinib is feasible and tolerable. The recommended dose of gemcitabine is 1,200 mg/m² when used with gefitinib 250 mg daily.