肺灌注显像在Ⅲ期非小细胞肺癌调强放疗中对功能肺的保护

目的 探讨肺灌注显像在Ⅲ期非小细胞肺癌(NSCLC)调强放疗(IMRT)保护功能肺的可行性。方法 选择拟行放疗的Ⅲ期NSCLC患者24例,分别行PET-CT和SPECT定位,图像传至治疗计划系统进行图像融合。根据SPECT图像确定功能肺(FL)和非功能肺(NFL),FL是指放射性计数为最大放射性计数的30%以上(包括30%)的区域,其他区域为NFL。肺灌注受损分为4级:0级,无灌注受损;1级,肿瘤及其周围局部肺灌注受损;2级,达1叶肺灌注受损;3级,超过1叶肺灌注受损。根据SPECT图像提供的肺功能信息制定IMRT计划进行优化,尽可能降低FL的照射体积剂量。采用配对t检验统计分析优化前后的IMRT计划的肺组织剂量参数变化。结果 患者均有不同程度的肺灌注缺损,其中肺灌注受损1级8例,2级6例,3级10例。根据SPECT提供的肺功能信息优化IMRT计划后WLV和FLV均有不同程度降低,而FLV降低程度更加明显。优化后WLV₁₀、WLV₁₅、WLV₂₀、WLV₂₅、WLV₃₀和FLV₁₀、FLV₁₅、FLV₂₀、FLV₂₅、FLV₃₀差异有统计学意义。结论 根据SPECT图像提供的肺功能信息优化IMRT计划以保护Ⅲ期NSCLC功能肺是可行的。     

The correlation of hematopoietic stem cells with cancer stem cells through the regulation of stromal cells in tumor microenvironment

Cancer stem cells are a small population of tumor cells that have many malignant features such as chemotherapy resistance, radiotherapy resistance, tumorigenicity and are responsible for tumor progression, disease recurrence and metastasis. Therefore, insight into the regulation of the biology of cancer stem cells is important to eradicate cancer. Recently, studies suggested that hematopoietic stem cells could incorporate into tumor stroma and differentiated into stromal cells and the cells derived from hematopoietic stem cells play an important role on tumor progress. Moreover, cancer cells competed with hematopoietic stem cells for occupancy of the hematopoietic stem cell niches to regulate bone metastasis and most cancer cells in bone marrow metastasis were cancer stem cells. Therefore, we hypothesize that cancer stem cells could promote hematopoietic stem cells incorporating into tumor microenvironment and resulting into transformation of hematopoietic stem cells to stromal cells, which could impact the biological behavior of cancer stem cells.     

Elevation of serum lactate dehydrogenase at posterior reversible encephalopathy syndrome onset in chemotherapy-treated cancer patients

The pathophysiology of posterior reversible encephalopathy syndrome (PRES) is incompletely understood; however, an underlying state of immune dysregulation and endothelial dysfunction has been proposed. We examined alterations of serum lactate dehydrogenase (LDH), a marker of endothelial dysfunction, relative to the development of PRES in patients receiving chemotherapy. A retrospective Institutional Review Board approved database of 88 PRES patients was examined. PRES diagnosis was confirmed by congruent clinical diagnosis and MRI. Clinical features at presentation were recorded. Serum LDH values were collected at three time points: prior to, at the time of, and following PRES diagnosis. Student’s t-test was employed. LDH values were available during the course of treatment in 12 patients (nine women; mean age 57.8 years [range 33–75 years]). Chemotherapy-associated PRES patients were more likely to be normotensive (25%) versus the non-chemotherapy group (9%). LDH levels at the time of PRES diagnosis were higher than those before and after (p = 0.0263), with a mean difference of 114.8 international units/L. Mean time intervals between LDH measurement prior to and following PRES diagnosis were 44.8 days and 51.4 days, respectively. Mean elapsed time between last chemotherapy administration and PRES onset was 11.1 days. In conclusion, serum LDH, a marker of endothelial dysfunction, shows statistically significant elevation at the onset of PRES toxicity in cancer patients receiving chemotherapy. Our findings support a systemic process characterized by endothelial injury/dysfunction as a factor, if not the prime event, in the pathophysiology of PRES.     

Pattern of lymph node metastases and its implication in radiotherapeutic clinical target volume in patients with non-small-cell lung cancer: a study of 2062 cases

Objective:

To study the pattern of lymph node metastasis (LNM) of non-small-cell lung cancer (NSCLC) and to clarify which node level should be included while undergoing radiotherapy (RT).

Methods:

A total of 2062 patients with NSCLC patients who had undergone thoracotomy were retrospectively examined. The clinicopathological factors related to LNM were analysed.

Results:

The LNM rates (the number of node-positive patients/the total number of patients) in patients with primary tumours in different lobes (left upper lobe, left lower lobe, right upper lobe, right middle lobe and right lower lobe) were 53.25%, 53.87%, 53.77%, 64.67% and 61.58%, respectively. We have found that in all of the clinicopathological factors, including sex, age, tumour location, histological type, maximum diameter, T stage, degree of differentiation and tumour growth pattern, only maximum diameter (p = 0.336) and histological type (p = 0.360) did not have significant correlation with LNM rate. All of the above factors except tumour growth pattern (p = 0.239) and maximum diameter (p = 0.613) were significantly associated with lymph node ratio [LNR, ratio between metastatic and examined lymph nodes (LNs)] in linear regression.

Conclusion:

For patients with NSCLC, LNM rate and LNR can be recommended as applicable parameters for LN involvement. Multiple clinicopathological factors should be considered comprehensively to design the clinical target volume for RT of NSCLC.

Advances in knowledge:

This article can provide evidence to radio-oncologists how to choose range of lymph nodal clinical target volume when they are treating inoperable patients with NSCLC patients by analysing data of patients after surgery.     

叶酸偶联的青霉素G酰化酶对叶酸受体阳性肿瘤细胞的靶向作用

目的 研究叶酸偶联的青霉素G酰化酶(F-PGA)对叶酸受体阳性肿瘤细胞的靶向作用.方法 用激光共聚焦显微镜观察宫颈癌HeLa、卵巢癌SKOV3和肺癌A549细胞对F-PGA以及游离叶酸(F-A)的摄取,并进一步用同位素示踪法加以验证和定量检测.结果 F-PGA与F-A相似,均能被叶酸受体阳性的HeLa和SKOV3肿瘤细胞选择性摄取,且有饱和性、可逆性、温度依赖性和高亲和性的特点,但不能被叶酸受体阴性的A549细胞摄取.结论 F-PGA与F-A都是通过叶酸受体介导,从而特异性地靶向于叶酸受体阳性肿瘤细胞的.     

Inhibition of phosphodiesterase-4 suppresses HMGB1/RAGE signaling pathway and NLRP3 inflammasome activation in mice exposed to chronic unpredictable mild stress

Inhibition of phosphodiesterase-4 (PDE4) produces robust anti-inflammatory and antidepressant-like effects in multiple animal models. However, the detailed mechanisms have not been well studied. Receptor for advanced glycation endproducts (RAGE) and inflammasome activation are implicated in the etiology of depression. Here, we aimed to investigate the involvement of RAGE and nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome in the antidepressant-like effects of PDE4 inhibition in mice. We found that inhibition of PDE4 by roflupram (ROF, 0.5, and 1.0 mg/kg, i.g.) exerted antidepressant-like effects in mice subjected to chronic unpredictable mild stress (CUMS). Simultaneously, ROF inhibited CUMS-induced microglial activation and restored the morphology of microglial cells in the hippocampus, as evidenced by reduced total process length, area, volume, number of branching points, number of terminal points and total sholl intersections of microglia. ROF also decreased the expression of ionized calcium-binding adapter molecule-1 and the level of interleukin-1β. Western blot analysis showed that PDE4 inhibition suppressed the high-mobility group box 1 protein (HMGB1)/RAGE signaling pathway, as the levels of HMGB1, RAGE, toll-like receptor 4, phosphorylated p38 mitogen-activated protein kinase, and nuclear factor κ-B were decreased in both hippocampus and cortex in mice after treatment with ROF. Moreover, ROF also attenuated the protein levels of NLRP3, the apoptosis-associated speck-like protein containing (ASC), and cysteine-requiring aspartate protease-1 (Caspase-1), which are key proteins in the NLRP3-mediated inflammasome signaling pathway. In summary, these results demonstrate that the down-regulation of HMGB1/RAGE signaling pathway and inflammasome suppression possibly contribute to the antidepressant-like effects of PDE4 inhibitors. And, ROF has potential as a candidate drug in the treatment of depression.     

College of American Pathologists Tumor Regression Grading System for Long-Term Outcome in Patients with Locally Advanced Rectal Cancer

BackgroundThe National Comprehensive Cancer Network''s Rectal Cancer Guideline Panel recommends American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Yet, the clinical significance of the AJCC/CAP TRG system has not been fully defined.Materials and MethodsThis was a multicenter, retrospectively recruited, and prospectively maintained cohort study. Patients with LARC from one institution formed the discovery set, and cases from external independent institutions formed a validation set to verify the findings from discovery set. Overall survival (OS), disease‐free survival (DFS), local recurrence‐free survival (LRFS), and distant metastasis‐free survival (DMFS) were assessed by Kaplan‐Meier analysis, log‐rank test, and Cox regression model.ResultsThe discovery set (940 cases) found, and the validation set (2,156 cases) further confirmed, that inferior AJCC/CAP TRG categories were closely /ccorrelated with unfavorable survival (OS, DFS, LRFS, and DMFS) and higher risk of disease progression (death, accumulative relapse, local recurrence, and distant metastasis) (all p < .05). Significantly, pairwise comparison revealed that any two of four TRG categories had the distinguished survival and risk of disease progression. After propensity score matching, AJCC/CAP TRG0 category (pathological complete response) patients treated with or without adjuvant chemotherapy displayed similar survival of OS, DFS, LRFS, and DMFS (all p > .05). For AJCC/CAP TRG1–3 cases, adjuvant chemotherapy treatment significantly improved 3‐year OS (90.2% vs. 84.6%, p < .001). Multivariate analysis demonstrated the AJCC/CAP TRG system was an independent prognostic surrogate.ConclusionAJCC/CAP TRG system, an accurate prognostic surrogate, appears ideal for further strategizing adjuvant chemotherapy for LARC.Implications for PracticeThe National Comprehensive Cancer Network recommends the American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) four‐category system to evaluate the pathologic response to neoadjuvant treatment for patients with locally advanced rectal cancer; however, the clinical significance of the AJCC/CAP TRG system has not yet been clearly addressed. This study found, for the first time, that any two of four AJCC/CAP TRG categories had the distinguished long‐term survival outcome. Importantly, adjuvant chemotherapy may improve the 3‐year overall survival for AJCC/CAP TRG1–3 category patients but not for AJCC/CAP TRG0 category patients. Thus, AJCC/CAP TRG system, an accurate surrogate of long‐term survival outcome, is useful in guiding adjuvant chemotherapy management for rectal cancer.     

A radiosensitivity gene signature in predicting glioma prognostic via EMT pathway

A 31-gene signature derived by integrating four different microarray experiments, has been found to have a potential for predicting radiosensitivity of cancer cells, but it was seldom validated in clinical cancer samples. We proposed that the gene signature may serve as a predictive biomarker for estimating the overall survival of radiation-treated patients. The significance of gene signature was tested in two previously published datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Altas (TCGA), respectively. In GEO data set, patients predicted to be radiosensitive(RS) had an improved overall survival when compared with radioresistant(RR) patients in either radiotherapy(RT)-treated or non radiotherapy(RT)-treated subgroups(p<0.0001 in the RT-treated group). Multivariate Cox regression analysis showed that the gene signature is the strongest predictor(p=0.0093) in the RT-treated subgroup of patients. However, it does not remain significant (p=0.7668) in non radiotherapy-treated group when adjusting for age and Karnofsky performance score (KPS) as covariates. Similarly, in the TCGA data set, radiotherapy-treated glioblastoma multiforme(GBM) patients assigned to RS group had an improved overall survival compared with RR group(p<0.0001). Geneset enrichment analysis(GSEA) analysis revealed that enrichment of epithelial mesenchymal transition(EMT) pathway was observed with radioresistant phenotype. These results suggest that the signature is a predictive biomarker for radiation-treated glioma patients'' prognostic.