Perfusion CT of head and neck cancer

We aim to review the technique and clinical applications of perfusion CT (PCT) of head and neck cancer. The clinical value of PCT in the head and neck includes detection of head and neck squamous cell carcinoma (HNSCC) as it allows differentiation of HNSCC from normal muscles, demarcation of tumor boundaries and tumor local extension, evaluation of metastatic cervical lymph nodes as well as determination of the viable tumor portions as target for imaging-guided biopsy. PCT has been used for prediction of treatment outcome, differentiation between post-therapeutic changes and tumor recurrence as well as monitoring patient after radiotherapy and/or chemotherapy. PCT has a role in cervical lymphoma as it may help in detection of response to chemotherapy and early diagnosis of relapsing tumors.     

Low-dose Radiation Induces Antitumor Effects and Erythrocyte System Hormesis

Objective: Low dose radiation may stimulate the growth and development of animals, increase life span,enhance fertility, and downgrade the incidence of tumor occurrence.The aim of this study was to investigate theantitumor effect and hormesis in an erythrocyte system induced by low-dose radiation. Methods: Kunming strainmale mice were subcutaneously implanted with S180 sarcoma cells in the right inguen as an experimental in situanimal model. Six hours before implantation, the mice were given 75mGy whole body X-ray radiation. Tumorgrowth was observed 5 days later, and the tumor volume was calculated every other day. Fifteen days later, all micewere killed to measure the tumor weight, and to observe necrotic areas and tumor-infiltration-lymphoreticularcells (TILs). At the same time, erythrocyte immune function and the level of 2,3-diphosphoglyceric acid (2,3-DPG) were determined. Immunohistochemical staining was used to detect the expression of EPO and VEGFR oftumor tissues. Results: The mice pre-exposed to low dose radiation had a lower tumor formation rate than thosewithout low dose radiation (P < 0.05). The tumor growth slowed down significantly in mice pre-exposed to lowdose radiation; the average tumor weight in mice pre-exposed to low dose radiation was lighter too (P < 0.05).The tumor necrosis areas were larger and TILs were more in the radiation group than those of the group withoutradiation. The erythrocyte immune function, the level of 2,3-DPG in the low dose radiation group were higherthan those of the group without radiation (P < 0.05). After irradiation the expression of EPO of tumor tissuesin LDR group decreased with time. LDR-24h, LDR-48h and LDR-72h groups were all statistically significantlydifferent from sham-irradiation group. The expression of VEGFR also decreased, and LDR-24h group was thelowest (P < 0.05). Conclusion: Low dose radiation could markedly increase the anti-tumor ability of the organismand improve the erythrocyte immune function and the ability of carrying O2. Low-dose total body irradiation,within a certain period of time, can decrease the expression of hypoxia factor EPO and VEGFR, which mayimprove the situation of tumor hypoxia and radiosensitivity of tumor itself.     

蜂毒素对内皮祖细胞微血管形成能力及血管内皮生长因子受体2磷酸化作用的影响

目的 观察蜂毒素对内皮祖细胞微血管形成的影响及探讨其作用机制。方法 通过MTT比色法、黏附实验、Transwell小室迁移实验、小管形成实验等分别测定蜂毒素对内皮祖细胞的增殖、黏附、迁移、小管形成能力的影响。并且通过Western blot法测定蜂毒素对内皮祖细胞VEGFR1、VEGFR2、 AKT、ERK1/2磷酸化的影响。结果 随着蜂毒素的作用浓度增大,其对内皮祖细胞增殖的抑制力越强,蜂毒素浓度在2 μg/ml以下时,不表现出明显的细胞毒性;与0 μg/ml组相比较,蜂毒素1和2 μg/ml浓度组对内皮祖细胞黏附、迁移和小管形成具有明显的抑制作用(P﹤0.05);蜂毒素可抑制内皮祖细胞磷酸化作用,并且下调VEGFR2的表达,VEGFR1的表达无明显变化。结论 蜂毒素能明显抑制大鼠骨髓来源的内皮祖细胞的增殖、黏附、迁移、小管形成的能力,其作用机制可能与蜂毒素抑制内皮祖细胞的磷酸化信号转导通路,从而下调VEGFR2蛋白表达。     

Increased placental trophoblast inclusions in placenta accreta

IntroductionTrophoblast inclusions (TIs) are often found in placentas of genetically abnormal gestations. Although best documented in placentas from molar pregnancies and chromosomal aneuploidy, TIs are also associated with more subtle genetic abnormalities, and possibly autism. Less than 3% of non-aneuploid, non-accreta placentas have TIs. We hypothesize that placental genetics may play a role in the development of placenta accreta and aim to study TIs as a potential surrogate indicator of abnormal placental genetics.MethodsForty cases of placenta accreta in the third trimester were identified in a search of the medical records at one institution. Forty two third trimester control placentas were identified by a review of consecutively received single gestation placentas with no known genetic abnormalities and no diagnosis of placenta accreta.ResultsForty percent of cases with placenta accreta demonstrated TIs compared to 2.4% of controls. More invasive placenta accretas (increta and percreta) were more likely to demonstrate TIs than accreta (47% versus 20%). Prior cesarean delivery was more likely in accreta patients than controls (67% versus 9.5%).DiscussionPlacenta accreta is thought to be the result of damage to the endometrium predisposing to abnormal decidualization and invasive trophoblast growth into the myometrium. However, the etiology of accreta is incompletely understood with accreta frequently occurring in women without predisposing factors and failing to occur in predisposed patients.ConclusionThis study has shown that TIs are present at increased rates in cases of PA. Further studies are needed to discern what underlying pathogenic mechanisms are in common between abnormal placentation and the formation of TIs.     

Inhibition of tumor angiogenesis in lung cancer by T4 phage surface displaying mVEGFR2 vaccine

Vascular endothelial growth factor (VEGF) has been known as a potential vasculogenic and angiogenic factor and its receptor (VEGFR2) is a major receptor to response to the angiogenic activity of VEGF. The technique that to break the immune tolerance of “self-antigens” associated with angiogenesis is an attractive approach for cancer therapy with T4 phage display system. In this experiment, mouse VEGFR2 was constructed on T4 phage nanometer-particle surface as a recombinant vaccine. T4-mVEGFR2 recombinant vaccine was identified by PCR and western blot assay. Immunotherapy with T4-mVEGFR2 was confirmed by protective immunity against Lewis lung carcinoma (LLC) in mice. The antibody against mVEGFR2 was detected by ELISPOT, ELISA and Dot ELISA. The inhibitive effects against angiogenesis were studied using CD31 and CD105 via histological analysis. VEGF-mediated endothelial cells proliferation and tube formation were inhibited in vitro by immunoglobulin induced by T4-mVEGFR2. The antitumor activity was substantiated from the adoptive transfer of the purified immunoglobulin. Antitumor activity and autoantibody production of mVEGFR2 could be neutralized by the depletion of CD4+T lymphocytes. These studies strongly suggest that T4-mVEGFR2 recombinant vaccine might be a promising antitumor approach.     

胶质瘤U87细胞培养上清诱导CD133+内皮细胞血管生成及其可能的机制

目的： 探讨胶质瘤U87细胞培养上清诱导CD133+内皮细胞血管生成及其可能的机制。 方法： 磁珠法分选脐血CD133+细胞,体外诱导为CD133+内皮细胞并以共聚焦显微镜加以鉴定。U87细胞培养上清作用于CD133+内皮细胞（以DMEM作用为对照）,体外血管生成实验检测其体外血管生成,Transwell法检测其迁移能力,Western blotting检测CD133+内皮细胞中VEGFR-1、VEGFR-2与基质金属蛋白酶9（matrix metalloproteinase,MMP-9）的表达,明胶酶谱检测MMP-9的活性。 结果： 脐血CD133+细胞体外诱导培养14 d后,约90%的细胞呈Dil-ac-LDL和FITC-UEA-1双阳性,具有内皮细胞特性,鉴定为CD133+内皮细胞。与DMEM对照组相比,U87细胞培养上清可诱导CD133+内皮细胞血管生成\[（40.7±3.3）vs（21.0±23）,P<0.05\],促进CD133+内皮细胞迁移\[(0.60±0.04) vs (0.27±0.02),P<0.05\]。U87细胞培养上清上调CD133+内皮细胞中VEGFR-2与MMP-9的表达（P<0.05）,而VEGFR-1的表达基本不变;U87细胞培养上清还可增强CD133+内皮细胞中MMP-9的酶活性。 结论： 胶质瘤U87细胞培养上清通过上调CD133+内皮细胞中VEGFR-2与MMP-9的表达促进内皮细胞血管生成。     

BMS-690514, a VEGFR and EGFR tyrosine kinase inhibitor, shows anti-tumoural activity on non-small-cell lung cancer xenografts and induces sequence-dependent synergistic effect with radiation

Background:

Non-small-cell lung cancer (NSCLC) is an aggressive disease in which vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are implicated in tumour growth, tumour resistance to radiation and chemotherapy, and disease relapse. We have investigated the anti-tumoural effects of BMS-690514, an inhibitor of both vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signalling pathways, as a single agent and in combination with ionising radiation (IR) on several NSCLC cell lines.

Methods:

Radiosensitisation of several NSCLC cell lines by BMS-690514 was assessed in vitro using clonogenic assay and in vivo using nude mice.

Results:

In vitro studies showed that BMS-690514 alone decreases clonogenic survival of NSCLC cells lines but no potential enhancement of IR response was observed in the combination. In tumour-bearing mice, BMS-690514 alone inhibits the growth of NSCLC xenografts, including the T790M mutation-harbouring H1975 tumour. The concomitant combination of BMS-690514 and radiation did not increase mice survival in comparison with treatment with IR alone. In contrast, BMS-690514 markedly enhances the anti-tumour effect of radiation in a sequential manner on H1299 and H1975 xenografts. Immunohistochemistry revealed a qualitative reduction in vessel area after administrations of BMS-690514, compared with vehicle-treated controls, suggesting that revascularisation may explain the schedule dependency of the tumour-growth delay observed.

Conclusion:

The results of association with radiation show that BMS-690514 may be a successful adjuvant to clinical radiotherapy. These findings are of translational importance because the clinical benefits of anti-EGFR and anti-VEGFR therapy might be schedule dependent.     

COMPARZ Post Hoc Analysis: Characterizing Pazopanib Responders With Advanced Renal Cell Carcinoma

BackgroundThe phase III COMPARZ study showed noninferior efficacy of pazopanib versus sunitinib in advanced renal cell carcinoma. In this COMPARZ post hoc analysis we characterized pazopanib responders, patient subgroups with better outcomes, and the effect of dose modification on efficacy and safety.Patients and MethodsPatients were randomized to pazopanib 800 mg/d (n = 557) or sunitinib 50 mg/d, 4 weeks on/2 weeks off (n = 553). Secondary end points included time to complete response (CR)/partial response (PR); the proportion of patients with CR/PR ≥10 months and progression-free survival (PFS) ≥10 months; efficacy in patients with baseline metastasis; and logistic regression analyses of patient characteristics associated with CR/PR ≥10 months. Median PFS, objective response rate (ORR), and safety were evaluated in patients with or without dose reductions or interruptions lasting ≥7 days.ResultsMedian time to response was numerically shorter for patients treated with pazopanib versus sunitinib (11.9 vs. 17.4 weeks). Similar percentages of pazopanib and sunitinib patients had CR/PR ≥10 months (14% and 13%, respectively), and PFS ≥10 months (31% and 34%, respectively). For patients without versus with adverse event (AE)-related dose reductions, median PFS, median overall survival, and ORR were 7.3 versus 12.5 months, 21.7 versus 36.8 months, and 22% versus 42% (all P < .0001) for pazopanib, and 5.5 versus 13.8 months, 18.1 versus 38.0 months, and 16% versus 34% (all P < .0001) for sunitinib; results were similar for dose interruptions.ConclusionDose modifications when required because of AEs were associated with improved efficacy, suggesting that AEs might be used as a surrogate marker of adequate dosing for individual patients.     

Adjuvant therapy in renal cell carcinoma

Localized renal cell carcinoma (RCC) has an associated risk of recurrence after nephrectomy. Several clinical risk models attempt to predict oncologic outcomes based on clinical and pathologic features. In addition, novel gene signatures have been developed to refine risk prediction based on tumor biology. Systemic therapies targeting angiogenic pathways that are effective in metastatic RCC failed to show an improvement in overall survival in the adjuvant setting. Immune checkpoint inhibitors have shown significant antitumor activity with prolonged and durable responses in metastatic RCC, which led to an interest in evaluating these agents in the adjuvant setting. In this review, clinical risk-predictive models, novel gene signatures, major clinical trials completed in the adjuvant setting, ongoing immune checkpoint inhibitor trials, and the perspective of adjuvant treatment in RCC are discussed.