TIL细胞联合IL-2瘤内注射对荷瘤小鼠作用的观察

目的用TILIL－2对荷瘤小鼠进行瘤体内注射，使肿瘤生长受到抑制。方法将荷瘤小鼠分为两组，腹腔注射组和瘤内注射组，每鼠给药量TIL0.5×107＋IL－2500U／次，每隔3～4天注射一次，共6次。测量肿瘤大小，病理切片进行分析。结果瘤内注射者肿瘤生长明显受到抑制，在病理切片中可见肿瘤周围组织中有大量淋巴细胞浸润而全身给药者治疗结果不及前者。结论瘤体内给药提高了肿瘤局部的免疫力，同时可以合理的安排杀伤细胞到达肿瘤部位的有效浓度，从而抑制了肿瘤细胞的增殖，也避免了全身用药所产生的毒副作用，是一种很有潜力的治疗手段。     

All-trans-retinoic acid counteract the tumor-stimulating effect of hepatectomy and increases survival of rats bearing liver metastases

Background

We previously demonstrated a stimulating effect of hepatectomy on residual tumor cells after resection of liver metastases. The aim of this study was to analyze the effect of all-trans-retinoic acid (ATRA) on the protumor effect of hepatectomy and survival of hepatectomized rats bearing liver metastases. We also explored whether ATRA interfered with the tumor promoting effect of hepatotropic growth factors (GFs).

Methods

The in vitro effect of ATRA on proliferation of S4MH rhabdomyosarcoma tumor cells was assessed when cultured with laparotomized or hepatectomized rat serum (HRS), or in the presence of GFs (hepatocyte growth factor, insulin growth factor 2, Platelet Derived Growth Factor (PDGF)-BB, and vascular endothelial growth factor). For the in vivo studies, rats were partially hepatectomized on day 10 after metastasis induction, one group being treated with ATRA from day 7 to 14, and a second receiving cyclophosphamide (CY; on days 10 and 14) alone or with ATRA. We determined the size and number of liver and lung metastases. Finally, we analyzed the effect of treatments on rat survival.

Results

Hepatotropic GFs increased cell proliferation in a similar manner to HRS. In vitro, ATRA blocked the protumor effect of both HRS and GFs. In vivo, ATRA reduced the size and number of liver and lung metastases, and significantly increased rat survival. Furthermore, adding ATRA to CY significantly increased survival compared with CY alone.

Conclusions

In our model, ATRA minimizes the tumor-stimulating effect of hepatectomy, reducing the number and size of liver metastases and improving survival. The results suggest that the ATRA may be useful for blocking the growth-promoting effect of hepatotropic GFs released after liver metastasis resection.     

Fluorescent-tilmanocept for tumor margin analysis in the mouse model

Background

Dendritic cells (DC) are localized in close proximity to cancer cells in many well-known tumors, and thus maybe a useful target for tumor margin assessment.

Materials and methods

[^99mTc]- cyanine 7 (Cy7)-tilmanocept was synthesized and in vitro binding assays to bone marrow-derived DC were performed. Fifteen mice, implanted with either 4T1 mouse mammary or K1735 mouse melanoma tumors, were administered 1.0 nmol of [^99mTc]-Cy7-tilmanocept via tail vein injection. After fluorescence imaging 1 or 2 h after injection, the tumor, muscle, and blood were assayed for radioactivity to calculate percent-injected dose. Digital images of the tumors after immunohistochemical staining for DC were analyzed to determine DC density.

Results

In vitro binding demonstrated subnanomolar affinity of [^99mTc]-Cy7-tilmanocept to DC (K_A = 0.31 ± 0.11 nM). After administration of [^99mTc]-Cy7-tilmanocept, fluorescence imaging showed a 5.5-fold increase in tumor signal as compared with preinjection images and a 3.3-fold difference in fluorescence activity when comparing the tumor with the surgical bed after tumor excision. Immunohistochemical staining analysis demonstrated that DC density positively correlated with tumor percent of injected dose per gram (r = 0.672, P = 0.03), and higher DC density was observed at the periphery versus center of the tumor (186 ± 54 K versus 64 ± 16 K arbitrary units, P = 0.001).

Conclusions

[^99mTc]-Cy7-tilmanocept exhibits in vitro and in vivo tumor-specific binding to DC and maybe useful as a tumor margin targeting agent.     

Tumor Growth Rate Provides Useful Information to Evaluate Sorafenib and Everolimus Treatment in Metastatic Renal Cell Carcinoma Patients: An Integrated Analysis of the TARGET and RECORD Phase 3 Trial Data

BackgroundResponse Evaluation Criteria in Solid Tumors (RECIST) criteria may not be sufficient to evaluate the response of targeted therapies in metastatic renal cell carcinoma (mRCC). The tumor growth rate (TGR) incorporates the time between evaluations and may be adequate.ObjectiveTo determine how TGR is modified along the treatment sequence and is associated with outcome in mRCC patients.Design, setting, and participantsMedical records from all patients prospectively treated at Gustave Roussy (IGR) in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) (sorafenib vs placebo, n = 84) and the RECORD (everolimus vs placebo, n = 43) phase 3 trials were analyzed. TGR was computed across clinically relevant periods: BEFORE treatment introduction (wash-out), UNDER (first cycle), at PROGRESSION (last cycle) and AFTER treatment discontinuation (washout). The association between TGR and outcome (overall survival [OS] and progression-free survival [PFS]) was computed in the entire TARGET cohort (n = 903).InterventionSorafenib, everolimus, or placebo.Outcome measurements and statistical analysisTGR, RECIST, OS, and PFS rates.Results and limitationsAlthough nearly all the patients (IGR) were classified as stable disease (RECIST) after the first cycle, the great majority of the patients exhibited a decrease in TGR UNDER compared with BEFORE (sorafenib: p < 0.00001; everolimus: p < 0.00001). In sorafenib-treated but not in everolimus-treated patients (IGR), TGR at PROGRESSION (last cycle) was still lower than TGR BEFORE (washout) (p = 0.012), while TGR AFTER progression (washout) was higher than TGR at PROGRESSION (last cycle) (p = 0.0012). Higher TGR (first cycle) was associated with worse PFS (hazard ratio [HR]: 3.61; 95% confidence interval [CI], 2.45–5.34) and worse OS (HR: 4.69; 95% CI, 1.54–14.39), independently from the Motzer score and from the treatment arm in the entire TARGET cohort.ConclusionsComputing TGR in mRCC patients is simple and provides clinically useful information for mRCC patients: (1) TGR is independently associated with prognosis (PFS, OS), (2) TGR allows for a subtle and quantitative characterization of drug activity at the first evaluation, and (3) TGR reveals clear drug-specific profiles at progression.     

Antigen affinity and antigen dose exert distinct influences on CD4 T-cell differentiation

Cumulative T-cell receptor signal strength and ensuing T-cell responses are affected by both antigen affinity and antigen dose. Here we examined the distinct contributions of these parameters to CD4 T-cell differentiation during infection. We found that high antigen affinity positively correlates with T helper (Th)1 differentiation at both high and low doses of antigen. In contrast, follicular helper T cell (T_FH) effectors are generated after priming with high, intermediate, and low affinity ligand. Unexpectedly, memory T cells generated after priming with very low affinity antigen remain impaired in their ability to generate secondary Th1 effectors, despite being recalled with high affinity antigen. These data challenge the view that only strongly stimulated CD4 T cells are capable of differentiating into the T_FH and memory T-cell compartments and reveal that differential strength of stimulation during primary T-cell activation imprints unique and long lasting T-cell differentiation programs.Following infection, T-cell receptor (TCR) interactions with foreign peptide/MHC (pMHC) drive the rapid clonal expansion and differentiation of T cells into distinct effector subsets specialized against different classes of microbes. An early bifurcation in CD4 T-cell responses results in the generation of T helper (Th)1 effectors, which regulate innate cell microbicidal function and follicular helper T (T_FH) cells, which migrate to B-cell follicles to regulate germinal center (GC) responses and antimicrobial antibody production (1). After pathogen is cleared, T cells undergo a contraction phase during which the majority of effectors die by apoptosis, leaving behind a population of long-lived memory cells to provide protection upon subsequent reinfection. The decision to differentiate into Th1 and T_FH lineages appears to occur very early in the immune response (2, 3). Initial T-cell priming by dendritic cells (DCs) is sufficient to induce fate-committed Th1 and T_FH cells as early as 3 d after infection, whereas maintenance and further expansion of the T_FH compartment depends on T-cell interactions with B cells (2). Similarly, memory T-cell differentiation occurs very early after infection and is critically dependent on B-cell interactions for optimal priming (4, 5). Importantly, CD4 T-cell differentiation is coupled to division, and unlike CD8 T-cell differentiation, requires constant antigen recognition (6, 7).Although the strength of TCR–pMHC interactions has been shown to directly modulate T-cell expansion and clonal dominance within the Th cell compartment (8, 9), how this influences CD4 T-cell fate is not well understood. Cumulative TCR signaling can be influenced by both antigen affinity and antigen dose (10). In terms of proliferation, higher antigen dose can compensate for lower antigen affinity to some extent, but several reports have shown independent effects on T-cell responses both in vitro and in vivo (10–12). These data indicate that antigen affinity and antigen dose may promote qualitatively distinct TCR signals. Recently, modulation of the overall TCR signal by varying either TCR affinity or antigen dose was shown to influence the pattern of effector T-cell differentiation, with higher affinity ligands or higher antigen dose promoting T_FH generation (13–15). However, another study examining high and low avidity CD4 T-cell responses during viral infection found significant differences in Th1 but not T_FH generation (16). Sustained TCR–pMHC interactions have also been shown to promote memory T-cell differentiation, which is associated with increased TCR avidity (17, 18). These studies, however, have focused on the development of the Th1 memory compartment, which is phenotypically and functionally distinct from the T_FH memory compartment (19, 20). Thus, although strong TCR signals resulting from high antigen affinity or high antigen dose can clearly affect the extent and quality of T-cell differentiation, whether or not T cells can discriminate these signals, and how this contributes to T-cell differentiation during infection, has not been determined.To address this question, we infected mice with varying concentrations of Listeria expressing either high or low affinity antigens for the TCR. By normalizing the degree of proliferation induced by high and low affinity antigens we were able to discern distinct influences of antigen affinity and antigen dose on Th cell differentiation. We observed a strong positive correlation between antigen affinity and Th1 differentiation that occurs early and is dose independent. Importantly, high antigen dose does not compensate for the low efficiency of Th1 differentiation induced by low affinity antigen. In contrast, early T_FH effector generation was observed after priming with high, intermediate, and low affinity antigen, but was not maintained at later time points under conditions of low antigen dose. In addition, we found that T cells activated by either high or low affinity antigen are equally capable of memory T-cell differentiation. Surprisingly, memory T cells generated by either low antigen affinity or low antigen dose maintained their biased effector lineages following recall activation with high affinity antigen. These data indicate that differential strength of stimulation during primary T-cell activation can imprint unique and long lasting T-cell differentiation programs.     

颈动脉体瘤的MR诊断

目的:探讨MR诊断颈动脉体瘤(CBT)的价值。材料与方法:4例经手术病理证实的CBT进行MRI和MRA检查。结果:4例CBT MR检查均显示颈总动脉分叉(common cartid artery bifurcation,CCAB)处类圆形或椭圆形肿瘤,包绕颈内、外动脉,T_1WI呈等或略高信号,T_2WI呈高信号;包膜完整。T_1WI、T_2WI均呈低信号。肿瘤中见多发蜿蜓纡曲的肿瘤小血管。MRA均示CCAB角杯状扩大及肿瘤血管丛。结论:MR不仅能直接显示肿瘤部位、形态、大小及颈动脉关系,也能显示肿瘤血管及CCAB角扩大,是CBT诊断与鉴别的理想方法。     

Molecuar biology of hepatocellular carcinoma and hepatitis B virus association

Summary The involvement of the hepatitis B virus in the pathogenesis of hepatocellular carcinoma was initially suggested on the basis of epidemiological studies. In recent years several kinds of experimental evidence have supported this hypothesis; however, the role played by hepatitis B virus in hepatocarcinogenesis still needs to be elucidated. Several groups of researchers are presently involved in establishing whether hepatitis B virus makes a specific genetic contribution to carcinogenesis or predisposes to neoplastic transformation by causing chronic inflammation and cell regeneration. A comprehensive examination of the data available in the literature suggests that the two hypotheses may not be mutually exclusive.     

选择性血管造影诊断胰腺肿瘤的临床应用价值

目的:探讨血管造影诊断胰腺肿瘤的临床应用价值。材料与方法:临床疑为胰腺良性肿瘤6例和恶性肿瘤5例共11例进行选择性血管造影。结果:血管造影7例阳性,4例阴性,与手术病理结果相符合。结论:选择性血管造影是诊断胰腺良性肿瘤的一种可靠方法。对小胰岛索瘤的定位诊断有独到之处。对胰腺癌手术可切除性的估价有一定帮助。