Diagnostic targeting of colon cancer using a novel fluorescent somatostatin conjugate in a mouse xenograft model

Colorectal carcinoma is one of the more prevalent, highly malignant human tumors, occurring in about 7% of the population. However, if diagnosed and treated in its early stages, colon cancer is curable. In our study, we used a mouse xenograft model to investigate the capability of a fluorescent conjugate of a novel synthetic somatostatin (SST) analog to improve detection of human colorectal tumors that are characterized by over-expressed SST receptors. Human HT-29 colon carcinomas were induced in nude mice. After administration of the fluorescent SST conjugate, in vivo low- and high-magnification fluorescence microscopy, as well as high-resolution spectrally resolved imaging were performed, and the time-dependent biodistribution was determined quantitatively (using fiber-optic spectroscopy). Administration of the conjugate (at concentrations of 6 mg/kg body weight) enabled targeting small (1-5 mm diameter) tumors with high sensitivity and selectivity. Toxicity studies at dosages up to 1,000 mg/kg body weight did not reveal any drug related abnormalities. In conclusion, the SST conjugate significantly enhanced the detection of HT-29 colon tumors by fluorescence imaging because of a 5- to 8-fold increase in the contrast between malignant and normal tissues.     

Epidermal growth factor receptor, somatostatin and Bcl-2 in human pancreatic tumor xenografts

Xenografted human pancreatic tumors (5 ductal adenocarcinomas, 1 leiomyosarcoma, altogether 26 samples) were investigated about their immunohistochemical expression of epidermal growth factor receptor (EGFR), somatostatin (SS) and bcl-2 protein. The expression of the EGFR varied from tumor to tumor. One originally negative carcinoma became immunoreactive during passagings, one tumor has lost its early positive expression, and in 3 cancer lines a phenotypically constant pattern was seen. SS immunoreactivity was practically absent in all tumor samples. Concerning bcl-2 expression, different staining patterns were observed among the carcinomas, but the leiomyosarcoma has retained its strong positivity during xenograftings. In the PZX-5 carcinoma line that was originally negative, the one month Sandostatin treatment induced the strong expression of bcl-2 protein suggesting a development of an acquired resistance against programmed cell death in this tumor.     

The sensitivity and specificity of FDG PET in distinguishing recurrent brain tumor from radionecrosis in patients treated with stereotactic radiosurgery.

Radiation necrosis and recurrent brain tumor have similar symptoms and are indistinguishable on both magnetic resonance imaging (MRI) and computed tomograph scans. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been proposed as a diagnostic alternative, particularly when co-registered with MRI. We studied 47 patients with brain tumors treated with stereotactic radiosurgery and followed with FDG PET. For all tumor types, the sensitivity of FDG PET for diagnosing tumor was 75% and the specificity was 81%. For brain metastasis without MRI co-registration, FDG PET had a sensitivity of 65% and a specificity of 80%. For brain metastasis with MRI co-registration, FDG PET had a sensitivity of 86% and specificity of 80%. MRI co-registration appears to improve the sensitivity of FDG PET, making it a useful modality to distinguish between radiation necrosis and recurrent brain metastasis.     

A potent immunotoxin targeting fibroblast activation protein for treatment of breast cancer in mice

Fibroblast activation protein (FAP) is highly expressed in the tumor‐associated fibroblasts (TAFs) of most human epithelial cancers. FAP plays a critical role in tumorigenesis and cancer progression, which makes it a promising target for novel anticancer therapy. However, mere abrogation of FAP enzymatic activity by small molecules is not very effective in inhibiting tumor growth. In this study, we have evaluated a novel immune‐based approach to specifically deplete FAP‐expressing TAFs in a mouse 4T1 metastatic breast cancer model. Depletion of FAP‐positive stromal cells by FAP‐targeting immunotoxin αFAP‐PE38 altered levels of various growth factors, cytokines, chemokines and matrix metalloproteinases, decreased the recruitment of tumor‐infiltrating immune cells in the tumor microenvironment and suppressed tumor growth. In addition, combined treatment with αFAP‐PE38 and paclitaxel potently inhibited tumor growth in vivo. Our findings highlight the potential use of immunotoxin αFAP‐PE38 to deplete FAP‐expressing TAFs and thus provide a rationale for the use of this immunotoxin in cancer therapy.     

FDG PET/CT在精确放疗中应用的初步研究

目的：研究FDG PET/CT在肿瘤病例中的成像特点和对精确放疗的影响.方法：2009年8月至2011年5月,72例肿瘤患者在放疗前接受GE Discovery PET/CT定位扫描.图像资料传至Varian Eclipse 8.6治疗计划系统.将FDG在各组织器官及肿瘤病灶中的聚积水平分为四个等级（＋-＋＋＋＋）,分析PET成像特点并探讨PET/CT图像融合对放疗的影响.结果：通常情况下,肿瘤病灶和正常脑组织、膀胱肾盏肾盂FDG聚积水平最高（＋＋＋＋）;肝脏、脾脏、椎体次之（＋＋＋）;大部分肌肉和胃肠道、胰腺FDG稍低（＋＋）;肺和皮肤最低（＋）.非肿瘤性FDG高聚积多见于左心室、咽喉周围、局部肠道内以及创伤或炎症病变等部位.PET/CT图像融合使肿瘤病灶更易被发现,因此约22％病例病灶数增加.此外,约62.5％放疗靶区受PET/CT融合图像影响发生了较明显改变.结论：FDG PET/CT在放疗的应用有利于复杂解剖部位肿瘤的边界确定及早期肿瘤病灶的发现和治疗,而非肿瘤性FDG高聚积是最主要的不良影响因素.     

Versican overexpression in human breast cancer lesions: Known and new isoforms for stromal tumor targeting

Proteoglycans play a key role in cancer development and progression by participating in the constitution of a specific fertile tumor microenvironment. As they are largely overexpressed in the malignant stroma, proteoglycans provide a reservoir of potential new targets for anticancer therapies, because they can serve to convey toxic payloads in the close proximity of cancer cells and subsequently destroy them. In this context, versican, a proteoglycan largely overexpressed in several solid cancers, bears the potential to be such an ideal target. As 4 main versican isoforms have been characterized, we sought to determine which isoform could represent the best target in human breast cancer. We used a series of 10 primary breast cancer lesions that were characterized as overexpressing the versican protein, when compared with matched normal breast tissues, using shotgun mass spectrometry and immunohistochemistry experiments. Quantitative polymerase chain reaction and western‐blotting experiments were used to evaluate versican isoform expression in breast cancer/normal tissue pairs for which ARN quality was excellent. All known isoforms were significantly overexpressed in the malignant lesions, both at the mRNA and at the protein levels. In the course of this study, we also identified and cloned a new alternatively spliced versican isoform, referred to as V4, which was also found to be upregulated in human breast cancer. This study provides for the first time a comprehensive mRNA and protein analysis of versican isoforms expression in human breast tissues, and offers insights into which therapeutic strategy would be best suited to target versican in human breast cancer lesions.     

Accuracy of positron emission tomography/computed tomography and clinical assessment in the detection of complete rectal tumor regression after neoadjuvant chemoradiation: long-term results of a prospective trial (National Clinical Trial 00254683)

BACKGROUND:

Neoadjuvant chemoradiation (CRT) therapy may result in significant tumor regression in patients with rectal cancer. Patients who develop complete tumor regression have been managed by treatment strategies that are alternatives to standard total mesorectal excision. Therefore, assessment of tumor response with positron emission tomography/computed tomography (PET/CT) after neoadjuvant treatment may offer relevant information for the selection of patients to receive alternative treatment strategies.

METHODS:

Patients with clinical T2 (cT2) through cT4NxM0 rectal adenocarcinoma were included prospectively. Neoadjuvant therapy consisted of 54 grays of radiation and 5‐fluorouracil‐based chemotherapy. Baseline PET/CT studies were obtained before CRT followed by PET/CT studies at 6 weeks and 12 weeks after the completion of CRT. Clinical assessment was performed at 12 weeks after CRT completion. PET/CT results were compared with clinical and pathologic data.

RESULTS:

In total, 99 patients were included in the study. Twenty‐three patients were complete responders (16 had a complete clinical response, and 7 had a complete pathologic response). The PET/CT response evaluation at 12 weeks indicated that 18 patients had a complete response, and 81 patients had an incomplete response. There were 5 false‐negative and 10 false‐positive PET/CT results. PET/CT for the detection of residual cancer had 93% sensitivity, 53% specificity, a 73% negative predictive value, an 87% positive predictive value, and 85% accuracy. Clinical assessment alone resulted in an accuracy of 91%. PET/CT information may have detected misdiagnoses made by clinical assessment alone, improving overall accuracy to 96%.

CONCLUSIONS:

Assessment of tumor response at 12 weeks after CRT completion with PET/CT imaging may provide a useful additional tool with good overall accuracy for the selection of patients who may avoid unnecessary radical resection after achieving a complete clinical response. Cancer 2012;3501–3511. © 2011 American Cancer Society.     

年轻女性子宫、卵巢生理性18F-FDG摄取与恶性肿瘤的鉴别

目的明确年轻女性患者子宫、卵巢生理性^18F—FDG摄取的特点,并与相应恶性肿瘤鉴别。方法经系列PET或PET／CT随访证实为子宫、卵巢生理性摄取患者22例（共47次检查）人生理组;另22例经病理证实有子宫或卵巢恶性病变者人肿瘤组。比较并分析增高区的最大标准摄取值与肝脏平均摄取的比值R。结果月经早期子宫内膜摄取最高（R达6．6）,排卵期卵巢和内膜摄取均明显（R最高2．6）,而肿瘤病灶形态和分布明显不同,摄取更高（P〈0．001）,以R=2．3为域值,诊断灵敏度、特异性和准确性分别为86．4％、91．5％和89．9％。结论PET显像中子宫、卵巢的生理摄取有特征表现,正确认识可避免误诊。     

Intra-individual comparison of 18F-FET and 18F-DOPA in PET imaging of recurrent brain tumors

Background

Both ¹⁸F-fluorodihydroxyphenylalanine (¹⁸F-DOPA) and ¹⁸F-fluoroethyltyrosine (¹⁸F-FET) have already been used successfully for imaging of brain tumors. The aim of this study was to evaluate differences between these 2 promising tracers to determine the consequences for imaging protocols and the interpretation of findings.

Methods

Forty minutes of dynamic PET imaging were performed on 2 consecutive days with both ¹⁸F-DOPA and ¹⁸F-FET in patients with recurrent low-grade astrocytoma (n = 8) or high-grade glioblastoma (n = 8). Time-activity-curves (TACs), standardized uptake values (SUVs) and compartment modeling of both tracers were analyzed, respectively.

Results

The TAC of DOPA-PET peaked at 8 minutes p.i. with SUV 5.23 in high-grade gliomas and 10 minutes p.i. with SUV 4.92 in low-grade gliomas. FET-PET peaked at 9 minutes p.i. with SUV 3.17 in high-grade gliomas and 40 minutes p.i. with SUV 3.24 in low-grade gliomas. Neglecting the specific uptake of DOPA into the striatum, the tumor-to-brain and tumor-to-blood ratios were higher for DOPA-PET. Kinetic modeling demonstrated a high flow constant k1 (mL/ccm/min), representing cellular internalization through AS-transporters, for DOPA in both high-grade (k1 = 0.59) and low-grade (k1 = 0.55) tumors, while lower absolute values and a relevant dependency from tumor-grading (high-grade k1 = 0.43; low-grade k1 = 0.33) were observed with FET.

Conclusions

DOPA-PET demonstrates superior contrast ratios for lesions outside the striatum, but SUVs do not correlate with grading. FET-PET can provide additional information on tumor grading and benefits from lower striatal uptake but presents lower contrast ratios and requires prolonged imaging if histology is not available in advance due to a more variable time-to-peak.     

Neovascular targeting chemotherapy: encapsulation of paclitaxel in cationic liposomes impairs functional tumor microvasculature

Cationic liposomes have been shown to be internalized selectively by angiogenic tumor endothelial cells after intravenous injection. Therefore, encapsulation of cytotoxic substances in cationic liposomes is a new approach to target tumor vasculature. It was the aim of our study to quantify the effects of paclitaxel encapsulated in cationic liposomes (MBT-0206) on tumor microvasculature and growth in vivo. Experiments were performed in the dorsal skinfold chamber preparation of Syrian Golden hamsters bearing syngeneic A-Mel-3 melanomas. Tumors were treated with intravenous infusion of MBT-0206 (20 mM) resulting in an effective paclitaxel dose of 5 mg/kg body weight (b.w.). Control animals received conventional paclitaxel in Cremophor EL (Taxol(R); 5 mg/kg b.w.), unloaded cationic liposomes (20 mM) or the solvent 5% glucose, respectively. Using intravital microscopy, tumor growth and effects on intratumoral microvasculature were analyzed. Tumor growth was significantly retarded after treatment with MBT-0206 compared to the treatment with paclitaxel. Analysis of intratumoral microcirculation revealed a reduced functional vessel density in tumors after application of liposomal paclitaxel. At the end of the observation time, vessel diameters were significantly smaller in animals treated with paclitaxel encapsulated in cationic liposomes while red blood cell velocity was less affected. This resulted in a significantly reduced blood flow in vessel segments and a reduced microcirculatory perfusion index in these animals. Histochemical TUNEL stain was vessel-associated after treatment with liposomal paclitaxel in contrast to few apoptotic tumor cells in the control groups. Our data demonstrate that encapsulation of paclitaxel in cationic liposomes significantly increased the antitumoral efficacy of the drug. Remarkable microcirculatory changes indicate that encapsulation of paclitaxel in cationic liposomes resulted in a mechanistic switch from tumor cell toxicity to an antivascular therapy.     

Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas

BACKGROUND:

The current study was conducted to evaluate the efficacy and safety of everolimus in the treatment of patients with nonfunctioning neuroendocrine tumors (NETs) or pheochromocytomas/paragangliomas.

METHODS:

Patients with histologically confirmed nonfunctioning NETs or pheochromocytomas/paragangliomas and with documented disease progression before study enrollment were eligible for the current study. Everolimus was administered daily at a dose of 10 mg for 4 weeks. Response was assessed by Response Evaluation Criteria In Solid Tumors (RECIST; version 1.0) every 8 weeks. The primary endpoint was the 4‐month progression‐free survival rate (PFSR). The hypothesis of the current study was that the 4‐month PFSR would increase from 50% to 65%. Safety was evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0).

RESULTS:

A total of 34 patients were enrolled. Of these, 27 patients had nonfunctioning NETs, 5 had pheochromocytomas, and 2 had paragangliomas. The 4‐month PFSR was 78%. Partial response (PR) was observed in 3 patients. Twenty‐eight patients had stable disease (SD) and 2 patients developed progressive disease (PD). The response rate (RR) and overall disease control rate (DCR) were 9.0% (95% confidence interval [95% CI], 0%‐18.6%) and 93.9% (95% CI, 85.8%‐100%), respectively. The PFS was 15.3 months (95% CI, 4.6 months‐26.0 months). Of the patients with nonfunctioning NETs, 3 achieved a PR and 23 had SD (RR, 11.1%; DCR, 100%); the PFS was 17.1 months (95% CI, 11.1 months‐23.0 months) and the 4‐month PFSR was 90.0%. Twenty‐one patients (80.8%) demonstrated tumor shrinkage. In 7 patients with pheochromocytomas/paragangliomas, 5 achieved SD, and 2 developed PD. The PFS was 3.8 months (95% CI, 0.5 months‐7.0 months) and the 4‐month PFSR was 42.9%. Four patients demonstrated tumor shrinkage. The major grade 3/4 adverse events were thrombocytopenia (14.7%), hyperglycemia (5.9%), stomatitis (5.9%), and anemia (5.9%).

CONCLUSIONS:

Everolimus was associated with high therapeutic efficacy and tolerability in patients with nonfunctioning NETs, and demonstrated modest efficacy in patients with pheochromocytomas/paragangliomas. Cancer 2012. © 2012 American Cancer Society.     

Acute changes in glucose uptake after treatment: the effects of carmustine (BCNU) on human glioblastoma multiforme

Summary Sequential positron emission tomographic scans with [¹⁸F]-2-fluorodeoxyglucose (PET-FDG) were performed on 6 patients with glioblastoma multiforme who were treated with adjuvant BCNU. Scans were acquired before and 24 hours after BCNU. All patients had prior brain irradiation. Ratios between the maximal tumor FDG uptake and the contralateral white matter FDG uptake, the glucose uptake ratio, were determined. Percent changes in the glucose uptake ratio between the baseline scan and the 24 hour post-treatment scan were of prognostic significance. Patients with the largest percent changes in FDG uptake had the shortest survival. In contrast, neither the baseline glucose uptake ratio nor the visual tumor grade accurately predicted length of survival.     

An animal model for in vivo evaluation of tumor glycolytic rates with positron emission tomography

We developed a method for evaluating tumor glycolytic rates in vivo with nude mice injected with 2-[F-18]fluoro-2-deoxy-d-glucose (FDG) and a dedicated animal positron emission tomography (PET) scanner. Animals were injected with NR-6 mouse fibroblast tumor cell lines. When tumors achieved a large enough size to be macroscopically visible, quantitative measurements of FDG uptake in vivo were obtained, using both standard nonlinear regression with the FDG tracer kinetic model to generate estimates of model parameters, including K_NLR, the rate constant for net phosphorylation of FDG. Additionally, we determined the values of K_PAT, the rate constant for net phosphorylation of FDG measured with a non-iterative graphical method. Estimates of K were highly correlated (r = 0.95) with both methods, and parametric images of K_PAT demonstrate both the tumor location and size, but are also scaled in units of phosphorylation of FDG. The method is suitable for serial studies of tumor glucose metabolism during and after therapeutic interventions, such as chemotherapeutic trials. © 1993 Wiley-Liss, Inc.     

F-18]Fluorodeoxyglucose positron emission tomography can predict pathological tumor stage and proliferative activity determined by Ki-67 in clinical stage IA lung adenocarcinomas

OBJECTIVE: To predict a malignant grade of lung cancer by fluorodeoxyglucose positron emission tomography (FDG-PET) scanning, we investigated the correlation between FDG uptake and pathological tumor stage, proliferative activities determined by Ki-67 and cyclin D1, and an alteration of p53, in clinical stage (c-stage) IA lung adenocarcinomas. METHODS: FDG-PET was performed for 71 patients with c-stage IA lung adenocarcinomas. FDG uptake was measured by a contrast ratio (CR) between the tumor and contralateral lung. Ki-67, cyclin D1 and p53 staining scores were examined by immunohistochemistry. RESULTS: The lesions with ground-glass opacity were found in 26 patients, and solid lesions in 45 by computed tomography. The pathological tumor stages (p-stage) were stage IA in 59 and more advanced stages in 12. The latter had significantly higher CR value than the former (P < 0.001). Patients with CR > or = 0.55 could be predicted to be at advanced tumor stages, with a sensitivity of 0.83 and a specificity of 0.82. The CR and staining scores of Ki-67 were significantly correlated with each other (P < 0.0001), and both the values were significantly higher in advanced tumor stages than in p-stage IA, and were also significantly higher in tumors with intratumoral lymphatic, vascular and pleural involvements than in those without such features (P < 0.05-0.0001). CONCLUSIONS: In c-stage IA lung adenocarcinomas, the FDG uptake can predict p-stage and tumor proliferative activity determined by Ki-67. For c-stage IA lung adenocarcinomas showing CR > or = 0.55, mediastinoscopy or neoadjuvant chemotherapy is indicated.     

Brain tumor protein synthesis and histological grades: A study by positron emission tomography (PET) with C11-L-Methionine

Summary Brain protein synthesis may be evaluated in vivo by a PET three compartment methionine model. 14 human brain tumor patients were studied. Protein synthesis rate (PSR) was increased in any glial tumor even in low grades, but this increase was statistically more important in anaplastic tumor.Radiotherapy action was evaluated in two patients. Local tumoral PSR was reduced to normal brain PSR after treatment. No difference was seen in normal cortex contralateral to the lesion between pre and post radiotherapy examination.11 C-L-Methionine incorporation measured by PET looks as a very sensitive method for studying tumor metabolism and treatment effects.     

Distant metastasis of prostate cancer: early detection of recurrent tumor with dual-phase carbon-11 choline positron emission tomography/computed tomography in two cases

Several types of recurrence may be detected by radiologic assessment after treatment in patients with prostate cancer. However, early detection of distant metastasis using positron emission tomography has so far never been published. We report two patients who underwent hormone therapy or surgical resection for prostate cancer. They developed distant metastases which were detected on whole body [C-11] choline positron emission tomography/computed tomography with significant elevation of serum PSA level. In one patient, recurrent tumor of the supraclavicular node (6 mm) diminished in size after subsequent hormone therapy. Surgical resection of recurrent tumor of the lung (12 mm) was performed in the other patient, the pathology of which confirmed the metastatic adenocarcinoma derived from the prostate. The recurrent tumor can be correctly detected by dual-phase whole body [C-11] choline positron emission tomography/computed tomography.     

PET/CT在儿童及青少年肿瘤患者中的应用

目的评价PET／CT在年轻肿瘤患者中的应用价值。方法回顾性分析我院行躯干PET／CT检查且年龄≤25岁的病例,共75例（男性35例,女性40例）89次检查。结果所患肿瘤前三位依次为淋巴瘤（31％）、卵巢肿瘤（16％）和神经内分泌肿瘤（8％）。PET／CT用于协助诊断（42％）、分期（11％）、疗效评估（27％）和复发监测（30％）。PET／CT对63％（22／35）的淋巴瘤诊断、分期、治疗评估和复发监测有重要意义,改变了58％（7／12）的卵巢肿瘤患者的诊疗决策,对40％的其他肿瘤患者有帮助。对年轻患者的图像分析须注意胸腺、卵巢和子宫内膜等生理性摄取。结论PET／CT对于指导儿童和青少年肿瘤诊疗具有较大价值,可在权衡辐照危害后合理选用。     

FDG-PET imaging for the evaluation of antiglioma agents in a rat model

The increasing development of novel anticancer agents demands parallel advances in the methods used to rapidly assess their therapeutic efficacy (TE) in the preclinical phase. We evaluated the ability of small-animal PET, using the (18)F-fluoro-deoxy-D-glucose (FDG) radiotracer, to predict the TE of a number of anticancer agents in the rat C6 glioma model following 3 days of treatment. Semi-quantitative measurements of changes in FDG uptake during the course of treatment (standardized uptake value response [SUV(r)]) were found to be significantly lower in tumors treated with the hypoxia-inducible factor-1alpha inhibitor YC-1 (15 mg/kg) than in tumors in the control group. No significant SUV(r) change was observed following a similar 3-day regimen with the proapoptotic agent NS1619 (20 microg/kg), the combination of YC-1 and NS1619, or the alkylating agent temozolomide (7.5 mg/kg). Quantitative immunohistochemical studies demonstrated significantly lower levels of glucose transporter-1 (GLUT-1) expression in the YC-1-treated tumors, thereby correlating with the low SUV(r) observed in this group. The ability of SUV(r) to predict gold-standard outcomes of TE was further validated as YC-1-treated tumors had decreased volumes compared to control tumors. As such, we successfully demonstrated the ability of FDG-PET to rapidly determine the TE of novel agents for the treatment of glioma in the preclinical phase of evaluation.     

Ewing sarcoma/primitive neuroectodermal tumor of the ureter:A case report and literature review

Ewing sarcoma/primary neuroectodermal tumors are rare,invasive,and small round blue cell tumors.There are few reports of its occurrence in the urinary system.Here,we present the first middle-aged female patient whose Ewing sarcoma primary site was in the ureter.The main clinical manifestation was intermittent hematuria.She was in good health after complete surgical resection and adjuvant radiotherapy.To date,there has been no recurrence or metastasis.Accurate early diagnosis and appropriate treatment can help prolong survival.18F-fluorodeoxyglucose positron emission tomography/computed tomography is expected to be an effective means of evaluating treatment effects and detecting metastasis and recurrence.In this article,besides introducing a case of Ewing sarcoma/primitive neuroectodermal tumor of the ureter,we review the literature to discuss the current status of diagnosis and treatment.