Targeting of liposome-associated calcipotriol to the skin: effect of liposomal membrane fluidity and skin barrier integrity

Many dermal diseases like psoriasis are characterized by major changes in skin barrier function, which challenge the reproducible delivery of drugs into specific layers of diseased skin. The purpose of this study was to elucidate how liposomal bilayer fluidity and barrier integrity affected the delivery of liposome-associated calcipotriol to the skin. Calcipotriol-containing gel state and liquid state dipalmitoylphosphatidyl-choline:dilauroylphosphatidylcholine liposomes were prepared by extrusion. Using Langmuir monolayers, calcipotriol was shown to affect the packing of the lipid membrane. The penetration of radioactively labeled lipid and calcipotriol into pig skin was examined using the Franz diffusion cell model, and tape stripping was applied to impose an impaired barrier. Distorting the skin barrier resulted in an enhanced penetration of lipid from both gel and liquid state liposomes. In addition, increased penetration of lipid from liquid state liposomes was observed compared to gel state liposomes into barrier-impaired skin. For barrier-impaired skin, an elevated calcipotriol-to-lipid ratio was found in the receptor fluid for both liposome compositions indicating that calcipotriol is released from the vesicles. This suggests that the liposome-mediated delivery of calcipotriol to the epidermis of diseased skin is affected by the fluidity of the liposomal membrane.     

Adenocarcinoma of the lung presenting as a mycetoma with an air crescent sign

An 89-year-old man was admitted to the hospital due to intermittent anterior chest wall pain for > 1 month. A chest radiograph obtained on November 9, 2004, demonstrated a mass with an irregular border, inside a thin-walled cavity, located in the superior segment of the left lower lobe. A chest CT scan revealed an irregular thin-walled cavity, 5.9 x 5.4 x 4 cm in size, with an air-crescent sign in the superior segment of the left lower lobe, and an intracavitary fungus ball-like mass. A bronchoscopic examination was performed, revealing only external compression of the left lower lobe bronchial lumen. Cultures from both the brushing cytology and brushing fungus specimens were negative. Since the patient was a heavy smoker and the chest radiograph obtained 23 months before had revealed no active pulmonary lesion, neoplastic growth was still highly suspected. Thus, an (18)F-fluoro-2-deoxyglucose positron emission tomography study was performed on November 25, and a mass with a slightly increased standard uptake value (3.17; cutoff value, 2.5) was found. He received a left lower lobe lobectomy on December 23, and a tumor with many septum-like structures connecting the surrounding pulmonary parenchymal tissue was found in the superior segment of the left lower lobe. The final pathologic diagnosis was adenocarcinoma of the lung (pT2N0M0). Thus, even though the chest radiograph and chest CT scan showed a typical air-crescent sign (ie, mass inside a cavity) favoring a mycetoma, the physician should still keep in mind that lung cancer may also unusually present in this way.     

1-[<Superscript>11</Superscript>C]-acetate PET imaging in head and neck cancer—a comparison with <Superscript>18</Superscript>F-FDG-PET: implications for staging and radiotherapy planning

Purpose The aim of this study was to evaluate the feasibility of using 1-[¹¹C]-acetate positron emission tomography (ACE-PET) to detect and delineate the gross tumour volume of head and neck cancer before radiotherapy, and to compare the results with those obtained using ¹⁸F-fluoro-2-deoxy-D-glucose (FDG) PET. Methods Ten patients with histologically verified squamous cell carcinoma were investigated by FDG-PET and dynamic ACE-PET prior to radiotherapy. The two scans were performed on the same day or on consecutive days, except in one patient in whom they were done 5 days apart. Diagnostic CT or MRI was performed in all patients. The image data sets were analysed both visually and semi-quantitatively. All primary tumours and metastases were delineated automatically by using the 50% threshold of maximum radioactivity corrected for background. The mean standardised uptake value (SUV) and the tumour volumes were evaluated and compared. Results All ten primary tumours were detected by ACE-PET, while nine primaries were detected by FDG-PET and CT and/or MRI. The ACE SUV tended to be lower than the FDG SUV (5.3±2.7 vs 9.6±7.0, p=0.07). The tumour volumes delineated with ACE were on average 51% larger than the FDG volumes (p<0.05). ACE-PET identified 20/21 lymph node metastases, while only 13/21 lesions were detected by FDG-PET and 16/21 lesions by CT or MRI. Conclusion ACE-PET appears promising for the staging of head and neck cancer. The biological information provided by both FDG and ACE must be carefully validated before it can be used in clinical routine for radiation treatment planning. More studies are needed to evaluate the differences in volumes and to confirm the clinical potential of both FDG and ACE-PET, especially in radiotherapy. The first two authors contributed equally to this paper.     

[<Superscript>18</Superscript>F]FDG-PET predicts complete pathological response of breast cancer to neoadjuvant chemotherapy

Purpose To evaluate, in breast cancer patients treated by neoadjuvant chemotherapy, the predictive value of reduction in FDG uptake with regard to complete pathological response (pCR). Methods Forty-seven women with non-metastatic, non-inflammatory, large or locally advanced breast cancer were included. Tumour uptake of FDG was evaluated before and after the first course of neoadjuvant chemotherapy. Four indices were used: maximal and average SUV without or with correction by body surface area and glycaemia (SUV_max, SUV_avg, SUV_max-BSA-G and SUV_avg-BSA-G, respectively). The predictive value of reduction in FDG uptake with respect to pCR was studied by logistic regression analysis. Relationships between baseline [¹⁸F]FDG uptake and prognostic parameters were assessed. Results The relative decrease in FDG uptake (ΔSUV) after the first course of neoadjuvant chemotherapy was significantly greater in the pCR group than in the non-pCR group (p < 0.000066). The four FDG uptake indices were all strongly correlated with each other. A decrease in SUV_max-BSA-G of 85.4% ± 21.9% was found in pCR patients, versus 22.6% ± 36.6% in non-pCR patients. ΔSUV_max-BSA-G <−60% predicted the pCR with an accuracy of 87% and ΔSUVs were found to be only factors predictive of the pCR at multivariate analysis. An elevated baseline SUV was associated with high mitotic activity (p < 0.0016), tumour grading (p < 0.004), high nuclear pleomorphism score (p < 0.03) and negative hormonal receptor status (p < 0.005). Conclusion In breast cancer patients, after only one course of neoadjuvant chemotherapy the reduction in FDG uptake is an early and powerful predictor of pCR.     

Stable isotope-resolved metabolomics and applications for drug development

Advances in analytical methodologies, principally nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS), during the last decade have made large-scale analysis of the human metabolome a reality. This is leading to the reawakening of the importance of metabolism in human diseases, particularly cancer. The metabolome is the functional readout of the genome, functional genome, and proteome; it is also an integral partner in molecular regulations for homeostasis. The interrogation of the metabolome, or metabolomics, is now being applied to numerous diseases, largely by metabolite profiling for biomarker discovery, but also in pharmacology and therapeutics. Recent advances in stable isotope tracer-based metabolomic approaches enable unambiguous tracking of individual atoms through compartmentalized metabolic networks directly in human subjects, which promises to decipher the complexity of the human metabolome at an unprecedented pace. This knowledge will revolutionize our understanding of complex human diseases, clinical diagnostics, as well as individualized therapeutics and drug response.In this review, we focus on the use of stable isotope tracers with metabolomics technologies for understanding metabolic network dynamics in both model systems and in clinical applications. Atom-resolved isotope tracing via the two major analytical platforms, NMR and MS, has the power to determine novel metabolic reprogramming in diseases, discover new drug targets, and facilitates ADME studies. We also illustrate new metabolic tracer-based imaging technologies, which enable direct visualization of metabolic processes in vivo. We further outline current practices and future requirements for biochemoinformatics development, which is an integral part of translating stable isotope-resolved metabolomics into clinical reality.     

移形上皮与鳞状上皮来源的恶性肿瘤摄取18F-FDG差异性的实验研究

[目的]探讨来自不同上皮来源的肿瘤组织葡萄糖代谢的差异,为临床PET/CT应用中如何判断上皮组织来源的恶性肿瘤葡萄糖摄取出现的假阳性和假阴性等问题提供理论依据.[方法] BALB/C裸鼠12只,随机分为2组,并且皮下分别接种膀胱癌EJ细胞和宫颈癌Hela细胞,1×106/0.2ml使其成瘤.行小动物PET扫描,取得葡萄糖标准化摄取值(SUV),测量SUVmax和SUVmean对肿瘤组织葡萄糖代谢进行评价.[结果]膀胱癌SUVmax:4.22±0.39,SUVmean:2.60±0.43;宫颈癌SUVmax:6.18±0.23,SUVmean:2.40±0.57.膀胱癌与宫颈癌的SUVmax值差异有统计学意义(t=-9.474,P＜0.01),而SUVmean值无统计学差异.[结论]鳞状上皮来源的肿瘤葡萄糖摄取要高于移形上皮来源的.     

Coronary Adventitial and Perivascular Adipose Tissue Inflammation in Patients With Vasospastic Angina

Background

Recent studies suggested that perivascular components, such as perivascular adipose tissue (PVAT) and adventitial vasa vasorum (VV), play an important role as a source of various inflammatory mediators in cardiovascular disease.