Changjing Zuo

Hypoxia Induced by Upconversion‐Based Photodynamic Therapy: Towards Highly Effective Synergistic Bioreductive Therapy in Tumors

Local hypoxia in tumors is an undesirable consequence of photodynamic therapy (PDT), which will lead to greatly reduced effectiveness of this therapy. Bioreductive pro-drugs that can be activated at low-oxygen conditions will be highly cytotoxic under hypoxia in tumors. Based on this principle, double silica-shelled upconversion nanoparticles (UCNPs) nanostructure capable of co-delivering photosensitizer (PS) molecules and a bioreductive pro-drug (tirapazamine, TPZ) were designed (TPZ-UC/PS), with which a synergetic tumor therapeutic effect has been achieved first by UC-based (UC-) PDT under normal oxygen environment, immediately followed by the induced cytotoxicity of activated TPZ when oxygen is depleted by UC-PDT. Treatment with TPZ-UC/PS plus NIR laser resulted in a remarkably suppressed tumor growth as compared to UC-PDT alone, implying that the delivered TPZ has a profound effect on treatment outcomes for the much-enhanced cytotoxicity of TPZ under PDT-induced hypoxia.

A Polyoxometalate Cluster Paradigm with Self-Adaptive Electronic Structure for Acidity/Reducibility-Specific Photothermal Conversion

Photothermal conversion is one of the most important keys in the fields of solar collection, photo-hyperthermia, etc., and its performance is highly dependent on the photothermal conversion materials used. Especially in cancer photo-hyperthermia, the presently available small-molecule- or nanomaterial-based agents still suffer from numerous drawbacks, such as nonspecific accumulation and inevitable side effects on normal tissues. Here we identify a Mo-based polyoxometalate cluster that can change its dimension from small (1 nm) to big (tens of nanometer), favoring its intratumoral accumulation, and enhance photothermal conversion in response to the intratumoral acidity and reducibility, demonstrating a previously unrealized tumor-specific photo-hyperthermia. Distinct from the well-researched nano-based agents, a unique electronic structure of this cluster has been identified as the origin of the observed acidity-induced self-assembly and reduction-promoted NIR absorbance. In addition to providing a promising clinical agent, this finding is expected to establish a new physicochemical paradigm for photothermal materials design based on clusters.

Focal autoimmune pancreatitis: Radiological characteristics help to distinguish from pancreatic cancer

AIM To identify the radiological characteristics of focal autoimmune pancreatitis (f-AIP) useful for differentiation from pancreatic cancer (PC). METHODS Magnetic resonance imaging (MRI) and triple-phase computed tomography (CT) scans of 79 patients (19 with f-AIP, 30 with PC, and 30 with a normal pancreas) were evaluated retrospectively. A radiologist measured the CT attenuation of the pancreatic parenchyma, the f-AIP and PC lesions in triple phases. The mean CT attenuation values of the f-AIP lesions were compared with those of PC, and the mean CT attenuation values of pancreatic parenchyma in the three groups were compared. The diagnostic performance of CT attenuation changes from arterial phase to hepatic phase in the differentiation between f-AIP and PC was evaluated using receiver operating characteristic (ROC) curve analysis. We also investigated the incidence of previously reported radiological findings for differentiation between f-AIP and PC. RESULTS The mean CT attenuation values of f-AIP lesions in enhanced phases were significantly higher than those of PC (arterial phase: 60 ± 7 vs 48 ± 10, P < 0.05; pancreatic phase: 85 ± 6 vs 63 ± 15, P < 0.05; hepatic phase: 95 ± 7 vs 63 ± 13, P < 0.05). The mean CT attenuation values of f-AIP lesions were significantly lower those of uninvolved pancreas and normal pancreas in the arterial and pancreatic phase of CT (P < 0.001, P < 0.001), with no significant difference at the hepatic phase or unenhanced scanning (P = 0.4, P = 0.1). When the attenuation value increase was equal or more than 28 HU this was considered diagnostic for f-AIP, and a sensitivity of 87.5%, specificity of 100% and an area under the ROC curve of 0.974 (95%CI: 0.928-1.021) were achieved. Five findings were more frequently observed in f-AIP patients: (1) sausage-shaped enlargement; (2) delayed homogeneous enhancement; (3) hypoattenuating capsule-like rim; (4) irregular narrowing of the main pancreatic duct (MPD) and/or stricture of the common bile duct (CBD); and (5) MPD upstream dilation ≤ 5 mm. CONCLUSION Analysis of a combination of CT and MRI findings could improve the diagnostic accuracy of differentiating f-AIP from PC.

Efficacy and safety of cinitapride in the treatment of mild to moderate postprandial distress syndrome-predominant functional dyspepsia.

Goals and Background: Functional dyspepsia (FD) is a complex disease with a variety of dyspeptic symptoms. Little is known about the clinical efficacy of cinitapride, a 5-HT4 agonist and D2 antagonist, in treating FD. Study: This randomized, double-blind, double-dummy, positive-controlled study compared the efficacy and safety of cinitapride (1 mg) and domperidone (10 mg) tid for 4 weeks in 383 consecutive patients with mild to moderate, postprandial distress syndrome–predominant dyspeptic symptoms according to Rome III criteria. The primary endpoint was the noninferiority of cinitapride compared with domperidone in relief of symptoms. The overall patient evaluation of treatment and open gastric emptying effects of both drugs were treated as the secondary endpoints. Results: The rates of symptom relief by cinitapride and domperidone after 4 weeks did not differ significantly on intension-to-treat analysis (85.8% vs. 81.8%, P=0.332). Cinitapride significantly reduced the overall severity of postprandial fullness, early satiation, and bloating (4.3±3.9 vs. 17.8±6.6, P<0.001); and it was superior to the effects of domperidone (5.4±4.9 vs. 18.4±6.9, P<0.001; P=0.021 between groups). Cinitapride also decreased the mean half-gastric emptying time from 131.1±119.4 to 86.5±18.7 minutes (P=0.0002). There was a positive relationship between symptoms and gastric emptying time (r=0.332, P=0.041). Cinitapride-related adverse events were observed in 9.1% of patients, including 1 patient with extrapyramidal symptoms. No patient experienced QT interval prolongation. Conclusions: This phase III trial has confirmed a noninferior efficacy of cinitapride over domperidone for patients with mild to moderate, postprandial distress syndrome–predominant FD. Cinitapride usage is well tolerated, but its cardiovascular events need further evaluation (NCT 01355276).

Upconversion nano-photosensitizer targeting into mitochondria for cancer apoptosis induction and cyt c fluorescence monitoring

Disruption of mitochondrial reactive oxygen species (mitoROS) plays a major role in cancer cell apoptosis. Here, we designed a core/shell-structured mitochondria-targeting upconversion-based nano-photosensitizer (TPP-UC(PS)) with a lanthanide-doped upconversion nanoparticle (UCNP) core coated by a photosensitizer (PS)-incorporated dense silica shell. Following irradiation with external near-infrared laser (NIR), TPP-UC(PS) in mitochondria caused serious mitochondrial matrix swelling for the activated upconversion-based photodynamic therapy (UC-PDT), and the mobilization of cytochrome c (cyt c) was amplified in response to the increased mitoROS. Specifically, this heme-containing cyt c could be monitored by varying TPP-UC(PS)’s upconversion luminescence signal (UCL), which may facilitate the in situ detection of cyt c for apoptosis research. As a proof of concept, our designed TPP-UC(PS) may provide significant opportunities for controlling cancer cell apoptosis under NIR stimulation and for studying apoptosis using the dynamic UCL, which is influenced by local cyt c.

Diagnosis and treatment of autoimmune pancreatitis: experience with 100 patients

BACKGROUND Autoimmune pancreatitis (AIP) is increasingly recognized as a unique subtype of pancreatitis. This study aimed to analyze the diagnosis and treatment of AIP patients from a tertiary care center in China. METHODS One hundred patients with AIP who had been treated from January 2005 to December 2012 in our hospital were enrolled in this study. We retrospectively reviewed the data of clinical manifestations, laboratory tests, imaging examinations, pathological examinations, treatment and outcomes of the patients. RESULTS The median age of the patients at onset was 57 years (range 23-82) with a male to female ratio of 8.1:1. The common manifestations of the patients included obstructive jaundice (49 patients, 49.0%), abdominal pain (30, 30.0%), and acute pancreatitis (11, 11.0%). Biliary involvement was one of the most extrapancreatic manifestations (64, 64.0%). Fifty-six (56.0%) and 43 (43.0%) patients were classified into focal-type and diffuse-type respectively according to the imaging examinations. The levels of serum IgG and IgG4 were elevated in 69.4% (43/62) and 92.0% (69/75) patients. Pathological analysis of specimens from 27 patients supported the diagnosis of lymphoplasmacytic sclerosing pancreatitis, and marked (>10 cells/HPF) IgG4 positive cells were found in 20 (74.1%) patients. Steroid treatment and surgery as the main initial treatments were given to 41 (41.0%) and 28 (28.0%) patients, respectively. The remission rate after the initial treatment was 85.0%. Steroid was given as the treatment after relapse in most of the patients and the total remission rate at the end of follow-up was 96.0%. CONCLUSIONS Clinical manifestations, laboratory tests, imaging and pathology examinations in combination could increase the diagnostic accuracy of AIP. Steroid treatment with an initial dose of 30 or 40 mg prednisone is effective and safe in most patients with AIP.

Cross-modality PET/CT and contrast-enhanced CT imaging for pancreatic cancer

AIM To explore the diagnostic value of the cross-modality fusion images provided by positron emission tomography/computed tomography (PET/CT) and contrast-enhanced CT (CECT) for pancreatic cancer (PC). METHODS Data from 70 patients with pancreatic lesions who underwent CECT and PET/CT examinations at our hospital from August 2010 to October 2012 were analyzed. PET/CECT for the cross-modality image fusion was obtained using TureD software. The diagnostic efficiencies of PET/CT, CECT and PET/CECT were calculated and compared with each other using a χ(2) test. P < 0.05 was considered to indicate statistical significance. RESULTS Of the total 70 patients, 50 had PC and 20 had benign lesions. The differences in the sensitivity, negative predictive value (NPV), and accuracy between CECT and PET/CECT in detecting PC were statistically significant (P < 0.05 for each). In 15 of the 31 patients with PC who underwent a surgical operation, peripancreatic vessel invasion was verified. The differences in the sensitivity, positive predictive value, NPV, and accuracy of CECT vs PET/CT and PET/CECT vs PET/CT in diagnosing peripancreatic vessel invasion were statistically significant (P < 0.05 for each). In 19 of the 31 patients with PC who underwent a surgical operation, regional lymph node metastasis was verified by postsurgical histology. There was no statistically significant difference among the three methods in detecting regional lymph node metastasis (P > 0.05 for each). In 17 of the 50 patients with PC confirmed by histology or clinical follow-up, distant metastasis was confirmed. The differences in the sensitivity and NPV between CECT and PET/CECT in detecting distant metastasis were statistically significant (P < 0.05 for each). CONCLUSION Cross-modality image fusion of PET/CT and CECT is a convenient and effective method that can be used to diagnose and stage PC, compensating for the defects of PET/CT and CECT when they are conducted individually.

(18)F-FDG PET/CT of adrenal lesions.

OBJECTIVE The purpose of this review is to describe FDG uptake characteristics of adrenal lesions, which can show increased FDG uptake on PET/CT. CONCLUSION Both benign and malignant adrenal lesions can show increased FDG uptake. Knowledge of the uptake characteristics of these lesions is helpful for increasing diagnostic accuracy and expanding the differential diagnosis for adrenal lesions.

Pulmonary embolism caused by right atrial myxoma on FDG PET/CT.

Pulmonary embolism derived from the right atrial myxoma is a rare event and can be difficult to recognize. A chest x-ray image from a 48-year-old woman with shortness of breath revealed multiple pulmonary nodules, which suggested lung metastases. An FDG PET/CT was performed for further evaluation. The images showed that the lung nodules had variable but mild FDG activity in general. There was 1 additional large FDG activity in the right atrium. The subsequent studies demonstrated that the patient experienced pulmonary embolism derived from the right atrial myxoma.

Development of a Novel PET Tracer [18F]AlF-NOTA-C6 Targeting MMP2 for Tumor Imaging

Background and Objective The overexpression of gelatinases, that is, matrix metalloproteinase MMP2 and MMP9, has been associated with tumor progression, invasion, and metastasis. To image MMP2 in tumors, we developed a novel ligand termed [18F]AlF-NOTA-C6, with consideration that: c(KAHWGFTLD)NH2 (herein, C6) is a selective gelatinase inhibitor; Cy5.5-C6 has been visualized in many in vivo tumor models; positron emission tomography (PET) has a higher detection sensitivity and a wider field of view than optical imaging; fluorine-18 (18F) is the optimal PET radioisotope, and the creation of a [18F]AlF-peptide complex is a simple procedure. Methods C6 was conjugated to the bifunctional chelator NOTA (1, 4, 7-triazacyclononanetriacetic acid) for radiolabeling [18F]AlF conjugation. The MMP2-binding characteristics and tumor-targeting efficacy of [18F]AlF-NOTA-C6 were tested in vitro and in vivo. Results The non-decay corrected yield of [18F]AlF-NOTA-C6 was 46.2–64.2%, and the radiochemical purity exceeded 95%. [18F]AlF-NOTA-C6 was favorably retained in SKOV3 and PC3 cells, determined by cell uptake. Using NOTA-C6 as a competitive ligand, the uptake of [18F]AlF-NOTA-C6 in SKOV3 cells decreased in a dose-dependent manner. In biodistribution and PET imaging studies, higher radioactivity concentrations were observed in tumors. Pre-injection of C6 caused a marked reduction in tumor tissue uptake. Immunohistochemistry showed MMP2 in tumor tissues. Conclusions [18F]AlF-NOTA-C6 was easy to synthesize and has substantial potential as an imaging agent that targets MMP2 in tumors.