Targeted Degradation of Proteins Localized in Subcellular Compartments by Hybrid Small Molecules.

Development of novel small molecules that selectively degrade pathogenic proteins would provide an important advance in targeted therapy. Recently, we have devised a series of hybrid small molecules named SNIPER (specific and nongenetic IAP-dependent protein ERaser) that induces the degradation of target proteins via the ubiquitin-proteasome system. To understand the localization of proteins that can be targeted by this protein knockdown technology, we examined whether SNIPER molecules are able to induce degradation of cellular retinoic acid binding protein II (CRABP-II) proteins localized in subcellular compartments of cells. CRABP-II is genetically fused with subcellular localization signals, and they are expressed in the cells. SNIPER(CRABP) with different IAP-ligands, SNIPER(CRABP)-4 with bestatin and SNIPER(CRABP)-11 with MV1 compound, induce the proteasomal degradation of wild-type (WT), cytosolic, nuclear, and membrane-localized CRABP-II proteins, whereas only SNIPER(CRABP)-11 displayed degradation activity toward the mitochondrial CRABP-II protein. The small interfering RNA-mediated silencing of cIAP1 expression attenuated the knockdown activity of SNIPER(CRABP) against WT and cytosolic CRABP-II proteins, indicating that cIAP1 is the E3 ligase responsible for degradation of these proteins. Against membrane-localized CRABP-II protein, cIAP1 is also a primary E3 ligase in the cells, but another E3 ligase distinct from cIAP2 and X-linked inhibitor of apoptosis protein (XIAP) could also be involved in the SNIPER(CRABP)-11-induced degradation. However, for the degradation of nuclear and mitochondrial CRABP-II proteins, E3 ligases other than cIAP1, cIAP2, and XIAP play a role in the SNIPER-mediated protein knockdown. These results indicate that SNIPER can target cytosolic, nuclear, membrane-localized, and mitochondrial proteins for degradation, but the responsible E3 ligase is different, depending on the localization of the target protein.

A multicenter, randomized, controlled, single-blind comparison phase III study to determine the efficacy and safety of gadobutrol 1.0 M versus gadopentetate dimeglumine following single injection in patients referred for contrast-enhanced MRI of the body regions or extremities.

PURPOSE: To demonstrate the noninferiority of gadobutrol-enhanced magnetic resonance imaging (MRI) compared with gadopentetate dimeglumine-enhanced MRI in Asian patients referred for contrast-enhanced imaging of the body or extremities. MATERIALS AND METHODS: A multicenter, parallel-group comparison study of Asian adults referred for contrast-enhanced MRI were randomized (1:1) to either gadobutrol or gadopentetate dimeglumine. Lesions were assessed for three primary visualization variables: degree of contrast enhancement, border delineation, and internal morphology. Secondary efficacy variables included number of lesions detected, match of MRI diagnosis with final clinical diagnosis, and sensitivity and specificity for malignant lesion detection. Safety was monitored for 24 ± 4 hours after contrast agent administration. RESULTS: A total of 363 patients received either gadobutrol (n = 168) or gadopentetate dimeglumine (n = 178). Mean total scores for three primary visualization variables were 9.39 and 9.34 for gadobutrol and gadopentetate dimeglumine, respectively. The proportion of patients with matched MRI and final diagnosis and sensitivity for malignant lesion detection was greater for unenhanced versus combined images (gadobutrol: 72.2% vs. 81.7%; gadopentetate dimeglumine: 76.2% vs. 82.2%, respectively). Both contrast agents were well tolerated. CONCLUSION: Gadobutrol (0.1 mmol/kg BW) was well tolerated and effective in Asian patients referred for contrast-enhanced MRI of the body or extremities.

Comparison of capability of abdominal 320-detector row CT and of 16-detector row CT for small vasculature assessment.

The purpose of our study was to compare the capability of the 320-detector row CT (area-detector CT: ADCT) using the step-and-shoot scan protocol for small abdominal vasculature assessment with that of the 16-detector row CT using the helical scan protocol. Contrast-enhanced abdominal CT for preoperative assessment was administered to 25 patients, 18 of whom, suspected of having lung cancer, underwent ADCT using the step-and-shoot scan protocol, while the remaining 7, suspected of having renal cell carcinoma, underwent 16-MDCT using the helical scan protocol. Two experienced abdominal radiologists independently assessed renal interlobar and arcuate as well as mesenteric marginal (Griffith point) arteries by means of a 5-point visual scoring systems. Kappa analysis was used for evaluation of interobserver agreement. To compare the visualization capability of the two systems, the scores for each of the arteries were compared by using the Mann-Whitney U-test. Overall interobserver agreements for both systems were almost perfect (κ>0.78). Visualization scores for renal interlobar and arcuate, (p<0.0001) and mesenteric marginal (Griffith point) arteries (p<0.05) were significantly higher for ADCT than for 16-detector row CT. ADCT using the step-and-shoot scan protocol for small abdominal vasculature assessment can be considered superior to 16-detector row CT using the helical scan protocol.

Is contrast material needed after treatment of malignant lymphoma in positron emission tomography/computed tomography?

PURPOSE: Positron emission tomography (PET)/computed tomography (CT) with (18)F-fluorodeoxyglucose is widely used for post-therapeutic surveillance of malignant lymphoma. Debate still exists as to whether intravenous contrast media during the CT stage of a PET/CT scan should be used. The purpose of this study was to investigate the clinical value of contrast agent in PET/CT in patients with lymphoma following treatment. PATIENTS AND METHODS: One hundred and twenty-two consecutive patients with malignant lymphoma underwent 146 PET/CT scans to monitor therapeutic response (n = 57) or surveillance during follow-up (n = 89). All patients had a conventional PET/CT scan with low-dose CT without contrast (ldCT), and then a full-dose CT scan with contrast (ceCT). Two datasets were interpreted separately and prevalence of discrepant results between the two methods was evaluated. In addition, differences of diagnostic performance were investigated for restaging. RESULTS: Both PET + ldCT and PET + ceCT were positive in 22 cases and negative in 35 cases when monitoring response to therapy. There were no cases in which these techniques demonstrated inconsistent findings. For restaging, the patient-based sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of PET + ldCT were 70, 91, 76, 87, and 84%, respectively, and those of PET + ceCT were 74, 92, 81, 89, and 87%, respectively. Discrepant results between the two methods occurred in only 2 of 89 cases (2%). CONCLUSION: PET/ceCT yielded more accurate findings than PET/ldCT in a limited number of cases. PET/ldCT may, therefore, be sufficient for routine PET/CT scanning for post-therapeutic assessment or restaging of lymphoma patients.

Gingival metastasis from ovarian mucinous cystadenocarcinoma as an initial manifestation (a rare case report).

The metastasis of malignant tumors to the oral cavity remains a rare clinical entity. Most metastatic tumors have the propensity for involving the mandible rather than the oral soft tissues. Herein, we describe an unusual case of ovarian mucinous cystadenocarcinoma that metastasized to the mandibular gingiva as an initial manifestation. There is little information regarding metastatic ovarian cancer to the oral cavity. A patient was a 54-year-old woman who developed the paresthesia and swelling of the right mandible after tooth extraction. A pantomograph revealed an osteolytic lesion in the right mandible. A biopsy taken from the gingiva showed mucinous adenocarcinoma, indicating the gingival metastasis of undiscovered primary cancer. A positron emission tomography and computed tomography using 18F-fluorodeoxyglucose depicted an ovarian tumor with multiple pelvic and paraaortic lymph node swellings. A magnetic resonance imaging (MRI) clearly demonstrated the presence of an ovarian cancer. Based on the imaging studies, the diagnosis of the gingival metastasis of an ovarian cancer was suspected. Serum CEA levels were elevated at 125.6 ng/ml (normal range, 0 - 5 ng/ml). She underwent the right segmental mandiblectomy with functional neck dissection and left salpingo-oophorectomy. The histology of surgical specimen confirmed the gingival metastasis of ovarian mucinous adenocarcinoma. Neoplastic cells in the gingiva infiltrated to the mandibular bone. She has been treated with adjuvant chemotherapy consisting of paclitaxel and carboplatin. This case emphasizes that although rare, metastatic ovarian cancer to the gingiva should be included in the differential diagnosis of tumors in the oral cavity.

Magnetic resonance imaging findings of endometrioid adenocarcinoma of the ovary.

PURPOSE: We assessed magnetic resonance imaging (MRI) features and clinical characteristics of ovarian endometrioid adenocarcinoma. MATERIALS AND METHODS: A total of 31 patients with 39 surgically proven ovarian endometrioid adenocarcinomas were analyzed retrospectively. Histologically, 13 lesions in 12 patients arose from proven endometriomas (group A), and 26 lesions in 19 patients did not coexist with endometrioma (group B). The morphological pattern of the lesion on MRI was classified as a solid or a cystic type: A solid type was defined as a solid component occupying more than half of the lesion; and a cystic type was a cystic lesion with one or more mural nodules. RESULTS: Altogether, 11 lesions in group A were the cystic type on MRI, whereas 24 lesions in group B were the solid type (P < 0.0001). Among the 11 cystic-type lesions in group A, the cysts of 5 lesions were hypointense on T1-weighted images, and the cysts of 6 lesions were hyperintense on T1- and T2-weighted images without "shading." The nuclear grade was higher (P = 0.0028) and the clinical stage more advanced (P = 0.0018) in group B compared to group A. CONCLUSION: MRI of ovarian endometrioid adenocarcinomas revealed two types: a solid type and a cystic type. The lesions arising from endometriomas tended to be the cystic type on MRI and have a good prognosis. Preexisting endometrioma in this entity rarely showed "shading" on T2-weighted images.

MRI findings of uterine lipoleiomyoma correlated with pathologic findings.

OBJECTIVE: Our objective was to describe the MRI findings of uterine lipoleiomyoma and to correlate them with histopathologic findings. CONCLUSION: Uterine lipoleiomyoma typically presents as a well-demarcated mass showing hyperintensity with hypointense amorphous bundles on T1- and T2-weighted images with chemical shift artifacts. The hyperintense region suppressed on chemical shift fat-suppressed sequences and the hypointense bundles enhanced by contrast material pathologically correspond to mature fat tissue and smooth muscle tissue, respectively. Even in an atypical case with a small volume of fat tissue in the mass, a fat-suppression MRI sequence is especially useful for the diagnosis.

[A case of advanced thymic cancer successfully treated with neoadjuvant intra-arterial infusion chemotherapy].

We report the case of a 68-year-old man with advanced thymic cancer who was diagnosed as having squamous cell carcinoma by percutaneous needle biopsy. The CT scan showed pre-cardiac and pulmonary invasion, therefore the tumor was classified as Masaoka's stage III. Induction systemic chemotherapy consisting of CDDP (70 mg/m2, day 1), ADM (40 mg/m2, day 1) and ETP (70 mg/m2, day 1-3) was performed for the purpose of reducing the tumor size; however, the tumor's size did not shrink. Therefore, second line chemotherapy combined with selective intra-arterial infusion chemotherapy and systemic chemotherapy consisting of CDDP (70 mg/m2, day 1; intra-arterial), ADM (30 mg/m2, day 1; intra-arterial), VCR (0.5 mg/m2, day 3; systemic) and CPA (500 mg/m2, day 3; systemic) was performed. After this treatment, the tumor was reduced in size, and an extended thymectomy was subsequently performed. The histological diagnosis of the resected tumor was squamous cell carcinoma. Examination of the resected tumor revealed extensive necrosis and only a few cancer cells. These results show that intra-arterial infusion chemotherapy may be effective for local control of advanced thymic cancer.