Clinical role of radiofrequency ablation for early-stage hepatocellular carcinoma in an advanced aging society.

AIM: It is unclear whether prognosis differs by age for early-stage hepatocellular carcinoma (HCC). We aimed to examine prognosis and recurrence after radiofrequency ablation (RFA) for early-stage HCC and to determine its prognostic factors for different age groups. METHODS: This retrospective study enrolled 1079 patients with initial early-stage HCC treated with RFA at two institutions. All patients in this study were divided into four groups: <70 years old (group1, n = 483), 70-74 years old (group2, n = 198), 75-79 years old (group3, n = 201), and ≥80 years old (group4, n = 197). Prognostic factors were evaluated by comparing survival and recurrence rates between each group. RESULTS: The median survival time and 5-year survival rates for each group were 113 months and 70.8% in group1, 99.2 months and 71.5% in group2, 91.3 months and 66.5% in group3, and 71 months and 52.6% in group 4, respectively. Group4 had a significantly shorter survival than the other groups (p < 0.05). There were no significant differences in recurrence-free survival among the groups. In group4, the most common cause of death was nonliver-related disease (69.4%). In all groups, modified albumin-bilirubin index grade was a factor contributing to prolonged prognosis, but only in group4 performance status (PS) was a significant factor (hazard ratio, 2.46; 95% confidence interval, 1.16-3.00; p = 0.009). CONCLUSION: For early-stage HCC in the elderly, preoperative evaluation of PS and management of other diseases could contribute to a prolonged prognosis.

Metastasis from Renal Cell Carcinoma to Ectopic Pancreas Diagnosed after Resection.

We herein report a 68-year-old man who underwent nephrectomy for right renal cell carcinoma 10 years prior. He remained under regular medical observation, and abdominal computed tomography showed tumors in the head and tail of the pancreas. He was diagnosed with pancreatic metastasis from renal cell carcinoma. He underwent surgical excision. The pathologic diagnosis proved that the pancreatic tumors were metastases from renal cell carcinoma and clarified that an ectopic pancreas in the duodenum had metastases as well. To our knowledge, this is the first case of metastasis to an ectopic pancreas.

A case of walled-off necrosis extending into the pelvic cavity successfully treated by endoscopic necrosectomy using a lumen-apposing metal stent.

A 31-year-old man developed massive walled-off necrosis extending into the pelvic cavity following severe acute alcoholic pancreatitis. Endoscopic ultrasound-guided fistula drainage was performed using a lumen-apposing metal stent, but this was insufficiently effective, and endoscopic necrosectomy was also performed, after which the patient improved. Percutaneous drainage and surgery are other options for the treatment of walled-off necrosis extending into the pelvic cavity, but a valuable case in which the patient improved with endoscopic treatment alone is presented.

Direct-acting antivirals improve survival and recurrence rates after treatment of hepatocellular carcinoma within the Milan criteria.

BACKGROUND: The effects of direct-acting antivirals (DAAs) on survival and recurrence rates after curative hepatocellular carcinoma (HCC) treatment in patients with hepatitis C virus (HCV) infection remain controversial. METHODS: This retrospective, multicenter study involved Child-Pugh class A patients within the Milan criteria who had a first diagnosis of HCC and survived 6 months or longer after undergoing hepatectomy or radiofrequency ablation (RFA). The DAA-treated group (DAA group) included 56 patients, and the DAA-untreated group (untreated group) included 261 patients. The study was conducted using the propensity score-matched (1:2) DAA group and untreated group, 56 and 112 patients, respectively. RESULTS: The survival rate at 48 months in the DAA group and the untreated group was 91.0% and 68.7%, respectively, showing significantly better survival in the DAA group (HR: 0.33; 95% CI 0.13-0.84; p = 0.021). The recurrence rate at 48 months was 36.7% and 66.7%, respectively, showing a significantly lower recurrence rate in the DAA group (HR, 0.46; 95% CI 0.27-0.77; p = 0.003). The median albumin-bilirubin (ALBI) score at 3 years post-HCC treatment was - 2.84 in the DAA group and - 2.34 in the untreated group. The ALBI score showed a significant improvement from baseline to 3 years post-HCC treatment (p = 0.001), whereas that in the untreated group showed a significant decline (p = 0.040). CONCLUSIONS: DAAs after HCC treatment prevents deterioration of hepatic functional reserve and significantly improves both recurrence and survival rates.

Discovery of a 3-pyridylacetic acid derivative (TAK-100) as a potent, selective and orally active dipeptidyl peptidase IV (DPP-4) inhibitor.

Inhibition of dipeptidyl peptidase IV (DPP-4) is an exciting new approach for the treatment of diabetes. To date there has been no DPP-4 chemotype possessing a carboxy group that has progressed into clinical trials. Originating from the discovery of the structurally novel quinoline derivative 1, we designed novel pyridine derivatives containing a carboxy group. In our design, the carboxy group interacted with the targeted amino acid residues around the catalytic region and thereby increased the inhibitory activity. After further optimization, we identified a hydrate of [5-(aminomethyl)-6-(2,2-dimethylpropyl)-2-ethyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid (30c) as a potent and selective DPP-4 inhibitor. The desired interactions with the critical active-site residues, such as a salt-bridge interaction with Arg125, were confirmed by X-ray cocrystal structure analysis. In addition, compound 30c showed a desired preclinical safety profile, and it was encoded as TAK-100.

Design and synthesis of 3-pyridylacetamide derivatives as dipeptidyl peptidase IV (DPP-4) inhibitors targeting a bidentate interaction with Arg125.

We have previously discovered nicotinic acid derivative 1 as a structurally novel dipeptidyl peptidase IV (DPP-4) inhibitor. In this study, we obtained the X-ray co-crystal structure between nicotinic acid derivative 1 and DPP-4. From these X-ray co-crystallography results, to achieve more potent inhibitory activity, we targeted Arg125 as a potential amino acid residue because it was located near the pyridine core, and some known DPP-4 inhibitors were reported to interact with this residue. We hypothesized that the guanidino group of Arg125 could interact with two hydrogen-bond acceptors in a bidentate manner. Therefore, we designed a series of 3-pyridylacetamide derivatives possessing an additional hydrogen-bond acceptor that could have the desired bidentate interaction with Arg125. We discovered the dihydrochloride of 1-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-methylpropyl)pyridin-3-yl]acetyl}-l-prolinamide (13j) to be a potent and selective DPP-4 inhibitor that could interact with the guanidino group of Arg125 in a unique bidentate manner.

Novel method for the evaluation of 3D conformation generators.

Conformation generation is a common and key process of computer-aided drug design. The reliability of the docking simulations, pharmacophore development, and 3D-QSAR analyses depends on the accuracy of conformations of small molecules used as input information for each program. Many conformation generators have been developed with the aim of efficiently generating all the putative bound conformations that small molecules adopt when they interact with macromolecules. Conformation generators have been evaluated by whether they can reproduce the experimentally determined bioactive conformations of bound small molecules. These bioactive conformations are usually obtained from publicly available crystal structures of protein-ligand complexes. However, it is difficult to obtain 2 or more than 2 bioactive conformations of one compound because multiple complex structures of a single molecule with various macromolecules are rarely available. Present methods, therefore, simply check whether a set of generated conformations includes the corresponding bioactive conformation. The overall validity of the entire set of generated conformations against bioactive conformation space has never been checked. In this work we developed a novel method for the evaluation of conformation generators, which makes it possible to measure the performance of a conformation generator based on its ability to reproduce the overall bioactive conformation space. We also determined the optimum parameter sets for OMEGA (OpenEye) based on the coverage of bioactive conformation space and computational efficiency. Our evaluation method elucidated that increasing the number of generated conformations is not necessary to obtain better reproducibility of the overall bioactive conformation space. Our method can be applied to the evaluation of the algorithm and/or design of the conformation generator program itself.

Quantum fluctuation of electronic wave-packet dynamics coupled with classical nuclear motions.

An ab initio electronic wave-packet dynamics coupled with the simultaneous classical dynamics of nuclear motions in a molecule is studied. We first survey the dynamical equations of motion for the individual components. Reflecting the nonadiabatic dynamics that electrons can respond to nuclear motions only with a finite speed, the equations of motion for nuclei include a force arising from the kinematic (nuclear momentum) coupling from electron cloud. To materialize these quantum effects in the actual ab initio calculations, we study practical implementation of relevant electronic matrix elements that are related to the derivatives with respect to the nuclear coordinates. Applications of the present scheme are performed in terms of the configuration state functions (CSF) using the canonical molecular orbitals as basis functions without transformation to particular diabatic basis. In the CSF representation, the nonadiabatic interaction due to the kinematic coupling is anticipated to be rather small, and instead it should be well taken into account through the off-diagonal elements of the electronic Hamiltonian matrix. Therefore it is expected that the nonadiabatic dynamics based on this CSF basis neglecting the kinematic coupling may work. To verify this anticipation and to quantify the actual effects of the kinematic coupling, we compare the dynamics with and without the kinematic-coupling terms using the same CSF set. Applications up to the fifth electronically excited states in a nonadiabatic collision between H(2) and B(+) shows that the overall behaviors of these two calculations are surprisingly similar to each other in an average sense except for a fast fluctuation reflecting the electronic time scale. However, at the same time, qualitative differences in the collision events are sometimes observed. Therefore it turns out after all that the kinematic-coupling terms cannot be neglected in the CSF-basis representation. The present applications also demonstrate that the nonadiabatic electronic wave-packet dynamics within ab initio quantum chemical calculation is feasible.