Quantitative Susceptibility Mapping: Basic Methods and Clinical Applications.

Quantitative susceptibility mapping (QSM), one of the advanced MRI techniques for evaluating magnetic susceptibility, offers precise quantitative measurements of spatial distributions of magnetic susceptibility. Magnetic susceptibility describes the magnetizability of a material to an applied magnetic field and is a substance-specific value. Recently, QSM has been widely used to estimate various levels of substances in the brain, including iron, hemosiderin, and deoxyhemoglobin (paramagnetism), as well as calcification (diamagnetism). By visualizing iron distribution in the brain, it is possible to identify anatomic structures that are not evident on conventional images and to evaluate various neurodegenerative diseases. It has been challenging to apply QSM in areas outside the brain because of motion artifacts from respiration and heartbeats, as well as the presence of fat, which has a different frequency to the proton. In this review, the authors provide a brief overview of the theoretical background and analyze methods of converting MRI phase images to QSM. Moreover, we provide an overview of the current clinical applications of QSM. Online supplemental material is available for this article. ©RSNA, 2022.

Significance of Frailty in Prognosis After Hepatectomy for Elderly Patients with Hepatocellular Carcinoma.

BACKGROUND: The concept of frailty becomes important for patients who undergo surgery in this recent aging society. The aim of this study is to investigate the frailty as a prognostic factor in elderly patients with hepatocellular carcinoma (HCC) who underwent hepatectomy. PATIENTS AND METHODS: A total of 92 patients over 75 years old who underwent hepatectomy were enrolled in this study. Frailty was defined as clinical frailty scale (CFS) ≥ 4. Patients were divided into two groups, i.e., frailty group (n = 21) and no-frailty group (n = 71), and clinicopathological features were compared between them. RESULTS: The frailty group showed significant higher PIVKA-II level and larger tumor diameter (p < 0.05). CRP level and modified Glasgow prognostic score were significantly higher in the frailty group (p < 0.05). The frailty group showed higher rate of postoperative complications of Clavien-Dindo III (p = 0.06) and longer postoperative stay (p = 0.08). Cancer-specific, overall, and disease-free survival rates were significantly worse in the frailty group (p < 0.05). Frailty was detected as an independent prognostic factor on multivariate analysis of cancer-specific survival. CONCLUSION: Frailty can estimate the prognosis of HCC patients who underwent hepatectomy.

Small-Scale Panel Comprising Diverse Gene Family Targets To Evaluate Compound Promiscuity.

Despite the recent advances in the life sciences and the remarkable investment in drug discovery research, the success rate of small-molecule drug development remains low. Safety is the second most influential factor of drug attrition in clinical studies; thus, the selection of compounds with fewer toxicity concerns is crucial to increase the success rate of drug discovery. Compounds that promiscuously bind to multiple targets are likely to cause unexpected pharmacological activity that may lead to adverse effects. Therefore, avoiding such compounds during early research stages would contribute to identifying compounds with a higher chance of success in the clinic. To evaluate the interaction profile against a wide variety of targets, we constructed a small-scale promiscuity panel (PP) consisting of eight targets (ROCK1, PDE4D2, GR, PPARγ, 5-HT2B, adenosine A3, M1, and GABAA) that were selected from diverse gene families. The validity of this panel was confirmed by comparison with the promiscuity index evaluated from larger-scale panels. Analysis of data from the PP revealed that both lipophilicity and basicity are likely to increase promiscuity, while the molecular weight does not significantly contribute. Additionally, the promiscuity assessed using our PP correlated with the occurrence of both in vitro cytotoxicity and in vivo toxicity, suggesting that the PP is useful to identify compounds with fewer toxicity concerns. In summary, this small-scale and cost-effective PP can contribute to the identification of safer compounds that would lead to a reduction in drug attrition due to safety issues.

Structure-based rational design of staurosporine-based fluorescent probe with broad-ranging kinase affinity for kinase panel application.

Selectivity profiling of compounds is important for kinase drug discovery. To this end, we aimed to develop a broad-range protein kinase assay by synthesizing a novel staurosporine-derived fluorescent probe based on staurosporine and kinase-binding related structural information. Upon structural analysis of staurosporine with kinases, a 4'-methylamine moiety of staurosporine was found to be located on the solvent side of the kinases, to which several linker units can be conjugated by either alkylation or acylation. However, such conjugation was suggested to reduce the binding affinities of the modified compound for several kinases, owing to the elimination of hydrogen bond donor moiety of NH-group from 4'-methylamine and/or steric hindrance by acyl moiety. Based on this structural information, we designed and synthesized a novel staurosporine-based probe without methyl group in order to retain the hydrogen bond donor, similar to unmodified staurosporine. The broad range of the kinase binding assay demonstrated that our novel fluorescent probe is an excellent tool for developing broad-ranging kinase binding assay.

Role of heat shock factor 1 expression in the microenvironment of intrahepatic cholangiocarcinomas.

BACKGROUND AND AIM: Heat shock factor 1 (HSF1), a master regulator of heat shock response, has been shown to play a multifaceted role in cancer progression. However, the clinical significance and biological effect of HSF1 expression in intrahepatic cholangiocarcinoma (IHCC) remain unknown. METHODS: Forty-nine patients with IHCC who underwent hepatic resection were enrolled in this study. HSF1 expression in tumor tissue was determined by immunohistochemistry, and patients were divided into two groups, those with high (n = 20) and low (n = 29) HSF1 expression. Clinicopathological factors including prognosis were compared in these two groups. RESULTS: HSF1 expression was significantly higher in tumors than in normal tissue. The overall survival rate was significantly lower in patients with high than low HSF1. Multivariate analysis showed that high HSF1 expression was a factor independently prognostic of patient survival. CONCLUSION: High HSF1 expression in tumor tissues may be a prognostic biomarker in patients with IHCC.

Effects of Cultivation Month and Genetic Background on Phenolic Content of Citrus tachibana Peel.

Species of the Citrus genus are known as rich sources of phenolic compounds. Peels of Citrus tachibana and Citrus unshiu are used in herbal formulations, sometimes in similar ways. In this study, we examined the effects of plant maturity and genetic background on the total phenolic contents and quantities of specific flavonoids in C. tachibana peel. In addition, we compared these values in C. tachibana and C. unshiu peels. The total phenolic contents and the contents of nobiletin, tangeretin, and hesperidin were higher in the extracts of the immature peel than in those of the mature peels of C. tachibana; moreover, the quantities of these compounds were also influenced by the genetic background of C. tachibana. In the extracts of C. unshiu peel, the contents of total phenolics, nobiletin, and tangeretin were lower than those of C. tachibana peel. However, the hesperidin content was higher in extracts of C. unshiu peel than those of C. tachibana peel. This study evaluated the phenolic and flavonoid contents of C. tachibana and C. unshiu in an effort to provide new insights into herbal medicines for further study and utilization.

Potential predictive factors for microvascular invasion in hepatocellular carcinoma classified within the Milan criteria.

BACKGROUND: Microvascular invasion (mvi) is an important risk factor for recurrent hepatocellular carcinoma (HCC), even after curative liver resection or orthotopic liver transplantation. However, mvi is difficult to detect preoperatively. The aim of this study was to clarify the risk factors of postoperative recurrence and investigate predictive factors of mvi before hepatectomy for HCC classified within the Milan criteria. METHODS: One hundred fifty-nine patients with hepatocellular carcinoma (HCC) classified within the Milan criteria, who underwent hepatectomy, were enrolled in this study. We investigated the risk factors of recurrence. In addition, we divided them into two groups: mvi-negative group and mvi-positive group, based on pathological findings after surgery. We compared the clinicopathological factors between the two groups and determined the risk factors for mvi. RESULTS: Overall survival rate at 1, 3, and 5 years were 91.6%, 80.5%, and 74.9%, and the recurrence-free survival rate at 1, 3, and 5-years were 72.3%, 51.6%, and 37.2%. Risk factor analysis for tumor recurrence revealed that total bilirubin, albumin, ICGR15, AFP-L3, tumor number, mvi, and tumor stage had a significant predictive value. Multivariate analysis revealed that tumor number and mvi were significant independent risk factors for tumor recurrence. Predictive analysis for risk factors of mvi revealed that multiple tumors and AFP-L3 > 10% were significant independent risk factors for mvi in HCC classified within the Milan criteria. CONCLUSIONS: The mvi was one of the independent risk factors for tumor recurrence in HCC classified within the Milan criteria. Multiple tumors and high AFP-L3 value were independent predictive factors for mvi.

Parallel fluorescent probe synthesis based on the large-scale preparation of BODIPY FL propionic acid.

We describe a methodology for quick development of fluorescent probes with the desired potency for the target of interest by using a method of parallel synthesis, termed as Parallel Fluorescent Probe Synthesis (Parallel-FPS). BODIPY FL propionic acid 1 is a widely used fluorophore, but it is difficult to prepare a large amount of 1, which hinders its use in parallel synthesis. Optimization of a synthetic scheme enabled us to obtain 50g of 1 in one batch. With this large quantity of 1 in hand, we performed Parallel-FPS of BODIPY FL-labeled ligands for estrogen related receptor-α (ERRα). An initial trial of the parallel synthesis with various linkers provided a potent ligand for ERRα (Reporter IC50=80nM), demonstrating the usefulness of Parallel-FPS.

Effective stepwise training and procedure standardization for young surgeons to perform laparoscopic left hepatectomy.

BACKGROUND: Laparoscopic hepatectomy remains one of the most difficult procedures for young surgeons to perform. We recently developed a new training method and standardization procedure for teaching young surgeons to perform laparoscopic left hepatectomy (Lap-LHx). The aim of this study was to assess the effectiveness of our method. METHODS: In 2004, we standardized a laparoscopic procedure for Lap-LHx, using a laparoscopy-assisted method as a stepping stone. The laparoscopic training method comprised the following three steps: (1) training in fundamental procedures using a dry box and checking by mentors; (2) detailed preoperative simulation using Vincent three-dimensional software for each patient; and (3) self-assessment including understanding of relevant anatomy and completion grade for each procedure using a check sheet and feedback by both mentors and a professor. Twenty-three Lap-LHx procedures performed during the study period were divided into two groups: those performed by young non-board-certified surgeons (n = 9) and those performed by senior board-certified surgeons (n = 14). RESULTS: The blood loss and operative time were similar in the young surgeon (194 g and 336 min, respectively) and senior surgeon groups (208 g and 322 min, respectively). CONCLUSION: Our standardized Lap-LHx procedure and stepwise training to perform it enable young surgeons to perform Lap-LHx as confidently and safely as more experienced surgeons.

[Experiences of Colonic Stents in Patients with Colonic Stenosis Due to Peritoneal Dissemination of Gastric Cancer].

Stoma is a treatment option often adopted for large bowel obstruction accompanying peritoneal dissemination of gastric cancer, but the invasiveness of this intervention can be an issue for patients with limited prognosis and reduced quality of life. In our hospital, colonic stenting for bowel obstruction due to peritoneal dissemination from gastric cancer was performed for 7 consecutive patients. Oral ingestion became possible in 5 cases, and colonic stent was considered a useful treatment choice for appropriate cases.

A novel Na(+) -Independent alanine-serine-cysteine transporter 1 inhibitor inhibits both influx and efflux of D-Serine.

NMDA receptor dysfunctions are hypothesized to underlie the pathophysiology of schizophrenia, and treatment with D-serine (D-Ser), an NMDA receptor coagonist, may improve the clinical symptoms of schizophrenia. Thus, upregulating the synaptic D-Ser level is a novel strategy for schizophrenia treatment. Na(+) -independent alanine-serine-cysteine transporter 1 (asc-1) is a transporter responsible for regulating the extracellular D-Ser levels in the brain. In this study, we discovered a novel asc-1 inhibitor, (+)-amino(1-(3,5-dichlorophenyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid (ACPP), and assessed its pharmacological profile. ACPP inhibited the D-[(3) H]Ser uptake in human asc-1-expressing CHO cells and rat primary neurons with IC50 values of 0.72 ± 0.13 and 0.89 ± 0.30 µM, respectively. In accordance with the lower asc-1 expression levels in astrocytes, ACPP did not inhibit D-Ser uptake in rat primary astrocytes. In a microdialysis study, ACPP dose dependently decreased the extracellular D-Ser levels in the rat hippocampus under the same conditions in which the asc-1 inhibitor S-methyl-L-cysteine (SMLC) increased it. To obtain insights into this difference, we conducted a D-[(3) H]Ser efflux assay using asc-1-expressing CHO cells. ACPP inhibited D-[(3) H]Ser efflux, whereas SMLC increased it. These results suggest that ACPP is a novel inhibitor of asc-1. © 2016 Wiley Periodicals, Inc.

Design and synthesis of potent and selective pyridazin-4(1H)-one-based PDE10A inhibitors interacting with Tyr683 in the PDE10A selectivity pocket.

Utilizing structure-based drug design techniques, we designed and synthesized phosphodiesterase 10A (PDE10A) inhibitors based on pyridazin-4(1H)-one. These compounds can interact with Tyr683 in the PDE10A selectivity pocket. Pyridazin-4(1H)-one derivative 1 was linked with a benzimidazole group through an alkyl spacer to interact with the OH of Tyr683 and fill the PDE10A selectivity pocket. After optimizing the linker length, we identified 1-(cyclopropylmethyl)-5-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (16f) as having highly potent PDE10A inhibitory activity (IC50=0.76nM) and perfect selectivity against other PDEs (>13,000-fold, IC50=>10,000nM). The crystal structure of 16f bound to PDE10A revealed that the benzimidazole moiety was located deep within the PDE10A selectivity pocket and interacted with Tyr683. Additionally, a bidentate interaction existed between the 5-alkoxypyridazin-4(1H)-one moiety and the conserved Gln716 present in all PDEs.

Liver regeneration after splenectomy in patients with liver cirrhosis.

AIM: Splenectomy is a well-known procedure to improve thrombocytopenia and liver function in patients with liver cirrhosis (LC). However, the effect of splenectomy on liver regeneration remains unclear. The aim of this study is to investigate the effect of splenectomy on liver regeneration. METHODS: Twenty patients with LC who underwent splenectomy were included in this study. Liver and splenic volumes were measured by a 3-D simulation imaging system. Liver volume (LV) and clinicopathological data were compared before and 6 months after splenectomy. Thereafter, patients were divided into two groups: the elevated LV group and the reduced LV group. Patient characteristics were compared between the two groups. RESULTS: Postoperative LV was increased in 14 patients compared with the preoperative state. Thrombocytopenia, leukopenia, total bilirubin and prothrombin time were improved after splenectomy. In the elevated LV group, four patients exhibited improved Child-Pugh grades after splenectomy, whereas no patients demonstrated improvement in the reduced LV group. The elevated LV group exhibited high albumin level, good indocyanine green retention rate at 15 min and large splenic volume compared with the same measurements in the decreased group. Patients with larger spleen volumes and higher albumin values before splenectomy showed increased rates of LV after splenectomy. CONCLUSION: Splenectomy for patients with LC improved pancytopenia and liver function. Especially, in patients with large spleen and high albumin levels, considerable increases in LV and improved liver function were observed.

[Surgical Outcome of Palliative Surgery for Gastric Cancer Patients with Bowel Obstruction Due to Peritoneal Dissemination].

A retrospective cohort analysis was performed for 21 consecutive patients who underwent palliative surgery for bowel obstruction due to peritoneal metastasis from gastric cancer. Surgical site infection occurred in 5 of 21 patients, but there were no severe(Clavien-Dindo Grade III or higher)complications, and symptoms of bowel obstruction were improved in 20 of 21 patients. The median survival time was 6.6 months. The survival rate was significantly worse for patients in modified Glasgow prognostic score(mGPS)group D compared with those in mGPS group non-D(p=0.0001). Surgery for malignant bowel obstruction was feasible and effective for palliation.

[Treatment Experience with Sorafenib for Lung Metastases of Hepatocellular Carcinoma Complicated with Interstitial Pneumonia].

A 74-year-old man was diagnosed with hepatocellular carcinoma(HCC; S4/8)and underwent anterior segment resection of the liver in 2015. He was hospitalized with a wound infection 2 months after surgery. On the 8th hospital day he complained of respiratory discomfort. A CT showed multiple lung metastases and a ground-glass appearance in both lungs. We diagnosed interstitial pneumonia with metastatic lung tumors. Steroid therapy was performed for the interstitial pneumo- nia(prednisolone 1,000mg/day×3 days), and sorafenib therapy was initiated for the metastatic lung cancer(starting from 200mg/day to 800mg/day). The prednisolone improved his symptoms. The lung metastatic tumors shrunk by the 36th hospital day after the CT. However, he developed difficulty in breathing again on the 58th hospital day, and again showed a ground-glass appearance in both lungs by CT. We thought it was drug-induced interstitial pneumonia and we discontinued oral sorafenib. He underwent steroid pulse therapy, but his symptoms did not improve and he died.

[Endoscopic Stent Placement to Alleviate Afferent Loop Syndrome Following Recurrence of Pancreatic Cancer].

We report a case of endoscopic stent placement to alleviate afferent loop syndrome following recurrence of pancreatic cancer. A 73-year-old man who had undergone pancreatic duodenectomy with portal vein resection for pancreatic cancer had developed a local recurrence and was treated with chemotherapy. He developed a high-grade fever and general fatigue, and laboratory data revealed anemia and a high inflammatory reaction; therefore, he was admitted to our hospital. CT scans revealed intestinal stenosis and upper dilatation, known as afferent loop syndrome, caused by the recurrence. We safely implanted a metallic stent(non-covered Niti-S stent, Century Medical, Inc.)at the point of intestinal stenosis using a double balloon endoscope. As the stent was adequately expanded and the afferent loop syndrome was relieved, the patient was discharged with a better quality of life and there were no complications associated with the stent until he died 6 months later.

[A Case of an Elderly Patient with Advanced Gastric Cancer Successfully Treated with Combination S-1 and Oxaliplatin Therapy].

The patient was an 80-year-old man. He had a chief complaint of epigastric pain. The upper gastrointestinal endoscopy showed a type 4 tumor of the stomach, and the CT scan showed multiple para-aortic lymph node metastases. The patient was diagnosed with cStage IV gastric cancer. At first, he could take only small amounts of liquid. After starting S-1 and oxaliplatin (SOX), he was able to resume a full diet and his general condition was improved. A CT scan after 4 courses of chemotherapy showed a significant reduction in the wall thickness of the stomach and the size of the lymph nodes. SOX chemotherapy could be a promising treatment option for elderly patients with advanced gastric cancer.

[A Case of Multiple Pancreatic Metastases from Renal Cell Carcinoma Diagnosed Using EUS-FNA].

The patient was a 79-year-old man, who underwent left nephrectomy for left renal cell carcinoma in 2007. In March 2015, he complained ofthirst, polydipsia, and polyuria. A slight elevation ofamylase levels was detected following laboratory testing. Abdominal CT revealed well-enhanced tumors in the pancreatic head and tail. MPD was dilated in the pancreatic body and tail. Endoscopic ultrasound-guided fine-needle aspiration(EUS-FNA)was used to obtain additional pathological findings. We diagnosed multiple pancreatic metastases from renal cell carcinoma using cell block sections from EUS-FNA ofthe pancreatic head tumor. We also identified worsening of diabetes control due to pancreatic disease. A subtotal stomachsparing pancreaticoduodenectomy and a distal pancreatectomy were performed in June 2015. Histological examination confirmed clear cell carcinoma metastases from RCC in both tumors. The patient remains alive without recurrence approximately 1 year after surgery. Glycemic control has improved with a decrease in insulin levels. Cell block sections from EUS-FNA are useful in the diagnosis of pancreatic disease. Although postoperative follow-up ofthe remnant pancreas is important, preservation ofthe pancreas should be considered for multiple pancreatic metastases when complete tumor removal is possible.

[Pathological Complete Response in a Case of Multiple Liver Metastases from Rectal Cancer Treated with XELOX plus Bevacizumab(Bev)Therapy].

The patient was a 56-year-old woman who had synchronous multiple liver metastases and underwent laparoscopic-assisted high anterior resection for rectal cancer. According to the Japanese classification of colorectal carcinoma(8th edition), the tumor was considered to be pStage IV (pT4bN2M1a[H3]). Following resection of the primary tumor, she received XELOX plus bevacizumab(Bev)therapy. After 5 courses, the tumors were markedly reduced in size. According to the RECIST criteria, the tumor response was determined to be a partial response(-44%). Therefore, on the basis of the morphologic response criteria, the patient had Group 1 disease. Because the chemotherapy seemed to be effective, we performed partial hepatectomies. Histologically, no cancer cells were detected in any of the resected tumors. After the partial hepatectomies, she received no additional chemotherapy. Her CEA levels decreased to a normal range and no tumor recurrence was detected over 2 and a half years. XELOX plus Bev therapy may be effective for unresectable multiple liver metastasis from rectal cancer.

Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor.

Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl)phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER)=6.2) despite the potent PDE10A inhibitory activity (IC50=0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER=1.4) and an excellent PDE10A inhibitory activity (IC50=0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3mg/kg by oral administration in mice.