Long-term effects of primary aldosteronism treatment on patients with primary aldosteronism and chronic kidney disease.

OBJECTIVE: Primary aldosteronism (PA) is a major cause of secondary hypertension and is associated with chronic renal injury. The glomerular filtration rate (GFR) in PA rapidly decreases after the removal of glomerular hyperfiltration due to aldosterone excess by adrenalectomy (ADX) or mineralocorticoid receptor antagonist (MRA) treatment and is stable in the long term. However, the effects of these treatments on the long-term renal function of PA patients with chronic kidney disease (CKD) is not well understood. DESIGN AND PATIENTS: In this single-center, retrospective study, acute and chronic changes in the estimated GFR (eGFR) were examined in 107 patients with PA, including 49 patients with post-treatment CKD　defined as eGFR < 60 ml/min/1.73 m2 . RESULTS: The reduction in eGFR observed 1 month after ADX in the CKD group (N = 31) was -20.1 ± 8.2 ml/min/1.73 m2 . Multivariate analysis showed that pre-treatment eGFR and plasma aldosterone concentration were independent predictive factors of the acute reduction in eGFR after ADX. The reduction of eGFR observed 1 month after MRA administration in the post-treatment CKD group (N = 18) was -9.2 ± 5.9 ml/min/1.73 m2 . Multivariate analysis showed that the duration of hypertension and pre-treatment eGFR were independent predictive factors of the acute reduction in eGFR after ADX administration. In 20 patients with CKD (N = 12 ADX and N = 8 MRA) followed for more than 5 years post-treatment, there was no further significant decline in eGFR over a follow-up period of 7 (6, 8) years nor any difference between the two treatment modalities. CONCLUSIONS: Our study suggests that treatment of PA in stage 3 CKD is safe and useful in preventing renal injury.

[Early Experience of Robot-assisted Mitral Valve Surgeries in Our Local Hospital].

We report the early experience of robot-assisted mitral valve repair in our local hospital. It took about two years from the application for the robot-assisted cardiac surgery until the first case of robot-assisted mitral repair. Since July 2020 to June 2022, we have performed 23 cases of robot-assisted mitral valve repair with da Vinci Xi system. There was no hospital death. The mean cross-clamp and total operation time were 118±22 and 295±41 min, respectively. Pre-discharge echocardiograms showed none-to-mild residual mitral regurgitation (MR) in all patients. The mean post-operative hospital stay was 7.6±5 days. Robot-assisted mitral valve repair could safely be started in our hospital. Early results were acceptable. Further experiences will be needed to confirm the efficacy of robotic mitral valve repair.

Genetic variation in the ATP binding cassette transporter ABCC10 is associated with neutropenia for docetaxel in Japanese lung cancer patients cohort.

BACKGROUND: Docetaxel is a widely used cytotoxic agent for treatments of various cancers. The ATP binding cassette (ABC) transporter / multidrug resistance protein (MRP) ABCC10/MRP7, involved in transporting taxanes, has been associated with resistance to these agents. Since genetic variation in drug transporters may affect clinical outcomes, we examined whether polymorphism of ABCC10 could affect clinical responses to docetaxel. METHODS: Using 18 NSCLC cell lines and CRISPR-based genome-edited HeLa cells, we analyzed whether genetic variants of ABCC10 (rs2125739, rs9349256) affected cytotoxicity to docetaxel. Subsequently, we analyzed genetic variants [ABCC10 (rs2125739), ABCB1 (C1236T, C3435T, G2677 T/A), ABCC2 (rs12762549), and SLCO1B3 (rs11045585)] in 69 blood samples of NSCLC patients treated with docetaxel monotherapy. Clinical outcomes were evaluated between genotype groups. RESULTS: In the cell lines, only one genetic variant (rs2125739) was significantly associated with docetaxel cytotoxicity, and this was confirmed in the genome-edited cell line. In the 69 NSCLC patients, there were no significant differences related to rs2125739 genotype in terms of RR, PFS, or OS. However, this SNP was associated with grade 3/4 neutropenia (T/C group 60% vs. T/T group 87%; P = 0.028). Furthermore, no patient with a T/C genotype experienced febrile neutropenia. CONCLUSIONS: Our results indicate that genetic variation in the ABCC10 gene is associated with neutropenia for docetaxel treatment.

[A Case of Rectus Sheath Hematoma Presenting Immediately after a Lumboperitoneal Shunt and Requiring Emergency Surgery:Importance of Abdominal Anatomy Knowledge].

As the incidence of idiopathic normal-pressure hydrocephalus (iNPH) rises in an aging society, the number of cerebrospinal fluid (CSF) shunts performed increases every year. The morbidity of iNPH in patients>65 years of age has been reported as 1.4%-2.9% in Japan. CSF shunts are rarely associated with mortality and are generally safe to perform, but subcutaneous hematomas and intestinal injuries are the major potential complications of the abdominal surgery for CSF shunts. In this report, we describe an uncommon case of rectus sheath hematoma (RSH) that occurred immediately after a lumboperitoneal shunt and required emergency surgery. RSHs have a reported mortality rate of 4% and require appropriate treatment. Many neurosurgeons rarely have in-depth knowledge of abdominal anatomy. To safely perform CSF shunting, we underscore the importance of precise knowledge of the abdominal anatomy, especially the features of blood vessels.

A Case of Thrombectomy for Loeffler's Endocarditis.

Loeffler's endocarditis, characterized by eosinophilic infiltration leading to thrombus formation and fibrosis in the ventricle, is associated with severe complications, such as embolism and heart failure. While anticoagulation and steroids are standard treatments, surgical thrombectomy is rarely reported. This is a case report of a 74-year-old man presented with an abnormal electrocardiogram. Echocardiography revealed a 38 × 29 mm mass in the left ventricular apex, and blood studies revealed hypereosinophilia, leading to a diagnosis of Loeffler's endocarditis. Despite warfarin treatment, the thrombus persisted. The left ventricular intracardiac thrombus exhibited significant mobility, and we decided to perform a thrombectomy via a trans-left ventricular approach. After the surgery, steroid therapy was initiated. The patient recovered without recurrence of the thrombus or deterioration in cardiac function. Left ventricular thrombectomy for Loeffler's endocarditis is considered a beneficial option to prevent thrombosis.

Gas Gangrene of the Spleen Caused by Clostridium perfringens After Mild Blunt Trauma.

Splenic gas gangrene caused by Clostridium perfringens is rare. A 73-year-old woman was referred to our hospital because of fatigue, dyspnea, and left hypochondrial pain. She had a history of blunt trauma to the left abdomen eight days ago. She presented with hypoxemia and a high inflammatory response on blood tests. A CT showed left pleural effusion and gas in the spleen. She was treated with antimicrobials and underwent splenectomy. C. perfringens was identified from blood and intraoperative ascites cultures. She recovered and was discharged on day 34 of hospitalization. As C. perfringens is part of the normal gut microbiota and can translocate to other parts of the body, this bacterium should be considered a splenic abscess pathogen when an intracorporeal anaerobic environment is suspected.

Single-Nucleus Analysis Reveals Tumor Heterogeneity of Aldosterone-Producing Adenoma.

BACKGROUND: Recent advances in omics techniques have allowed detailed genetic characterization of aldosterone-producing adenoma (APA). The pathogenesis of APA is characterized by tumorigenesis-associated aldosterone synthesis. The pathophysiological intricacies of APAs have not yet been elucidated at the level of individual cells. Therefore, a single-cell level analysis is speculated to be valuable in studying the differentiation process of APA. METHODS: We conducted single-nucleus RNA sequencing of APAs with KCNJ5 mutation and nonfunctional adenomas obtained from 3 and 2 patients, respectively. RESULTS: The single-nucleus RNA sequencing revealed the intratumoral heterogeneity of APA and identified cell populations consisting of a shared cluster of nonfunctional adenoma and APA. In addition, we extracted 2 cell fates in APA and obtained a cell population specialized in aldosterone synthesis. Genes related to ribosomes and neurodegenerative diseases were upregulated in 1 of these fates, whereas those related to the regulation of glycolysis were upregulated in the other fate. Furthermore, the total RNA reads in the nucleus were higher in hormonally activated clusters, indicating a marked activation of transcription per cell. CONCLUSIONS: The single-nucleus RNA sequencing revealed intratumoral heterogeneity of APA with KCNJ5 mutation. The observation of 2 cell fates in KCNJ5-mutated APAs provides the postulation that a heterogeneous process of cellular differentiation was implicated in the pathophysiological mechanisms underlying APA tumors.

Electron Spin Resonance (ESR) Dating of Calcareous Fault Gouge of the Ushikubi Fault, Central Japan.

The ages of fault events of active faults have been estimated using electron spin resonance (ESR) signals of siliceous gouges. This technique of ESR method is limited by obtaining only ages that are greater than tens of millennia. So this study focuses on developing a new technique of using calcareous gouges to gain an insight into the ages of latest seismogenic event within the Holocene. For the first time, signal B of the ESR method has been used to estimate the age of the Ushikubi fault from calcareous gouge. This technique proved reliable because the mean age (1.9 ka) obtained agrees with previous works on indirect age determination of latest fault events by utilizing radiocarbon dating in the study area. However, the result from the ESR technique showed an increase relative to the age of 1 ka that was obtained by the radiocarbon dating method. This disparity may be due to a high dose rate value of 50 Gy/h of artificial irradiation that was used to determine the equivalent dose (ED). Moreover, isochronal experiment revealed that the gouge did not comprise pure carbonates but consisted of a mixture of calcite and quartz grains. A younger age value would have been obtained if a lower artificial irradiation dose rate and a relatively pure carbonate fault gouge were used in the ED determination.

Increased serum extracellular vesicle miR-144-3p and miR-486a-3p in a mouse model of adipose tissue regeneration promote hepatocyte proliferation by targeting Txnip.

Adipose-derived stem cells are expected to be applied to regenerative medicine for various incurable diseases including liver cirrhosis. Although microRNAs contained in extracellular vesicles (EV-miRNAs) have been implicated in their regenerative effects, the precise mechanism has not been fully elucidated. Tamoxifen-inducible adipocyte-specific insulin receptor knockout (iFIRKO) mice are known to exhibit acute adipose tissue regeneration with increased numbers of adipose stem and progenitor cells (ASPCs). Because adipose tissue is the major source of circulating EV-miRNAs, we investigated alterations in serum EV-miRNAs in iFIRKO mice. A comprehensive analysis using miRNA sequencing on serum EVs revealed that most EV-miRNAs were decreased due to the loss of mature adipocytes, but there were 19 EV-miRNAs that were increased in the serum of iFIRKO mice. Among them, miR-144-3p and miR-486a-3p were found to be increased in the liver as well as serum EVs. While the expression levels of pri-miR-144-3p and pri-miR-486a-3p were not increased in the liver, they were elevated in the adipose tissue, suggesting that these miRNAs may be delivered from ASPCs increased in the adipose tissue to the liver via EVs. Increased hepatocyte proliferation was observed in the liver of iFIRKO mice, and we found that both miR-144-3p and miR-486a-3p have a function to promote hepatocyte proliferation by suppressing Txnip expression as a target gene. miR-144-3p and miR-486a-3p can be candidate therapeutic tools for conditions requiring hepatocyte proliferation, such as liver cirrhosis, and our current study suggests that examining EV-miRNAs secreted in vivo may lead to the discovery of miRNAs involved in regenerative medicine that have not been identified by in vitro analysis.

[Successful chemotherapy with a docetaxel regimen for primary signet-ring cell carcinoma of the urinary bladder-a case report].

Primary signet-ring cell carcinoma of the bladder is rare and has a poor prognosis. In addition, there are few successful chemotherapies for it. We report a case of chemotherapy with a docetaxel regimen which was efficacious in a 64-year-old Japanese man suffering from the disease. The onset of bilateral hydronephrosis led to the detection of his bladder tumor, and its pathological diagnosis was signet-ring cell carcinoma(immunohistochemistry showed cytokeratin 7+/20±). He was treated with chemotherapy rather than with surgery because the tumor invaded the abdominal wall and groin. To treat his disease, we performed 2 courses of a chemotherapy regimen comprised of S-1 and cisplatin, but it was not efficacious. We chose docetaxel as a second-line chemotherapy regimen,(60mg/m2, tri-weekly), and a clinical examination including contrast-enhanced CT showed that his disease had successfully responded to the chemotherapy.

Early and Midterm Outcomes of "No-Touch" Saphenous Vein Grafts in Japanese Institutions.

INTRODUCTION: There have been several attempts to overcome the poor graft patency of saphenous vein grafts. "No-touch" saphenous vein graft (NT-SVG) could be a solution to improve graft patency. We aimed to investigate the early and midterm outcomes of coronary artery bypass grafting (CABG) using NT-SVGs in our hospitals. METHODS: This is a retrospective study of 105 patients who underwent CABG using 130 NT-SVGs between August 2013 and December 2021. NT-SVGs were harvested with about a 5-mm margin of surrounding tissue on both sides of the vein with minimal manipulation. Then, the NT-SVG was dilated by natural arterial pressure without manual distension. After surgery, most of NT-SVGs were assessed by cardiac catheterization or multidetector computed tomography (MDCT) to determine early graft patency. Late graft assessments by MDCT were performed about every five years after surgery. RESULTS: The early graft patency of NT-SVGs was 100% (125/125); however, two cases of graft twisting were found. Both cases spontaneously resolved. Leg wound infections of NT-SVG harvesting site were seen in 6.2% of patients. Peripheral neuropathy of the legs such as skin numbness and tingling were frequently observed, which lasted up to one year, but no more than two years after surgery. The midterm graft patency of NT-SVGs was excellent (five-year patency of NT-SVGs was 95.8%). CONCLUSION: The early and midterm graft patency of NT-SVGs was satisfactory. Although leg wound complications can be seen on the harvesting NT-SVG site, the "no-touch" harvesting technique of SVG could improve graft patency and clinical outcomes of CABG.

Heterogeneous circulating miRNA profiles of PBMAH.

Objective: Primary bilateral macronodular adrenal hyperplasia (PBMAH), a rare cause of Cushing syndrome, is often diagnosed as a bilateral adrenal incidentaloma with subclinical cortisol production. Circulating microRNAs (miRNAs) are a characteristic of adrenocortical adenomas, but miRNA expression in PBMAH has not been investigated. We aimed to evaluate the circulating miRNA expression in patients with PBMAH and compare them with those in patients with non-functioning adrenocortical adenoma (NFA) and cortisol-producing adrenocortical adenoma (CPA). Methods: miRNA profiling of plasma samples from four, five, and five patients with NFA, CPA, and PBMAH, respectively, was performed. Selected miRNA expressions were validated using quantitative RT-PCR. Results: PBMAH samples showed distinct miRNA expression signatures on hierarchical clustering while NFA and CPA samples were separately clustered. PBMAH was distinguished from the adenoma group of NFA and CPA by 135 differentially expressed miRNAs. Hsa-miR-1180-3p, hsa-miR-4732-5p, and hsa-let-7b-5p were differentially expressed between PBMAH and adenoma (P = 0.019, 0.006, and 0.003, respectively). Furthermore, PBMAH could be classified into two subtypes based on miRNA profiling: subtype 1 with a similar profile to those of adenoma and subtype 2 with a distinct profile. Hsa-miR-631, hsa-miR-513b-5p, hsa-miR-6805-5p, and hsa-miR-548av-5p/548k were differentially expressed between PBMAH subtype 2 and adenoma (P = 0.027, 0.027, 0.027, and 1.53E-04, respectively), but not between PBMAH, as a whole, and adenoma. Conclusion: Circulating miRNA signature was identified specific for PBMAH. The existence of subtype-based miRNA profiles may be associated with the pathophysiological heterogeneity of PBMAH.

New possibilities for egg white lysozyme: heat-denatured lysozyme partially inactivates select foot-and-mouth disease virus strains.

Foot-and-mouth disease (FMD) is one of the most contagious diseases of cloven-hoofed animals. Disinfectants are used to inactivate FMD virus (FMDV) in Japan. Reports that heat-denatured lysozyme inactivates bacteria as well as viruses, such as norovirus and hepatitis A virus, led us to determine its effects on FMDV. We show here that heat-denatured lysozyme partially inhibited the infectivity of FMDV O/JPN/2010-1/14C but of FMDVs A/TAI/46-1/2015 and Asia1/Shamir (ISR/3/89). Further, heat-denatured lysozyme variably reduced RNA loads of FMDVs O/JPN/2010-1/14C, O/MOG/2/Ca/BU/2017, O/Taiwan/1997, Asia1/Shamir (ISR/3/89), Asia1/TUR/49/2011, SAT1/KEN/117/2009, SAT2/SAU/6/2000 and SAT3/ZIM/3/83 but could not those of O/JPN/2000, A/TAI/46-1/2015, A22/IRQ/24/64, A15/TAI/1/60 and C/PHI/7/84. These findings indicate that heat-denatured lysozyme may serve as a new disinfectant against FMDV.

Silicon nanorod formation from powder feedstock through co-condensation in plasma flash evaporation and its feasibility for lithium-ion batteries.

Si nanowires/nanorods are known to enhance the cycle performance of the lithium-ion batteries. However, viable high throughput production of Si nanomaterials has not yet attained as it requires in general expensive gas source and low-rate and multiple-step approach. As one of the potential approaches, in this work, we report the fast-rate Si nanorod synthesis from low-cost powder source by the modified plasma flash evaporation and the fundamental principle of structural formation during gas co-condensation. In this process, while Si vapors are formed in high temperature plasma jet, molten copper droplets are produced separately at the low temperature region as catalysts for growth of silicon nanorods. Si rods with several micrometers long and a few hundred of nanometers in diameter were produced in a single process at rates up to 40 µm s-1. The growth of the Si nanorods from powder source is primarily characterized by the vapor-liquid-solid growth which is accelerated by the heat extraction at the growth point. The battery cells with the Si nanorods as the anode have shown that a higher capacity and better cyclability is achieved for the nanorods with higher aspect ratios.

Variants of SLC22A16 Predict the Efficacy of Platinum Combination Chemotherapy in Advanced Non-small-cell Lung Cancer.

BACKGROUND: Organic cation transporter 6 (OCT6) encoded by solute carrier family 22 member 16 (SLC22A16) is involved in regulating cellular sensitivity and resistance to platinum derivatives. SLC22A16 has functional genetic variants but the association between these variants and the effectiveness of antitumor drugs remains unexplored. PATIENTS AND METHODS: This study retrospectively analyzed data from 160 patients with advanced non-small cell lung cancer treated with platinum-based combination chemotherapy for first-line chemotherapy between October 2010 and May 2018. We investigated the association between the genetic variant of SLC22A16 and clinical outcomes. RESULTS: Patients with the rs714368 GG genotype had a shorter progression-free survival than those with AA or AG. Gene polymorphism was not associated with adverse effects. The predictive effect of rs714368 was confirmed in multivariate analysis using a Cox proportional hazards model. CONCLUSION: A genetic variant of SLC22A16 is a potential predictive biomarker for response to platinum-based chemotherapy for non-small cell lung cancer.

Beating Thermal Coarsening in Nanoporous Materials via High-Entropy Design.

Controlling the feature sizes of 3D bicontinuous nanoporous (3DNP) materials is essential for their advanced applications in catalysis, sensing, energy systems, etc., requiring high specific surface area. However, the intrinsic coarsening of nanoporous materials naturally reduces their surface energy leading to the deterioration of physical properties over time, even at ambient temperatures. A novel 3DNP material beating the universal relationship of thermal coarsening is reported via high-entropy alloy (HEA) design. In newly developed TiVNbMoTa 3DNP HEAs, the nanoporous structure is constructed by very fine nanoscale ligaments of a solid-solution phase due to enhanced phase stability by maximizing the configuration entropy and suppressed surface diffusion. The smallest size of 3DNP HEA synthesized at 873 K is about 10 nm, which is one order of magnitude smaller than that of conventional porous materials. More importantly, the yield strength of ligament in 3DNP HEA approaches its theoretical strength of G/2π of the corresponding HEA alloy even after thermal exposure. This finding signifies the key benefit of high-entropy design in nanoporous materials-exceptional stability of size-related physical properties. This high-entropy strategy should thus open new opportunities for developing ultrastable nanomaterials against its environment.

Nestin Expression Affects Resistance to Chemotherapy and Clinical Outcome in Small Cell Lung Cancer.

Objectives: Small cell lung cancer (SCLC) is an aggressive and highly metastatic lung cancer subtype. Nestin is a member of the intermediate filament family and serves as a potential proliferative and multipotency marker in neural progenitor and stem cells. Aberrant expression of nestin is linked to poor prognosis in different cancers, including non-small cell lung cancer. However, the association between nestin expression and clinicopathological feature or prognosis has remained unclear for SCLC. This study examined whether nestin expression was associated with malignant features and clinical outcomes in SCLC. Materials and Methods: Using previously established Nestin knock-down cells and a newly established Nestin-overexpressing cell line, we examined the relationship between nestin expression and cell proliferation in vitro and in vivo and chemosensitivity. We also analyzed nestin expression in three drug-resistant lung cancer cell lines. Furthermore, we examined samples from 84 SCLC patients (16 patients with surgical resection, and 68 patients with biopsy), and immunohistochemically analyzed nestin expression. Results: Nestin expression correlated positively with cell proliferation, but negatively with chemosensitivity. Nestin expression in drug-resistant cell lines was upregulated compared to their parental cells. Among the 84 SCLC patients, 24 patients (28.6%) showed nestin-positive tumor. Nestin-positive ratio tended to be higher in operated patients than in biopsied patients. Nestin-positive and -negative patients showed no significant differences in response rate (RR) or progression-free survival (PFS) following first-line chemotherapy. However, positive expression of nestin was associated with shorter PFS following second-line chemotherapy (median PFS: nestin-positive, 81 days vs. nestin-negative, 117 days; P = 0.029). Conclusions: Nestin expression may be associated with malignant phenotype and worse outcome in SCLC patients.

Value of TTF-1 expression in non-squamous non-small-cell lung cancer for assessing docetaxel monotherapy after chemotherapy failure.

Docetaxel is one of the standard second/third-line treatments for non-small-cell lung cancer (NSCLC) following a failed response to prior cytotoxic chemotherapy. The predictive biomarker for the effectiveness of docetaxel therapy remains undetermined. However, thyroid transcription factor-1 (TTF-1) is known to be a good prognostic factor for a variety of chemotherapies. To investigate the association between TTF-1 expression and docetaxel monotherapy outcome, 82 patients with non-squamous NSCLC who received second/third-line docetaxel monotherapy were retrospectively screened. All backgrounds were well-balanced whether or not tumor TTF-1 was expressed, and the present clinical outcomes were similar to those reported by previous clinical studies. A better clinical outcome was indicated in TTF-1 positive compared with TTF-1 negative patients, with disease control rates of 69% vs. 42%, respectively (P=0.03) and median overall survival of 393 days vs. 221.5 days, respectively (P<0.01). Furthermore, progression free survival tended to be longer in TTF-1 positive compared with TTF-1 negative patients (median, 100 days vs. 67 days; P=0.09). Multivariate analysis revealed that TTF-1 positivity was a unique significant predictor for assessing overall survival after docetaxel monotherapy. TTF-1 positivity may be useful for predicting survival outcome in patients who received docetaxel monotherapy after failure of prior chemotherapy.

ABCC11 gene polymorphism as a potential predictive biomarker for an oral 5-fluorouracil derivative drug S-1 treatment in non-small cell lung cancer.

PURPOSE: ABCC11/MRP8 (ABCC11) is an ATP-binding cassette transporter that is involved in regulating cellular sensitivity and resistance for many anti-cancer drugs. Since 5-fluorouracil (5-FU) is one of the substrates for ABCC11, we examined whether ABCC11 is a predictive marker for an oral 5-FU derivative drug S-1 treatment in non-small cell lung cancer (NSCLC). METHODS: Real-time PCR and MTS assay were carried on 21 human NSCLC cell lines. The drug resistance capabilities of ABCC11 are evaluated by analyzing the resistance profiles of a clone of HeLa cell in which the pump was ectopically expressed. Blood samples of 106 NSCLC patients were collected. RESULTS: There was a significant correlation between dihydropyrimidine dehydrogenase (DPD) gene expression and the IC50 for 5-FU. We then classified NSCLC cell lines into two groups based on the phenotype of the SNP538 (G > A) in ABCC11: a combined G/G and G/A group, and an A/A group. The distribution of the IC50 for 5-FU in combination with a potent inhibitor of DPD 5-chloro-2, 4-dihydropyrimidine (CDHP), which is contained in S-1, showed a significant reduction in the A/A group compared with the combined G/G and G/A group. Next, the clinical usefulness of the ABCC11 SNP in treatment containing S-1 was examined in 106 NSCLC patients, and the disease control rate was found to be significantly better in the A/A group than in the combined G/G and G/A group. CONCLUSIONS: These results indicate that the SNP538(G > A) in the ABCC11 gene is a potential determinant for S-1 treatment.