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Xuemei He,1 Kazuya Narushima,2 Masahiro Kojima,2 Chisato Nagai,2 Kexin Li1 1Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Key Laboratory of Assessment of Clinical Drugs Risk and Individual Application, Beijing, People’s Republic of China; 2Research & Development Division, Kyowa Kirin Co., Ltd, Tokyo, JapanCorrespondence: Kexin Li, Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Key Laboratory of Assessment of Clinical Drugs Risk and Individual Application, Beijing, People’s Republic of China, Email kexinli6202@163.comPurpose: This study explored the pharmacokinetics (PK), pharmacodynamics (PD), and safety of evocalcet (KHK7580), a new calcimimetic agent, in healthy Chinese subjects following single and multiple doses.Methods: This was a single-center, open-label phase I trial conducted in China. The study started from the single-dose cohorts (1, 3, 6, 12 mg evocalcet, step-by-step administration) and proceeded to the multiple-dose cohort (6 mg evocalcet once daily for eight days). Blood and urine samples were collected at the designated time points for pharmacokinetic and pharmacodynamic analysis. Safety was evaluated by treatment-emergent adverse events (TEAEs), clinical laboratory tests, vital signs, electrocardiograms (ECGs), and ophthalmological examination.Results: Among 42 enrolled subjects, eight in each single-dose cohort and 10 in multiple-dose cohort, 40 subjects completed the study. In single-dose cohorts, tmax was 1.00– 2.00 h and declined biphasically. The mean t1/2 was 15.99– 20.84 h. Evocalcet exposure in AUC0-inf, AUC0-t, and Cmax showed a dose-proportional increase. In the multiple-dose cohort, tmax was 2.00 h and declined biphasically after multiple administrations. The accumulation was negligible. Ctrough levels were similar across days and steady from 24 hours after the first administration. The mean t1/2 was 15.59 h. PD analysis showed that evocalcet decreased intact parathyroid hormone and corrected calcium levels in a dose-dependent manner. Seventeen (40.5%) subjects reported TEAEs. No serious or severe TEAE occurred.Conclusion: In healthy Chinese subjects, evocalcet demonstrated dose-dependent PK and PD properties and was well-tolerated.Keywords: evocalcet, calcimimetic agents, secondary hypoparathyroidism, pharmacokinetic, pharmacodynamic, safety

Abstract: Amorphous carbon (AC) sheet surfaces were modified with ammonia (NH3) plasma in order to form primary amino groups on AC surfaces. The NH3 plasma modification formed both nitrogen- and oxygen-containing groups on the AC sheet surfaces, and the contact angle of water against the modified AC surfaces decreased from 76° to 64°–56°. The formation of primary amino groups preferred NH3 plasma operated at a low rf power (5–10W) to that at a high power. The concentration of primary amino groups was strongly influenced by how much rf power the NH3 plasma was operated. The NH3 plasma operated at 10W was a preferable condition for the formation of primary amino groups on the AC sheet surfaces, and their concentration was 1.3–1.4 N(amino)-atoms/100 C-atoms. [Copyright &y& Elsevier]

A scoring system to discriminate between uncomplicated and complicated appendicitis is beneficial to determine the optimal treatment for acute appendicitis. We developed a scoring system to discriminate between uncomplicated and complicated appendicitis and assessed the clinical usefulness of the scoring system using external validation. A total of 299 patients with acute appendicitis were retrospectively reviewed. One hundred and ninety-nine patients were assigned to the model development group, while the other 100 patients were assigned to an external validation group. A scoring system for complicated appendicitis was created using a final multivariate logistic regression model with six independent predictors. The area under the receiver operating characteristic curve of the scoring system was 0.882 (95% confidence interval: 0.835-0.929). The cutoff point of the scoring system was 12, and the sensitivity and specificity were 82.9% and 86.2%, respectively. In the external validation group, the area under the receiver operating characteristic curve of the scoring system was 0.868 (95% confidence interval 0.794-0.942), and there was no significant difference between the groups in the area under the receiver operating characteristic curve (P = 0.750). Our newly developed scoring system may contribute to prompt determination of the optimal treatment for acute appendicitis., (© 2024. The Author(s).)

There is no preoperative imaging accurately diagnose malignancy of gastrointestinal stromal tumor (GIST). To evaluate the usefulness of preoperative [ 18 F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in the malignant diagnosis and prognostic analysis of GIST. Eighty-nine consecutive patients with GIST who underwent curative surgery were reviewed retrospectively. PET scan was performed within 2-3 weeks before surgery and maximum standardized uptake values (SUVmax) were assessed for GIST. The relationship between prognostic factors and prognosis of GIST and SUVmax were evaluated. Tumor size, mitotic count, and Ki-67 index showed significant positive correlations with the SUVmax. When the cutoff value was set as SUVmax 5.68, the accuracy was 86.5% for the high-risk group, 76.4% for the recurrence group, and 73.0% for the death group. The group with SUVmax ≥ 5.68 demonstrated a significantly lower 10-year relapse-free survival than the group with SUVmax < 5.68 (55.2% vs. 98.2%, P < 0.001), while the group with SUVmax ≥ 5.68 demonstrated a significantly lower 10-year overall survival than the group with SUVmax < 5.68 (68.0% vs. 97.6%, P < 0.001). In GISTs, FDG-PET is a very useful imaging marker for the diagnosis of malignant GISTs, such as those in high-risk and poor-prognosis groups., (© 2023. The Author(s).)

The selective phosphatidylinositol 3-kinase δ inhibitor zandelisib demonstrated favorable safety and efficacy [objective response rate (ORR) 79%] in patients with B-cell malignancies in a phase 1b study in the US and Switzerland. In this phase 1 dose-escalation study (NCT03985189), 9 Japanese patients with relapsed/refractory indolent non-Hodgkin's lymphoma (R/R iNHL) received zandelisib on a continuous daily schedule (45 or 60 mg) until progressive disease/unacceptable toxicity. No dose-limiting toxicities were observed. The maximum tolerated dose was not reached. At a median follow-up of 17.5 months, Grade ≥ 3 treatment-emergent adverse events that occurred in 2 or more patients were neutrophil count decreased (55.6%; 5/9) and diarrhea (33.3%; 3/9). Immune-related toxicities, including hepatobiliary disorder, aspartate/alanine aminotransferase increased, diarrhea/colitis, organizing pneumonia, stomatitis, and rash, led to zandelisib discontinuation in 4 patients. The investigator-assessed ORR, based on modified Lugano criteria, was 100%, including 2 complete responses (22.2%; in follicular lymphoma patients receiving 60 mg/day). Median duration of response, progression-free survival, and time to response were 7.9, 11.1, and 1.9 months, respectively. Zandelisib demonstrated a manageable safety profile at 60 mg, the recommended phase 2 dose (RP2D) in Japanese patients. The RP2D resulted in favorable pharmacokinetics and anti-tumor efficacy in Japanese patients with R/R iNHL.Trial registration. NCT03985189 (ClinicalTrials.gov)., (© 2022. The Author(s).)

Background and Purpose: The right colic artery(RCA)and gastrocolic trunk(GCT)traverse around the pancreas and duodenum and branch divergently, thus, complicating right-sided colon cancer surgery. The usefulness of pancreatic/duodenum 3DCT imaging(pancreas/duodenum CT: PDCT)for laparoscopic right-sided colon cancer surgery was investigated., Patient and Method: The patient was a woman, in her 80's with 2 sites of ascending colon cancer:(1)A-C, cT4b(retroperitoneum) N2aM0, Stage Ⅲc;(2)A, cT3N1bM0, Stage Ⅲb. A radical surgery was planned. Contrast-enhanced CT colonography( CTC)was performed preoperatively, and 3 3DCT images(CTC, arteriovenous 3DCT, and PDCT)were created using Workstation: Ziostation 2®(Ziosoft). These 3DCT images were combined and used for preoperative simulation and intraoperative navigation., Result: Composite images of CTC and arterial 3DCT identified the dominance of ileocolic artery(ICA)and RCA. In addition, a composite venous 3DCT image confirmed the branching and course of ileocolic vein(ICV)and right colic vein(RCV). Composite images of PDCT and arteriovenous 3DCT showed that the RCA branched from the superior mesenteric artery at the level of the third part of duodenum and ran ventral to the pancreatic head, while the RCV branched from the GCT in front of the pancreatic head, with the right gastroepiploic vein(RGEV). A laparoscopic combined ileal and retroperitoneal resection and D3 lymph node dissection with ICA/V and RCA/V root dissection were planned. Surgical simulation facilitated the identification of ICA/V and RCA/V and surgical procedure. The operative time was 310 minutes, and blood loss was 90 mL. Histopathological examination confirmed the diagnosis of(1)pT3(SS)N1bM0, Stage Ⅲb and(2)pT3 (SS)N1aM0, Stage Ⅲb. The patient was discharged 10 days post-surgery, without any complications. Currently, there is no apparent recurrence at 1-year follow-up., Conclusion: PDCT clarified the location of the RCA and GCT in relation to the pancreas and duodenum and complemented the laparoscopic right-sided colon cancer surgery.

This study aimed to evaluate the uptake of the clinical effectiveness of [S-methyl- 11 C]-L-methionine positron emission tomography/computed tomography (MET PET/CT) in patients with esophageal cancer and to investigate MET PET/CT imaging parameters to assess early response for esophageal cancer with neoadjuvant carbon ion radiotherapy (CIRT). MET PET/CT scans were performed in nineteen patients before and 3 weeks after completion of CIRT. After Surgery, the effect of neoadjuvant CIRT was investigated by examining the relationship between each parameter of MET uptake and the histological assessment (grade and tumor residual ratio). Four parameters of MET uptake were the maximum and minimum standardized uptake values of pre and post CIRT (pre-SUVmax, pre-SUVmean, post-SUVmax, and post-SUVmean). MET PET/CT imaging of esophageal cancer was clearly demonstrated. The post-SUVmax was the most suitable parameter. When the cutoff value was set as post-SUVmax = 6.21, the sensitivity, the specificity, and the accuracy of Grades 3 were 100.0%, 63.6%, and 78.9%, respectively. And there was a positive relationship between the tumor residual ratio and post-SUVmax (R 2  = 0.38, p < 0.005). MET PET/CT is clinically useful for the assessment of early response to neoadjuvant CIRT in esophageal cancer. Particularly, post-SUVmax is considered a promising PET imaging parameter., (© 2022. The Author(s).)

Background: Several studies have assessed various clinical variables to identify risk factors for postoperative complications in patients with acute appendicitis. However, few studies have focused on the relationships between systemic inflammatory variables and postoperative complications in patients with acute appendicitis. We investigated the relationships between postoperative complications and systemic inflammatory variables, and assessed the clinical utility of these variables as predictors of postoperative complications in patients with acute appendicitis., Methods: We retrospectively reviewed 181 patients who underwent immediate appendectomy for acute appendicitis. All postoperative complications were classified as infectious or noninfectious, and we evaluated the relationships between postoperative complications and clinical factors including the preoperative neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio., Results: In total, 28 patients (15.5%) had postoperative Clavien-Dindo grade II-IV complications; 17 patients (9.4%) and 11 patients (6.1%) were categorized as the infectious and noninfectious complication groups, respectively. The cutoff value of the preoperative neutrophil-to-lymphocyte ratio for all complications was 11.3, and multivariate analysis revealed that the preoperative neutrophil-to-lymphocyte ratio was an independent predictor of any postoperative complication (odds ratio: 4.223, 95% confidence interval: 1.335-13.352; P = 0.014). The cutoff value of the preoperative neutrophil-to-lymphocyte ratio for infectious complications was 11.4, and multivariate analysis revealed that the preoperative neutrophil-to-lymphocyte ratio was an independent predictor of infectious complications (odds ratio: 4.235, 95% confidence interval: 1.137-15.776; P = 0.031)., Conclusions: In patients with acute appendicitis, the preoperative neutrophil-to-lymphocyte ratio may be a useful predictor of all postoperative complications, especially infectious complications., (© 2022. The Author(s).)

NaPi2b is primarily expressed in the small intestine, lungs, and testes and plays an important role in phosphate homeostasis. The inhibition of NaPi2b, responsible for intestinal phosphate absorption, is considered to reduce serum phosphate levels, making it a promising therapeutic approach for hyperphosphatemia. Using a novel phosphate uptake inhibitor 3 (IC 50 = 87 nM), identified from an in-house compound collection in human NaPi2b-transfected cells as a prototype compound, we conducted its derivatization based on a Ro5-deviated strategy to develop orally administrable small-molecule NaPi2b inhibitors with nonsystemic exposure. Consequently, compound 15 , a zwitterionic compound with a potent in vitro phosphate uptake inhibitory activity (IC 50 = 64 nM) and a low membrane permeability (Pe < 0.025 × 10 -6 cm/s), was developed. Compound 15 showed a low bioavailability ( F = 0.1%) in rats and a reduction in phosphate absorption in the rat intestinal loop assay comparable to sevelamer hydrochloride, a clinically effective phosphate binder for treating hyperphosphatemia.

Background and Purpose: Stoma site marking is performed by inspection and palpation of the body surface. In stoma site, it is estimated that transverse colon is epigastric lesion and sigmoid colon is left hypogastric lesion. We try making colostomy simulation(Cs)3D-CT by which stoma site marking is able to be performed considering exact form of colon., Patient and Method: The patient was 50s man with advanced rectal cancer and unresectable multiple liver metastases. Colonostomy was scheduled for strong rectal stenosis. Standard contrast-enhanced CT scan was performed before operation, and 3D-CT imaging was maked using Workstation Ziostation2(ziosoft, Tokyo, Japan). 3D-CT imaging of abdominal wall was maked by synthesizing 3D-CT imaging of body surface and rectus abdominis muscle. Cs3D-CT is maked by synthesizing CT colonography and 3D-CT imaging of abdominal wall., Result: The simulation of stoma site marking was performed using Cs3D-CT. Inferior epigastric artery(IEA)was identified, it was to simulate elevated colons and the stoma sites to enable easy elevation of colon through rectus abdominis muscle avoiding injury of IEA. It was possible to measure the distance from navel to stoma site marking on 3D-CT imaging, final stoma site marking was decided by applying the simulation to real stoma site marking. The difficulty of operation was assessed from positional relationship between colon and abdominal wall. It seemed to be relatively easy to elevate sigmoid colon because sigmoid colon was directly under the rectus abdominis muscle. Sigmoidostomy was scheduled considering rectal cancer, and trephine sigmoidostomy with double orifices was performed in fact., Conclusion: Cs3D-CT was possible to simulate colostomy considering the exact form of colon and positional relationship to abdominal wall and to perform stoma site marking considering the exact form of rectus abdominis muscle and position of IEA. Using Cs3D-CT, it seems to be able to perform optimal stoma site marking which is difficult by conventional method.

Background: Several studies have demonstrated that diverse systemic inflammatory-based prognostic parameters predict a poor prognosis in patients with gastric cancer. However, few studies have focused on the relationships between postoperative complications and systemic inflammatory-based prognostic parameters after curative gastrectomy. We investigated the relationships between postoperative complications and these parameters and assessed the clinical utility of the parameters as predictors of postoperative complications in patients with stage I-III gastric cancer., Methods: We retrospectively reviewed 300 patients who underwent curative gastrectomy for stage I-III gastric cancer. All postoperative complications were classified as infectious or noninfectious. We evaluated the relationships between postoperative complications and clinical factors, including systemic inflammatory-based prognostic parameters., Results: In total, 101 patients (33.7%) had postoperative Clavien-Dindo grade II-IV complications, and 54 (18.0%) patients developed infectious complications including pancreatic fistula, pneumonia, anastomotic leak, intra-abdominal abscess, and cholecystitis. The relationships between postoperative complications and systemic inflammatory-based prognostic parameters were evaluated by the areas under the receiver operating characteristic curves. Postoperative pneumonia was identified as the most sensitive complication to the systemic inflammatory-based prognostic parameters. Multivariate analysis revealed that preoperative neutrophil-to-lymphocyte ratio (odds ratio, 14.621; 95% confidence interval, 1.160-184.348; p = 0.038) was an independent predictor of pneumonia., Conclusions: Preoperative neutrophil-to-lymphocyte ratio may be a useful predictor of postoperative pneumonia in patients with stage I-III gastric cancer after curative gastrectomy., (© 2021. Société Internationale de Chirurgie.)

Background and Purpose: Simulation computed tomography colonography(sCTC), which combines CTC and 3-dimensional vascular imaging, is popular for the surgery of colorectal cancer. We experience anomaly, called arc of Riolan(aR), rarely but its definition and details are unclear. Using sCTC, we identified aR and investigated the simulation of aR-conserving high ligation., Patient and Method: The patients were 3 cases of sigmoid colorectal cancer with aR in 369 patients who underwent sCTC before colorectal cancer surgery. We identified the running morphology of aR. And we classified Griffiths' point as presence(P)and absence(A). Narrow or mesh-shaped artery which were ischemic risk factors of intestinal tract was P groups and normal artery was A groups in the marginal artery of splenic flexure. We simulated aR-conserving lymph node dissection using sCTC., Result: Case 1. The patient was 60-year-old man with rectal cancer, cT4aN1M0, Stage Ⅲa. The running morphology of aR was between the left branch of middle colic artery(MCA lt)and LCA. Griffiths point: P. Surgical simulation was D3 lymph node dissection with preservation of aR and high ligation of IMA. Pathological findings was pT3N1M0, Stage Ⅲa. Case 2. The patient was 65-year-old woman with sigmoid colon cancer, cT3N2M0, Stage Ⅲb. The running morphology of aR was between MCA lt and IMA. Griffiths point: P. Surgical simulation was D3 lymph node dissection with preservation of aR and high ligation of IMA. Pathological findings was pT3N2M0, Stage Ⅲb. Case 3. The patient was 75-year-old woman with sigmoid colon cancer, cT1bN0M0, Stage Ⅰ. The running morphology of aR was between first jejunal artery and IMA. Griffiths point: A. Surgical simulation was D3 lymph node dissection with preservation of aR and high ligation of IMA. Pathological findings was pT1bN0M0, Stage Ⅲb., Conclusion: Using sCTC, we could identify the various running morphology of aR and simulate aR-conserving lymph node dissection in high ligation.