Analysis of the Medication Persistence Rate for and Adherence to Oral 5-Aminosalicylic Acid Preparations in Japanese Patients with Ulcerative Colitis: Study Using a Nationwide Claims Database.

INTRODUCTION: 5-aminosalicylic acid (5-ASA) is the first-line drug for the treatment of mild-to-moderate ulcerative colitis (UC). Three oral sustained-release formulations are often used. However, no unified view of their actual use in routine medical practice has been presented to date. METHODS: Using a health insurance claims database, we extracted patients with an initial diagnosis of mild-to-moderate UC during the period from December 1, 2017, to March 31, 2022. For the three types of oral 5-ASA formulation, we calculated and compared descriptive statistics of medication persistence rates (MPR), proportions of days covered (PDC), and adherence proportion (PDC ≥80%) in the extracted population. RESULTS: An oral 5-ASA formulation was used in combination with a topical preparation (cohort 1) in 899 patients, and oral 5-ASA was used alone (cohort 2) in 1,829 patients. In cohort 1, MPR at days 151-180 with concomitant use of topical formulation was significantly higher for the Multi Matrix System™ (MMX) formulation (65.2%) compared with that for pH-dependent formulation (51.7%, p < 0.025), while MPR tended to be higher for MMX than for the time-dependent formulation (56.4%, not significant). During days 151-180 after starting the oral formulation, MPR for MMX (66.7% and 65.8%) was higher than for pH-dependent (55.9% and 55.3%) and time-dependent (57.6% and 55.9%) formulations in cohorts 1 + 2 and 2, respectively. In cohort 1, there was a significant difference between MMX (68.3%) and pH-dependent (57.1%) formulations, but no significant difference was seen with time-dependent formulations (61.8%). In terms of the proportion of adherence until day 180, MMX was significantly better than the other formulations. CONCLUSION: The analyses of the three oral 5-ASA formulations suggested that both MPR and medication adherence were better for the MMX formulation than for time-dependent or pH-dependent formulations.

Combination of 15N Tracer and Microbial Analyses Discloses N2O Sink Potential of the Anammox Community.

Although nitrogen removal by partial nitritation and anammox is more cost-effective than conventional nitrification and denitrification, one downside is the production and accumulation of nitrous oxide (N2O). The potential exploitation of N2O-reducing bacteria, which are resident members of anammox microbial communities, for N2O mitigation would require more knowledge of their ecophysiology. This study investigated the phylogeny of resident N2O-reducing bacteria in an anammox microbial community and quantified individually the processes of N2O production and N2O consumption. An up-flow column-bed anammox reactor, fed with NH4+ and NO2- and devoid of oxygen, emitted N2O at an average conversion ratio (produced N2O: influent nitrogen) of 0.284%. Transcriptionally active and highly abundant nosZ genes in the reactor biomass belonged to the Burkholderiaceae (clade I type) and Chloroflexus genera (clade II type). Meanwhile, less abundant but actively transcribing nosZ strains were detected in the genera Rhodoferax, Azospirillum, Lautropia, and Bdellovibrio and likely act as an N2O sink. A novel 15N tracer method was adapted to individually quantify N2O production and N2O consumption rates. The estimated true N2O production rate and true N2O consumption rate were 3.98 ± 0.15 and 3.03 ± 0.18 mgN·gVSS-1·day-1, respectively. The N2O consumption rate could be increased by 51% (4.57 ± 0.51 mgN·gVSS-1·day-1) with elevated N2O concentrations but kept comparable irrespective of the presence or absence of NO2-. Collectively, the approach allowed the quantification of N2O-reducing activity and the identification of transcriptionally active N2O reducers that may constitute as an N2O sink in anammox-based processes.

[A Case of Effective Peritoneo-Venous Shunt for Refractory Malignant Ascites in a Gastric Cancer Patient with Peritoneal Dissemination].

This paper reports a case of refractory ascites in a patient with gastric cancer. A peritoneo-venous shunt(PVS)was inserted in the patient, which contributed to extending the duration of home-based care as well as improving the patient's quality of life. The patient was a female in her 70s. She was diagnosed with gastric cancer and underwent total gastrectomy. Five years and 7 months after the surgery, she was diagnosed with peritoneal recurrence. Ascites temporarily decreased following chemotherapy, but gradually worsened thereafter. Since the patient required frequent puncture drainage for the ascites, cell-free concentrated ascites reinfusion therapy(CART)was performed. However, on the day prior to the scheduled second course of CART, marked abdominal distension was observed. Therefore, a PVS was inserted. No PVS-associated complications were observed. Following the insertion of the PVS, the patient's abdominal circumference and body weight markedly improved. Best supportive care(BSC)was provided to the patient as she became weak after undergoing several courses of chemotherapy on an outpatient basis. On the other hand, the PVS was working properly. The patient was able to continue her daily life activities at home. She died from the cancer after 164 days of the PVS insertion.

Stimulus-selective induction of the orphan nuclear receptor NGFIB underlies different influences of angiotensin II and potassium on the human adrenal gland zona glomerulosa-specific 3ß-HSD isoform gene expression in adrenocortical H295R cells.

In the adrenal, the type I 3ß-hydroxysteroid dehydrogenase (HSD3B1) is expressed exclusively in the zona glomerulosa (ZG), where aldosterone is produced. Angiotensin II (AngII) and potassium (K(+)) are the major physiological regulators of aldosterone synthesis. However, their respective roles in regulation of aldosterone synthesis are not fully defined, particularly in terms of transcriptional regulation of steroidogenic enzyme genes. We previously showed that AngII can stimulate expression of HSD3B1. But, K(+) responsiveness of this gene has remained unexplored. Here, we report that K(+) stimulation lacks the ability to induce HSD3B1 expression in human adrenocortical H295R cells. Both AngII and K(+) were able to enhance transcription of the aldosterone synthase gene (CYP11B2). Promoter analysis revealed that although both AngII and K(+) activate transcription from the Ca(2+)/cAMP-responsive element (CRE) located in the CYP11B2 promoter, the orphan nuclear receptor NGFIB-responsive element (NBRE) located in the HSD3B1 promoter fails to respond to K(+), being only able to enhance transcription after AngII treatment. We found that induction of de novo protein synthesis of NGFIB occurs only after AngII treatment. This sharply contrasts with the phosphorylation that occurs in response to both AngII and K(+) on the CREB/ATF family transcription factor ATF2. Chromatin immunoprecipitation assay confirmed that the NGFIB protein occupies the HSD3B1 promoter only after AngII, while ATF2 binds to the CYP11B2 promoter in response to both AngII and K(+). These data provide evidence that downstream signals from AngII and K(+) can be uncoupled in the regulation of HSD3B1 in the human adrenocortical H295R cells.

[Surgical Simulation-CT Colonography for Laparoscopic Assisted Sigmoid Colectomy Preserving the Inferior Mesenteric Artery and Vein].

D2 lymph node dissection in laparoscopic surgery for early colon cancer requires selective vessel dissection, making it technically very difficult. Using surgical simulation-CT colonography (simulation-CTC), we could perform laparoscopic assisted sigmoid colectomy preserving the inferior mesenteric artery (IMA) and vein (IMV) more accurately and safely. The case described here was a type 0-Ip sigmoid colon cancer with a tumor size of 13 mm. Endoscopic mucosal resection was performed to confirm a pathological diagnosis of pT1b (4,000 mm) and v1. Sigmoid colectomy was planned, and simulation-CTC was performed, which demonstrated that the cancer was located in the proximal sigmoid colon and supplied by the first sigmoid colon artery (S1). To maintain the blood flow to the distal sigmoid colon, selective S1 resection preserving the IMA and IMV was planned. At the operation, S1, which branches off from the IMA near the bifurcation of the abdominal aorta, was dissected, and the vein accompanying S1, which branches from the IMV in the same area as S1, was dissected. The operation was performed accurately according to the plan, showing that simulation-CTC can be very useful.

Is the outcome of a salvage surgery for T4 thoracic esophageal squamous cell carcinoma really poor?

BACKGROUND: Among patients with T4 thoracic esophageal squamous cell carcinoma (TESCC), it is unclear whether the outcomes of late responders who undergo high-dose chemoradiotherapy (CRT) followed by salvage esophagectomy differs from those of early responders who undergo low-dose CRT followed by esophagectomy. METHODS: A total of 153 patients with T4 TESCC were treated with CRT. The first evaluation was performed after 40 Gy of CRT for downstaging. Of these, 28 patients could be downstaged, and underwent subsequent surgery (early responders). For the remaining patients, additional CRT was administered, and patients were re-evaluated after treatment and underwent salvage surgery. In total, 40 patients (early + late responders) were analyzed. RESULTS: The primary tumors exhibited a grade 3 response in six (21.4 %) of the early responders and two (16.7 %) of the late responders (p = 1.000). The rate of residual tumor in the primary tumor was 80 % (32/40 patients). The proportions of resected lymph nodes and positive metastatic nodes were similar between early and late responders (p = 0.406 and p = 0.859, respectively). The 5-year overall survival rates among the early and late responders were 25.9 and 36.5 %, respectively, and the median survival times were 24.8 and 24.3 months (p = 0.925), respectively. The 5-year cause-specific survival rates in the early and late responder groups were 61.5 and 72.9 % (p = 0.425), respectively. CONCLUSION: The outcomes of both early and late responders to CRT were similar, and salvage surgery for T4 TESCC outweighs the risks in patients with T4 TESCC.

Efficacy and safety of elobixibat in combination with or switched from conventional treatments of chronic constipation: A retrospective observational study.

Background and Aim: Elobixibat is a triple mode of action laxative that increases water secretion into the colon, promotes colonic motility, and reestablishes the defecation desire. This study aims to evaluate the effectivity and safety of elobixibat in chronic constipation (CC) patients refractory to conventional laxatives. Methods: A single-center retrospective observational study was conducted in refractory CC patients diagnosed according to the Rome IV criteria and received elobixibat between April 2018 and June 2022 at Osaka Saiseikai Nakatsu Hospital. Data were collected for spontaneous bowel movement (SBM), Bristol stool form scale (BSFS) scores, abdominal symptoms, and adverse events. Results: Eligible 311 patients were selected for the analysis. Two-week Elobixibat treatment significantly increased SBM (times/week) from 2.9 ± 1.9 to 4.3 ± 1.9 (P < 0.0001). The BSFS score improved significantly from 3.2 ± 1.7 to 4.4 ± 1.4 (P < 0.0001). The percentages of patients with hard stool were decrease and that with normal stools were increase. Improvements in abdominal symptoms (sensation of incomplete bowel evacuation, straining, abdominal pain and distention, and difficulty defecating) were also significant (P < 0.05). These constipation symptoms were improved irrespective of patient characteristics or previous laxatives. The 43.9% of previous laxatives were discontinued at the start of or after starting elobixibat treatment. A few adverse events were observed, elobixibat was well tolerated. Conclusion: Elobixibat was effective in patients who were refractory to other laxatives, irrespective of previous therapy or patient characteristics. Elobixibat may contribute to resolving polypharmacy with single mode of action laxatives.

Elobixibat improves rectal sensation in patients with chronic constipation aged ≥60 years: a randomised placebo-controlled study.

OBJECTIVE: High rectal sensory thresholds (RSTs) are associated with chronic constipation (CC), especially in older patients. Bile acids (BAs) affect the RSTs of healthy individuals. Here, we aimed to investigate the effects of the BA transporter inhibitor elobixibat in patients with CC aged ≥60 years. DESIGN: We prospectively compared the RSTs of 17 patients with CC aged ≥60 years with those of 9 healthy individuals of the same age range. We next performed a prospective, randomised, parallel-group, double-blind, placebo-controlled clinical trial of 17 patients with CC who administered elobixibat or placebo daily for 1 week. Using barostat methodology, their first constant sensation volume (FCSV), defaecatory desire volume (DDV), and maximum tolerable volume (MTV) thresholds; their rectal compliance; and their faecal BA concentrations were measured before and after treatment. RESULTS: There were no significant differences in the RSTs of healthy individuals and patients with CC, but all of these tended to be higher in the latter group. Elobixibat increased the desire to defaecate, significantly reduced the threshold for FCSV (p=0.0018), and tended to reduce the threshold for DDV (p=0.0899) versus placebo. However, there were no differences in the MTV or rectal compliance of the two groups. The total faecal BA concentration increased, and particularly that of secondary BAs in the elobixibat group. Elobixibat was most efficacious in participants with a longer duration of CC and a history of treatment for CC. CONCLUSION: Elobixibat reduces the RSTs of patients with CC aged ≥60 years, which may be important for its therapeutic effects. TRIAL REGISTRATION NUMBER: jRCTs061200030.

Totally laparoscopic pancreas-sparing duodenectomy.

Pancreas-sparing duodenectomy (PSD) is a practical surgical procedure for patients with duodenal adenoma, which is difficult to resect endoscopically. We describe how we performed a totally laparoscopic PSD to resect a duodenal adenoma in a 64-year-old woman, who had been referred for treatment of a 50-mm villous polypoid mass in the second portion of the duodenum. We performed end-to-side anastomosis between the common duct of the bile and pancreatic ducts and the jejunal limb intracorporeally following the duodenal resection. A biliary leak developed, but resolved spontaneously and the patient was discharged on postoperative day (POD) 32. The surgical margin was free of neoplastic change. Although there is limited experience and appropriate indications must await future studies, this case demonstrates that laparoscopic PSD is feasible, safe, and effective for selected patients.

[Laparoscopic pancreatic resection of pancreatic cancer].

Laparoscopic pancreatic resection of pancreatic cancer is still not universally accepted as an alternative approach to open surgery because of technical difficulties and a lack of consensus regarding the adequacy of this approach for malignancy. Ten patients with pancreatic cancer underwent laparoscopic pancreatic resection, including pancreaticoduodenectomy and distal pancreatectomy in our institution. Eight of the 10 patients recovered without any complications and were discharged on the 10-29th postoperative day. The remaining 2 patients developed pancreatic fistula and were discharged on the 46 and 60th postoperative day, respectively. All lesions were well clear of surgical margins in 6 patients (R0). In the remaining 4 patients, microscopic neoplastic change was found at the surgical margin (R1). Those 4 patients developed tumor recurrence, including liver metastases or peritoneal dissemination, and 3 of the 4 died of the primary disease. Although experience is limited, laparoscopic pancreatic resection of pancreatic cancer can be feasible, safe, and effective in carefully selected patients. However, the benefit of this procedure has yet to be confirmed. Not only adequate experience in pancreatic surgery but also expertise in laparoscopy is mandatory, and careful selection of patients is essential for successful application of this procedure.

[A case of long-term survival after resection for postoperative solitary adrenal metastasis from esophageal adenocarcinoma].

A 71-year-old man presented with chief complains of hoarseness and dysphagia. He was diagnosed to have an advanced esophageal adenocarcinoma in the middle thoracic esophagus for which chemoradiation therapy was started. Partial response was observed and he was referred to our hospital thereafter. After detailed examination, he underwent a subtotal esophagectomy followed by two-field lymphadenectomy in May 2001. Histopathological examination revealed a complete response. Ten months later, hematological examination showed a high serum CEA level and CT scan disclosed mediastinal lymph node recurrences. He received a course of systemic chemotherapy so called FP therapy and five months later, a course of combination chemotherapy with 700 mg/m2 5-FU on days 1-5 and 70 mg/m2 nedaplatin on day 1 was administered. Because the high serum CEA level sustained afterward, FDG-PET was undertaken in March 2003. The right adrenal gland showed an intense abnormal FDG uptake and CT scan detected a low density mass in the area. Since no metastases could be identified in other sites, right adrenalectomy was performed. Pathological finding was poorly-differentiated tubular adenocarcinoma. Five years and eleven months after adrenalectomy, he died of pneumonia with no signs of recurrence. Surgical resection may contribute to improving the prognosis of solitary adrenal metastasis of esophageal cancer without the other noncurative factors.

[Regional treatment of esophageal liver metastasis by intra-arterial low-dose 5-FU therapy].

The prognosis of esophageal liver metastasis remains poor because of the high incidence of synchronous metastasis in other area and insufficient response to systemic chemotherapy. We assessed loco-regional anticancer potential of intra-arterial 5-FU chemotherapy for esophageal liver metastasis aimed at combination with systemic chemotherapy, radiotherapy and ablation therapy as a multidisciplinary treatment. Six patients of esophageal cancer with liver metastasis and without extra-hepatic metastasis were enrolled. Intra-aortic chemotherapy consisted of 5-FU (250 mg/body) in a one-shot infusion or a continuous infusion for 7 days with 2-week intervals until failure. The responses of liver metastasis were 2 cases of CR, 3 of PR and 1 of SD. The response rate and the local control rate were 83% and 100%, respectively. The maximum time to progression was 53 months. Grade 3/4 toxicity was not observed. Two cases had catheter failure and the treatment was interrupted. Liver metastases were controlled well until death in all cases except one. Low-dose intra-aortic 5-FU chemotherapy provided a good regional response and a combination with systemic chemotherapy may prolong survival for the patients of liver metastasis of esophageal cancer.

Pharmacological characterization of a novel potent, selective, and orally active orexin 2 receptor antagonist, SDM-878.

AIMS: Recently, we identified a novel orexin 2 (OX2 ) receptor antagonist, SDM-878 (2-(3-(2-(1H-pyrazol-1-yl)nicotinoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-methoxyisonicotinonitrile). The purpose of the present study is to characterize the in vitro and in vivo pharmacological effects of SDM-878. METHODS: The in vitro potency and selectivity of SDM-878 were examined in CHO cells that exhibit stable expression of human orexin 1 (OX1 ), human orexin 2 (OX2 ), rat OX1 , and rat OX2 receptors. Then, the plasma half-life, oral bioavailability, and brain penetration of SDM-878 were examined in rats. The in vivo effect of SDM-878 in rats was tested using electroencephalography (EEG). The target engagement of SDM-878 in the rat brain was examined using the antagonistic effect against hyperlocomotion caused by the intracerebroventricular administration of the OX2 receptor agonist, ADL-OXB ([Ala11 , d-Leu15 ]-orexin B). RESULTS: SDM-878 showed potent inhibitory activities for human and rat OX2 receptors with IC values of 10.6 and 8.8 nM, respectively, and approximately 1000-fold selectivity against the OX1 receptor. In rat studies, SDM-878 exhibited a relatively short half-life in plasma, oral bioavailability, and good brain penetration. These data indicate that SDM-878 is a potent, selective, orally active, and brain-penetrable OX2 receptor antagonist. In behavioral studies using rats, SDM-878 (100 mg/kg) antagonized hyperlocomotion caused by intracerebroventricular administration of ADL-OXB. SDM-878 exhibited a potent sleep-promoting effect at the same dose (100 mg/kg) in a rat EEG study. CONCLUSION: Our results suggest that SDM-878 is likely to be a good pharmacological tool for investigating the role of the OX2 receptor and may have therapeutic potential for the treatment of insomnia.

[Evaluation of hepatic arterial infusion chemotherapy for liver metastasis from gastric cancer].

We performed hepatic arterial infusion (HAI) chemotherapy for 11 patients with liver metastasis from gastric cancer, who had no other metastasis. The main antineoplastic drug was 5-fluorouracil (5-FU). The catheter was inserted into the hepatic artery using the GDA coiling method by interventional radiologic technique in 9 patients, and by operative treatment in 2 patients. The response rate for 10 patients was 91% (CR 3, PR 7, PD 1). The survival time from the beginning of the HAI chemotherapy was 8-34 months. The causes of withdrawal from the chemotherapy were PD in 7 patients and catheter troubles in 4 patients. There was no patient suffering from severe adverse effect. The HAI chemotherapy was effective and useful for patients with liver metastasis of gastric cancer. We thought a gastric cancer patient with liver metastasis who didn't have an uncontrollable other organ metastasis was a good target for this regimen.

[Evaluation of preoperative chemoradiation therapy for lower rectal carcinoma using DWIBS].

We investigated the efficacy of diffusion-weighed whole body imaging with background body signal suppression (DWIBS) in assessing effects of chemoradiation therapy (CRT) on rectal carcinoma. DWIBS was performed in patients (n=12) with primary rectal carcinoma undergoing preoperative CRT before and 3 weeks after the treatment. Each patient received a total irradiation dose of 45 Gy at a single dose of 1.8 Gy administered once daily. Parallel to this, in the 1st, 3rd and 5th weeks 350 mg/m2 5-fluorouracil and 35 mg/m2 l-leucovorin were administered for 5 days. The apparent diffusion coefficient (ADC) was measured by DWIBS and surgical resection of the tumors enabled a correlation of ADC values with the pathological findings. With respect to histopathological grading of regression, two, five and five cases exhibited Grade 3, Grade 2 and Grade 1, respectively. In all patients, ADC values were higher after completion of CRT compared to those before it( 1.23+/-0.26x10(-3) mm2/s vs 0.75+/-0.13x10(-3) mm2/s, p<0.001). After completion of CRT, mean ADC values were 1.71+/-0.38x10(-3) mm2/s, 1.25+/-0.10x10(-3) mm2/s and 1.02+/-0.08x10(-3) mm2/s for Grade 3, Grade 2 and Grade 1, respectively. These preliminary results indicate that DWIBS may be a valuable tool to assess effects of CRT on rectal carcinoma by using appropriate cut-off values.

[Diffusion-weighted MR imaging for postoperative nodal recurrence of esophageal squamous cell cancer in comparison with FDG-PET].

We evaluated the power of DWIBS in patients with postoperative lymph node recurrence of esophageal cancer and compared with FDG-PET findings. Forty-seven suspected lesions by MDCT were enrolled. No significant difference between DWIBS and PET was observed in sensitivity (95% vs 97%), PPV (83% vs 90%) and overall accuracy rate (81% vs 87%). The ADCs (x10(-3) mm2/s) of recurrent nodes, primary cancer and normal esophagus were 1.124, 1.058 and 2.079, respectively. ADCs of recurrent nodes were significantly lower than those of normal esophagus (p<0.0001). The cut-off ADC line of 1.5 revealed 100% overall accuracy for separating the recurrent lesion from normal esophagus. Noninvasive DWIBS may become a valid modality to discriminate nodal recurrence of esophageal cancer by no means inferior to PET.

Orexin 2 receptor is involved in orexin A-induced hyperlocomotion in rats.

BACKGROUND: The orexin system regulates various functions, including sleep/wake cycles, feeding, and cognition. Orexin A and orexin B are endogenous neuropeptides for both orexin 1 (OX1) and orexin 2 (OX2) receptors. Orexin A has a potent agonistic activity for both the receptors and is known to increase locomotor activity in rats. However, it has not been elucidated how each receptor contributes to orexin A-induced hyperlocomotion. METHODS: We examined the effects of an OX1 receptor antagonist, SB 334867, and an OX2 receptor antagonist, EMPA, as well as an OX1 and OX2 receptor antagonist on hyperlocomotion caused by intracerebroventricular administration of orexin A or an OX2 receptor agonist, ADL-OXB ([Ala11,d-Leu15]-orexin B), in rats. RESULTS: EMPA (100 mg/kg, ip) but not SB 334867 (3-10 mg/kg, ip) showed antagonistic effects on ADL-OXB-induced hyperlocomotion without affecting the spontaneous locomotor activity. Both EMPA (100 mg/kg, ip) and the OX1 and OX2 receptor antagonist (3-30 mg/kg, po) antagonized orexin A-induced hyperlocomotion, while SB 334867 (3‒-10 mg/kg, ip) showed no effects. CONCLUSIONS: Our results suggest that orexin A-induced hyperlocomotion is mainly mediated by the activation of the OX2 receptor.

[Quality characteristics and nonclinical/clinical profiles of Etanercept BS SC [MA]].

Etanercept is a dimeric genetic recombinant glycoprotein consisting of Fc domain of human Immunoglobulin G1 and the extracellular domain of human tumor necrosis factor (TNF) receptor type II. Etanercept exerts therapeutic effects on inflammatory diseases such as rheumatoid arthritis and juvenile idiopathic arthritis by neutralizing biological activities of TNFα/Lymphotoxin (LT) α. Mochida Pharmaceutical and LG Chem have developed syringe, pen, and vial products of Etanercept BS (biosimilar) as the first biosimilar of Enbrel in Japan. The active ingredient of those products "Etanercept biosimilar 1" has the identical primary structure to that of Enbrel. The development of the Etanercept BS, including evaluations of quality attributes, nonclinical and clinical studies was performed in accordance with "Policies on Assurance of Quality, Safety and Efficacy of Biosimilars". The quality attributes of Etanercept BS were similar to those of Enbrel, and the binding affinities to TNFα/LTα, TNFα neutralizing activity, nonclinical pharmacokinetics and toxicological profiles of Etanercept BS were comparable to Enbrel. Additionally, the pharmacokinetic profile and efficacy of Etanercept BS were equivalent to those of Enbrel and there was no clinically significant difference in safety profiles between them in Phase I and Phase III clinical studies. The marketing approval application of the Etanercept BS with the same indications as Enbrel filed by Mochida Pharmaceutical was approved in January 2018 and the products will be launched by Ayumi Pharmaceutical in the near future. The Etanercept BS, which is as highly effective as Enbrel is expected to make beneficial therapies more easily accessible to patients.

Real-Time Recording of Circadian Per1 and Per2 Expression in the Suprachiasmatic Nucleus of Freely Moving Rats.

Measuring real-time gene activity in the brains of freely moving animals presents a challenging issue in neuroscience research. Circadian gene expression in neurons of the suprachiasmatic nucleus (SCN), a small nucleus in the hypothalamus, is reflected in behavioral rhythmicity. Cellular oscillatory gene expression is generated by a transcription-translation feedback loop of clock genes including 2 oscillatory genes, Per1 and Per2. Here we have succeeded in real-time monitoring of Per1 and Per2 transcription separately by detecting the bioluminescence of luciferase (luc) reporters using a plastic optical fiber inserted into the SCN of freely moving rats. Per1-luc and Per2-luc rhythms peaked in the middle and late subjective day, respectively, which was confirmed by quantitative PCR-based measurements of SCN tissue samples. Studies of in vivo transcriptional states of clock genes in freely moving animals should improve our understanding of how clock gene expression is reflected in behavior.

Successful resection of metachronous para-aortic, Virchow lymph node and liver metastatic recurrence of rectal cancer.

A 66-year-old female presented with the main complaint of defecation trouble and abdominal distention. With diagnosis of rectal cancer, cSS, cN0, cH0, cP0, cM0 cStage II, Hartmann's operation with D3 lymph node dissection was performed and a para-aortic lymph node and a disseminated node near the primary tumor were resected. Histological examination showed moderately differentiated adenocarcinoma, pSS, pN3, pH0, pP1, pM1 (para-aortic lymph node, dissemination) fStage IV. After the operation, the patient received chemotherapy with FOLFIRI regimen. After 12 cycles of FOLFIRI regimen, computed tomography (CT) detected an 11 mm of liver metastasis in the postero-inferior segment of right hepatic lobe. With diagnosis of liver metastatic recurrence, we performed partial hepatectomy. Histological examination revealed moderately differentiated adenocarcinoma as a metastatic rectal cancer with cut end microscopically positive. After the second operation, the patient received chemotherapy with TS1 alone for 2 years. Ten months after the break, CT detected a 20 mm of para-aortic lymph node metastasis and a 10 mm of lymph node metastasis at the hepato-duodenal ligament. With diagnosis of lymph node metastatic recurrences, we performed lymph node dissection. Histological examination revealed moderately differentiated adenocarcinoma as metastatic rectal cancer in para-aortic and hepato-duodenal ligament areas. After the third operation, we started chemotherapy with modified FOLFOX6 regimen. After 2 cycles of modified FOLFOX6 regimen, due to the onset of neutropenia and liver dysfunction, we switched to capecitabine alone and continued it for 6 mo and then stopped. Eleven months after the break, CT detected two swelling 12 mm of lymph nodes at the left supraclavicular region. With diagnosis of Virchow lymph node metastatic recurrence, we started chemotherapy with capecitabine plus bevacizumab regimen. Due to the onset of neutropenia and hand foot syndrome (Grade 3), we managed to continue capecitabine administration with extension of interval period and dose reduction. After 2 years and 2 mo from starting capecitabine plus bevacizumab regimen, Virchow lymph nodes had slowly grown up to 17 mm. Because no recurrence had been detected besides Virchow lymph nodes for this follow up period, considering the side effects and quality of life, surgical resection was selected. We performed left supraclavicular lymph node dissection. Histological examination revealed moderately differentiated adenocarcinoma as a metastatic rectal cancer. After the fourth operation, the patient selected follow up without chemotherapy. Now we follow up her without recurrence and keep her quality of life high.