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Background: Immune checkpoint inhibitors (ICIs) are widely adapted for recurrent or metastatic head and neck cancer (RM-HNC), and various studies on its prognostic factors have been reported. We aimed to elucidate the prognostic factors of ICI treatment for RM oral cancer (RM-OC) in a retrospective study., Methods: We retrospectively reviewed patients with RM-OC treated with ICIs (nivolumab and pembrolizumab) at our department from May 2017 to February 2023. The objective response rate (ORR) for ICI treatment and the relationship between several potential prognostic factors, progression-free survival (PFS), and overall survival (OS) were analyzed statistically., Results: The investigation enrolled 31 patients, 16 with nivolumab and 15 with pembrolizumab. There were no significant differences in the ORR or disease control rate between the nivolumab and pembrolizumab groups (p = 0.4578 and 0.2524). In multivariate analysis, the prognostic nutritional index (PNI) and C-reactive protein to albumin ratio (CAR) exhibited statistical correlations with PFS, whereas the use of antibiotics and proton pump inhibitors (PPIs), neutrophil to lymphocyte ratio (NLR), and PNI demonstrated statistical associations with OS., Conclusion: Our findings imply that the use of antibiotics and PPIs, which can modify the gut microbiota, may also serve as a prognostic determinant for ICI treatment in RM-OC, consistent with previous studies. Additionally, PNI may be essential in affecting the survival rates of both PFS and OS and could be an exceedingly valuable inflammatory biomarker for RM-OC., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The establishment and maintenance of a pregnancy requires proper interaction between the endocrine and immune systems in the uterus. Therefore, it is crucial to understand how changes in endometrial cytokine levels facilitate reproduction. This study aimed to investigate how representative cytokines sequentially changed in the endometrium and whether conception could be attributed to these changes. In this study, artificial insemination was performed twice in 160 sows and ovulation was examined every 3 h using transrectal ultrasonography. Uterine endometrial tissues were obtained via repeated biopsies at 2, 4, 6, 8, 12, 16, and 20 h after ovulation and interleukin (IL)-2, IL-4, IL-6, and IL-8 expression was examined using real-time polymerase chain reaction. The conception rate was 91.9%. The IL-2 levels showed no differences in conception or time. The expression peaks of IL-4 and IL-6 were delayed in sows that failed to conceive within 4-6 h and 2 h, respectively, compared to those that did conceive. In sows that conceived, IL-8 was highest after 2 h, and no difference was observed at other time point, regardless of conception. In sows that failed to conceive, the increase in IL-8 levels might have been cancelled or terminated before the first sampling time. These results highlight the importance of timely increases and subsequent declines in the levels of some cytokines for the establishment of pregnancy. Differences in uterine capacity start just after ovulation; detection and correction of these deviations can improve the reproductive efficiency of sows.

The relationship between cancer stem cells (CSCs) in oral squamous cell carcinoma (OSCC) and programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) remains unclear. Therefore, the present study aimed to clarify the association between the CD44v3 high /CD24 low immunophenotype of CSCs in OSCC and PD-L1/PD-1 co-expression, and to assess the prognostic effect of CSCs in terms of immune checkpoint molecules. Formalin-fixed, paraffin-embedded tissue samples and clinicopathological data from 168 patients with OSCC were retrospectively retrieved. Immunohistochemical staining and reverse transcription quantitative polymerase chain reaction were applied to a tissue microarray of the invasive front of each case. Semi-automated cell counting was used to assess CD44v3, CD24, PD-L1 and PD-1 expression by immunohistochemistry (IHC) using a digital image analysis program. Associations between immunological markers and clinicopathological variables were estimated. Patients with the CSC immunophenotype CD44v3 high /CD24 low , and patients with a high PD-L1/PD-1-positive cell density in the tumor parenchyma and stroma had significantly lower survival rates. Furthermore, patients with the CSC immunophenotype (CD44v3 high /CD24 low ) and high PD-L1/PD-1 co-expression had even lower survival rates (P<0.01, log-rank test). Notably, there was a positive correlation between CD44v3 and PD-L1 expression (τ=0.1096, P=0.0366, Kendall rank correlation coefficient) and a negative correlation between CD24 and PD-1 expression (τ=-0.1387, P=0.0089, Kendall rank correlation coefficient). Additionally, the high CD44v3 expression group, as determined by IHC, exhibited significantly decreased expression of U2 small nuclear RNA auxiliary factor 1 (U2AF1) at the mRNA level compared with that in the low CD44v3 expression group (P<0.001, Mann-Whitney U test), and U2AF1 and PD-L1 mRNA expression exhibited a significant negative correlation (τ=-0.3948, P<0.001, Kendall rank correlation coefficient). In conclusion, CSCs in OSCC may evade host immune mechanisms and maintain CSC stemness via PD-L1/PD-1 co-expression, resulting in unfavorable clinical outcomes., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Todoroki et al.)

There are a few reports that focus on radiotherapy (RT) and cetuximab (CET) therapy exclusively for oral cancer. This retrospective study aimed to investigate the efficacy and safety of RT and CET therapy for locally advanced (LA) or recurrent/metastatic (R/M) oral squamous cell carcinoma (OSCC). Seventy-nine patients from 13 hospitals who underwent RT and CET therapy for LA or R/M OSCC between January 2013 and May 2015 were enrolled in the study. Response, overall survival (OS), disease-specific survival (DSS), and adverse events were investigated. The completion rate was 62/79 (78.5%). The response rates in patients with LA and R/M OSCC were 69% and 37.8%, respectively. When only completed cases were examined, the response rates were 72.2% and 62.9%, respectively. The 1- and 2-year OS were 51.5% and 27.8%, respectively (median, 14 months), for patients with LA OSCC, and 41.5% and 11.9% (median, 10 months) for patients with R/M OSCC. The 1- and 2-year DSS were 61.8% and 33.4%, respectively (median, 17 months), for patients with LA OSCC, and 76.6% and 20.4% (median, 12 months) for patients with R/M OSCC. The most common adverse event was oral mucositis (60.8%), followed by dermatitis, acneiform rash, and paronychia. The completion rate was 85.7% in LA patients and 70.3% in R/M patients. The most common reason for noncompletion was an inadequate radiation dose due to worsening general conditions in R/M patients. Although the standard treatment for LA or R/M oral cancer is concomitant RT with high-dose cisplatin (CCRT) and the efficacy of RT and CET therapy for oral cancer is not considered to be as high as that for other head and neck cancers, it was thought that RT and CET therapy could be possible treatments for patients who cannot use high-dose cisplatin.

A 66-year-old woman underwent total mastectomy with level Ⅰ and Ⅱ axillary lymph node dissection for right breast cancer in July 2007. The pathology results indicated the presence of T2N0M0 invasive ductal carcinoma(tubule forming type), that was estrogen receptor-positive and human epidermal growth factor 2-negative. She received postoperative adjuvant therapy with oral anastrozole(ANA)for 5 years. Eleven years after surgery, at the age of 77 years, a chest X-ray examination during a routine health checkup identified a mass shadow in the right lung. Further investigation revealed bilateral multiple lung metastases due to breast cancer recurrence. Histological examination of a tissue obtained by computed tomography(CT)-guided lung biopsy confirmed that the histological type and subtype were identical to those found in the initial surgery. Hence, endocrine therapy with ANA plus CDK4/6 inhibitor was started in November 2018. However, the first CDK4/6 inhibitor, palbociclib, caused severe myelosuppression even when the dose was reduced by 2 levels. Therefore in January 2019, the patient was switched to abemaciclib, with the dose reduced by 1 level initially and then reduced by 2 levels from August 2019. In June 2019, new multiple lung metastases appeared, and the patient was switched from ANA to fulvestrant, after which complete response was achieved in 6 months. CT in June 2021 showed no recurrence, and the patient(now 80-year-old)continues to take abemaciclib plus fulvestrant therapy.

A 62-year-old woman underwent upper endoscopy in January 2009 to reveal the presence of an extrinsic compression measuring approximately 3 cm in the anterior wall of the gastric antrum. Further examinations suggested that it was caused by peritoneal cancer of an unknown origin; thus, staging laparoscopy was performed in May 2009. Multiple white nodules of varying sizes were found scattered throughout the right upper quadrant of the abdomen and the right abdomen. Based on a biopsy of the greater omentum, the patient was diagnosed with papillary serous adenocarcinoma. As no abnormalities were observed in the uterus and ovary, it was suspected that the patient had primary peritoneal cancer. Hence, in July 2009, the patient underwent resection of the greater omentum, gastric pylorus, gall bladder, and right hemicolon where the tumors were localized, as well as bilateral adnexectomy. Based on intraoperative findings and postoperative histology, the patient was diagnosed with high-grade primary peritoneal serous adenocarcinoma and received paclitaxel and carboplatin therapy. Subsequent follow-up examinations, including positron emission tomography-computed tomography(PET-CT), indicated repeated recurrences in the mesentery, the pelvic floor, and around the remnant stomach. After identifying these recurrences, the patient was treated with platinum-based drugs, experiencing repeated response and cessation cycles. Since September 2019, the patient has received olaparib therapy. PET-CT examination performed in September 2020 indicated that the patient remained in complete remission.

This study aimed to develop a computer application (software) for use by visiting nurses, physicians, and patients/caregivers, to support their care of long-term indwelling urinary catheters in the community. Development of this application involved: (1) confirmation of the intended purpose, users, and application construction; (2) establishment of the functional requirements for data sharing and communication among visiting nurses, physicians, and patients/caregivers; (3) design of three constituent "versions" of the application to be used by visiting nurses, physicians, and patients/caregivers, respectively; and (4) testing of the data sharing and communication functions. The application was designed to facilitate the prevention, assessment, and response to occlusion of indwelling urinary catheters during long-term use at home. This application is characterized by: (1) a unique design of three application "versions" that each reflect the specific care roles of its respective user group; (2) data sharing among the three groups according to their respective roles; and (3) the inclusion of caregivers as users. This article proposes a model that can inform the design of future applications for nursing professionals and patients and caregivers and provide a basis for future research on the development of healthcare applications supporting improvements in care., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Comorbidities among cancer patients are becoming more common. Comorbidity and relative dose intensity (RDI)are 2 major host-dependent prognostic factors for diffuse large B-cell lymphoma(DLBCL), but the clinical evidence demonstrating a relationship between those 2 factors is limited., Methods: We retrospectively analyzed the clinical records of patients with de novo DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone(R-CHOP) therapy at the Okitama Public General Hospital between January 2010 and October 2018 to evaluate the relationship between comorbidity and RDI., Results: A total of 104 patients with a median age of 73 years(range, 36-90 years)were included. More than half of the patients(n=58, 55.8%)had at least one comorbidity. 3-year progression-free survival(p=0.043)and 3- year overall survival(p=0.049)were lower in the comorbidity group than in the no comorbidity group. The RDI was also lower in the comorbidity group than in the no comorbidity group(p=0.011). Univariate analysis of various factors influencing the RDI revealed that the presence of comorbidity was associated with insufficient RDI(p=0.016), but multivariate analysis revealed that only age ≥75(p<0.001)was independently associated with insufficient RDI., Conclusions: Our results demonstrated that the presence of comorbidity was associated with insufficient RDI and poor treatment outcome in DLBCL patients treated with R-CHOP. To optimize the RDI maintenance to achieve better outcomes for DLBCL patients, further investigation of comorbidities is required.

Tolvaptan, a vasopressin V 2 receptor antagonist, is approved in Japan for the treatment of fluid retention in patients with heart failure (HF), and in the United States for hyponatremia. The efficacy and safety of tolvaptan in patients with HF with reduced ejection fraction (HFrEF) have been demonstrated previously. However, its efficacy in patients with HF having preserved (HFpEF) and mid-range (HFmrEF) ejection fraction (EF) remains uncertain. The present subgroup analysis from the post-marketing surveillance SMILE Study aims to explore the efficacy and safety of tolvaptan across the HF subgroups (HFrEF, HFpEF, and HFmrEF).Patients with HF accompanied by fluid retention who received tolvaptan were enrolled. Primary endpoints were: change in body weight, 24-hour urine volume, congestive symptoms, and safety over 14-day treatment. Of the 3,349 patients enrolled, left ventricular EF data were available for 1,741 patients; 45.7% had HFpEF. Tolvaptan treatment resulted in body weight reduction and increases in 24-hour urine volume across the 3 subgroups. Congestive symptoms significantly improved over the 14-day treatment in all subgroups. The frequency of adverse events (AEs) was comparable across the subgroups; thirst was the most common AE.Tolvaptan provides a safe and effective option for treating fluid retention in patients with HFpEF, as well as HFmrEF and HFrEF.

Background: We previously demonstrated that lubrication of an endotracheal tube (ETT) cuff with K-Y™ jelly strongly and significantly inhibited the increase in cuff pressure during nitrous oxide (N 2 O) exposure in vitro. However, in our previous study, we identified critical differences between some influential factors, such as the amount of lubricant retained on the cuff, and studied temperature differences between laboratory and clinical conditions. Therefore, it remained unclear whether this effect holds true in clinical settings., Methods: We first sought to study how changes in the amount of K-Y™ jelly and temperature influence the inhibitory effects of the lubricant on the increase in N 2 O-induced cuff pressure in vitro. Furthermore, we aimed to determine whether the application of K-Y™ jelly inhibits the increase in ETT cuff pressure during general anesthesia using N 2 O in adult patients., Results: In the laboratory studies, we found that K-Y™ jelly inhibited the cuff pressure increase dose-dependently when the dose of K-Y™ jelly was varied (P = 0.02), and that such an inhibitory effect decreased with an increase in the studied temperature (P = 0.019). In the clinical study, lubrication with K-Y™ jelly slightly, but significantly, delayed the increase in ETT cuff pressure during general anesthesia with N 2 O (P = 0.029). However, the inhibitory effect in the clinical settings was smaller than that in vitro., Conclusions: Lubrication of the ETT cuff with K-Y™ jelly may delay the increase in cuff pressure during general anaesthesia with N 2 O. However, the clinical significance of this effect may be limited., Trial Registration: UMIN Clinical Trials Registry: UMIN000031377 on March 1, 2019.

Background: In Japan, tolvaptan is indicated for patients with heart failure and volume overload who have inadequate response to other diuretics. In contrast to the USA and Europe, tolvaptan can be used in Japan in patients with normal sodium levels., Methods and results: In this multicenter, non-interventional, post-marketing surveillance study, prospective data from 3,349 patients treated with tolvaptan over a 5-year period were analyzed to identify benefits and risks. By Day 2 of treatment, 76.9% of evaluable patients had an increase in baseline 24-h urine volume (tolvaptan responders). Mean change in body weight was similar between 7.5 mg and 15 mg dosage groups (-3.6±3.9 kg and -3.7±4.0 kg, respectively). Improvement or disappearance rates for congestive symptoms from baseline to Day 14 ranged from 77.7% for lower limb edema to 51.1% for 3rd sound. Adverse drug reactions were reported in 18.1% of patients, most frequently thirst (8.4%). No case of central pontine myelinolysis was reported. All-cause mortality was significantly lower in patients with improved sodium concentration and increased 24-h urine volume., Conclusions: The effectiveness and safety of tolvaptan in real-world clinical settings was confirmed in this large-scale analysis. The 7.5-mg dose was equally as effective as the 15-mg dose and had a better safety profile. Improvements in all-cause mortality were suggested in tolvaptan responders.

Quantum information processing requires quantum registers based on coherently interacting quantum bits. The dipolar couplings between nitrogen vacancy (NV) centres with nanometre separation makes them a potential platform for room-temperature quantum registers. The fabrication of quantum registers that consist of NV centre arrays has not advanced beyond NV pairs for several years. Further scaling up of coupled NV centres by using nitrogen implantation through nanoholes has been hampered because the shortening of the separation distance is limited by the nanohole size and ion straggling. Here, we demonstrate the implantation of C 5 N 4 H n from an adenine ion source to achieve further scaling. Because the C 5 N 4 H n ion may be regarded as an ideal point source, the separation distance is solely determined by straggling. We successfully demonstrate the fabrication of strongly coupled triple NV centres. Our method may be extended to fabricate small quantum registers that can perform quantum information processing at room temperature.

Aims: Augmentation therapy is an option for patients with major depressive disorder who do respond sufficiently to adequate dosages of selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, but little is known about application of this strategy in everyday practice., Methods: This prospective, multi-center, observational study investigated the effectiveness and safety of aripiprazole augmentation in Japanese patients with inadequate response to conventional antidepressant therapy in real-world clinical practice. The primary endpoint was mean change in the (Japanese version) Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to study end. Safety was assessed by monitoring adverse events., Results: There were 1103 patients in the safety population and 1090 patients in the effectiveness population. Mean change in the MADRS total score at study end was -14.9 ± 12.3 (p < .001 vs baseline). The remission rate increased from 34.5% at Month 6 to 43.3% at Month 12, suggesting additional benefit with continued treatment. The type of primary antidepressant (paroxetine, fluvoxamine, sertraline, milnacipran, duloxetine, mirtazapine, or escitalopram) had no influence on the effectiveness of aripiprazole augmentation therapy. A baseline MADRS total score of <33 points and an elapsed time of <176 days from an episode of depression to the start of aripiprazole treatment increased the likelihood of achieving remission; 24.8% of patients experienced at least one adverse event, but no new safety signals were identified., Conclusions: Aripiprazole augmentation therapy appears to be effective and safe in Japanese patients with depression/depressive symptoms treated in everyday clinical practice, taking into account factors associated with achieving remission.

Objective: Fluorescence visualization devices are screening devices that can be used to examine lesions of the oral mucosa non-invasively. We observed oral squamous cell carcinoma (OSCC) and leukoplakia using the IllumiScan   (Shofu, Kyoto, Japan) fluorescence visualization device and examined its usefulness and characteristics., Methods: We investigated 31 OSCC and nine leukoplakia in patients who were examined using the IllumiScan and treated in our department from January 2017 to February 2018. Images taken with the IllumiScan were analyzed using image analysis software. We also examined the lesions using narrowband imaging (NBI). Additionally, the IllumiScan and NBI images and the non-stained areas of iodine staining method (IOM) were visually evaluated., Results: The average luminance of OSCC in the keratinized mucosa was significantly lower than that of OSCC in non-keratinized mucosa. The average luminance of OSCC was significantly lower than that of leukoplakia. Even in keratinized mucosa where IOM is impossible to use, the OSCC lesion exhibited fluorescence visualization loss., Conclusion: The application of the fluorescence visualization device to the oral mucosa may be useful for distinguishing between cancer and normal areas and can be used to detect OSCC in the keratinized mucosa. The use of the IllumiScan in combination with other conventional screening methods may lead to a better diagnosis., Competing Interests: The authors have declared financial relationships, which are detailed in the next section.

A 65-year-old woman underwent mastectomy and dissection of a level I axillary lymph node in January 2002 for left breast cancer. The diagnosis was T1N0M0 scirrhous carcinoma that was estrogen receptor-positive, progesterone receptorpositive, and human epidermal growth factor receptor 2-negative. After 3 years 10 months, during which the patient underwent adjuvant therapy with oral aromatase inhibitors, she developed bilateral multiple lung metastases. These were treated with the anticancer agents anthracycline and taxane. Progressive disease(more and larger lung metastases)was diagnosed in April 2013, and bevacizumab plus paclitaxel combination therapy was started. After completion of 4 courses, a lung abscess appeared, which was conjectured to represent rapid tumor necrosis that had become infected. As several tumors remained solid even after the lung abscess improved, the patient received 18 courses of eribulin monotherapy. Computed tomography in April 2016 revealed only patches of linear or cord-like scarring in both lungs, with no metastatic or recurrent foci. In this case, a patient with recurrent breast cancer responded to the sequential administration of bevacizumab plus paclitaxel combination therapy followed by eribulin monotherapy.

Purpose: The retromolar canal (RMC) and foramen (RMF) are anatomic variants in the retromolar area of the mandible. The purpose of this study was to clarify the relationship between the RMC and RMF and related complications, and to reveal how the RMC could impact the mandibular anatomy using cone-beam computed tomography (CBCT) and panoramic images (PAN)., Materials and Methods: CBCT and PAN images of 50 patients were retrospectively analyzed to investigate the morphology of the RMC and RMF, and their impact on impacted third molar surgery and orthognathic surgery., Results: In PAN images, neither the RMC nor RMF was detected. In CBCT images, the RMCs were detected in 26% (13/50) of the patients. A double RMC was detected on one side of one patient. The diameter of the RMC ranged from 0.8 to 2.9 mm (mean; 1.5 ± 0.6 mm), and the RMF ranged from 0.6 to 2.3 mm (mean; 1.1 ± 0.5 mm). No patients experienced unexpected bleeding. Unilateral postoperative hypoesthesia of the buccal gingiva in the molar region was reported in 6.7% of patients with the RMC., Conclusions: Hypoesthesia of the buccal gingiva in the lower molar region may be the main complication when the RMC is damaged.

Background: It has been 7 years since tolvaptan was approved in Japan for the indication of heart failure in patients with volume overload; the drug can be used in patients with normonatremia. Hypernatremia was identified as a significant adverse event to be prevented., Methods and results: We compiled and analyzed data from 3,349 patients over 5 years to identify patients at high risk of hypernatremia with tolvaptan treatment. The incidence of hypernatremia, defined as serum sodium ≥150 mEq/L, was 3.65%. Baseline serum sodium concentrations, serum potassium concentrations, blood urea nitrogen : creatinine ratio, initial tolvaptan dose, and age were identified as risk factors for hypernatremia. A hypernatremia risk score was developed using the odds ratios for these factors. The high-risk population was defined as patients with a risk score ≥17.80., Conclusions: To prevent the occurrence of hypernatremic events in patients taking tolvaptan, we recommend a very low starting dose (i.e., 3.75 mg/day) in patients identified as being at high risk of hypernatremia using our new scoring process.

The objective of this study was to investigate cyclical changes in endometrial thickness in relation to progesterone (P 4 ) and estradiol-17β (E 2 ) concentrations during natural and induced estrus in 15 cows. In the prostaglandin (PG) F 2α -induced estrus group, ultrasonography (USG) at 6-h intervals was used to determine endometrial thickness 48-24 h before the PGF 2α treatment until 24 h after ovulation (ovulation = Day 0). In the natural estrus group, USG was performed every 48 h from Day 3 to Days 15-18 after the first ovulation, and then every 6 h until 24 h after ovulation. Endometrial thickness was standardized using Day 13 as a reference day. Blood was collected during every USG examination and plasma P 4 and E 2 concentrations were determined. Endometrial thickness of the induced estrus group (n = 11) was greater than that of the natural estrus group (n = 9) between 60 and 12 h before ovulation (P < 0.05). In the natural estrus group, prior to an increase in endometrial thickness, a decrease in P 4 and an increase in E 2 were detected. In the induced estrus group, based on the time of ovulation, an increase in endometrial thickness was detected at the same time of a decrease in P 4 before an increase in E 2 . These results suggest that decreases in P 4 concentrations may be a cue to changes in endometrial thickness, while increases in E 2 concentrations appear to sustain and/or enhance these changes.

For examining pig ovaries, which have complex structures, laparoscopy is a useful technique, but requires general anesthesia; therefore, it cannot be performed repeatedly within a short period of time. We report a transvaginal endoscopy-based technique for conducting ovarian examinations without general anesthesia. Sows were sedated in pig stalls. Using a colonoscope, the vaginal wall was punctured with a trocar. To avoid the trocar being caught in the broad ligament of the uterus or the connective tissue around the vagina, the trocar was inserted close to the external uterine os and between the 2:00 and 3:00 or the 9:00 and 10:00 positions (in a clockwise direction). Then, a urethroscope was inserted into the abdomen, and an examination was carried out after the ovaries had been moved towards the urethroscope camera via rectal palpation. This less invasive procedure may allow repeated examinations and will increase our understanding of ovarian dynamics in pigs.

Aim: The aim of this trial (ClinicalTrials.gov identifier: NCT01280721) was to investigate the long-term safety profile of tolvaptan in Japanese patients with autosomal dominant polycystic kidney disease (ADPKD)., Methods: This open-label multicenter trial was conducted to examine adverse drug reactions (ADRs) related to tolvaptan up to an additional 3 years in 135 Japanese patients who participated in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial at doses of 60-120 mg/d. Blood samples were collected at baseline; at weeks 1, 2, and 3; at month 3; and every 3 months thereafter., Results: In total, 134/135 (>99%) patients experienced ADRs. The most frequent ADRs were thirst (77.0%), pollakiuria (57.0%), polyuria (37.8%), and hyperuricemia (14.8%). Any unexpected ADRs were not reported in this trial. Most ADRs occurred early during treatment. Fourteen patients (10.4%) experienced hepatic events, and 8 (5.9%) experienced >3-fold increases above the upper limits of normal in serum alanine aminotransferase or aspartate aminotransferase levels between 3 and 9 months following tolvaptan initiation, which recovered after drug interruption. Of the 8 patients, 7 (5.2%) were previously allocated to the placebo arm in the TEMPO 3:4 trial and 4 (3.0%) discontinued due to the hepatic events. One patient (0.7%) was previously allocated to tolvaptan and experienced similar events in the TEMPO 3:4 trial. None of the hepatic ADRs met Hy's Law laboratory criteria., Conclusion: ADRs observed in this extension trial were similar to those identified in the TEMPO 3:4 trial and hepatic events were not progressive., Competing Interests: Disclosure SH has received honoraria for presentations, paid travels, a payment for writing an expert report, and research funding from Otsuka Pharmaceutical; in addition, he has been a medical advisor of the TEMPO Extension Japan trial. SM has received honoraria for presentations, paid travel, and research funding from Otsuka Pharmaceutical. TO, MY, HT, and KN are employees of Otsuka. SM and SH belong to an endowed department sponsored by Otsuka Pharmaceutical Co, Ltd. The authors report no other conflicts of interest in this work.

Aim: Loop diuretics and spironolactone are used in patients with hepatic edema, but they are sometimes associated with insufficient responses as well as adverse events. Tolvaptan, a vasopressin type 2 receptor antagonist, was approved for hepatic edema in 2013. A large-scale post-marketing surveillance study has been carried out to evaluate the effectiveness and safety of tolvaptan in real-world clinical settings., Methods: Patients with hepatic cirrhosis with insufficient response to conventional diuretics were enrolled. The observational period was up to 6 months. Changes in body weight and clinical symptoms were measured to evaluate effectiveness. The incidence of adverse drug reactions was summarized as a safety measure., Results: Of 970 patients enrolled, 463 were included in the safety analysis. Of this group, 340 were included in the effectiveness analysis. Decreases in body weight from baseline were -2.38 kg on day 7 and -3.52 kg on day 14. Ascites and bloated feeling was significantly improved within 14 days. The mean change in body weight depended on estimated glomerular filtration rate levels. The most frequently reported adverse drug reaction was thirst (6.9% of patients). Serum sodium level of ≥146 mEq/L was observed in 12 patients (2.7%)., Conclusions: In the real-world clinical setting, tolvaptan showed aquaretic effectiveness in patients with cirrhosis. The mean change in body weight depended on renal function. We recommend tolvaptan use for hepatic cirrhosis at a stage in which the renal function is maintained., (© 2016 The Japan Society of Hepatology.)

Complications from anterior approaches to the cervical spine are uncommon with normal anatomy. However, variant anatomy might predispose one to an increased incidence of injury during such procedures. We hypothesized that left vertebral arteries that arise from the aortic arch instead of the subclavian artery might take a more medial path in their ascent making them more susceptible to iatrogenic injury. Fifty human adult cadavers were examined for left vertebral arteries having an aortic arch origin and these were dissected along their entire cervical course. Additionally, two radiological databases of CTA and arteriography procedures were retrospectively examined for cases of aberrant left vertebral artery origin from the aortic arch over a two-year period. Two cadaveric specimens (4%) were found to have a left vertebral artery arising from the aortic arch. The retrospective radiological database analysis identified 13 cases (0.87%) of left vertebral artery origin from the aortic arch. Of all cases, vertebral arteries that arose from the aortic arch were much more likely to not only have a more medial course (especially their preforaminal segment) over the cervical vertebral bodies but also to enter a transverse foramen that was more cranially located than the normal C6 entrance of the vertebral artery. Spine surgeons who approach the anterior cervical spine should be aware that an aortic origin of the left vertebral artery is likely to be closer to the midline and less protected above the C6 vertebral level. Clin. Anat. 30:811-816, 2017. © 2017Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)