Ultrasound Neuromodulation of an Anti-Inflammatory Pathway at the Spleen Improves Experimental Pulmonary Hypertension.

BACKGROUND: Inflammation is pathogenically implicated in pulmonary arterial hypertension; however, it has not been adequately targeted therapeutically. We investigated whether neuromodulation of an anti-inflammatory neuroimmune pathway involving the splenic nerve using noninvasive, focused ultrasound stimulation of the spleen (sFUS) can improve experimental pulmonary hypertension. METHODS: Pulmonary hypertension was induced in rats either by Sugen 5416 (20 mg/kg SQ) injection, followed by 21 (or 35) days of hypoxia (sugen/hypoxia model), or by monocrotaline (60 mg/kg IP) injection (monocrotaline model). Animals were randomized to receive either 12-minute-long sessions of sFUS daily or sham stimulation for 14 days. Catheterizations, echocardiography, indices of autonomic function, lung and heart histology and immunohistochemistry, spleen flow cytometry, and lung single-cell RNA sequencing were performed after treatment to assess the effects of sFUS. RESULTS: Splenic denervation right before induction of pulmonary hypertension results in a more severe disease phenotype. In both sugen/hypoxia and monocrotaline models, sFUS treatment reduces right ventricular systolic pressure by 25% to 30% compared with sham treatment, without affecting systemic pressure, and improves right ventricular function and autonomic indices. sFUS reduces wall thickness, apoptosis, and proliferation in small pulmonary arterioles, suppresses CD3+ and CD68+ cell infiltration in lungs and right ventricular fibrosis and hypertrophy and lowers BNP (brain natriuretic peptide). Beneficial effects persist for weeks after sFUS discontinuation and are more robust with early and longer treatment. Splenic denervation abolishes sFUS therapeutic benefits. sFUS partially normalizes CD68+ and CD8+ T-cell counts in the spleen and downregulates several inflammatory genes and pathways in nonclassical and classical monocytes and macrophages in the lung. Differentially expressed genes in those cell types are significantly enriched for human pulmonary arterial hypertension-associated genes. CONCLUSIONS: sFUS causes dose-dependent, sustained improvement of hemodynamic, autonomic, laboratory, and pathological manifestations in 2 models of experimental pulmonary hypertension. Mechanistically, sFUS normalizes immune cell populations in the spleen and downregulates inflammatory genes and pathways in the lung, many of which are relevant in human disease.

What can cause cancer patients to attempt suicide? Thiamine deficiency mimicking the symptoms of major depressive disorder.

OBJECTIVES: Thiamine deficiency (TD) presents with various physical and psychiatric symptoms, but no cases with depression-like symptoms have been reported. METHODS: We report a patient with cancer who appeared to attempt suicide as a consequence of depressive mood likely related to TD. RESULTS: The patient was a 58-year-old woman diagnosed with recurrent endometrial cancer, with lung metastasis and pelvic dissemination. The patient apparently attempted suicide was referred to the psycho-oncology department. At the time of the examination, major depressive disorder was suspected based on her mental symptoms, but when thiamine was administered intravenously in response to her poor dietary intake, her palpitations, dyspnea, anorexia, and insomnia improved, and her suicidal ideation disappeared at her reexamination 1 hour later after thiamine administration. SIGNIFICANCE OF RESULTS: It is likely that the observed palpitations, dyspnea, anorexia, and insomnia, as well as the severe depression and the attempted suicide, which were thought to be physical symptoms associated with depression, were actually related to TD. Suicidal ideation and attempted suicide are conspicuous as psychiatric symptoms. However, in such cases, rather than simply starting treatment for depression, it is necessary to consider reversible TD as a cause of these symptoms and perform differential diagnosis to confirm the physical illness.

Risk of pneumonitis in non-small cell lung cancer patients with preexisting interstitial lung diseases treated with immune checkpoint inhibitors: a nationwide retrospective cohort study.

BACKGROUND: Chemotherapy for non-small cell lung cancer (NSCLC) patients with preexisting interstitial lung diseases (ILDs) increases the risk of developing pneumonitis. However, the association between pneumonitis and immune checkpoint inhibitors (ICIs) and related factors remains unclear. METHODS: We conducted a retrospective cohort study using a nationwide inpatient database. We included patients (aged ≥ 20 years) newly diagnosed with ILD and NSCLC and who started chemotherapy (ICIs or conventional chemotherapy) between January 2016 and December 2019. The primary endpoint was the onset of pneumonitis. We estimated the cumulative incidence function of pneumonitis and compared it with patients taking ICIs and patients receiving conventional chemotherapy using Gray's test. We calculated the subdistribution hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of pneumonitis using Fine and Gray's model to adjust for sex, age, smoking status, histology of NSCLC, surgical history, and medical histories, considering death as the competing risk. RESULTS: We identified 1177 patients (mean age 72 years, 13.8% female), of which 328 and 849 were in the ICI and conventional chemotherapy groups, respectively. There was no significant difference in the cumulative incidence function of pneumonitis between the two groups (p = 0.868). The adjusted subdistribution HR for the incidence of pneumonitis was 1.08 (95% CI: 0.74-1.57). Age (≥ 65 years) (HR: 1.86, 95% CI: 1.11-3.10) and smoking history (HR: 2.04, 95% CI: 1.02-4.11) were associated with developing pneumonitis. CONCLUSION: The risk of developing pneumonitis with ICIs for NSCLC patients with preexisting ILD was similar to that with conventional chemotherapy.

14- and 17-Membered Macrocycles Containing Amide, Amino, and Carbamate Groups in The Monocyclic Skeleton: An Accidental Byproduct Obtained from a Residue after Separation.

A 14-membered cyclic compound (3) containing amide, amino, and carbamate groups, which was serendipitously obtained in the oily residue after the separation of 4-benzyl-1,4,7,10-tetraazacyldododecane-2,6-dione (2a) and 4,16-dibenzyl-1,4,7,10,13,16,19,22-octaazacyclo-tetracosane-2,6,14,18-tetraone (2b), is reported. The structure of 3 is formally a CO2 insertion between positions 3 and 4 of the 12-membered ring in 2a. The CO2 insertion was confirmed in the synthesis of diethyl 2,2'-(benzylazanediyl)diacetate (1) by the reaction of benzylamine with ethyl bromoacetate using K2CO3 as the base. In addition, the selective synthesis of 3 and ethyl N-benzyl-N-((2-ethoxy-2-oxoethoxy)carbonyl)glycinate (5) and their kinetic behavior are reported. The reaction of 5 with triethylenetetramine afforded a 17-membered macrocycle (7), which was obtained in an 18% yield. Compounds 6 and 8 were prepared from 3 and 7 by introducing benzyl groups to improve their solubility in organic solvents. Titration experiments using 1H NMR showed that both 6 and 8 exhibit Li+ selectivity.

Impact of immediate general anesthesia in the emergency room on prevention of rebleeding after subarachnoid hemorrhage.

BACKGROUND: Aneurysm rebleeding is fatal in patients with aneurysmal subarachnoid hemorrhage (aSAH). We aimed to investigate whether immediate general anesthesia (iGA) management in the emergency room, upon arrival, prevents rebleeding after admission and reduces mortality following aSAH. METHODS: The clinical data of 3033 patients with World Federation of Neurosurgical Societies (WFNS) grade 1, 2, or 3 aSAH from the Nagasaki SAH Registry Study between 2001 and 2018 were retrospectively analyzed. iGA was defined as sedation and analgesia using intravenous anesthetics and opioids combined with intubation induction. We calculated crude and adjusted odds ratios to evaluate the associations between iGA and the risk of rebleeding/death using multivariable logistic regression models with fully conditional specification for multiple imputations. In the analysis of the relationship between iGA and death, we excluded patients with aSAH who died within 3 days after the onset of symptoms. RESULTS: Of the 3033 patients with aSAH who met the eligibility criteria, 175 patients (5.8%) received iGA (mean age, 62.4 years; 49 were male). Heart disease, WFNS grade, and lack of iGA were independently associated with rebleeding in the multivariable analysis with multiple imputations. Among the 3033 patients, 15 were excluded due to death within 3 days after the onset of symptoms. After excluding these cases, our analysis revealed that age, diabetes mellitus, history of cerebrovascular disease, WFNS grade, Fisher grade, lack of iGA, rebleeding, postoperative rebleeding, no shunt operation, and symptomatic spasm were independently associated with mortality. CONCLUSIONS: Management by iGA was associated with a 0.28-fold decrease in the risks of both rebleeding and mortality in patients with aSAH, even after adjusting for the patient's history of diseases, comorbidities, and aSAH status. Thus, iGA can be a treatment for the prevention of rebleeding before aneurysmal obliteration treatment.

Recent Trend of Using Computed Tomography to Diagnose Pediatric Appendicitis at the First Hospital Visit: A Descriptive Study Using a Medical Claims Database.

OBJECTIVE: We recognize that computed tomography (CT) should not be used to diagnosis pediatric appendicitis due to radiation exposure. However, few studies have recently shown a trend in its use. This study aimed to investigate the annual use of CT for the diagnosis of pediatric appendicitis at the first hospital visit. METHODS: This was a descriptive study using nationwide claims data. We extracted the data of children younger than 15 years who underwent imaging tests to diagnose acute and suspected appendicitis at the first visit between January 2008 and September 2018. We summarized the patient characteristics and the percentage of CT, ultrasonography (US), or CT/US utilization by year, age, and department. RESULTS: We identified 6658 children who underwent CT (2349 [35.8%]), US (53,57 [54.5%]), and CT/US (634 [9.7%]). The annual CT use dropped from 43.1% in 2012 to 29.4% in 2018. According to age group, the highest percentage of CT use in 2018 was 84.6% in preschool children, followed by adolescents (40.3%), upper-grade (26.0%), and lower-grade (15.0%) children. Data of annual CT use by department revealed that CT usage was much higher in internal and emergency medicine than in pediatrics. Furthermore, adolescents accounted for approximately 50% of CT use in internal medicine. CONCLUSIONS: The percentage of CT use for pediatric appendicitis at the first visit declined annually. However, CT use still tended to be higher in preschool- and adolescent-aged children, or in departments other than pediatrics. Further studies are required to clarify the clinical benefits of CT use to diagnose pediatric appendicitis.

Can depressed cancer patients with a borderline thiamine concentration develop deficiency within a short time period?

BACKGROUND: Despite increasing reports of thiamine deficiency (TD) among cancer patients, there remain some patients with borderline thiamine concentrations (BTC). However, it is unclear whether such patients subsequently develop TD. METHODS: Here, we report cases of cancer patients progressing to TD within a short time period after presentation with BTC (24-28 ng/ml). CASE 1: A 49-year-old female with lung cancer. During treatment for depression, the patient showed a decreased appetite, and a blood sample revealed BTC (25 ng/ml). Fourteen days later, she reported a continued loss of appetite, and despite the absence of the 3 classical signs of Wernicke encephalopathy (WE), additional testing showed a thiamine level of 23 ng/ml, leading to a diagnosis of TD. CASE 2: A 65-year-old female developed depression during chemotherapy for angiosarcoma. Her blood sample revealed BTC (25 ng/ml). Seven days later, despite the absence of the classical signs of WE, a further testing revealed a thiamine level of 20 ng/ml. CASE 3: A 41-year-old female developed depression during chemotherapy for ovarian cancer. No loss of appetite was observed, but a blood sample revealed BTC (25 ng/ml). Seven days later, despite the absence of the classical signs of WE or decreased appetite, further testing revealed a thiamine level of 19 ng/ml. SIGNIFICANCE OF RESULTS: Depressed cancer patients with BTC may develop TD within a short time frame. To prevent TD, health-care professionals should maintain an awareness of its potential and the need for regular testing of thiamine level or prophylactic replacement therapy.

The Association Between Hypouricemia and Cardiometabolic Diseases: Analyzing Nationwide Data From Medical Checkup and Health Insurance Records.

OBJECTIVES: The aims of this study were to evaluate the association between hypouricemia and cardiometabolic diseases, such as hypertension, dyslipidemia, and reduced kidney function, and to explore the sex-specific optimal range for serum uric acid (sUA) associated with the lowest risk for these diseases. METHODS: In this cross-sectional study, we identified individuals with sUA data between April 2018 and March 2019 and recorded the frequency of cardiometabolic comorbidities according to sUA. Univariable and multivariable logistic regression analyses were performed for the overall population and after classifying by sex to assess the association between sUA and cardiometabolic comorbidities. RESULTS: Among 796,508 individuals, a J-shaped association was observed between the sUA level and cardiometabolic diseases in the overall population. The adjusted odds ratios (95% confidence interval) for hypertension, dyslipidemia, and reduced renal function in individuals with sUA ≤1.0 mg/dL compared with those with sUA ranging between 2.1 and 3.0 mg/dL were 1.38 (1.13-1.69), 1.52 (1.30-1.78), and 2.17 (1.47-3.20), respectively. A J-shaped association between sUA and hypertension was observed only in women. The optimal range of sUA associated with the lowest risk for hypertension was assumed to be <6 mg/dL in men and 1-4 mg/dL in women. A J-shaped association between the sUA and dyslipidemia and reduced renal function was observed in both men and women. The optimal range of sUA for dyslipidemia and reduced renal function was approximately 2-5 mg/dL in men and 1-4 mg/dL in women. CONCLUSIONS: Excess and extremely low uric acid levels may be related to an increased cardiometabolic risk.

Trends and patterns in the practice of pediatric sedation for magnetic resonance imaging in Japan: A longitudinal descriptive study from 2012 to 2019.

BACKGROUND: Worldwide, pediatric sedation for magnetic resonance imaging is a standard practice; however, there are few studies on its trends and patterns. AIMS: This study aimed to investigate the trends and patterns of pediatric sedation for magnetic resonance imaging in Japan and determine the incidence of and risk factors for adverse events/interventions. METHODS: This longitudinal descriptive study assessed children (age < 15 years) who underwent sedation for magnetic resonance imaging between April 2012 and December 2019 in Japan using a nationwide claims database. We assessed the patients' demographic characteristics, time trends in sedatives, sedative patterns by age, and adverse events/interventions within two post-sedation days. Further, we used multivariable logistic regression models to explore factors related to the incidence of adverse events/interventions. RESULTS: We identified 29 187 cases (median age, 2.0 years; 55.2% males). The most common sedative was triclofos sodium (n = 18 812, 51.7%). There was an increasing trend in barbiturate use (17.0% [2012] to 25.0% [2019]) and decreasing trends in the use of triclofos sodium (56.4% [2012] to 47.7% [2019]) and chloral hydrate (15.6% [2012] to 10.8% [2019]). We identified 534 adverse events/interventions in 460 cases (1.5%). Multivariable logistic regression analyses revealed that the incidence of adverse events/interventions mainly increased with the number of sedatives (≥3; adjusted odds ratio, 5.10; 95% confidence interval, 3.67-7.10) and unscheduled setting (adjusted odds ratio, 6.28; 95% confidence interval, 4.85-8.61); further, it decreased with high hospital procedure volume (adjusted odds ratio, 0.62; 95% confidence interval, 0.49-0.78). CONCLUSIONS: Based on a Japanese real-world setting, there is an increasing trend in barbiturate use and decreasing trends in the use of triclofos sodium and chloral hydrate in pediatric sedation for magnetic resonance imaging. Low hospital procedure volumes were associated with an increased risk of adverse events/interventions.

Wernicke encephalopathy in a caregiver: A serious physical issue resulting from stress in a family member caring for an advanced cancer patient.

OBJECTIVE: It is well known that the burden on the families of cancer patient extends across many aspects, but there have been no reports of family members developing delirium due to the burden of caring for a cancer patient. METHODS: We reported a caregiver who developed Wernicke encephalopathy (WE) while caring for a family member with advanced cancer. RESULTS: The subject was a 71-year-old woman who had been caring for her husband, diagnosed with gastric cancer and liver metastases, for 5 months. She visited the "caregivers' clinic" after referral by an oncologist who was worried about a deterioration in her mental condition that had appeared several weeks previously. The woman had a history of diabetes mellitus. Some giddiness was observed and, based on her inability to answer questions, her level of consciousness was checked and some disorientation was observed. She was diagnosed with delirium. A blood sample was collected to investigate the cause of the delirium, but the test data showed no hypoglycemia. Her appetite had declined since her husband was diagnosed with cancer. Thiamine deficiency was suspected as thiamine stores in the body are depleted within about 18 days and her loss of appetite had continued for 5 months. On intravenous injection of 100 mg of thiamine, her consciousness level was returned to normal in 1 h. A diagnosis of WE was supported by the patient's abnormally low serum thiamine level. SIGNIFICANCE OF THE RESULTS: The family members of cancer patients may develop a loss of appetite due to the burden of caring, resulting in WE. When providing care for signs of distress in family members, it is necessary to pay attention not only to the psychological aspects but also to their level of consciousness and physical aspects, particularly the possibility of serious illness resulting from reduced nutritional status.

Pulmonary Pleomorphic Carcinoma Harboring EGFR Mutation Successfully Treated with Osimertinib: A Case Report.

Pulmonary pleomorphic carcinoma (PPC) is well-known for its aggressive nature that is usually resistant to platinum-based chemotherapy. On the other hand, the efficacy of an immune checkpoint inhibitor-based regimen in PPC has been elucidated. PPCs harboring epidermal growth factor receptor (EGFR) mutations are extremely rare, and the efficacy of EGFR-tyrosine kinase inhibitors in PPC is limited compared to their efficacy in EGFR-mutated adenocarcinoma. A 43-year-old female patient presenting with a lung mass with multiple brain metastases, carcinomatous pericarditis, and multiple bone metastases was referred to our department. Transbronchial biopsy confirmed the diagnosis of PPC harboring an EGFR mutation with exon 19 deletion. Subsequently, she was treated with osimertinib, a third-generation EGFR-tyrosine kinase inhibitor, which resulted in partial response with shrinkage of the primary lesion and brain metastases. This partial response remained durable for 11 months with an ongoing regimen. The current case suggests that osimertinib would show promising effects as a first-line treatment for PPCs harboring EGFR mutations, as well as a reasonable sequence of therapy followed by immune checkpoint inhibitor-based regimens.

Proximity Proteomics Has Potential for Extracellular Vesicle Identification.

Extracellular vesicles (EVs) are biomarkers and mediators of intercellular communication. In biological samples, EVs are secreted by various types of cells. The proteomic identification of proteins expressed in EVs has potential to contribute to research and clinical applications, particularly for cancer. In this study, the proximity-labeling method-based proteomic approach was used for EV identification, labeling membrane components proximal to a given molecule on the EV membrane surface. Due to the small labeling range, proteins on the surface of the same EVs are likely to be labeled by selecting a given EV surface antigen. The protein group of cancer cell-secreted EV (cEV), which abundantly expresses a close homologue of L1 (CHL1), was examined using a model mouse for lung cancer (LC). cEV-expressed proteins were identified by proteomic analysis of enzyme-mediated activation of radical sources by comparing serum EVs from wild-type and LC mice. SLC4A1 was found to be co-expressed in CHL1-expressing EVs, highlighting EVs expressing both CHL1 and SLC4A1 as candidates for cEVs. Serum EVs expressing both CHL1 and caspase 14 were significantly elevated in LC patients compared with healthy individuals. Thus, the combination of proximity labeling and proteomic analysis allows for effective EV identification.

Wernicke encephalopathy in a lung cancer patient receiving home medical care.

OBJECTIVE: Cancer patients often want to spend their final days at home, and it is essential that general practitioners have knowledge of and technical skills related to cancer medicine and symptom relief. Recent clinical studies have revealed that Wernicke encephalopathy (WE) is quite common in cancer patients. However, there have been no reports to date on WE in cancer patients undergoing home medical care. METHODS: From a series of cancer patient undergoing home medical care, we reported a patient with lung cancer who developed WE. RESULTS: An 84-year-old female with lung cancer undergoing home medical care developed an impaired mental state and an attention deficit. Her symptoms fulfilled the diagnostic criteria for delirium. WE was suspected as the patient's food intake had fallen from normal a month previously to somewhere between 50% or just a few mouthfuls. This diagnosis was supported by abnormal serum thiamine and the disappearance of delirium after thiamine administration. SIGNIFICANCE OF THE RESULTS: When delirium occurs in cancer patients undergoing home treatment, it is necessary to suspect thiamine deficiency as a potential cause, as appropriate diagnosis and treatment can prevent irreversible brain-related sequelae.

Reversible dementia due to vitamin B12 deficiency in a lung cancer patient: Relevance of preoperative evaluation.

OBJECTIVE: Cognitive dysfunction has a negative effect on cancer treatment; however, in a cancer setting, specific treatments can restore cognitive function. Such conditions are known as reversible dementia, with one of these being vitamin B12 (VB12) deficiency. However, there have been no reports of VB12 deficiency identified by preoperative evaluation in cancer patients. METHOD: We studied a patient who was referred to the Department of Psycho-oncology on suspicion of cognitive decline prior to lung cancer surgery. Preoperative evaluation revealed VB12 deficiency. RESULTS: The patient was an 82-year-old woman diagnosed with lung cancer. She also presented with cognitive decline and, therefore, was referred to the Department of Psycho-oncology for preoperative evaluation. The patient scored 19 points on a Mini-Mental State Examination (MMSE), which is indicative of cognitive decline. As the onset of symptoms occurred several months previously and they were subacute, the possibility of reversible dementia was considered. Extensive examination revealed VB12 deficiency, and VB12 replacement therapy normalized the MMSE score to 25 points before surgery. SIGNIFICANCE OF THE RESULTS: When cognitive decline is observed in cancer patients, it is necessary to actively evaluate the serum levels of some B vitamins, including VB12.

Bevacizumab-Containing Chemoimmunotherapy for Recurrent Non-Small-Cell Lung Cancer after Chemoradiotherapy: Case Report.

Chemoimmunotherapy has become the standard of care as the first-line treatment of advanced or recurrent non-small-cell lung cancer (NSCLC). The bevacizumab-containing chemoimmunotherapy regimen is theoretically more effective than a non-bevacizumab-containing regimen via two mechanisms: a superior outcome of bevacizumab-containing chemothrerapy than the standard platinum doublet regimen, and the synergistic effect of bevacizumab with an immune checkpoint inhibitor (ICI). Bevacizumab effectively normalizes vascularization, especially when the vascular bed is damaged by previous treatment. Bevacizumab promotes immunomodulation when used with ICI. We describe a patient with nonsquamous NSCLC who returned 2.5 years after definitive chemoradiotherapy for postoperative locoregional recurrence in the right supraclavicular lymph node. Considering the destroyed vascular bed due to prior chemoradiotherapy, attaining vascular normalization was critical for effective drug delivery. The patient was treated with a bevacizumab-containing chemoimmunotherapy regimen, which resulted in a complete metabolic response. The patient responded well for 23 months and is receiving ongoing treatment. Thus, bevacizumab-containing chemoimmunotherapy could be advantageous in some recurrent cases after chemoradiotherapy.

Comparison of intrathecal morphine with continuous patient-controlled epidural anesthesia versus intrathecal morphine alone for post-cesarean section analgesia: a randomized controlled trial.

BACKGROUND: Several neuraxial techniques have demonstrated effective post-cesarean section analgesia. According to previous reports, it is likely that patient-controlled epidural analgesia (PCEA) without opioids is inferior to intrathecal morphine (IM) alone for post-cesarean section analgesia. However, little is known whether adding PCEA to IM is effective or not. The aim of this study was to compare post-cesarean section analgesia between IM with PCEA and IM alone. METHODS: Fifty patients undergoing elective cesarean section were enrolled in this prospective randomized study. Patients were randomized to one of two groups: IM group and IM + PCEA group. All patients received spinal anesthesia with 12 mg of 0.5% hyperbaric bupivacaine, 10 µg of fentanyl, and 150 µg of morphine. Patients in IM + PCEA group received epidural catheterization through Th11-12 or Th12-L1 before spinal anesthesia and PCEA (basal 0.167% levobupivacaine infusion rate of 6 mL/h, bolus dose of 3 mL in lockout interval of 30 min) was commenced at the end of surgery. A numerical rating scale (NRS) at rest and on movement at 4,8,12,24,48 h after the intrathecal administration of morphine were recorded. In addition, we recorded the incidence of delayed ambulation and the number of patients who requested rescue analgesics. We examined NRS using Bonferroni's multiple comparison test following repeated measures analysis of variance; p < 0.05 was considered as statistically significant. RESULTS: Twenty-three patients in each group were finally analyzed. Mean NRS at rest was significantly higher in IM group than in IM + PCEA group at 4 (2.7 vs 0.6), 8 (2.2 vs 0.6), and 12 h (2.5 vs 0.7), and NRS during mobilization was significantly higher in IM group than in IM + PCEA group at 4 (4.9 vs 1.5), 8 (4.8 vs 1.9), 12 (4.9 vs 2), and 24 h (5.7 vs 3.5). The number of patients who required rescue analgesics during the first 24 h was significantly higher in IM group compared to IM + PCEA group. No significant difference was observed between the groups in incidence of delayed ambulation. CONCLUSIONS: The combined use of PCEA with IM provided better post-cesarean section analgesia compared to IM alone. TRIAL REGISTRATION: UMIN-CTR (Registration No. UMIN000032475). Registered 6 May 2018 - Retrospectively registered.

MicroRNA Let-7c Contributes to Paclitaxel Resistance via Aurora-B in Endometrial Serous Carcinoma.

The incidence of endometrial cancer has rapidly risen over recent years. Paclitaxel, a key drug for endometrial cancer treatment, inhibits microtubule depolymerization and induces apoptosis in cancer cells. Endometrial serous carcinoma (ESC) accounts for < 10% of all endometrial carcinomas, but its aggressive nature makes it responsible for close to 40% of cancer deaths. Thus, novel therapeutic targets are required for ESC. To identify microRNAs that promote paclitaxel resistance, we established two paclitaxel-resistant cell lines from USPC1 human ESC cells by exposing paclitaxel to parental cells for 12 weeks. Paclitaxel concentrations were increased every 2 weeks, and after 12 weeks of paclitaxel exposure, two replicate paclitaxel-resistant cell lines were established (USPC1-PTSR1 and USPC1-PTXR2). The microarray analysis was performed using USPC1 cells and USPC1-PTXR1 cells, and eight candidate microRNAs were thus selected as potential mediators of paclitaxel sensitivity. Among these candidate microRNAs, let-7c precursor treatment of paclitaxel-resistant USPC1-PTXR1 cells caused the greatest increase in paclitaxel-mediated cytotoxicity. Let-7c inhibition conversely decreased paclitaxel-induced apoptosis. It is known that let-7a microRNA, a member of the let-7 family, inhibits growth of endometrial carcinoma cells targeting Aurora-B that controls progression through each phase of mitosis. We thus studied whether let-7c mediates Aurora-B expression in ESC cells. The expression levels of Aurora-B mRNA and protein were higher in USPC-PTXR1 cells compared with USPC1 cells. Let-7c inhibition increased Aurora-B expression in USPC1 cells but decreased Aurora-B expression in USPC1-PTXR1 cells. These results indicate that let-7c mediates paclitaxel resistance via inhibition of Aurora-B expression in ESC cells.

Osimertinib-Associated Toxic Epidermal Necrolysis in a Lung Cancer Patient Harboring an EGFR Mutation-A Case Report and a Review of the Literature.

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are life-threatening dermatologic adverse events in the same category, caused by a delayed-type drug hypersensitivity reaction. Although skin toxicity is common during treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), osimertinib-associated TEN is quite rare-thus far, only one report has been published from China. We report a case of an 80-year-old Japanese woman with lung adenocarcinoma harboring an EGFR-sensitizing mutation who was treated with osimertinib as the first-line treatment. Forty-six days after osimertinib induction, diffuse erythematous rash rapidly spread over the patient's trunk along with vesicles and purpuric macules; furthermore, she developed targetoid erythema on the face. Despite osimertinib discontinuation and corticosteroid treatment, diffuse erythema with Nikolsky's sign, general epidermal detachment, erosion and loose blisters developed over her entire body including the face. Based on her symptoms, TEN was diagnosed and thus, intravenous immunoglobulin was immediately administered for 4 days. The treatment ameliorated TEN-associated skin toxicity and caused epithelialization. Reports on osimertinib-associated SJS/TEN are scarce and only one report each on SJS and TEN from China is available. This is the first report of osimertinib-associated TEN from Japan. Cases of EGFR-TKI-associated SJS/TEN have been reported predominantly from Asian countries, suggesting ethnicity and genetic linkage play a role in the underlying mechanism.

A descriptive epidemiological study on the treatment options for head and neck cancer: Transition before and after approval of cetuximab.

PURPOSE: Chemoradiotherapy is among the effective treatment modalities for head and neck cancer (HNC). We aimed to elucidate the factors affecting drug selection by describing the actual situation of chemoradiotherapy for HNC in Japan and the transition in treatment selection before and after the approval of cetuximab. METHOD: We used a claims database involving multiple hospitals nationwide. The study included patients diagnosed with HNC between April 2008 and August 2015 who underwent chemoradiotherapy. The anticancer drugs used were categorized into four groups, namely, cetuximab, cisplatin, other platinum agents, and other agents. After assessing patient background and transition in concomitant drugs, we performed multinomial logistic regression analysis to determine factors that affect patient drug selection. RESULTS: This study analyzed 2777 patients whose median age was 66 years. A cisplatin-based regimen remained the most commonly used concomitant drug even after cetuximab approval. In multinomial logistic regression analysis, the odds ratio and 95% confidence interval (CI) in terms of age (66 y or older vs less than 65 y) relative to the cisplatin group were 3.01 (95% CI, 2.26-4.02) for the cetuximab group; 1.76 (95% CI, 1.22-2.48) for the other platinum agent group; and 3.09 (95% CI, 2.39-3.99) for the other agent group. CONCLUSION: This study showed the current practices in concomitant medication used in chemoradiotherapy for HNC patients in Japan, the transition in anticancer drugs used before and after cetuximab approval, and the factors affecting the selection of concomitant drugs.

CRISPR/Cas9-mediated homologous recombination in tobacco.

KEY MESSAGE: Co-transformation of multiple T-DNA in a binary vector enabled CRISPR/Cas9-mediated HR in tobacco. HR occurred in a limited region around the gRNA target site. In this study, CRISPR/Cas9-mediated homologous recombination (HR) in tobacco (Nicotiana tabacum L. 'SR-1') was achieved using binary vectors comprising two (T1-T2) or three (T1-T2-T3) independent T-DNA regions. For HR donor with the tobacco acetolactate synthase gene, SuRB, T-DNA1 contained ΔSuRBW568L, which lacked the N-terminus region of SuRB and was created by three nucleotide substitutions (ATG to GCT; W568L), leading to herbicide chlorsulfuron (Cs) resistance, flanked by the hygromycin (Hm)-resistant gene. T-DNA2 consisted of the hSpCas9 gene and two gRNA inserts targeting SuRB and An2. For the 2nd HR donor with the tobacco An2 gene encoding a MYB transcription factor involved in anthocyanin biosynthesis, T-DNA3 had a 35S promoter-driven An2 gene lacking the 3rd exon resulting in anthocyanin accumulation after successful HR. After selecting for Hm and Cs resistance from among the 7462 Agrobacterium-inoculated explants, 77 independent lines were obtained. Among them, the ATG to GCT substitution of endogenous SuRB was detected in eight T1-T2-derived lines and two T1-T2-T3-derived lines. Of these mutations, four T1-T2-derived lines were bi-allelic. All the HR events occurred across the endogenous SuRB and 5' homology arm of the randomly integrated T-DNA1. HR of the SuRB paralog, SuRA, was also found in one of the T1-T2-derived lines. Sequence analysis of its SuRA-targeted region indicated that the HR occurred in a limited (< 153 bp) region around the gRNA target site. Even though some T1-T2-T3-derived lines introduced three different T-DNAs and modified the An2 gRNA target site, no signs of HR in the endogenous An2 could be observed.