Efficacy and Safety of Immune Checkpoint Inhibitor Combination Therapy for Dysphagia in Patients with Advanced Esophageal Cancer.

Background/Objectives: Recently, pembrolizumab plus 5-fluorouracil and cisplatin (FP), nivolumab plus FP, and nivolumab plus ipilimumab have become the first-line treatments for patients with advanced esophageal cancer. However, the treatment efficacy in primary tumors has not been reported. We assessed the outcomes of these treatments in advanced esophageal cancer, specifically focusing on esophageal dysphagia improvements and the primary tumor response. Methods: This retrospective study was conducted between October 2021 and November 2023. We investigated 23 patients with esophageal cancer and dysphagia who received an immune checkpoint inhibitor (ICI) plus FP or nivolumab plus ipilimumab. Results: The median progression-free survival (PFS) was 10.6 months (95% confidence interval [CI]: 9.0-12.5), and the median overall survival was not reached (95%CI: 13.0-NA). Improvement in dysphagia was observed in 19/23 (82.6%) patients, with a median time to improvement of 26 days (range: 15-77 days) and a median dysphagia PFS of 12.6 months (range: 8.1-NA months). Ten patients experienced immune-related adverse events (irAEs): seven had interstitial pneumonia, and three had thyroid dysfunction, pituitary dysfunction, and rash, respectively. Conclusions: Although there was a high frequency of irAEs, ICI for esophageal cancer achieved high response rates and prolonged survival. The observed improvement in dysphagia suggests the potential efficacy of the treatment against primary tumors.

CA125 Kinetics as a Potential Biomarker for Peritoneal Metastasis Progression following Taxane-Plus-Ramucirumab Administration in Patients with Advanced Gastric Cancer.

Currently, no established marker exists for predicting peritoneal metastasis progression during chemotherapy, although they are major interruptive factors in sequential chemotherapy in patients with advanced gastric cancer (AGC). This multicenter retrospective study was conducted from June 2015 to July 2019, analyzing 73 patients with AGC who underwent taxane-plus-ramucirumab (TAX/RAM) therapy and had their serum carbohydrate antigen 125 (CA125) concentrations measured. Of 31 patients with elevated CA125 levels above a cutoff of 35 U/mL, 25 (80.6%) had peritoneal metastasis. The CA125 concentrations before TAX/RAM treatment were associated with ascites burden. The overall survival was significantly shorter in the CA125-elevated group. CA125 kinetics, measured at a median of 28 days after chemotherapy, were associated with the ascites response (complete or partial response: -1.86%/day; stable disease: 0.28%/day; progressive disease: 2.33%/day). Progression-free survival in the CA125-increased group, defined by an increase of 0.0067%/day using receiver operating characteristic curve analysis, was significantly poorer among patients with peritoneal metastases. In conclusion, this study highlights that CA125 kinetics can serve as an early predictor for the progression of peritoneal metastasis during TAX/RAM treatment.

The Efficacy and Safety of Nivolumab Plus mFOLFOX6 in Gastric Cancer with Severe Peritoneal Metastasis.

(1) Background: Nivolumab plus chemotherapy is established as a first-line treatment for advanced gastric cancer (AGC). While mFOLFOX6 is commonly used for AGC with severe peritoneal metastasis, the efficacy of nivolumab combined with it remains uncertain. We evaluated the outcomes of nivolumab plus mFOLFOX6 for AGC with severe peritoneal metastasis in clinical practice. (2) Methods: This multicenter retrospective study was conducted between December 2021 and June 2023. We investigated AGC patients with massive ascites or inadequate oral intake due to severe peritoneal metastasis and who received nivolumab plus mFOLFOX6. (3) Results: Among 106 patients treated with nivolumab plus chemotherapy, 21 (19.8%) had severe peritoneal metastasis, with 14 receiving nivolumab plus mFOLFOX6. The median progression-free survival was 7.4 months (95%CI 1.9-10.1), and the median overall survival was 10.7 months (95%CI 5.3-NA), with four patients (28.5%) surviving more than 12 months. Improved ascites and oral intake were observed in 6/14 patients (42.8%) and 10/11 patients (90.9%), respectively. The major grade 3 or more adverse events included leukopenia (28.5%) and neutropenia (21.4%), with no severe immune-related adverse events reported. (4) Conclusions: The safety and moderate efficacy of nivolumab plus mFOLFOX6 were suggested even in AGC patients with severe peritoneal metastasis.

Liver metastasis affects progression pattern during immune checkpoint inhibitors monotherapy in gastric cancer.

Introduction: The efficacy of immune checkpoint inhibitors (ICIs) is heterogeneous at each metastatic site, and tumor progression pattern is associated with survival; however, it remains unclear in gastric cancer (GC). Therefore, we aimed to clarify the progression pattern in response to ICIs in patients with GC, and we analyzed its mechanism focusing on the intratumoral immune cells. Methods: Patients who received ICIs were retrospectively classified into non-systemic and systemic progression groups based on their radiological assessments. Moreover, the best percentage change in target lesions from each organ was compared. Results: Among 148 patients, the non-systemic progression group showed a significant improvement in overall survival (OS) compared with the systemic progression group (median, 5.6 months vs. 3.3 months; HR, 0.53; 95%CI, 0.32-0.89; p = 0.012). Poor performance status (HR, 1.73, 95%CI, 1.00-2.87) and systemic progression (HR, 3.09, 95%CI, 1.95-4.82) were associated with OS. Of all metastatic sites, the liver showed the poorest percentage change, and liver metastasis (OR, 2.99, 95%CI, 1.04-8.58) was associated with systemic progression. Hence, intratumoral CD8+ T-cell density was lower in patients with liver metastasis than in those without liver metastasis after ICIs, although the density of CD4+ T-cells (Th1, Th17, and Treg) and CD163+ cells (TAM) were not significantly different. Conclusion: The new progression pattern was associated with OS in GC. Liver metastasis may be a predictive factor of systemic progression during ICIs by regulating intratumoral CD8+ T-cells.

The Importance of Follow-Up and Evaluation of Intraoperative Findings to Determine Surgical Indications for Retractile Testis.

Objectives: Ascending testis or acquired undescended testis develops in approximately 30% of cases of retractile testis, and orchiopexy is recommended for these cases. This study aimed at assessing the intraoperative anatomical findings of ascending testis and acquired undescended testis in search of better management for retractile testis. Methods: We retrospectively collected data of patients with confirmed diagnosis of retractile testis between February 2012 and November 2021. Orchiopexy was performed for cases with ascending testis and for patients with increasing difference of right and left testicular volume. The site of gubernaculum attachment and patent processus vaginalis were evaluated during surgery. Results: A total of 119 testes in 71 patients with retractile testis were included in this study. Sixteen retractile testes in 12 patients (17%) underwent orchiopexy. The weight at birth was significantly higher, and bilateral retractile testes were significantly more common in the follow-up group than in the surgical intervention group. In the surgical intervention group, the abnormal site of gubernaculum attachment was found in 12 out of 16 testes (75%), and patent PV was found in nine out of sixteen testes (56%). Sites of gubernaculum attachment in testes with patent PV were significantly higher than in sites with closed processus vaginalis, and all testes with patent processus vaginalis had abnormal site of gubernaculum attachment. Conclusion: Patients with ascending testis and acquired undescended testis have clinical features and intraoperative abnormal findings similar to a cryptorchidism. Therefore, our surgical indication for retractile testis is considered appropriate.

Factors, Including Clinical Trial Eligibility, Associated with Induction of Third-Line Treatment for Advanced Gastric Cancer.

INTRODUCTION: Third-line chemotherapy has been suggested to improve survival in patients with gastric cancer. This study aimed to identify factors associated with the induction of third-line chemotherapy for advanced gastric cancer, focusing on patient eligibility for clinical trial. METHODS: We retrospectively analyzed 335 patients treated for unresectable or recurrent gastric cancer between April 2009 and May 2020. The patients were grouped into those that met the key eligibility criteria for clinical trial (136 patients, 40.6%) and those that did not (199 patients, 59.4%) before receiving first-line chemotherapy. RESULTS: The overall survival (OS) was 16.8 months (95% CI: 14.0-19.6) and 9.3 months (95% CI: 7.8-11.0) in the eligible and ineligible group, respectively. Multivariate analyses to identify the risk factors associated with the induction of third-line chemotherapy revealed ineligibility of clinical trial (OR 1.95; 95% CI: 1.15-3.31), number of metastatic sites (OR 1.99; 95% CI: 1.23-3.22), low albumin concentration (OR 2.24; 95% CI: 1.14-4.38), and a lack of complete or partial response to first-line treatment (OR 1.85; 95% CI: 1.05-3.26). Indeed, in responders to first-line treatment for ineligible patients, the median OS was 17.7 months (95% CI: 10.6-27.9), respectively. CONCLUSIONS: Treatment outcomes were different for those eligible for clinical trials and those who were not. However, this study suggested that patients who responded to first-line treatment have more favorable prognosis when treated with salvage chemotherapy, even if they were deemed ineligible for clinical trials.

Efficacy and Safety of FOLFOX in Advanced Gastric Cancer Initially Presenting With Disseminated Intravascular Coagulation.

BACKGROUND/AIM: Advanced gastric cancer (AGC) rarely presents with disseminated intravascular coagulation (DIC) at the time of diagnosis. Chemotherapy should be selected in consideration of hematological toxicities because these patients are at high risk of hemorrhagic complications. The leucovorin, fluorouracil, and oxaliplatin (FOLFOX) regimen is an effective and less toxic regimen for patients with AGC and poor performance status. PATIENTS AND METHODS: The present study assessed overall survival of all patients receiving first-line chemotherapy with and without DIC using Kaplan-Meier methods and examined the clinicopathological factors, DIC parameters, response, and survival of five patients with AGC and DIC who received FOLFOX in the first-line setting between February 2017 and February 2020. RESULTS: Among the patients, four patients (80%) recovered from DIC after a median of 12 days of FOLFOX therapy (range=12-25), and their platelet count gradually increased within 1 week after the start of chemotherapy. The median progression-free survival and overall survival were 46 (range=22-296) and 115 days (range=83-324), respectively. No patients experienced adverse events necessitating treatment discontinuation, including gastrointestinal bleeding and thrombocytopenia. Moreover, all patients received second-line treatment after progression, and one patient exhibited improvement of DIC symptoms following nab-paclitaxel and ramucirumab treatment. CONCLUSION: FOLFOX therapy is well tolerated and effective in patients with AGC initially presenting with DIC and subsequent second-line treatment might be crucial for better prognosis.

Myosteatosis as a novel predictor of urinary incontinence after robot-assisted radical prostatectomy.

OBJECTIVES: To evaluate the impact of sarcopenia and myosteatosis on urinary incontinence after prostatectomy. METHODS: We retrospectively reviewed consecutive patients who underwent robot-assisted radical prostatectomy without nerve sparing between December 2012 and March 2019. Psoas muscle index and average total psoas density, which were measured on preoperative computed tomography images at level L3, were used to evaluate sarcopenia and myosteatosis, respectively. In addition, several magnetic resonance imaging variables associated with pelvic muscles, the urethra and the prostate were measured. Urinary continence was defined as non-use or use of just one incontinence pad per day. Logistic regression analyses aimed to identify the predictors of urinary incontinence 3 and 12 months after surgery. RESULTS: Overall, 121 patients were included in the analysis. The incidence rates of urinary incontinence 3 and 12 months after surgery were 42% (51/121 cases) and 16% (19/121 cases), respectively. Logistic multivariable analysis showed that low average total psoas density was the only significant independent predictor of urinary incontinence 3 months after surgery (P < 0.01), and low obturator internus muscle thickness (P = 0.01), short membranous urethral length (P = 0.01) and low average total psoas density (P < 0.01) were significant independent predictors of urinary incontinence 12 months after surgery. By contrast, psoas muscle index was not statistically associated with urinary incontinence after surgery. CONCLUSIONS: Myosteatosis (low average total psoas density) could be a novel predictor of urinary incontinence after robot-assisted radical prostatectomy.

Pharmacological Inhibition of miR-130 Family Suppresses Bladder Tumor Growth by Targeting Various Oncogenic Pathways via PTPN1.

Previously, we have revealed that the miR-130 family (miR-130b, miR-301a, and miR-301b) functions as an oncomiR in bladder cancer. The pharmacological inhibition of the miR-130 family molecules by the seed-targeting strategy with an 8-mer tiny locked nucleic acid (LNA) inhibits the growth, migration, and invasion of bladder cancer cells by repressing stress fiber formation. Here, we searched for a functionally advanced target sequence with LNA for the miR-130 family with low cytotoxicity and found LNA #9 (A(L)^i^i^A(L)^T(L)^T(L)^G(L)^5(L)^A(L)^5(L)^T(L)^G) as a candidate LNA. LNA #9 inhibited cell growth in vitro and in an in vivo orthotopic bladder cancer model. Proteome-wide tyrosine phosphorylation analysis suggested that the miR-130 family upregulates a wide range of receptor tyrosine kinases (RTKs) signaling via the expression of phosphorylated Src (pSrcTyr416). SILAC-based proteome analysis and a luciferase assay identified protein tyrosine phosphatase non-receptor type 1 (PTPN1), which is implicated as a negative regulator of multiple signaling pathways downstream of RTKs as a target gene of the miR-130 family. The miR-130-targeted LNA increased and decreased PTPN1 and pSrcTyr416 expressions, respectively. PTPN1 knockdown led to increased tumor properties (cell growth, invasion, and migration) and increased pSrcTyr416 expression in bladder cancer cells, suggesting that the miR-130 family upregulates multiple RTK signaling by targeting PTPN1 and subsequent Src activation in bladder cancer. Thus, our newly designed miR-130 family targeting LNA could be a promising nucleic acid therapeutic agent for bladder cancer.

Radiation inducible MafB gene is required for thymic regeneration.

The thymus facilitates mature T cell production by providing a suitable stromal microenvironment. This microenvironment is impaired by radiation and aging which lead to immune system disturbances known as thymic involution. Young adult thymus shows thymic recovery after such involution. Although various genes have been reported for thymocytes and thymic epithelial cells in such processes, the roles of stromal transcription factors in these remain incompletely understood. MafB (v-maf musculoaponeurotic fibrosarcoma oncogene homolog B) is a transcription factor expressed in thymic stroma and its expression was induced a day after radiation exposure. Hence, the roles of mesenchymal MafB in the process of thymic regeneration offers an intriguing research topic also for radiation biology. The current study investigated whether MafB plays roles in the adult thymus. MafB/green fluorescent protein knock-in mutant (MafB+/GFP) mice showed impaired thymic regeneration after the sublethal irradiation, judged by reduced thymus size, total thymocyte number and medullary complexity. Furthermore, IL4 was induced after irradiation and such induction was reduced in mutant mice. The mutants also displayed signs of accelerated age-related thymic involution. Altogether, these results suggest possible functions of MafB in the processes of thymic recovery after irradiation, and maintenance during aging.

ALKBH4 promotes tumourigenesis with a poor prognosis in non-small-cell lung cancer.

The human AlkB homolog family (ALKBH) of proteins play a critical role in some types of cancer. However, the expression and function of the lysine demethylase ALKBH4 in cancer are poorly understood. Here, we examined the expression and function of ALKBH4 in non-small-cell lung cancer (NSCLC) and found that ALKBH4 was highly expressed in NSCLC, as compared to that in adjacent normal lung tissues. ALKBH4 knockdown significantly induced the downregulation of NSCLC cell proliferation via cell cycle arrest at the G1 phase of in vivo tumour growth. ALKBH4 knockdown downregulated E2F transcription factor 1 (E2F1) and its target gene expression in NSCLC cells. ALKBH4 and E2F1 expression was significantly correlated in NSCLC clinical specimens. Moreover, patients with high ALKBH4 expression showed a poor prognosis, suggesting that ALKBH4 plays a pivotal tumour-promoting role in NSCLC.

Development of a highly sensitive method for the quantitative analysis of modified nucleosides using UHPLC-UniSpray-MS/MS.

There are more than 150 types of naturally occurring modified nucleosides, which are believed to be involved in various biological processes. Recently, an ultrahigh performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UHPLC-ESI-MS/MS) technique has been developed to measure low levels of modified nucleosides. A comprehensive analysis of modified nucleosides will lead to a better understanding of intracellular ribonucleic acid modification, but this analysis requires high-sensitivity measurements. In this perspective, we established a highly sensitive and quantitative method using the newly developed ion source, UniSpray. A mass spectrometer was used with a UniSpray source in positive ion mode. Our UHPLC-UniSpray-MS/MS methodology separated and detected the four major nucleosides, 42 modified nucleosides, and dG15N5 (internal standard) in 15 min. The UniSpray method provided good correlation coefficients (>0.99) for all analyzed nucleosides, and a wide range of linearity for 35 of the 46 nucleosides. Additionally, the accuracy and precision values satisfied the criteria of <15% for higher concentrations and <20% for the lowest concentrations of all nucleosides. We also investigated whether this method could measure nucleosides in biological samples using mouse tissues and non-small cell lung cancer clinical specimens. We were able to detect 43 and 31 different modified nucleosides from mouse and clinical tissues, respectively. We also found significant differences in the levels of N6-methyl-N6-threonylcarbamoyladenosine (m6t6A), 1-methylinosine (m1I), 2'-O-methylcytidine (Cm), 5-carbamoylmethyluridine (ncm5U), 5-methoxycarbonylmethyl-2-thiouridine (mcm5S2U), and 5-methoxycarbonylmethyl-2'-O-methyluridine (mcm5Um) between cancerous and noncancerous tissues. In conclusion, we developed a highly sensitive methodology using UHPLC-UniSpray-MS/MS to simultaneously detect and quantify modified nucleosides, which can be used for analysis of biological samples.

Conventional Direct Smear Yields Diagnostic Indicators of Gastric-Type Mucinous Carcinoma Compared with Cytomorphological Features Identified by Liquid-Based Cervical Cytology.

INTRODUCTION: Gastric-type mucinous carcinoma (GAS) of the uterine cervix is an adenocarcinoma subtype with a gastric phenotype that poses diagnostic pitfalls in cervical screening cytology because of its blunt morphologic atypia and the limited utility of human papillomavirus testing and ancillary immunochemical staining. Despite the recent widespread uptake of liquid-based cytology (LBC) systems, the cytomorphological features of GAS in LBC samples and the differential features between GAS and usual-type endocervical adenocarcinoma (UEA) remain unclear. METHODS: Eight GAS cases, all of which were surgically treated following histological confirmation, were examined. Direct Papanicolaou-stained smears and LBC samples were reviewed and compared with 10 UEA cases as controls. Featured cytomorphological findings were as follows: background (mucinous, inflammatory, or necrotic), cell crowding (size of neoplastic cell clusters), cytoplasm (golden mucin and cell border), and nuclei (nuclear chromatin and nucleoli). RESULTS: Of 18 adenocarcinomas, 16 were detected against a non-mucinous background in LBC samples, most of which were accompanied by mild to moderate inflammation. Clusters comprising >300 neoplastic cells were identified in both GAS and UEA in conventional smears (CSs), while no LBC samples harboured clusters as large as these. Cell borders of GAS were more distinct than those of UEA in CSs (p < 0.001), although fewer populations of neoplastic clusters revealed distinct cell borders in both GAS and UEA in LBC samples. Three of 8 and 2 of 8 GAS cases had golden mucin in CSs and in LBC samples, respectively, which was not detected in UEA at all. Nucleoli against fine nuclear chromatin were more pronounced in GAS than in UEA on CS (p = 0.03), although the difference between GAS and UEA was not apparent in LBC samples. DISCUSSION/CONCLUSION: This study demonstrated that the diagnostic clues to detect GAS using the conventional approach, namely distinct cell borders and prominent nucleoli, are not useful for excluding UEA in LBC samples. Conventional cervical smears may indicate a diagnosis of GAS; however, specific high-risk HPV detection approaches, such as HPV test or immunocytochemical p16/Ki-67 dual staining, are desirable to differentiate GAS from UEA in the setting of LBC with ambiguous cytomorphological features.

Cancer type­SLCO1B3 promotes epithelial­mesenchymal transition resulting in the tumour progression of non­small cell lung cancer.

Non­small cell lung cancer (NSCLC) is one of the most common histologically defined subtypes of lung cancer. To identify a promising molecular target for NSCLC therapy, we performed gene expression analysis at the exon level using postoperative specimens of NSCLC patients. Exon array and real­time PCR analyses revealed that an alternative splicing variant of solute carrier organic anion transporter family member 1B3 (SLCO1B3) called cancer type­SLCO1B3 (Ct­SLCO1B3) was significantly upregulated in the NSCLC samples. SLCO1B3 expressed in the liver [liver type (Lt)­SLCO1B3] was found to be localised in the cell membrane, whereas Ct­SLCO1B3 was detected in the cytoplasm of NSCLC cells. RNAi­mediated knockdown of Ct­SLCO1B3 inhibited in vitro anchorage­independent cell growth, cell migration, and in vivo tumour growth of A549 cells. Overexpression of Ct­SLCO1B3 but not Lt­SLCO1B3 upregulated anchorage­independent cell growth and cell migration of NCI­H23 cells. Mechanistically, Ct­SLCO1B3 was found to regulate the expression of epithelial­mesenchymal transition (EMT)­related genes. The upregulation of E­cadherin was discovered to be especially pivotal to phenotypes of Ct­SLCO1B3­suppressed A549 cells. These findings suggest that Ct­SLCO1B3 functions as a tumour­promoting factor via regulating EMT­related factors in NSCLC.

Natural History of Asymptomatic Pseudoaneurysm Soon After Robot-assisted Partial Nephrectomy: Single-center Prospective Study.

OBJECTIVE: To prospectively investigate the natural history of asymptomatic pseudoaneurysm after robotic-assisted partial nephrectomy. METHODS: Robotic-assisted partial nephrectomy was undertaken for 67 patients between July 2014 and July 2018. Patients who could not undergo enhanced CT were excluded, so 60 patients were finally included in the present study. We prospectively investigated the presence of pseudoaneurysm based on early enhanced CT scan on postoperative day 7. According to our treatment policy, patients with symptomatic pseudoaneurysm underwent selective transarterial embolization. Meanwhile, patients with asymptomatic pseudoaneurysm were observed with follow-up CT imaging, regardless of the size of the aneurysm. RESULTS: Overall incidence of pseudoaneurysm on postoperative day 7 was 18% (11/60 cases). The median size of the pseudoaneurysm was 9 mm (quartile: 6-12 mm). Two patients with symptomatic pseudoaneurysm underwent selective transarterial embolization. Nine patients had asymptomatic pseudoaneurysm; in 8 of these it disappeared without therapeutic intervention. The median period from surgery to confirmed disappearance of the aneurysm was 19 days (quartile 14-32 days). In the remaining 1 patient, small asymptomatic pseudoaneurysm (2 mm) could still be observed even 1 year after surgery. CONCLUSION: Our study showed high incidence of pseudoaneurysm 1 week after robotic-assisted partial nephrectomy that mostly disappeared without therapeutic intervention. Routine enhanced CT screening and pre-emptive embolization may not be necessary for asymptomatic renal artery pseudoaneurysm.

A report of three cancer patients on opioid analgesia receiving spinal anesthesia: abrupt pain elimination without respiratory depression.

BACKGROUND: Complete removal of pain with regional anesthesia has been reported to cause fatal respiratory depression in opioid-dependent patients, which leads us to choose general anesthesia. We hereby report three cases of chronically opioid-treated cancer patients operated under spinal anesthesia without respiratory event. CASE PRESENTATION: Case 1: a 32-year-old female treated with high-dose morphine for her cancer pain was planned for cesarean section. Case 2: a 65-year-old female on moderate dose of oxycodone was planned for surgery of her femoral bone fracture. Case 3: a 65-year-old male on low-dose oxycodone was planned for intramedullary nailing for metastatic femoral bone tumor. In all three cases, spinal anesthesia was chosen. Continuous respiratory monitoring revealed no apnea or bradypnea. CONCLUSION: Spinal anesthesia was safely performed without respiratory depression in chronic opioid users for cancer pain.

MicroRNA-130b functions as an oncomiRNA in non-small cell lung cancer by targeting tissue inhibitor of metalloproteinase-2.

Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer-related death worldwide. Although many molecular-targeted drugs for NSCLC have been developed in recent years, the 5-year survival rate of patients with NSCLC remains low. Therefore, an improved understanding of the molecular mechanisms underlying the biology of NSCLC is essential for developing novel therapeutic strategies for the treatment of NSCLC. In this study, we examined the role of miR-130b in NSCLC. Our results showed that high expression of miR-130b in clinical specimens was significantly associated with poor overall survival in patients with NSCLC. Moreover, miR-130b expression was significantly increased in NSCLC clinical specimens from patients with vascular and lymphatic invasion. Consistent with this, overexpression of miR-130b promoted invasion and matrix metalloproteinase-2 (MMP-2) activity in A549 cells. Argonaute2 immunoprecipitation and gene array analysis identified tissue inhibitor of metalloproteinase-2 (TIMP-2) as a target of miR-130b. Invasion activity promoted by miR-130b was attenuated by TIMP-2 overexpression in A549 cells. Furthermore, TIMP-2 concentrations in serum were inversely correlated with relative miR-130b expression in tumor tissues from the same patients with NSCLC. Overall, miR-130b was found to act as an oncomiR, promoting metastasis by downregulating TIMP-2 and invasion activities in NSCLC cells.

A sensitive and efficient procedure for the high-throughput determination of nine urinary metabolites of pyrethroids by GC-MS/MS and its application in a sample of Japanese children.

Four pyrethroids (PYRs), metofluthrin, profluthrin, tefluthrin, and transfluthrin, which were newly developed and have relatively high vapor activity at ambient temperature, are now playing a key role in safely controlling insects in our daily lives. We developed a sensitive and high-throughput determination method for urinary metabolites derived from the newly developed PYR, e.g., 2,3,5,6-tetrafluoro-1,4-benzenedimethanol (HOCH2-FB-Al), 2,3,5,6-tetrafluorobenzyl alcohol (FB-Al), and other PYR metabolites such as trans-chrysanthemumdicarboxylic acid (trans-CDCA) and 3-phenoxybenzoic acid (3PBA). After high temperature acid hydrolysis of 2 mL urine sample in 24-deep well plate, the PYR metabolites were extracted by semi-automated liquid-liquid extraction with tert-butyl methyl ether. N,O-Bis (trimethylsilyl) trifluoroacetamide containing 1% trimethylchlorosilane or 1,1,1,3,3,3-hexafluoroisopropanol were used for the derivatization of PYR metabolites, and the derivatized metabolites were analyzed separately by GC-MS/MS equipped with dual injector system (DB-5MS and mid- to high-polarity phase Rtx-65 columns). The derivatization and evaporation conditions were mainly optimized for improving sensitivity and reproducibility. The mean within-run day precisions were less than 18.4% (relative standard deviation, %RSD) with low detection limits ranging from 0.01 µg/L for HOCH2-FB-Al to 0.06 µg/L for trans-CDCA. This method was successfully applied to urine samples obtained from 50 3-year-old children with high detection frequencies (e.g., 82% for HOCH2-FB-Al and 84% for FB-Al). This method may be a pivotal tool for developing risk assessment from PYR exposure in the general population.

The Effectiveness of Saireito, a Traditional Japanese Herbal Medicine, in Reducing Postoperative Edema after Acquired Ptosis Surgery: A Prospective Controlled Trial.

BACKGROUND: Persistent edema is a common complication after the surgical treatment of blepharoptosis; however, no objective methods have been established for evaluating or treating this condition. We focused on the Japanese herbal medicine, Saireito, and evaluated its efficacy in reducing postoperative edema. METHODS: This was a prospective, nonrandomized, and controlled study. We evaluated the incidence of postoperative edema in a Control group using a subjective patient-assessed visual analog scales (VASs) to assess swelling, pain, itching, and local warmth and an objective surgeon-assessed VAS to evaluate swelling. Swelling was also assessed by an objective computer-based analysis of digital images. These methods were used to evaluate the effects of Saireito (8.1 g/day) for 8 weeks. RESULTS: A total of 49 patients and 80 eyelids were enrolled. Twenty-nine patients and 48 eyelids were assigned to the Control group, and 20 patients and 32 eyelids were assigned to the Saireito group. Our analysis of the Control group indicated that postoperative edema persisted for up to 8 weeks. On the other hand, the postoperative edema in the Saireito group was mostly eliminated at 8 weeks. The computer-based analysis of digital images showed that the edema tended to be reduced in the Saireito group compared with the Control group. CONCLUSION: Saireito might be effective for reducing postoperative edema after blepharoptosis surgery and almost completely eliminated it at 8 weeks after surgery. This study was a preliminary and nonrandomized study; therefore, the randomized and placebo-controlled study will be needed in the next step.