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Background: Retinopathy of prematurity (ROP) is a significant cause of blindness in infants. Appropriate therapeutic intervention is essential because retinal detachment due to the progression of ROP is critical to visual function. The intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents has been increasingly applied to inhibit the development and progression of ROP. In this study, we compared the efficacy of single intravitreal bevacizumab (IVB) and ranibizumab (IVR) injections for the treatment of ROP. Methods: A total of 39 eyes in 21 patients with severe ROP and IVB (15 eyes of 8 patients) and IVR (24 eyes of 13 patients) were retrospectively reviewed. Patient background, the severity of ROP, and the percentage of cases in which ROP regressed without additional treatment were compared between the two groups. Results: Patient background and ROP severity were not significantly different between the two groups. Recurrence was observed in one eye of one patient in the IVB group, and thirteen eyes in seven patients in the IVR group required additional laser photocoagulation, which was significantly different in the two groups (p < 0.01, Fisher's exact test). In the IVR group, two eyes of two patients underwent vitreous surgery. Conclusion: Compared with IVR, IVB is likely to control the severity of ROP with a single treatment. [ABSTRACT FROM AUTHOR]

Background: Driver mutations at BRAF V600 are frequently identified in papillary thyroid cancer and anaplastic thyroid cancer (ATC), in which BRAF inhibitors have shown clinical effectiveness. This Japanese phase 2 study evaluated the efficacy and safety of a BRAF inhibitor, encorafenib, combined with an MEK inhibitor, binimetinib, in patients with BRAF V600-mutated thyroid cancer. Methods: This phase 2, open-label, uncontrolled study was conducted at 10 institutions targeted patients with BRAF V600-mutated locally advanced or distant metastatic thyroid cancer not amenable to curative treatment who became refractory/intolerant to ≥1 previous vascular endothelial growth factor receptor-targeted regimen(s) or were considered ineligible for those. The primary endpoint was centrally assessed objective response rate (ORR). The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: We enrolled 22 patients with BRAFV600E-mutated thyroid cancer: 17 had differentiated thyroid cancer (DTC), and 5 had ATC. At data cutoff (October 26, 2022), the median follow-up was 11.5 (range = 3.4–19.0) months. The primary endpoint of centrally assessed ORR was 54.5% (95% confidence interval [CI] 32.2–75.6; partial response in 12 patients and stable disease in 10). The ORRs in patients with DTC and ATC were 47.1% (8 of 17) and 80.0% (4 of 5), respectively. The medians for DOR and PFS by central assessment and for OS were not reached in the overall population, the DTC subgroup, or the ATC subgroup. At 12 months, the rate of ongoing response was 90.9%, and the PFS and OS rates were 78.8% and 81.8%, respectively. All patients developed ≥1 adverse events (AEs): grade 3 AEs in 6 patients (27.3%). No patients developed grade 4–5 AEs. The most common grade 3 AE was lipase increased (4 patients [18.2%]). Those toxicities were mostly manageable with appropriate monitoring and dose adjustment. Conclusions: Treatment with encorafenib plus binimetinib met the primary endpoint criteria and demonstrated clinical benefit in patients with BRAFV600E-mutated thyroid cancer regardless of its histological type, such as DTC or ATC, with no new safety concerns identified. Encorafenib plus binimetinib could thus be a new treatment option for BRAF V600-mutated thyroid cancer. Clinical Trial Registration number: Japan Registry of Clinical Trials: jRCT2011200018 [ABSTRACT FROM AUTHOR]

Local low‐frequency vibration promotes blood flow and wound healing in hard‐to‐heal diabetic foot ulcers (DFUs). However, vibration treatment is challenging in patients with DFUs due to wound management difficulties and low adherence. Consequently, developing wearable self‐care devices becomes imperative for effective wound healing. This study introduces a wearable vibration dressing and assesses its impact on wound healing in hyperglycemic rats. Low‐frequency vibration at 52 Hz was applied to the wound for 40 min/day in awake rats. Relative wound areas on post‐wounding days (PWDs) 4–7 were significantly smaller and the wound closure rate was significantly higher in the vibration group than in the control group (p < 0.05, respectively). The total haemoglobin at baseline and after vibration on post‐wounding day 7 was significantly larger in the vibration group than in the control group (p < 0.05). On PWD 7, the thickness of the granulation tissue was significantly higher in the vibration group than in the control group (p < 0.05). Moreover, the number of blood vessels at the wound site and vascular endothelial growth factor A protein expression were significantly higher in the vibration group than in the control group (p < 0.05, respectively). The ratio of (CD68+/iNOS+)/(CD163+) macrophages in the vibration group was significantly lower than that in the control group (p < 0.05). These results indicate the potential of wearable vibration dressings as new self‐care devices that can promote angiogenesis and blood flow, improve inflammation, and enhance wound healing in DFUs. [ABSTRACT FROM AUTHOR]

Gastric acid secretion inhibitors such as proton pump inhibitors (PPIs) and vonoprazan may change the duration of treatment with bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, for cancer. However, there are no data on this prolongation effect. Here, we aimed to determine whether the use of PPIs or vonoprazan in patients with cancer receiving bevacizumab affected the duration of bevacizumab treatment. This observational study was conducted at two national university hospitals in Japan and involved 222 patients using oral PPIs (N = 190) or vonoprazan (N = 32) at the start of bevacizumab treatment between January 2015 and December 2018. Patients who received only one course of bevacizumab were excluded. The primary endpoint was the duration of bevacizumab treatment. The duration of bevacizumab treatment varied significantly between the PPI and vonoprazan groups. For cancer types other than colorectal cancer (breast, lung, brain, and ovarian cancers), the median duration of treatment was 217 days (p < 0.05) and was longer in the vonoprazan group than in the PPI group. However, for colorectal cancer, the median duration of bevacizumab treatment was 147 days longer in the PPI group than in the vonoprazan group. Selection of appropriate gastric acid secretion inhibitors may improve the therapeutic efficacy of anti-VEGF drugs, including bevacizumab. Oestrogen is a key regulator of this effect and may be responsible for the varying association between PPI or vonoprazan administration and the difference in bevacizumab treatment duration between colon cancer and other cancer types. [ABSTRACT FROM AUTHOR]

Coronavirus disease (COVID-19) often causes persistent symptoms long after infection, referred to as "long COVID" or post-acute COVID-19 syndrome (PACS). This phenomenon has been studied primarily concerning B-cell immunity, while the involvement of T-cell immunity is still unclear. This retrospective study aimed to examine the relationship among the number of symptoms, cytokine levels, and the Enzyme-linked immunosorbent spot (ELISPOT) assay data in patients with COVID-19. To examine inflammatory conditions, plasma interleukin (IL)-6, IL-10, IL-18, chemokine ligand 9 (CXCL9), chemokine ligand 3 (CCL3), and vascular endothelial growth factor (VEGF) levels were analyzed using plasma obtained from COVID-19 recovery patients and healthy controls (HC). These levels were significantly higher in the COVID-19 group than those in the HC group. ELISPOT assays were performed to investigate the correlation between COVID-19 persistent symptoms and T-cell immunity. Cluster analysis of ELISPOT categorized COVID-19 recovery patients in the ELISPOT-high and -low groups, based on the values of S1, S2, and N. The number of persistent symptoms was significantly higher in the ELISPOT-low group than those in the ELISPOT-high group. Thus, T cell immunity is critical for the rapid elimination of COVID-19 persistent symptoms, and its measurement immediately after COVID-19 recovery might predict long-term COVID-19 or PACS. [ABSTRACT FROM AUTHOR]

Background: Although the efficacy of atezolizumab has been demonstrated in randomized controlled trials, its long‐term efficacy and association with adverse events in real‐world practice are unknown. This study was designed to shed light on these issues. Methods: In this multicenter retrospective study, data were collected from patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab in seven institutions in Japan. The authors focused on the efficacy and adverse events related to vascular endothelial growth factor (VEGF) inhibition. Results: A total of 123 patients were enrolled in this study. The median progression‐free survival (PFS) for the first‐line treatment group was 8.0 months (95% confidence interval [CI], 6.1–9.9), whereas the median PFS for the second‐ or later‐line treatment group was 4.1 months (95% CI, 2.6–5.7), which was significantly worse than that of the first‐line treatment group (p =.005). Twenty‐seven patients had interrupted bevacizumab treatment. Proteinuria accounted for the largest proportion of bevacizumab treatment interruptions. The cumulative incidence rate of bevacizumab interruption due to anti‐VEGF–related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus than in those without (p =.026). The landmark analysis showed that patients experienced bevacizumab interruption by 24 weeks from treatment initiation had poorer PFS than those who did not (p =.013). Conclusions: The PFS of atezolizumab plus bevacizumab as first‐line treatment mostly replicates that of a global phase 3 trial. Interrupted bevacizumab treatment was more common in patients with hypertension and/or diabetes mellitus, which may be associated with worsening long‐term PFS. Plain language summary: Atezolizumab plus bevacizumab has been the standard front line systemic therapy for advanced hepatocellular carcinoma.With the growing incidence of fatty liver due to metabolic syndrome as a background liver disease for hepatocellular carcinoma, the rate of comorbid hypertension and diabetes mellitus has been increasing accordingly.The present study demonstrated the cumulative incidence rate of bevacizumab interruption due to anti‐VEGF–related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus.The landmark analysis clarified that interruption of bevacizumab might be a risk of impaired efficacy of atezolizumab plus bevacizumab over the long term in patients with advanced hepatocellular carcinoma. This report demonstrated that the cumulative incidence rate of bevacizumab interruption due to anti‐VEGF–related adverse events was significantly higher in patients with comorbid hypertension and/or diabetes mellitus during atezolizumab plus bevacizumab for advanced hepatocellular carcinoma. Interruption of bevacizumab might be a risk of impaired efficacy of atezolizumab plus bevacizumab over the long term in patients with advanced hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Introduction: The tumor microenvironment (TME) in colorectal cancer (CRC) includes the gut microbiome, immune cells, angiogenic factors, and fibroblasts and plays a major role in cancer progression. The Immunoscore (IS) is based on tumor infiltration by immune cells that are known prognostic biomarkers for CRC. However, the interrelation between the IS, microbiome, and other TME factors in human CRC remains unclear. Patients and methods: A cohort of 94 patients with CRC was examined at the Shiga University of Medical Science Hospital in Japan. The expression levels of CD3, CD8, CD31, and alpha-smooth muscle actin (α-SMA) in the primary tumor were evaluated by immunohistochemistry. The IS was calculated based on the results of the CD3 and CD8 staining assays. Microbiomes in patients with CRC were examined by amplicon sequencing. Results: The expression levels of α-SMA and tumor-infiltrating lymphocytes in patients with CRC were negatively correlated (P = 0.006). A high IS was associated with high abundance of Lachnospiraceae in the microbiomes of patients with CRC. Conclusion: Lymphocyte infiltration into the primary tumor was marked by reduced density of cancer-associated fibroblasts and enrichment of the Lachnospiraceae family in the gut microbiome, which may influence CRC progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Pain is experienced by ~55% of patients who undergo anti-cancer treatment. However, many genetic factors that are involved in the efficacy of opioid analgesics in the treatment of cancer pain remain unidentified. The aim of our genome-wide association study (GWAS) was to comprehensively explore genetic variations that are associated with opioid analgesic requirements in the treatment of cancer pain. We identified several single-nucleotide polymorphisms (SNPs) that are associated with opioid analgesic requirements, two of the most potent of which were the rs1283671 and rs1283720 SNPs in the ANGPT1 gene region, and SNPs in the SLC2A14 gene were also associated with the phenotype. These results indicate that these SNPs in the ANGPT1 and SLC2A14 genes could serve as markers that predict the efficacy of opioid analgesics in the treatment of cancer pain. Considerable individual differences have been widely observed in the sensitivity to opioids. We conducted a genome-wide association study (GWAS) in patients with cancer pain to identify potential candidate single-nucleotide polymorphisms (SNPs) that contribute to individual differences in opioid analgesic requirements in pain treatment by utilizing whole-genome genotyping arrays with more than 650,000 markers. The subjects in the GWAS were 428 patients who provided written informed consent and underwent treatment for pain with opioid analgesics in a palliative care unit at Higashi-Sapporo Hospital. The GWAS showed two intronic SNPs, rs1283671 and rs1283720, in the ANGPT1 gene that encodes a secreted glycoprotein that belongs to the angiopoietin family. These two SNPs were strongly associated with average daily opioid requirements for the treatment of pain in both the additive and recessive models (p < 5.0000 × 10−8). Several other SNPs were also significantly associated with the phenotype. In the gene-based analysis, the association was significant for the SLC2A14 gene in the additive model. These results indicate that these SNPs could serve as markers that predict the efficacy of opioid analgesics in cancer pain treatment. Our findings may provide valuable information for achieving satisfactory pain control and open new avenues for personalized pain treatment. [ABSTRACT FROM AUTHOR]

Angiogenesis is a hallmark of cancer development. This study sought to determine the recommended dose of aflibercept, a recombinant fusion protein targeting VEGF-A, VEGF-B and placental growth factor (PlGF), combined with docetaxel in Japanese patients with advanced solid malignancies. This phase I study was planned to include 12 patients following a 3 + 3 algorithm to determine the maximum tolerated dose of aflibercept combined with docetaxel in patients with metastatic or unresectable solid tumors (trial registration: NCT00545246). Docetaxel (75 mg/m2 every 3 weeks or 60 mg/m2 after protocol amendment) was combined with escalating doses of aflibercept (2, 4 and 6 mg/kg every 4 weeks). Free and VEGF-bound aflibercept were measured to assess free aflibercept in excess of the VEGF-bound form. At the starting dose of the combination, 3 of 6 patients treated experienced febrile neutropenia. After reducing the docetaxel dose to 60 mg/m2 in step 2 and permitting therapeutic granulocyte colony-stimulating factor (G-CSF) use, 2 of 3 patients in both cohorts experienced febrile neutropenia. Five patients (42%) had a partial response and 4 patients had stable disease (33%). Free aflibercept in excess of the VEGF-bound form was not maintained at this dose level. The dose limiting toxicity (DLT) of aflibercept combined with docetaxel was febrile neutropenia, which occurred in 2 of 3 Japanese patients at the lowest aflibercept dose level (2 mg/kg) combined with docetaxel (60 mg/m2) and therapeutic G-CSF use. A recommended dose for further studies was not determined because of the DLT at the starting dose. [ABSTRACT FROM AUTHOR]

Background: Hemodialysis (HD) is a common renal replacement therapy for patients with renal failure. Cardiovascular and cerebrovascular diseases are known to shorten survival periods and worsen the quality of life of HD patients. Atherosclerosis is a major cause of vascular diseases, and various factors such as abnormality of lipid metabolism and increased macrophage activity, oxidative stress, and endothelial dysfunction are associated with its pathogenesis and progression. Further, endothelial stem cells (ESCs) have been reported to play important roles in endothelial functions. Royal jelly (RJ) affects atherosclerosis- and endothelial function-related factors. The main aim of this trial is to investigate whether oral intake of RJ can maintain endothelial function in HD patients. In addition, the effects of RJ intake on atherosclerosis, ESC count, inflammation, and oxidative stress will be analyzed.Methods: This will be a multicenter, prospective, double-blind, randomized controlled trial. We will enroll 270 participants at Nagasaki Jin Hospital, Shinzato Clinic Urakami, and Maeda Clinic, Japan. The participants will be randomized into RJ and placebo groups. The trial will be conducted according to the principles of the Declaration of Helsinki, and all participants will be required to provide written informed consent. The RJ group will be treated with 3600 mg/day of RJ for 24 months, and the placebo group will be treated with starch for 24 months. The primary endpoint will be the change in flow-mediated dilation (FMD), a parameter of endothelium function, from the time before treatment initiation to 24 months after treatment initiation. The secondary and other endpoints will be changes in FMD; ESC count; serum levels of vascular endothelial cell growth factor, macrophage colony-stimulating factor, 8-hydroxydeoxyguanosine, and malondialdehyde; the incidence of cardiovascular diseases, cerebrovascular diseases, and stenosis of blood access; and safety.Discussion: This trial will clarify whether oral intake of RJ can maintain endothelial function and suppress the progression of atherosclerosis in HD patients. In addition, it will clarify the effects of RJ on ESCs, oxidative stress, and angiogenic activity in blood samples.Trial Registration: The Japan Registry of Clinical Trials  jRCTs071200031 .  Registered on 7 December 2020. [ABSTRACT FROM AUTHOR]

Sweet potato shochu oil is one of the by-products of sweet potato shochu production. We investigated the functionality and industrial use of shochu oil as a food-derived raw material. Because of the increased incidence of self-consciousness in people owing to thinning hair, in this study, we examined the hair growth-inducing effects of shochu oil. Minoxidil, the only topical medication approved for hair growth treatment in Japan, was used as a control for the evaluation of hair growth-promoting activity of shochu oil. Human follicle dermal papilla cells treated with shochu oil showed upregulated expression of vascular endothelial growth factor in a concentration-dependent manner, indicating that shochu oil induced the activation of the hair growth cycle. In vivo , epidermal treatment with shochu oil also promoted hair growth in C3H mice. More than 35 components were detected in shochu oil via gas chromatography–mass spectrometry. The main components, accounting for 98.5% of shochu oil, were as follows, in order of decreasing concentration: ethyl palmitate, ethyl linoleate, ethyl oleate, ethyl stearate, ethyl caprate, ethyl laurate, ethyl myristate, and ethyl α-linolenate. Among these, ethyl palmitate, ethyl linoleate, and ethyl α-linolenate promoted hair growth in C3H mice. These results indicate that shochu oil can be used as a hair restorer. To the best of our knowledge, this study is the first to demonstrate the hair growth-promoting activity of shochu oil. [ABSTRACT FROM AUTHOR]

Objectives: This study compared indocyanine green (ICG)-enhanced fluorescence optical imaging (FOI) and musculoskeletal ultrasound (MSUS), and explored the significance of the FOI findings based on the association between the FOI and MSUS findings and serum biomarkers in patients with rheumatoid arthritis (RA). The study also explored the association between the FOI findings and patients' joint destruction at the joint-area level.Method: We enrolled 50 consecutive patients with active RA from among the patients hospitalized from May 2014 to March 2016 at Nagasaki University Hospital, Japan. FOI images were acquired with the Xiralite® fluorescence imaging system and compared with the patients' clinical examination results and MSUS findings. On the same day, the patients' clinical disease activity and levels of serum biomarkers (including vascular endothelial growth factor) were obtained.Results: Although the FOI detected synovitis with high sensitivity, the frequency of positive findings and the diagnostic performance with MSUS as the reference standard for FOI differed considerably among the phases of FOI as well as among the affected joint regions. The FOI scores were positively correlated with clinical disease activity, MSUS scores, and serum biomarkers. The severity of FOI-proven synovitis was associated with the presence of MSUS-proven bone erosion.Conclusion: FOI is effective for detecting joint inflammation in RA patients, with high accuracy. The severity of the FOI score was closely associated with the joint destruction at the joint-area level. However, the significance of positive FOI findings differed depending on not only the phase of FOI but also the affected joint regions. [ABSTRACT FROM AUTHOR]

Objective: The purpose of our study was to determine the 4-year visual and anatomic outcomes of intravitreal aflibercept treatment for neovascular age-related macular degeneration (AMD) using a treat-and-extend (TAE) regimen. Methods: We retrospectively reviewed the medical records of 39 patients with neovascular AMD who were treated continuously with intravitreal aflibercept injections using the TAE regimen for at least 4 years. The outcome measures were the best-corrected visual acuity (BCVA) and central macular thickness (CMT) on spectral-domain optical coherence tomography. The BCVAs were measured as decimal values and converted to the corresponding Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores for statistical analysis. The Wilcoxon signed-rank test was used to compare the differences in BCVAs and CMTs. Results: The mean ETDRS letter scores improved significantly from 63.9 at baseline to 70.4, 67.8, 67.2, and 67.3 at 1, 2, 3, and 4 years, respectively. The mean baseline CMT was 380 µm, which decreased significantly to 229, 231, 221, and 210 µm at 1, 2, 3, and 4 years, respectively. The mean numbers of injections were 7.9, 6.0, 5.5, and 5.4 at 1, 2, 3, and 4 years, respectively. The percentages of patients with a treatment interval of 12 weeks or more were 46.2%, 46.2%, 43.6%, and 46.2% at 1, 2, 3, and 4 years, respectively. At year 4, 30.8% of the patients had a treatment interval of 7 weeks or less, whereas 25.6% had 16 weeks or more. Conclusion: Intravitreal aflibercept TAE treatment may be an effective and efficient method for treating patients with neovascular AMD up to 4 years of follow-up. The TAE regimen is a potential tool to optimize appropriate treatment intervals, avoiding both undertreatment and overtreatment of neovascular AMD. [ABSTRACT FROM AUTHOR]

The concept of angiogenic therapy emerged in the early 1990s. The method employs genes that encode growth factors to promote formation of new vessels and remodeling of collateral vessels. Since the procedure involved in this therapy usually only consists of local injections of vectors, the process is minimally invasive, quick, and simple to perform. However, since the first clinical evidence of the effects of gene therapy with vascular endothelial growth factor (VEGF) was observed in patients with peripheral artery disease, to date only two angiogenic therapy drugs have been approved, one in Russia and another in Japan, which seem a very small number, in view of the large volume of investment made in pre-clinical and clinical studies. After all, can we conclude that angiogenic therapy is a reality? [ABSTRACT FROM AUTHOR]

Aims/Introduction: To determine the current clinical preferences of anti‐vascular endothelial growth factor (VEGF) treatment protocols for diabetic macular edema (DME) in Japan. Materials and Methods: This was a descriptive cross‐sectional study. Answers to a questionnaire consisting of 16 questions were obtained from 176 of 278 (63.3%) surveyed ophthalmologists. Results: The results showed that 81.2% preferred intravitreal injections of anti‐VEGF antibodies as the first‐line therapy. The most important indicators for beginning anti‐VEGF therapy were: the best‐corrected visual acuity in 44.3% and the retinal thickness in 30.7%. In the loading phase, 53.4% preferred a single injection, and in the maintenance phase, 75.0% preferred the pro re nata regimen. Financial limitation (85.8%) was reported as the most important difficulty in the treatment. For combination therapy with anti‐VEGF treatment, panretinal photocoagulation, focal photocoagulations and a sub‐Tenon steroid injection were preferred. The contraindications for anti‐VEGF therapy were: prior cerebral infarction (72.7%). Regarding the use of both approved anti‐VEGF agents in Japan, ranibizumab and aflibercept, 39.8% doctors used them appropriately. Conclusions: Our results present the current clinical preferences of anti‐VEGF treatment for DME in Japan. The best‐corrected visual acuity and the retinal thickness are important indicators to institute this therapy. The majority of the ophthalmologists use anti‐VEGF treatment as first‐line therapy and prefer the 1 + pro re nata regimen. We show the current clinical preferences of anti‐VEGF)treatments for DME in Japan. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the incidence of early recurrent hemorrhage in submacular hemorrhage secondary to type 3 neovascularization or retinal angiomatous proliferation (RAP) and its influence on visual prognosis.Methods: This retrospective study included 32 eyes with submacular hemorrhage secondary to type 3 neovascularization or RAP that underwent anti-vascular endothelial growth factor (VEGF) therapy. The eyes exhibiting an increase in the extent of hemorrhage within 6 months after hemorrhage development were included in the early recurrent hemorrhage group, and the remaining eyes were included in the non-early recurrent hemorrhage group. The best-corrected visual acuities (BCVAs) measured at the time of hemorrhage development and at 12 months were compared between the two groups.Results: During the follow-up period, 8 eyes underwent vitrectomy to clear vitreous hemorrhage, and the remaining 24 eyes underwent anti-VEGF monotherapy. In the early recurrent hemorrhage group (n = 12), the mean logarithm of the minimal angle of resolution BCVA at the time of hemorrhage development and after 12 months was 1.17 ± 0.40 (Snellen equivalents: 20/295) and 2.35 ± 0.59 (20/4477), respectively. In the non-early recurrent hemorrhage group (n = 20), the corresponding values were 1.07 ± 0.43 (20/234) and 1.44 ± 0.71 (20/550), respectively. The BCVA at 12 months was significantly worse in the early recurrent hemorrhage group (P = 0.003) despite comparable BCVA at diagnosis between the two groups (P = 1.000).Conclusions: Early recurrent hemorrhage was noted in 37.5% of eyes with submacular hemorrhage secondary to type 3 neovascularization or RAP and was closely associated with a poor prognosis. [ABSTRACT FROM AUTHOR]

POEMS syndrome is a rare plasma cell dyscrasia presenting with polyneuropathy, λ-type M protein, vascular endothelial growth factor elevation, and systemic manifestations. The standard treatment has not been established, but autologous stem cell transplantation (ASCT) has exhibited effectiveness in this syndrome. However, the efficacy and long-term outcomes of ASCT have not been systematically studied. To clarify the efficacy and long-term outcomes of ASCT-treated patients in Japan, we performed a multicenter retrospective study assessing the clinical course of patients registered to the Japan Society for Hematopoietic Cell Transplantation Transplant Registry Unified Management Program (TRUMP) database. Between January 2000 and December 2011, 95 patients (58 men) were registered to the TRUMP database with a median age of 53 years (range, 28 to 72). The conditioning regimen was melphalan in 93 of 94 patients (99%), and 69 patients (74.2%) received a melphalan dose ≥ 200 mg/m 2 . The median CD34 cell dose was 2.47 × 10 6 /kg (range, .31 to 20). After ASCT, patient performance status was dramatically improved (Eastern Cooperative Oncology Group performance status 0 to 1: 20.0% versus 71.6%, P  < .0001). Over a median follow-up of 46.6 months 10 patients died, and 5-year overall survival was 88.8% (n = 95). Progression-free survival at 3 years was 78.3% (n = 70; median follow-up, 54.4 months). These data support the promising role of ASCT in patients with POEMS syndrome for both prolonging survival and improving quality of life. However, disease recurrence remains a major issue for long-term survivors. [ABSTRACT FROM AUTHOR]

Background Angiopoietin-like protein 8 (ANGPTL8) is considered to be metabolically multifunctional. One notable function still to be elucidated definitively is a betatrophic role in protecting and preserving pancreatic beta-cell function. There is, however, a paucity of data regarding the role of ANGPTL8 in the etiology of type 2 diabetes (T2D), but some findings of human research have suggested the potential for significant involvement. Objective To examine the frequency of T2D and impaired glucose tolerance (IGT) in Japanese subjects with the ANGPTL8 R59W variant. Methods ANGPTL8 R59W (Rs2278426, c.194C > T) was determined by polymerase chain reaction–restriction fragment length polymorphism using the restriction enzyme FokI in 797 consecutive Japanese individuals. Subjects with triglyceride levels greater than or equal to 150 mg/dL were considered to be hypertriglyceridemic. Results Genotype frequencies of ANGPTL8 R59W were as follows: wild-type RR (C/C) 53.5%, RW (C/T) 36.6%, and WW (T/T) 9.9%. T2D and IGT were significantly prevalent in WW and RW subjects relative to RR among all 797 subjects ( P = .0138) and also in hypertriglyceridemic subjects ( P = .0015). In multiple logistic regression models for the existence of T2D and IGT in hypertriglyceridemic subjects, the odds ratio for heterozygote RW and homozygote WW genotypes to wild-type RR was 2.406 ( P = .0017) after controlling the risk factors of age, gender, and body mass index as covariates. Conclusions The frequency of ANGPTL8 R59W is significantly higher in Japanese subjects than in other ethnic groups. The rates of T2D and IGT were greater in subjects with the R59W variant. These findings indicate that ANGPTL8 is a participant in diabetes and a potential therapeutic target for T2D prevention, especially in East Asians. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to monitor anti-vascular endothelial growth factor (anti-VEGF) treatment regimens for wet age-related macular degeneration (wAMD) in clinical practice and to determine how they impact the physician, patient, and caregiver treatment experience. Materials and methods: This was a qualitative analysis based on semistructured interviews with 20 ophthalmologists who had practiced both pro re nata (PRN) and treat-and-extend (T & E) anti-VEGF regimens for wAMD. Interview questions were constructed to assess how the different regimens affected patient and caregiver experiences (in the opinion of the ophthalmologist) in addition to the ophthalmologist's own experience. The interview included questions relating to 1) issues and benefits of PRN and T & E; 2) logistical and operational issues of introducing proactive therapy, especially T & E, to PRN practice; and 3) actions taken to handle the issues raised in 2). Results: A total of 18 interview results were eligible for analysis. The study demonstrated that the benefits of T & E compared with PRN included decreased burden of patient consultations, decreased patient and caregiver emotional burden, and a sustained period of macular dryness. The issues associated with T&E were increased number of injections and financial burden from prolonged treatment duration. The ophthalmologists also experienced difficulty explaining the significance of proactive injections to patients. Countermeasures to operational issues experienced by ophthalmologists varied by practice. Conclusion: Patients, caregivers, and the practicing ophthalmologists experienced benefits associated with a T&E regimen. However, in order to encourage better understanding of the T & E regimen, including its smooth implementation and significance for patients, a formal T & E treatment guideline providing standard practice should be considered. [ABSTRACT FROM AUTHOR]

Background Elpamotide is an HLA-A*24:02-restricted epitope peptide of vascular endothelial growth factor receptor 2 (VEGFR-2) and induces cytotoxic T lymphocytes (CTLs) against VEGFR-2/KDR. Given the high expression of VEGFR-2 in biliary tract cancer, combination chemoimmunotherapy with elpamotide and gemcitabine holds promise as a new therapy. Patients and Methods Patients with unresectable advanced or recurrent biliary tract cancer were included in this single-arm phase II trial, with the primary endpoint of overall survival. Survival analysis was performed in comparison with historical control data. The patients concurrently received gemcitabine once a week for 3 weeks (the fourth week was skipped) and elpamotide once a week for 4 weeks. Results Fifty-five patients were registered, of which 54 received the regimen and were included in the full analysis set as well as the safety analysis set. Median survival was 10.1 months, which was longer than the historical control, and the 1-year survival rate was 44.4 %. Of these patients, injection site reactions were observed in 64.8 %, in whom median survival was significantly longer (14.8 months) compared to those with no injection site reactions (5.7 months). The response rate was 18.5 %, and all who responded exhibited injection site reactions. Serious adverse reactions were observed in five patients (9 %), and there were no treatment-related deaths. Conclusion Gemcitabine and elpamotide combination therapy was tolerable and had a moderate antitumor effect. For future development of therapies, it will be necessary to optimize the target population for which therapeutic effects could be expected. [ABSTRACT FROM AUTHOR]

Aim To evaluate the effects of fibroblast growth factor ( FGF)-2 on the healing of surgical periodontal defects in rats with early, streptozotocin-induced diabetes. Materials and Methods Fifty Wistar rats were assigned to streptozotocin-induced diabetes or non-diabetes group. Periodontal defects were surgically created at maxillary first molars. Defects were treated with hydroxypropyl cellulose ( HPC) or FGF-2 with HPC. Defect fill was evaluated by microcomputed tomography. Histological and immunohistochemical analyses were performed. Results Compared to vehicle alone, FGF-2 treatment yielded significantly greater bone volume and trabecular thickness in diabetes group. Diabetes group displayed reduced new bone formation and significantly longer epithelial down-growth compared to non-diabetes group. In diabetes group, FGF-2 treatment increased PCNA-positive cells and new bone formation after 2 weeks and suppressed epithelial down-growth, but new cementum formation was minimal even after 4 weeks. In diabetes group, overexpression of vascular endothelial growth factor was evident in cells within connective tissue, and no significant enhancement was observed by FGF-2 treatment. FGF-2 increased the expression of α-smooth muscle actin in diabetes group. Conclusions Treatment of surgical periodontal defects in diabetic rats with the single application of FGF-2 provided beneficial effects primarily on new bone formation via increasing cell proliferation and regulating angiogenesis. [ABSTRACT FROM AUTHOR]

The article examines a possible association between aortic dissection and vascular endothelial growth factor pathway inhibitors (VPIs) like bevacizumab, sunitinib, and sorafenib. As of October 2015, eight VPIs were approved in Japan for treating various malignant tumors such as renal cell carcinoma, hepatocellular carcinoma, and soft tissue sarcomas.

Transport and Golgi organisation protein 1 (TANGO), also known as MIA3, belongs to the melanoma inhibitory activity (MIA) gene family. Although MIA acts as an oncogene, MIA2 and TANGO have a tumour-suppressive function in several malignancies; accordingly, the role and function of the MIA gene family in tumours remain controversial. Here the roles of TANGO were investigated in oral squamous cell carcinoma (OSCC). We analysed expression and function of TANGO in human OSCC cell lines. TANGO expression was also examined in 171 cases of primary OSCC by immunohistochemistry and statistically assessed the correlation between TANGO positivity and the clinicopathological parameters including vessel density. By TANGO knockdown in OSCC cells, the growth and invasion were repressed and apoptosis was induced. Activities of platelet-derived growth factor beta polypeptide (PDGFB) and Neuropilin2 were inhibited by TANGO knockdown. TANGO immunoreactivity was detected in 35.1% (60/171) cases of OSCC. TANGO expression was strongly associated with tumour progression, nodal metastasis, clinical stage and number of blood or lymph vessels in OSCC. Patients showing TANGO-expression fared significantly worse disease-free survival than cases without TANGO expression. These findings suggest that TANGO might promote angiogenesis and lymphangiogenesis by upregulation of PDGFB and Neuropilin2 in OSCC. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to determine the significance of miR-126 and miR-20b in colorectal carcinogenesis. Methods: We analyzed the expressions of miR-126 and miR-20b in 136 colorectal tumors from 39 microsatellite stable (MSS) tumors, 23 high microsatellite instability (MSI-H) tumors, 16 Lynch syndrome, and 58 familial adenomatous polyposis (FAP) tumors including adenoma, intramucosal carcinoma, and invasive carcinoma. Results: All four kinds of tumors showed underexpression of both miR-126 and miR-20b. The frequency of miR-126 downregulation was 100.0% in FAP adenomas, 85.7% in FAP intramucosal carcinomas, 78.9% in invasive carcinomas, 81.3% in Lynch syndrome tumors, 68.4% in MSS tumors, and 65.4% in MSI-H tumors. The frequency of miR-20b downregulation was 64.0% in FAP adenomas, 50.0% in FAP intramucosal carcinomas, 73.3% in invasive carcinomas, 62.5% in Lynch syndrome tumors, 79.5% in MSS tumors, and 91.3% in MSI-H tumors. The current study demonstrated underexpression of miR-126 and miR-20b in various types of colorectal cancer. These findings support the hypothesis that angiogenesis results from underexpressions of miR-126 and miR-20b and occurs as an early event in colorectal carcinogenesis. Conclusions: Underexpression of miR-126 and miR-20b was observed in various types of colorectal cancer, and occurs as an early event of colorectal carcinogenesis in FAP tumors. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim To determine novel prognostic factors and treatment modalities for uterine carcinosarcoma ( UCS). Methods We performed immunohistochemical staining of estrogen receptor ( ER)-α, ER-β, progesterone receptor, gonadotropin-releasing hormone receptor, vascular endothelial growth factor ( VEGF), platelet-derived endothelial cell growth factor ( PD-ECGF) and platelet-derived growth factor receptor ( PDGFR)-β in a clinicopathological study of 15 UCS patients. Results No significant differences were found between the sarcomatous and carcinomatous components with respect to expression of ER-α, ER-β and progesterone receptor. However, VEGF was significantly more frequently expressed in the carcinomatous component, while PD-ECGF and PDGFR-β were significantly more frequently expressed in the sarcomatous component. Only one patient showed gonadotropin-releasing hormone receptor expression in the sarcomatous component. Moreover, ER-β expression in resected specimens, increased serum levels of carbohydrate antigen ( CA)-125 and C-reactive protein ( CRP), and thrombocytosis were determined as significant UCS prognostic factors. Conclusion Combination of anti- VEGF therapy and anti- PD-ECGF or anti- PDGFR-β therapy would be expected in advanced or recurrent UCS. Furthermore, careful monitoring for early detection of recurrence should be performed when UCS patients showed preoperative increase in serum CA-125 levels, CRP and platelet counts, and ER-β expression in biopsied or surgically resected specimens. [ABSTRACT FROM AUTHOR]

Background. Pancreatic neuroendocrine tumors (NETs) are rare but are frequently diagnosed at advanced stages and require systemic therapy. Patients and methods. This multicenter, open-label, phase II study evaluated sunitinib in Japanese patients with well-differentiated pancreatic NET. Patients received sunitinib 37.5 mg/day on a continuous daily dosing (CDD) schedule. The primary endpoint was clinical benefit rate (CBR; percentage of complete responses [CRs] plus partial responses [PRs] plus stable disease [SD] ≥24 weeks). Secondary endpoints included objective response rate (ORR), tumor shrinkage, progression-free survival (PFS) probability, safety, pharmacokinetics, and biomarkers. Results. Twelve patients received treatment. The CBR was 75 % (95 % confidence interval [CI], 43-94) and included 6 patients with a PR and 3 with SD. The ORR was 50 % (95 % CI, 21-79). PFS probability was 91 % (95 % CI, 54-99) at 6 months and 71 % (95 % CI, 34-90) at 12 months. Commonly reported treatment-emergent (all-causality), any-grade adverse events included diarrhea ( n = 10), hand-foot syndrome and hypertension (both n = 8), fatigue and headache (both n = 7), and neutropenia ( n = 6). No deaths on study were reported; one death due to disease progression occurred >28 days after end of treatment. Sunitinib on a CDD schedule resulted in sustained drug concentrations without accumulation across cycles. Tumor responses in all 12 patients did not appear to correlate with decreases in chromogranin A levels. Conclusions. Sunitinib 37.5 mg/day on a CDD schedule demonstrated antitumor activity in Japanese patients with unresectable, well-differentiated pancreatic NET. Commonly reported adverse events were consistent with the known safety profile of sunitinib. [ABSTRACT FROM AUTHOR]

The article discusses the effect of intra-articular injection of MicroRNA-210 (miRNA miR-210) on ligament healing in a rat model. It examines the effect of intra-articular injection of miRNA miR-210 on acceleration of anterior cruciate ligament (ACL) healing. It states that the injection of double-stranded miR-210 promoted the healing of partially torn ACLs by the enhancement of angiogenesis through the upregulation of vascular endothelial growth factor and fibroblast growth factor 2.

Background: The present study investigated tumor proliferation in a tumor model using murine ovarian cancer cells with increased carbonyl reductase (CR) expression. Methods: CR cDNA was transfected into murine T-Ag-MOSE ovarian cancer cells by lipofection. CR-transfected cells (CR induction group) or empty vector-treated cells (control group) were injected into the backs of 8-week-old nude mice at a concentration of 0.5 χ 106 per 0.2 mL. Subsequent tumor proliferation in both groups was observed for 5 weeks. Results: The control group showed an increase in tumor volume during the 5 weeks of observation. However, tumor volume in the CR induction group increased up to the second week but then decreased continuously until the fifth week of observation. The tumor growth curves for the two groups showed a significant difference (Mann-Whitney U test, P < 0.001). Histological and biochemical experiments were performed using tumor tissues isolated in the third week. Necrosis and inflammatory cell infiltration were noted for tumors in the CR induction group. Also, the number of apoptotic cells was significantly increased in the CR induction group compared with the control group (P < 0.001). Milk fat globule EGF factor 8, an "eat-me" signal for phagocytes such as macrophages, was expressed extensively in the tumor cytoplasm and interstitial cells of the CR induction group, and engulfment of apoptotic cells by macrophages was observed. Vascular endothelial growth factor expression in tumors was notably decreased in the CR induction group compared with the control group. Conclusion: Increased necrosis due to engulfing of apoptotic cells by phagocytes attracted by increased milk fat globule EGF factor 8 was considered to be the mechanism of spontaneous tumor regression in the CR induction group. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is the second most common malignancy in Japan. Treatment with inhibitors of the vascular endothelial growth factor (VEGF) signalling pathway has proven benefit in metastatic CRC. Cediranib is an oral highly potent VEGF signalling inhibitor that inhibits all three VEGF receptors. Patients and methods: In this phase II, double-blind, placebo-controlled study, 172 patients with metastatic CRC were randomised to receive once-daily cediranib (20 or 30 mg) or placebo, each combined with modified FOLFOX6 (mFOLFOX6). The primary objective was comparison of progression-free survival (PFS). Results: The comparison of cediranib 20 mg versus placebo met the primary objective of PFS prolongation [hazard ratio = 0.70 (95% confidence interval 0.44–1.11), P = 0.167], which met the protocol-defined criterion of P < 0.2. Median PFS was 10.2 versus 8.3 months, respectively. The PFS comparison for cediranib 30 mg versus placebo did not meet the criterion. The most common adverse events (AEs) in the cediranib-containing groups were diarrhoea and hypertension. Conclusions: Cediranib 20 mg plus mFOLFOX6 met the predefined criteria in terms of improved PFS compared with placebo plus mFOLFOX6. Cediranib 20 mg was generally well tolerated and the AE profile was consistent with previous studies. [ABSTRACT FROM PUBLISHER]

Aims: To report the incidence of infectious and noninfectious endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor (VEGF) from a multicenter clinical trial in Japan. Methods: A retrospective multicenter review of the data of patients who received intravitreal anti-VEGF injections between January 2007 and March 2011 was undertaken. Cases with the clinical diagnosis of endophthalmitis resulting from intravitreal injection were identified and reviewed. Results: A total of 5,236 intravitreal anti-VEGF injections (1,209 intravitreal injections of bevacizumab, 3,827 injections of ranibizumab, and 200 injections of pegaptanib sodium) had been administered. Five patients (0.095%), all of whom had received bevacizumab, were diagnosed as having endophthalmitis after the intravitreal injection. All patients visited the institutes for re-examination within 1-2 days after the injection. Among the 5 patients, 2 (0.038%) were culture positive for Streptococcus oralis and Enterococcus faecalis, respectively. The remaining 3 eyes (0.057%) developed presumed noninfectious endophthalmitis. Conclusion: Although endophthalmitis is a rare complication associated with intravitreal injection, in this series intravitreal anti-VEGF injection caused infectious or noninfectious endophthalmitis at a relatively high frequency. Further investigations are needed to consider an appropriate injection protocol for minimizing the incidence rates of endophthalmitis, and to assess the optimal treatment protocol for intravitreal injection-related endophthalmitis although it was difficult to differentiate these two entities. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Objective: Anxiety and depressive mood are sometimes accompanied by modulation of neuroendocrine and immune functions. The aim of this study was to identify circulating immune mediators reflecting anxiety and depressive mood in healthy young adults. Methods: Anxiety and depressive mood in 209 healthy medical students (125 males and 84 females, aged 20.7±2.7years (mean±SD)) were assessed by the Spielberger state-trait anxiety inventory (STAI) and the Zung self-rating depression scale (Zung-SDS), respectively. Cortisol and chromogranin A (CgA) levels in saliva were measured using enzyme immunoassay kits, and 50 different mediators in sera were measured by a multiplex-suspension array system. The level of statistical significance was set at α =0.05. Results: Forty-four mediators were measurable in sera, and each mediator showed substantial individual variations. After determining Pearson correlation coefficients, we selected candidate cytokines whose levels were associated with STAI-state (2 cytokines), STAI-trait (8 cytokines), or SDS scores (8 cytokines). The candidate cytokines plus interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and macrophage migration inhibitory factor were then subjected to multiple regression analysis adjusted for gender, BMI, and salivary concentrations of cortisol and CgA. Vascular endothelial growth factor (VEGF) was independently and negatively associated with both trait anxiety (p <0.05) and depressive mood (p <0.01). IL-1β showed independently positive association with depressive mood (p <0.05). Interactions between these two cytokines and gender or BMI were not observed. Conclusion: Besides IL-1β, circulating VEGF may be a potential biomarker for negative mood states in healthy young adults. [Copyright &y& Elsevier]

Purpose: To determine whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and response to treatment with photodynamic therapy (PDT) for age-related macular degeneration (AMD) in a Japanese population. Design: Prospective, case-control study. Participants: One hundred ten patients with exudative AMD treated by verteporfin PDT were recruited prospectively at the Department of Ophthalmology, Saitama Medical University Hospital, Saitama, Japan. Methods: The patients were genotyped for 4 single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay. Main Outcome Measures: The treatment outcomes and genotypes of CFH, HTRA1, VEGF, and PEDF polymorphisms. Results: Best-corrected visual acuity 1 year after PDT was significantly increased in patients with the HTRA1-rs11200638 GG genotype as compared with patients with the GA or AA genotypes (P = 2.9×10−2, 7.0×10−4, respectively). The rate of recurrence in the 12-month period after PDT was also associated with HTRA1-rs11200638 genotype (P = 3.12×10−2). Patients with the AA genotype of HTRA1-rs11200638 had an approximately 6-fold greater risk of the recurrence than patients with the GG genotype (P = 5.58×10−3). Significant differences were demonstrated in the mean time interval from the initial treatment to the time of recurrence for the genotypes of CFH-rs1410996/–rs2274700 (P = 8.50×10−3). Conclusions: The HTRA1-rs11200638 and CFH-rs1410996/-rs2274700 variants were associated with response to PDT in this study population. These variants may be used for genetic biomarkers to estimate visual outcomes and recurrences in the response to PDT with significant predictive power. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. [Copyright &y& Elsevier]

The aim of this study was to investigate the safety and pharmacokinetics of motesanib (AMG 706), a small-molecule antagonist of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and c-Kit in Japanese patients with advanced solid tumors. Patients were administered motesanib orally once daily (QD) at doses of 50, 100, and 125 mg QD. The total study duration for each patient consisted of three cycles of 28 days per cycle. The primary endpoints were the incidence of dose-limiting toxicities (DLTs), estimation of the maximum tolerated dose (MTD), and assessment of pharmacokinetic parameters of motesanib. Fifteen patients were enrolled and received motesanib. No DLTs were observed and, therefore, the MTD was not reached. Motesanib had acceptable toxicity at doses up to 125 mg QD. The pharmacokinetics of motesanib appears to be dose proportional. No objective responses per RECIST were observed. However, all 15 patients achieved stable disease, and five patients had durable (>24 weeks) stable disease. The results of this study demonstrate that motesanib is tolerable in Japanese patients at doses up to 125 mg QD. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Masuyama H, Segawa T, Sumida Y, Masumoto A, Inoue S, Akahori Y, Hiramatsu Y. Different profiles of circulating angiogenic factors and adipocytokines between early- and late-onset pre-eclampsia. BJOG 2010;117:314–320. Objective Circulating angiogenic factors have been shown to be important in the pathophysiology of pre-eclampsia. Blood levels of adipocytokines differ in pre-eclampsia relative to controls and may also play an important role in disease pathogenesis. Differences in the circulating levels of these molecules were compared between matched normotensive controls and women with pre-eclampsia with onset before or at/after 32 weeks, and according to whether the women were of normal weight (18.5 < body mass index < 25) or overweight. Design A cross-sectional study of 110 pregnant Japanese women who visited the Department of Obstetrics and Gynecology, Okayama University Hospital, Okayama, Japan. Setting Tertiary referral centre serving 2000 births. Methods Serum concentrations of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), soluble endoglin (sEng), adiponectin and leptin were measured in women with pre-eclampsia and in normotensive controls matched for age, gestational week, parity and body mass index. Main outcome measures Serum levels of sFlt-1, PlGF, the sFlt-1/PlGF ratio, sEng, adiponectin and leptin. Results The sFlt-1/PlGF ratio in early-onset pre-eclampsia was significantly higher than that in late-onset pre-eclampsia (112.0 ± 30.2 versus 45.4 ± 43.8, P = 0.037). There was a significant elevation of leptin in both subtypes relative to controls (early: 58.6 ± 18.3 ng/ml versus 26.0 ± 6.7 ng/ml, P = 0.001; late: 39.5 ± 9.2 ng/ml versus 22.0 ± 4.3 ng/ml, P = 0.005), but adiponectin was increased only in late-onset pre-eclampsia (36.5 ± 13.4 μg/ml versus 12.0 ± 4.3 μg/ml, P = 0.003). Significant differences in angiogenic factors and adiponectin were found between normal and overweight women only in late-onset pre-eclampsia. Conclusions These data suggest that there are different profiles of angiogenic factors and adipocytokines between women who develop early- and late-onset pre-eclampsia. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma is an intractable cancer, with no effective therapy other than surgical resection. Elevated vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions are associated with the progression of cholangiocarcinoma. We therefore examined whether inhibition of VEGFR and EGFR could be a potential therapeutic target for cholangiocarcinoma. Vandetanib (ZD6474, ZACTIMA), a VEGFR-2/EGFR inhibitor, was evaluated. Four human cholangiocarcinoma cell lines were molecularly characterised and investigated for their response to vandetanib. In vitro, two cell lines (OZ and HuCCT1), both of which harboured KRAS mutation, were refractory to vandetanib, one cell line (TGBC24TKB) was somewhat resistant, and another cell line (TKKK) was sensitive. The most sensitive cell line (TKKK) had EGFR amplification. Vandetanib significantly inhibited the growth of TKKK xenografts at doses > or = 12.5 mg kg(-1) day(-1) (P<0.05), but higher doses (50 mg kg(-1) day(-1), P<0.05) of vandetanib were required to inhibit the growth of OZ xenografts. Vandetanib (25 mg kg(-1) day(-1)) also significantly (P=0.006) prolonged the time to metastasis in an intravenous model of TKKK metastasis. Inhibiting both VEGFR and EGFR signalling appears a promising therapeutic approach for cholangiocarcinoma. The absence of KRAS mutation and the presence of EGFR amplification may be potential predictive molecular marker of sensitivity to EGFR-targeted therapy in cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

Background: Many recent studies point to the importance, in diabetic patients, of vascular endothelial function as an early marker of not only macrovascular complications but also of microangiopathy. The aim of this study is to investigate the relationship between diabetic retinopathy and endothelial function in elderly diabetic patients by using brachial artery flow-mediated dilation (FMD). Methods: We studied 71 type 2 diabetic patients aged 65 years or older without cardiovascular diseases. The subjects were categorized as three groups: (i) without diabetic retinopathy ( n = 49); (ii) with non-proliferative diabetic retinopathy group ( n = 15); and (iii) those with preproliferative or proliferative diabetic retinopathy ( n = 7). Brachial artery FMD measurement was performed by high-resolution ultrasonography. The Kruskal–Wallis test, the χ2 test and multivariate logistic regression analysis were used to identify associations between both retinopathy and clinical characteristics and FMD. Results: There were no differences in clinical characteristics between the three groups. FMD of the three groups were significantly decreased correlating with the severity of retinopathy (8.03% vs 5.40% vs 2.30%; P = 0.003). Multivariate logistic regression analysis showed that there was a significant correlation between diabetic retinopathy and FMD (odds ratio 0.801; P = 0.009). Conclusion: Our study suggests that FMD has a relation to microangiopathy in elderly diabetic subjects. Prospective studies will be required to determine whether this test has any clinical use for identifying elderly diabetic patients who are likely to develop diabetic retinopathy. [ABSTRACT FROM AUTHOR]

The article focuses on the role played by receptor-binding cancer antigen expressed on SiSo cells (RCAS1) in the regulation of tumor growth through angiogenesis in human uterine cancer, based on study conducted in Japan. The study constructed small interfering ribonucleic acid (siRNA) to target RCAS1. It investigated the correlation between RCAS1 expression and angiogenesis in the transfected cells from nude mice. It found that the introduction of RCAS1-encoding gene increased expression of vascular endothelial growth factors (VEGF).

The article discusses the two vascular endothelial growth factor receptor 3 (VEGFR3) mutations in Japanese families with Milroy's disease. It notes that one of the mentioned families had a missense mutation in the tyrosine kinase 1 domain, while the other had one nucleotide deletion at the invariant sequence of a splice donor site. Information on their case reports, their VEGFR3 analyses, and the results of their study is offered.

Background: Three vascular endothelial growth factor (VEGF) inhibitors, Bevacizumab (BEV), ramucirumab (RAM), and aflibercept (AFL), are widely used for metastatic colorectal cancer (mCRC) patients who are treated with second-line chemotherapy. The difference in outcome between the three drugs has not been evaluated. In contrast to epidermal growth factor receptor inhibitors, VEGF inhibitors have few candidate predictors of efficacy., Methods: Consecutive mCRC patients who were treated with second-line chemotherapy were retrospectively enrolled. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were assessed. Subgroup analyses of prognostic and predictive efficacy markers were performed., Results: A total of 119 (41.2%), 107 (37.0%), and 63 patients (21.8%) were treated with FOLFIRI +BEV, RAM, or AFL, respectively. ORR, PFS, and OS showed no significant differences between three groups. However, the frequency of grade 3 or 4 adverse events (AEs) in the FOLFIRI +AFL group was significantly higher than that in the other groups (p < 0.001). Patients with grade 3 or 4 AEs, especially hypertension and neutropenia within the first four cycles of treatment had significantly longer PFS and OS than those without AEs, irrespective of treatment with VEGF inhibitors (p < 0.001). PFS in patients without prior BEV exposure was also significantly longer than that in patients with prior BEV exposure (p = 0.003)., Conclusions: Chemotherapeutic efficacy did not differ between the groups. Grade 3 or 4 AEs within the first four cycles of treatment and prior BEV exposure may be an effective predictor of treatment efficacy in mCRC patients administered VEGF inhibitors as second-line chemotherapy., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background AGOC has a poor prognosis with limited benefits from treatments following failure of chemotherapy (CT). Regorafenib (BAY 73-4506)(REG) is an oral multi-kinase inhibitor targeting kinases involved in angiogenesis (VEGFR1-3, TIE-2), tumor microenvironment (PDGFR-β, FGFR), and oncogenesis (RAF, RET and KIT). INTEGRATE (phase 2) demonstrated REG effectiveness in prolonging PFS in AGOC pts, with a positive OS trend and less toxicity than other REG trials at the same doses. REG was effective across all regions/subgroups, with regional differences noted in magnitude of effect. INTEGRATE II (phase 3) will explore whether REG is effective in prolonging survival in all patients, and in the Asian sub-population Methods International randomised phase III, double-blind, placebo-controlled trial with 2:1 (REG:placebo)(PBO) randomisation and stratification by tumour location, geographic region, and prior VEGF inhibitors. Histologically confirmed AGOC patients, with evaluable metastatic or locally advanced disease refractory to/relapsed following at least 2 lines of CT, will receive best supportive care plus 160mg REG or matched placebo orally on days 1-21 of each 28 day cycle until disease progression or prohibitive adverse events. Primary endpoint is OS. Secondary endpoints: PFS, response rate, quality of life, safety, identification of prognostic/predictive biomarkers for study endpoints, and REG PK across geographical regions. 350 patients (50% from Asia, with at least 50 patients to be recruited from Japan) randomized in a 2:1 ratio will provide 90% power to detect a hazard ratio (HR) for OS of 0.67 with a 2-sided α of 0.05 assuming PBO median survival is 4.5 mos. The sample size accommodates an interim analysis undertaken once 2/3 of required events have occurred. Results 27 ANZ, 8 Canadian, 15 Korean, 5 Taiwanese, and 2 Japanese sites have been activated with 106 patients enrolled. Remaining Japanese/US sites expected to activate through Q1/Q2 2019. [ABSTRACT FROM AUTHOR]

Objectives: Vascular endothelial growth factor (VEGF) promotes angiogenesis, mediates vascular permeability, and activates and recruits monocytes. VEGF is produced in activated alveolar macrophages, in epithelioid cells, and in multinuclear giant cells of pulmonary sarcoid granulomas. Recent reports have shown that a polymorphism at - 627 of the VEGF gene is related to VEGF protein production, and a polymorphism at + 813 is associated with VEGF plasma levels. We investigated the roles of such polymorphisms in the development and extent of sarcoidosis., Methods: We examined polymorphisms of the VEGF gene in 103 Japanese patients with sarcoidosis and 146 healthy Japanese control subjects. The position - 627 polymorphism was determined using the TaqMan (TaqMan Laboratory, University of Pittsburgh Cancer Institute; Pittsburgh, PA) polymerase chain reaction (PCR) method. For genotyping of the position + 813 polymorphism, the PCR restriction fragment length polymorphism method was performed., Results: As for + 813 genotypes, the less-common genotypes CT and TT were found more often in control subjects than in patients (odds ratio, 0.490; 95% confidence interval, 0.276 to 0.868). A significant increase in the frequency of the T allele (p = 0.005, Pc = 0.020 after Bonferroni correction) was observed in control subjects. As for - 627 genotypes, the mean value of the FEV(1)/FVC percentage in GG type was lower than that in CC or CG type, however, the other clinical findings did not suggest airway diseases in the GG type., Conclusions: We suggest that in VEGF gene polymorphisms the T allele at + 813 may decrease susceptibility to sarcoidosis.

Aim: To determine whether plasma vascular endothelial growth factor (VEGF) level is elevated in Type 2 diabetic patients with an early stage of diabetic nephropathy., Methods: We studied 71 Japanese Type 2 diabetic patients with normal serum creatinine level (<100 micromol/l) (age 63.0 [60.3-65.6] years old, diabetes duration 15.6 [14.0-17.3] years, HbA1c 7.36% [7.06-7.66%], mean [95% confidence interval, CI]): normoalbuminuric patients (n=36); microalbuminuric patients (n=21); and proteinuric patients (n=14). Plasma VEGF concentration was measured by a quantitative sandwich enzyme immunoassay technique., Results: Plasma VEGF concentration was not related to the degree of albuminuria: normoalbuminuric patients (25 [13-95] ng/l, median [25th-75th percentile]); microalbuminuric patients (33 [15-120] ng/l); and proteinuric patients (54 [17-107] ng/l). Plasma VEGF level in patients with retinopathy (25 [15-95] ng/l, n=30) was not elevated as compared to those without retinopathy (53 [14-126] ng/l, n=34). Plasma VEGF tended to correlated negatively with diabetes duration (R's=-.217, P=.0690) and HbA1c (R's=-.221, P=.0647), whereas there was no correlation between plasma VEGF level and age, serum creatinine or urinary albumin to creatinine ratio (ACR) of the patients, respectively. Plasma VEGF level in the group of patients with HbA1c equal to or below the median (<7.2%) was significantly higher than that in the group of patients with HbA1c above the median (>7.2%) (P<.05)., Conclusions: The results suggested that Type 2 diabetic patients with microalbuminuria and those with retinopathy are not necessarily associated with an elevation of circulating plasma VEGF concentration. Plausible association between plasma VEGF level and glycemic control remains to be seen.

Objective: Because it is difficult to predict the behavior of thymomas on the basis of morphology alone, other methods for determining tumor aggressiveness must be explored. This study investigated the correlation between angiogenic grade and invasiveness in thymic epithelial tumors., Methods: Immunohistochemical studies of 46 surgically resected thymic epithelial tumors (18 noninvasive thymomas, 20 invasive thymomas, and 8 thymic carcinomas) were conducted. To highlight the microvessels, we used a specific monoclonal antibody against factor VIII. Expression of vascular endothelial growth factor and basic fibroblast growth factor was determined by using polyclonal antibodies., Results: Mean microvessel density readings for noninvasive thymomas, invasive thymomas, and thymic carcinomas were 4.6 +/- 3.2, 12.4 +/- 7.5, and 34.4 +/- 16.7, respectively. Stages I, II, III, and IV of thymoma had microvessel density readings of 4.6 +/- 3.2, 8.5 +/- 4.3, 13.8 +/- 7.7, and 22.0 +/- 6.8, respectively. These findings suggest a significant correlation between microvessel density and tumor invasiveness. Vascular endothelial growth factor expression in noninvasive thymomas, invasive thymomas, and thymic carcinomas was present in 1 (5.6%) of 18, 11 (55.0%) of 20, and 5 (62.5%) of 8 patients, respectively, thereby indicating a distinct association between vascular endothelial growth factor expression and increased microvessel density. Basic fibroblast growth factor expression was present in only 8 patients., Conclusions: In patients with thymic epithelial tumors, there appears to be a significant correlation between tumor angiogenesis and invasiveness. Furthermore, our data suggests that this angiogenesis in thymic epithelial tumors might be, at least in part, dependent on vascular endothelial growth factor expression.