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We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m2. Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study.

Pancreatic ductal adenocarcinoma (PDAC) is the most life-threating disease among all digestive system malignancies. We developed a blood mRNA PDAC screening system using real-time detection PCR to detect the expression of 56 genes, to discriminate PDAC from noncancer subjects. We undertook a clinical study to assess the performance of the developed system. We collected whole blood RNA from 53 PDAC patients, 102 noncancer subjects, 22 patients with chronic pancreatitis, and 23 patients with intraductal papillary mucinous neoplasms in a per protocol analysis. The sensitivity of the system for PDAC diagnosis was 73.6% (95% confidence interval, 59.7%-84.7%). The specificity for noncancer volunteers, chronic pancreatitis, and patients with intraductal papillary mucinous neoplasms was 64.7% (54.6%-73.9%), 63.6% (40.7%-82.8%), and 47.8% (26.8%-69.4%), respectively. Importantly, the sensitivity of this system for both stage I and stage II PDAC was 78.6% (57.1%-100%), suggesting that detection of PDAC by the system is not dependent on the stage of PDAC. These results indicated that the screening system, relying on assessment of changes in mRNA expression in blood cells, is a viable alternative screening strategy for PDAC.

IntroductionPreviously, we conducted a clinical trial to evaluate the safety and efficacy of transdermal electrical stimulation (TdES) with skin electrodes to improve the visual functions in patients with retinitis pigmentosa (RP). No adverse events were related to the treatment during follow-up examinations, and TdES significantly improved the mean visual acuity and visual field sensitivity.Methods and analysisWe developed a study protocol for a prospective, multicentre, randomised, double-masked and sham-controlled clinical trial, planned to commence on June 2021. We intend to compare the maintenance or improvement in best-corrected visual acuity, and safety of TdES using skin electrodes between patients with RP and the sham group. The primary endpoint comprises the superiority of the logarithm of the minimum angle of resolution (logMAR) visual acuity change at week 24 from baseline in the treatment and sham groups. Secondary endpoints involve the comparison of the treatment and sham groups at week 24 for the logMAR visual acuity, early treatment diabetic retinopathy study visual acuity, the mean deviation value of Humphrey field analyser 10-2, monocular Humphrey Esterman visual field test score, ellipsoid zone length, central foveal thickness and 25-item National Eye Institute Visual Function Questionnaire score. We intend to enrol 50 patients from three Japanese institutions within 1 year and follow them up for 1 years.Ethics and disseminationThe protocol was approved by the institutional review board at the Chiba University Hospital and two other institutions, and was registered with the Japan Registry of Clinical Trials on 17 May 2021. The trial will be conducted in accordance with the principles of the Declaration of Helsinki, and is in accordance with Good Clinical Practice standards. The findings will be published in a peer-reviewed journal.Trial registration numberJRCT2032210094.

Indocyanine green (ICG) fluorescent lymphography might be useful for assessing patients undergoing lymphatic surgery for secondary lymphedema. The present clinical trial aimed to confirm whether ICG fluorescent lymphography would be useful in evaluating lymphedema, identifying lymphatic vessels suitable for anastomosis, and confirming patency of lymphaticovenular anastomosis in patients with secondary lymphedema.The present phase III, multicenter, single-arm, open-label, clinical trial (HAMAMATSU-ICG study) investigated the accuracy of lymphedema diagnosis via ICG fluorescent lymphography compared with lymphoscintigraphy, rate of identification of lymphatic vessels at the incision site, and efficacy for confirming patency of lymphaticovenular anastomosis. The external diameter of the identified lymphatic vessels and the distance from the skin surface to the lymphatic vessels using preoperative ICG fluorescent lymphography were measured intraoperatively under surgical microscopy.When the clinical decision for surgery at each research site was made, the standard diagnosis of lymphedema was considered correct. For the 26 upper extremities, a central judgment committee who was unaware of the clinical presentation confirmed the imaging diagnosis was accurate for 100.0% of cases, whether the assessments had been performed via lymphoscintigraphy or ICG lymphography. In contrast, for the 88 lower extremities, the accuracy of the diagnosis compared with the diagnosis by the central judgment committee was 70.5% and 88.2% for lymphoscintigraphy and ICG lymphography, respectively. The external diameter of the identified lymphatic vessels was significantly greater in the lower extremities than in the upper extremities (0.54 ± 0.21 mm vs 0.42 ± 0.14 mm; P .0001). Also, the distance from the skin surface to the lymphatic vessels was significantly longer in the lower extremities than in the upper extremities (5.8 ± 3.5 mm vs 4.4 ± 2.6 mm; P = .01). For 263 skin incisions, with the site placement determined using ICG fluorescent lymphography, the rate of identification of lymphatics vessels suitable for anastomosis was 97.7% (95% confidence interval, 95.1%-99.2%). A total of 267 lymphaticovenular anastomoses were performed. ICG fluorescent lymphography was judged as "useful" for confirming patency after the anastomosis in 95.1% of the cases.ICG fluorescent lymphography could be useful for improving the treatment of patients with secondary lymphedema from the outpatient setting to surgery.

IntroductionConcurrent chemoradiotherapy is considered the standard treatment strategy for locally advanced cervical cancer. Most recent reports indicate that patients with bulky tumours or adenocarcinoma subtypes have poorer local control. Carbon-ion radiotherapy (CIRT) with the concurrent use of chemotherapy has shown promising results in such cases of difficult-to-treat uterine cervical cancer. Programmed death-ligand 1 (PD-L1) upregulation was observed in tumour tissue samples from patients who had undergone CIRT. Thus, a combination of CIRT and anti-PD-L1 antibody may suppress metastasis by activating antitumour immune response, in addition to exhibiting strong local effects.ObjectiveWe will assess the safety and tolerability (primary endpoint) of the concomitant use of durvalumab, an anti-PD-L1 antibody, with CIRT and weekly cisplatin for locally advanced cervical cancer.Methods and analysisThis study is a non-randomised, open-label, prospective phase 1b study. Up to 10 patients with histologically proven uterine cervical cancer at stage IIB, IIIA, IIIB, IIIC1 or IVA as per International Federation of Gynecology and Obstetrics (2018) staging will be enrolled. All patients will receive CIRT of 74.4 Gy relative biological effectiveness in 20 fractions over 5 weeks (four fractions per week). Weekly cisplatin at a dose of 40 mg/m2will be administrated up to five times. Durvalumab at a dose of 1500 mg/body will be administrated at weeks 2 and 6. Safety and tolerability will be evaluated based on the frequency of dose-limiting toxicities until 92 days after CIRT starts. Patients will be followed-up strictly as per the scheduled protocol for 1 year after CIRT initiation.Ethics and disseminationThe Human Research Ethics Committees of QST Hospital (#C21-002) and Chiba University (#2021006) have approved this study protocol. The findings will be published in peer-reviewed journals and presented at scientific conferences.Trial registration numberJapan Registry of Clinical Trials (jRCT2031210083), registered on 12 May 2021.

Introduction Secondary lymphoedema of the extremities is an important quality-of-life issue for patients who were treated for their malignancies. Indocyanine green (ICG) fluorescent lymphography may be helpful for assessing lymphoedema and for planning lymphaticovenular anastomosis (LVA). The objective of the present clinical trial is to confirm whether or not ICG fluorescent lymphography using the near-infrared monitoring camera is useful for assessing the indication for LVA, for the identification of the lymphatic vessels before the conduct of LVA, and for the confirmation of the patency of the anastomosis site during surgery. Methods and analysis This trial is a phase III, multicentre, single-arm, open-label clinical trial to assess the efficacy and safety of ICG fluorescent lymphography when assessing and treating lymphoedema of patients with secondary lymphoedema who are under consideration for LVA. The primary endpoint is the identification rate of the lymphatic vessels at the incision site based on ICG fluorescent lymphograms obtained before surgery. The secondary endpoints are 1) the sensitivity and specificity of dermal back flow determined by ICG fluorescent lymphography as compared with 99mTc lymphoscintigraphy—one of the standard diagnostic methods and 2) the usefulness of ICG fluorescent lymphography when confirming the patency of the anastomosis site after LVA. Ethics and dissemination The protocol for the study was approved by the Institutional Review Board of each institution. The trial was filed for and registered at the Pharmaceuticals and Medical Devices Agency in Japan. The trial is currently on-going and is scheduled to end in June 2020. Trial registration number jRCT2031190064; Pre-results., Highlights • This study will examine the efficacy of a highly safe drug, indocyanine green for evaluating lymphatic anatomy. • This is the first, multicentre, prospective, systematised clinical trial of Indocyanine green lymphography. • The present clinical trial will not allow the assessment of the therapeutic efficacy of lymphaticovenular anastomosis.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 μg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population., Koda et al. present the results of a randomized phase 3 trial comparing granulocyte colony-stimulating factor versus placebo in patients with acute spinal cord injury. While the primary endpoint was not met, a sub-analysis revealed a trend towards superior efficacy of G-CSF versus placebo in an elderly population.

IntroductionProgestin therapy is the only fertility-sparing treatment option for patients with atypical endometrial hyperplasia (AEH) and endometrial cancer (EC). However, the results of three meta-analyses revealed a high remission rate, as well as an association with a high rate of relapse. We previously conducted a phase II of medroxyprogesterone acetate (MPA) plus metformin as a fertility-sparing treatment for AEH and EC patients, and reported that metformin inhibited disease relapse after remission.Methods and analysisA randomised, open, blinded-endpoint design phase IIb dose response trial was planned to commence in July 2019. The trial aims to identify the appropriate dose of metformin to be combined with MPA therapy for fertility-sparing treatment of patients with AEH and EC. The primary endpoint of the trial is the 3-year relapse-free survival (RFS) rate. The secondary endpoints are RFS rate, the overall rate of response to MPA therapy, the conception rate after treatment, the outcome of pregnancy, toxicity evaluation and changes in insulin resistance and body mass index. A total of 120 patients will be enrolled from 15 Japanese institutions within a 2.5-year period and followed up for at least 3 years.Ethics and disseminationThe protocol was approved by the institutional review board at Chiba University Hospital and boards at 14 other institutions. The trial will be conducted according to the principles of the World Medical Association’s Declaration of Helsinki and in accordance with Good Clinical Practice (GCP) standards. The trial findings will be published in a peer-reviewed journal.Trial registration numberJapan Registry of Clinical Trials (jRCT2031190065).

The BIM deletion polymorphism is reported to be associated with poor outcomes of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) treated with EGFR-TKIs, including gefitinib. We have shown that a histone deacetylase inhibitor, vorinostat, can epigenetically restore BIM function and apoptosis sensitivity to EGFR-TKIs in EGFR-mutant NSCLC cells with BIM deletion polymorphisms. The purpose of this study is to determine the feasibility of combined treatment of vorinostat with gefitinib in BIM deletion polymorphism positive EGFR-mutant NSCLC patients. BIM deletion polymorphism positive EGFR-mutant NSCLC patients treated with at least one EGFR-TKI and one regimen of chemotherapy are being recruited to this study. Vorinostat (200-400 mg) will be administered orally once daily on days 1-7, and gefitinib 250 mg orally once daily on days 1-14. With a fixed dose of gefitinib, the dose of vorinostat will be escalated following a conventional 3+3 design. The primary endpoint is to define the maximum tolerated dose (MTD) of vorinostat combined with 250 mg of gefitinib. This is the first phase I study of combined therapy with vorinostat and gefitinib for NSCLC patients double selected for an EGFR mutation and BIM deletion polymorphism. J. Med. Invest. 64: 321-325, August, 2017.

Summary Background Genetic studies have indicated possible involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the pathogenesis of Kawasaki disease. We aimed to assess safety and efficacy of ciclosporin, an immunosuppressant targeting this pathway, for protection of patients with Kawasaki disease against coronary artery abnormalities. Methods We did a randomised, open-label, blinded endpoints trial involving 22 hospitals in Japan between May 29, 2014, and Dec 27, 2016. Eligible patients predicted to be at higher risk for intravenous immunoglobulin (IVIG) resistance were randomly assigned to IVIG plus ciclosporin (5 mg/kg per day for 5 days; study treatment) or IVIG (conventional treatment) groups, stratified by risk score, age, and sex. The primary endpoint was incidence of coronary artery abnormalities using Japanese criteria during the 12-week trial, assessed in participants who received at least one dose of study drug and who visited the study institution at least once during treatment. This trial is registered to Center for Clinical Trials, Japan Medical Association, number JMA-IIA00174. Findings We enrolled 175 participants. One patient withdrew consent after enrolment and was excluded and one patient (in the study treatment group) was excluded from analysis because of lost echocardiography data. Incidence of coronary artery abnormalities was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0·46; 95% CI 0·25–0·86; p=0·010). No difference was found in the incidence of adverse events between the groups (9% vs 7%; p=0·78). Interpretation Combined primary therapy with IVIG and ciclosporin was safe and effective for favourable coronary artery outcomes in Kawasaki disease patients who were predicted to be unresponsive to IVIG. Funding Japan Agency for Medical Research and Development (grant CCT-B-2503).

BACKGROUND The Therapeutic Angiogenesis by Cell Transplantation (TACT) trial demonstrated the efficacy and safety of autologous bone marrow-derived mononuclear cells (BM-MNCs) in patients with critical limb ischemia (CLI). The present study aimed to assess the long-term clinical outcomes of therapeutic angiogenesis using autologous BM-MNC implantation under advanced medical treatment in Japan.Methods and Results:The study was retrospective, observational, and non-controlled. We assessed no-option CLI patients who had BM-MNC implantation performed in 10 institutes. Overall survival (OS), major amputation-free (MAF), and amputation-free survival (AFS) rates were primary endpoints of this study. The median follow-up duration was 31.7 months. The 10-year OS rate was 46.6% in patients with arteriosclerosis obliterans (ASO) (n=168), 90.5% in patients with thromboangiitis obliterans (TAO) (n=108), and 67.6% in patients with collagen disease-associated vasculitis (CDV) (n=69). The 10-year MAF rate was 70.1%, 87.9%, and 90.9%, respectively. The 10-year AFS rate was 37.8%, 80.9%, and 61.2%, respectively. Major adverse cardiovascular events occurred in 6.0% of patients with ASO, 1.9% of patients with TAO, and no patients with CDV. CONCLUSIONS Therapeutic angiogenesis using autologous BM-MNC implantation may be feasible and safe in patients with no-option CLI, particularly those with CLI caused by TAO or CDV.

The BIM deletion polymorphism is reported to be associated with poor outcomes of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) treated with EGFR-TKIs, including gefitinib. We have shown that a histone deacetylase inhibitor, vorinostat, can epigenetically restore BIM function and apoptosis sensitivity to EGFR-TKIs in EGFR-mutant NSCLC cells with BIM deletion polymorphisms. The purpose of this study is to determine the feasibility of combined treatment of vorinostat with gefitinib in BIM deletion polymorphism positive EGFR-mutant NSCLC patients. BIM deletion polymorphism positive EGFR-mutant NSCLC patients treated with at least one EGFR-TKI and one regimen of chemotherapy are being recruited to this study. Vorinostat (200-400 mg) will be administered orally once daily on days 1-7, and gefitinib 250 mg orally once daily on days 1-14. With a fixed dose of gefitinib, the dose of vorinostat will be escalated following a conventional 3+3 design. The primary endpoint is to define the maximum tolerated dose (MTD) of vorinostat combined with 250 mg of gefitinib. This is the first phase I study of combined therapy with vorinostat and gefitinib for NSCLC patients double selected for an EGFR mutation and BIM deletion polymorphism. J. Med. Invest. 64: 321-325, August, 2017.

Preparations of Tripterygium wilfordii, "Thunder God vine", have been used in China to treat rheumatoid arthritis. Rheumatoid arthritis, as well as solid tumors, is closely associated with neovascularization. Antiarthritic drugs therefore may modulate tumor growth as well as neovascularization. We found that a compound purified from T. wilfordii, the nortriterpenoid, demethylzeylasteral (TZ-93), inhibited the proliferation of vascular endothelial cells approximately 30 times more effectively than it did for the proliferation of human tumor cells. In in vitro assays using bovine aortic endothelial cells, TZ-93 at non-toxic doses inhibited cell migration, expression of urokinase-type plasminogen activator (uPA) mRNA and uPA activity. Exogenous addition of uPA restored the inhibitory effect of TZ-93 on cell migration. In dorsal air-sac assays in BALB/c mice, the oral administration of 3 mg/kg/day TZ-93 for 5 days partially inhibited, and 30 mg/kg/day almost completely abrogated, the development of capillary networks induced by human hepatoblastoma cells. Similarly, 0.3 mg/kg/day TZ-93 partially inhibited, and 3 or 30 mg/kg/day almost completely blocked, the growth of mouse B16-F10 melanoma cells in a tumor implantation assay. The highest dose of TZ-93 significantly reduced the growth of well-vascularized tumors with volumes of more than 500 mm3. TZ-93 treatment of tumor-bearing mice significantly decreased the density of microvessels in the tumors. We conclude that TZ-93 may be useful in treating highly vascularized and metastatic tumors as well as other angiogenic diseases.

To investigate if neurotensin (NT) could induce activation of urokinase-type plasminogen activator (uPA) in vascular endothelial cells, we utilized the acetyl-NT (8–13) analogue, TJN-950, in which the C-terminal leucine is reduced to leucinol. TJN-950 inhibited the binding of 125I-NT to membranes of newborn rat brains and of COS-7 cells transfected with rat NT receptor cDNA, but at 104 higher doses than NT (8–13). However, TJN-950 was as effective as NT in inducing the fibrinolytic activity in bovine vascular aortic and human umbilical vein endothelial cells, and enhanced the migration of vascular endothelial cells. Moreover, administration of TJN-950 induced neovascularization in the rat cornea in vivo. TJN-950 had no effect on expression of uPA, plasminogen activator inhibitor-1 or uPA receptor mRNA. The binding of 125I-TJN-950 to cell membranes was blocked by unlabeled uPA and TJN-950, but not the amino-terminal or 12–32 fragment of uPA. TJN-950 may enhance uPA activity in vascular endothelial cells by interacting with the uPA receptor, resulting in induction of angiogenesis.

金沢大学医薬保健研究域医学系, Background: There is evidence that phosphodiesterase type-5 is effective for the treatment of pulmonary arterial hypertension (PAH). Methods and Results: A phase III, multicenter, open-label clinical trial of sildenafil 20 mg t.i.d. was conducted in 21 Japanese patients with PAH to examine its efficacy, safety, and pharmacokinetics. The present trial consisted of a screening period and 12-week treatment. Patients who were enrolled in the present trial increased their 6-min walking distance of administration increased at week 12 by 84.2 m from baseline. Hemodynamic parameters (eg, mean pulmonary artery pressure and pulmonary vascular resistance), Borg dyspnea scores, and plasma brain natriuretic peptide concentrations also improved compared to baseline. Most patients improved or sustained WHO functional class. Seven subjects, who were examined for the pharmacokinetics of sildefanil, showed relatively large interindividual variations in the Cmax, AUC0-8, Css,av, and Ctrough of the drug. Any serious adverse events, severe adverse events, and deaths were not observed. Most of events of undeniable causality were mild or moderate in severity. Sildefanil was well tolerated by the subjects. Conclusions: Sildenafil 20 mg t.i.d. was effective and safe for Japanese patients with PAH.

Synthese de l'O-α-L-arabinofuranosyl-6 O-α-D-glucopyranosyl-4 β-D-glucopyranoside de methyle et de l'O-[O-α-L-arabinofuranosyl-6 β-D-glucopyranosyl]-4 β-D-glucopyranoside de methyle

Water-soluble polysaccharides, designated as GIa and GIb, were isolated from the bark of Melia azadirachta (Meliaceae) and their inhibiting effect on subcutaneously inoculated Sarcoma-180 was tested. GIa and GIb each gave a single peak on ultracentrifugation and gel filtration. Methylation, periodate oxidation and 13C-NMR spectroscopic studies suggested that GIa is composed of the following repeating unit ; α-D-Glc 1→4α-D-Glc 1→4α-D-Glc 1→4α-D-Glc 1→4α-D-Glc 6←1α-L-Araf. GIb is a branched arabinofucoglucan, containing a main chain of (1→4)-linked α-D-glucopyranosyl units substituted in the 6 position with side chains of α-L-arabinofuranosyl units. 3-O-substituted fucopyranose is attached to the α-(1→4) glucose units at the 4 position in the main chain.