Nara Medical University Hospital

We previously showed that the availability of a nonamer peptide derived from certain HLA class I signal sequences is a necessary requirement for the stabilization of endogenous HLA-E expression on the surface of 721.221 cells. This led us to examine the ability of HLA-E to protect HLA class I transfectants from natural killer (NK) cell-mediated lysis. It was possible to implicate the CD94/NKG2A complex as an inhibitory receptor recognizing this class Ib molecule by using as target a .221 transfectant selectively expressing surface HLA-E. HLA-E had no apparent inhibitory effect mediated through the identified Ig superfamily (Ig-SF) human killer cell inhibitory receptors or ILT2/LIR1. Further studies of CD94/NKG2+ NK cell-mediated recognition of .221 cells transfected with different HLA class I allotypes (i.e., -Cw4, -Cw3, -B7) confirmed that the inhibitory interaction was mediated by CD94/NKG2A recognizing the surface HLA-E molecule, because only antibodies directed against either HLA-E, CD94, or CD94/NKG2A specifically restored lysis. Surface stabilization of HLA-E in cold-treated .221 cells loaded with appropriate peptides was sufficient to confer protection, resulting from recognition of the HLA class Ib molecule by the CD94/NKG2A inhibitory receptor. Consistent with the prediction that the ligand for CD94/NKG2A is expressed ubiquitously, our examination of HLA-E antigen distribution indicated that it is detectable on the surface of a wide variety of cell types.

Hypoxia has been proposed as an important microenvironmental factor in the development of tissue fibrosis; however, the underlying mechanisms are not well defined. To examine the role of hypoxia-inducible factor-1 (HIF-1), a key mediator of cellular adaptation to hypoxia, in the development of fibrosis in mice, we inactivated Hif-1alpha in primary renal epithelial cells and in proximal tubules of kidneys subjected to unilateral ureteral obstruction (UUO) using Cre-loxP-mediated gene targeting. We found that Hif-1alpha enhanced epithelial-to-mesenchymal transition (EMT) in vitro and induced epithelial cell migration through upregulation of lysyl oxidase genes. Genetic ablation of epithelial Hif-1alpha inhibited the development of tubulointerstitial fibrosis in UUO kidneys, which was associated with decreased interstitial collagen deposition, decreased inflammatory cell infiltration, and a reduction in the number of fibroblast-specific protein-1-expressing (FSP-1-expressing) interstitial cells. Furthermore, we demonstrate that increased renal HIF-1alpha expression is associated with tubulointerstitial injury in patients with chronic kidney disease. Thus, we provide clinical and genetic evidence that activation of HIF-1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis by increasing expression of extracellular matrix-modifying factors and lysyl oxidase genes and by facilitating EMT.

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer.

Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), β-catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-β), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei, Albatrellus confluens, Cordyceps militaris, Ganoderma lucidum, Poria cocos and Silybum marianum, together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks.

Deregulation of angiogenesis--the growth of new blood vessels from an existing vasculature--is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding "the most important target" may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the "Halifax Project" within the "Getting to know cancer" framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleanolic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the "hallmarks" of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.

Seventeen patients who had recalcitrant chronic adhesive capsulitis were operated on between 1979 and 1986 and were followed for an average of 6.8 years. At operation, the major cause of the restricted glenohumeral movement was found to be contracture of the coracohumeral ligament and rotator interval. Release of the contracted structures relieved pain and restored motion of the shoulder in all patients. Histological study showed fibrosis, hyalinization, and fibrinoid degeneration in the contracted connective tissues, as well as fibrosis of the subsynovial tissue and an absence of the synovial cell layer on the joint side of the rotator interval. The contracture of the coracohumeral ligament and rotator interval appears to be the main lesion in chronic adhesive capsulitis. Resection of these structures, combined with appropriate exercise, will relieve pain and restore motion to the shoulder.

Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology.

BACKGROUND: Marrow mesenchymal cells are useful in regenerative medicine because they contain stem cells, but there have been few reports of clinical applications. The authors developed a new wound treatment technique by improving marrow mesenchymal cell culture methods and placing cultured cells in an artificial skin material. This new treatment was useful for tissue regeneration in 20 patients with skin wounds. METHODS: Marrow mesenchymal cells from a 46-year-old man were cultured and placed in artificial dermis made of collagen sponge. This composite graft was implanted subcutaneously into the back of a nude mouse and removed 10 days later; immunohistological analysis confirmed regeneration of subcutaneous tissue using human marrow mesenchymal cells. Next, in 20 patients (nine men and 11 women; average age, 64.8 years; range, 22 to 91 years) with intractable dermatopathies, 10 to 20 ml of bone marrow fluid was aspirated from the ilium and cultured in medium containing either fetal calf or autologous serum. The resulting cultured cells were placed in artificial dermis made of collagen sponge, and this composite graft was used to treat skin wounds. RESULTS: The wound mostly healed in 18 of the 20 patients; the remaining two patients died of causes unrelated to transplantation. In all patients, autologous marrow mesenchymal cell transplantation was shown to be therapeutically effective. CONCLUSIONS: In skin regeneration therapy using a marrow mesenchymal cell/artificial dermis composite graft, skin regeneration is possible with bone marrow aspiration, a minimally invasive procedure. Compared with existing skin grafting techniques, the present technique is practical and much less invasive.

Prophylaxis with emicizumab, a subcutaneously administered bispecific humanized monoclonal antibody, promotes effective hemostasis in persons with hemophilia A (PwHAs). The primary efficacy, safety, and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHAs with/without factor VIII (FVIII) inhibitors who were enrolled in the phase 3 HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies (NCT02622321, NCT02795767, NCT02847637, NCT03020160) have been pooled to establish a long-term efficacy, safety, and pharmacokinetics profile. Across a median efficacy period of 120.4 weeks (interquartile range, 89.0-164.4) (data cutoff 15 May 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval [CI], 1.1-1.7). ABRs declined and then stabilized at <1 in an analysis of 24-week treatment intervals; at weeks 121 to 144 (n = 170), the mean treated ABR was 0.7 (95% CI, 0-5.0). During weeks 121 to 144, 82.4% of participants had 0 treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported no treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participant discontinued because of adverse events beyond the 5 previously described. This data cutoff includes the previously reported 3 thrombotic microangiopathies (one in the PwHA with fatal rectal hemorrhage) and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use, as well as a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHAs of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified.

Chronic hypoxia accelerates renal fibrosis. The chief mediator of the hypoxic response is hypoxia-inducible factor 1 (HIF-1) and its oxygen-sensitive component HIF-1alpha. HIF-1 regulates a wide variety of genes, some of which are closely associated with tissue fibrosis. To determine the specific role of HIF-1 in renal fibrosis, we generated a knockout mouse in which tubular epithelial expression of von Hippel-Lindau tumor suppressor (VHL), which acts as a ubiquitin ligase to promote proteolysis of HIF-1alpha, was targeted. We investigated the effect of VHL deletion (i.e., stable expression of HIF-1alpha) histologically and used the anti-HIF-1alpha agent [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole] (YC-1) to test whether inhibition of HIF-1alpha could represent a novel approach to treating renal fibrosis. The area of renal fibrosis was significantly increased in a 5/6 renal ablation model of VHL-/- mice and in all VHL-/- mice at least 60 wk of age. Injection of YC-1 inhibited the progression of renal fibrosis in unilateral ureteral obstruction model mice. In conclusion, HIF-1alpha appears to be a critical contributor to the progression of renal fibrosis and could be a useful target for its treatment.

BACKGROUND AND PURPOSE: Very few reports are available on serial changes in the human brain after severe hypoglycemic injury. The aim of this study was to investigate sequential neuroradiological changes in brains of patients after hypoglycemic coma compared with those after cardiac arrest previously studied with the same methods. METHODS: We repeatedly studied CT scans and MR images obtained at 1.5 T in four vegetative patients after profound hypoglycemia associated with diabetes mellitus. RESULTS: In all patients, consecutive CT scans showed symmetrical, persistent low-density lesions with transient enhancement in the caudate and lenticular nuclei and transient enhancement in the cerebral cortex 7 to 14 days after onset. Serial MR images consistently revealed symmetrical lesions of persistent hyperintensity and hypointensity on T1- and T2-weighted images, respectively, in the caudate and lenticular nuclei, cerebral cortex, substantia nigra, and/or hippocampus from 8 days to 12 months after onset. CONCLUSIONS: Repeated MR images revealed specific lesions in the bilateral basal ganglia, cerebral cortex, substantia nigra, and hippocampus, which suggests the particular vulnerability of these areas to hypoglycemia in the human brain. We speculate that the localized lesions represent tissue degeneration, including some combination of selective neuronal death, proliferation of astrocytic glial cells, paramagnetic substance deposition, and/or lipid accumulation. The absence of localized hemorrhages on MR images in hypoglycemic encephalopathy is in marked contrast to the presence of regional minor hemorrhages in postischemic-anoxic encephalopathy.

Current management of hemophilia A includes prophylaxis with factor VIII (FVIII) replacement every 2 to 3 days. BAX 855, Baxalta's pegylated full-length recombinant FVIII (rFVIII), was designed to increase half-life and, thus, reduce the frequency of prophylactic infusions while maintaining hemostatic efficacy. BAX 855 was evaluated in previously treated patients with severe hemophilia A who were aged 12 to 65 years. A phase 1 study compared the pharmacokinetic (PK) profile of BAX 855 with that of licensed rFVIII (Advate). In a pivotal study, the annualized bleeding rate (ABR), PK parameters, and efficacy of bleeding treatment were assessed. In the phase 1 study, the mean half-life (T1/2) and the mean residence time of BAX 855 compared with Advate were 1.4- to 1.5-fold higher. These results were confirmed in the pivotal study. The pivotal study met its primary endpoint: Prophylaxis with BAX 855 resulted in an ABR that was significantly lower than half the ABR of on-demand treatment (P < .0001). The median ABR was 1.9, and 39.6% of compliant subjects had no bleeding episodes during prophylaxis, whereas subjects treated on-demand had a median ABR of 41.5. BAX 855 was also efficacious for the treatment of bleeding episodes, with 95.9% of bleeding episodes treated with 1 to 2 infusions and 96.1% having efficacy ratings of excellent/good. No FVIII inhibitory antibodies or safety signals were identified. These studies provide evidence that BAX 855 was safe and efficacious for on-demand treatment and prophylaxis administered twice weekly in patients with hemophilia A. The trials were registered at www.clinicaltrials.gov as #NCT01736475 and #NCT01599819.

OBJECTIVES: To prospectively evaluate the safety and efficacy of combined unenhanced and gadoxetic acid disodium (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) imaging compared with unenhanced MR imaging and triphasic contrast-enhanced spiral computed tomography (CT) for the detection and characterization of focal liver lesions. MATERIALS AND METHODS: The study was reviewed and approved by the institutional review board at each of the 15 centers involved in the study, and informed written consent was given by all patients. In total, 178 patients with suspected focal hepatic lesions (based, in most patients, on CT, tumor marker and ultrasound examinations) underwent combined MR imaging with a single, rapid injection of Gd-EOB-DTPA 0.025 mmol/kg, including T1-weighted dynamic and delayed MR images 20 to 40 minutes postinjection. Triphasic contrast-enhanced CT, the comparator examination, was performed within 4 weeks of MR imaging. Standard of references (SOR) were resection histopathology and intraoperative ultrasonography, or combined CT during arterial portography and CT hepatic arteriography; in cases where, although the major lesions were treated, some lesion(s) were not treated, follow-up superparamagnetic iron oxide-enhanced MR imaging was additionally performed. All images were assessed for differences in lesion detection and characterization (specific lesion type) by on-site readers and 3, blinded (off-site) reviewers. All adverse events (AEs) occurring within 72 hours after Gd-EOB-DTPA administration were reported. RESULTS: Overall, 9.6% of patients who received Gd-EOB-DTPA reported 21 drug-related AEs. A total of 151 patients were included in the efficacy analysis. Combined MR imaging showed statistically higher sensitivity in lesion detection (67.5%-79.5%) than unenhanced MR imaging (46.5%-59.1%; P < 0.05 for all). Combined MR imaging also showed higher sensitivity in lesion detection than CT (61.1%-73.0%), with the results being statistically significant (P < 0.05) for on-site readers and 2 of 3 blinded readers. Higher sensitivity in lesion detection with combined MR imaging compared with CT was also clearly demonstrated in the following subgroups: lesions with a diameter <or=20 mm (lesions <or=10 mm: 38.0%-55.4% vs. 26.1%-47.3%, respectively; lesions 10-20 mm: 71.1%-87.3% vs. 65.7%-78.4%, respectively); in cirrhotic patients (64.5%-75.4% vs. 54.5%-70.3%, respectively); and in patients with hepatocellular carcinoma (66.6%-78.6% vs. 59.1%-71.6%, respectively). Combined MR imaging demonstrated a higher proportion of correctly characterized lesions (50.5%-72.1%) than unenhanced MR imaging (30.2%-50.0%; P < 0.05 for all), whereas there were no significant differences compared with CT (49.0%-68.1%), except for one blinded reader (P < 0.05). CONCLUSION: In this study, hepatocyte-specific Gd-EOB-DTPA was shown to be safe and to improve the detection and characterization of focal hepatic lesions compared with unenhanced MR imaging. When compared with spiral CT, Gd-EOB-DTPA enhanced MRI seems to be beneficial especially for the detection for smaller lesions or hepatocellular carcinoma underlying cirrhotic liver.

BACKGROUND: Nivolumab showed improvement in overall survival (OS) in ATTRACTION-2, the first phase 3 study in patients with gastric/gastroesophageal junction (G/GEJ) cancer treated with ≥ 2 chemotherapy regimens. The 2-year follow-up results of ATTRACTION-2 are presented herein. METHODS: ATTRACTION-2 was a randomized, double-blind, placebo-controlled, phase 3 trial (49 sites; Japan, South Korea, and Taiwan). The median (min-max) follow-up period was 27.3 (24.1-36.3) months. The primary endpoint was OS. A subanalysis of OS was performed based on best overall response and tumor-programmed death ligand-1 (PD-L1) expression status. RESULTS: Overall, 493 of 601 screened patients were randomized (2:1) to receive nivolumab (330) or placebo (163). OS (median [95% confidence interval; CI]) was significantly longer in the nivolumab group (5.26 [4.60-6.37] vs 4.14 [3.42-4.86] months in placebo group) at the 2-year follow-up (hazard ratio [95% CI], 0.62 [0.51-0.76]; P < 0.0001). A higher OS rate was observed in the nivolumab vs placebo group at 1 (27.3% vs 11.6%) and 2 years (10.6% vs 3.2%). The OS benefit was observed regardless of tumor PD-L1 expression. Among patients with a complete or partial response (CR or PR) in the nivolumab group, the median OS (95% CI) was 26.6 (21.65-not applicable) months; the OS rates at 1 and 2 years were 87.1% and 61.3%, respectively. No new safety signals were identified. CONCLUSIONS: Nivolumab treatment resulted in clinically meaningful long-term improvements in OS in patients with previously treated G/GEJ cancer. The long-term survival benefit of nivolumab was most evident in patients with a CR or PR.

Recently the authors proposed a new staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histological heterogeneity. Herein is proposed a convenient version of this system. Scores for fibrosis, bile duct loss, and chronic cholestasis were combined for staging: stage 1, total score of 0; stage 2, score 1-3; stage 3, score 4-6; and stage 4, score 7-9. Cholangitis activity (CA) and hepatitis activity (HA) were graded as CA0-3, and HA0-3, respectively. Analysis of interobserver agreement was then conducted. Digital images of 62 needle liver biopsy specimens of PBC were recorded as virtual slides on DVDs that were sent to 28 pathologists, including five located overseas. All participants were able to apply this version in all 62 cases. For staging, kappa was 0.385 (fair agreement) and the concordance rate was 63.9%. For necroinflammatory activity, the kappa and concordance rate were 0.110 (slight agreement) and 36.9% for CA, and 0.197 (slight agreement) and 47% for HA, respectively. In conclusion, this new staging and grading system for PBC seems to be more convenient and practical than those used at present, but more instruction and guidance are recommended for the grading of necroinflammatory activity in practice.

BACKGROUND: The Japanese Society for Surgery of the Foot (JSSF) is developing a QOL questionnaire instrument for use in pathological conditions related to the foot and ankle. The main body of the outcome instrument (the Self-Administered Foot Evaluation Questionnaire, SAFE-Q version 2) consists of 34 questionnaire items, which provide five subscale scores (1: Pain and Pain-Related; 2: Physical Functioning and Daily Living; 3: Social Functioning; 4: Shoe-Related; and 5: General Health and Well-Being). In addition, the instrument has nine optional questionnaire items that provide a Sports Activity subscale score. The purpose of this study was to evaluate the test-retest reliability of the SAFE-Q. PATIENTS AND METHODS: Version 2 of the SAFE-Q was administered to 876 patients and 491 non-patients, and the test-retest reliability was evaluated for 131 patients. In addition, the SF-36 questionnaire and the JSSF Scale scoring form were administered to all of the participants. Subscale scores were scaled such that the final sum of scores ranged between zero (least healthy) to 100 (healthiest). RESULTS: The intraclass correlation coefficients were larger than 0.7 for all of the scores. The means of the five subscale scores were between 60 and 75. The five subscales easily separated patients from non-patients. The coefficients for the correlations of the subscale scores with the scores on the JSSF Scale and the SF-36 subscales were all highly statistically significantly greater than zero (p < 0.001). The means for the five JSSF Scale classification groups fell within a relatively narrow range, indicating that the SAFE-Q labels are sufficiently similar to permit their use for all of the JSSF Scale classifications. CONCLUSION: The present study revealed that the test-retest reliability is high for each subscale. Consequently, the SAFE-Q is valid and reliable. In the future, it will be beneficial to test the responsiveness of the SAFE-Q.

PURPOSE: A multicenter survey was conducted to explore the role of adjuvant surgery for initially unresectable pancreatic cancer with a long-term favorable response to non-surgical cancer treatments. METHODS: Clinical data including overall survival were retrospectively compared between 58 initially unresectable pancreatic cancer patients who underwent adjuvant surgery with a favorable response to non-surgical cancer treatments over 6 months after the initial treatment and 101 patients who did not undergo adjuvant surgery because of either unchanged unresectability, a poor performance status, and/or the patients' or surgeons' wishes. RESULTS: Overall mortality and morbidity were 1.7 and 47 % in the adjuvant surgery group. The survival curve in the adjuvant surgery group was significantly better than in the control group (p < 0.0001). The propensity score analysis revealed that adjuvant surgery was a significant independent prognostic variable with an adjusted hazard ratio (95 % confidence interval) of 0.569 (0.36-0.89). Subgroup analysis according to the time from initial treatment to surgical resection showed a significant favorable difference in the overall survival in patients who underwent adjuvant surgery over 240 days after the initial treatment. CONCLUSION: Adjuvant surgery for initially unresectable pancreatic cancer patients can be a safe and effective treatment. The overall survival rate from the initial treatment is extremely high, especially in patients who received non-surgical anti-cancer treatment for more than 240 days.

PURPOSE This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer. MATERIALS AND METHODS Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m 2 for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m 2 once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety. RESULTS Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks. CONCLUSION Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer.

BACKGROUND: Acquired hemophilia A (AHA) is a rare bleeding disorder caused by an autoantibody to coagulation factor (F) VIII. It is characterized by soft tissue bleeding in patients without a personal or family history of bleeding. Bleeding is variable, ranging from acute, life-threatening hemorrhage, with 9-22% mortality, to mild bleeding that requires no treatment. AHA usually presents to clinicians without prior experience of the disease, therefore diagnosis is frequently delayed and bleeds under treated. METHODS: Structured literature searches were used to support expert opinion in the development of recommendations for the management of patients with AHA. RESULTS: Immediate consultation with a hemophilia center experienced in the management of inhibitors is essential to ensure accurate diagnosis and appropriate treatment. The laboratory finding of prolonged activated partial thromboplastin time with normal prothrombin time is typical of AHA, and the diagnosis should be considered even in the absence of bleeding. The FVIII level and autoantibody titer are not reliable predictors of bleeding risk or response to treatment. Most patients with AHA are elderly; comorbidities and underlying conditions found in 50% of patients often influence the clinical picture. Initial treatment involves the control of acute bleeding with bypassing agents. Immunosuppressive treatment to eradicate the FVIII inhibitor should be started as soon as the diagnosis is confirmed to reduce the time the patient is at risk of bleeding. CONCLUSIONS: These recommendations aim to increase awareness of this disorder among clinicians in a wide range of specialties and provide practical advice on diagnosis and treatment.

The mainstay in the management of invasive bladder cancer continues to be radical cystectomy. With regard to improvement of quality of life, however, therapies that preserve the bladder are desirable. We investigated the use of intravesical PLK-1 small interfering RNA (siRNA) against bladder cancer. Patients with bladder cancers expressing high levels of PLK-1 have a poor prognosis compared with patients with low expression. Using siRNA/cationic liposomes, the expression of endogenous PLK-1 could be suppressed in bladder cancer cells in a time- and dose-dependent manner. As a consequence, PLK-1 functions were disrupted. Inhibition of bipolar spindle formation, accumulation of cyclin B1, reduced cell proliferation, and induction of apoptosis were observed. In order to determine the efficacy of the siRNA/liposomes in vivo, we established an orthotopic mouse model using a LUC-labeled bladder cancer cell line, UM-UC-3(LUC). PLK-1 siRNA was successfully transfected into the cells, reduced PLK-1 expression, and prevented the growth of bladder cancer in this mouse model. This is the first demonstration, to our knowledge, of inhibition of cancer growth in the murine bladder by intravesical siRNA/cationic liposomes. We believe intravesical siRNA instillation against bladder cancer will be useful as a therapeutic tool.