Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study.

BACKGROUND: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). RESULTS: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. CONCLUSIONS: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.

Incidence and risk factors for hip fracture in elderly patients undergoing lumbar spine surgery: a nationwide database study with 11-year follow-up.

Impaired functional movement may occur after spinal surgery, which increases risk of fall episode and hip fracture. Patients with long-segment thoracolumbar spine fusions had a significantly higher risk of hip fracture than those with only discectomies. Fall prevention is necessary due to the highly increased hip fracture risk. INTRODUCTION: Spinal surgeries are performed to treat spondylolisthesis, fractures, scoliosis, or other deformities. Impaired balance mechanisms and functional movement may occur after spinal surgery. Fall episodes may cause hip fractures, which have negative impacts on quality of life and increase mortality. The incidence of hip fracture after spinal surgery is still unknown. The aim of this study was to examine the association between various types of spinal surgeries and hip fractures in the elderly by using a nationwide database. We hypothesized that the spinal surgeries may increase hip fracture risk in the elderly. METHODS: We used the National Health Insurance Research Database (NHIRD) to identify 3345 patients undergoing spinal surgery and a random dataset to identify 6690 age-, sex- and Charlson comorbidity index (CCI)-matched controls to compare the incidence of hip fractures in an 11-year follow-up period. We also enrolled 82,730 patients with spinal surgeries from the inpatient dataset to investigate the impact of different types of spinal surgeries. RESULTS: Patients who received spinal surgeries had higher risks of hip fractures, especially patients aged 60 to 79 years and female patients. The patients with long-segment thoracolumbar spinal fusions had a significantly higher risk of hip fracture than those with only discectomies. Short segmental lumbar spine fusions also slightly increased the risk of hip fracture compared with discectomies. CONCLUSION: Fall prevention for the elderly undergoing lumbar spinal surgery is necessary due to the highly increased hip fracture risk.

Ultrafast energy- and momentum-resolved dynamics of magnetic correlations in the photo-doped Mott insulator Sr2IrO4.

Measuring how the magnetic correlations evolve in doped Mott insulators has greatly improved our understanding of the pseudogap, non-Fermi liquids and high-temperature superconductivity. Recently, photo-excitation has been used to induce similarly exotic states transiently. However, the lack of available probes of magnetic correlations in the time domain hinders our understanding of these photo-induced states and how they could be controlled. Here, we implement magnetic resonant inelastic X-ray scattering at a free-electron laser to directly determine the magnetic dynamics after photo-doping the Mott insulator Sr2IrO4. We find that the non-equilibrium state, 2 ps after the excitation, exhibits strongly suppressed long-range magnetic order, but hosts photo-carriers that induce strong, non-thermal magnetic correlations. These two-dimensional (2D) in-plane Néel correlations recover within a few picoseconds, whereas the three-dimensional (3D) long-range magnetic order restores on a fluence-dependent timescale of a few hundred picoseconds. The marked difference in these two timescales implies that the dimensionality of magnetic correlations is vital for our understanding of ultrafast magnetic dynamics.

Dissecting alternative splicing in the formation of Miltenberger glycophorin subtype III (GYP.Mur).

BACKGROUND AND OBJECTIVES: Miltenberger subtype III (Mi.III, GP.Mur) is one of the most important red cell phenotypes in the fields of transfusion in South-East Asia. GP.Mur is believed to evolve from homologous gene recombination events between glycophorin A (GYPA) and glycophorin B (GYPB). GYP.Mur differs from GYPB in only seven nucleotides dispersed near the region of 3' exon 3 of GYP.Mur. The goal of this study was to dissect how these nucleotide variants affected splicing of exon 3. MATERIALS AND METHODS: We first designed two minigene constructs: one containing GYP.Mur from exon 2 to exon 4 and the other containing GYPB in the same region. To test how these nucleotide variations between GYP.Mur and GYPB affected the splicing, a repertoire of the GYP.Mur-like minigene constructs with different point mutations were created. These minigene variants were evaluated for their abilities to induce splicing of exon 3 using a heterologous expression system. RESULTS: (1) GYP.Mur minigene expressed exons 2, 3 and 4, whereas GYPB minigene expressed only exon 2 and exon 4. (2) The single nucleotide alteration at the position of the 5' splice site of glycophorin intron 3 reversed the splicing decision. (3) The nucleotide variations between GYP.Mur and GYPB other than that at the 5' splice site showed very little or no effect on splicing of exon 3. CONCLUSION: Splicing of the glycophorin B-A-B hybrids (GYP.Mur and GYP.BUN) and unsplicing of GYPB follow the GU-AG rule strictly.

A novel allele, HLA-A*11:127N, was identified in a Taiwanese individual by the sequence-based typing method.

A one nucleotide replacement in codon 171 of HLA-A*11:01:01 results in a novel allele, HLA-A*11:127N.

Outbreak of ertapenem-resistant Enterobacter cloacae urinary tract infections due to a contaminated ureteroscope.

BACKGROUND: Outbreaks of urinary tract infections (UTIs) due to contaminated ureteroscopes have been rarely reported. AIM: To report such an outbreak at a regional teaching hospital in southern Taiwan. METHODS: From October to December 2010, ertapenem-resistant Enterobacter cloacae were identified from urine cultures of 15 patients who had undergone ureteroscopy prior to the infection. Three batches of surveillance cultures were obtained from the environmental objects and healthcare workers related to the procedures. Pulsed-field gel electrophoresis (PFGE) was used for bacterial typing. Antimicrobial susceptibility was assessed by disc diffusion and E-test methods. Polymerase chain reaction and sequencing were used to analyse ß-lactamase genes. FINDINGS: A total of 70 specimens were obtained during the first surveillance operation. One ertapenem-resistant E. cloacae was isolated from a ureteroscope. Although the disinfection protocols for ureteroscopes were revised and implemented, seven additional UTI cases were identified thereafter. The pathogen was identified from two subsequent surveillance cultures and was not eliminated until ethylene oxide sterilization was added to the disinfection protocol. PFGE revealed that all 15 isolates from the patients and the three isolates from the ureteroscope shared a common pattern with minor variance. Most isolates were resistant to gentamicin, levofloxacin, ceftriaxone, ceftazidime, and ertapenem. All isolates were susceptible to amikacin, imipenem, and meropenem. SHV-12 and IMP-8 genes were simultaneously identified in 16 of the 18 isolates. CONCLUSION: The outbreak of ertapenem-resistant E. cloacae was caused by a contaminated ureteroscope and was terminated by the implementation of a revised disinfection protocol for ureteroscopes.

ASCORE: an up-to-date cardiovascular risk score for hypertensive patients reflecting contemporary clinical practice developed using the (ASCOT-BPLA) trial data.

A number of risk scores already exist to predict cardiovascular (CV) events. However, scores developed with data collected some time ago might not accurately predict the CV risk of contemporary hypertensive patients that benefit from more modern treatments and management. Using data from the randomised clinical trial Anglo-Scandinavian Cardiac Outcomes Trial-BPLA, with 15 955 hypertensive patients without previous CV disease receiving contemporary preventive CV management, we developed a new risk score predicting the 5-year risk of a first CV event (CV death, myocardial infarction or stroke). Cox proportional hazard models were used to develop a risk equation from baseline predictors. The final risk model (ASCORE) included age, sex, smoking, diabetes, previous blood pressure (BP) treatment, systolic BP, total cholesterol, high-density lipoprotein-cholesterol, fasting glucose and creatinine baseline variables. A simplified model (ASCORE-S) excluding laboratory variables was also derived. Both models showed very good internal validity. User-friendly integer score tables are reported for both models. Applying the latest Framingham risk score to our data significantly overpredicted the observed 5-year risk of the composite CV outcome. We conclude that risk scores derived using older databases (such as Framingham) may overestimate the CV risk of patients receiving current BP treatments; therefore, 'updated' risk scores are needed for current patients.

Effects of post materials and length on the stress distribution of endodontically treated maxillary central incisors: a 3D finite element analysis.

Traditionally, using a long post can cause progressive removal of the root structure, complicate the ability to re-treat the tooth if necessary and make it difficult to apply an adhesive bonding agent into the root canal. It is unclear if a shorter post length can be applied when a light translucent glass fibre post and adhesive resin cement are used. The aim of this study was to evaluate the biomechanical performance of endodontically treated teeth restored with three post materials, glass-fibre, stainless steel and cast-nickel chromium posts and cores of different lengths of 7, 10 and 13 mm. A 3D finite element analysis model of the maxillary central incisor was constructed. An occlusal load of 300 N was applied to a node at the palatal surface of the crown at 45 degrees to the long axis of the tooth. von Mises stress analyses were carried out in three regions. Simulated data were collected for plotting various pattern graphics and conducting statistical tests. The pattern graphics showed that when the post length changed from 13 to 7 mm, the stress patterns were even and flat in all fibre-post groups, while the stress patterns of the metal-post groups showed an M-shaped peak and trough. Statistical tests showed that the shorter fibre post was superior to the longer metal post in some situations. Within the limitations of this study, it was concluded that when a metal post is used, the post should be as long as possible, while the biomechanical performance of a glass-fibre post combined with a composite resin core was less sensitive to post length.

Developmental trajectory of dynamic resource utilization during walking: toddlers with and without Down syndrome.

After years of walking practice 8-10-year-old children with typical development (TD) and those with Down syndrome (DS) show uniquely different but efficient use of dynamic resources to walk overground and on a treadmill [Ulrich, B.D., Haehl, V., Buzzi, U., Kubo, M., & Holt, K.G. (2004). Modeling dynamic resource utilization in populations with unique constraints: Preadolescents with and without Down syndrome. Human Movement Science, 23, 133-156]. Here we examined the use of global stiffness and angular impulse when walking emerged and across the ensuing months of practice in eight toddlers with TD and eight with DS. Participants visited our lab when first able to walk four to six steps, and at one, three, four, and six months of walking experience. For all visits, toddlers walked overground at their preferred speeds and for the last two visits on a treadmill. Toddlers with TD and DS demonstrated clear and similar developmental trajectories over this period with more similarities than differences between groups. At six months stiffness and impulse values were higher than previously observed for 8-10-year-old children. Stiffness values increased significantly throughout this period, though rate of change slowed for the TD group by three months of experience. Impulse values rose sharply initially and slowed to plateau during the latter months. Treadmill data illustrated toddlers' capacity to adapt dynamic resource use to imposed changes in speed, particularly well after six months of practice. Consistent with our studies of preadolescents and older adults, toddlers with DS produced significantly wider normalized step width than their TD peers. We propose that the challenge of upright bipedal locomotion constrains toddlers with TD and DS to generate similar, necessary and sufficient stiffness and impulse values to walk as they gain control and adapt to playful and self-imposed perturbations of gait over the first six months. The plateau in impulse and slow-down of stiffness increases over the latter months may be the first signs of a downward trend to the lower values produced by older children with several years of walking experience.

Artificial vascular graft for inferior vena cava reconstruction in living donor liver transplantation: a case report.

Artificial grafts are not recommended because of the high incidence of thrombogenic effects. However, in some situations, such as emergency or when no vascular bank is available, an artificial graft must be used. We present a case in which a polytetrafluoroethyline graft was used as a conduit to reconstruct the retrohepatic vena cava severed during living donor liver transplantation (LDLT). A 48-year-old woman had end-stage primary biliary cirrhosis for 5 years received a right lobe liver graft from her son. The retrohepatic vena cava was divided and ligated in several sequences. The upper end of the severed retrohepatic vena cava retracted into the liver parenchyma. The lower end of the severed vena cava was distended, with multiple stitches. A 16-mm artificial graft was used as a conduit to replace the inferin vena cava for outflow reconstruction. The patient tolerated the complicated procedure well. No anticoagulant was used throughout the entire course. The patient has been well with excellent liver function after follow-up for more than 5 years. Magnetic resonance imaging and Doppler ultrasonographic studies showed good patency of the cava with no evidence of thrombosis. We suggest use of an artificial graft in living donor liver transplantation, in particular in urgent situations when autologous or allogeneic vessels are not available.

A novel role for the retinoic acid-catabolizing enzyme CYP26A1 in Barrett's associated adenocarcinoma.

Vitamin A deficiency is associated with carcinogenesis, and upregulation of CYP26A1, a major retinoic acid (RA)-catabolizing enzyme, has recently been shown in cancer. We have previously demonstrated alterations of RA biosynthesis in Barrett's oesophagus, the precursor lesion to oesophageal adenocarcinoma. The aims of this study were to determine CYP26A1 expression levels and functional effects in Barrett's associated carcinogenesis. Retinoic acid response element reporter cells were used to determine RA levels in non-dysplastic and dysplastic Barrett's cell lines and endoscopic biopsies. CYP26A1 expression levels, with or without induction by RA and lithocholic acid, were determined by quantitative reverse transcriptase-PCR (RT-PCR) and immunohistochemistry. CYP26A1 promoter activity was determined by a luciferase reporter construct. CYP26A1 was stably overexpressed in GihTERT cells, which were evaluated for gene-expression changes (pathway array and quantitative RT-PCR), cellular proliferation (cytometric DNA profile and colorimetric assay) and invasion (in vitro matrigel assay) with or without the CYP inhibitor ketaconazole. RA levels decreased progressively with the degree of dysplasia (P<0.05) and were inversely correlated with CYP26A1 gene levels and activity (P<0.01). CYP26A1 expression was increased synergistically by RA and lithocholic acid (P<0.05). Overexpression of CYP26A1 led to induction of c-Myc, epidermal growth factor receptor and matrix metalloproteinase 3 as well as downregulation of tissue inhibitor metalloproteinase 1 and 3. Functional effects of CYP26A1 overexpression were increased proliferation (P<0.01) and invasion in vitro (P<0.01), which were inhibited by ketaconazole. Overexpression of CYP26A1 causes intracellular RA depletion and drives the cell into a highly proliferative and invasive state with induction of other known oncogenes.

Three-dimensional computed tomography for detection of tracheobronchial foreign body aspiration in children.

Foreign body aspiration (FBA) into the tracheobronchial tree is a frequent and serious cause of respiratory problems in children. Chest X-ray (CXR) is often inaccurate in diagnosing FBA when the object is radiolucent. Three-dimensional computed tomography (CT) is a noninvasive technique that can detect the narrowing of the airway resulting from the presence of a foreign body. We conducted a retrospective study comparing the performance of CT scan and CXR in the diagnosis of FBA. Eleven patients (mean age 2.1 years) with a history suggestive of foreign body aspiration were examined by three-dimensional chest CT and CXR during the study. The presence of foreign bodies was confirmed and they were removed by rigid or flexible bronchoscopy under general anesthesia. Foreign body aspiration (FBA) was detected in all the 11 patients by CT scan (sensitivity, 100%), but CXR of three of the patients showed no evidence of FBA (sensitivity, 72.7%). The foreign bodies were located in the right main bronchus (n = 4), the left main bronchus (n = 5), and the trachea (n = 2). The mean length of hospital stay was 3.8 days. In our study, three-dimensional chest CT scan was more sensitive than CXR in detecting the presence of aspirated foreign bodies in children. The superior sensitivity and short time required for CT should help to reduce delays in diagnosis. These benefits may prompt further studies to determine whether CT could be used to reduce the number of unnecessary bronchoscopies performed in children being evaluated for FBA.

Control of human mesothelin-expressing tumors by DNA vaccines.

Mesothelin has been implicated as a potential ideal target antigen for the development of antigen-specific cancer immunotherapy for the control of mesothelin-expressing cancers such as ovarian cancer, mesothelioma and pancreatic adenocarcinoma. In the current study, we utilized a DNA vaccine encoding human mesothelin (pcDNA3-Hmeso) to treat C57BL/6 mice challenged with luciferase-expressing, Hmeso-expressing ovarian cancer cell line, Defb29 Vegf-luc/Hmeso. The therapeutic effect of the tumor-challenged mice was followed by noninvasive bioluminescence imaging systems. The mechanism of the antitumor effect was characterized by depletion of subsets of lymphocytes as well as adopted transfer of serum from pcDNA3-Hmeso-vaccinated mice. We found that vaccination with pcDNA3-Hmeso DNA vaccine generates a significant antitumor effect and promotes survival in mice challenged with Defb29 Vegf-luc/Hmeso. Furthermore, we found CD4+ and CD8+ T-cell immune responses as well as the humoral immune responses are important for the observed antitumor effects in vaccinated mice. Our data indicated that vaccination with DNA vaccine targeting Hmeso could generate potent antitumor effects against mesothelin-expressing tumors through both T cell-mediated immunity as well as antibody-mediated immunity.

CXCR4 expression is associated with pelvic lymph node metastasis in cervical adenocarcinoma.

The aim of this study is to investigate the expression of CXCR4 receptor in cervical adenocarcinoma and related mechanisms involved in pelvic lymph node metastasis. Immunohistochemistry was used to evaluate the expression of CXCR4 and the association of pelvic lymph node metastasis in archived tissue from clinical stage IB cervical adenocarcinomas (n = 37) and from benign specimens obtained at hysterectomy for other causes (n = 48). The HeLa cell (cervical adenocarcinoma-derived cell) line that expresses CXCR4 was used to study the interaction between the CXCR4 receptor and stromal cell-derived factor 1alpha (SDF-1alpha). Cell migration assays, cell numbers, flow cytometry, cell proliferation assay, and western blot were used to study the function of CXCR4 and its downstream signal transduction. The positive cases were semiquantitatively divided into three score classes according to their staining. Tumors with strong CXCR4 stainings were more likely to have pelvic lymph node metastasis than those with weak or negative stainings (87.5% vs 34.5%; P = 0.014). Only 25% of the benign specimens had weak or negative staining for CXCR4. Functioning CXCR4 receptor was expressed on HeLa cells. SDF-1alpha provoked significant signal transduction events, including chemotaxis and rescue from apoptosis. These actions were apparently mediated by the activation and phosphorylation of the extracellular signal-regulated kinase 1/2 and AKT pathways. We conclude CXCR4 expression is associated with cervical adenocarcinoma cell migration and proliferation, and primary cervical adenocarcinoma cells expressing CXCR4 are significantly more likely to metastasize to pelvic lymph nodes.

Production of a monoenergetic electron bunch in a self-injected laser-wakefield accelerator.

Production of a monoenergetic electron bunch in a self-injected laser-wakefield accelerator is investigated with a tomographic method which resolves the electron injection and acceleration processes. It is found that all the electrons in the monoenergetic electron bunch are injected at the same location in the plasma column and then accelerated with an acceleration gradient exceeding 2 GeV/cm. The injection position shifts with the position of pump-pulse focus, and no significant deceleration is observed for the monoenergetic electron bunch after it reaches the maximum energy. The results are consistent with the model of transverse wave breaking and beam loading for the injection of monoenergetic electrons. The tomographic method adds a crucial dimension to the whole array of existing diagnostics for laser beams, plasma waves, and electron beams. With this method the details of the underlying physical processes in laser-plasma interactions can be resolved and compared directly to particle-in-cell simulations.

Tomography of injection and acceleration of monoenergetic electrons in a laser-wakefield accelerator.

A tomographic diagnosis method was developed to systematically resolve the injection and acceleration processes of a monoenergetic electron beam in a laser-wakefield accelerator. It was found that all the monoenergetic electrons are injected at the same location in the plasma column and accelerated from 5 to 55 MeV energy in 200 microm distance. This is a direct measurement of the real acceleration gradient in a laser-wakefield accelerator, and the experimental data are consistent with the model of transverse wave breaking and beam loading for monoenergetic electron injection.

Spatially localized self-injection of electrons in a self-modulated laser-wakefield accelerator by using a laser-induced transient density ramp.

By using a laser-induced transient density ramp, we demonstrate self-injection of electrons in a self-modulated laser-wakefield accelerator with spatial localization. The number of injected electrons reaches 1.7 x 10(8). The transient density ramp is produced by a prepulse propagating transversely to drill a density depression channel via ionization and expansion. The same mechanism of injection with comparable efficiency is also demonstrated with a transverse plasma waveguide driven by Coulomb explosion.

Early-onset sigmoid colon perforation during concurrent chemoradiation in a patient with cervical cancer.

Radiation-induced colon perforation is a rare adverse effect caused by vascular and connective tissue injury to the rectosigmoid colon. It usually occurs a few months to years after radiotherapy for gynecological cancer. Herein, we present a patient who developed sigmoid colon perforation during concurrent chemoradiotherapy for cervical cancer. The patient was a 64-year-old clinical stage IIB woman who received concurrent chemoradiotherapy as a standard treatment. The chemotherapeutic protocol was cisplatin 50 mg/m(2) and 5-fluorouracil 4000 mg, starting together with radiotherapy. After the completion of external beam radiation for 4500 cGy, the patient developed sigmoid colon perforation presenting with fecal peritoneum and sepsis. An emergency end ileostomy with resection of entire sigmoid colon was performed and the patient was discharged 3 months later in good condition. Clinicians must be highly suspicious of serious bowel perforation, even if the full dose of radiation has not been completed. Whether or not the chemotherapy was the trigger factor is in need of further clarification.