Non-robotic minimally invasive gastrectomy as an independent risk factor for postoperative intra-abdominal infectious complications: A single-center,retrospective and propensity score-matched analysis

BACKGROUND Minimally invasive surgery for gastric cancer(GC) has gained widespread use as a safe curative procedure especially for early GC.AIM To determine risk factors for postoperative complications after minimally invasive gastrectomy for GC.METHODS Between January 2009 and June 2019, 1716 consecutive patients were referred to our division for primary GC. Among them, 1401 patients who were diagnosed with both clinical and pathological Stage Ⅲ or lower GC and underwent robotic gastrectomy(RG) or laparoscopic gastrectomy(LG) were enrolled. Retrospective chart review and multivariate analysis were performed for identifying risk factors for postoperative morbidity.RESULTS Morbidity following minimally invasive gastrectomy was observed in 7.5% of the patients. Multivariate analyses demonstrated that non-robotic minimally invasive surgery, male gender, and an operative time of ≥ 360 min were significant independent risk factors for morbidity. Therefore, morbidity was compared between RG and LG. Accordingly, propensity-matched cohort analysis revealed that the RG group had significantly fewer intra-abdominal infectious complications than the LG group(2.5% vs 5.9%, respectively; P = 0.038), while no significant differences were noted for other local or systemic complications.Multivariate analyses of the propensity-matched cohort revealed that non-robotic minimally invasive surgery [odds ratio = 2.463(1.070–5.682); P = 0.034] was a significant independent risk factor for intra-abdominal infectious complications.CONCLUSION The findings showed that robotic surgery might improve short-term outcomes following minimally invasive radical gastrectomy by reducing intra-abdominal infectious complications.     

Non–clinical efficacy,safety and stable clinical cell processing of induced pluripotent stem cell‐derived anti–glypican‐3 chimeric antigen receptor‐expressing natural killer/innate lymphoid cells

The use of allogeneic, pluripotent stem‐cell‐derived immune cells for cancer immunotherapy has been the subject of recent clinical trials. In Japan, investigator‐initiated clinical trials will soon begin for ovarian cancer treatment using human leukocyte antigen (HLA)‐homozygous‐induced pluripotent stem cell (iPSC)‐derived anti–glypican‐3 (GPC3) chimeric antigen receptor (CAR)‐expressing natural killer/innate lymphoid cells (NK/ILC). Using pluripotent stem cells as the source for allogeneic immune cells facilitates stringent quality control of the final product, in terms of efficacy, safety and producibility. In this paper, we describe our methods for the stable, feeder‐free production of CAR‐expressing NK/ILC cells from CAR‐transduced iPSC with clinically relevant scale and materials. The average number of cells that could be differentiated from 1.8‐3.6 × 10⁶ iPSC within 7 weeks was 1.8‐4.0 × 10⁹. These cells showed stable CD45/CD7/CAR expression, effector functions of cytotoxicity and interferon gamma (IFN‐γ) production against GPC3‐expressing tumor cells. When the CAR‐NK/ILC cells were injected into a GPC3‐positive, ovarian‐tumor‐bearing, immunodeficient mouse model, we observed a significant therapeutic effect that prolonged the survival of the animals. When the cells were injected into immunodeficient mice during non–clinical safety tests, no acute systemic toxicity or tumorigenicity of the final product or residual iPSC was observed. In addition, our test results for the CAR‐NK/ILC cells generated with clinical manufacturing standards are encouraging, and these methods should accelerate the development of allogeneic pluripotent stem cell‐based immune cell cancer therapies.     

Optimal cut-off value of preprocedural geriatric nutritional risk index for predicting the clinical outcomes of patients undergoing endovascular revascularization for peripheral artery disease

BackgroundMalnutrition measured by the geriatric nutritional risk index (GNRI) was reported to be associated with poor prognosis for patients with peripheral artery disease (PAD). However, the optimal cut-off value of preprocedural GNRI for critical limb ischemia (CLI) and intermittent claudication (IC) is unknown. We aimed to determine its optimal cut-off value for CLI or IC patients requiring endovascular revascularization.MethodsWe explored data of 2246 patients (CLI: n = 1061, IC: n = 1185) registered in the Tokyo-taMA peripheral vascular intervention research COmraDE (TOMA-CODE) registry, which prospectively enrolled consecutive PAD patients who underwent endovascular revascularization in 34 hospitals in Japan from August 2014 to August 2016. The optimal cut-off values of GNRI were assessed by the survival classification and regression tree (CART) analyses, and the survival curve analyses for major adverse cardiovascular and limb events (MACLEs) were performed for these cut-off values.ResultsIn addition to the first cut-off value of 96.2 in CLI and 85.6 in IC, the survival CART provided an additional cut-off value of 78.2 in CLI and 106.0 in IC for further risk stratification. The survival curve was significantly stratified by the GNRI-based malnutrition status in both CLI [high risk: 47.7% (51/107), moderate: 30.1% (118/392), and low: 10.2% (53/520), log–rank p < 0.001] and IC [high risk: 14.3% (7/49), moderate: 4.5% (29/646), and low: 0.5% (2/407), log–rank p < 0.001]. The multivariate Cox-proportional hazard analysis showed that a higher GNRI was significantly associated with a better outcome in both CLI [hazard ratio (HR) per 1-point increase: 0.97, 95% CI: 0.96–0.98, p < 0.001] and IC (HR: 0.94, 95% CI: 0.91–0.97, p < 0.001).ConclusionsPreprocedural nutritional status significantly stratified future events in patients with PAD. Given that the optimal cut-off value of GNRI in CLI was almost 10-points lower than that of IC, using a disease-specific cut-off value is important for risk stratification.     

Longitudinal evaluation of local muscle conditions in a rat model of gastrocnemius muscle injury using an in vivo imaging system

This study aimed to evaluate the time course of local changes during the acute phase of gastrocnemius muscle strain, in a rat model, using an in vivo imaging system. Thirty‐eight, 8‐week‐old Sprague‐Dawley male rats were used in our study. Experimental injury of the right gastrocnemius muscle was achieved using the drop‐mass method. After inducing muscle injury, a liposomally formulated indocyanine green derivative (LP‐iDOPE, 7 mg/kg) was injected intraperitoneally. We evaluated the muscle injuries using in vivo imaging, histological examinations, and enzyme‐linked immunosorbent assays. The fluorescence peaked approximately 18 h after the injury, and decreased thereafter. Histological examinations revealed that repair of the injured tissue occurred between 18 and 24 h after injury. Quantitative analyses for various cytokines demonstrated significant elevations of interleukin‐6 and tumor necrosis factor‐α at 3 and 18 h post‐injury, respectively. The time course of fluorescence intensity, measured using in vivo imaging, demonstrated that the changes in cytokine levels and histopathologic characteristics were consistent. Specifically, these changes reached peaked 18 h post‐injury, followed by trends toward recovery. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1034–1038, 2015.     

Generation and characterization of a novel shoulder contracture mouse model

Frozen shoulder is a relatively common disorder that leads to severe pain and stiffness in the shoulder joint. Although this disorder is self‐limiting in nature, the symptoms often persist for years, resulting in severe disability. Recent studies using human specimens and animal models have shown distinct changes in the gene expression patterns in frozen shoulder tissue, indicating that novel therapeutic intervention could be achieved by controlling the genes that are potentially involved in the development of frozen shoulder. To achieve this goal, it is imperative to develop a reliable animal joint contracture model in which gene expression can be manipulated by gene targeting and transgenic technologies. Here, we describe a novel shoulder contracture mouse model. We found that this model mimics the clinical presentation of human frozen shoulder and recapitulates the changes in the gene expression pattern and the histology of frozen shoulder and joint contracture in humans and other larger animal models. The model is highly reproducible, without any major complications. Therefore, the present model may serve as a useful tool for investigating frozen shoulder etiology and for identifying its potential target genes. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1732–1738, 2015.     

Spin jam induced by quantum fluctuations in a frustrated magnet

Since the discovery of spin glasses in dilute magnetic systems, their study has been largely focused on understanding randomness and defects as the driving mechanism. The same paradigm has also been applied to explain glassy states found in dense frustrated systems. Recently, however, it has been theoretically suggested that different mechanisms, such as quantum fluctuations and topological features, may induce glassy states in defect-free spin systems, far from the conventional dilute limit. Here we report experimental evidence for existence of a glassy state, which we call a spin jam, in the vicinity of the clean limit of a frustrated magnet, which is insensitive to a low concentration of defects. We have studied the effect of impurities on SrCr_9pGa_12-9pO₁₉ [SCGO(p)], a highly frustrated magnet, in which the magnetic Cr³⁺ (s = 3/2) ions form a quasi-2D triangular system of bipyramids. Our experimental data show that as the nonmagnetic Ga³⁺ impurity concentration is changed, there are two distinct phases of glassiness: an exotic glassy state, which we call a spin jam, for the high magnetic concentration region (p > 0.8) and a cluster spin glass for lower magnetic concentration (p < 0.8). This observation indicates that a spin jam is a unique vantage point from which the class of glassy states of dense frustrated magnets can be understood.Understanding glassy states found in dense frustrated magnets has been an intellectual challenge since peculiar low-temperature glassy behaviors were observed experimentally in the quasi-2D SrCr_9pGa_12-9pO₁₉ (SCGO) (1–3) and in the 3D pyrochlore Y₂Mo₂O₇ (4). Immediately following, theoretical investigations (5–9) were performed to see if an intrinsic spin freezing transition is possible in a defect-free situation, aided by quantum fluctuations, as in the order-by-fluctuations phenomenon (10, 11). Quantum fluctuations at T = 0 were shown to select a long-range ordered state in the 2D kagome isotropic antiferromagnet (AFM) (5, 6), later expanded to the isotropic pyroclore and SCGO (9). Anisotropic interactions were also considered as a possible origin of the glassy kagome AFM (7). For an XY pyrochlore AFM, thermal fluctuations were found to induce a conventional Neel order (8). Experimental works were also performed to investigate if the glassy states are extrinsic due to site defects or random couplings or intrinsic to the magnetic lattice (12, 13). The consensus is that the low-temperature spin freezing transitions in SCGO(p) near the clean limit (p ≈ 1) is not driven by site defects (13).The nature of the frozen state in SCGO has been investigated by numerous experimental techniques, including bulk susceptibility (1–3), specific heat (2, 14), muon spin relaxation (μSR) (15), nuclear magnetic resonance (NMR) (13, 16), and elastic and inelastic neutron scattering (17). Observed are spin glassy behaviors, such as field-cooled and zero-field-cooled (FC/ZFC) hysteresis in bulk susceptibility (3), as well as non-spin-glassy behaviors, such as a quadratic behavior of specific heat at low T, C_v ∝ T² (14), linear dependence of the imaginary part of the dynamic susceptibility at low energies, χ″(ω) ∝ ω (17), and a broad but prominent momentum dependence of the elastic neutron scattering intensity (17). The interpretation of the frozen state below T_f is still controversial. One possibility suggested was a spin liquid with unconfined spinons or resonating valence bond state, based on NMR and μSR studies (15, 16). Many-body singlet excitations were also suggested to be responsible for the C_v ∝ T² behavior (14).Recently, some of us presented an alternative scenario involving a spin jam state by considering the effects of quantum fluctuations in the disorder-free quasi-2D ideal SCGO lattice with a simple nearest neighbor (NN) spin interaction Hamiltonian ? = J∑_NNS_i ? S_j (18, 19). The spin jam framework provided a qualitatively coherent understanding of all of the low-temperature behaviors such as that a complex energy landscape is responsible for the frozen state without long-range order (18), and Halperin−Saslow (HS)-like modes for the C_v ∝ T² and χ″(ω) ∝ ω behaviors (5, 18). In this system, which we refer to as the ideal SCGO model (iSCGO), semiclassical magnetic moments (or spins) are arranged in a triangular network of bipyramids and interact uniformly with their NN (18, 19). The microscopic mechanism for the spin jam state is purely quantum mechanical. The system has a continuous and flat manifold of ground states at the mean field level, including locally collinear, coplanar, and noncoplanar spin arrangements. Quantum fluctuations lift the classical ground state degeneracy (order by fluctuations), resulting in a complex rugged energy landscape that has a plethora of local minima consisting of the locally collinear states separated from each other by potential barriers (18). Although the work of ref. 18 dealt with a similar phase space constriction by quantum fluctuations as the aforementioned other theoretical works did, we would like to stress here the difference between the two: Whereas the other works mainly focused on the selection of the long-range-ordered (LRO) energetic ground state, the work of ref. 18 showed that the short-range-ordered (SRO) states that exist at higher energies are long-lived, dominate entropically over the LRO states, and govern the low-T physics.The introduction of nonmagnetic impurities into a topological spin jam state breaks some of the constraints in the system, and possibly allows local transitions between minima, with a time scale dependent on the density of impurities. At a sufficiently high vacancy concentration, the system exits the spin jam state and becomes either paramagnetic or an ordinary spin glass at lower temperatures. Here we try to identify and explore the spin jam regime in an experimentally accessible system. The three most important signatures we seek for the existence of a spin jam state, different from conventional spin glass states, are (i) a linear dependence of the imaginary part of the dynamic susceptibility at low energies, χ″(ω) ∝ ω, (ii) intrinsic short range static spin correlations, and (iii) insensitivity of its physics to nonmagnetic doping near the clean limit. In the rest of the paper, we provide experimental demonstration of these properties.Experimentally, there are, so far, two materials, SrCr_9pGa_12-9pO₁₉ [SCGO(p)] (1–3, 13–17, 20) and qs-ferrites like Ba₂Sn₂ZnGa₃Cr₇O₂₂ (BSZGCO) (21), in which the magnetic Cr³⁺ (3d³) ion surrounded by six oxygen octahedrally, form distorted quasi-2D triangular lattice of bipyramids (20, 21) as shown in Fig. 1A, and thus may realize a spin jam state. We would like to emphasize that these systems are very good insulators (resistivity ρ > ?10¹³?Ω ? cm at 300 K) and the Cr³⁺ (t2g3) ion has no orbital degree of freedom. Furthermore, the neighboring Cr ions share one edge of oxygen octahedral, and thus the direct overlap of the t2g3 orbitals of the neighboring Cr³⁺ ions make the AFM NN Heisenberg exchange interactions dominant and further neighbor interactions negligible (22, 23), as found in Cr₂O₃ (24) and ZnCr₂O₄ (25).Open in a separate windowFig. 1.(A) In SrCr_9pGa_12-9pO₁₉ [SCGO(p)], the magnetic Cr³⁺ (3d³, s = 3/2) ions form the kagome−triangular−kagome trilayer (Top). The blue and red spheres represent kagome and triangular sites, respectively. When viewed from the top of the layers, they form the triangular network of bipyramids (Bottom). (B) The p−T phase diagram of SCGO(p) constructed by bulk susceptibility and elastic neutron scattering measurements on powder samples with various p values. The freezing temperatures, T_f, marked with blue square and black circle symbols are obtained by bulk susceptibility and elastic neutron scattering measurements, respectively. Note that the values of T_f are much lower than the Curie–Weiss temperatures (see Fig. S1). Filled blue squares represent the data obtained from samples whose crystal structural parameters including the Cr/Ga concentrations were refined by neutron diffraction measurements (see Fig. S2 and Fig. S3).