Carbon monoxide-induced autophagy enhances human mesenchymal stromal cell function via paracrine actions in murine polymicrobial sepsis.

Sepsis is a life-threatening process due to organ dysfunction resulting from severe infections. Mesenchymal stromal cells (MSCs) are being investigated as therapy for sepsis, along with conditioning regimens to improve their function. Carbon monoxide (CO) gas, which is cytoprotective at low doses, induces autophagy and is a mediator of inflammation. We evaluated CO-induced autophagy in human MSCs (hMSCs), and its impact on cell function in murine cecal ligation and puncture. Conditioning of hMSCs with CO ex vivo resulted in enhanced survival and bacterial clearance in vivo, and neutrophil phagocytosis of bacteria in vitro. Decreased neutrophil infiltration and less parenchymal cell death in organs were associated with increased macrophage efferocytosis of apoptotic neutrophils, promoting resolution of inflammation. These CO effects were lost when the cells were exposed to autophagy inhibition prior to gas exposure. When assessing paracrine actions of CO-induced autophagy, extracellular vesicles (EVs) were predominantly responsible. CO had no effect on EV production, but altered their miRNA cargo. Increased expression of miR-145-3p and miR-193a-3p by CO was blunted with disruption of autophagy, and inhibitors of these miRNAs led to a loss of neutrophil phagocytosis and macrophage efferocytosis. Collectively, CO-induced autophagy enhanced hMSC function during sepsis via paracrine actions of MSC-derived EVs.

Visceral Adipose Tissue Reduction Measured by Deep Neural Network Architecture Improved Reflux Esophagitis Endoscopic Grade.

INTRODUCTION: Visceral obesity is a risk factor for reflux esophagitis (RE). We investigated the risk of RE according to visceral adipose tissue (VAT) measured by deep neural network architecture using computed tomography (CT) and evaluated the longitudinal association between abdominal adipose tissue changes and the disease course of RE. METHODS: Individuals receiving health checkups who underwent esophagogastroduodenoscopy (EGD) and abdominal CT at Seoul National University Healthcare System Gangnam Center between 2015 and 2016 were included. Visceral and subcutaneous adipose tissue areas and volumes were measured using a deep neural network architecture and CT. The association between the abdominal adipose tissue area and volume and the risk of RE was evaluated. Participants who underwent follow-up EGD and abdominal CT were selected; the effects of changes in abdominal adipose tissue area and volume on RE endoscopic grade were investigated using Cox proportional hazards regression. RESULTS: We enrolled 6,570 patients who underwent EGD and abdominal CT on the same day. RE was associated with male sex, hypertension, diabetes, excessive alcohol intake, current smoking status, and levels of physical activity. The VAT area and volume increased the risk of RE dose-dependently. A decreasing VAT volume was significantly associated with improvement in RE endoscopic grade (hazard ratio: 3.22, 95% confidence interval: 1.82-5.71). Changes in subcutaneous adipose tissue volume and the disease course of RE were not significantly correlated. DISCUSSION: Visceral obesity is strongly associated with RE. VAT volume reduction was prospectively associated with improvement in RE endoscopic grade dose-dependently. Visceral obesity is a potential target for RE treatment.

High-Statistics Measurement of Collins and Sivers Asymmetries for Transversely Polarized Deuterons.

New results are presented on a high-statistics measurement of Collins and Sivers asymmetries of charged hadrons produced in deep inelastic scattering of muons on a transversely polarized ^{6}LiD target. The data were taken in 2022 with the COMPASS spectrometer using the 160 GeV muon beam at CERN, statistically balancing the existing data on transversely polarized proton targets. The first results from about two-thirds of the new data have total uncertainties smaller by up to a factor of three compared to the previous deuteron measurements. Using all the COMPASS proton and deuteron results, both the transversity and the Sivers distribution functions of the u and d quark, as well as the tensor charge in the measured x range are extracted. In particular, the accuracy of the d quark results is significantly improved.

Final COMPASS Results on the Transverse-Spin-Dependent Azimuthal Asymmetries in the Pion-Induced Drell-Yan Process.

The COMPASS Collaboration performed measurements of the Drell-Yan process in 2015 and 2018 using a 190 GeV/c π^{-} beam impinging on a transversely polarized ammonia target. Combining the data of both years, we present final results on the amplitudes of five azimuthal modulations, which correspond to transverse-spin-dependent azimuthal asymmetries (TSAs) in the dimuon production cross section. Three of them probe the nucleon leading-twist Sivers, transversity, and pretzelosity transverse-momentum dependent (TMD) parton distribution functions (PDFs). The other two are induced by subleading effects. These TSAs provide unique new inputs for the study of the nucleon TMD PDFs and their universality properties. In particular, the Sivers TSA observed in this measurement is consistent with the fundamental QCD prediction of a sign change of naive time-reversal-odd TMD PDFs when comparing the Drell-Yan process with deep inelastic scattering. Also, within the context of model predictions, the observed transversity TSA is consistent with the expectation of a sign change for the Boer-Mulders function.

Epigallocatechin-3-gallate restores mitochondrial homeostasis impairment by inhibiting HDAC1-mediated NRF1 histone deacetylation in cardiac hypertrophy.

Decompensated cardiac hypertrophy is accompanied by impaired mitochondrial homeostasis, whether histone acetylation is involved in this process is yet to be determined. The role of HDAC1-mediated NRF1 histone deacetylation was investigated in transverse aortic constriction (TAC)-induced hypertrophy in rats and phenylephrine (PE)-induced hypertrophic cardiomyocytes. Administration of epigallocatechin-3-gallate (EGCG), an inhibitor of HDAC1, restored cardiac function, decreased heart/body weight and fibrosis, increased the ratio of mtDNA/nDNA and the percentage of LysoTracker+ CMs in TAC, compared with TAC without receiving EGCG. In PE-treated hypertrophic H9C2 cells, EGCG attenuated cell hypertrophy and increased LC3B II+MitoTracker+ puncta, as well as the ratio of mtDNA/nDNA. Interestingly, NRF1 but not PGC-1α expression was decreased in TAC- or PE-induced hypertrophic hearts or cells, respectively, while EGCG upregulated both NRF1 and PGC-1α in vitro. EGCG treatment also increased the interaction between PGC-1α and NRF1. In addition to inhibiting HDAC1 expression, EGCG decreased the binding of HDAC1 and increased the binding of acH3K9 or acH3K14 in the promotor regions of PGC-1α and NRF1. In neonatal rat cardiomyocytes, restored NRF1, TFAM and FUNDC1 were abolished by the overexpression of HDAC1. Collectively, data suggest that NRF1 reduction was averted by EGCG via inhibiting HDAC1-mediated histone deacetylation. Acetylation of NRF1 histone may play a key role in maintaining mitochondrial homeostasis associated with cardiac hypertrophy.

Impact of Neoadjuvant Chemotherapy (NAC) on Biomarker Expression in Breast Cancer.

Background and Objectives: This study aimed to explore biomarker change after NAC (neoadjuvant chemotherapy) and to investigate biomarker expression as a prognostic factor in patients with residual disease (RD) after NAC. Materials and Methods: We retrospectively evaluated 104 patients with invasive breast cancer, who underwent NAC and surgery at Pusan National University Hospital from 2015 to July 2022. The expression of the biomarker was assessed, and the overall survival (OS) and disease-free survival (DFS) were investigated. Results: After NAC, 24 patients (23.1%) out of 104 total patients had a pathological complete response (pCR). We found that changes in at least one biomarker were observed in 41 patients (51.2%), among 80 patients with RD. In patients with RD after NAC (n = 80), a subtype change was identified in 20 patients (25.0%). Any kind of change in the HER2 status was present 19 (23.7%) patients. The hormone receptor (HR)+/HER2+ subtype was significantly associated with better disease-free survival (DFS) (HR, 0.13; 95% CI, 0.02-0.99; p = 0.049). No change in p53 was associated with better DFS, and negative-to-positive change in p53 expression after NAC was correlated with worse DFS (p < 0.001). Negative-to-positive change in p53 was an independent, worse DFS factor in the multivariate analysis (HR,18.44; 95% CI, 1.86-182.97; p = 0.013). Conclusions: Biomarker change and subtype change after NAC were not infrequent, which can affect the further treatment strategy after surgery. The expression change of p53 might have a prognostic role. Overall, we suggest that the re-evaluation of biomarkers after NAC can provide a prognostic role and is needed for the best decision to be made on further treatment.

Engineered Human Antibody with Improved Endothelin Receptor Type A Binding Affinity, Developability, and Serum Persistence Exhibits Excellent Antitumor Potency.

Endothelin receptor A (ETA), a class A G protein-coupled receptor (GPCR), is a promising tumor-associated antigen due to its close association with the progression and metastasis of many types of cancer, such as colorectal, breast, lung, ovarian, and prostate cancer. However, only small-molecule drugs have been developed as ETA antagonists with anticancer effects. In a previous study, we identified an antibody (AG8) with highly selective binding to human ETA through screening of a human naïve immune antibody library. Although both in vitro and in vivo experiments indicated that the identified AG8 had anticancer effects, there is a need for improvement in biochemical and physicochemical properties such as the ETA binding affinity, thermostability, and productivity. In this study, we engineered the framework regions of AG8 and isolated an anti-ETA antibody (MJF1) exhibiting significantly improved thermostability and ETA binding affinity. Subsequently, our previously isolated PFc29, an Fc variant with an enhanced pH-dependent human FcRn binding profile, was introduced to MJF1, and the resulting Fc-engineered anti-ETA antibody (MJF1-PFc29) inhibited the proliferation of tumor cells comparably to MJF1 and showed a 4.2-fold increased serum half-life in human FcRn transgenic mice. Moreover, MJF1-PFc29 elicited higher tumor growth inhibition in colorectal cancer xenograft mice compared to MJF1. Our results demonstrate that the engineered human anti-ETA antibody MJF1-PFc29 has great therapeutic potential and high antitumor potency against various types of cancers including colorectal cancer.

Glycan-Controlled Human PD-1 Variants Displaying Broad-Spectrum High Binding to PD-1 Ligands Potentiate T Cell.

Although therapeutic immunoglobulin G (IgG) antibodies that regulate the activity of immune checkpoints bring innovation to the field of immuno-oncology, they are still limited in their efficiency to infiltrate the tumor microenvironment due to their large molecular size (150 kDa) and the necessity of additional engineering works to ablate effector functions for antibodies targeting immune cells. To address these issues, the human PD-1 (hPD-1) ectodomain, a small protein moiety of 14-17 kDa, has been considered as a therapeutic agent. Here, we used bacterial display-based high-throughput directed evolution to successfully isolate glycan-controlled (aglycosylated or only single-N-linked glycosylated) human PD-1 variants exhibiting over 1000-fold increased hPD-L1 binding affinity compared to that of wild-type hPD-1. The resulting hPD-1 variants, aglycosylated JYQ12 and JYQ12-2 with a single-N-linked glycan chain, showed exceptionally high binding affinity to hPD-L1 and very high affinity to both hPD-L2 and mPD-L1. Moreover, the JYQ12-2 efficiently potentiated the proliferation of human T cells. hPD-1 variants with significantly improved binding affinities for hPD-1 ligands could be used as effective therapeutics or diagnostics that can be differentiated from large-sized IgG antibody-based molecules.

Independent effect of cardiometabolic syndromes and depression on dementia in Parkinson's disease: A 12-year longitudinal follow-up study of a nationwide cohort.

BACKGROUND: We aimed to investigate the incidence rate of Parkinson's disease dementia (PDD) according to age and disease duration by sex. Furthermore, we explored the effect of each cardiometabolic syndrome and depression on the incidence of PDD. METHODS: Using data from the Korean National Health Insurance Service, 79,622 patients with de novo Parkinson's disease (PD) aged ≥40 years between January 2002 and December 2010 were followed to December 2019. We analyzed the incidence of PDD according to age at PD diagnosis and disease duration. To determine cardiometabolic syndromes and depression that affected PDD, we used Fine and Gray competing regression after controlling for age and sex. RESULTS: During the 12.5-year follow-up period, the incidence of PDD increased with age at PD diagnosis (0.81-45.31 per 1000 person-years among those aged 40-44 and over 80 years, respectively) and longer disease duration (22.68 per 1000 person-years in 1-2 years to 34.16 per 1000 person-years in 15-16 years). Hypertension (subdistribution hazard ratio [SHR] = 1.11; 95% confidence interval [CI] 1.07-1.16), diabetes (SHR = 1.09; 95% CI 1.05-1.14), dyslipidemia (SHR = 1.15; 95% CI 1.11-1.20), and depression (SHR = 1.36; 95% CI 1.30-1.41) independently increased the risk for PDD. CONCLUSIONS: Our findings provide insights into cardiometabolic syndromes as modifiable risk factors for incident PDD. Furthermore, our results will help in designing public health policies with respect to controlling cardiometabolic syndromes and depression to prevent incident PDD in patients with PD.

The Effect of Intrathecal Morphine on Postoperative Opioid Consumption in Patients Undergoing Abdominal Surgery for Gynecologic Malignancy: A Randomized Sham-Controlled Trial.

BACKGROUND: Surgery for gynecologic malignancy via midline-laparotomy leads to severe postoperative pain. Adequate pain control while sparing opioid consumption does offer benefits in postoperative complications and recovery. Intrathecal morphine (ITM) provides simple and effective analgesia. In this randomized trial, we compared postoperative opioid consumption in patients who received either ITM or a sham procedure. METHODS: We enrolled 68 adult patients undergoing open gynecologic oncology surgery from June 2021 to November 2021. They were randomly allocated to the ITM group (ITM; 200 µg injection) or sham group (sham procedure) to achieve a final 1:1 ratio between groups. We compared opioid consumption and pain severity during 72 hours after surgery. The variables regarding postoperative recovery and patient-centered outcomes were collected. The primary outcome is cumulative intravenous (IV) opioid consumption 24 hours after surgery. RESULTS: The median (interquartile range) cumulative IV opioid consumption during 24 hours after surgery was 18 mg (12-29) in the ITM group and 36 mg (27-42) in the sham group (median difference, 13; 95% confidence interval, 7.2-20.7; P < .001). Patient satisfaction regarding pain control was statistically significantly higher in the ITM group than in the sham group at postoperative 24 and 48 hours ( P < .001 and P = .005, respectively). There were no significant differences in the variables associated with postoperative recovery and frequency of complications requiring treatment. CONCLUSIONS: ITM is a safe and effective analgesic method after curative intent laparotomy for gynecologic malignancy. ITM provides better pain relief, reduces opioid consumption, and improves patient satisfaction without additional evident adverse events.

mTOR Inhibition Increases Transcription Factor E3 (TFE3) Activity and Modulates Programmed Death-Ligand 1 (PD-L1) Expression in Translocation Renal Cell Carcinoma.

The efficacy of programmed death ligand (PD-L)-1/PD-1 checkpoint blockade in renal cell carcinoma (RCC) remains unknown. The effects of mTOR inhibitors are uncertain, and patients may develop resistance to them. The limited understanding of cancer cell-intrinsic mTOR-mediated pathways remains a challenge in developing effective treatments. Whether transcription factor (TF)-E3 regulates PD-L1 expression and the tumor microenvironment was investigated, and the effects of an mammalian target of rapamycin (mTOR) inhibitor on translocation RCC were explored. TFE3 was overexpressed in clear cell RCC cell lines, and PD-L1 expression was analyzed by Western blot analysis. PD-L1 activity in translocation RCC was analyzed in relation to TFE3 expression via TFE3 knockdown and treatment with an mTOR inhibitor. The results were correlated with the gene expression profile, evaluated using digital multiplex analysis. TFE3 and PD-L1 expression were positively correlated in RCC cells. TFE3 overexpression was associated with the expression of PD-L1 in RCC. Furthermore, mTOR inhibition was associated with enhanced PD-L1 expression via TFE3 activation in translocation RCC. These data support the feasibility of combination therapy based on mTOR inhibition and PD-L1 blockade as a novel strategy for the treatment of patients with translocation RCC.

Independent effect of neurogenic orthostatic hypotension on mild cognitive impairment in Parkinson's disease.

PURPOSE: Orthostatic hypotension (OH) is an associative or causative factor of cognitive impairment in Parkinson's disease (PD). However, the association between mild cognitive impairment (MCI) and neurogenic OH directly associated with the presence of alpha-synuclein in PD remains unclear. We aimed to evaluate the relationship between MCI and neurogenic OH in patients with de novo PD. We also investigated the patterns of neuropsychological performance according to neurogenic OH. METHODS: A total of 456 patients with PD-normal cognition (PD-NC, n = 204) or PD-MCI (n = 252) were recruited from multiple centers in Korea. All patients underwent comprehensive neuropsychological tests and tilt-table tests to evaluate cognitive function and neurogenic OH. We used logistic regression analysis and multivariate analysis of covariance to determine the association between MCI and neurogenic OH and the pattern of neuropsychological performance according to neurogenic OH. RESULTS: Neurogenic OH (odds ratio = 3.66, 95% confidence interval 2.06 to 6.47) was independently associated with MCI in patients with de novo PD, regardless of orthostatic symptoms, while nonneurogenic OH was not. Patients with PD with neurogenic OH exhibited worse performance in frontal-executive function and visual memory function than those without neurogenic OH. CONCLUSION: Our findings provide insight into neurogenic OH as an important clinical factor with cognitive impairment in individuals with PD and vice versa. Therefore, the evaluation of cognitive function is necessary in PD patients with neurogenic OH.

Predictor of atrial fibrillation recurrence in patients who underwent a tricuspid valve operation with modified Cox maze procedure.

BACKGROUND: Recurrence of any atrial arrhythmia after surgical ablation is known as a negative predictor of cardiovascular events and total mortality. However, there have been no focused studies for atrial fibrillation (AF) recurrence prediction in patients with significant tricuspid regurgitation (TR), and the risk-benefit estimation of surgical ablation in tricuspid valve (TV) surgery is not fully established. METHOD: We screened 385 patients who underwent a TV operation between 2001 and 2017. After excluding patients who did not undergo a maze operation, 158 patients were enrolled. Enrolled patients were divided by recurrence of AF. We analyzed the difference between the AF recurrence group and no AF recurrence group, and AF recurrence factors in terms of clinical risk factors and echocardiographic risk factors. The hazard ratio (HR) and 95% confidence intervals (CIs) were presented using a Cox proportional hazard model. RESULTS: Among 158 patients, AF recurred in 65 patients within 10 years. For AF prediction, age was most the important clinical factor and right atrium (RA) diameter was the most important echocardiographic parameters. In patients with a larger RA diameter over 49.2 mm, the prevalence of AF recurrence was higher (HR 4.322, 95% CI [2.185-8.549], log rank p value < .001). In clinical outcome, there was no significant difference between the AF recurrence group and the no recurrence group in terms of death, TR recurrence, heart failure, and stroke. However, the risk of permanent pacemaker (PPM) insertion was higher in the AF recurrence group (HR 10.240, 95% CI [1.257-83.480], log rank p value .007) compared to the no recurrence group. CONCLUSION: Age and RA enlargement are key predictors of AF recurrence after TV operation with the CM procedure in patients with significant TR.

Impact of comprehensive optical diagnosis training using Workgroup serrAted polypS and Polyposis classification on detection of adenoma and sessile serrated lesion.

OBJECTIVES: Many interventions have been attempted to improve adenoma detection rate (ADR) and sessile serrated lesion detection rate (SDR), and one of these interventions is educational training to recognize polyp characteristics. This study aimed to investigate the change in polyp detection rates of endoscopists before and after comprehensive training through the Gangnam-Real Time Optical Diagnosis (Gangnam-READI) program. METHODS: Fifteen gastroenterologists participated in a 1-year comprehensive training program that consisted of ex vivo and in vivo training that encompasses knowledge and skills in endoscopic characterization of colonic polyps using the Workgroup serrAted polypS and Polyposis (WASP) classification. We evaluated the impact of the training program by comparing the overall and individual ADR and SDR 6 months before and after the training. RESULTS: Overall, 18,280 polyps (9337 adenomas and 855 sessile serrated lesion) were collected. The optical diagnosis training had no significant impact on the difference in ADR after training compared to before training (47.7% vs. 46.5%, P = 0.608). A tendency for a decrease in ADR variance was noted among the endoscopists after training (74.9 vs. 32.7, P = 0.121). The overall pre-training period SDR was 4.5% and showed a statistically significant increase to 5.6%, 8.0%, and 7.1% in the first and second half of the training period, and post-training period, respectively (P = 0.003). The optical diagnosis training did not decrease variance in SDR (8.9 vs. 8.8, P = 0.985). CONCLUSION: Comprehensive optical diagnosis training with WASP classification has a significant impact on increasing the overall SDR of expert endoscopists.

Improved Accuracy in Optical Diagnosis of Colorectal Polyps Using Convolutional Neural Networks with Visual Explanations.

BACKGROUND & AIMS: Narrow-band imaging (NBI) can be used to determine whether colorectal polyps are adenomatous or hyperplastic. We investigated whether an artificial intelligence (AI) system can increase the accuracy of characterizations of polyps by endoscopists of different skill levels. METHODS: We developed convolutional neural networks (CNNs) for evaluation of diminutive colorectal polyps, based on efficient neural architecture searches via parameter sharing with augmentation using NBIs of diminutive (≤5 mm) polyps, collected from October 2015 through October 2017 at the Seoul National University Hospital, Healthcare System Gangnam Center (training set). We trained the CNN using images from 1100 adenomatous polyps and 1050 hyperplastic polyps from 1379 patients. We then tested the system using 300 images of 180 adenomatous polyps and 120 hyperplastic polyps, obtained from January 2018 to May 2019. We compared the accuracy of 22 endoscopists of different skill levels (7 novices, 4 experts, and 11 NBI-trained experts) vs the CNN in evaluation of images (adenomatous vs hyperplastic) from 180 adenomatous and 120 hyperplastic polyps. The endoscopists then evaluated the polyp images with knowledge of the CNN-processed results. We conducted mixed-effect logistic and linear regression analyses to determine the effects of AI assistance on the accuracy of analysis of diminutive colorectal polyps by endoscopists (primary outcome). RESULTS: The CNN distinguished adenomatous vs hyperplastic diminutive polyps with 86.7% accuracy, based on histologic analysis as the reference standard. Endoscopists distinguished adenomatous vs hyperplastic diminutive polyps with 82.5% overall accuracy (novices, 73.8% accuracy; experts, 83.8% accuracy; and NBI-trained experts, 87.6% accuracy). With knowledge of the CNN-processed results, the overall accuracy of the endoscopists increased to 88.5% (P < .05). With knowledge of the CNN-processed results, the accuracy of novice endoscopists increased to 85.6% (P < .05). The CNN-processed results significantly reduced endoscopist time of diagnosis (from 3.92 to 3.37 seconds per polyp, P = .042). CONCLUSIONS: We developed a CNN that significantly increases the accuracy of evaluation of diminutive colorectal polyps (as adenomatous vs hyperplastic) and reduces the time of diagnosis by endoscopists. This AI assistance system significantly increased the accuracy of analysis by novice endoscopists, who achieved near-expert levels of accuracy without extra training. The CNN assistance system can reduce the skill-level dependence of endoscopists and costs.

Triangle Singularity as the Origin of the a_{1}(1420).

The COMPASS Collaboration experiment recently discovered a new isovector resonancelike signal with axial-vector quantum numbers, the a_{1}(1420), decaying to f_{0}(980)π. With a mass too close to and a width smaller than the axial-vector ground state a_{1}(1260), it was immediately interpreted as a new light exotic meson, similar to the X, Y, Z states in the hidden-charm sector. We show that a resonancelike signal fully matching the experimental data is produced by the decay of the a_{1}(1260) resonance into K^{*}(→Kπ)K[over ¯] and subsequent rescattering through a triangle singularity into the coupled f_{0}(980)π channel. The amplitude for this process is calculated using a new approach based on dispersion relations. The triangle-singularity model is fitted to the partial-wave data of the COMPASS experiment. Despite having fewer parameters, this fit shows a slightly better quality than the one using a resonance hypothesis and thus eliminates the need for an additional resonance in order to describe the data. We thereby demonstrate for the first time in the light-meson sector that a resonancelike structure in the experimental data can be described by rescattering through a triangle singularity, providing evidence for a genuine three-body effect.

Characteristics of interval gastric neoplasms detected within two years after negative screening endoscopy among Koreans.

BACKGROUND: In Korea, where gastric cancer is highly prevalent, biennial endoscopy is recommended among individuals over 40. Even under regular screening, some are still diagnosed at advanced stages. We aimed to identify characteristics of interval gastric neoplasms (IGNs) with rapid progression. RESULTS: Newly-diagnosed gastric neoplasms detected in screening endoscopy between January 2004 and May 2016 were reviewed. Among them, those who had previous endoscopy within 2 years were enrolled. Endoscopic findings, family history of gastric cancer, smoking, and H. pylori status were analysed. Totally, 297 IGN cases were enrolled. Among them, 246 were endoscopically treatable IGN (ET-IGN) and 51 were endoscopically untreatable IGNs (EUT-IGN) by the expanded criteria for endoscopic submucosal dissection. Among EUT-IGNs, 78% were undifferentiated cancers (40/51) and 33% showed submucosal invasion (13/40). They were median 2.0 cm in size and more commonly located in the proximal stomach than ET-IGNs (70.6% vs. 41.9%, p < 0.001). EUT-IGN was independently related with age < 60 (OR, 2.09; 95%CI, 1.03-4.26, p = 0.042), H. pylori (OR, 2.81; 95%CI, 1.20-6.63, p = 0.018), and absent/mild gastric atrophy (OR, 2.67; 95%CI, 1.25-5.72, p = 0.011). Overall and disease-specific survival were not significantly different between the two groups, however EUT-IGN tended to have short disease-specific survival (overall survival, p = 0.143; disease-specific survival, p = 0.083). CONCLUSIONS: Uniform screening endoscopy with two-year interval seems not enough for rapid-growing gastric neoplasms, such as undifferentiated cancers. They tended to develop in adults younger than 60 with H. pylori infection without severe gastric atrophy. More meticulous screening, especially for proximal lesions is warranted for adults younger than 60 with H. pylori infection before development of gastric atrophy.

Pancytopenia after administration of hyperthermic intraperitoneal chemotherapy with mitomycin-C: local therapy and systemic toxicity.

Cytoreductive surgery (CRS) coupled with hyperthermic intraperitoneal chemotherapy (HIPEC) has become the standard of treatment for many cancers with peritoneal metastasis. Mitomycin-C (MMC), the most common chemotherapy utilized with HIPEC, is associated with neutropenia but the degree of hematologic toxicity is unclear when splenectomy is included as part of CRS with MMC. We present an interesting case of pancytopenia following treatment with HIPEC using MMC and comment on the possible role of splenectomy in exacerbating its cytotoxic effects. Our unique case highlights potential hematologic toxicity following MMC-HIPEC and splenectomy. It suggests that spleen removal may enhance toxicity profiles of chemotherapy such as MMC. Because MMC is the preferred agent of choice used in CRS-HIPEC, future studies should investigate optimal MMC dosing and patient selection when splenectomy is performed to balance survival benefit with hematologic toxicities.

Subcortical and brainstem hemiatrophy accompanied by iron deposition in a patient with hemiparkinsonism-hemiatrophy syndrome: a case report.

BACKGROUND: There is no established pathogenesis of hemiparkinsonism-hemiatrophy syndrome (HPHA), and the varied clinical presentations have been reported in several case studies. To the best of our knowledge, the present report describes the first case of HPHA with unusual brain imaging findings. CASE PRESENTATION: A 20-year-old man presented with a 6-month history of weakness and clumsiness in his right limbs. He showed right-sided parkinsonism with dystonic hand posture; however, body asymmetry was not noted. Brain imaging revealed hemiatrophy of the left hemisphere subcortical structures and brainstem, and iron deposition in the left globus pallidus and substantia nigra. In addition, dopamine transporter imaging demonstrated normal presynaptic dopaminergic function. The patient was treated with levodopa, which had little to no effect. CONCLUSIONS: This case demonstrates the unique imaging characteristics of HPHA associated with widespread brain hemiatrophy and iron deposition. Further studies are needed to elucidate the diagnostic criteria for this heterogeneous syndrome.

Expression of Stromal Cell-Derived Factor-1 by Mesenchymal Stromal Cells Impacts Neutrophil Function During Sepsis.

OBJECTIVES: Sepsis results in organ dysfunction caused by a dysregulated host response, in part related to the immune response of a severe infection. Mesenchymal stromal cells are known to modulate the immune response, and expression of stromal cell-derived factor-1 regulates mobilization of neutrophils from the bone marrow. We are investigating the importance of stromal cell-derived factor-1 in mesenchymal stromal cells and its role in promoting neutrophil function after the onset of cecal ligation and puncture-induced sepsis. Stromal cell-derived factor-1 expression was silenced in mesenchymal stromal cells, compared with the control scrambled construct mesenchymal stromal cells. DESIGN: Animal study and cell culture. SETTING: Laboratory investigation. SUBJECTS: BALB/c mice. INTERVENTIONS: Polymicrobial sepsis was induced by cecal ligation and puncture. shSCR mesenchymal stromal cells and shSDF-1 mesenchymal stromal cells were delivered by tail vein injections to septic mice. The mice were assessed for survival, bacterial clearance, and the inflammatory response during sepsis in each of the groups. Mesenchymal stromal cells were also assessed for their ability to promote bacterial phagocytosis by neutrophils. MEASUREMENTS AND MAIN RESULTS: Injection of shSCR mesenchymal stromal cells after the onset of sepsis led to an increase in mouse survival (70%) at 7 days, whereas survival of mice receiving shSDF-1 mesenchymal stromal cells was significantly diminished (33%). The loss of survival benefit in mice receiving shSDF-1 mesenchymal stromal cells was associated with less efficient bacterial clearance compared with shSCR mesenchymal stromal cells. Although shSCR mesenchymal stromal cells, or their conditioned medium, were able to increase neutrophil phagocytosis of bacteria, this effect was significantly blunted with shSDF-1 mesenchymal stromal cells. Assessment of peritoneal inflammation revealed that neutrophils were significantly increased and more immature in septic mice receiving shSDF-1 mesenchymal stromal cells. This response was associated with hypocellularity and increased neutrophil death in the bone marrow of mice receiving shSDF-1 mesenchymal stromal cells. CONCLUSIONS: Expression of stromal cell-derived factor-1 in mesenchymal stromal cells enhances neutrophil function with increased phagocytosis, more efficient clearance of bacteria, and bone marrow protection from depletion of cellular reserves during sepsis.