Alternative localization of HEME OXYGENASE 1 in plant cells regulates cytosolic heme catabolism.

Heme, an organometallic tetrapyrrole, is widely engaged in oxygen transport, electron delivery, enzymatic reactions, and signal transduction. In plants, it is also involved in photomorphogenesis and photosynthesis. HEME OXYGENASE 1 (HO1) initiates the first committed step in heme catabolism, and it has generally been thought that this reaction takes place in chloroplasts. Here, we show that HO1 in both Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) has two transcription start sites (TSSs), producing long (HO1L) and short (HO1S) transcripts. Their products localize to the chloroplast and the cytosol, respectively. During early development or de-etiolation, the HO1L/HO1S ratio gradually increases. Light perception via phytochromes and cryptochromes elevates the HO1L/HO1S ratio in the whole seedling through the functions of ELONGATED HYPOCOTYL 5 (HY5) and HY5 HOMOLOG (HYH) and through the suppression of DE-ETIOLATED 1 (DET1), CONSTITUTIVE PHOTOMORPHOGENESIS 1 (COP1), and PHYTOCHROME INTERACTING FACTORs (PIFs). HO1L introduction complements the HO1-deficient mutant; surprisingly, HO1S expression also restores the short hypocotyl phenotype and high pigment content and helps the mutant recover from the genomes uncoupled (gun) phenotype. This indicates the assembly of functional phytochromes within these lines. Furthermore, our findings support the hypothesis that a mobile heme signal is involved in retrograde signaling from the chloroplast. Altogether, our work clarifies the molecular mechanism of HO1 TSS regulation and highlights the presence of a cytosolic bypass for heme catabolism in plant cells.

Larger Tumor Size and Elevated Serum Chromogranin A Levels Predict Metastatic Disease on DOTATATE Imaging in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

PURPOSE: DOTATATE PET/CT (DOTATATE) is superior to conventional imaging in detecting metastasis for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, limited availability, high-cost, and additive radiation exposure necessitate guidelines for its use. This study seeks to investigate the relationship between clinical characteristics and metastasis on DOTATATE. METHODS: This was a retrospective analysis of 815 patients who underwent DOTATATE at UCLA from 2014 to 2022. After applying inclusion and exclusion criteria, the study cohort consisted of 163 patients with pathologically diagnosed GEP-NETs, who either underwent primary tumor resection within 1-year prior, or had not undergone resection at the time of DOTATATE imaging. The presence of metastasis was determined using DOTATATE. Fisher's exact test, chi-squared test, and Mann-Whitney test were conducted to compare intergroup difference. Multivariate analysis was performed to identify clinical characteristics associated with metastasis on DOTATATE. RESULTS: Of patients with GEP-NETs, 40.5% (n = 66) were diagnosed with metastases by using DOTATATE. Those with metastatic disease were more likely to exhibit a larger primary tumor size (median 3.4 vs. 1.2, cm, P < 0.001), elevated serum chromogranin A level (CgA, median 208 vs. 97, mg/ml, P = 0.005), and higher tumor grade (P < 0.001). Primary tumor size ≥2 cm and serum CgA level ≥150 ng/mL for metastatic disease had a sensitivity and specificity of 64% and 89%, and 72% and 59%, respectively. Multivariate analysis demonstrated that primary tumor size (≥2/<2, cm, odds ratio [OR] 47.90, P < 0.001), tumor functionality (functional/nonfunctional, adjusted OR 10.17 P = 0.008), serum CgA level (≥150/<150, ng/ml, OR 6.25, P = 0.005), and tumor grade G2 (G2/G1, OR 9.6, P < 0.001) were independently associated with metastases on DOTATATE. CONCLUSIONS: Among patients with GEP-NETs, primary tumor size ≥2 cm, serum CgA level ≥150 ng/mL, and tumor grade G2 are associated with an increased risk of metastases on DOTATATE, and these predictors may be helpful to identify patients where DOTATATE is indicated for complete staging.

Machine Learning Based Prediction of Postoperative Pancreatic Fistula Following Pancreaticoduodenectomy.

OBJECTIVE: To develop a novel machine learning (ML) model to predict clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD). SUMMARY BACKGROUND DATA: Accurate prognostication of CR-POPF may allow for risk stratification and adaptive treatment strategies for potential PD candidates. However, antecedent models, such as the modified Fistula Risk Score (mFRS), are limited by poor discrimination and calibration. METHODS: All records entailing PD within the 2014-2018 ACS NSQIP were identified. Additionally, patients undergoing PD at our institution between 2013 and 2021 were queried from our local data repository. An eXtreme Gradient Boosting (XGBoost) model was developed to estimate the risk of CR-POPF using data from the ACS NSQIP and evaluated using institutional data. Model discrimination was estimated using the area under the receiver operating characteristic (AUROC) and precision recall curve (AUPRC). RESULTS: Overall, 12,281 and 445 patients undergoing PD were identified within the 2014-2018 ACS NSQIP and our institutional registry, respectively. Application of the XGBoost and mFRS scores to the internal validation dataset revealed that the former model had significantly greater AUROC (0.72 vs. 0.68, P<0.001) and AUPRC (0.22 vs. 0.18, P<0.001). Within the external validation dataset, the XGBoost model remained superior to the mFRS with an AUROC of 0.79 (95% CI 0.74-0.84) versus 0.75 (95% CI 0.70-0.80, P<0.001). In addition, AUPRC was higher for the XGBoost model, compared to the mFRS. CONCLUSIONS: Our novel ML model consistently outperformed the previously validated mFRS within internal and external validation cohorts, thereby demonstrating its generalizability and utility for enhancing prediction of CR-POPF.

Laparoscopic surgery reduced frequency of postoperative small bowel obstruction, and hospital stay compared with open surgery in a cohort of patients with colorectal cancer: a propensity score matching analysis.

BACKGROUND: Laparoscopic surgery (LS) is reported to reduce postoperative complications and hospital stay compared with open surgery (OP). Because patient selection may have been biased in previous studies, propensity score matching (PSM) analysis was used in this study to test the benefits of LS compared with OP. METHODS: A total of 759 patients with stage I-III colorectal cancer undergoing curative surgery were retrospectively reviewed. To minimize confounding bias between LS and OP groups, a 1:1 PSM analysis was performed based on adjuvant chemotherapy, age, albumin, body mass index, American Society of Anesthesiologists physical status depth of tumor, gender, lymph node dissection, maximum tumor size, obstructive tumor, previous abdominal surgery, pathological stage, tumor differentiation, and tumor location. Statistical analyses including chi-square test, Mann-Whitney U test, univariate analyses and Kaplan-Meier method and log-rank test were performed using the data after PSM to investigate the benefits of LS compared with OP. RESULTS: After PSM analysis, 460 patients remained in the study. The LS group had lower intraoperative blood loss (34 ± 70 vs 237 ± 391, mL; P < 0.001), lower frequency of postoperative small bowel obstruction (SBO) (17/213 vs 30/230; P = 0.045), lower rate of nasogastric tube insertion (7/223 vs 17/213; P = 0.036), and shorter postoperative hospital stay (13 ± 10 vs 25 ± 47, day; P < 0.001) than the OP group. Univariate analyses showed that LS significantly reduced the risk of postoperative SBO (odds ratio [OR] 0.532; 95% confidence interval [CI] 0.285-0.995; P = 0.048) and nasogastric tube insertion (OR 0.393; 95% CI 0.160-0.967; P = 0.042) compared with OP. There were no significant differences in OS and RFS between the groups. CONCLUSIONS: LS reduced intraoperative blood loss, frequency of postoperative SBO, rate of nasogastric tube insertion, and postoperative hospital stay compared with OP.

The retrograde signaling protein GUN1 regulates tetrapyrrole biosynthesis.

The biogenesis of the photosynthetic apparatus in developing seedlings requires the assembly of proteins encoded on both nuclear and chloroplast genomes. To coordinate this process there needs to be communication between these organelles, but the retrograde signals by which the chloroplast communicates with the nucleus at this time are still essentially unknown. The Arabidopsis thaliana genomes uncoupled (gun) mutants, that show elevated nuclear gene expression after chloroplast damage, have formed the basis of our understanding of retrograde signaling. Of the 6 reported gun mutations, 5 are in tetrapyrrole biosynthesis proteins and this has led to the development of a model for chloroplast-to-nucleus retrograde signaling in which ferrochelatase 1 (FC1)-dependent heme synthesis generates a positive signal promoting expression of photosynthesis-related genes. However, the molecular consequences of the strongest of the gun mutants, gun1, are poorly understood, preventing the development of a unifying hypothesis for chloroplast-to-nucleus signaling. Here, we show that GUN1 directly binds to heme and other porphyrins, reduces flux through the tetrapyrrole biosynthesis pathway to limit heme and protochlorophyllide synthesis, and can increase the chelatase activity of FC1. These results raise the possibility that the signaling role of GUN1 may be manifested through changes in tetrapyrrole metabolism, supporting a role for tetrapyrroles as mediators of a single biogenic chloroplast-to-nucleus retrograde signaling pathway.

The preoperative pan-immune-inflammation value is a novel prognostic predictor for with stage I-III colorectal cancer patients undergoing surgery.

PURPOSE: The pan-immune-inflammation value (PIV) is useful for stratifying outcomes in patients with metastatic colorectal cancer. However, it is unclear whether preoperative PIV can predict the surgical outcomes of patients with stage I-III colorectal cancer who receive surgery. METHODS: The records of 758 patients with stage I-III colorectal cancer who received surgical treatment were retrospectively reviewed. The preoperative PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. The cut-off value was determined using a receiver operating characteristic curve for overall survival. RESULTS: The cut-off value of the preoperative PIV was 376. Five hundred sixty-eight patients (74.9%) had low values (≤ 376), and 190 (25.1%) had high values (> 376). Univariate and multivariate analyses revealed that the PIV (> 376/ ≤ 376) (HR 2.485; 95% CI 1.552-3.981, P < 0.001) was significantly associated with overall survival, as well as age (> 60/ ≤ 60, years) (HR 1.988; 95% CI 1.038-3.807, P = 0.038), globulin-to-albumin ratio (> 0.83/ ≤ 0.83) (HR 2.013; 95% CI 1.231-3.290, P = 0.005) and postoperative complication (C-D grade III-V/0-II) (HR 1.991; 95% CI 1.154-3.438, P = 0.013). The Kaplan-Meier method and log-rank test showed significant differences in overall survival between patients with stage I-III disease with high (> 376) and low (≤ 376) PIVs. CONCLUSION: The preoperative PIV is useful for predicting surgical outcomes in patients with stage I-III colorectal cancer.

Prognostic significance of preoperative hyaluronic acid level in patients with hepatocellular carcinoma.

BACKGROUND: Serum hyaluronic acid (HA) levels are increased in patients with solid tumors, and may predict outcomes. However, as HA levels also correlate with the degree of liver fibrosis, the prognostic significance of serum HA levels in patients with hepatocellular carcinoma (HCC) is unclear. METHODS: A total of 656 consecutive patients who underwent hepatic resection for HCC were divided into two groups by serum HA level (high HA [≥200 ng/mL], n = 248; low HA [<200 ng/mL], n = 408). Clinicopathological characteristics and postoperative survival were compared between groups. Moreover, 1:1 propensity score matching analysis was applied to adjust characteristics between groups. RESULTS: Both the 5-year overall and relapse-free survival rates (OSR and RFSR) in the low HA group were significantly better than those in the high HA group (59.8% vs. 38.6%, respectively, p < 0.001 and 24.5% vs. 13.1%, respectively, p < 0.001). After propensity score matching, two comparable groups of 124 patients each were obtained. However, both the 5-year OSR and RFSR in the low HA group remained significantly better than those in the high HA group (57.4% vs. 38.3%, respectively, p = 0.006 and 22.5% vs. 14.7%, respectively, p = 0.003). CONCLUSION: High preoperative HA level predicts poor postoperative survival of patients with HCC. undergoing hepatic resection.

Repressor Activity of SqrR, a Master Regulator of Persulfide-Responsive Genes, Is Regulated by Heme Coordination.

Reactive sulfur species (RSS) are involved in bioactive regulation via persulfidation of proteins. However, how cells regulate RSS-based signaling and RSS metabolism is poorly understood, despite the importance of universal regulation systems in biology. We previously showed that the persulfide-responsive transcriptional factor SqrR acts as a master regulator of sulfide-dependent photosynthesis in proteobacteria. Here, we demonstrated that SqrR also binds heme at a near one-to-one ratio with a binding constant similar to other heme-binding proteins. Heme does not change the DNA-binding pattern of SqrR to the target gene promoter region; however, DNA-binding affinity of SqrR is reduced by the binding of heme, altering its regulatory activity. Circular dichroism spectroscopy clearly showed secondary structural changes in SqrR by the heme binding. Incremental change in the intracellular heme concentration is associated with small, but significant reduction in the transcriptional repression by SqrR. Overall, these results indicate that SqrR has an ability to bind heme to modulate its DNA-binding activity, which may be important for the precise regulation of RSS metabolism in vivo.

Impact of Primary Tumor Location on Survival After Curative Resection in Patients with Colon Cancer: A Meta-Analysis of Propensity Score-Matching Studies.

BACKGROUND: Recent retrospective subgroup analyses of patients with unresectable colon cancer (CC) receiving systemic chemotherapy have demonstrated that there is a significant difference in treatment outcome between patients with right-sided CC (RSCC) and those with left-sided CC (LSCC). However, it is impossible to divide patients with CC randomly into RSCC and LSCC groups before surgery. Therefore, the aim of this study is to explore the impact of primary tumor location (PTL) on survival after curative surgery for patients with CC using propensity score-matching (PSM) studies instead of randomization. MATERIALS AND METHODS: We performed a comprehensive electronic search of the literature up to January 2019 to identify studies that had used databases allowing comparison of postoperative survival between patients with RSCC and those with LSCC. To integrate the impact of PTL on 5-year overall survival (OS) after curative surgery, a meta-analysis was performed using random-effects models to calculate the risk ratio (RR) and 95% confidence interval (CI) for the selected PSM studies. RESULTS: Five studies involving a total of 398,687 patients with CC were included in this meta-analysis. Among 205,641 patients with RSCC, 69,091 (33.6%) died during the observation period, whereas among 193,046 patients with LSCC, 63,380 (32.8%) died during the same period. These results revealed that patients with RSCC and those with LSCC had almost the same 5-year OS (RR, 0.98; 95% CI, 0.89-1.07; p = .64; I2 = 97%). CONCLUSION: This meta-analysis has demonstrated that there was no significant difference in 5-year OS between patients with RSCC and those with LSCC after curative resection. IMPLICATIONS FOR PRACTICE: To integrate the impact of primary tumor location (PTL) on 5-year overall survival (OS) after curative surgery, five propensity score-matching (PSM) studies involving a total of 398,687 patients with colon cancer (CC) were included in this meta-analysis. Among 205,641 patients with right-sided CC (RSCC), 69,091 (33.6%) died during the observation period, whereas among 193,046 patients with left-sided CC (LSCC), 63,380 (32.8%) died during the same period. These results revealed that patients with RSCC and those with LSCC had almost the same 5-year OS (risk ratio, 0.98; 95% confidence interval, 0.89-1.07; p = .64; I2 = 97%).

PD-L1 is induced on the hepatocyte surface via CKLF-like MARVEL transmembrane domain-containing protein 6 up-regulation by the anti-HBV drug Entecavir.

Chronic hepatitis B is now controllable when treated with nucleoside reverse transcriptase inhibitors (NRTIs), which inhibit hepatitis B virus (HBV) replication. However, once the NRTIs are discontinued, most patients relapse, necessitating lifelong NRTIs treatment. HBV infection relapse is assumed to be caused by the persistent existence of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. The mechanism by which cccDNA-positive hepatocytes escape immune surveillance during NRTIs treatment remains elusive. Entecavir (ETV), a commonly used NRTI, post-transcriptionally up-regulates programmed cell death-ligand 1 (PD-L1), an immune checkpoint molecule, on the cell surface of hepatocytes regardless of HBV infection. Up-regulation by ETV depends on up-regulation of CKLF-like MARVEL transmembrane domain-containing 6, a newly identified potent regulator of PD-L1 expression on the cell surface. ETV-treated hepatic cells suppressed the activity of primary CD3 T cells and programmed cell death protein-1 (PD-1)-over-expressed Jurkat cells. Finally, ETV induces PD-L1 in primary hepatocytes infected by HBV. These results provide evidence that ETV considerably up-regulates PD-L1 on the cell surface of infected hepatocytes, which may be one of the mechanisms by which infected hepatocytes subvert immune surveillance.

Omentectomy Does Not Affect the Postoperative Outcome of Patients With Locally Advanced Gastric Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE: To explore the influence of omentectomy on postoperative outcomes in patients with locally advanced gastric cancer (LAGC). BACKGROUND: Although several meta-analyses have investigated the influence of bursectomy on postoperative outcomes in patients with LAGC, no meta-analyses have explored the influence of omentectomy on postoperative outcomes in such patients. METHODS: We performed a comprehensive electronic search of the literature up to December 2020 to identify studies that compared postoperative outcomes between patients with LAGC who did and did not undergo omentectomy. A meta-analysis was performed using random-effects models to calculate the risk ratio (RR) and 95% confidence interval (CI), and heterogeneity was analyzed using I2 statistics. RESULTS: Eight retrospective studies involving a total of 2658 patients with LAGC who underwent surgery were included in this meta-analysis. Among them, 3 propensity score matching (PSM) studies demonstrated that the 5-y recurrence-free survival (RFS) rate was 72.9% (314/431) in patients with LAGC who did not undergo omentectomy, whereas it was 70.3% (303/431) in those who did. The results revealed no significant difference in 5-y RFS between groups (RR, 0.91; 95% CI, 0.74-1.13; P = 0.41; I2 = 0%). Two PSM studies also revealed no significant difference in 5-y overall survival (OS) between groups (RR, 0.77; 95% CI, 0.52-1.13; P = 0.18; I2 = 47%). CONCLUSIONS: The results of these meta-analyses show that omentectomy had no significant influence on 5-y OS, especially 5-y RFS, in patients with LAGC.

Impact of Advanced Technique on Improvement in the Retrievable Inferior Vena Cava Filter Retrieval Rate.

BACKGROUND: It is recommended to remove retrievable inferior vena cava filters (r-IVCFs) when they are no longer needed because their presence may give rise to serious complications related to prolonged placement of the filter. An advanced filter retrieval technique may help improve the retrieval rate.Methods and Results:107 consecutive patients (mean age; 61±18 years, male 53%) in whom r-IVCF retrieval was attempted were prospectively enrolled between April 2012 and December 2018. The frequently used advanced techniques were sling technique and biopsy forceps dissection technique. Retrieval success was 75% with standard retrieval technique alone; however, the overall retrieval success rate improved to 98% with advanced techniques. We observed few serious complications related to the retrieval procedure. Logistic multivariate analysis identified prolonged indwelling time (P=0.0011) and embedded hook in the caval wall (P=0.0114) as independent predictors, and the cutoff value for the indwelling time for requirement of advanced technique was 80 days. CONCLUSIONS: Advanced retrieval techniques helped improve the retrieval rate without serious complications. We may need to consider the referral of patients to centers with expertise in advanced retrieval techniques when the indwelling time is >80 days, and pre-retrieval CT image shows a hook embedded in the vessel wall.

Gilteritinib versus chemotherapy in Japanese patients with FLT3-mutated relapsed/refractory acute myeloid leukemia.

BACKGROUND: Until recently, no effective targeted therapies for FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P < 0.001). METHODS: We evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC. RESULTS: Median OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%). CONCLUSION: Findings in Japanese patients are consistent with those of the overall ADMIRAL study population.

Is left-sided involvement of hepatocellular carcinoma an important preoperative predictive factor of poor outcome?

BACKGROUND: The tumor location is the most simple clinical factor and important in liver surgery to make surgical procedure. However, no previous study has investigated the prognostic differences and clinical features of hepatocellular carcinoma showing specific laterality. This study is the first report to focus on the laterality and aimed to lead to more simple and useful predictive factor rather than recent complicated predictive models. METHODS: Patients who underwent liver resection for the first time for single tumors located within each lobe between 2000 and 2018 were enrolled. We divided them into two groups based on tumor location: a right-sided group and a left-sided group. Univariable and multivariable analyses were performed to assess survival differences in relation to several other factors. RESULTS: There were 595 eligible patients; the 5-year survival rates and disease-free survival rates were 49.5% and 19.1% in the left-sided group and 55.6% and 24.5% in the right-sided group, respectively (p = 0.026). Statistical analyses revealed that the following preoperative prognostic factors were independently significant (p < 0.05) in the left-sided group: indocyanine green retention rate at 15 min, alpha fetoprotein, protein induced by vitamin K absence or antagonists-II level, and larger tumor size. CONCLUSION: The left-sided group had a poorer prognosis than the right-sided group. A left-sided tumor location is a significant preoperative factor predictive of poor outcome in patients with hepatocellular carcinoma.

Sulfide-responsive transcriptional repressor SqrR functions as a master regulator of sulfide-dependent photosynthesis.

Sulfide was used as an electron donor early in the evolution of photosynthesis, with many extant photosynthetic bacteria still capable of using sulfur compounds such as hydrogen sulfide (H2S) as a photosynthetic electron donor. Although enzymes involved in H2S oxidation have been characterized, mechanisms of regulation of sulfide-dependent photosynthesis have not been elucidated. In this study, we have identified a sulfide-responsive transcriptional repressor, SqrR, that functions as a master regulator of sulfide-dependent gene expression in the purple photosynthetic bacterium Rhodobacter capsulatus SqrR has three cysteine residues, two of which, C41 and C107, are conserved in SqrR homologs from other bacteria. Analysis with liquid chromatography coupled with an electrospray-interface tandem-mass spectrometer reveals that SqrR forms an intramolecular tetrasulfide bond between C41 and C107 when incubated with the sulfur donor glutathione persulfide. SqrR is oxidized in sulfide-stressed cells, and tetrasulfide-cross-linked SqrR binds more weakly to a target promoter relative to unmodified SqrR. C41S and C107S R. capsulatus SqrRs lack the ability to respond to sulfide, and constitutively repress target gene expression in cells. These results establish that SqrR is a sensor of H2S-derived reactive sulfur species that maintain sulfide homeostasis in this photosynthetic bacterium and reveal the mechanism of sulfide-dependent transcriptional derepression of genes involved in sulfide metabolism.

[Systemic varicella-zoster infection during ixazomib-containing multiagent chemotherapy for multiple myeloma].

A 58-year-old man received high-dose melphalan with autologous peripheral blood stem cell transplantation for multiple myeloma in stringent complete response (sCR). Relapse occurred 4 years after the transplantation, and he was placed on ixazomib, lenalidomide, and dexamethasone (IRd) and achieved sCR. On the 10th day of the 10th course of IRd, he developed fever followed by generalized skin eruption with vesicles, headache, and dizziness. Varicella-zoster virus (VZV) antigen from the vesicle and VZV-DNA from the cerebrospinal fluid were detected, and he was diagnosed with systemic VZV infection. He was placed on intravenous acyclovir (ACV), and the infection resolved completely. VZV infection has been recognized as an important complication associated with the use of proteasome inhibitors; however, to our knowledge, there have been no reported cases of serious systemic VZV infection associated with ixazomib. The clinical course of this case strongly suggests the importance of prophylaxis for VZV infection during treatment with ixazomib.

[Chronic active Epstein-Barr virus infection with multiple vascular lesions successfully treated by cord blood transplantation].

An 18-year-old woman presented with fever and liver dysfunction. Computed tomography showed lymphadenopathy, hepatosplenomegaly, and vascular lesions such as aneurysms and irregularities at multiple arteries, including coronary arteries. Based on the high copy number of Epstein-Barr virus (EBV)-DNA in the peripheral blood, EBV-infected CD4+T cells, and the proliferation of EBER-positive cells in the bone marrow, chronic active EBV infection (CAEBV) was diagnosed. Although the fever and liver dysfunction improved as a result of the initial immunosuppressive therapy and multiagent chemotherapy, EBV-DNA remained high. Moreover, she experienced repeated episodes of angina pectoris due to coronary arterial lesions. Therefore, cord blood transplantation was performed after reduced-intensity conditioning. EBV-DNA decreased quickly after initiating the conditioning and became undetectable at day 7 after the transplant. Vascular lesions did not progress after the transplant, and the patient's angina pectoris resolved. At 2.5 years after the transplant, she is alive without disease recurrence. The prognosis of CAEBV with vascular lesions is especially poor. Although the indication for allogeneic hematopoietic stem cell transplantation (HSCT) is difficult to determine in such cases, the clinical course of our case suggests that allogenic HSCT could be safely performed under appropriate management and could successfully control not only CAEBV but also vascular lesions.

[Preoperative C-reactive protein predicts recurrence after curative resection in advanced gastric cancer patients receiving postoperative adjuvant chemotherapy using S-1].

New chemotherapeutic regimens such as S-1 plus docetaxel, S-1 plus oxaliplatin and capecitabine plus oxaliplatin are reported to be effective and safe as postoperative adjuvant chemotherapy (PAC) for advanced gastric cancer (GC) patients. Although the use of these PACs is increasing, it is still unclear how to choose the best regimen for advanced GC patients. Therefore, we aimed to investigate which clinical characteristics are associated with recurrence after curative surgery in patients receiving S-1 as PAC. Thirty-nine patients who received a PAC regimen with S-1 for more than 1 year after curative surgery for advanced GC were enrolled. Univariate and multivariate analyses using the Cox proportional hazard model were performed to detect clinical characteristics that correlated with recurrence. Patients were divided into two groups, recurrence, and non-recurrence, and receiver operating characteristic (ROC) curve analysis was used to identify the cut-off values. Kaplan-Meier analysis and the log-rank test were used for comparison of relapse-free survival (RFS). Fifteen patients had a recurrence after surgery (38.5%, 15/39). Multivariate analysis using clinical characteristics revealed that preoperative C-reactive protein (CRP) (>0.3/≤0.3, mg/dL) (HR 10.73;95% C.I., 1.824-63.14;P=0.009) was significantly associated with recurrence. Kaplan-Meier analysis and the log-rank test demonstrated that preoperative CRP (>0.3/≤0.3, mg/dL) was also significantly associated with RFS (P<0.001). Therefore, preoperative CRP is significantly associated with recurrence and RFS after curative surgery in advanced GC patients receiving S-1 as PAC.

Late-onset visceral varicella-zoster virus infection presented as acute liver failure after allogeneic hematopoietic stem cell transplantation.

Although much less common than localized zoster, initial presentation of varicella-zoster virus (VZV) as visceral infection can occur especially after allogeneic hematopoietic stem cell transplantation (HSCT). We herein report a case of post-transplant visceral VZV infection presenting as fatal acute liver failure. It developed 4 years after allogeneic HSCT when a long-term prophylactic anti-VZV agent administration was discontinued. VZV should be listed as a causative pathogen of acute liver failure even years after allogeneic HSCT. Indication for, and duration of anti-VZV prophylaxis should be further investigated.