Aging-associated and CD4 T-cell-dependent ectopic CXCL13 activation predisposes to anti-PD-1 therapy-induced adverse events.

Clinical success of immune-checkpoint blockade (ICB) cancer immunotherapy is compromised by increased risk of immune-related adverse events (irAEs). However, mechanistic action(s) of immune responses underlying development of irAE remain not fully explored. Here, we found that in tumor-bearing aged, but not young, mice, antiprogrammed death receptor (PD)-1 therapy elicited irAE-like multiorgan dysfunctions with ectopic accumulation of T and B cells in damaged organs. In this preclinical model, the organ toxicities were mediated by immunoglobulin G (IgG) deposition because administration of IG from ICB-treated aged mice induced the pathogenicity specifically in naïve aged hosts. Mechanistically, CD4 T-cell-derived interleukin (IL)-21 upregulated B-cell-homing chemokine, CXCL13, preferentially in irAE organs from aged mice treated with anti-PD-1 therapy. The ICB-induced pathogenicity was alleviated by B-cell depletion or by blockade of IL-21 or CXCL13 activity. These results suggest that age-associated immune regulatory milieu contributes to the formation of tertiary lymphoid structure-like lymphocytic aggregates in irAE organs and irAE-related toxicity employing IL-21-CXCL13-auto-antibody axis. Supporting this, a systemic increase in CXCL13 and Il21 expression in CD4 T cells correlated with irAE incidence in ICB-treated patients. These findings provide rationale for therapeutic usefulness of CXCL13 in irAE management.

Evaluation for Blood Concentration and Efficacy/Safety of Continuous Administration of Thiamylal in Children.

BACKGROUND: Thiamylal exerts excellent sedative effects. However, it is not routinely used because of its serious adverse effects. This study aimed to clarify the target blood concentration range and infusion rate of thiamylal in children by measuring its blood concentration and evaluating its relationship with efficacy and adverse effects. METHODS: This study was approved by the Ethics Committee of Japanese Red Cross Kumamoto Hospital. The authors included 10 children aged between 1 and 7 years who had received continuous intravenous (IV) infusion of thiamylal for the management of refractory status epilepticus, excluding those who met the exclusion criteria. After a 2 mg/kg bolus injection of thiamylal, continuous IV infusion was initiated at a rate of 2-3 mg/kg/h. Thiamylal concentration in the blood was measured using high-performance liquid chromatography. The State Behavioral Scale and the frequency of bolus injections were used to evaluate efficacy. Blood pressure and heart rate were measured to evaluate adverse effects. Statistical analyses of the time to awakening and the factors affecting it were also conducted. RESULTS: The State Behavioral Scale score during thiamylal administration was -2 or lower in all cases, suggesting that the depth of sedation was sufficient. The frequency of bolus injections decreased in a blood concentration-dependent manner, suggesting that the frequency tended to decrease, especially at thiamylal blood concentrations of 20 mcg/mL or higher. An increase of the infusion rate to 3 mg/kg/h was recommended, because the blood concentration may not reach 20 mcg/mL at an infusion rate of 2 mg/kg/h. There was also a case in which a rapid increase in blood concentration accompanied by a decrease in blood pressure and heart rate was observed when the infusion rate was increased to 4 mg/kg/h. Furthermore, the time to awakening after the end of administration correlated with the highest blood concentration during administration; therefore, delayed awakening was noted when using a high dose of thiamylal. CONCLUSIONS: The target blood concentration of thiamylal in children should be 20-30 mcg/mL, and the infusion rate should be based on 3 mg/kg/h.

Clinical impact of cerebral infarction in patients with non-small cell lung cancer.

BACKGROUND: Lung cancer patients have a high risk of cerebral infarction, but the clinical significance of cerebral infarction in advanced non-small cell lung cancer (NSCLC) remains unclear. This study aimed to comprehensively investigate the incidence, prognostic impact, and risk factors of cerebral infarction in patients with NSCLC. METHODS: We retrospectively examined 710 consecutive patients with advanced or post-operative recurrent NSCLC treated between January 2010 and July 2020 at Kumamoto University Hospital. Cerebral infarction was diagnosed according to the detection of high-intensity lesions on diffusion-weighted magnetic resonance imaging regardless of the presence of neurological symptoms during the entire course from 3 months before NSCLC diagnosis. The prognostic impact and risk factors of cerebral infarction were evaluated based on propensity score matching (PSM) and multivariate logistic regression analysis. RESULTS: Cerebral infarction occurred in 36 patients (5%). Of them, 21 (58%) and 15 (42%) patients developed asymptomatic and symptomatic cerebral infarction, respectively. PSM analysis for survival showed that cerebral infarction was an independent prognostic factor (hazards ratio: 2.45, 95% confidence interval (CI): 1.24-4.85, P = 0.010). On multivariate logistic regression analysis, D-dimer (odds ratio [OR]: 1.09, 95% CI 1.05-1.14, P < 0.001) and C-reactive protein (OR: 1.10, 95% CI 1.01-1.19, P = 0.023) levels were independent risk factors. CONCLUSION: Cerebral infarction occurred in 5% of NSCLC patients, and asymptomatic cerebral infarction was more frequent. Cerebral infarction was a negative prognostic factor and was associated with hyper-coagulation and inflammation. The high frequency of asymptomatic cerebral infarction and its risk in NSCLC patients with these conditions should be recognized.

Predictors of hematoma as a complication in pediatric kidney biopsies.

BACKGROUND: Kidney biopsies are crucial in the diagnosis of kidney diseases but they carry the risk of various complications, most commonly hematoma. Here we tried to identify the predictors of hematomas as a complication of kidney biopsies and we constructed an algorithm to stratify the risk. METHODS: The present report retrospectively reviewed 118 pediatric percutaneous kidney biopsies of native kidneys in 102 children (59 females) with the median age of 9 years (range: 1-19 years) at Kumamoto University Hospital between August 2008 and October 2019. We defined hematoma size using the hematoma index: the short axis of the hematoma/major axis of the kidney on ultrasonography. The inclusion criteria for a hematoma as a complication of a kidney biopsy were hematoma index ≥0.1 and the presence of concomitant, post-kidney biopsy fever or flank pain. RESULTS: Eight patients presented with a hematoma as a complication. All had hematoma index ≥0.1 and age ≥6 years. On univariate logistic analysis, these patients had a larger hemoglobin (Hgb) decrease on post-biopsy day 1, which was unrelated to a Hgb decrease 2 h after the biopsy, than the patients with no hematoma. All eight patients with a hematoma presented with a fever or flank pain on post-biopsy days 5 to 7, underscoring the need to observe patients with decreased Hgb carefully for about 1 week after a biopsy. CONCLUSION: Predictors of hematoma as a complication in children after a kidney biopsy were hematoma index ≥0.1, age >6 years, and Hgb decrease ≥15% on post-biopsy day 1.

Clinical Implications and Molecular Characterization of Drebrin-Positive, Tumor-Infiltrating Exhausted T Cells in Lung Cancer.

T cells express an actin-binding protein, drebrin, which is recruited to the contact site between the T cells and antigen-presenting cells during the formation of immunological synapses. However, little is known about the clinical implications of drebrin-expressing, tumor-infiltrating lymphocytes (TILs). To address this issue, we evaluated 34 surgical specimens of pathological stage I-IIIA squamous cell lung cancer. The immune context of primary tumors was investigated using fluorescent multiplex immunohistochemistry. The high-speed scanning of whole-slide images was performed, and the tissue localization of TILs in the tumor cell nest and surrounding stroma was automatically profiled and quantified. Drebrin-expressing T cells were characterized using drebrin+ T cells induced in vitro and publicly available single-cell RNA sequence (scRNA-seq) database. Survival analysis using the propensity scores revealed that a high infiltration of drebrin+ TILs within the tumor cell nest was independently associated with short relapse-free survival and overall survival. Drebrin+ T cells induced in vitro co-expressed multiple exhaustion-associated molecules. The scRNA-seq analyses confirmed that the exhausted tumor-infiltrating CD8+ T cells specifically expressed drebrin. Our study suggests that drebrin-expressing T cells present an exhausted phenotype and that tumor-infiltrating drebrin+ T cells affect clinical outcomes in patients with resectable squamous cell lung cancer.

Factors related to satisfaction of cancer patients with transfer arrangements made by university hospitals at the end-of-life in Japan: a cross-sectional questionnaire survey of bereaved family members.

PURPOSE: Cancer patients in university hospitals often face a difficult decision regarding transfer to other care settings at the end-of-life. Arrangements for a satisfying transfer are important for reducing the psychosocial impact of the transition, but few studies have evaluated this aspect. This study aimed to identify factors related to the satisfying arrangement of transfers to other care settings from university hospitals. METHODS: A total of 400 bereaved family members of cancer patients in Japan participated in this cross-sectional web-based questionnaire survey. Statistical methods including decision tree analysis were conducted to identify factors significantly associated with satisfying transfer arrangements. RESULTS: More than 60% of cancer patients were satisfied with the transfer arrangements made by university hospitals. Decision tree analysis revealed that the factor most significantly associated with satisfaction with transfer arrangements was "satisfaction with contents of the explanation about transfer." The following significant factors were also extracted: "timing of being informed of transfer," "presence of primary care physician," and "presence of trustworthy staff." "Satisfaction with overall care from university hospital staff" and "involvement of palliative care team" were identified as factors contributing to a high degree of satisfaction with transfer arrangements. CONCLUSION: In order to make satisfying transfer arrangements from university hospitals for cancer patients at the end-of-life, healthcare professionals should provide satisfactory explanations about the transfer process in order to meet the information needs of patients. To be effective, healthcare professionals should initiate transfer arrangements prior to cancer treatment, while simultaneously building trusting relationships with patients.

Clinical characteristics of patients with ischemic stroke after the 2016 Kumamoto earthquake, a multi-center study.

OBJECTIVE: To investigate the clinical characteristics of patients with ischemic stroke following the 2016 Kumamoto earthquake. METHODS: We retrospectively studied patients with ischemic stroke admitted to 5 stroke centers for 1 year after the earthquake. We compared clinical characteristics in these patients (the post-earthquake group) to those in the patients with ischemic stroke admitted during the same period from the previous 3 years (the pre-earthquake group). Additionally, we analyzed the trend of the incidence rate of stroke before and after the earthquake. RESULTS: A total of 1979 patients were admitted after the earthquake; 5670 (1,890/year on average) patients were admitted before the earthquake. A first-ever ischemic stroke (71 vs. 75%) and premorbid modified Rankin Scale > 1 (26 vs. 29%) were found significantly more frequently in patients after the earthquake. National Institutes of Health Stroke Scale score ≤ 2 at discharge (60 vs. 65%) was found more frequently in patients after the earthquake, although non-discharge to home (65 vs. 70%) was more frequent in patients after the earthquake. Trend analysis revealed a decrease of small vessel occlusion and large artery atherosclerosis in the month after the earthquake. CONCLUSIONS: The 2016 Kumamoto earthquake may have affected the characteristics of stroke during the early phase of the earthquake and increased the difficulty in returning home.

Omental metastasis as a predictive risk factor for unfavorable prognosis in patients with stage III-IV epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer has a clear predilection for the omentum as the site of metastasis; however, its contribution to clinical outcomes remains unresolved. This study aimed to evaluate the prognostic significance and efficacy of chemotherapy in the presence of omental metastasis. METHODS: A retrospective cohort study was performed in 56 patients with stage III-IV ovarian cancer who underwent primary debulking surgery between 2004 and 2018 at Kumamoto University Hospital. RESULTS: Thirty-six (64.3%) patients were categorized into the omental metastasis-positive group, whereas 20 (35.7%) patients were in the omental metastasis-negative group. The 5-year overall survival rates were 43.4% in the omental metastasis-positive group and 93.8% in the omental metastasis-negative group. Statistically significant differences were observed in overall survival (p = 0.002) and progression-free survival (p = 0.036) between the omental metastasis-positive and metastasis-negative groups. Notably, multivariate analysis demonstrated that the existence of omental metastasis is an independent risk factor for overall survival in patients with stage III-IV ovarian cancer (hazard ratio 8.90, 95% confidence interval 1.16-69.77; p = 0.038). Furthermore, the omental metastasis-positive group had significantly lower overall response rates to chemotherapy for recurrent disease, compared to the omental metastasis-negative group (31.6% vs. 85.7%, p = 0.026). CONCLUSION: Our present data demonstrated that omental metastasis is closely associated with an unfavorable prognosis due to increased chemoresistance in patients with stage III-IV ovarian cancer. Elucidating the biological mechanism of omental metastasis will shed light on novel therapeutic approaches for the management of advanced ovarian cancer patients.

Clinical outcomes and predictive value of programmed cell death-ligand 1 expression in response to anti-programmed cell death 1/ligand 1 antibodies in non-small cell lung cancer patients with performance status 2 or greater.

BACKGROUND: Anti-programmed cell death protein-1/ligand-1 (anti-PD-1/PD-L1) therapy is promising for patients with non-small-cell lung cancer (NSCLC); however, clinical trials have focused on patients with a performance status (PS) 0 or 1. This study aimed to evaluate the clinical outcomes and correlation between PD-L1 expression status and tumor response to anti-PD-1/PD-L1 therapy among NSCLC patients with poor PS (i.e., PS ≥ 2). METHODS: In total, 130 patients with NSCLC and PS ≥ 2 treated with anti-PD-1/PD-L1 monotherapy at 12 institutions between January 2016 and August 2019 were retrospectively reviewed. PD-L1 expression status was divided into four groups: < 1%, 1-49%, ≥ 50%, and unknown. RESULTS: The objective response rate and PS improvement rate were 23 and 21% and were higher in the PD-L1 ≥ 50% group than in other groups (P < 0.01). Median progression-free survival (PFS) was 62 days and was longer in the PD-L1 ≥ 50% group than in other groups (P = 0.03). Multivariate analyses revealed that PD-L1 expression is significantly associated with prolonged PFS (PD-L1 < 1%; reference; 1-49%, hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.04-0.99, P = 0.05; ≥ 50%, HR 0.12, 95% CI 0.02-0.71, P = 0.02; unknown, HR 0.30, 95% CI 0.08-1.22, P = 0.09). CONCLUSIONS: NSCLC patients with poor PS and PD-L1 ≥ 50% are expected to benefit from anti-PD-1/PD-L1 therapy, despite a modest overall response among NSCLC patients with poor PS. Accordingly, PD-L1 expression provides useful information regarding decision-making for anti-PD-1/PD-L1 therapy even in these populations.

Pre-hospital Diagnosis of Large Vessel Occlusion in Patients Being Transported by Helicopter.

BACKGROUND: During the helicopter transportation of patients suspected of large vessel occlusion (LVO), an accurate and rapid decision-making process is required. AIMS: We attempted to create an algorithm for the pre-hospital diagnosis of the presence of LVO in patients suspected of stroke using data from patients transported urgently by helicopter. METHODS: One hundred and sixty-five patients transported by helicopter were divided into two subgroups: a training dataset and a validation dataset. We extracted clinical information obtained on site, the unadjusted score of the National Institutes of Health Stroke Scale, and previously reported pre-hospital scales as an LVO screen. On the basis of the analyses of these factors, an algorithm was devised to predict the presence of LVO and its predictive accuracy was evaluated using the validation dataset. RESULTS: Ischemic stroke with LVO was diagnosed in 36 out of 121 cases (29.8%) in the training dataset and in 10 out of 44 cases (22.7%) in the validation dataset. Combining five factors (conjugate deviation, upper limb paresis, atrial fibrillation, Japan Coma Scale ≥ 200, and systolic blood pressure ≥ 180), an algorithm was created to classify cases into six groups with different likelihoods of LVO presence. The algorithm predicted correctly 6 out of 10 cases in the validation dataset. Furthermore, it definitively ruled out 17 out of 34 cases in the validation dataset. CONCLUSIONS: Using the newly created algorithm, emergency staff could easily and accurately distinguish patients suitable for urgent endovascular thrombectomy from patients with non-LVO or stroke mimics.

A mutant MATR3 mouse model to explain multisystem proteinopathy.

Mutations in the Matrin 3 (MATR3) gene have been identified as a cause of amyotrophic lateral sclerosis (ALS) or vocal cord and pharyngeal weakness with distal myopathy (VCPDM). This study investigated the mechanism by which mutant MATR3 causes multisystem proteinopathy (MSP) including ALS and VCPDM. We first analyzed the muscle pathology of C57BL/6 mice injected with adeno-associated viruses expressing human WT or mutant (S85C) MATR3. We next generated transgenic mice that overexpress mutant (S85C) MATR3, driven by the CMV early enhancer/chicken ß-actin promoter, and evaluated their clinicopathological features. Intramuscular injection of viruses expressing WT and mutant MATR3 induced similar myogenic changes, including smaller myofibers with internal nuclei, and upregulated p62 and LC3-II. Mutant MATR3 transgenic mice showed decreased body weight and lower motor activity. Muscle histology demonstrated myopathic changes including fiber-size variation, internal nuclei and rimmed vacuoles. Spinal cord histology showed a reduced number of motor neurons, and activation of microglia and astrocytes. Comprehensive proteomic analyses of muscle demonstrated upregulation of proteins related to chaperones, stress response, protein degradation, and nuclear function. Overexpression of WT and mutant MATR3 similarly caused myotoxicity, recapitulating the clinicopathological features of MSP. These models will be helpful for analyzing MSP pathogenesis and for understanding the function of MATR3. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A Comparison of the Frequency of Prescription and Pharmacy Revisits between Baloxavir Marboxil and Neuraminidase Inhibitors in Influenza-Infected Pediatric Patients during the 2019-2020 Influenza Season.

The novel anti-influenza virus agent baloxavir marboxil is a selective inhibitor of an influenza cap-dependent endonuclease. Although a single oral dose in tablet form of baloxavir marboxil is expected to improve drug compliance and rapidly reduce viral titers for pediatric patients with influenza, there is a concern that baloxavir marboxil-resistant influenza A variants could be generated. In this study, we investigated the frequency of prescription and pharmacy revisits for baloxavir marboxil at an outpatient clinic compared with that of neuraminidase inhibitors in pediatric patients with influenza. A total of 475 pediatric patients who were infected with the influenza virus visited the pharmacy between December 2019 and March 2020. Baloxavir marboxil (n = 149), oseltamivir (n = 161) and laninamivir (n = 162) were mainly prescribed and only a few patients were treated with peramivir (n = 2) or zanamivir (n = 1). Baloxavir marboxil-, oseltamivir- and laninamivir-treated pediatric patients were enrolled, and a log-rank test showed that the revisits of pediatric patients who were taking baloxavir marboxil was lower than those for oseltamivir (p < 0.001). Moreover, Cox proportional hazards models also revealed that baloxavir marboxil decreased the risk of revisits in comparison to oseltamivir (hazard ratio 0.28, 95% confidence interval 0.11-0.70, p = 0.006), while no difference was found between laninamivir and baloxavir marboxil. Although there is a need to acquire appropriate and relevant information concerning resistant viruses, our results suggest that baloxavir marboxil may be a useful drug for treating pediatric patients with influenza infections.

A Randomized Phase 2 Trial of Antibiotic Prophylaxis Versus No Intervention for Muscle Biopsy in A Neurology Department.

Muscle biopsy can be used to confirm the diagnosis of neuromuscular diseases. However, it is unclear whether antibiotic prophylaxis prior to muscle biopsy is needed to prevent surgical site infection (SSI). We are conducting a phase 2, single-center, open-labeled, prospective randomized trial to clarify the need for antibiotic prophylaxis in patients at low risk for SSI undergoing muscle biopsy. Patients will be randomized to an antibiotic prophylaxis group or a control group, and the incidence of SSI will be compared between the groups. Our findings will clarify the need for antibiotic prophylaxis in this patient population.

Cancer therapy with major histocompatibility complex-deficient and interferon ß-producing myeloid cells derived from allogeneic embryonic stem cells.

We previously established a method to generate myeloid cells with a proliferative capability from pluripotent stem cells and designated them iPS-ML. Human iPS-ML cells share features with physiological macrophages including the capability to infiltrate into cancer tissues. We observed therapeutic effects of human iPS-ML cells expressing interferon ß (iPS-ML/interferon (IFN)-ß) in xenograft cancer models. However, assessment of host immune system-mediated therapeutic and adverse effects of this therapy is impossible by xenograft models. We currently evaluated the therapeutic effects of a mouse equivalent of human iPS-ML/IFN, a mouse embryonic stem (ES) cell-derived myeloid cell line producing IFN (ES-ML/IFN). The ES-MLs producing IFN-ß (ß-ML) and IFN-γ (γ-ML) and originating from E14 ES cells derived from the 129 mouse strain (H-2b ) were generated, and the MHC (H-2Kb , Db , and I-Ab ) genes of the ES-ML/IFN were disrupted using the clustered regularly interspaced short palindromic repeats (CRISPR)/CAS9 method. We used the ES-ML/IFN to treat allogeneic BALB/c mice (H-2d ) transplanted with Colon26 cancer cells. Treatment with ß-ML but not with γ-ML cells repressed the growth of colon cancer in the peritoneal cavity and liver. The transferred ES-ML/IFN infiltrated into cancer tissues and enhanced infiltration of T cells into cancer tissues. ES-ML/IFN therapy increased the number of immune cells in the lymphoid organs. Sensitization of both cancer antigen-specific CD8+ T cells and natural killer (NK) cells were enhanced by the therapy, and CD8+ T cells were essential for the therapeutic effect, implying that donor MHC-deficient ß-ML exhibited a therapeutic effect through the activation of host immune cells derived from allogeneic recipient mice. The results suggested the usefulness of HLA-deficient human iPS-ML/IFN-ß cells for therapy of HLA-mismatched allogeneic cancer patients.

Trousseau's syndrome triggered by an immune checkpoint blockade in a non-small cell lung cancer patient.

PD-1 blockade therapy activates T cells by blocking the interaction between PD-1 and PD-L1 and promotes IFN-γ and Th1 cytokine production. In turn, IFN-γ and Th1 cytokines produced by activated T cells promote TF synthesis in monocytes/macrophages, which results in hypercoagulability leading to thrombosis.

Protective effect of bevacizumab on chemotherapy-related acute exacerbation of interstitial lung disease in patients with advanced non-squamous non-small cell lung cancer.

BACKGROUND: Acute exacerbation of interstitial lung disease (AE-ILD) is the most serious complication in lung cancer patients with pre-existing ILD receiving chemotherapy. The role of vascular endothelial growth factor (VEGF) in pathogenesis of AE-ILD is conflicting. The influence of bevacizumab (Bev), a monoclonal antibody against VEGF, on lung cancer patients with pre-existing ILD remains unclear. We examined the effect of Bev on reducing AE-ILD risk in non-squamous non-small cell lung cancer (NSCLC) patients receiving chemotherapy. METHODS: We analysed incidence of AE-ILD and outcomes of 48 patients with advanced non-squamous NSCLC with ILD who received first-line chemotherapy with (Bev group, n = 17) and without (non-Bev group, n = 31) Bev between July 2011 and July 2016. Gray's test, which was competing risk analysis during the study period, was performed for both groups. RESULTS: The most common regimen used for first-line chemotherapy was the combination of carboplatin plus pemetrexed (PEM) in both groups. The incidences of chemotherapy-related AE-ILD 120 days after first-line chemotherapy initiation were significantly lower in the Bev than in the non-Bev groups (0% vs. 22.6%, p = 0.037, Gray's test). However, there were no differences in development of progressive disease of lung cancer and other events as the competing risk factors of AE-ILD between the two groups. Only patients receiving PEM-containing regimens also showed a significant difference in the incidence of AE-ILD between the two groups (p = 0.044). The overall-cumulative incidence of AE-ILD during the first-line and subsequent chemotherapy was 29.2% (14 of the 48). The median progression-free survival was significantly longer in the Bev than in the non-Bev groups (8.0 vs. 4.3 months, p = 0.026). CONCLUSIONS: The addition of Bev to chemotherapy regimens may reduce the risk of chemotherapy-related AE-ILD in patients with lung cancer.

Correction to: Long-term results of intersphincteric resection for low rectal cancer in Japan.

In the original publication Fig. 2 and Table 4 were incorrectly published. The corrected figure and table are given in this Correction.

Long-term results of intersphincteric resection for low rectal cancer in Japan.

Intersphincteric resection (ISR) is the ultimate sphincter-preserving procedure for low rectal cancer. A questionnaire about the standardization of ISR was given to 2125 patients who underwent curative ISR for low rectal cancer between 2005 and 2012 at 127 affiliated institutions of the Japanese Society for Cancer of the Colon and Rectum (JSCCR), and the results were compared with the results of a systematic review. The findings revealed that although mortality and morbidity were relatively low and the survival rate after ISR was good, the rates of local recurrence and postoperative fecal incontinence were relatively high. The radicality of ISR was compared with that of abdominoperineal resection and low anterior resection using the propensity score matching prognosis analysis of patients in the JSCCR nationwide registry. The local recurrence rate was significantly higher after ISR, and especially high in patients with T3 (invasion into the external anal sphincter) and T4 disease. These results provide evidence about the factors related to fecal incontinence after ISR. As measures for the standardization of ISR, it is important to reconfirm that ISR is not indicated for patients with cT3 and cT4 disease and those with poor preoperative defecatory function, based on the ISR indication criteria.

Is 123I-MIBG Scintigraphy Beneficial or Excessive for the Diagnosis of Parkinson's Disease in the Early Phase?

INTRODUCTION/OBJECTIVE: In most cases, abnormal cardiac 123I-meta-iodobenzylguanidine (MIBG) scintigraphy increases the probability of a diagnosis of Parkinson's disease (PD) in patients with parkinsonian features. In our study, we validated the additional value of 123I-MIBG scintigraphy beyond providing information on neurological findings and response to dopaminergic therapy for the diagnosis of PDin the early phase. METHODS: We investigated 77 cases of PD (Hoehn and Yahr Stages I-III) and 73 cases of atypical parkinsonian disorder (APD), including 35 patients with multiple system atrophy, 19 with corticobasal syndrome, and 19 with progressive supranuclear palsy. Two multiple logistic regression models were developed to predict the probability of PD based on APD. Common covariates were resting tremor, vertical supranuclear palsy, apraxia, cerebellar symptoms, and response to dopaminergic therapy with MIBG scintigraphy (reference model) or without it (MIBG-added model). The net reclassification index (NRI) was examined and net benefit using decision curve analysis was performed to examine the additional clinical value of MIBG scintigraphy. Finally, we estimated the cost-effectiveness of MIBG scintigraphy. RESULTS: The MIBG-added model significantly improved the ability to classify PD or APD compared with the reference model (NRI index 1.390, p < 0.001). However, the decision curve of the reference model ranked equally with the MIBG-added model up to a risk threshold of 0.8. In addition, MIBG scintigraphy was not cost-effective. CONCLUSIONS: Although MIBG scintigraphy has statistical usefulness for PD diagnosis, there may be little additional benefit in the early phase of PD beyond the neurological findings and response to dopaminergic therapy regarding clinical effectiveness and cost-effectiveness. It may be of greatest value when neurological findings that do not match PD are observed during the clinical course.

Immune-suppressive effects of interleukin-6 on T-cell-mediated anti-tumor immunity.

Accompanied by the growing clinical applications of immunotherapy in the treatment of cancer patients, development of novel therapeutic approaches to reverse the immune-suppressive environment in cancer patients is eagerly anticipated, because the success of cancer immunotherapy is currently limited by immune-suppressive effects in tumor-bearing hosts. Interleukin (IL)-6, a pleotropic proinflammatory cytokine, participates in tumor cell-autonomous processes that are required for their survival and growth, and is therefore known as a poor prognostic factor in cancer patients. In addition, an emerging role of IL-6 in modulating multiple functions of immune cells including T cells, dendritic cells, and macrophages is responsible for the dysfunction of innate and adaptive immunity against tumors. Therefore, the IL-6-targeting approach is of value as a promising strategy for desensitization and prevention of immune-suppressive effects, and should be an effective treatment when combined with current immunotherapies. The aim of the present review is to discuss the immune-suppressive aspects of IL-6, notably with modification of T-cell functions in cancer patients, and their relationship to anti-tumor immune responses and cancer immunotherapy.