Sapporo Toho Hospital

ABSTRACT Neoantigen-reactive CD4+ T cells play a key role in the anti-tumor immune response. However, the majority of epithelial tumors are negative for HLA class II (HLA-II) surface expression, and less is known about the processing of HLA-II antigens. Here, we directly identified naturally presented HLA-II neoantigens in HLA-II negative colorectal cancer (CRC) tissue using a proteogenomic approach. The neoantigens were immunogenic and induced patient CD4+ T cells with a Th1-like memory phenotype that produced IFN-γ, IL2 and TNF-α. Multiplex immunohistochemistry (IHC) demonstrated an interaction between Th cells and HLA-II-positive antigen-presenting cells (APCs) at the invasive margin and within the tertiary lymphoid structures (TLS). In our CRC cohort, the density of stromal APCs was associated with HLA-II antigen presentation in the tumor microenvironment (TME), and the number of TLS was positively correlated with the number of somatic mutations in the tumors. These results demonstrate the presence of neoantigen-specific CD4+ surveillance in HLA-II-negative CRC and suggest a potential role for macrophages and dendritic cells (DCs) at the invasive margin and in TLS for antigen presentation. Stromal APCs in the TME can potentially be used as a source for HLA-II neoantigen identification.

Febrile urinary tract infection (f-UTI) is a common complication after ureterorenoscopic lithotripsy (URSL) but is sometimes lethal. In this article, we analyzed the factors of post URSL f-UTI. We retrospectively evaluated the association between the development of f-UTI and patients, stones, and perioperative factors in 695 cases in which URSL was performed at our institution from September 2015 to 2018. Seventy-six of the 695 patients (10.9%) had postoperative f-UTI. Elderly (p＝0.013), female (p＝0.02), and hypertension (p＝0.001) patients had significantly higher rates of f-UTI. Renal stone (p＝0.001) cases showed significantly higher rates of f-UTI. Preoperative urine positive culture (p＝0.045), preoperative f-UTI (p＜0.001), URSL procedure using flexible ureteroscopy (p＝0.048), non-stone-free (p＝0.006), long operation time (p＝0.011), preoperative urinary stent insertion due to preoperative f-UTI (p＜0.001), were factors associated with post-operative f-UTI. Multivariate analysis revealed that hypertension (OR＝2.08, p＝0.008) and preoperative f-UTI (OR＝3.739, p＝0.033) were independent factors of postoperative f-UTI. Patients with hypertension or preoperative f-UTI should be managed more carefully during the perioperative period, suspecting that they are more likely to develop postoperative f-UTI.

CD8+ T cells recognize peptides displayed by HLA class I molecules on cell surfaces, monitoring pathologic conditions such as cancer. Advances in proteogenomic analysis of HLA ligandomes have demonstrated that cells present a subset of cryptic peptides derived from noncoding regions of the genome; however, the roles of cryptic HLA ligands in tumor immunity remain unknown. In the current study, we comprehensively and quantitatively investigated the HLA class I ligandome of a set of human colorectal cancer and matched normal tissues, showing that cryptic translation products accounted for approximately 5% of the HLA class I ligandome. We also found that a peptide encoded by the long noncoding RNA (lncRNA) PVT1 was predominantly enriched in multiple colorectal cancer tissues. The PVT1 gene is located downstream of the MYC gene in the genome and is aberrantly overexpressed across a variety of cancers, reflecting its oncogenic property. The PVT1 peptide was recognized by patient CD8+ tumor-infiltrating lymphocytes, as well as peripheral blood mononuclear cells, suggesting the presence of patient immune surveillance. Our findings show that peptides can be translated from lncRNAs and presented by HLA class I and that cancer patient T cells are capable of sensing aberrations in noncoding regions of the genome.

ObjectiveThis post hoc analysis evaluated long‐term efficacy and safety in patients with focal to bilateral tonic‐clonic seizures (FBTCS) or generalized tonic‐clonic seizures (GTCS) who entered open‐label extension (OLEx) studies to receive long‐term adjunctive perampanel.MethodsPatients aged 12 years and older who completed phase II or III randomized, double‐blind, placebo‐controlled studies could enter an OLEx study, each comprising a blinded conversion period followed by an open‐label maintenance period (32‐424 weeks; maximum perampanel dose = 12 mg/d). Exposure, seizure outcomes, and treatment‐emergent adverse events (TEAEs) were analyzed.ResultsBaseline characteristics were generally balanced between patients with FBTCS (n = 720) and GTCS (n = 138). Mean (standard deviation) cumulative duration of perampanel exposure was 102.3 (70.3) weeks (FBTCS) and 83.9 (38.4) weeks (GTCS). Retention rates were 50.0% for up to 4 years (FBTCS) and 49.2% for up to 2 years (GTCS). Across OLEx treatment durations, median reductions in seizure frequency per 28 days were 66.7% (FBTCS) and 80.6% (GTCS). Fifty percent and 75% responder and seizure‐freedom rates were 59.5%, 45.3%, and 18.4%, respectively (FBTCS), and 72.5%, 51.5%, and 16.7%, respectively (GTCS). Efficacy was sustained for up to 4 years (FBTCS) and up to 3 years (GTCS), even when accounting for early dropouts. TEAE incidence was highest during Year 1 (FBTCS, 85.3%; GTCS, 86.2%); most common were dizziness and somnolence. During Year 1, serious TEAEs were reported in 81 (11.3%; FBTCS) and 10 (7.2%; GTCS) patients. TEAEs were consistent with the known safety profile of perampanel; no new safety signals were identified with long‐term treatment.SignificanceThis post hoc analysis suggests long‐term (up to 4 years) adjunctive perampanel (up to 12 mg/d) is efficacious and well tolerated in patients (aged 12 years and older) with FBTCS or GTCS.

To develop a novel simple quantitative scoring model for predicting stone-free status after a flexible ureteroscopy lithotripsy procedure by standardizing the complexity of ureteral stone characteristics. We retrospectively reviewed 586 patients with renal or ureteral stones who underwent flexible ureteroscopy lithotripsy at Abiko Toho Hospital, Chiba, Japan, from 2015 to 2018. Multivariate regression was applied to examine the relationship between preoperative descriptors and stone-free status, and a nomogram was developed using significant predictors. Next, the individual components of the nomogram were assigned points to form a simple scoring system. The predictive performance of this new scoring system was compared with the STONE score at optimal cut-off values using receiver operating characteristic curve and area under the curve analyses. Multivariate logistic regression findings showed that factors associated with stone-free status were length, Hounsfield unit and stone location. A nomogram prediction model was developed with an area under the curve value of 0.845, then consequently used to develop a new simple score system termed the T.O.HO. score consisting of three stone characteristics: (T)allness (1-5points), (O)ccupied lesion (1-3points) and (HO)unsfield units evaluation (1-3points). The T.O.HO. score was significantly higher in stone remaining (7.66) than stone-free (5.27; P<0.001) cases. The area under the curve for the T.O.HO. score was 0.833 at an optimal cut-off value of 7, whereas that for the STONE score was 0.683 at an optimal cut-off value of 9, showing the superiority of this new scoring system. The T.O.HO. score is a useful tool for predicting stone-free status in patients who have undergone a flexible ureteroscopy lithotripsy procedure.

甲状腺乳頭癌術後の左頸部リンパ節再発に対する頸部リンパ節郭清術後に両側乳糜胸となった症例を経験した.症例は83歳女性で,術後3日目に呼吸困難を発症した.頸部の乳糜漏を認めなかったため,ドレーンは術後2日目に抜去していた.両側胸水を認め,心不全に基づく胸水などを否定した後に胸腔穿刺を行った.廃液に多量の乳糜を認めたため乳糜胸と診断した.保存的治療では胸水は減少せず,胸管を結紮することにより治癒させることができた.左頸部リンパ節郭清術後の乳糜漏は少なくない合併症であるが,両側乳糜胸はまれである.左頸部リンパ節郭清後の呼吸困難の場合は両側乳糜胸も念頭に置くべきと考える.

Biomarkers that can accurately predict treatment response are required for indicating optimal neoadjuvant treatments. The current study assessed the predictive value of secreted protein acidic and rich in cysteine (SPARC) mRNA expression for the response to neoadjuvant nab-paclitaxel (nab-PTX) therapy in patients with breast cancer. It was hypothesized that SPARC expression can affect the response to albumin-bound taxanes, including nab-PTX since SPARC binds albumin with a high affinity. Pre-therapeutic specimens of core needle biopsies were analyzed from 50 patients in a phase II trial of neoadjuvant nab-PTX and the factors that were associated with a pathological complete response (pCR) were assessed. The pre-therapeutic tumor mRNA levels of chemotherapy-related proteins were quantified, including SPARC, and the correlations with post-therapeutic clinicopathological factors were assessed, including with pCR. The results demonstrated that pre-therapeutic SPARC mRNA expression was significantly higher in non-pCR patients compared with patients with pCR (92.37±55.33 vs. 56.53±30.19; P=0.027). A cutoff point of 48.5 was determined using receiver operating characteristic (ROC) curve analysis (sensitivity, 83.3%; specificity, 50.0%), and patients were classified into low and high SPARC expression groups. High SPARC expression was associated with histological grade (P=0.035), estrogen receptor expression (P=0.037), and progesterone receptor expression (P=0.002) but not with HER2 (P=0.895), and Ki-67 LI (P=0.743) expression. The results of the current study indicated that a high SPARC mRNA expression was a negative predictor of pCR following neoadjuvant nab-PTX therapy regardless of breast cancer subtype. The phase II study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the National Hospital Organization Takasaki General Medical Center (Registration nos. H23-9 and H23-33).

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that may lead to liver cirrhosis or hepatocellular carcinoma. Here, we examined the diagnostic utility of tri-antennary tri-sialylated mono-fucosylated glycan of alpha-1 antitrypsin (AAT-A3F), a non-invasive glycobiomarker identified in a previous study of NASH diagnosis. This study included 131 biopsy-proven Japanese patients with NAFLD. We evaluated the utility of AAT-A3F in NASH diagnosis, and conducted genetic analysis to analyse the mechanism of AAT-A3F elevation in NASH. Serum AAT-A3F concentrations were significantly higher in NASH patients than in NAFL patients, and in patients with fibrosis, lobular inflammation, and ballooning. Hepatic FUT6 gene expression was significantly higher in NASH than in NAFL. IL-6 expression levels were significantly higher in NASH than in NAFL and showed a positive correlation with FUT6 expression levels. The serum-AAT-A3F levels strongly correlated with hepatic FUT6 expression levels. AAT-A3F levels increased with fibrosis, pathological inflammation, and ballooning in patients with NAFLD and may be useful for non-invasive diagnosis of NASH from the early stages of fibrosis.

Low‐grade appendiceal mucinous neoplasms are rare and difficult to diagnose preoperatively because of a lack of characteristic symptoms. A 24‐year‐old female with no symptoms before pregnancy underwent an elective cesarean section at 38 weeks of gestation because of cephalo‐pelvic disproportion. Although no abnormalities were detected in the newborn, uterus, or uterine adnexa, a sausage‐like, swollen appendix was noted. The patient underwent appendectomy. Pathology showed the tumor was a low‐grade appendiceal mucinous neoplasm.

This post hoc analysis assessed the long-term safety, tolerability, and efficacy of perampanel in Asian patients with refractory focal seizures; an additional analysis assessed the effect of perampanel on focal impaired awareness seizures (FIAS) with focal to bilateral tonic-clonic (FBTC) seizures. In this subanalysis, data from Asian patients ≥12years of age who had focal seizures with FBTC seizures despite taking one to 3 concomitant antiepileptic drugs at baseline, and who had entered either the long-term extension phase of 3 phase-3 perampanel trials (study 307) or the 10-week extension phase of study 335, were analyzed for the effect of perampanel on duration of exposure, safety, and seizure outcomes. Of 874 Asian patients included in the analysis, 205 had previously received placebo during the double-blind phase-3 trials and 669 had previously received perampanel 2-12mg/day; 313 had FIAS with FBTC seizures at core study baseline. The median duration of exposure to perampanel was 385.0days, and the retention rate at oneyear was 62.6%. Overall, during the first 52weeks of perampanel treatment, 777 patients (88.9%) had treatment-emergent adverse events (TEAEs), most of which were mild to moderate in severity. The most frequent TEAEs were dizziness (47.1%), somnolence (22.3%), and nasopharyngitis (17.4%). During the first 52weeks of perampanel treatment, median percent change in seizure frequency per 28days from pre-perampanel baseline for all focal seizures was -28.1%, and -51.7% for FIAS with FBTC seizures. The 50% responder rate relative to pre-perampanel baseline for all focal seizures was 33.8%, and 51.1% for FIAS with FBTC seizures. Long-term treatment with perampanel in Asian patients had safety, tolerability, and efficacy similar to that of the global population in the phase-3 trials and extension study 307. The safety profile and response rate suggest benefit for an Asian population of patients with refractory epilepsy.