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Abstract To evaluate preliminary results of proton radiotherapy (PRT) for pediatric patients with rhabdomyosarcoma (RMS). From 1987 to 2014, PRT was conducted as initial radiotherapy in 55 patients (35 males, 20 females, median age 5 years, range 0–19) with RMS at four institutes in Japan. Thirty‐one, 18, and six patients had embryonal, alveolar, and other RMS, respectively. One, 11, 37, and six patients were in IRSG groups I, II, III, and IV, respectively, and the COG risk group was low, intermediate, and high for nine, 39, and seven patients, respectively. The irradiation dose was 36–60 GyE (median: 50.4 GyE). The median follow‐up period was 24.5 months (range: 1.5–320.3). The 1‐ and 2‐year overall survival rates were 91.9% (95% CI: 84.3–99.5%) and 84.8% (95% CI 75.2–94.3%), respectively, and these rates were 100% and 100%, 97.1% and 90.1%, and 57.1% and 42.9% for COG low‐, intermediate‐, and high‐risk groups, respectively. There were 153 adverse events of Grade ≥3, including 141 hematologic toxicities in 48 patients (87%) and 12 radiation‐induced toxicities in nine patients (16%). Proton‐specific toxicity was not observed. PRT has the same treatment effect as photon radiotherapy with tolerable acute radiation‐induced toxicity.

Abstract A 77‐year‐old male patient underwent esophagogastroduodenoscopy at his family doctor, and an easily hemorrhagic depressed lesion was noted near the anterior wall of the gastric antrum. A biopsy revealed moderately differentiated tubular adenocarcinoma > poorly differentiated adenocarcinoma, and the patient was referred to our department for further examination. A 15‐mm 0–IIc lesion is seen near the anterior wall of the gastric antrum and narrow band imaging magnifying endoscopy revealed obscured glandular duct structures and corkscrew pattern vascular structures. We diagnosed the patient with early‐stage gastric cancer [L, Ant, 15mm, cType0‐IIc, cT1(M‐SM1), cN0, cM0, cStage IA] after an esopahogastroduodenoscopy examination at our hospital, and endoscopic submucosal dissection was performed. Histopathological images with hematoxylin and eosin staining showed tumor cells with pale cytoplasm and the immunostaining for alpha‐fetoprotein, sal‐like protein 4, and Glypican3 was positive. The patient was pathologically diagnosed with gastric adenocarcinoma with enteroblastic differentiation, pT1b1 (SM, 0.4 mm), type 0–IIc, 15 mm, UL (‐), Ly0, and V0. Gastric adenocarcinoma with enteroblastic differentiation is one of the representative histological types of alpah‐fetoprotein‐producing gastric cancer. Alpha‐fetoprotein‐producing gastric cancer is infrequent, accounting for at least 3% of all gastric cancers, and is generally highly malignant. Most cases are already advanced upon diagnosis, and finding them in the early stage is rare. Therefore, pathological findings that may indicate the gastric adenocarcinoma with enteroblastic differentiation should be noted even in early gastric cancer.

Abstract Adult T‐cell leukaemia/lymphoma (ATL) remains incurable. The NF‐κB and interferon regulatory factor 4 (IRF4) signalling pathways are among the critical survival pathways for the progression of ATL. TGF‐β‐activated kinase 1 (TAK1), an IκB kinase‐activating kinase, triggers the activation of NF‐κB. The resorcylic acid lactone LL‐Z1640‐2 is a potent irreversible inhibitor of TAK1/extracellular signal‐regulated kinase 2 (ERK2). We herein examined the therapeutic efficacy of LL‐Z1640‐2 against ATL. LL‐Z1640‐2 effectively suppressed the in vivo growth of ATL cells. It induced in vitro apoptosis and inhibited the nuclear translocation of p65/RelA in ATL cells. The knockdown of IRF4 strongly induced ATL cell death while downregulating MYC. LL‐Z1640‐2 as well as the NF‐κB inhibitor BAY11‐7082 decreased the expression of IRF4 and MYC at the protein and mRNA levels, indicating the suppression of the NF‐κB‐IRF4‐MYC axis. The treatment with LL‐Z1640‐2 also mitigated the phosphorylation of p38 MAPK along with the expression of CC chemokine receptor 4. Furthermore, the inhibition of STAT3/5 potentiated the cytotoxic activity of LL‐Z1640‐2 against IL‐2‐responsive ATL cells in the presence of IL‐2. Therefore, LL‐Z1640‐2 appears to be an effective treatment for ATL. Further studies are needed to develop more potent compounds that retain the active motifs of LL‐Z1640‐2.

Abstract Background In monarchE and Postoperative Therapy with Endocrine and TS‐1 (POTENT) trials, abemaciclib and S‐1 have, respectively, shown to be effective as adjuvant therapies for luminal breast cancer (BC), although whether patients who meet the criteria are at high risk of recurrence compared to non‐eligible patients is still unknown. Here, we investigated recurrence risk according to the criteria of each trial in Japanese patients. Methods We reviewed the records of 992 patients who received surgery at Chiba University Hospital for stage I–III BC from January 2017 to May 2022 and selected 553 analytic cohort patients and retrospectively analyzed the relapse‐free survival of the patients as the primary endpoint. High‐recurrence risk was defined according to monarchE trial and POTENT trial. Results The 5‐year RFS for monarchE cohort 1 and cohort 2 eligible patients were 77.78% and 89.33%, respectively, which were significantly lower than monarchE non‐eligible patients (98.31%; p

Abstract Background Since the human papillomavirus vaccines do not eliminate preexisting infections, nonsurgical alternative approaches to cervical intraepithelial neoplasia (CIN) have been required. We previously reported that FOXP4 (forkhead box transcription factor P4) promoted proliferation and inhibited squamous differentiation of CIN1‐derived W12 cells. Since it was reported that FOXP expressions were regulated by the androgen/androgen receptor (AR) complex and AR was expressed on the CIN lesions, in this study we examined the effects of androgen on CIN progression. Methods Since AR expression was negative in W12 cells and HaCaT cells, a human male skin‐derived keratinocyte cell line, we transfected AR to these cell lines and investigated the effects of dihydrotestosterone (DHT) on their proliferation and squamous differentiation. We also examined the immunohistochemical expression of AR in CIN lesions. Results DHT reduced the intranuclear expression of FOXP4, attenuating cell proliferation and promoting squamous differentiation in AR‐transfected W12 cells. Si‐RNA treatments showed that DHT induced the expression of squamous differentiation‐related genes in AR‐transfected W12 cells via an ELF3‐dependent pathway. DHT also reduced FOXP4 expression in AR‐transfected HaCaT cells. An immunohistochemical study showed that AR was expressed in the basal to parabasal layers of the normal cervical epithelium. In CIN1 and 2 lesions, AR was detected in atypical squamous cells, whereas AR expression had almost disappeared in the CIN3 lesion and was not detected in SCC, suggesting that androgens do not act to promote squamous differentiation in the late stages of CIN. Conclusion Androgen is a novel factor that regulates squamous differentiation in the early stage of CIN, providing a new strategy for nonsurgical and hormone‐induced differentiation therapy against CIN1 and CIN2.

Abstract Objective Among standard treatments for infantile spasms, adrenocorticotropic hormone (ACTH) is reported as the best treatment, but ACTH is ineffective in one‐half of the patients. To establish precision medicine, we examined pharmacoresistance of focal epileptic spasms (ES), generalized ES, and generalized ES combined with focal seizures, diagnosed based on the revised seizure classification of ILAE in 2017. Methods We conducted a retrospective nationwide study in Japan on the long‐term seizure outcome of ES. Long‐term seizure outcome was evaluated by seizure‐free rate, seizure‐free period, and Kaplan‐Meier curve. Seizure‐free was defined as seizure control for longer than 2 months. Results From the medical history of 501 patients, 325 patients had generalized ES only (GES group) at the start of the first treatment, 125 patients had generalized ES after focal seizure onset (FS‐GES group), seven patients had focal ES after focal seizure onset (FS‐FES group), and 24 patients had generalized ES combined with focal seizures after focal seizure onset (FS‐GES + FS group). Seizure‐free period of ES (generalized ES and focal ES) [mean (95% confidence interval)] was 2.7 (0.0‐5.4) months in GES group, 1.1 (0.1‐2.2) months in FS‐GES group, 1.0 (0.2‐1.9) months in FS‐GES + FS group, and 0.1 (−0.2‐0.5) months in FS‐FES group. Seizure‐free rate, seizure‐free period, and Kaplan‐Meier curve of generalized ES were almost the same in GES group and FS‐GES group, with characteristics of superior response to ACTH. Mean seizure‐free period of generalized ES combined with focal seizures was significantly shorter in FS‐GES + FS group than in GES group. Mean seizure‐free period of focal ES in FS‐FES group was extremely short with exceedingly early relapse. Significance Pharmacoresistance was different in generalized ES, focal ES, and generalized ES combined with focal seizures. ES with focal features or with focal seizures may have focal lesions, thus consider surgical options earlier in the course.

Introduction Although preoperative bradycardia has been reported in several pheochromocytoma cases, postoperative bradycardia has not. This is the first case report of complete atrioventricular dissociation and sinus arrest occurring after pheochromocytoma resection. Case presentation A 38‐year‐old woman was referred for a left adrenal incidentaloma. Twenty‐four hour urinary collection showed elevated noradrenaline. Iodine‐123‐meta‐iodobenzylguanidine scintigraphy showed high tracer uptake in the left adrenal region. Open left adrenalectomy was performed, and histopathological examination confirmed the diagnosis of pheochromocytoma. Thirty minutes following surgery, complete atrioventricular dissociation and sinus arrest developed. Vagal reflex attenuation due to decreased noradrenaline after tumor removal and perioperative pain and fear were believed to be the causes. A temporary pacemaker was implanted to prevent sudden death due to vagal overstimulation. Conclusion Vagal reflex attenuation after pheochromocytoma resection can result in complete atrioventricular dissociation and sinus arrest. Adequate preoperative preparation and close monitoring during and after surgery are imperative.

Abstract A 30‐year‐old man with severe hypoalbuminemia (serum albumin: 0.9 g/dL) was admitted with severe bilateral leg edema and unilateral pleural effusion. Serum anti‐SS‐A and SS‐B antibody levels were abnormally elevated, and his symptoms fulfilled the diagnostic criteria for Sjögren's syndrome. Technetium‐99m albumin scintigraphy revealed protein leakage from a large area of the small intestine. Immunohistochemistry revealed perivascular deposition of C1q, C3d, and immunoglobulin G in the duodenal mucosa. The patient was diagnosed with protein‐losing gastroenteropathy associated with Sjögren's syndrome. Within 2 months of treatment with oral prednisolone and mycophenolate mofetil, the clinical symptoms of hypoalbuminemia and Sjögren's syndrome disappeared completely.

Background Myocardial extracellular volume fraction (ECV), measured by cardiac magnetic resonance imaging, is a useful prognostic marker for patients who have undergone aortic valve replacement (AVR) for aortic stenosis. However, the prognostic significance of ECV measurements based on computed tomography (CT) is unclear. This study evaluated the association between ECV measured with dual‐energy CT and clinical outcomes in patients with aortic stenosis who underwent transcatheter or surgical AVR. Methods and Results We retrospectively enrolled 95 consecutive patients (age, 84.0±5.0 years; 75% women) with severe aortic stenosis who underwent preprocedural CT for transcatheter AVR planning. ECV was measured using iodine density images obtained by delayed enhancement dual‐energy CT. The primary end point was a composite outcome of all‐cause death and hospitalization for heart failure after AVR. The mean ECV measured with CT was 28.1±3.8%. During a median follow‐up of 2.6 years, 22 composite outcomes were observed, including 15 all‐cause deaths and 11 hospitalizations for heart failure. In Kaplan‐Meier analysis, the high ECV group (≥27.8% [median value]) had significantly higher rates of composite outcomes than the low ECV group (

Perirectal abscesses often occur in the dorsal portion of the perirectal tissues. We report a patient who presented with fever, pain on defecation, and dysuria. He was found to have a perirectal abscess in the anterior perineum pressing on the urethra. After emergency surgery to drain the abscess, the symptoms improved.

Introduction: The electromagnetic interference (EMI) of active implantable medical devices (AIMDs) due to 125–135 kHz and HF (13.56MHz) radio-frequency identification (RFID) reader/writers are discussed based on in vitro experiments. The purpose of this paper is to clarify the detailed EMI occurrence conditions of both implantable cardiac pacemakers and implantable cardioverter defibrillators (ICDs) when used in proximity to commercial lowband RFID reader/writers. Methods and results: A total of 20 types of pacemakers and 7 types of ICDs from 9 manufacturers are used in the experiments. The tested RFID reader/writers are 4 types of 125–135 kHz antennas and 26 types of HF antennas. The test system is newly constructed based on the one previously proposed for the estimation of EMI due to mobile phones. The measured reactions are missing of pacing pulses and generation of asynchronous pulses for pacemaker functions and inappropriate tachyarrhythmia detection and delivery of therapy for ICDs. In addition, measured EMI characteristics strongly depend on intermittent period of RFID signals. However, all AIMDs tested return to normal operation once removed from RFID exposure. Conclusion: The detailed EMI characteristics of AIMDs and low-band RFID reader/ writers are obtained to prevent adverse interactions.

Although it is now accepted that killer-cell inhibitory receptors (KIRs), which were molecularly cloned in 1995, deliver negative signals to natural killer (NK) cells regarding the recognition of target cells, it is still unclear how the expression of these receptors on lymphocytes is regulated. Therefore, we investigated the regulation of expression of representative KIRs, CD158a and CD158b, by cytokines such as interleukin-2 (IL-2), IL-4 and interferon-γ (IFN-γ). Neither IL-4 nor IFN-γ affected the expression of CD158a/b, but incubation for 48 h with IL-2, which enhances the killer activity of NK cells, upregulated the expression of the KIRs. This upregulation by IL-2 was also observed in CD16-positive cells sorted from total lymphocytes. In contrast, IL-4, which is a downregulator of IL-2-induced killer responses, did not change the level of CD158a/b expression when added after the IL-2 treatment. These findings suggest that IL-2 plays an important role in the regulation of CD158a/b expression, and might be involved in controlling NK activity via regulating expression of these molecules.

We examined the tumor necrosis factor α (TNFα)-induced apoptosis of vascular endothelial cells from the standpoint of ion channels. Cultured vascular endothelial cells from bovine carotid artery were used. Apoptosis was determined by a propidium iodide assay. Treatment of the endothelial cells with TNFα and cycloheximide for 6h induced nuclear fragmentation in a TNFα dose-dependent manner (1-10 ng/ml). Concomitant treatment of endothelial cells with TNFα at a dose of 10ng/ml and cycloheximide at a dose of 10 micro g/ml elicited endothelial cell apoptosis as high as 23.4±4.1% at 6h after administration. However, 10 ng/ml TNFα alone elicited a little apoptosis at 6h after its administration (% apoptosis=4.1±0.8%). Cycloheximide (10 μg/ml) did not induce apoptosis at all. Concomitant treatment of endothelial cells with 1 m mol/l of 4,4-diisothiocyanatostilbene-2,2-disulfonic acid, which is a chloride bicarbonate exchanger blocker, partially inhibited the TNFα and cycloheximide-induced endothelial cell apoptosis. On the other hand, endothelial cell apoptosis due to TNFα and cycloheximide was completely inhibited by benzyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene (50 μmol/l), an inhibitor of caspase. Moreover, pyrrolidine dithiocarbanate, an inhibitor of nuclear factor kappa B (NF-κB), also suppressed endothelial cell apoptosis induced by TNFα and cycloheximide completely. These findings suggest that the endothelial cell apoptosis induced by TNFα and cycloheximide is closely related to not only chloride ions, but also both NF-κB and caspase activation. That is to say, there is a possibility that chloride ions or bicarbonate (pH) may play an important role in signal transduction such as NF-κB and caspase activation in the apoptosis induced by TNFα and cycloheximide.