First detailed case report of a pediatric patient with neuronal intranuclear inclusion disease diagnosed by NOTCH2NLC genetic testing.

INTRODUCTION: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterized clinically by eosinophilic hyaline intranuclear inclusions in neuronal and other somatic cells. Skin biopsies are reportedly useful in diagnosing NIID, and the genetic cause of NIID was identified as a GGC repeat expansion in NOTCH2NLC in recent years. The number of adult patients diagnosed via genetic testing has increased; however, there have been no detailed reports of pediatric NIID cases with GGC expansions in NOTCH2NLC. This is the first detailed report of a pediatric patient showing various neurological symptoms from the age of 10 and was ultimately diagnosed with NIID via skin biopsy and triplet repeat primed polymerase chain reaction analyses. CASE REPORT: This was an 18-year-old female who developed cyclic vomiting, distal dominant muscle weakness, and sustained miosis at 10 years. Nerve conduction studies revealed axonal degeneration, and her neuropathy had slowly progressed despite several rounds of high-dose methylprednisolone and intravenous immunoglobulin therapy. At 13 years, she had an acute encephalopathy-like episode. At 15 years, brain MRI revealed slightly high-intensity lesions on diffusion-weighted and T2-weighted imaging in the subcortical white matter of her frontal lobes that expanded over time. At 16 years, esophagography, upper gastrointestinal endoscopy, and esophageal manometry revealed esophageal achalasia, and per-oral endoscopic myotomy was performed. At 18 years, we diagnosed her with NIID based on the findings of skin specimen analyses and a GGC repeat expansion in NOTCH2NLC. CONCLUSION: NIID should be considered as a differential diagnosis in pediatric patients with various neurological symptoms.

Quantitative pretreatment EEG predicts efficacy of ACTH therapy in infantile epileptic spasms syndrome.

OBJECTIVE: This study aimed to determine the correlation between outcomes following adrenocorticotrophic hormone (ACTH) therapy and measurements of relative power spectrum (rPS), weighted phase lag index (wPLI), and graph theoretical analysis on pretreatment electroencephalography (EEG) in infants with non-lesional infantile epileptic spasms syndrome (IESS). METHODS: Twenty-eight patients with non-lesional IESS were enrolled. Outcomes were classified based on seizure recurrence following ACTH therapy: seizure-free (F, n = 21) and seizure-recurrence (R, n = 7) groups. The rPS, wPLI, clustering coefficient, and betweenness centrality were calculated on pretreatment EEG and were statistically analyzed to determine the correlation with outcomes following ACTH therapy. RESULTS: The rPS value was significantly higher in the delta frequency band in group R than in group F (p < 0.001). The wPLI values were significantly higher in the delta, theta, and alpha frequency bands in group R than in group F (p = 0.007, <0.001, and <0.001, respectively). The clustering coefficient in the delta frequency band was significantly lower in group R than in group F (p < 0.001). CONCLUSIONS: Our findings demonstrate the significant differences in power and functional connectivity between outcome groups. SIGNIFICANCE: This study may contribute to an early prediction of ACTH therapy outcomes and thus help in the development of appropriate treatment strategies.

Prospective analysis of factors precluding the initiation of durvalumab from an interim analysis of a phase II trial of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small cell lung cancer in Japan (SAMURAI study).

Background: The standard of care for unresectable, locally advanced non-small cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC trial. Disease progression and pneumonitis were reported as the main reasons to preclude the initiation of durvalumab in multiple retrospective studies. However, the transition rate and the reasons for failure to proceed to consolidation therapy with durvalumab after CRT were not evaluated prospectively. Although phase II studies in Japan have shown high efficacy and tolerability of CRT with cisplatin + S-1 (SP), no prospective study using durvalumab after SP-based CRT has yet been reported. We therefore conducted a phase II study to verify the efficacy and safety of durvalumab following SP-based CRT. In this interim analysis, we report the transition rate and the reasons for its failure. Methods: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m2, day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab every 2 weeks for up to 12 months. The primary endpoint was 12 month progression-free survival rate. Results: Fifty-nine patients were enrolled, of whom 86.4% (51/59) proceeded to durvalumab. All of them initiated durvalumab within 42 days after CRT [median 18 days (range: 3-38)], including 27.5% (14/51) in <14 days. Common reasons for failure to proceed to durvalumab were disease progression (2/59, 3.4%) and adverse events (6/59, 10.2%). Among the latter cases, four resumed treatment and proceeded to durvalumab within 42 days on off-protocol. The objective response rate and the disease control rate were 62.7% and 93.2%, respectively. The incidences of ⩾grade 3 pneumonitis, febrile neutropenia, and esophagitis were 0%, 8.5%, and 3.4%, respectively. Conclusion: Regarding durvalumab after CRT, this interim analysis of the SAMURAI study clarified the high transition rate, early introduction, and reasons for failure to proceed to consolidation therapy, which were not determined in the PACIFIC trial. Trial registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.

Hematoma in Epicardial Fat From Sinus of Valsalva Aneurysm.

Hematoma in epicardial fat is a rare finding on noncontrast computed tomography imaging. We describe a case with hematoma in epicardial fat that helped to diagnose an oozing, ruptured mycotic sinus of Valsalva aneurysm. (Level of Difficulty: Advanced.).

Thyroid hypogenesis is associated with a novel AKT3 germline variant that causes megalencephaly and cortical malformation.

The molecular mechanisms involved in thyroid organogenesis have not been fully elucidated. We report a patient with a de novo germline AKT3 variant, NM_005465.7:c.233A > G, p.(Gln78Arg), who presented with congenital hypothyroidism in addition to typical AKT3-related brain disorders. The report of this patient contributes to delineating the associated yet uncertain endocrine complications of this AKT3 disease-causing variant.

Silica-associated systemic lupus erythematosus with lupus nephritis and lupus pneumonitis: A case report and a systematic review of the literature.

INTRODUCTION: Several epidemiological studies have shown that silica exposure triggers the onset of systemic lupus erythematosus (SLE); however, the clinical characteristics of silica-associated SLE have not been well studied. PATIENT CONCERNS: A 67-year-old man with silicosis visited a primary hospital because of a fever and cough. His respiratory condition worsened, regardless of antibiotic medication, and he was referred to our hospital. DIAGNOSIS: The patient showed leukopenia, lymphopenia, serum creatinine elevation with proteinuria and hematuria, decreased serum C3 level, and was positive for anti-double stranded DNA antibody, anti-nuclear antibody, and direct Coombs test. He was diagnosed with SLE. Renal biopsy was performed, and the patient was diagnosed with lupus nephritis (class IV-G(A/C) + V defined by the International Society of Nephrology/Renal Pathology Society classification). Computed tomography revealed acute interstitial pneumonitis, bronchoalveolar lavage fluid showed elevation of the lymphocyte fraction, and he was diagnosed with lupus pneumonitis. INTERVENTIONS: Prednisolone (50 mg/day) with intravenous cyclophosphamide (500 mg/body) were initiated. OUTCOMES: The patient showed a favorable response to these therapies. He was discharged from our hospital and received outpatient care with prednisolone slowly tapered off. He had cytomegalovirus and herpes zoster virus infections during treatment, which healed with antiviral therapy. REVIEW: We searched for the literature on sSLE, and selected 11 case reports and 2 population-based studies. The prevalence of SLE manifestations in sSLE patients were comparative to that of general SLE, particularly that of elderly-onset SLE. Our renal biopsy report and previous reports indicate that lupus nephritis of sSLE patients show as various histological patterns as those of general SLE patients. Among the twenty sSLE patients reported in the case articles, three patients developed lupus pneumonitis and two of them died of it. Moreover, two patients died of bacterial pneumonia, one developed aspergillus abscesses, one got pulmonary tuberculosis, and one developed lung cancer. CONCLUSION: Close attention is needed, particularly for respiratory system events and infectious diseases, when treating patients with silica-associated SLE using immunosuppressive therapies.

Successful surgical repair of traumatic aortic dissection utilizing the Najuta stent graft in a patient with pre-existing situs inversus and anomalous neck vessels.

We report the case of a 39-year-old man who underwent surgical repair for traumatic Stanford type B acute aortic dissection. He was involved in a traffic accident, resulting in multiple rib fractures and a sternum fracture. On investigation, he was also found to have anatomical anomalies, namely, situs inversus and abnormality in the aortic arch and neck vessels. Thoracic endovascular aortic repair was performed as it is a less invasive procedure, thus recommended in such cases. A fenestrated thoracic endovascular aortic repair using the Najuta stent graft was found to be effective in this case where the anomalous anatomy was pre-existing.

Involuntary movements as a prognostic factor for acute encephalopathy with biphasic seizures and late reduced diffusion.

BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is characterized by biphasic seizures and white matter lesions with reduced diffusion, which are often accompanied by involuntary movements. The neurological outcomes of AESD vary from normal to mild or severe sequelae, including intellectual disability, paralysis, and epilepsy. The present study aimed to clarify the prognostic factors of AESD, including involuntary movements. METHODS: We enrolled 29 patients with AESD admitted to Tottori University Hospital from 1991 to 2020 and retrospectively analyzed their clinical data. Neurological outcomes were assessed by the Pediatric Cerebral Performance Category score and cerebral paralysis as neurological sequelae. RESULTS: Of the 29 patients, 12 had favorable outcomes and 17 had unfavorable outcomes. Univariate analysis revealed that the presence of underlying diseases, a decline in Glasgow Coma Scale (GCS) score 12-24 h after early seizures, and involuntary movements were associated with unfavorable outcomes. In multivariate analysis, a decline in GCS score and involuntary movements were associated with unfavorable outcomes. The sensitivities and specificities of underlying diseases, a decline of ≥ 3 points in GCS score 12-24 h after early seizures, and involuntary movements for unfavorable outcomes were 53% and 92%, 92% and 65%, and 59% and 92%, respectively. CONCLUSIONS: The appearance of involuntary movements may be associated with unfavorable outcomes of AESD. The prognostic factors identified herein are comparable with previously known prognostic factors of consciousness disturbances after early seizures.

Predicting the Onset of Acute Encephalopathy With Biphasic Seizures and Late Reduced Diffusion by Using Early Laboratory Data.

Background: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) often causes various neurological sequelae, necessitating early and objective differentiation of AESD from a febrile seizure (FS). Therefore, we developed a scoring system that predicts AESD onset using only early laboratory data. Methods: We selected patients with AESD or FS admitted to the Tottori University Hospital between November 2005 and September 2020 and collected laboratory data from onset to discharge in patients with FS and from onset to the second neurological events in patients with AESD. Results: We identified 18 patients with AESD and 181 patients with FS. In comparison with patients with FS, patients with AESD showed statistically significant increases in ammonia (NH3), blood sugar (BS), and serum creatinine (Cr) levels, and the white blood cell (WBC) count, and a significant decrease in pH at <3 h from onset. We set the cut-off values and adjusted the weight of each of these parameters based on data obtained <3 h from onset and proposed a scoring system for predicting AESD. This system showed 91% sensitivity and 94% specificity for distinguishing AESD from FS. These accuracies were only slightly improved by the addition of information related to consciousness and seizure duration (sensitivity, 91%; specificity, 96%). Conclusion: NH3, BS, and Cr levels, WBC count, and pH were significantly different between patients with AESD and patients with FS at <3 h from seizure onset. This scoring system using these data may enable the prediction of AESD onset for patients under sedation or without precise clinical information.

JME-001 phase II trial of first-line combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable malignant pleural mesothelioma.

BACKGROUND: JME-001 is a phase II trial assessing the efficacy and safety of cisplatin, pemetrexed, and nivolumab as first-line therapy in malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Patients with untreated, unresectable MPM with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 were included. The primary endpoint is the centrally reviewed objective response rate. The secondary endpoints include (1) response rate assessed by investigators, (2) disease control rate, (3) overall survival, (4) progression-free survival, (5) duration of response, and (6) time to response. Safety and adverse events will also be evaluated. Cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and nivolumab (360 mg/body) were administered intravenously every 3 weeks with a total of 4-6 cycles. If patients did not progress during the combination phase, maintenance therapy with nivolumab was administered until disease progression or unacceptable toxicity. Tissue samples were required and collected for programmed death ligand 1 analysis. RESULTS: Eighteen patients (mean age 69.2 years, 15 men) were enrolled between January 2018 and May 2019. The ECOG PS was 0 in 3 patients and 1 in 15 patients. Fourteen (77.8%; 95% CI 52.4% to 93.6%) patients had an objective response. The disease control rate was 94.4% (95% CI 72.7% to 99.9%). Fourteen (77.8%) patients had partial response (PR), three had stable disease, and one was not evaluable. Tumor shrinkage was observed in 10/14 (71.4%) patients with epithelioid, and 2/2 (100%) patients with sarcomatoid or biphasic histological subtype had PR. Ten (55.6%) patients experienced grade 3 or worse adverse events, including disorder of metabolism or nutrition (33.3%), loss of appetite (27.8%), anemia (16.7%), and hyponatremia (11.1%). No treatment-related deaths occurred. CONCLUSIONS: The safety and efficacy of this study strongly support a definitive trial of this combination.Trial registration numberUMIN000030892.

Nivolumab for malignant peritoneal mesothelioma.

Malignant peritoneal mesothelioma (MPeM) is a highly malignant neoplasm of the peritoneum, which carries a poor prognosis. A 70-year-old man, who was employed in the shipbuilding industry and exposed to asbestos for 50 years, was found to have a low-density lesion in the peritoneum around the liver and spleen, associated with multiple mediastinal and parasternal lymphadenopathy. Laparoscopic exploration was performed, and biopsy specimen analysis led to a diagnosis of MPeM. Initial systemic chemotherapy comprising cisplatin and pemetrexed yielded a modest cytoreductive effect. However, 4 months later, the patient presented with abdominal distension and anorexia. CT images revealed massive ascites, bowel obstruction and an enlarged intra-abdominal tumour, which was considered progression of the MPeM. The patient was treated with nivolumab. Bowel obstruction was improved after the first administration, and his sense of abdomen distension completely disappeared after the third administration. This case supports the utility of immunotherapy in MPeM.

Integral approach to biomacromolecular structure by analytical-ultracentrifugation and small-angle scattering.

Currently, a sample for small-angle scattering (SAS) is usually highly purified and looks monodispersed: The Guinier plot of its SAS intensity shows a fine straight line. However, it could include the slight aggregates which make the experimental SAS profile different from the monodispersed one. A concerted method with analytical-ultracentrifugation (AUC) and SAS, named as AUC-SAS, offers the precise scattering intensity of a concerned biomacromolecule in solution even with aggregates as well that of a complex under an association-dissociation equilibrium. AUC-SAS overcomes an aggregation problem which has been an obstacle for SAS analysis and, furthermore, has a potential to lead to a structural analysis for a general multi-component system.

Acute mitral valve endocarditis at the 24th gestational week.

Infective endocarditis during pregnancy and subsequent cardiac surgery are rare and carry a high mortality risk for both the mother and fetus. We report our experience with a previously healthy, 22-year-old woman affected by acute active mitral endocarditis due to Streptococcus gordonii at the 24th gestational week, who wished to continue with the pregnancy. Due to cardiogenic shock, an intra-aortic balloon pump was inserted. Our patient successfully underwent mitral valve replacement with normothermic high-flow cardiopulmonary bypass and continuous intraoperative fetus monitoring. She delivered a 2524-g baby vaginally at the 38th gestational week. Both the mother and child were confirmed to be doing well at the 1-year follow-up. Although this was the first case, urgent cardiac surgery and a subsequent childbirth went well by prompt decision of each department.

Rebiopsy with Thoracoscopy under Local Anesthesia for the Detection of EGFR T790M Mutation.

A 70-year-old woman underwent right upper lobectomy for adenocarcinoma of the lung (pT1bN2M0 stage IIIA). Five years after the surgery, lymph node recurrence was detected. Gefitinib was administered because epidermal growth factor (EGFR) exon 19 deletion mutation was detected in the previously resected surgical specimen. After a treatment of first-generation EGFR tyrosine kinase inhibitors, an FDG-PET/CT scan demonstrated abnormal FDG uptake in the pleura indicating pleural dissemination. Pleurocentesis revealed tumor cells in the pleural fluid; however, EGFR mutation testing failed due to inadequate tumor cellularity. Thoracoscopy under local anesthesia revealed multiple nodules on the parietal pleura. A biopsy specimen confirmed the diagnosis of lung adenocarcinoma with pleural dissemination and revealed EGFR exon 20-T790M mutation.

Spontaneous ascending aortic rupture in a pregnant woman with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF-1) is an autosomal dominant disorder that affects 1 in 3000 individuals. Vascular involvement in NF-1 is a well-recognized, but rare, feature of this disease. In pregnant women, the risk of aortic dissection or rupture is elevated during pregnancy and the postpartum period. We report a pregnant woman who had a history of NF-1 with a spontaneous ascending aortic rupture. This rupture was successfully treated by emergent surgery. The mother and the 28-week-gestation newborn recovered uneventfully. During 7 years of follow-up, aorta of the patient shows no significant change. A review of the literature regarding the pathogenesis of this condition is also presented.

Esophagobronchial Fistula in a Patient with Squamous Cell Carcinoma of the Lung: A Case Report.

A 73-year-old man was referred to our hospital after a 2-week history of bloody sputum and cough. Computed tomography (CT) images of the chest showed a mass grouped with mediastinal lymph nodes, and bronchoscopy showed a projecting mass in the right main bronchus. After a transbronchial biopsy, the patient was diagnosed with squamous cell carcinoma (T4N2M0 stage IIIB). The patient was treated with systemic chemotherapy, consisting of cisplatin (40 mg/m2, days 1 and 8) and docetaxel (30 mg/m2, days 1 and 8), and concurrent thoracic irradiation at a daily dose of 2 Gy. On day 35 of treatment, the patient complained of a sore throat and cough. A CT of the chest showed punctate low-attenuation foci between the esophagus and bronchus. Gastrointestinal endoscopy and bronchoscopy demonstrated a fistula in the middle intrathoracic esophagus and the left main bronchus. The patient's symptoms gradually improved, and the fistula was closed after the suspension of chemoradiotherapy. Radiotherapy was resumed and completed on day 82. However, on day 108, he developed a fever and cough, and a tumor with fistula was revealed in the right main bronchus. He had an esophageal stent inserted, but he later died of sudden hemoptysis.

Adenocarcinoma of the Lung Acquiring Resistance to Afatinib by Transformation to Small Cell Carcinoma: A Case Report.

A 65-year-old woman visited our hospital due to right chest pain and dyspnea on exertion. Chest radiography revealed decreased permeability of the right lung. Computed tomography demonstrated a huge mass in the right upper lobe and right pleural effusion. Right pleural effusion cytology yielded a diagnosis of adenocarcinoma and was positive for mutation of epidermal growth factor receptor (EGFR; exon 21 L858R). Afatinib was selected for the initial treatment. Multiple tumors regressed remarkably, but then rapidly progressed 3 months later. We performed re-biopsy to detect the mechanism of resistance to afatinib. Histopathology revealed a mixture of small cell carcinoma (SCC) and adenocarcinoma harboring same EGFR mutation. To the best of our knowledge, this is the first report of transformation to SCC after treatment with afatinib.

10-year results of On-X bileaflet mechanical heart valve in the aortic position: low target INR regimen in Japanese.

OBJECTIVES: This study was designed to establish clinical outcomes after aortic valve replacement (AVR) with On-X bileaflet mechanical heart valve. METHODS: Between 2006 and 2014, AVR was performed to 686 patients. Of them, 78 patients using On-X valve were enrolled. The mean age was 65 ± 11 years (ranged 33-85); 65% were men; and 81% were in sinus rhythm preoperatively. Calcific or degenerative tricuspid aortic valve was present in 73%. Concomitant procedures included coronary artery bypass grafting (22%), Bentall (8%), mitral valve procedure (3%) and other (9%). They postoperatively received lower dose warfarin [international normalized ratio (INR), 1.5-2.0] and 100 mg aspirin daily. The follow-up duration averaged 5 years (386.6 patient-years). The follow-up rate was 97.3%. RESULTS: In-hospital mortality rates were 3.8% (n = 3). Late mortality rates were 2.6% per patient-years (n = 10). Five-year Kaplan-Meier survival rates were 84%. Freedom from major adverse valve-related stroke and cerebral bleeding events was 93.3% (n = 5, 1.29% per patient-years) and 98.6% (n = 1, 0.26% per patient-years, mild subdural hematoma). The incidence of stroke was two patients of transient ischemic attack, two patients of paralytic event, one patient of asymptomatic stroke (self-interruption of anticoagulation). The median INR was 1.92 ± 0.53, ranged from 1.00 to 8.98 (n = 1181) and 51% of all measured INR values were in the therapeutic range of 1.5-2.0. CONCLUSIONS: AVR using On-X valve with low target INR regimen and low-dose aspirin resulted in a significantly low risk of bleeding.

[Delayed Diagnosis of Aortic Dissection Following Thrombolytic Therapy in a Patient with Acute Ischemic Stroke;Report of a Case].

Diagnosis of aortic dissection complicating cerebral ischemic stroke is difficult. A 60-year-old patient presented at an emergency department of a hospital with a sudden development of left-sided weakness, but without chest pain. During administration of recombinant tissue plasminogen activator with diagnosis of cerebral infarction, he developed symptomatic hypotension and was transferred to our hospital. His chest computed tomography revealed Stanford type A aortic dissection. Replacement of the ascending aorta and aortic arch was successfully performed on the 4th day.