Necroptosis in alveolar epithelial cells drives lung inflammation and injury caused by SARS-CoV-2 infection.

COVID-19, caused by SARS-CoV-2 infection, results in irreversible or fatal lung injury. We assumed that necroptosis of virus-infected alveolar epithelial cells (AEC) could promote local inflammation and further lung injury in COVID-19. Since CD8+ lymphocytes induced AEC cell death via cytotoxic molecules such as FAS ligands, we examined the involvement of FAS-mediated cell death in COVID-19 patients and murine COVID-19 model. We identified the occurrence of necroptosis and subsequent release of HMGB1 in the admitted patients with COVID-19. In the mouse model of COVID-19, lung inflammation and injury were attenuated in Fas-deficient mice compared to Fas-intact mice. The infection enhanced Type I interferon-inducible genes in both groups, while inflammasome-associated genes were specifically upregulated in Fas-intact mice. The treatment with necroptosis inhibitor, Nec1s, improved survival rate, lung injury, and systemic inflammation. SARS-CoV-2 induced necroptosis causes cytokine induction and lung damage, and its inhibition could be a novel therapeutic strategy for COVID-19.

Advanced Adenosquamous Carcinoma of the Ampulla of Vater Treated with Adjuvant Chemotherapy after Pancreaticoduodenectomy.

Introduction: Adenosquamous carcinoma (ASC) of the ampulla of Vater (AmV) is rare. The prognosis is generally worse in patients undergoing resection of ASC of the AmV than in those undergoing resection of adenocarcinoma of the AmV because the former shows early recurrence after surgery. A treatment strategy for ASC of the AmV has not been established, and the efficacy of adjuvant chemotherapy after curative resection is unclear. Given the paucity of data, we report a case of ASC of the AmV that was curatively resected and treated with adjuvant chemotherapy. Case Presentation: A 66-year-old man presented with pruritus and anorexia. Contrast-enhanced computed tomography revealed a tumor measuring 1.6 cm in diameter located at the AmV and distal bile duct. Biopsy revealed adenocarcinoma of the AmV. The patient underwent subtotal stomach-preserving pancreaticoduodenectomy. Histopathological examination contradictorily revealed ASC of the AmV and lymph node metastases. The postoperative course of the patient was uneventful, and he was discharged on day 25. The patient underwent S-1 adjuvant chemotherapy for 6 months and did not exhibit any postoperative recurrence for a follow-up duration of 28 months. Conclusion: Although treatment strategy for ASC of the AmV has not been established, our case shows that surgery followed by S-1 adjuvant chemotherapy could improve prognosis of patients with such tumors. However, further research is required to determine the efficacy of adjuvant chemotherapy and treatment strategies for resectable ASC of the AmV.

A case of advanced breast cancer with Gitelman syndrome.

Gitelman syndrome (GS) is a rare, mostly autosomal recessive disease this is a salt-losing tubulopathy caused by mutation of genes encoding sodium chloride (NCCT) and magnesium transporters in the thiazide-sensitive segments of the distal nephron. We encountered a 45-year-old female who has suffered from whole-body weakness because of hypokalemia for 8 years and diagnosed with Gitelman syndrome clinically. She visited the hospital with a complaint of an unrelieved hard mass of the left breast. The tumor was diagnosed as human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We herein report this first case of a breast cancer patient with Gitelman syndrome who developed other neoplasms including colon polyp, adrenal adenoma, an ovarian cyst, and multiple uterine fibroids and provide a review of the pertinent literature.

[Primary mediastinal large B-cell lymphoma, spindle cell variant demonstrating atypical image findings].

The patient was a 40-year-old woman referred to our hospital after an anterior mediastinal tumor was detected. Imaging findings revealed a tumor with irregular margins and a marked tendency to infiltrate, with some calcification. Rather than malignant lymphoma, thymic carcinoma or high-grade invasive thymoma was suspected. Endobronchial ultrasound-guided transbronchial needle aspiration biopsy and computed tomography-guided needle biopsy were performed, but no diagnosis was made. Mediastinal tumor biopsy by video-assisted thoracic surgery led to the diagnosis of primary mediastinal large B-cell lymphoma, spindle cell variant. A retrospective examination of the needle biopsy specimens revealed that some tissues considered to have been crushed were composed of spindle-shaped lymphoma cells. This study indicates that it is crucial to note that there is a subtype of primary mediastinal large B-cell lymphoma with an unusual pathological morphology.

A feasibility study comparing gel immersion endoscopic resection and underwater endoscopic mucosal resection for superficial nonampullary duodenal epithelial tumors.

BACKGROUND: Although gel immersion endoscopic resection (GIER) is a potential alternative to underwater endoscopic mucosal resection (UEMR) for superficial nonampullary duodenal epithelial tumors (SNADETs), comparisons between the two are currently insufficient. METHODS: 40 consecutive procedures performed in 35 patients were retrospectively reviewed; the primary outcome was procedure time, and the secondary outcomes were en bloc and R0 resection rates, tumor and specimen size, and adverse events. RESULTS: Lesions were divided into GIER (n = 22) and UEMR groups (n = 18). The median (range) procedure time was significantly shorter in the GIER group than in the UEMR group (2.75 [1-3.5] minutes vs. 3 2 3 4 5 6 7 8 9 10 minutes; P = 0.01). The en bloc resection rate was 100 % in the GIER group, but only 83.3 % in the UEMR group. The R0 resection rate was significantly higher in the GIER group than in the UEMR group (95.5 % vs. 66.7 %; P = 0.03). The median specimen size was larger in the GIER group than in the UEMR group (14 mm vs. 7.5 mm; P < 0.001). The tumor size was not significantly different between the groups and no adverse events were observed. CONCLUSIONS: GIER is efficacious and safe to treat SNADETs, although additional studies are needed.

Surgical resection of arteriovenous malformation of the pancreatic head with acute pancreatitis: a case report.

Arteriovenous malformations (AVMs) are uncommon in the gastrointestinal tract, particularly in the pancreas. AVMs cause complications, including gastrointestinal bleeding, portal hypertension and pancreatitis. Therefore, a treatment strategy is not yet established. Surgical treatment or transcatheter arterial embolization is performed in patients with AVM, considering their conditions. A 54-year-old man presented with acute abdominal pain was diagnosed with acute pancreatitis due to AVM of the pancreatic head using dynamic computed tomography. Endoscopic ultrasonography further revealed meandering blood vessels in the pancreatic head. The patient underwent subtotal stomach-preserving pancreaticoduodenectomy. Histological examination revealed AVM of the pancreatic head with chronic pancreatitis. The patient had a good postoperative clinical course and was discharged on postoperative day 22. He remained asymptomatic. Pancreaticoduodenectomy can be considered an effective treatment method for selected cases of symptomatic AVM of the pancreatic head.

Zoonotic infection caused by Onchocerca japonica (Nematoda: Filarioidea) in a 69-year-old woman in Kanto Region, Eastern Honshu, Japan.

Reports of zoonotic infections caused by the filarial nematode Onchocerca japonica have recently increased in Japan. A 69-year-old woman living in Sosa City, Chiba Prefecture, Kanto Region, Honshu, developed a painful nodule at the metacarpophalangeal joint of the index finger of her right hand. The causative agent was identified as a female O. japonica based on the histopathological characteristics (i.e., cuticle with transverse triangular ridges but without inner striae) of the biopsy specimens of the nodule. The species identification was corroborated by cox1 gene sequencing of the worm tissues isolated from paraffin-embedded sections of the specimens. Subsequent to the excision of the nodule, followed by anthelmintic treatment, the patient remained asymptomatic. Human infection with O. japonica has not previously been reported in Kanto Region, Eastern Honshu. The present case is likely linked to the recent expansion of the geographic range of the Japanese wild boar into this area.

Heat-Killed Lactococcus lactis subsp. cremoris H61 Altered the Iron Status of Young Women: A Randomized, Double-Blinded, Placebo-Controlled, Parallel-Group Comparative Study.

Women are prone to iron deficiency because of increased iron excretion associated with menstruation. This is often treated by oral iron supplementation, although this treatment can cause side effects, such as stomach pain and nausea, with low absorption of ingested iron. Previously, a significant increase in serum iron was observed in association with the consumption of foods containing Lactococcus lactis subsp. cremoris H61 (H61). However, the causal relationship between H61 ingestion and elevated serum iron is still unclear. Therefore, in this study, we aimed to determine the effects of H61 ingestion on the iron status of young women. Healthy young Japanese women (18-25 years of age) ingested either heat-killed H61 or placebo for 4 weeks. Serum iron, transferrin saturation, and ferritin were significantly elevated in the H61 group but remained unchanged in the placebo group. Compared to before the intervention, iron intake remained unchanged during the intervention period, so the change in the iron status of the H61 group was not due to increased iron intake. These results suggest that heat-killed H61 may elevate iron status by enhancing iron absorption.

Usefulness of renal diffusion-weighted magnetic resonance imaging for early diagnosis of tubulointerstitial nephritis and uveitis (TINU) syndrome.

A teenage girl presented with fever after aspirin use. Examination revealed no organ-specific symptoms. The serum creatinine level and urine analysis findings were normal. The drug lymphocyte stimulation test was positive for aspirin. Diffusion-weighted magnetic resonance imaging (DW-MRI) revealed hyperintensity in both kidneys although serum creatinine was only mildly elevated. A subsequent kidney biopsy confirmed acute interstitial nephritis (AIN). She later developed uveitis and the final diagnosis was tubulointerstitial nephritis and uveitis (TINU) syndrome, possibly triggered by aspirin, requiring systemic and topical corticosteroid therapies. TINU syndrome should be considered in young patients with fever of unknown origin and a history of nonsteroidal anti-inflammatory drug use. This is the first reported case suggesting the usefulness of DW-MRI, which is safe for children without exposure to ionising radiation, in detecting early-stage AIN before apparent kidney impairment.

Possible Association of Energy Availability with Transferrin Saturation and Serum Iron during Summer Camp in Male Collegiate Rugby Players.

Low energy availability (LEA) may persist in rugby players. However, timely assessment of energy balance is important but is difficult. Therefore, a practical index that reflects energy availability (EA) is essential. A total of 19 male college rugby players participated in a 2-week pre-season summer camp. Their blood sample was collected after overnight fast prior to (Pre), in the middle (Middle), and after (Post) the camp. Their physical activity in the first half of the camp was calculated using the additive factor method in the forwards (FW; numbers 1-8) and backs (BK; numbers 9-15). The participants were categorized as tight five (T5; numbers 1-5), back row (BR; numbers 6-8), and BK for analysis. All the participants lost weight during the camp (range: from -5.9% to -0.1%). Energy balance in the first half of the camp was negative. Transferrin saturation (TSAT) and serum iron levels significantly decreased to half, or even less, compared with the Pre levels at week 1 and remained low. The changes in TSAT and serum iron levels exhibited a significant positive correlation with the changes in body weight (R = 0.720; R = 0.627) and with energy intake (R = 0.410; R = 461) in T5. LEA occurs in rugby summer camp but is difficult to assess using weight change. Alternately, TSAT and serum iron levels after overnight fast may be better predictors of LEA.

The efficacy of prophylactic clip closure of mucosal defects after colorectal endoscopic submucosal dissection on delayed bleeding.

OBJECTIVE: Although prophylactic clip closure after endoscopic mucosal resection may prevent delayed bleeding, information regarding colorectal endoscopic submucosal dissection (CR-ESD) is lacking. Therefore, this study evaluated the effect of prophylactic clip closure on delayed bleeding rate after CR-ESD. MATERIALS AND METHODS: A total of 614 CR-ESD procedures performed in 561 patients were retrospectively reviewed. The primary outcome, which was delayed bleeding rate, was analyzed between the prophylactic clip closure and non-closure groups. Furthermore, the predictors of delayed bleeding were also evaluated. RESULTS: The patients were divided into the clip closure group (n = 275) and non-closure group (n = 339). Delayed bleeding rate was significantly lower in the closure group than in non-closure group (6 cases [2.2%] vs. 20 cases [5.9%], p = .026). The univariate logistic regression analyses revealed that delayed bleeding was significantly associated with laterally spreading tumor-granular-nodular mixed type (LST-G-Mix; odds ratio [OR], 3.77; 95% confidence interval [CI], 1.70-8.34; p = .001). By contrast, prophylactic clip closure was significantly associated with low delayed bleeding rate (OR, 0.36; 95%CI, 0.14-0.90; p = .029). The multivariate logistic regression analyses revealed LST-G-Mix as a significant independent delayed bleeding predictor (OR, 3.25; 95%CI, 1.45-7.32; p = .004), whereas, prophylactic clip closure was identified as a significant independent preventive factor of delayed bleeding (OR, 0.39; 95%CI, 0.15-1.00; p = .049). CONCLUSIONS: Prophylactic clip closure after CR-ESD is associated with low delayed bleeding rate. LST-G-Mix promotes delayed bleeding, and performing prophylactic clip closure may be advisable.

Monoclonal B-cell Lymphocytosis Exacerbated by Prednisolone Therapy for Dermatomyositis.

Lymphoproliferative diseases have been associated with various autoimmune diseases. We experienced a case of non-chronic lymphocytic leukemia type monoclonal B-cell lymphocytosis (MBL) that was exacerbated by increasing prednisolone for dermatomyositis and then improved by decreasing the dosage. Because MBL is difficult to diagnose, cases like ours may not be rare. These findings will facilitate our understanding of the mechanism underlying lymphoproliferative diseases and autoimmune diseases.

Granulomatosis with polyangiitis complicated with refractory optic neuritis and maxillary osteomyelitis.

We report a case of a 61-year-old man with granulomatosis with polyangiitis (GPA) complicated with refractory optic neuritis and maxillary osteomyelitis. He had been treated with prednisolone (PSL) as cryptogenic organizing pneumonia in the respiratory department for 2 years. Afterward, he complained tenderness of paranasal sinuses and rapidly progressive visual loss of the left eye. Although both MPO-ANCA and PR3-ANCA were negative, he was diagnosed as GPA based on the American College of Rheumatology 1990 criteria. Ophthalmologic and oral examination revealed left optic neuritis and destructive maxillary bone. Magnetic resonance imaging (MRI) showed the optic neuritis and inflammation around the optic nerve. This finding suggested that the direct spread of inflammation from paranasal sinuses caused the optic neuritis. In a short time, increasing a dose of PSL and administration of intravenous cyclophosphamide were initiated. Antibiotics were also administered to treat sinusitis. Although his visual acuity of the left eye deteriorated to no light perception temporarily, it finally improved after treatment and findings of MRI were also improved. In contrast, destruction of maxilla bone had been progressing. This is a rare case of GPA complicated with optic neuritis due to sinusitis and maxillary osteomyelitis.

Learning curve for endoscopic submucosal dissection of early colorectal neoplasms with a monopolar scissor-type knife: use of the cumulative sum method.

OBJECTIVE: Although scissor-type knives such as the Stag-Beetle (SB) Knife Jr are expected to result in a safe and easy colorectal endoscopic submucosal dissection (CR-ESD), information regarding the learning curve is lacking. Therefore, this study evaluated the learning curve with using SB Knife Jr. MATERIALS AND METHODS: We retrospectively reviewed 507 CR-ESD procedures performed in 464 patients using SB Knife Jr. The primary endpoint was a learning curve to achieve a satisfactory complete resection rate. The secondary endpoints were learning curves to achieve a satisfactory en bloc resection rate, curative resection rate, and resection speed. RESULTS: The complete, en bloc, and curative resection rates were 91.9%, 95.9%, and 84.0%, respectively. Moving average analysis showed that 39 cases were required for a complete resection rate of >80%, 41 for an en bloc resection rate of >90%, and 50 for a curative resection rate of >75%. We divided the procedure into three phases using the cumulative sum method: I, II, and III (cases 1-36, 37-119, and 120-507, respectively). Although we found no significant between-phase differences, the complete resection rate showed an increasing trend in Phase III (83.3 vs. 89.2 vs. 93.3%; p = .099). The en bloc resection rate (91.7 vs. 91.6 vs. 97.2%; p = .047) and resection speed (20.5 vs. 7.2 vs. 6.8 min/cm2; p < .001) were greater in Phase III. Despite the larger specimen size (27.3 vs. 38.2 vs. 40.4 mm; p < .001) and more severe fibrosis (p < .001) in Phase III, the procedure time was shorter (73.8 vs. 57.8 vs. 54.2 min; p = .041). The curative resection rate was not significantly different between phases. CONCLUSIONS: SB Knife Jr enables safe and easy CR-ESD during the introductory period compared to the conventional tip-type knife and has an acceptable learning curve. Therefore, using this knife will encourage the widespread adoption of CR-ESD in Asian general hospitals and non-Asian countries.

Recent progress in synchrotron radiation 3D-4D nano-imaging based on X-ray full-field microscopy.

The advent of high-flux, high-brilliance synchrotron radiation (SR) has prompted the development of high-resolution X-ray imaging techniques such as full-field microscopy, holography, coherent diffraction imaging and ptychography. These techniques have strong potential to establish non-destructive three- and four-dimensional nano-imaging when combined with computed tomography (CT), called nano-tomography (nano-CT). X-ray nano-CTs based on full-field microscopy are now routinely available and widely used. Here we discuss the current status and some applications of nano-CT using a Fresnel zone plate as an objective. Optical properties of full-field microscopy, such as spatial resolution and off-axis aberration, which determine the effective field of view, are also discussed, especially in relation to 3D tomographic imaging.

[Primary leptomeningeal lymphoma with oculomotor paralysis as the initial presentation].

An 85-year-old man presented with right eye ptosis and visual abnormalities. Due to a lack of abnormal findings on plain magnetic resonance imaging (MRI) and laboratory examination, prednisolone therapy was initiated, and ocular myasthenia gravis and ocular symptoms subjectively improved. However, anorexia and conscious disorder appeared during the same period, and he was hospitalized for scrutiny. After admission, left eye adduction disorder and bilateral abduction nerve paralysis were also observed. Enhanced MRI revealed cranial nerve and leptomeninx enhancement. Subsequently, the patient developed seizures and died on the 10th day of hospitalization without being diagnosed. An autopsy revealed infiltration of B-cell lymphoma cells into the subarachnoid space, particularly in the parietal lobe. Similar infiltration was observed in the cerebellum, brainstem, spinal cord, and bilateral oculomotor nerve. Primary leptomeningeal lymphoma is a rare form of primary central nervous system lymphoma without simultaneous parenchymal brain lesions. Clinicians should be aware of this form of lymphoma and carefully monitor its possible occurrence, even when patients are already being treated for other neurological diseases.

Computer-assisted detection of metastatic lung tumors on computed tomography.

BACKGROUND: This retrospective study examined the performance of computer-assisted detection in the identification of pulmonary metastases. METHODS: Fifty-five patients (41.8% male) who underwent surgery for metastatic lung tumors in our hospital from 2005 to 2012 were included. Computer-assisted detection software configured to display the top five nodule candidates according to likelihood was applied as the first reader for the preoperative computed tomography images. Results from the software were classified as "metastatic nodule", "benign nodule", or "false-positive finding" by two observers. RESULTS: Computer-assisted detection identified 85.3% (64/75) of pulmonary metastases that radiologists had detected, and 3 more (4%, 3/75) that radiologists had overlooked. Nodule candidates identified by computer-assisted detection included 86 benign nodules (median size 3.1 mm, range 1.2-18.7 mm) and 121 false-positive findings. CONCLUSIONS: Computer-assisted detection identified pulmonary metastases overlooked by radiologists. However, this was at the cost of identifying a substantial number of benign nodules and false-positive findings.

Massive Hemoptysis Due to the Rupture of Thoracic Aortic Aneurysm Caused by Leukemic Cell Infiltration in a Patient With Chronic Myelomonocytic Leukemia.

Hemoptysis is occasionally experienced in patients with hematological malignancies who have respiratory tract infection and severe thrombocytopenia. Thrombocytopenia due to hematological disease is one cause of hemoptysis. Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy characterized by both a myeloproliferative neoplasm and a myelodysplastic syndrome. This malignancy often infiltrates various extramedullary organs and has a poor prognosis. An 84-year-old Japanese man with CMML was suffered from hemoptysis and dyspnea. When he arrived at the emergency room, hemoptysis stopped. His white blood cell count was 866 × 109/L with 3.5% blast cells and 36.5% monocytes; hemoglobin was 6.7 g/dL; platelets count was 19 × 109/L; and C-reactive protein was 16.23 mg/dL. Chest X-ray examination revealed an invasion shadow near the mediastinum in the left upper lung field. Chest computed tomography revealed a tumorous lesion in the left upper lobe, which had progressed to the mediastinum and formed an infiltration shadow around it. He was administered the antibiotics and the hemostatic agents under hospitalization. He also received blood transfusion for anemia and thrombocytopenia. Rapid improvement in oxygenation was observed along with a rapid decrease in blood levels in the sputum. On the eighth days of hospitalization, however, the patient newly developed massive hemoptysis and died. Autopsy revealed rupture of a thoracic pseudoaneurysm due to infiltration of leukemia cells in the tunica media and lung. Clinicians should consider thoracic aortic aneurysms as a possible cause of hemoptysis even in cases with small hemoptysis. It should be noted that in CMML patients, direct infiltration of leukemia cells in the vascular wall can cause aneurysm formation.

Effects of Early Initiation of Solid Versus Liquid Diet after Endoscopic Submucosal Dissection on Quality of Life and Postoperative Outcomes: A Prospective Pilot Randomized Controlled Trial.

BACKGROUND/AIMS: Feeding recommendations after endoscopic submucosal dissection (ESD) for gastric neoplasms are not established and based on clinical experience. METHODS: This was a prospective pilot randomized controlled trial. Patients undergoing ESD for gastric neoplasms were randomly assigned to solid (n = 50) or liquid diet (n = 50) groups. Beginning the day after hemostasis confirmation until discharge, the solid diet group started on a diet of rice porridge, whereas the liquid diet group started on a liquid diet, with gradual transition to solid food. The primary endpoint was delayed bleeding rate. The secondary endpoints were quality of life (QOL), ulcer-stage, hospital fees, and post-ESD symptoms. RESULTS: Delayed bleeding occurred in the solid diet group (2%) but not in the liquid diet group. The QOL evaluation using European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-STO22 showed better score in the solid diet group. The patients who felt dietary restriction at discharge was of a larger number in the liquid diet group (p = 0.019). More patients experienced appetite loss (p = 0.038), constipation (p = 0.022), and dietary restriction (p = 0.037) in the liquid diet group during hospitalization. The other endpoints were equivalent between the groups. CONCLUSION: Early initiation of solid foods after ESD is feasible and associated with higher QOL, potentially rendering conventional liquid diets unnecessary, although additional studies are needed (Trial registration number: UMIN000013297).

Multiple cystic lung lesions and autoimmune thrombocytopaenia developing after chemotherapy for pulmonary indolent B-cell lymphoma with plasmacytic differentiation.

Among lung malignancies, primary pulmonary lymphoma is rare and many of them are indolent B-cell lymphomas. We describe a case of primary pulmonary indolent B-cell lymphoma with plasmacytic differentiation, which exacerbated with the manifestation of macroglobulinaemia and was successfully treated using chemotherapy. The patient subsequently developed pulmonary cysts and thrombocytopaenia due to autoimmune pathology and was successfully treated using prednisolone. This case suggests that in indolent B-cell lymphoma with plasmacytic differentiation, immunoglobulin M level should be carefully followed even if it is within the normal range at lymphoma onset. Additionally, new cystic pulmonary infiltrates that develop during the post-treatment follow-up of an indolent pulmonary B-cell lymphoma may indicate pulmonary lymphoma recurrence, but there is also a possibility of an immunological complication.