Evaluation of flow dynamics in distal stent graft-induced new entry using 4D flow MRI.

Distal stent graft-induced new entry may occur after stent grafting for aortic dissection. Four-dimensional magnetic resonance imaging is useful for predicting outcomes, showing accelerated flow and increased wall shear stress, indicating further false lumen expansion.

Extended optical waveguide theory with magneto-optical effect and magnetoelectric effect.

Optical waveguide theory is essential to the development of various optical devices. Although there are reports on the theory of optical waveguides with magneto-optical (MO) and magnetoelectric (ME) effects, a comprehensive theoretical analysis of waveguides considering these two effects has not yet been published. In this study, the conventional waveguide theory is extended by considering constitutive relations that account for both MO and ME effects. Using the extended waveguide theory, the propagation properties are also analyzed in a medium where metamaterials and magnetic materials are arranged such that MO and ME effects can be controlled independently. It has been confirmed that the interaction between MO and ME effects occurs depending on the arrangement of certain metamaterials and the direction of magnetization. This suggests a nonreciprocal polarization control that rotates the polarization in only one direction when propagating in plane wave propagation and enhances the nonreciprocal nature of the propagating waves in waveguide propagation.

Association of immune-related pneumonitis with clinical benefit of anti-programmed cell death-1 monotherapy in advanced non-small cell lung cancer.

BACKGROUND: The association between the development of checkpoint inhibitor pneumonitis (CIP) with tumor response and survival has remained unclear so far. The aim of the present study was to evaluate the association between CIP and the clinical efficacy of anti-programmed cell death-1 antibody in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Between January 2016 and August 2019, 203 advanced NSCLC patients were administered with nivolumab or pembrolizumab. Comparisons were made between patients with and without CIP. We evaluated the time-to-treatment failure (TTF), progression-free survival (PFS), and overall survival (OS). RESULTS: CIP was observed in 28 (14%) patients. CIP was associated with a longer PFS (18.9 months [95% confidence interval, CI: 8.7 months-not reached] vs. 3.9 months [95% CI: 3.4-5.1 months, p < 0.01]) and longer OS (27.4 [95% CI: 20.7 months-not reached] vs. 14.8 months [95% CI: 11.2-17.9 months, p = 0.003]). Most patients discontinued the immune checkpoint inhibitor (ICI) treatment when they developed CIP. Seven patients (25%) lived for more than 300 days from treatment discontinuation and did not show any long-term tumor growth after treatment discontinuation. CONCLUSION: CIP was associated with prolonged PFS and OS. Additionally, 25% of CIP patients did not show any tumor growth for long periods after treatment discontinuation. Careful management of CIP can help in obtaining the best clinical efficacy from anti-PD-1 antibody.

Relationship between Programmed Cell Death Protein Ligand 1 Expression and Immune-related Adverse Events in Non-small-cell Lung Cancer Patients Treated with Pembrolizumab.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs). A correlation between the development of irAEs and efficacy has been suggested; however, it is unclear whether there is a relationship between programmed death ligand 1 (PD-L1) expression and the development of these events. METHODS: We performed a retrospective study of advanced or metastatic non-small cell lung cancer (NSCLC) patients who were treated with pembrolizumab monotherapy at our institution between May 2015 and April 2018 (n = 44). Patients were categorized into two groups, specifically those with irAEs (irAE group) or without (non-irAE group), and we evaluated the objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Predictors of irAEs were examined by multivariate analysis. RESULTS: irAEs of any grade occurred in 31 (70.5%) patients. The median PFS was 10.9 months in the irAE group versus 3.7 months in the non-irAE group (P < 0.001). ORR and DCR were also higher in the irAE group than in the non-irAE group. Furthermore, high PD-L1 expression (≥50%) was a predictive factor of irAE based on logistic regression (P = 0.004). CONCLUSIONS: In patients with advanced NSCLC treated with pembrolizumab monotherapy, ORR, DCR, and PFS were significantly better in the irAE group than in the non-irAE group. High PD-L1 expression, at the time of pretreatment, was identified as an independent predictor of irAE development. We believe that more careful management of irAEs for individuals with high PD-L1 expression is needed to improve clinical benefits. Further, PD-L1 expression might be useful for ICI risk management.

A Remarkable Clinical Response to Pembrolizumab in a Rare Spindle Cell Carcinoma of the Lung.

Spindle cell carcinoma of the lung consists of only spindle-shaped tumor cells, and accounts for approximately 13.3% of all sarcomatoid carcinomas (SCs), which are a rare subtype of poorly differentiated non-small cell lung cancer (NSCLC). Spindle cell carcinoma of the lung has very poor prognosis owing to resistance to chemotherapy and radiotherapy. This case report describes a 76-year-old man who presented with complaints of dry cough and right-sided neck pain and was later diagnosed with spindle cell carcinoma of the lung. He had a medical history of type 2 diabetes, angina pectoris, atrial fibrillation, hypertension, hyperlipidemia, and hepatitis B and a 20 pack-year history of smoking. A computed tomography (CT) scan revealed a mass with a thick-walled cavity in the right upper lobe of the lung. His neck pain was consistent with PET-CT images, indicating metastases due to invasion of lung cancer cells. The expression of PD-L1 in more than 90% of the tumor cells of the lung biopsy tissue led to the administration of pembrolizumab. The lung and metastatic tumors dramatically decreased in size after 9 weeks, and no tumor regrowth was observed over 11 courses of pembrolizumab administration. To the best of our knowledge, there are no previous reports describing the use of pembrolizumab for spindle cell carcinoma of the lung. This case report suggests that immunotherapy could be a promising treatment option for rare types of lung cancers, including spindle cell carcinoma.

[Two-debranching Thoracic Endovascular Aortic Repair for Thoracic Aortic Aneurysm Complicated by Idiopathic Thrombocytopenic Purpura;Report of a Case].

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease in which the number of platelets decreases due to auto-antibodies against platelets. We report that thoracic endovascular aortic repair (TEVAR) was successfully performed for a thoracic aortic aneurysm complicated by ITP. The patient was a man of 77 years of age. He had a history of splenectomy due to ITP. He was admitted to our hospital with an aneurysm of the aortic arch that enlarged to a maximum minor axis of 63 mm. An operation was planned. Because of ITP, it was judged that replacement of the aortic arch using a cardio-pulmonary pump would be associated with a high risk of bleeding. Thus, 2-debranching TEVAR was selected and performed with no hemorrhagic complications. He was discharged from the hospital on the 12th day after surgery. We believe that 2-debranching TEVAR is effective for reducing perioperative bleeding in patients with ITP.

Pitfalls of Retrograde Cardioplegia Cannulation: Left Atrium Dissection.

Left atrial dissection is a rare complication of cardiac surgery. We present a case of left atrial dissection that occurred during a partial arch repair for Stanford acute type A aortic dissection. Because no entry was found in the left atrium by transesophageal echocardiography, and there were no issues weaning from cardiopulmonary bypass, we decided that no surgical intervention was necessary. Transthoracic echocardiography and computed tomography showed the remaining dissection on postoperative day 7; however, on postoperative day 14, it had completely disappeared.

[Lung Cancer and Respiratory Infections].

The frequency of respiratory infections as an infection in cancer patients is high. Several factors increase the risk of respiratory infections in cancer patients. These include airway obstruction, disruption of mucosal surfaces and treatment-related factors, such as radiation and chemotherapy. It has also been reported that the frequency and mortality of drug-induced lung injury associated with antineoplastic drugs are high in Japan. In the diagnosis and treatment of drug-induced lung disease, it is important to distinguish pneumonia as an infectious disorder. Immune checkpoint inhibitors(ICIs)have been widely introduced to treat several types of malignancies. It is currently believed that ICIs do not increase the risk of infections. However, immune-related adverse events(irAEs)induced by ICIs may necessitate the administration of immunosuppressive agents, which could cause opportunistic infections. Furthermore, several reports describe reactivation tuberculosis without irAEs or immunosuppressants. Further studies are needed to prevent the development of tuberculosis in patients receiving ICIs.

Association Between Skin Reaction and Clinical Benefit in Patients Treated with Anti-Programmed Cell Death 1 Monotherapy for Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Anti-programmed cell death 1 antibody is a standard therapy for advanced non-small cell lung cancer (NSCLC). However, immune-related adverse events (irAEs), such as skin reactions, are frequently observed. Although skin reactions are associated with clinical efficacy in melanoma, this association in advanced NSCLC and predictors of irAEs remain unclear. Accordingly, this study identified potential correlations of skin reactions with clinical efficacy and clinical predictors of development of skin reactions. SUBJECTS, MATERIALS, AND METHODS: We retrospectively surveyed patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital (n = 155) during January 2016 to April 2018. Treatment efficacy was evaluated in patients with and without skin reactions, and associated predictive markers were determined. A 6-week landmark analysis was conducted to assess the clinical benefit of early skin reactions. RESULTS: Skin reactions were observed in 51 patients with a median time to onset of 6.4 weeks. The overall response rate (ORR) was significantly higher in patients with skin reactions (57% vs. 19%, p < .001). Median progression-free survival (PFS) durations of 12.9 and 3.5 months and overall survival durations of not reached and 11.4 months were observed in patients with and without skin reactions, respectively. In the 6-week landmark analysis, the ORR was significantly higher in patients with skin reactions, and skin reactions were significantly associated with increased PFS. A multivariate analysis identified pre-existing rheumatoid factor (RF) as an independent predictor of skin reactions. CONCLUSION: Skin reactions appeared beneficial in patients treated with nivolumab/pembrolizumab for advanced NSCLC and could be predicted by pre-existing RF. Further large-scale validations studies are warranted. IMPLICATIONS FOR PRACTICE: This single-institutional medical record review that included 155 patients with advanced non-small cell lung cancer who were treated with nivolumab or pembrolizumab monotherapy revealed that overall response rate and progression-free survival were significantly better in patients with skin reactions. Pre-existing rheumatoid factor was an independent predictor of skin reactions.

Association of low body surface area with dose reduction and/or discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis: a pilot study.

BACKGROUND: We have often encountered adverse events requiring dose reduction and/or discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis. OBJECTIVES: The objectives of this study were to clarify the incidence of dose reduction and/or discontinuation following the commercialization of nintedanib and to investigate predictors of dose reduction and/or discontinuation of nintedanib at our hospital. METHODS: We retrospectively identified 25 patients who had received nintedanib 150 mg twice daily at Sendai Kousei Hospital and categorized them into two groups according to whether they had or had not required dose reduction and/or discontinuation and sought to identify predictors of dose reduction and/or discontinuation. RESULTS: Seventeen patients developed adverse events, which included diarrhea (n=10, 44%), hepatotoxicity (n=7, 28%), and anorexia (n=2, 16%). No adverse event-related deaths occurred during the study period. Patients who required dose reduction and/or discontinuation were significantly older than those who did not (72 years vs 67 years; P=0.047). Body surface area (BSA) was significantly lower in the group that needed dose reduction and/or discontinuation than in the group that did not (1.63 m2 vs. 1.78 m2; P=0.028). Multivariate logistic regression revealed that the association of low BSA with dose reduction and/or discontinuation was statistically significant. CONCLUSIONS: A low BSA was associated with dose reduction and/or discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis. Further studies in larger patient samples are needed to validate these findings.

Profiling Preexisting Antibodies in Patients Treated With Anti-PD-1 Therapy for Advanced Non-Small Cell Lung Cancer.

Importance: Administration of anti-programmed cell death protein 1 (anti-PD-1) is now standard therapy in advanced non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors, including anti-PD-1, have not been assessed in patients with subclinical disease with advanced NSCLC, and no useful clinical biomarkers have been associated with immune-related adverse events (irAEs) among these patients treated with anti-PD-1. Objective: To assess the safety and efficacy of anti-PD-1 treatment in patients with subclinical disease with advanced NSCLC and with or without preexisting autoimmune markers, including rheumatoid factor, antinuclear antibody, antithyroglobulin, and antithyroid peroxidase; and to assess potential clinical biomarkers that may be meaningfully and conveniently associated with clinical benefit or with irAEs following anti-PD-1 treatment. Design, Setting, and Participants: This medical records analysis retrospectively evaluated 137 patients who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital in Japan between January 2016 and January 2018. Treatment efficacy and irAEs were evaluated along with candidate factors that may be associated with irAEs. Exposures: Absence or presence of specific autoimmune markers and antibodies before treatment. Main Outcomes and Measures: Preexisting antibodies and autoimmune markers, progression-free survival (PFS), and irAEs. Results: Of 137 patients with advanced NSCLC, 105 were men, the median age was 68 (range, 36-88) years, 99 underwent nivolumab monotherapy, 38 underwent pembrolizumab monotherapy, and 134 had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median PFS was 6.5 (95% CI, 4.4-12.9) months among patients with examined preexisting antibodies and 3.5 (95% CI, 2.4-4.1) months among patients without, suggesting significantly better prognosis in the former. The hazard ratio for disease progression or death in the presence of the examined preexisting antibodies was 0.53 (95% CI, 0.36-0.79; P = .002). The PFS was significantly longer among patients with any preexisting antibodies than among those without. The examined preexisting antibodies (48 patients [73%]) and rheumatoid factor (26 patients [39%]) were more common among patients who developed irAEs. Multivariate analysis indicated that the presence of the examined preexisting antibodies was independently associated with irAEs (odds ratio, 3.25; 95% CI, 1.59-6.65; P = .001). Skin reactions were more frequent among patients with preexisting rheumatoid factor (47% vs 24%, P = .02), whereas thyroid dysfunction was more frequent among patients with preexisting antithyroid antibodies (20% vs 1%, P < .001). Conclusions and Relevance: The presence of the examined preexisting antibodies was associated with clinical benefit and with the development of irAEs in patients with NSCLC treated with nivolumab or pembrolizumab. Thus, the presence of these autoimmune markers may help determine the risk-benefit ratio for individual patients with NSCLC, maximizing therapeutic benefits while minimizing irAEs.

Descending necrotizing mediastinitis in a healthy young adult.

A 26-year-old man with right lower mandibular and chest pain, fever, and respiratory distress was urgently transported to our hospital. CT images revealed gas collection and an abscess from the neck to the mediastinum with bilateral pleural effusion. Descending necrotizing mediastinitis (DNM) induced by an odontogenic infection of a right mandibular molar abscess was diagnosed. The cervical and mediastinal areas were drained, extensive debridement was performed, necrotic tissue was excised, and broad-spectrum antibiotics were administered immediately. Prompt diagnosis and intensive care were necessary for managing the DNM, and the patient was discharged with no comorbidities.

Drug-induced interstitial lung disease in the treatment of malignant lymphoma as a potential diagnostic marker: a comparison of serum Krebs von Lungen-6 and thymus and activation-regulated chemokine/CC chemokine ligand 17.

PURPOSE: Cure-oriented treatment of malignant lymphoma (ML) is possible even in an advanced stage; however, the progression of drug-induced interstitial lung disease (DILD) sometimes accounts for poor clinical outcomes. This study aims to assess the incidence and clinical characteristics of DILD among patients with ML and compares the serum level of Krebs von den Lungen-6 (KL-6) with that of circulating thymus and activation-regulated chemokine (TARC)/CC chemokine ligand 17 (CCL17) as a diagnostic biomarker for DILD. PATIENTS AND METHODS: Between July 2011 and August 2016, we enrolled 36 patients with ML who were undergoing systemic chemotherapy at our hospital. Then, we evaluated the serum concentration of KL-6 and TARC/CCL17 by a sandwich-type electrochemiluminescence immunoassay and enzyme-linked immunosorbent assay, respectively. RESULTS: DILD developed in 22.2% of patients with ML. All patients recovered immediately after the discontinuation of causative drug and/or glucocorticoid therapy. Although the sensitivity of both TARC/CCL17 and KL-6 was almost equal, the mean concentration of serum KL-6 after the progression of interstitial lung disease was significantly higher than that before progression. CONCLUSION: DILD developed in patients who were treated with first-line rituximab combined regimen. Remarkably, TARC/CCL17 and KL-6 seemed approximately equal as a predictive biomarkers for DILD; however, KL-6 was more specific than TARC/CCL17.

Publication of lung cancer clinical trials in the Japanese Clinical Trial Registry.

INTRODUCTION: Since June 2005, the University Hospital Medical Information Network-Clinical Trial Registry (UMIN-CTR) has been an International Committee of Medical Journal Editors (ICMJE)-approved clinical trial registry in Japan. The number of clinical trials registered in the UMIN-CTR has increased annually. To date, no report exists regarding the publishing of clinical trials registered in the UMIN-CTR. Therefore, we evaluated the publication frequency of clinical trials registered in the UMIN-CTR in Japan. METHODS: We targeted trials that assessed the treatment effect of chemotherapy or molecular targeting drugs for lung cancer. We included trials registered between June 2005 and January 2010, and identified published trials through a computer-based search of MEDLINE and Google Scholar. The cumulative publication rate of the trials was calculated using Kaplan-Meier analysis. RESULTS: In our study, 179 trials met the inclusion criteria. Of these, 46.4% (83/179) trials were published by the end of the cut-off period. With regard to publication, differences existed between the information recorded in the UMIN-CTR database and the actual searched results. The publication rate between groups was insignificantly different; however, whether a clinical study group did or did not conduct a trial differed significantly (53.3% vs. 36.1%; P = 0.024). Phase II studies with positive results were more likely to be published (84.4%); however, the overall publication rate was low (41.8%), which may reflect publication bias. CONCLUSIONS: The UMIN-CTR fundamentally functions as the unique ICMJE-approved clinical trial registry in Japan. However, it seems insufficient to require it as the official clinical database.

Observational study of chemotherapy-induced Clostridium difficile infection in patients with lung cancer.

BACKGROUND: Diarrhea post-antibiotic use is primarily attributed to Clostridium difficile infection (CDI)-induced mucosal lesions, and evidence of CDI in patients undergoing chemotherapy without prior antibiotic treatment is also increasing. However, few studies have investigated the relationship between chemotherapy use and diarrhea. This study aimed to determine whether the incidence of CDI increased in patients with lung cancer undergoing chemotherapy even without prior antibiotic treatment. METHODS: We conducted a retrospective study and investigated the presence of Clostridium difficile (C. difficile) and its toxins in patients who experience diarrhea during chemotherapy. If grade 2 or higher diarrhea was noted, a stool culture was performed to detect anaerobic organisms and C. difficile toxins A and B. RESULTS: A total of 345 consecutive patients (492 in terms of chemotherapy regimens) were enrolled in the study. Grade 2 or higher diarrhea was observed in patients using 36 (7.3%) of these regimens, among which CDI without prior antibiotic exposure was confirmed in patients using 8 regimens (22.2%). CONCLUSIONS: CDI may remain undetected in patients undergoing chemotherapy even in those who had not received antibiotic treatment previously, unless due attention is paid to its possibility. Testing for C. difficile toxins is highly recommended to expedite timely treatment for diarrhea in such patients. Further studies are needed to clarify the relationship between chemotherapy drug use and CDI to facilitate prevention.

Association of Immune-Related Adverse Events with Clinical Benefit in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Nivolumab.

BACKGROUND: Immune-related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study aimed to evaluate whether the development of irAEs correlates with treatment response in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We conducted a retrospective study of patients who received nivolumab monotherapy at Sendai Kousei Hospital (n = 70). The patients were categorized into two groups based on the incidence of irAEs: those with irAEs (irAE group) or those without (non-irAE group). Treatment efficacy was evaluated in each group. The patients were further categorized into responders and nonresponders, and predictive factors of treatment response were determined. RESULTS: The objective response rate was 57% in the irAE group versus 12% in the non-irAE group. Median progression-free survival was 12.0 months in the irAE versus 3.6 months in the non-irAE group. The incidence of both irAEs and pre-existing antithyroid antibody was significantly higher in responders than in nonresponders. Multivariate analysis identified incidence of irAEs and pre-existing antithyroid antibody as an independent predictor of treatment response. CONCLUSION: Objective response rate and progression-free survival were significantly better in the irAE than in the non-irAE group in patients with advanced NSCLC treated with nivolumab monotherapy. The development of irAEs was associated with clinical efficacy, and the presence of pre-existing antithyroid antibody might be correlated with treatment response to nivolumab monotherapy. IMPLICATIONS FOR PRACTICE: Immune-related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study evaluted whether the development of irAEs correlates with treatment response in advanced non-small-cell lung cancer. Results showed that the objective response rate and progression-free survival were significantly better in the patients who developed irAEs than in the patients who did not develop irAEs, and the incidence of irAEs and positivity for antithyroid antibody at pretreatment were independent predictors of treatment response of nivolumab monotherapy. Therefore, the development of irAEs predicts clinical benefit and suggests that cautious management of irAEs can lead to achieving maximum clinical benefit from nivolumab monotherapy.

Patients with osteosarcoma and soft tissue sarcoma might become "cancer refugees" in some Japanese regional cities.

PURPOSE: "Rare cancer" is defined as malignancy with a disease prevalence (age-adjusted incidence rate) of less than six per 100,000 population. Proper treatments which these patients need cannot always be performed unless they find dedicated facilities. Patients tend to be desperate, searching for advice and care. Thus, they are called "cancer refugees". Osteosarcoma and soft tissue sarcoma (OS/STS) are representative rare cancers in Japan. We conducted a retrospective analysis of patients with OS/STS to improve the current treatment modalities in a Japanese regional city. PATIENTS AND METHODS: Twenty-one patients with OS/STS who were hospitalized to receive standard chemotherapy or palliative treatment were enrolled between October 2011 and January 2017. Patients with non-Hodgkin's lymphoma (NHL) and advanced cancer who were treated in the palliative care unit (PCU) of the Kawasaki Medical School General Medical Center were recruited as the control groups. We analyzed the difference in residential area between patients with OS/STS and the control groups. RESULTS: Approximately one-third of patients with OS/STS were referred from hospitals outside of Okayama prefecture. The ratio of patients with OS/STS referred from Okayama city and/or the same medical administration area of Okayama prefecture was lower than that of patients with NHL and advanced cancer who were treated in the PCU. CONCLUSION: Because the medical environment of patients with OS/STS in Japanese local cities has not been consolidated, completing medical care within the patient's own medical administration area is difficult. Thus, some patients with OS/STS may become "cancer refugees" who are unable to receive standard therapy near their residence.

Ceftriaxone-associated pancreatitis captured on serial computed tomography scans.

A 74-year-old man was treated with ceftriaxone for 5 days and subsequently experienced epigastric pain. Computed tomography (CT) was performed 7 and 3 days before epigastralgia. Although the first CT image revealed no radiographic signs in his biliary system, the second CT image revealed dense radiopaque material in the gallbladder lumen. The third CT image, taken at symptom onset, showed high density in the common bile duct and enlargement of the pancreatic head. This is a very rare case of pseudolithiasis involving the common bile duct, as captured on a series of CT images.

Accidental aspiration of denture cleanser tablets caused severe mucosal edema in upper airway.

A 78-year-old man accidentally swallowed denture cleanser tablets (Polident® ). Although he immediately spat them out, he felt difficulty in breathing. Observation using a fiber optic bronchoscope revealed a constricted glottis with edema and redness. The instillation of 1% xylocaine with epinephrine to the epiglottis and larynx reduced the edema and enabled the bronchoscope to pass the glottis. Red and edematous mucosa of the trachea and major bronchus were also observed. We should be aware that accidental aspiration of denture cleansers may cause laryngeal edema.