Cytokine Release Syndrome with Relative Adrenal Insufficiency Induced by Ipilimumab and Nivolumab Combination Therapy for Clear Cell Renal Cell Carcinoma.

Combination therapy with ipilimumab and nivolumab is indicated for many types of cancers; however, several patients experience immune-related adverse events (irAEs). We herein report a case of cytokine release syndrome (CRS) in a 63-year-old woman with stage IV left clear cell renal cell carcinoma. Our patient developed CRS while taking prednisolone, 43 days after the start of ipilimumab and nivolumab administration. The patient was treated with steroid pulse therapy, which improved the symptoms of shock and respiratory failure. Increased vascular permeability and relative adrenal insufficiency are considered to be the main pathogeneses. The early administration of high-dose steroids is crucial as a replacement for corticosteroids.

Exacerbation of Eosinophilic Granulomatosis With Polyangiitis After Administering Dupilumab for Severe Asthma and Eosinophilic Rhinosinusitis With Nasal Polyposis.

Eosinophilic granulomatosis with polyangiitis (EGPA) refers to systemic vasculitis in patients with bronchial asthma and eosinophilic rhinosinusitis. Dupilumab has been approved for the treatment of asthma, eosinophilic rhinosinusitis, and atopic dermatitis. A man in his 50s with a history of asthma and eosinophilic rhinosinusitis with nasal polyposis developed high fever and dyspnea while undergoing dupilumab treatment. Laboratory examinations identified hypereosinophilia. Chest radiography and computed tomography revealed right-sided tracheal dislocation, extensive consolidation, and ground-glass opacities with traction bronchiectasis. Evidence of interstitial pneumonia, eosinophilia, and increased eosinophil counts in the bronchoalveolar lavage fluid was observed. We diagnosed the patient with EGPA and administered corticosteroids, which improved his symptoms and radiographic signs. Although the relationship between EGPA and dupilumab treatment is unclear, EGPA may have been exacerbated by dupilumab in this case. Therefore, when administering dupilumab to patients with partial symptoms of EGPA, care should be taken to monitor for adverse symptom development and exacerbation.

Non-small Cell Lung Cancer With Proto-Oncogene B-Raf V600E Presenting a Distinctive Clinical Course: A Case Report.

Cases of proto-oncogene B-Raf (BRAF) V600E mutation are rare, accounting for 1%-4% of non-small cell lung cancers (NSCLCs), and its clinical features remain unclear. Here, we report a case of BRAF mutation-positive lung adenocarcinoma with an atypical clinical course and long-term survival. The patient was a 63-year-old female nonsmoker who was diagnosed with stage IA adenocarcinoma after surgical resection. Five years after the surgery, cancer recurred and was treated with various cytotoxic anticancer agents. During the course of treatment, the patient was found to be BRAF V600E mutation-positive and was treated with molecular-targeted drugs. Although multiple brain, subcutaneous, and tonsillar metastases appeared, the progression was significantly slower, and the patient survived for 14 years and three months after the diagnosis. There have been few case reports of long-term survival in BRAF-positive lung cancer, and more cases need to be accumulated in the future to gather more information. Based on this case, we speculate that sensitivity to cytotoxic anticancer agents such as pemetrexed (PEM) and maintenance of performance status (PS), in addition to molecular-targeted agents, are important for long-term survival.

Prolonged persistence of SARS-CoV-2 infection during A+AVD therapy for classical Hodgkin's lymphoma: A case report.

We describe a case of coronavirus disease 2019 (COVID-19) in a patient with mixed cellularity classical Hodgkin lymphoma (cHL) undergoing brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) therapy. A 43-year-old man presented to our hospital with a complaint of fever, for which he was diagnosed with COVID-19 after a positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and antiviral therapy with favipiravir and ciclesonide was started subsequently. The fever persisted for the first few days of treatment, but his respiratory status was stable, and he became asymptomatic and afebrile on day 9. Although the PCR tests remained positive, he met the updated discharge criteria of the World Health Organization (WHO) on day 12. However, his fever recurred, and his condition worsened on day 16. A chest X-ray showed a new opacity. It is likely that favipiravir and ciclesonide treatment probably did not completely eliminate the virus in the patient, and therefore the infection persisted. We added remdesivir from day 21, and the improvement was remarkable. He was discharged on day 29 after two consecutive PCR test results were negative. PCR tests are not mandatory for the updated WHO discharge criteria. However, even after antiviral therapy, COVID-19 patients with hematologic malignancies may have prolonged active infection with impaired viral excretion. Depending on the background disease and comorbidities, there may be some patient populations for whom it is not appropriate to simply comply with the current discharge criteria. Therefore, more emphasis may be needed on PCR examinations.

A case of non-small cell lung cancer with danazol-dependent aplastic anemia induced by pembrolizumab.

Programmed cell death protein 1 immune checkpoint inhibitor is an effective treatment for non-small cell lung cancer. Although hematological immune-related adverse events induced by antiprogrammed-cell-death-protein-1 immunotherapy have been reported, they are rare, and there remain many unknowns. We report the case of a 77-year-old woman with non-small cell lung cancer and pembrolizumab-induced danazol-dependent aplastic anemia. Sixteen days after she received pembrolizumab with carboplatin and pemetrexed as first-line treatments, she developed pancytopenia, including severe thrombocytopenia (1 × 109/L) with oral bleeding, epistaxis, and systemic purpura. We initially diagnosed immune-related thrombocytopenia based on an elevated level of platelet-associated immunoglobulin G (922ng/107 cells), but her thrombocytopenia was refractory to prednisolone (1mg/kg) and thrombopoietin receptor agonists. We eventually diagnosed aplastic anemia based on the findings of bone marrow hypoplasia. Treatment with cyclosporine and danazol 300mg (7.5mg/kg) was initiated. Eighteen days later, her blood cell count increased, and we reduced danazol to 100mg. Twenty-four days after the reduction of danazol, her platelet count dropped again to 14 × 109/L; subsequently, increasing danazol improved her platelet count in a few days. Although aplastic anemia was recovered, she died owing to lung cancer progression. In this case, the thrombocytopenia was noticeable initially; however, pancytopenia appeared a month later, and we diagnosed her with aplastic anemia. Platelet counts improved rapidly with the use of danazol. No effective treatment has yet been established for aplastic anemia induced by antiprogrammed-cell-death-protein-1 immunotherapy, but our case suggests that danazol is an effective therapy.

High levels of anti-SSA/Ro antibodies in COVID-19 patients with severe respiratory failure: a case-based review : High levels of anti-SSA/Ro antibodies in COVID-19.

We treated two patients with severe respiratory failure due to coronavirus disease 2019 (COVID-19). Case 1 was a 73-year-old woman, and Case 2 was a 65-year-old-man. Neither of them had a history of autoimmune disease. Chest computed tomography scans before the antiviral therapy showed bilateral multiple patchy ground-glass opacities (GGO) consistent with COVID-19 pneumonia. The GGO regressed over the course of the antiviral treatment; however, new non-segmental patchy consolidations emerged, which resembled those of interstitial lung disease (ILD), specifically collagen vascular disease-associated ILD. We tested the patients' sera for autoantibodies and discovered that both patients had high anti-SSA/Ro antibody titers. In Case 1, the patient recovered with antiviral therapy alone. However, in Case 2, the patient did not improve with antiviral therapy alone but responded well to corticosteroid therapy (methylprednisolone) and made a full recovery. The relationship between some immunological responses and COVID-19 pneumonia exacerbation has been discussed previously; our discovery of the elevation of anti-SSA/Ro antibodies suggests a contribution from autoimmunity functions of the immune system. Although it is unclear whether the elevation of anti-SSA/Ro antibodies was a cause or an outcome of aggravated COVID-19 pneumonia, we hypothesize that both patients developed aggravated the COVID-19 pneumonia due to an autoimmune response. In COVID-19 lung injury, there may be a presence of autoimmunity factors in addition to the known effects of cytokine storms. In patients with COVID-19, a high level of anti-SSA/Ro52 antibodies may be a surrogate marker of pneumonia severity and poor prognosis.

Carcinoembryonic antigen and CYFRA 21-1 responses as prognostic factors in advanced non-small cell lung cancer.

BACKGROUND: It is unclear whether changes in serum tumor marker expression post-treatment are of prognostic value. We investigated the associations between changes in serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) after first-line treatment and overall survival (OS) in non-small cell lung cancer (NSCLC). METHODS: Advanced NSCLC patients (April 2010 to December 2015) with elevated serum CEA or CYFRA 21-1 were included. The associations between tumor marker changes after treatment initiation and OS were analyzed. RESULTS: Ninety-six and 55 patients were CEA- and CYFRA 21-1-positive, respectively. The serum CEA response at 4 months and CYFRA 21-1 responses at 1 and 4 months were significantly associated with OS in the univariate analyses (P=0.025, P=0.016 and P<0.001, respectively). Moreover, in the multivariate analyses, serum CYFRA 21-1 response at 4 months was significantly associated with improved OS (P=0.038). CONCLUSIONS: In NSCLC patients, serum CEA and CYFRA 21-1 responses after treatment initiation may predict longer OS.

Prognostic impact of pleural effusion in EGFR-mutant non-small cell lung cancer patients without brain metastasis.

BACKGROUND: In epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), brain metastasis is known as a poor prognosis factor. However, prognostic factors in the patients without brain metastasis remain unclear. In this study, we aimed to clarify the differences between metastatic site and prognosis in common EGFR-mutant NSCLC patients without brain metastasis. METHODS: Chemotherapy-naïve, advanced EGFR-mutant NSCLC patients without brain metastasis diagnosed between January 2010 and March 2016 were enrolled. We evaluated prognosis according to the presence or absence of bone metastases, liver metastasis, and pleural effusion. RESULTS: A total of 50 EGFR-mutant NSCLC patients without brain metastasis were enrolled. The median progression-free survival and overall survival were significantly shorter in patients with pleural effusion than in those patients without (progression-free survival 7.0 months, 95% confidence interval [CI] 3.7-13.0 vs. 13.0 months, 95% CI 9.1-21.7, hazard ratio [HR] 2.29, 95% CI 1.11-4.73, P = 0.020; overall survival 19.5 months, 95% CI 5.7-28.8 vs. 55.3 months, 95% CI 24.0-not evaluable, HR 3.00, 95% CI 1.35-6.68, P = 0.005). Pleural effusion was an independent factor of poor prognosis for progression-free survival (HR 3.44, 95% CI 1.50-7.88, P = 0.003) and overall survival (HR 2.34, 95% CI 1.00-5.44, P = 0.049). CONCLUSION: Pleural effusion might be a poor prognosis factor for advanced EGFR-mutant NSCLC patients without brain metastasis treated with first-generation EGFR-tyrosine kinase inhibitors. Further precision medicine according to the metastatic site is required.

Pulmonary pleomorphic carcinoma with pseudoprogression during nivolumab therapy and the usefulness of tumor markers: A case report.

Pseudoprogression was reported as one of the unconventional responses during immune checkpoint inhibitor therapy. A 70-year-old man with pulmonary pleomorphic carcinoma received nivolumab therapy. Pleural effusion and pulmonary metastasis increased, however then shrank and serum cytokeratin 19 fragment levels decreased. Serum tumor marker might help to distinguish pseudoprogression.

[REACTIVATION OF TUBERCULOSIS PRESENTING WITH EMPYEMA DUE TO ANTICANCER CHEMOTHERAPY FOR DIFFUSE LARGE B CELL LYMPHOMA].

A 79-year-old man with a history of tuberculosis was found to have chronic empyema in the right lung and was diagnosed with malignant diffuse large-cell lymphoma (Ann Arbor stage IIE). After completion of one course of rituximab plus cyclophosphamide, pirarubicin, vincristine, and prednisolone (R-CHOP) chemotherapy, the patient developed lung abscess and sepsis caused by Streptococcus intermedius. This condition was treated with antimicrobial agents, and chemotherapy was resumed. After the second course, the chemotherapy regimen was continued without prednisolone, and after administration of the third course, a chest wall mass was found in the right lung. An acid-fast bacillus smear test of the abscess aspirate was positive, and Mycobacterium tuberculosis was detected in a polymerase chain reaction assay, leading to a diagnosis of perithoracic tuberculosis. Chemotherapy for the lymphoma was discontinued, and treatment with four oral antitubercular agents was started. This treatment led to remission of perithoracic tuberculosis. In Japan, tuberculous scar and chronic empyema are relatively common findings, and relapse of tuberculosis should always be considered for patients with these findings during chemotherapy and immunosuppressive therapy.

[Henoch-schönlein purpura induced by erlotinib (Tarceva): a case report].

Erlotinib is a newly developed molecular-targeting or molecular-targeted drug with selective inhibitory activity for tyrosine kinase of the epidermal growth factor receptor. A adverse drug reactions including diarrhea, skin eruptions are considered mild. We report a case of recurrent adenocarcinoma of the lung in a 68-year-old woman who suffered from Henoch-Schönlein purpura induced by erlotinib. She received daily administration of erlotinib 150 mg as second-line chemotherapy. Her tumors decreased in size and pleural effusion disappeared, so we considered erlotinib effective. However after 3 months of treatment with erlotinib, the patient presented palpable purpuric lesions mostly located on her lower legs. We diagnosed Henoch-Schönlein purpura based on skin histological findings. Erlotinib was reduced but continued, with improvement of the eruptions. Henoch-Schönlein purpura is often accompanied by systemic manifestations, such as renal disease and arthritis, so more careful follow-up is warranted.

An inhaled inducible nitric oxide synthase inhibitor reduces damage of Candida-induced acute lung injury.

Excessive nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS) aggravates acute lung injury (ALI) by producing peroxynitrite. We previously showed by immunostaining that the expression of iNOS was suppressed by inhalation of N(G)-nitro-L-arginine methyl ester in mice with Candida-induced ALI. This study tested the hypothesis that a novel iNOS inhibitor suppresses not only iNOS expression, but also iNOS messenger RNA (mRNA) production by interrupting a positive feedback loop at the time of NO production in Candida-induced ALI. Mice were pretreated by inhalation of saline or ONO-1714, a selective iNOS inhibitor, and were given an intravenous injection of Candida albicans to induce ALI. After inhalation of 1 mM aerosolized ONO-1714, the nitrite-nitrate concentration in bronchoalveolar lavage fluid (BALF) at 24 h was significantly lower than that after inhalation of saline. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels and neutrophils in BALF were decreased by inhalation of ONO-1714. Inhalation of ONO-1714 markedly suppressed nitrotyrosine production and inhibited the expression of iNOS mRNA as well as proteins in the lung. Survival was prolonged by inhalation of ONO-1714. We conclude that pretreatment with inhaled ONO-1714 suppresses the production of peroxinitrite and decreases oxidative stress associated with peroxinitrite in Candida-induced ALI.

Overexpression of manganese superoxide dismutase by N-acetylcysteine in hyperoxic lung injury.

BACKGROUND: Exposure of animals to hyperoxia causes lung injury, characterized by diffuse alveolar damage and exudation of plasma into the alveolar space. Reactive oxygen species (ROS) play an important role in the development of hyperoxic lung injury. Mitochondrial oxidative phosphorylation is one of the major sources of ROS. N-acetylcysteine (NAC) is a precursor of glutathione (GSH), which functions as an antioxidant by reducing hydrogen peroxide to water and alcohols. NAC has been shown to diminish lung injury in a large variety of animal models. AIM: We elucidated the mechanism underlying the protective effects of NAC in hyperoxia-induced lung injury. METHODS: Male BALB/c mice were exposed to 98% oxygen for 72 h. The mice inhaled NAC or saline twice a day from 72 h before oxygen exposure to the end of experiment. RESULTS: Inhaled NAC increased the GSH level in lung homogenate. NAC also attenuated cellular infiltrations in both bronchoalveolar lavage fluid (BALF) and lung tissue. The total protein level in BALF and the level of 8-isoprostane, a marker of lipid peroxidation, in lung homogenate were decreased by inhalation of NAC. Inhaled NAC induced the overexpression of Mn superoxide dismutase (MnSOD) mRNA and protein, but did not alter the expressions of other antioxidant enzymes, including CuZnSOD, extracellular SOD, and glutathione peroxydase 1. CONCLUSION: These findings suggest that the antioxidant properties of NAC in hyperoxic lung injury involve a decrease in mitochondrial ROS in association with the induction of MnSOD, in addition to its role as a precursor of GSH.

A novel potent inhibitor of inducible nitric oxide synthase, ONO-1714, reduces hyperoxic lung injury in mice.

STUDY OBJECTIVES: High-concentration oxygen therapy is used to treat tissue hypoxia, but hyperoxia causes lung injury. Overproduction of nitric oxide by nitric oxide synthase (NOS) is thought to promote hyperoxic lung injury. The present study was conducted to examine the role of inducible nitric oxide synthase (iNOS) in hyperoxic lung injury in mice. MEASUREMENTS AND RESULTS: Mice were exposed to >98% oxygen for 72 h, and ONO-1714 (0.05 mg/kg) (ONO) was subcutaneously administered to block iNOS. Hyperoxia significantly increased total cell count, protein concentration, and nitrites/nitrates in the bronchoalveolar lavage fluid and proinflammatory cytokines in the lung tissue. ONO significantly prevented the increases in all of these variables. ONO suppressed histologic evidence of lung injury. ONO markedly inhibited iNOS protein expression and nitrotyrosine production in lung homogenates. After exposure to hyperoxia, alveolar epithelial cells stained positively for 8-hydroxy-2'-deoxyguanosine, a proper marker of oxidative DNA damage by reactive oxygen species. ONO attenuated this finding. CONCLUSIONS: NOS play important roles in the pathogenesis of hyperoxic lung injury. Selective iNOS inhibitors may be useful for the treatment of hyperoxic lung injury.

[Spinal cord metastases in lung cancer: a clinical review of four cases].

We report 4 cases of spinal cord metastases of lung cancer detected by MRI. Histologically, 3 of the 4 cases were small cell carcinoma and the other was adenocarcinoma. All 3 cases of small cell carcinoma had neoplastic meningitis. MRI taken in these cases showed the multiple nodules in the cauda equina, which were seeded from brain metastases. One of them had intramedullary spinal cord metastases, which appeared as enlargement of the spinal cord or nodules in the spinal cord on MRI. Leg paralysis and incontinence progressed in all cases. The other case of adenocarcinoma had epidural spinal cord compression due to spinal metastasis. In this case irradiation and corticosteroids relieved her leg and back pain. Spinal cord metastases should be considered as a differential diagnosis in patients with numbness, pain or weakness in the extremities.

[A case of sarcoidosis with diffuse pulmonary arteriovenous malformations].

A 27-year-old woman was admitted because of right dry eye and blurred vision. She was given a diagnosis of uveitis due to sarcoidosis. Chest X-ray film showed bilateral hilar lymphadenopathy and multiple nodules in both lungs. The nodules were considered to be associated with sarcoidosis. However chest CT demonstrated that the nodules were well-defined and connected with two vessels. We diagnosed diffuse pulmonary arteriovenous malformations (AVMs) by 3D-CT. In three of sixteen AVMs, the feeding vessels were more than 3 mm wide in diameter on pulmonary arteriography, and those were embolized by platinum coils. The embolotherapy of diffuse AVMs could not ameliorate the shunt fraction sufficiently, but should reduce the possibility of the catastrophic complication of brain abscess.

Fluoroscopy-guided barium marking for localizing small pulmonary lesions before video-assisted thoracic surgery.

PURPOSE: To evaluate the effectiveness of fluoroscopy-guided barium marking for localization of small peripheral pulmonary lesions before video-assisted thoracic surgery (VATS) resection. MATERIAL & METHODS: Twenty-one patients with peripheral pulmonary lesions 15 mm or less in diameter who were scheduled to undergo VATS resection were studied. A catheter was inserted bronchoscopically into the target segment and guided to a presumed lesion. The tip of the catheter was confirmed fluoroscopically to be at the exact spot determined beforehand. A 50% (weight/volume) barium sulfate suspension was instilled into the bronchus through the catheter, and the site of barium marking was ascertained by CT scanning. RESULTS: The average instilled volume of barium was 0.42+/-0.07 ml. On CT scans, barium spots were superimposed on the target lesions in 19 of the 21 patients and were only 6-7 mm from the lesions in the other 2. Barium was well preserved in all patients at the time of VATS resection. A mild cough persisted for about 1 week in one patient, but the other patients had no specific complications. CONCLUSION: Fluoroscopy-guided barium marking is a safe, convenient, and reliable method for localization of small pulmonary lesions before VATS resection.

[Severe asthma complicated with large mucoid impaction: successful removal with balloon catheter].

A 28-year-old woman was hospitalized for renal transplantation. She suffered an asthma attack after transplantation. Once this attack had ended after medical treatment, she again experienced dyspnea after the 11th treatment day. A chest CT showed mucoid impaction in the left main bronchus, atelectasis in the left lower lobe, and pneumomediastinum. A huge mucoid impaction was removed with a balloon catheter under mechanical ventilation without exacerbation of the mediastinal emphysema. Mucoid impaction should be taken into account as a cause of dyspnea in severe asthma if the maximum dose of beta-stimulant is not effective.

[Six cases of thymic carcinoma: a clinical review].

Thymic carcinoma is rarer than thymoma and carries a very poor prognosis. No standard treatment has yet been established. Chemotherapy and radiation therapy are usually given to patients in whom surgery is not indicated. We clinically review six patients with thymic carcinoma (three men and three women) who were admitted to our hospital from 1992 through 2002. Their ages ranged from 56 to 81 years (median 70.5). Four patients had chest pain, two were unable to swallow, and in one, who was asymptomatic, the tumor was detected by chance. Histologically, five cases were squamous cell carcinomas, and one was a lymphoepithelioma-like carcinoma. Four of the six patients had distant metastasis at diagnosis. Only one patient was able to undergo surgery, two received radiation therapy alone, and three were administered chemoradiation. The response to the chemoradiation was progression of the disease in two patients and no change in one. The response to radiation therapy was partial response in one patient and no change in one. In summary, chest pain is the most common symptom of thymic carcinoma. A symptomatic case suggests a poor prognosis resulting from the clinical behavior of thymic carcinoma, such as early distant metastasis or direct invasion of surrounding organs. Histologically, squamous cell carcinoma is the most common, and thymic carcinoma appears to be generally resistant to chemotherapy and radiotherapy.