Cytokine release syndrome following durvalumab and tremelimumab in advanced hepatocellular carcinoma: A case report with cytokine and damage-associated molecular pattern analysis.

Cytokine release syndrome (CRS) is a systemic inflammatory syndrome that causes fatal circulatory failure due to hypercytokinemia, and subsequent immune cell hyperactivation caused by therapeutic agents, pathogens, cancers, and autoimmune diseases. In recent years, CRS has emerged as a rare, but significant, immune-related adverse event linked to immune checkpoint inhibitor therapy. Furthermore, several previous studies suggested that damage-associated molecular patterns (DAMPs) could be involved in malignancy-related CRS. In this study, we present a case of severe CRS following combination therapy with durvalumab and tremelimumab for advanced hepatocellular carcinoma, which recurred during treatment, as well as an analysis of cytokine and DAMPs trends. A 35-year-old woman diagnosed with hepatocellular carcinoma underwent a partial hepatectomy. Due to cancer recurrence, she started a combination of durvalumab and tremelimumab. Then, 29 days post-administration, she developed fever and headache, initially suspected as sepsis. Despite antibiotics, her condition worsened, leading to disseminated intravascular coagulation and hemophagocytic syndrome. The clinical course and elevated serum interleukin-6 levels led to a CRS diagnosis. Steroid pulse therapy was administered, resulting in temporary improvement. However, she relapsed with increased interleukin-6, prompting tocilizumab treatment. Her condition improved, and she was discharged on day 22. Measurements of inflammatory cytokines interferon-γ, tumor necrosis factor-α, and DAMPs, along with interleukin-6, using preserved serum samples, confirmed marked elevation at CRS onset. CRS can occur after the administration of any immune checkpoint inhibitor, with the most likely trigger being the release of DAMPs associated with tumor collapse.

Advanced Lung Adenocarcinoma with Nivolumab-associated Dermatomyositis.

We herein report a 42-year-old man with advanced lung adenocarcinoma and nivolumab-associated dermatomyositis. Nivolumab, an anticancer drug that is classified as an immune checkpoint inhibitor, often induces immune-related adverse events (irAEs). However, there have so far been no reports regarding nivolumab-associated dermatomyositis. This patient was diagnosed with dermatomyositis due to the presence of proximal muscle weakness with abnormal electromyography and magnetic resonance imaging findings; skin lesions, such as heliotrope rash, shawl sign, and periungual erythema; and an elevated serum aldolase level after nivolumab administration. It is important to consider drug-associated dermatomyositis in the differential diagnosis of patients presenting with skin lesions and muscle weakness after nivolumab treatment.

Early-stage diffuse panbronchiolitis in a young patient confirmed by video-assisted lung biopsy: A case report.

A 29-year-old man presented with sputum and cough, which were pointed out by his neighbors. A high-resolution chest computed tomography scan showed well-defined multiple centrilobular nodules and a tree-in-bud pattern. Chest auscultation revealed coarse crackles. He did not report any nasal sinus symptoms. We subsequently performed a video-assisted lung biopsy; the specimen confirmed diffuse panbronchiolitis. Subsequently, sinusitis was confirmed by an otolaryngologist. His symptoms gradually improved following treatment with erythromycin. We report a case of early-stage diffuse panbronchiolitis in a young patient, with multiple intralobular nodules, no bronchiectasis, and a good clinical course.

Distinct Benefit of Overall Survival between Patients with Non-Small-Cell Lung Cancer Harboring EGFR Exon 19 Deletion and Exon 21 L858R Substitution.

BACKGROUND: Exon 19 deletion (Del19) and exon 21 L858R substitution (L858R), which account for 90% of epidermal growth factor receptor (EGFR) mutations as common mutations, are associated with favorable outcomes with EGFR-tyrosine kinase inhibitors (TKIs) compared with other uncommon EGFR mutations in non-small-cell lung cancer (NSCLC). However, whether there are differences in overall survival (OS) between patients with these common EGFR mutations remains controversial. METHODS: The subjects studied were 74 NSCLC patients with common EGFR mutations treated with gefitinib or erlotinib. Using univariate and multivariate analyses, we retrospectively compared the clinicopahological characteristics of patients harboring Del19 with those harboring L858R. RESULTS: Compared with patients harboring L858R, EGFR-TKIs provided a significant OS benefit in patients harboring Del19 (p = 0.024), as well as favorable therapeutic responses (p = 0.045) and progression-free survival (PFS) benefits (p = 0.031). In multivariate analyses, Del19 was independently associated with PFS (p = 0.029) and OS (p = 0.009), whereas no parameters other than pleural dissemination at the initial treatment were associated with EGFR mutation types. CONCLUSION: Del19 and L858R have distinct prognostic implications and may require individual therapeutic strategies.

A comparison of head-out mist bathing, with or without facial fanning, with head-out half-body low-water level bathing in humans--a pilot study.

To reduce the risks of Japanese-style bathing, half-body bathing (HBLB) has been recommended in Japan, but discomfort due to the cold environment in winter prevents its widespread adoption. The development of the mist sauna, which causes a gradual core temperature rise with sufficient thermal comfort, has reduced the demerits of HBLB. We examined head-out 42 °C mist bathing with 38 °C HBLB up to the navel to see if it could improve thermal comfort without detracting from the merits of HBLB, with and without the effects of facial fanning (FF). The subjects were seven healthy males aged 22-25 years. The following bathing styles were provided: (1) HBLB-head-out half-body low bathing of 38 °C up to the navel (20 min); (2) HOMB-head-out mist bathing of 42 °C and HBLB of 38 °C (20 min); and (3) HOMBFF-HOMB with FF (20 min). HOMB raised the core temperature gradually. HOMBFF suppressed the core temperature rise in a similar fashion to HOMB. Increases in blood pressure and heart rate usually observed in Japanese traditional-style bathing were less marked in HOMBs with no significant difference with and without FF. The greatest body weight loss was observed after Japanese traditional-style bathing, with only one-third of this amount lost after mist bathing, and one-sixth after HBLB. HOMB increased thermal sensation, and FF also enhanced post-bathing invigoration. We conclude that HOMB reduces the risks of Japanese traditional style bathing by mitigating marked changes in the core temperature and hemodynamics, and FF provides thermal comfort and invigoration.

Effects of isotonic and isometric exercises with mist sauna bathing on cardiovascular, thermoregulatory, and metabolic functions.

To clarify the effects of isometric and isotonic exercise during mist sauna bathing on the cardiovascular function, thermoregulatory function, and metabolism, six healthy young men (22 ± 1 years old, height 173 ± 4 cm, weight 65.0 ± 5.0 kg) were exposed to a mist sauna for 10 min at a temperature of 40 °C, and relative humidity of 100 % while performing or not performing ∼30 W of isometric or isotonic exercise. The effect of the exercise was assessed by measuring tympanic temperature, heart rate, systolic and diastolic blood pressure, chest sweat rate, chest skin blood flow, and plasma catecholamine and cortisol, glucose, lactate, and free fatty acid levels. Repeated measures ANOVA showed no significant differences in blood pressure, skin blood flow, sweat rate, and total amount of sweating. Tympanic temperature increased more during isotonic exercise, and heart rate increase was more marked during isotonic exercise. The changes in lactate indicated that fatigue was not very great during isometric exercise. The glucose level indicated greater energy expenditure during isometric exercise. The free fatty acid and catecholamine levels indicated that isometric exercise did not result in very great energy expenditure and stress, respectively. The results for isotonic exercise of a decrease in lactate level and an increase in plasma free fatty acid level indicated that fatigue and energy expenditure were rather large while the perceived stress was comparatively low. We concluded that isotonic exercise may be a more desirable form of exercise during mist sauna bathing given the changes in glucose and free fatty acid levels.

Rapidly progressive respiratory failure in mixed connective tissue disease: report of an autopsy case.

A 64-year-old woman presented with exertional dyspnea. The case was diagnosed as mixed connective tissue disease (MCTD) due to presence of swollen fingers, Raynaud's phenomenon, muscle weakness, positive anti-U1RNP antibody, pericarditis and interstitial pneumonia. Although the histology from a transbronchial lung biopsy (TBLB) indicated organizing pneumonia, corticosteroid therapy was postponed for two months at the patient's request. She died 8 weeks later from acute progressive interstitial pneumonia in spite of the administration of intravenous cyclophosphamide combined with prednisolone. The autopsy revealed exudative and organizing diffuse alveolar damage (DAD). Previous reports have shown that DAD is an extremely rare pulmonary complication in MCTD. This report presents a case of MCTD with acute respiratory failure. This case thus suggests that this therapy should be administered as soon as possible.

Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma in Sjögren's syndrome showing only the LIP pattern radiologically.

A 49-year-old woman with a 20-year history of Sjögren's syndrome (SS) was incidentally found to have an abnormal chest X-ray along with dyspnea and desaturation. Chest CT findings showed multiple cystic shadows, ground glass opacity, and small nodule-like lymphocytic interstitial pneumonia (LIP), which have been previously reported. She was diagnosed by surgical lung biopsy to have mucosa-associated lymphoid tissue (MALT) lymphoma. It was difficult to detect the presence of lymphoma by the use of only CT findings. Pulmonary involvement of SS occurs in various forms so that SS patients with pulmonary involvement should undergo open biopsy to reach a definitive diagnosis.

Mammalian target of rapamycin: a central node of complex signaling cascades.

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth and metabolism in response to diverse external stimuli. In the presence of mitogenic stimuli, mTOR transduces signals that activate the translational machinery and promote cell growth. mTOR functions as a central node in a complex net of signaling pathways that are involved both in normal physiological, as well as pathogenic events. mTOR signaling occurs in concert with upstream Akt and tuberous sclerosis complex (TSC) and several downstream effectors. During the past few decades, the mTOR-mediated pathway has been shown to promote tumorigenesis through the coordinated phosphorylation of proteins that directly regulate cell-cycle progression and metabolism, as well as transcription factors that regulate the expression of genes involved in the oncogenic processes. The importance of mTOR signaling in oncology is now widely accepted, and agents that selectively target mTOR have been developed as anti-cancer drugs. In this review, we highlight the past research on mTOR, including clinical and pathological analyses, and describe its molecular mechanisms of signaling, and its roles in the physiology and pathology of human diseases, particularly, lung carcinomas. We also discuss strategies that might lead to more effective clinical treatments of several diseases by targeting mTOR.

Pathological findings and pulmonary dysfunction after acute respiratory distress syndrome for 5 years.

We report the pathological findings of the lung after acute respiratory distress syndrome (ARDS), and pulmonary function tests during five years of follow-up. A 39-year-old woman, treated for acute myelogenous leukemia, developed ARDS. She recovered from ARDS but suffered from pulmonary aspergillosis. Her aspergilloma was removed surgically. Her lung function tests and diffusing capacity of the lung for carbon monoxide (DL(CO)) improved but diffusion impairment remained five years after recovery. Pathological examination of the resected material showed sclerosis in lobular septa and scattered fibrosis in alveolar ducts except for the aspergillosis. These fibrotic changes may be causally associated with her loss of DL(CO).

Tracheobronchitis in a patient with Crohn's disease.

A 19-year-old Japanese man who had been diagnosed with Crohn's disease (CD) suffered from dry cough and fever over 38 degrees C for three days prior to hospitalization. On admission, his colonic CD condition was stable, neither active nor in remission. Computed tomography of the chest showed small elevated tracheobronchial lesions. Bronchoscopy showed diffuse whitish granular lesions in the trachea and bronchi. The pathological findings in the biopsy showed inflammatory infiltration suggesting Crohn's tracheobronchitis. Thereafter, he was treated with inhaled Fluticasone propionate 400 microg/day. After one week his dry cough improved, and after two weeks bronchoscopic findings were improved.

[A rare case of primary Sjögren's syndrome complicated by secondary lymphoid interstitial pneumonia].

A 61-year-old woman was referred to our hospital because of an abnormal chest X-ray shadow. She was diagnosed as having primary Sjögren's syndrome based on sicca syndrome, polyclonal hyper-gamma-globulinemia, and positive results for anti-Ro/SS-A and anti-La/SS-B antibodies. Her chest CT scan revealed bilateral ground-glass shadows and septal thickning in the lower lung field (Fig. 2a). Biopsy specimens obtained by video-assisted thoracoscopy (VATS) showed a dense interstitial lymphoid infiltrate, including lymphocytes and plasma cells, predominantly in the alveolar septae (Fig. 3, a-c). Malignant lymphoma was excluded on the basis of immunohistopathological studies (Fig. 4). A diagnosis of lymphoid interstitial pneumonia was made according to the 2002 American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification (International Classification). After administration of prednisolone and azathioprin, the ground-glass shadows on the chest CT rapidly improved (Fig. 2b). The clinico-radiologic-pathologic diagnosis based on the VATS procedure and the International Classification is appropriate and effective for treating collagen vascular disease-associated interstitial lung disease.

[A case of desquamative interstitial pneumonia in the fibrotic stage].

A 39-year-old man with bronchial asthma was admitted because of fever, muscle pain and body weight loss. Chest CT showed ground-glass opacification, multiple lung cysts and fine reticulation with traction bronchiectasis predominantly in the bilateral lower lobes. Histopathological findings from video-assisted thoracoscopic surgical biopsy showed severe fibrosis of the alveolar wall, interstitial fibrosis which appeared to be of similar duration, and accumulation of eosinophils and macrophages in the alveolar spaces. According to the ATS consensus classification of desquamative interstitial pneumonia (DIP), there is little fibrosis with only mild or moderate thickening of alveolar walls and no scarring fibrosis causing remodeling of the lung architecture. This case was compatible with the ATS consensus classification of desquamative interstitial pneumonia (DIP) without severe fibrosis of the alveolar wall. Finally, we diagnosed DIP in the fibrosing stage because the findings of chest CT were typical and the pathological findings showed the presence of increased amounts of cuboidal epithelium hyperplasia and intraalveolar acidophilic macrophages within a part of moderate interstitial fiblosis. Then we started orally corticosteroid therapy, and as a result he responded well.

Psycho-educational Horseback Riding to Facilitate Communication Ability of Children with Pervasive Developmental Disorders.

In this study, we applied a novel psycho-educational horseback riding (PEHR) program to the treatment of four Japanese children with pervasive developmental disorders (PDD) in order to facilitate the acquisition of verbal and nonverbal communication skills. The behavioral changes in each child were evaluated using a psychological and behavioral scale. The scale for evaluating the effect of Human-Equips-Interaction on Mental activity (HEIM scale) was designed to assess the behavioral improvement of children based on the following 10 items: Human relationships, Imitation, Emotional expression, Sudden physical movement, Fixative behavior, Adaptation to change, Visual response, Fear or nervousness, and Verbal and nonverbal communication. After taking part in the PEHR program for several months, all subjects showed remarkably improved HEIM scores and marked improvements were observed in eye contact with others (instructors, side walkers, and leaders) in the riding area. A statistical difference was found in items 1, 2, 3, 6, 7, 8, and 9. However, no statistical difference was found in items 4, 5, and 10. As the program progressed, the children showed enhanced verbal and nonverbal communication skills, and became more expressive in their emotional and empathetic interaction with their parents. These observations suggest that the normal functioning of pleasurable emotions and empathy may facilitate further improvements in joint attention, imitation and empathy, and may result in successful verbal expression by PDD children. Therefore, horseback riding can play a very important role in the psycho-educational support required for the communication ability of PDD children.

[A case of airway-limiting type relapsing polychondritis].

A 59-year-old woman was referred to our hospital for chronic cough and myalgia. Polymyalgia rheumatica (PMR) and bronchial asthma were first diagnosed, and she was prescribed 15 mg/day prednisolone. PMR improved immediately. However, her chronic cough continued, and wheezing was heard on chest auscultation. The flow-volume loop showed a severe expiratory flow limitation and a notching sign at early expiration. Diffuse thickening and narrowing at the trachea and bilateral main bronchus were shown on chest CT. On flexible bronchoscope the trachea and bilateral main bronchus collapsed on expiration. We suspected relapsing polychondritis (RP), but she had no findings of saddle nose or deformity of the external ear. Therefore, biopsy of the tracheal cartilage was done. RP was diagnosed by the modified criteria of Damiani and the histology confirmed degeneration of the tracheal cartilage. She was treated by high dose corticosteroids, and her symptoms improved. This case report emphasizes the need to consider the possibility of RP as a cause of chronic cough or intractable asthma.