Amino acid influx via LAT1 regulates iron demand and sensitivity to PPMX-T003 of aggressive natural killer cell leukemia.

Aggressive natural killer cell leukemia (ANKL) is a rare hematological malignancy with a fulminant clinical course. Our previous study revealed that ANKL cells proliferate predominantly in the liver sinusoids and strongly depend on transferrin supplementation. In addition, we demonstrated that liver-resident ANKL cells are sensitive to PPMX-T003, an anti-human transferrin receptor 1 inhibitory antibody, whereas spleen-resident ANKL cells are resistant to transferrin receptor 1 inhibition. However, the microenvironmental factors that regulate the iron dependency of ANKL cells remain unclear. In this study, we first revealed that the anti-neoplastic effect of PPMX-T003 was characterized by DNA double-strand breaks in a DNA replication-dependent manner, similar to conventional cytotoxic agents. We also found that the influx of extracellular amino acids via LAT1 stimulated sensitivity to PPMX-T003. Taken together, we discovered that the amount of extracellular amino acid influx through LAT1 was the key environmental factor determining the iron dependency of ANKL cells via adjustment of their mTOR/Myc activity, which provides a good explanation for the different sensitivity to PPMX-T003 between liver- and spleen-resident ANKL cells, as the liver sinusoid contains abundant amino acids absorbed from the gut.

Two cases of idiopathic pulmonary fibrosis evaluated by dynamic digital radiography for diaphragmatic motion and disease progression.

Forced vital capacity has been utilized as a parameter of disease progression in idiopathic pulmonary fibrosis (IPF); however, its measurement is difficult when patients do not understand or cooperate. Dynamic digital radiography (DDR) enables sequential chest X-ray imaging during breathing, with lower radiation doses compared to conventional fluoroscopy or computed tomography. There is accumulating evidence showing that parameters obtained from DDR, particularly those related to diaphragmatic dynamics, are correlated with pulmonary function parameters, and are useful for pathophysiological evaluation. We herein present two cases that suggest parameters obtained from DDR during supine normal tidal breathing may predict disease progression of IPF.

Real-world clinical outcomes of treatment with molnupiravir for patients with mild-to-moderate coronavirus disease 2019 during the Omicron variant pandemic.

It is unclear whether molnupiravir has a beneficial effect on vaccinated patients infected with the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We here evaluated the efficacy of molnupiravir in patients with mild-to-moderate coronavirus disease 2019 (COVID-19) during the Omicron variant surge in Fukushima Prefecture, Japan. We enrolled patients with mild-to-moderate COVID-19 who were admitted to hospitals between January and April, 2022. Clinical deterioration after admission was compared between molnupiravir users (n = 230) and non-users (n = 690) after 1:3 propensity score matching. Additionally, we performed forward stepwise multivariate logistic regression analysis to evaluate the association between clinical deterioration after admission and molnupiravir treatment in the 1:3 propensity score-matched subjects. The characteristics of participants in both groups were balanced as indicated by covariates with a standardized mean difference of < 0.1. Regarding comorbidities, there was no imbalance between the two groups, except for the presence of hypertension, dyslipidemia, diabetes mellitus, and cardiac disease. The clinical deterioration rate was significantly lower in the molnupiravir users compared to the non-users (3.90% vs 8.40%; P = 0.034). Multivariate logistic regression analysis demonstrated that receiving molnupiravir was a factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.206-0.973; P = 0.042), independent of other covariates. This real-world study demonstrates that molnupiravir contributes to the prevention of deterioration in COVID-19 patients after hospitalization during the Omicron variant phase.

Transport Form and Pathway from the Intestine to the Peripheral Tissues and the Intestinal Absorption and Metabolism Properties of Oleamide.

This study aimed to obtain information on the transport form and pathway from the intestine to the peripheral tissues and on the intestinal absorption and metabolism properties of oleamide (cis-9-octadecenamide). Oleamide was primarily transported via the portal vein. Density gradient centrifugation indicated that plasma oleamide was enriched in the fractions containing albumin in the portal and peripheral blood. Oleamide formed a complex with albumin in an endothermic reaction (apparent Kd = 4.4 µM). The CD36 inhibitor inhibited the oleamide uptake into the intestinal epithelial Caco-2 cells, and oleamide decreased the cell surface CD36 level. The fatty acid amide hydrolase (FAAH) inhibitor increased the transepithelial transport of oleamide across Caco-2 cells and the plasma oleamide concentration in mice intragastrically administered with oleamide. These results indicate that oleamide is transported primarily via the portal vein as a complex with albumin. Furthermore, we suggest that oleamide is taken up via CD36 in the small intestine and degraded intracellularly by FAAH.

Clinical effect of early administration of tocilizumab following the initiation of corticosteroid therapy for patients with COVID-19.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in Wuhan in December 2019, and has since caused a global pandemic. The efficacy of several drugs has been evaluated, and it is now evident that tocilizumab has a beneficial effect, especially combined with corticosteroids, in patients with Coronavirus Disease 2019 (COVID-19). However, the optimal timing of tocilizumab administration has not yet been established. The goal of the present study was to determine the optimal timing of tocilizumab administration after starting corticosteroid therapy in patients with COVID-19. METHODS: We retrospectively analyzed the clinical characteristics of patients who were hospitalized for COVID-19 and treated with tocilizumab and corticosteroids in our hospital. The patients were divided into concurrent and sequential groups. The concurrent group received tocilizumab ≤24 h after corticosteroids, and the sequential group received tocilizumab >24 h after corticosteroid administration. RESULTS: The baseline clinical characteristics of tocilizumab administration were similar between the two groups. White blood cell counts were significantly lower and C-reactive protein levels were significantly higher in the concurrent group than the sequential group. In the concurrent group, tocilizumab administration led to a significant decrease in maximum body temperature. In addition, there were significantly more oxygen-free days in the concurrent group than in the sequential group. However, survival rate was not significantly different between the concurrent and the sequential groups. CONCLUSIONS: In the combination therapy with tocilizumab and corticosteroids, early administration of tocilizumab after starting corticosteroid treatment is effective when treating COVID-19.

Real-world clinical outcomes of treatment with casirivimab-imdevimab among patients with mild-to-moderate coronavirus disease 2019 during the Delta variant pandemic.

Background: Mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may reduce the efficacy of neutralizing monoclonal antibody therapy against coronavirus disease 2019 (COVID-19). We here evaluated the efficacy of casirivimab-imdevimab in patients with mild-to-moderate COVID-19 during the Delta variant surge in Fukushima Prefecture, Japan. Methods: We enrolled 949 patients with mild-to-moderate COVID-19 who were admitted to hospital between July 24, 2021 and September 30, 2021. Clinical deterioration after admission was compared between casirivimab-imdevimab users (n = 314) and non-users (n = 635). Results: The casirivimab-imdevimab users were older (P < 0.0001), had higher body temperature (≥ 38°C) (P < 0.0001) and greater rates of history of cigarette smoking (P = 0.0068), hypertension (P = 0.0004), obesity (P < 0.0001), and dyslipidemia (P < 0.0001) than the non-users. Multivariate logistic regression analysis demonstrated that receiving casirivimab-imdevimab was an independent factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.263-0.763; P = 0.0023). Furthermore, in 222 patients who were selected from each group after matching on the propensity score, deterioration was significantly lower among those receiving casirivimab-imdevimab compared to those not receiving casirivimab-imdevimab (7.66% vs 14.0%; p = 0.021). Conclusion: This real-world study demonstrates that casirivimab-imdevimab contributes to the prevention of deterioration in COVID-19 patients after hospitalization during a Delta variant surge.

Development of dermatomyositis after anti-transcriptional intermediary factor 1-γ antibody seroconversion during treatment for small cell lung cancer.

BACKGROUND: Inflammatory myositis, such as dermatomyositis, is sometimes complicated by cancer and is recognized as cancer-associated myositis. Although some autoimmune antibodies are considered to be involved in the development of myositis in cancer patients, the precise mechanism has not been clarified. The findings of the present case shed light on the mechanism by which anti-transcriptional intermediary factor 1 (TIF1)-γ Ab was produced and the pathogenesis of cancer-associated myositis. CASE PRESENTATION: We describe a case of dermatomyositis that developed in a 67-year-old man who had been diagnosed with small cell lung cancer of clinical T4N3M0 stage IIIB/limited disease during treatment. He received systemic chemotherapy and radiation therapy, and dermatomyositis developed along with a significant decrease in tumor size. TIF1-γ Ab, which is one of the myositis-specific antibodies, was found to be seroconverted. In addition, immunohistochemical analysis showed that cancer cells were positive for the TIF1-γ antigen. CONCLUSION: The findings of the present case suggest that transcriptional intermediary factor 1-γ, which is released from tumor cells, induces the production of TIF1-γ Ab, leading to the development of dermatomyositis.

Usefulness of diurnal variation of fractional exhaled nitric oxide for predicting early therapeutic response to asthma treatment.

OBJECTIVE: Fractional exhaled nitric oxide (FeNO) is considered to be an adjunct for asthma management, although its usefulness remains controversial. Therefore, it may be necessary for new approaches to use FeNO for asthma management. We evaluated whether diurnal variations of FeNO can predict response to asthma treatment. METHODS: This pilot study consisted of 22 uncontrolled asthmatics and 16 healthy subjects. FeNO and peak expiratory flow (PEF) were measured by themselves twice daily at home for three weeks (asthmatics) or two weeks (healthy subjects), and daily mean and diurnal variations of FeNO and PEF levels were calculated. In uncontrolled asthmatics, treatment was intensified a week after study entry, and then control status was reevaluated after three to four weeks. Asthmatics were then divided into two groups; good or poor responders. RESULTS: Diurnal variations of FeNO levels, as well as daily mean FeNO and PEF levels, in uncontrolled asthmatics before intensive treatment were significantly higher than those in healthy subjects, regardless of treatment response (p < 0.01). Furthermore, in the good responders, diurnal variations of FeNO levels were significantly decreased in the 1st week (p < 0.05) of intensive treatment, whereas the daily mean FeNO levels significantly dropped in the 2nd week (p < 0.05). In the poor responders, no such changes were observed in FeNO levels. In terms of PEF, only the daily mean levels were significantly elevated after the initiation of intensive treatment, regardless of treatment response. CONCLUSIONS: Diurnal variations of FeNO may contribute to predicting early therapeutic response to asthma treatment.

Styrene Maleic Acid Copolymer-Based Micellar Formation of Temoporfin (SMA@ mTHPC) Behaves as A Nanoprobe for Tumor-Targeted Photodynamic Therapy with A Superior Safety.

Tumor-targeted photodynamic therapy (PDT) using polymeric photosensitizers is a promising anticancer therapeutic strategy. Previously, we developed several polymeric nanoprobes for PDT using different polymers and PDT agents. In the study, we synthesized a styrene maleic acid copolymer (SMA) micelle encapsulating temoporfin (mTHPC) that is a clinically used PDT drug, SMA@mTHPC, with a hydrodynamic size of 98 nm, which showed high water solubility. SMA@mTHPC maintained stable micelle formation in physiological aqueous solutions including serum; however, the micelles could be disrupted in the presence of detergent (e.g., Tween 20) as well as lecithin, the major component of cell membrane, suggesting micelles will be destroyed and free mTHPC will be released during intracellular uptake. SMA@mTHPC showed a pH-dependent release profile, for which a constant release of ≈20% per day was found at pH 7.4, and much more release occurred at acidic pH (e.g., 6.5, 5.5), suggesting extensive release of free mTHPC could occur in the weak acidic environment of a tumor and further during internalization into tumor cells. In vitro cytotoxicity assay showed a lower cytotoxicity of SMA@mTHPC than free mTHPC; however, similar in vivo antitumor effects were observed by both SMA@mTHPC and free THPC. More importantly, severe side effects (e.g., body weight loss, death of the mice) were found during free mTHPC treatment, whereas no apparent side effects were observed for SMA@mTHPC. The superior safety profile of SMA@mTHPC was mostly due to its micelle formation and the enhanced permeability and retention (EPR) effect-based tumor accumulation, as well as the tumor environment-responsive release properties. These findings suggested SMA@mTHPC may become a good candidate drug for targeted PDT with high safety.

Efficacy of early antifibrotic treatment for idiopathic pulmonary fibrosis.

BACKGROUND: Although antifibrotic drugs, including nintedanib and pirfenidone, slow the progression of idiopathic pulmonary fibrosis (IPF), there is little data about the timing of start of antifibrotic treatment in real-world clinical practice. The present study aimed to clarify the efficacy of nintedanib and pirfenidone in patients with early-stage IPF. METHODS: We compared survival and disease progression between patients with IPF with Japanese Respiratory Society (JRS) disease severity system stage I with and without oxygen desaturation on the 6-min walk test (6MWT) and increased the gender-age-physiology (GAP) staging. We examined the efficacy of antifibrotic drugs in patients with early-stage IPF. RESULTS: The severity of stage I IPF (n = 179) according to the JRS criteria consisted of the following GAP staging criteria: stage I, 111 cases; stage II, 58 cases; stage III, 10 cases. The duration from the initial visit to disease progression and survival time was significantly shorter in JRS stage I patients with oxygen desaturation on the 6MWT or with increased GAP staging (unfavorable group) compared with patients without those factors. In the unfavorable group, the relative decline in percentage predicted forced vital capacity (%FVC) over 6 months was significantly lower in patients undergoing antifibrotic treatment compared with non-treated patients. CONCLUSION: Antifibrotic drugs have a beneficial effect on the decline in %FVC in Japanese patients with early-stage IPF who have oxygen desaturation on the 6MWT or increased GAP staging.

[Associations between psychological attitudes toward exercise and fitness club membership resignation among new members: A cohort study].

Objectives　Approximately 40% of new fitness club (FC) members drop out within the first six months; however, the factors associated with FC membership resignation are largely unknown. This study aimed to identify the association between psychological attitudes toward exercise and FC membership resignation.Methods　We conducted a cohort study enrolling participants from 17 FCs. All individuals who became members at FCs between April 1st, 2015 and March 31st, 2016 (n=5,421) were invited to participate in the study, and those who agreed to participate completed a self-administered baseline questionnaire (n=2,934). We excluded participants aged <20 years (n=167) and those with missing values (n=702). Psychological factors were evaluated using the short version of the perceived benefit and barriers to exercise scale. Participants were followed until September 30th, 2016, at which time we assessed the FC membership drop-out rate. Cox proportional-hazards models were used to evaluate the association between perceived benefits/barriers of exercise and FC membership resignation. Sub-analyses were then conducted, stratifying by gender and age group.Results　A total of 2,065 participants were included in the analyses. The mean (standard deviation) age was 39.0 (15.0) years and 28.8% were male. Over 10.1 (4.4) months of newly-joined member follow-up, the FC membership drop-out rate was 24.6 instances per 1000 person-months. Multivariable analyses revealed no significant factors associated with FC membership drop-out. However, men aged 40-59 years who had a high physical benefit score and who perceived improving physical fitness as a benefit, were less likely to resign their memberships (hazard ratio [HR], 95% confidence interval [CI], 0.72 [0.52-1.00]). However, women aged <40 years with a high discomfort score and who saw discomfort as a barrier were more likely to resign membership (HR, 1.10 [1.01-1.19]). Women aged 40-59 years with high social benefit scores and who perceived social interaction as a benefit were less likely to resign their memberships, as were women with higher lack of motivation to exercise scores and who perceived lack of motivation as a barrier to exercise (HR for social benefit, 0.84 [0.74-0.97]; HR for lack of motivation, 0.85 [0.73-0.99]). Among both male and female participants aged ≥60 years, higher self-improvement scores, indicating that peer recognition was perceived as a benefit of exercise, was associated with higher HR for drop-out (men, 2.52 [1.10-5.81]; women, 1.31 [1.00-1.72]).Conclusions　The results revealed gender and age differences in the association between the perceived benefits/barriers of exercise and FC membership dropout. Implementing programs based on enrollees' characteristics and psychological factors may contribute to preventing FC dropout in the future.

Oleamide rescues tibialis anterior muscle atrophy of mice housed in small cages.

Skeletal muscle atrophy causes decreased physical activity and increased risk of metabolic diseases. We investigated the effects of oleamide (cis-9,10-octadecanamide) treatment on skeletal muscle health. The plasma concentration of endogenous oleamide was approximately 30 nm in male ddY mice under normal physiological conditions. When the stable isotope-labelled oleamide was orally administered to male ddY mice (50 mg/kg), the plasma concentration of exogenous oleamide reached approximately 170 nm after 1 h. Male ddY mice were housed in small cages (one-sixth of normal size) to enforce sedentary behaviour and orally administered oleamide (50 mg/kg per d) for 4 weeks. Housing in small cages decreased tibialis anterior (TA) muscle mass and the cross-sectional area of the myofibres in TA muscle. Dietary oleamide alleviated the decreases in TA muscle and resulted in plasma oleamide concentration of approximately 120 nm in mice housed in small cages. Housing in small cages had no influence on the phosphorylation levels of Akt serine/threonine kinase (Akt), mechanistic target of rapamycin (mTOR) and ribosomal protein S6 kinase (p70S6K) in TA muscle; nevertheless, oleamide increased the phosphorylation levels of the proteins. Housing in small cages increased the expression of microtubule-associated protein 1 light chain 3 (LC3)-II and sequestosome 1 (p62), but not LC3-I, in TA muscle, and oleamide reduced LC3-I, LC3-II and p62 expression levels. In C2C12 myotubes, oleamide increased myotube diameter at ≥100 nm. Furthermore, the mTOR inhibitor, Torin 1, suppressed oleamide-induced increases in myotube diameter and protein synthesis. These results indicate that dietary oleamide rescued TA muscle atrophy in mice housed in small cages, possibly by activating the phosphoinositide 3-kinase/Akt/mTOR signalling pathway and restoring autophagy flux.

Acute exacerbation in chronic bird fancier's lung with pleuroparenchymal fibroelastosis.

A 71-year-old non-smoker woman was admitted to our hospital complaining of a six-month history of dry cough. She had kept java sparrow for nine years and has been raising budgerigars for the previous eight months. High-resolution computed tomography (HRCT) images of the chest revealed reticulonodular lesions predominantly in the bilateral upper lobes. Surgical lung biopsy specimens showed non-caseous epithelioid cell granulomas in the alveolar spaces, including irregular and centrilobular fibrosis with pleuroparenchymal fibroelastosis. When she started using a duck feather duvet at home, she developed dyspnoea and chest HRCT abnormalities progressively deteriorated. The results of precipitation of antibodies against duck feather, java sparrow, and budgerigars dropping extracts were positive in sera. Consequently, the patient was diagnosed as having chronic bird fancier's lung with acute exacerbation caused by the use of a feather duvet. After combination treatments with corticosteroid and cyclosporine, her respiratory symptoms and reticulonodular shadow immediately improved.

Monomorphic Epitheliotropic Intestinal T-cell Lymphoma Involving the Lung and Brain: A Rare Case Study.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a primary intestinal T-cell lymphoma and other organ involvement is very rare. A rare case of MEITL involving the lung and brain is herein reported. The patient developed panperitonitis with a small intestinal perforation, and emergency surgery was performed. The pathological findings from the surgical specimens demonstrated atypical lymphoid cells which were positive for CD3, CD8, and CD56. Moreover, the pathological findings of lung specimens taken by bronchoscopy were consistent with those of the small intestine. It is therefore important to include the possibility of MEITL in the differential diagnosis of cancer patients.

Clinical significance of thyroid hormone and antibodies in patients with idiopathic interstitial pneumonia.

BACKGROUND: Hypothyroidism was recently reported to be common and to predict mortality in patients with idiopathic pulmonary fibrosis (IPF). In addition, a high prevalence of hypothyroidism was shown in patients with idiopathic pleuroparenchymal fibroelastosis. However, in idiopathic interstitial pneumonia (IIP), a clinical significance of thyroid function has not been clarified in detail. The goal of this study was to investigate the clinical significance of thyroid function and the presence of thyroid antibodies in IIP. METHODS: We have reviewed IIP patients, and analyzed the positivity of thyroid antibodies at first. Next, the relationship of clinical characteristics with thyroid function and the positivity of thyroid antibodies was analyzed. Lastly, the positivity of thyroid antibodies and other autoantibodies was evaluated. RESULTS: In IIP patients, thyroglobulin and thyroid peroxidase antibodies were positive in 17 and 16%, respectively, and 22% of patients had either or both antibodies. Subclinical and/or overt hypothyroidism was confirmed in 7% of IIP patients. The free thyrotropin level had a significant positive correlation with vital capacity and a significant negative correlation with the C-reactive protein and surfactant protein-A levels, and erythrocyte sedimentation ratio (ESR). In addition, autoantibodies suggestive of connective tissue diseases (CTDs) were positive in more than two thirds of IIP patients with the thyroid antibody, and the positive rate of antinuclear and proteinase-3 anti-neutrophil cytoplasmic antibodies was significantly higher in IIP patients with thyroid antibodies than those without the antibodies. CONCLUSIONS: Although thyroid dysfunction is not frequent, thyroid hormones and thyroid antibodies are possibly involved in the pathogenesis of IIP and their evaluation may be clinically useful to identify the clinical phenotype of IIP with autoimmune features.

Clinical Characteristics of Cough Frequency Patterns in Patients with and without Asthma.

BACKGROUND: Cough is a frequent symptom of asthma. Cough frequency (CoFr) monitoring devices are now available to objectively measure cough counts and offer a novel endpoint to assess asthma. However, little is known about CoFr in asthma. OBJECTIVE: The aims were, first, to determine whether unique features of CoFr exist in asthmatic and nonasthmatic patients and, secondly, to evaluate relationships between CoFr and pathophysiological parameters of asthma. METHODS: In the current study, 73 asthmatic and 63 nonasthmatic patients suffering from persistent cough were enrolled. At study entry, the Leicester Cough Questionnaire (LCQ health status), cough visual analog scale (VAS), Leicester Cough Monitor (LCM), fractional exhaled nitric oxide (FeNO) measurements, and spirometry were performed. In asthmatic patients, the bronchial hyperresponsiveness (BHR) test was conducted if applicable. In 28 asthmatic and 17 nonasthmatic patients, LCQ, VAS, and LCM were examined before and after treatment. RESULTS: CoFr during nighttime (asleep) was significantly higher in asthmatic patients than in nonasthmatic patients. Twenty-four-hour CoFr significantly decreased after appropriate treatment and was correlated with changes in VAS and LCQ in all patients. The improvement in cough in asthmatic patients was greater during nighttime than during daytime (awake). CoFr in asthmatic patients was significantly correlated with BHR, but not with FeNO. CONCLUSIONS: In asthmatic patients, nocturnal CoFr can be associated with BHR, was significantly higher before treatment, but improved more after treatment compared with nonasthmatic patients. Monitoring nocturnal CoFr may provide unique and valuable information on making an early prediction of therapeutic effects in asthma.

Hypomyelinating leukodystrophy-associated mutation of RARS leads it to the lysosome, inhibiting oligodendroglial morphological differentiation.

Pelizaeus-Merzbacher disease (PMD) is a central nervous system (CNS) demyelinating disease in human, currently known as prototypic hypomyelinating leukodystrophy 1 (HLD1). The gene responsible for HLD1 encodes proteolipid protein 1 (PLP1), which is the major myelin protein produced by oligodendrocytes. HLD9 is an autosomal recessive disorder responsible for the gene differing from the plp1 gene. The hld9 gene encodes arginyl-tRNA synthetase (RARS), which belongs to a family of cytoplasmic aminoacyl-tRNA synthetases. Herein we show that HLD9-associated missense mutation of Ser456-to-Leu (S456L) localizes RARS proteins as aggregates into the lysosome but not into the endoplasmic reticulum (ER) and the Golgi body. In contrast, wild-type proteins indeed distribute throughout the cytoplasm. Expression of S456L mutant constructs in cells decreases lysosome-related signaling through ribosomal S6 protein phosphorylation, which is known to be required for myelin formation. Cells harboring the S456L mutant constructs fail to exhibit phenotypes with myelin web-like structures following differentiation in FBD-102b cells, as part of the mammalian oligodendroglial cell model, whereas parental cells exhibit them. Collectively, HLD9-associated RARS mutant proteins are specifically localized in the lysosome with downregulation of S6 phosphorylation involved in myelin formation, inhibiting differentiation in FBD-102b cells. These results present some of the molecular and cellular pathological mechanisms for defect in myelin formation underlying HLD9.

A case of primary lung squamous cell carcinoma mimicking malignant mesothelioma producing granulocyte colony stimulating factor with chemotherapy (cisplatin and gemcitabine)-associated thrombotic thrombocytopenic purpura (TTP); An autopsy case report.

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy. In recent years, an extensive variety of drugs, including certain cytotoxic agents, have been reported to be associated with TTP. Additionally, several studies have reported that granulocyte colony-stimulating factor (G-CSF) was produced by lung carcinoma. G-CSF-producing carcinoma also produces various other cytokines, which may cause vascular endothelial damage and trigger TTP development. However, there has been no report describing G-CSF-producing carcinoma combined with TTP. We report a rare case of pseudomesothliomatous squamous cell lung carcinoma producing G-CSF along with chemotherapy associated TTP. MATERIALS AND METHODS: A 66-year-old man with pseudomesotheliomatous primary squamous cell lung carcinoma was treated with chemotherapy consisting of cisplatin and gemcitabine as the first line treatment. However, thrombocytopenia, acute renal dysfunction and acute respiratory failure occurred after starting the first chemotherapy cycle. As a result, the patient died, and an autopsy was performed. RESULTS: According to the autopsy findings, a diagnosis of primary lung squamous cell carcinoma producing G-CSF associated with TTP was made. CONCLUSION: Chemotherapy-related TTP should be considered when anemia and thrombocytopenia progress rapidly in patients who are under chemotherapy treatment. Furthermore, the current case may provide a possible link between TTP and G-CSF-producing tumor.