Real-world outcomes of chemotherapy for lung cancer patients undergoing hemodialysis: A multicenter retrospective cohort study (NEJ-042).

INTRODUCTION: Malignant tumors are the major cause of death in hemodialysis patients. Management of these patients remains challenging as there is no evidence that chemotherapy is beneficial, and a lack of information about actual clinical practice. METHODS: This multicenter retrospective study included hemodialysis patients who were diagnosed with lung cancer from January 2002 to June 2018. We reviewed their clinical information including patient characteristics associated with lung cancer and end-stage renal disease, regimen, efficacy and safety of chemotherapy, and outcomes. RESULTS: A total of 162 patients from 22 institutions in Japan were registered. Of 158 eligible patients, 91 received chemotherapy (80 as palliative chemotherapy and 11 as chemoradiotherapy) and 67 received best supportive care only regardless of cancer stage. In small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients who received cytotoxic chemotherapy, the objective response rates (ORR) and median overall survival (OS) were 68.1 %, 12.3 months and 37.0 %, 8.5 months, respectively. The ORR and median OS in patients with EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKI) were 44.4 % and 38.6 months. The treatment-related adverse events (Grade 3 or higher) induced by cytotoxic chemotherapy were myelosuppression and febrile neutropenia; treatment-related death (TRD) was observed in one patient. TRD occurred in 3 of 18 patients who received EGFR-TKI. CONCLUSION: Chemotherapy should be considered for hemodialysis patients with EGFR-mutant NSCLC and SCLC. However, the survival benefits of chemotherapy for NSCLC patients with EGFR-wild type are unclear; physicians should carefully consider whether to offer chemotherapy to this patient subset.

[Anti-Hu antibody positive sensory neuronopathy causing painful legs and moving toes (PLMT) in a 75-year-old female with small cell lung cancer (SCLC)].

The case is a 75-year-old female. She had dysesthesia in the distal extremities and truncal ataxia, and they had progressed in two months. Neurological examination revealed the findings of segmental dysesthesia in the distal extremities, impaired deep sensations in the trunk and four limbs, and painful legs and moving toes (PLMT). After workup, she was diagnosed with small cell lung cancer and her blood sample was positive for anti-Hu antibody. We concluded that her neurological symptoms were attributable to sensory neuronopathy associated with paraneoplastic syndrome. No cases with PLMT caused by paraneoplastic syndrome have been reported so far. She had chemotherapy to lung cancer and Duloxetine without improvement of PLMT. On the other hand, intravenous immunoglobulin treatment improved lightening pain in the toes without improvement of moving toes.

[A case of myasthenia gravis with invasive thymoma associated with diffuse panbronchiolitis, alopecia, dysgeusia, cholangitis and myositis].

A 43-year-old man was admitted to our hospital because of diplopia, ptosis, and dysphagia that had begun three years previously. He was diagnosed with myasthenia gravis (MG) and invasive thymoma and treated with corticosteroid, thymectomy, and radiation therapy. Ten years after the thymectomy, computed tomography (CT) showed metastasis of the thymoma in the left lower lobe of the lung. Two years after this recurrence, when the patient was 55, respiratory symptoms such as wheezing, persistent cough, and dyspnea appeared. Chronic sinusitis, diffuse centrilobular opacities on CT, and positivity for HLA-B54 led to a diagnosis of diffuse panbronchiolitis (DPB). Despite treatment with clarithromycin, the respiratory symptoms worsened. The patient developed alopecia and body hair loss at the age of 56 followed by dysgeusia, cholangitis, and myositis with positivity for anti-Kv1.4 antibodies. Although treatment with an increased dose of corticosteroid improved hair loss, dysgeusia, cholangitis, and myositis, he died of progression of DPB and serious respiratory infection at the age of 58. In this case, various autoimmune disorders occurred together with MG as complications of thymoma. Although alopecia, dysgeusia, and myositis are already known as complications of MG associated with thymoma, cholangitis is not well-recognized since there have been few reports suggesting a causal relationship between cholangitis and thymoma. Furthermore, DPB caused by immunodeficiency and respiratory tract hypersensitivity associated with thymoma and HLA-B54, respectively, is the distinctive feature of our case. Neurologists should be aware that various organs can be damaged directly and indirectly by abnormal T cells from thymoma in patients with MG.

Microscopic polyangiitis accompanied by pleuritis as the only pulmonary manifestation of occupational silica exposure.

A 68-year-old man, who had worked for processing quartz-containing stones for more than 50 years, complained of low-grade fever and arthralgia. Mediastinal lymph nodes were markedly swollen on chest computed tomography. Pathological findings of the lymph node were compatible with silicosis, with a high titer of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA). During follow-up with prednisolone treatment, pleuritis and uveitis developed as manifestations of vasculitis. Thus, he was diagnosed with MPO-ANCA-associated vasculitis with occupational silica exposure, possibly microscopic polyangiitis (MPA). This case is rare, because pleuritis was the only pulmonary manifestation, without interstitial pneumonia, alveolar hemorrhage or glomerulonephritis.

Suppressive influences of IFN-alpha on IL-17 expression in human CD4+ T cells.

We examined the direct effects of IFN-alpha on the development of Th17 with a system using immobilized anti-CD3, which permits activation of CD4+ T cells in the complete absence of accessory cells. Highly purified CD4+ T cells obtained from healthy donors were stimulated with immobilized anti-CD3 with or without IFN-alpha. IFN-alpha suppressed the production of IL-17 of immobilized anti-CD3-stimulated CD4+ T cells in a dose-response manner. Accordingly, IFN-alpha inhibited IL-17 mRNA expression in immobilized anti-CD3-stimulated CD4+ T cells. IFN-alpha did not affect the production of TGF-beta or IL-6, but inhibited RORC mRNA expression of anti-CD3-stimulated CD4+ T cells. These results indicate that IFN-alpha suppresses IL-17 expression and Th17 differentiation through down-regulation of RORC mRNA expression. It is therefore suggested that these effects might play a role in the mode of action of IFN-alpha in the treatment of various inflammatory diseases.

Mucosa associated lymphoid tissue (MALT) lymphoma of the thymus with trisomy 18.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) of the thymus is rare and little is known about its karyotype abnormality. MALT lymphoma in general shows a good prognosis, but some reports suggest that the presence of trisomy 18 predicts recurrence. Here, we report a patient with MALT lymphoma of the thymus and the left parotid gland accompanied by Sjogren's syndrome. The karyotype analysis revealed that this is the first case of thymic MALT lymphoma with trisomy 18, which we believe is worth reporting. We also review cases with thymic MALT lymphoma previously reported in the literature.

An adult case of multiple squamous papillomas of the trachea associated with human papilloma virus type 6.

A 72-year-old woman with primary biliary cirrhosis complained of dry cough and wheezing. Chest computed tomography showed a tumor arising from the posterior wall of the trachea. Bronchoscopic examination revealed that the tumor was cauliflower-like, with two small polypoid tumors. They were diagnosed as multiple squamous papillomas. The main tumor was recurrent and removed by repeated microwave coagulation therapy (MCT) through bronchoscopy, whereas the two polypoid tumors were likely to disappear spontaneously. Human papilloma virus (HPV) type 6 DNA was detected in the tumor by polymerase chain reaction (PCR) amplification, suggesting that this virus was the cause of her papillomas.

[A Japanese case of melioidosis presenting as multiple organ lesions accompanied by sepsis and disseminated intravascular coagulation, after a visit to Thailand].

A 65-year-old man with diabetes mellitus reporting fever and urination disturbance on a flight from Bangkok back to Japan in July 2003 was admitted elsewhere for acute prostatitis. Despite intravenous antibiotics, his condition deteriorated. On admission to our hospital, he suffered from respiratory failure, with laboratory data showing disseminated intravascular coagulation (DIC). Computed tomography (CT) shows infiltrative and nodular shadows in both lung fields and low-density areas in the left kidney and prostate gland, consistent with pneumonia and abscesses in these organs. He also developed broad osteomyelitis in the right lower extremity with cellulitis and arthritis in the right hand, knee, and foot. Blood, urine, and joint fluid culture all yielded Burkholderia pseudomallei, so he was diagnosed with melioidosis. Treatment was started with meropenem and minocycline, then meropenem was changed to imipenem. His symptoms gradually improved after ciprofloxacin was added, so all intravenous antibiotics were discontinued and he underwent oral treatment with chloramphenicol, minocycline, and sulfamethoxazole/trimethoprim in September 2003. He developed fever again, however, and oral therapy was discontinued and intravenous antibiotics restarted. After resolution of fever, oral maintenance therapy was initiated again with levofloxacin and minocycline in October, and his condition remained stable. After discharge in April 2004, he has been followed up with no evidence of relapse. This is considered to be the seventh case of melioidosis reported in Japan. Our patient manifested multiple organ lesions with sepsis and DIC, and was difficult to treat, but clinical symptoms improved in long-term antibiotic administration. With travelers to Southeast Asia increasing, greater attention must be paid to imported infectious diseases, such as melioidosis.

[A case of small cell lung cancer under hemodialysis with chronic renal failure treated with amrubicin while measuring blood concentration of the drug].

We reported a case of small cell lung cancer treated with amrubicin while receiving hemodialysis. An 83-year-old man with chronic renal failure being treated by hemodialysis was admitted because of a left hilar mass. Small cell lung cancer with liver metastasis (cT2NOM1) was diagnosed. Two courses of chemotherapy with amrubicin resulted in partial response. Toxicity was relatively mild. We measured blood concentration of amrubicin during the first course of chemotherapy. There was no significant difference in blood cell and plasma concentration of amrubicin hydrochloride and amrubicinol between days when he received hemodialysis and when he did not receive hemodialysis. Thus, we considered that amrubicin hydrochloride may be a good candidate for the treatment of small cell lung cancer patients with chronic renal failure under hemodialysis.

Differential effects of IFN-alpha on the expression of various TH2 cytokines in human CD4+ T cells.

BACKGROUND: In both human subjects and mice, T helper cells are classified into 2 subsets, TH1 and TH2 cells, on the basis of the cytokines they produce. Although IFN-alpha has been shown to enhance human TH1 responses, its influences on human TH2 responses have not yet been fully characterized. In addition, the mechanism for induction of TH1 responses by IFN-alpha has not been fully delineated. OBJECTIVE: The present study was undertaken to explore the direct effects of IFN-alpha on the expression of various cytokines in human CD4+ T cells with a system using immobilized anti-CD3, which permits activation of CD4+ T cells in the complete absence of accessory cells. METHODS: Highly purified CD4+ T cells obtained from healthy donors were stimulated with immobilized anti-CD3 with or without IFN-alpha and IL-12 in the complete absence of accessory cells. The production of cytokines was estimated by means of ELISA. The expression of mRNA for various cytokines, as well as transcription factors, was evaluated by using quantitative PCR. RESULTS: IFN-alpha enhanced IL-4 protein and mRNA expression in immobilized anti-CD3-stimulated CD4+ T cells, irrespective of the presence of IL-12, whereas IFN-alpha suppressed the expression of IL-5 and IL-13. Of note, IFN-alpha enhanced the expression of mRNA for c-Maf, T-bet, and Fox-P3, irrespective of the presence of IL-12, but not that for GATA-3, in anti-CD3-stimulated CD4+ T cells. CONCLUSION: These results indicate that IFN-alpha enhances the induction of TH1 responses through upregulation of T-bet mRNA expression, as well as the induction of TH2 responses through upregulation of c-Maf mRNA expression, followed by IL-4 expression. Moreover, the data also suggest that IFN-alpha might suppress the expression of IL-5 and IL-13 in differentiated TH2 cells.