Prognostic impact of concomitant pH-regulating drugs in patients with non-small cell lung cancer receiving epidermal growth factor receptor tyrosine kinase inhibitors: the Tokushukai REAl-world Data project 01-S1.

PURPOSE: This study aimed to examine the prognostic impact of concomitant pH-regulating drug use in patients with epidermal growth factor receptor (EGFR)-mutation-positive non-small-cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs). METHODS: We conducted a nationwide retrospective cohort study and reviewed clinical data of consecutive patients with NSCLC treated with the first-line EGFR-TKIs in 46 hospitals between April 2010 and March 2020. Cox regression analyses were conducted to examine the differences in overall survival (OS) between patients treated with and without concomitant pH-regulating drugs, including potassium-competitive acid blockers (P-CABs), proton pump inhibitors (PPIs), and H2-receptor antagonists (H2RAs). RESULTS: A total of 758 patients were included in the final dataset, of which 307 (40%) were administered concomitant pH-regulating drugs while receiving frontline EGFR-TKIs. After adjusting for basic patient characteristics, patients administered gefitinib, erlotinib, afatinib, and osimertinib with concomitant pH-regulating drugs had lower OS than those without concomitant pH-regulating drugs, with hazard ratios of 1.74 (with a 95% confidence interval of 1.34-2.27), 1.33 (0.80-2.22), 1.73 (0.89-3.36), and 5.04 (1.38-18.44), respectively. The 2-year OS rates of patients receiving gefitinib with or without concomitant pH-regulating drugs were 65.4 and 77.5%, those for erlotinib were 55.8 and 66.6%, and those for afatinib were 63.2 and 76.9%, respectively. The 1-year OS rates of patients receiving osimertinib with or without concomitant pH-regulating drugs were 88.1% and 96.9%, respectively. CONCLUSION: In addition to the first-generation EGFR-TKIs, the second- and third-generation EGFR-TKIs also resulted in OS deterioration in patients with EGFR mutation-positive NSCLC when used concurrently with pH-regulating drugs.

Stepwise prolongation of overall survival from first to third generation EGFR-TKIs for EGFR mutation-positive non-small-cell lung cancer: the Tokushukai REAl-world Data project (TREAD 01).

OBJECTIVE: The introduction of new-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has afforded promising overall survival outcomes in clinical trials for non-small-cell lung cancer. We aim to investigate the current adoption rate of these agents and the real-world impact on overall survival among institutions. METHODS: In a nationwide retrospective cohort study of 46 Tokushukai Medical Group hospitals in Japan, we analyzed clinical data of consecutive patients with non-small-cell lung cancer receiving EGFR-TKIs between April 2010 and March 2020. Univariate and multivariate Cox regression analyses examined the associations between overall survival and patient/tumor-related factors and first-line EGFR-TKIs. RESULTS: A total of 758 patients (58.5% females; median age, 73 years) were included. Of 40 patients diagnosed in 2010, 72.5% received gefitinib, whereas 81.3% of 107 patients diagnosed in 2019 received osimertinib as the first-line EGFR-TKI. With a median follow-up of 15.8 months, the median overall survival was 28.4 months (95% confidence interval, 15.3-31.0). In a multivariate Cox regression analysis, age, body mass index, disease status, EGFR mutational status and first-line epidermal growth factor receptor tyrosine kinase inhibitor were identified as significant prognostic factors after adjusting for background factors including study period, hospital volume and hospital type. The estimated 2-year overall survival rates for gefitinib, erlotinib, afatinib and osimertinib were 70.1% (95% confidence interval 59.7-82.4), 67.8% (95% confidence interval 55.3-83.2), 75.5% (95% confidence interval 64.7-88.0) and 90.8% (95% confidence interval 84.8-97.3), respectively. The median time to treatment failure of gefitinib, erlotinib, afatinib and osimertinib were 12.8, 8.8, 12.0 and 16.9 months or more, respectively. CONCLUSIONS: Our real-world data revealed that the swift and widespread utilization of newer-generation EGFR-TKIs in patients with EGFR mutation-positive non-small-cell lung cancer, and that these newer-generation EGFR-TKIs can prolong overall survival regardless of hospital volume or type. Therefore, osimertinib could be a reasonable first choice treatment for these patients across various clinical practice settings.

An adrenal incidentaloma that had appeared to produce dehydroepiandrosterone-sulfate in excess before immunohistochemical study of the tumor.

Adrenal incidentaloma is a clinically unapparent adrenal mass more than one cm in diameter detected during imaging performed not for adrenal disease. A 34-year-old man was evaluated for AI with a diameter of 3.5 cm in the left adrenal. He was obese with body mass index of 33,9. Blood pressure was 110-120/90 mmHg. The general laboratory tests were unremarkable. An adrenal hormone screening set revealed that ACTH was 6.9 pg/mL, cortisol 14.9 µg/dL, renin activity 0.9 ng/mL/h, aldosterone 79.4 pg/mL, dehydroepiandrosterone-sulfate (DHEA-S) measured on two occasions 5,217 ng/mL and 6,477 ng/mL (gender- and age-adjusted reference values, 1,060-4,640 ng/mL). The levels of metanephrine and normetanephrine were normal. The tumor was thought to produce solely DHEA-S. The excised left adrenal tissue contained a tumor with a diameter of 26 mm and neighboring adrenal tissue. The tumor consisted mostly of acidophil cells without necrosis, capsular or vascular invasion, and mitosis. Immunohistochemical study revealed followings: the cells of the tumors were stained positive for 3ß-hydroxysteroid dehydrogenase, and 17α-hydroxylase, and 11ß-hydroxylase, weakly positive for DHEA sulphotransferase, and negative for aldosterone synthetase. The atrophy of neighboring tissue was presumably caused by excess cortisol production. Four months after surgery, the cortisol level was 11.2 µg/dL and DHEA-S level 1,462 ng/mL. The tumor is considered to be a cortisol-producing adenoma with modestly excessive DHEA-S production rather than isolated DHEA-S-producing adenoma. Immunohistochemical study of steroidogenic enzymes is a valuable addition to blood hormone measurement to clarify steroid production profile.

Decreased plasma acetaminophen glucuronide/acetaminophen concentration ratio warns the onset of acetaminophen-induced liver injury.

Acetaminophen (APAP)-induced liver injury (AILI) is the most common cause of acute liver failure. Although the mechanisms that trigger AILI are well known, it is less understood how to halt AILI progression and facilitate liver recovery. Therefore, it is necessary to understand the pathophysiology of APAP hepatotoxicity in patients and to examine predictive/preventive markers. In a clinical study, we had a case in which aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels increased in a patient with a low ratio of APAP glucuronide concentration (AP-G)/APAP plasma concentration. Then a reverse translational study was conducted for clarifying this clinical question. The relationship between plasma AP-G/APAP concentration ratio and the levels of AST and ALT was examined by in vivo and in vitro experiments. In in vivo experiments, 10-week-old rats showed lower UGT activity, lower AP-G/APAP concentration ratios, and higher AST and ALT levels than 5-week-old rats. This suggests an inverse correlation between the AP-G/APAP concentration ratio and the AST, ALT levels in APAP-treated rats. Furthermore, as a result of the in vitro experiment, it was confirmed that the cell viability decreased when the AP-G/APAP concentration ratio in the culture medium decreased. Since the decrease in the plasma AP-G/APAP concentration ratio appears earlier than the increase of AST and ALT levels, the ratio might be a presymptomatic marker of AILI. When APAP is used for a long time, it is recommended to perform therapeutic drug monitoring of the AP-G/APAP concentration ratio, which is a predictive/preventive marker of AILI.

Anti-nucleocapsid antibodies enhance the production of IL-6 induced by SARS-CoV-2 N protein.

A cytokine storm induces acute respiratory distress syndrome, the main cause of death in coronavirus disease 2019 (COVID-19) patients. However, the detailed mechanisms of cytokine induction due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unclear. To examine the cytokine production in COVID-19, we mimicked the disease in SARS-CoV-2-infected alveoli by adding the lysate of SARS-CoV-2-infected cells to cultured macrophages or induced pluripotent stem cell-derived myeloid cells. The cells secreted interleukin (IL)-6 after the addition of SARS-CoV-2-infected cell lysate. Screening of 25 SARS-CoV-2 protein-expressing plasmids revealed that the N protein-coding plasmid alone induced IL-6 production. The addition of anti-N antibody further enhanced IL-6 production, but the F(ab')2 fragment did not. Sera from COVID-19 patients also enhanced IL-6 production, and sera from patients with severer disease induced higher levels of IL-6. These results suggest that anti-N antibody promotes IL-6 production in SARS-CoV-2-infected alveoli, leading to the cytokine storm of COVID-19.

A phase 3 multicenter open-label maintenance study to investigate the long-term safety of sodium zirconium cyclosilicate in Japanese subjects with hyperkalemia.

BACKGROUND: Hyperkalemia is associated with many chronic diseases and renin-angiotensin-aldosterone system inhibitor therapy. Sodium zirconium cyclosilicate (SZC), an oral, highly selective cation-exchanger, is approved for the treatment of hyperkalemia. METHODS: This phase 3, multicenter, open-label, single-arm, flexible-dose study assessed the safety and efficacy of SZC in Japanese patients with hyperkalemia during a correction phase of up to 3 days and long-term (1 year) maintenance phase (NCT03172702). RESULTS: Overall, 150 patients received treatment during both study phases; the study population was generally representative of hyperkalemic Japanese patients in clinical practice. Most patients (78.7%) had three doses of SZC during the correction phase. All but one patient received SZC for ≤ 48 h before transitioning to the maintenance phase. In the maintenance phase, mean (standard deviation; SD) exposure to the study drug was 319.4 (98.1) days and mean (SD) dose was 7.38 (2.85) g/day. Adverse events (AEs) were reported in 131 patients (87.3%); most were mild. The most common treatment-related AEs as evaluated by investigators were constipation (6.7%), peripheral edema (4.0%), and hypertension (2.7%). In the correction phase, 78.7% of patients were normokalemic at 24 h and 98.7% within 48 h; ≥ 65.5% maintained normokalemia throughout the maintenance phase. CONCLUSION: After a year of exposure, SZC treatment was well tolerated by Japanese patients and potassium levels were well controlled.

A Case of Anti-CRMP5 Paraneoplastic Neurological Syndrome Induced by Atezolizumab for Small Cell Lung Cancer.

We herein report a 76-year-old man who developed irritability and forgetfulness 5 months after the introduction of atezolizumab for the treatment of small cell lung cancer (SCLC). Brain magnetic resonance imaging showed lesions of the striatum, and an investigation of the serum revealed a high titer of anti-CRMP5 antibody. After stopping atezolizumab and starting steroid pulse therapy, these clinical features improved. Given these findings, it is considered that CRMP5-assciated striatal encephalitis was induced by atezolizumab in this case with SCLC.

Multidisciplinary Lung Cancer Tumor Board Connecting Eight General Hospitals in Japan via a High-Security Communication Line.

PURPOSE: The complexity of lung cancer treatment is rapidly increasing, necessitating the use of multidisciplinary approaches for improving outcomes. Although it is common for institutions to have their own tumor boards, tumor boards connecting several general hospitals, and therefore allowing for more diverse opinions, are not prevalent. MATERIALS AND METHODS: A tumor board connecting eight hospitals was formed to discuss patients for whom formulating a treatment strategy was difficult. Physicians and hospital staff accessed a high-security communication line via LiveOn ( Japan Media Systems Corporation, Tokyo, Japan), which is completely isolated from the Internet and password protected, that enables each hospital to share the electronic medical records and images of relevant patients at other hospitals on desktop computers in real time. The lung cancer tumor board began in April 2017 and has since been held every Tuesday evening for 1 hour. Preparatory records containing the age, sex, histology, TNM classification, background, and discussion points for each patient are created before each tumor board meeting. After the tumor board discussion, all conclusions and related articles used in the board are added to the minutes, which are finalized as Microsoft Word files, consolidated, and archived. These files can be retrieved later using key words. RESULTS: From April 2017 to June 2018, 202 patients were discussed. Although TNM classification was not changed for any patient, diverse opinions led to a change in the proposed strategy for 49 of 202 patients. CONCLUSION: The multidisciplinary tumor board was useful in obtaining various opinions from the perspectives of different experts. This should be evaluated in a prospective study.

Fulminant onset of insulin-dependent diabetes with positive anti-GAD antibody titers during treatment with nivolumab in a patient with NSCLC.

Programmed cell death-1 (PD-1) and programmed cell death-ligand-1 (PD-L1) inhibitors have been highlighted in the field of cancer treatment. The interaction between PD-1 and PD-L1 is thought to play an important role in the regulation of the self-immune tolerance mechanism, so blocking these molecules may cause serious immune-related adverse events (IrAE), including fulminant insulin-dependent (type 1) diabetes. Here, we describe a patient with fulminant type 1 diabetes induced by nivolumab, an anti-PD-1 antibody. The patient, a 78-year-old man, was being treated with nivolumab as a third-line treatment for squamous cell carcinoma of the lung. After three cycles, he experienced an abrupt flare-up of the blood glucose within half a day. His blood glucose further increased without clinical symptoms until his hospital visit. Laboratory data showed the complete exhaustion of intrinsic insulin and the elevation of serum antibody titer to glutamic acid decarboxylase (GAD). Although the patient was previously diagnosed with non-insulin-dependent (type 2) diabetes, his disease activity had been well controlled with oral medication and low-dose insulin therapy until just before the flare-up. Because of the laboratory findings and the extremely rapid onset of hyperglycemia, a diagnosis of fulminant, rather than the rapid onset, type 1 diabetes related to nivolumab therapy was strongly suspected. Our case study indicates that fulminant hyperglycemia can occur extremely rapidly. The blood glucose of patients receiving PD-1 antibody therapy should be closely monitored.

Central nervous system relapse of Whipple's disease.

A 50-year-old man presented with a 12 kg weight loss in 8 months. Upper gastrointestinal endoscopy findings showed strong erosion and diffuse bleeding in the duodenum. Histopathological findings showed PAS staining-positive macrophages consistent with Whipple's disease. He was treated with trimethoprim-sulfamethoxazole. His condition initially improved. However, during his 6-year course of treatment he developed a central nervous system relapse. Tropheryma whipplei DNA was detected by a polymerase chain reaction in his cerebrospinal fluid. This relapse was successfully treated with ceftriaxone sodium (CTRX). We considered that as initial therapy for Whipple's disease, it would be important to administer CTRX for at least a few months, due to its high translatability to CSF.

A patient with hypereosinophilic syndrome that manifested with acquired hemophilia and elevated IgG4: a case report.

INTRODUCTION: Hypereosinophilic syndrome is defined as a prolonged state (more than six months) of eosinophilia (greater than 1500 cells/µL), without an apparent etiology and with end-organ damage. Hypereosinophilic syndrome can cause coagulation abnormalities. Among hypereosinophilic syndrome types, the lymphocytic variant (lymphocytic hypereosinophilic syndrome) is derived from a monoclonal proliferation of T lymphocytes. Here, we describe the case of a patient with lymphocytic hypereosinophilic syndrome who presented with a coagulation abnormality. To the best of our knowledge, this is the first such report including a detailed clinical picture and temporal cytokine profile. CASE PRESENTATION: A 77-year-old Japanese man presented to our facility with massive hematuria and hypereosinophilia (greater than 2600 cells/µl). His eosinophilia first appeared five years earlier when he developed femoral artery occlusion. He manifested with multiple hematomas and prolonged activated partial thromboplastin time. His IgG4 level was remarkably elevated (greater than 2000 mg/dL). Polymerase chain reaction tests of peripheral blood and bone marrow identified lymphocytic hypereosinophilic syndrome. His prolonged activated partial thromboplastin time was found to be due to acquired hemophilia. Glucocorticoids suppressed both the hypereosinophilia and coagulation abnormality. However, tapering of glucocorticoids led to a relapse of the coagulation abnormality alone, without eosinophilia. Tumor necrosis factor α, interleukin-5, and/or eotaxin-3 may have caused the hypereosinophilia, and interleukin-10 was correlated with the coagulation abnormality. CONCLUSIONS: To the best of our knowledge, this is the first case in which lymphocytic hypereosinophilic syndrome and IgG4-related disease have overlapped. In addition, our patient is only the second case of hypereosinophilic disease that manifested with acquired hemophilia. Our patient relapsed with the coagulation abnormality alone, without eosinophilia. This report shows that the link between eosinophilia, IgG4, and clinical manifestations is not simple and provides useful insight into the immunopathology of hypereosinophilic syndrome and IgG4-related disease.

[Hyponatremia caused by pituitary metastasis of lung cancer].

A 57-year-old man was admitted with headache, vomiting, and bloody sputum. We diagnosed large cell lung cancer T4N2M1 (pituitary metastasis), Stage IV. When hospitalized, low values of cortisol and hyponatremia were found. A hormone stimulation test was performed, because we suspected hypopituitarism. The reaction of adrenocorticotropic hormone (ACTH) to the corticotropin-releasing hormone (CRH) loading test was good, but the reaction of serum cortisol was minimal. After corticosteroid administration, his serum sodium normalized. Limited ACTH reserve according to insufficient pituitary function was suggested as a cause of the hyponatremia. He received gamma-knife therapy, however his pituitary gland tumor did not decrease in size. Clinical symptoms such as visual field disturbance, oculomotor paresis, and visual impairment progressed, and he died about 5 months later. We report a case of hyponatremia in a patient with pituitary metastasis of lung cancer, as it is comparatively rare.

[Pneumatosis cystoides intestinalis in a patient with lung cancer].

We report a case of pneumatosis cystoides intestinalis (PCI) in a patient with lung cancer. A 60-year-old woman was admitted with multiple lung tumors and multiple brain tumors. She was given steroid hormones to reduce her brain edema. Total resection of a brain tumor yielded a pathological diagnosis of metastatic squamous cell carcinoma. During treatment, X-ray and CT images revealed intestinal pneumatosis and free air in the abdominal cavity, but a physical examination revealed no abnormal findings. She was given a diagnosis of PCI, and received conservative treatment. Her intestinal gas cysts and intra-abdominal free air disappeared spontaneously. PCI is an uncommon but important condition in which gas is found in a linear or cystic form in the submucosa or subserosa of the bowel wall. It is important to consider PCI as a possible complication in lung cancer patients who are given steroid hormones and systemic chemotherapy in the long-term.

Single nucleotide polymorphism in ABCG2 is associated with irinotecan-induced severe myelosuppression.

Irinotecan is an anti-neoplastic agent that is widely used for treating colorectal and lung cancers, but often causes toxicities such as severe myelosuppression and diarrhea. In this study, we performed a two-stage case-control association study for irinotecan-induced severe myelosuppression (grades 3 and 4). In the first stage, 23 patients who developed severe myelosuppression and 58 patients who did not develop any toxicity were examined for 170 single nucleotide polymorphisms (SNPs) in 14 genes involved in the metabolism and transport of irinotecan. A total of five SNPs were identified to show the possible association with severe myelosuppression (P(Fisher)<0.01) and were further examined in 7 cases and 20 controls in the second stage of the study. An intronic SNP, rs2622604, in ABCG2 showed P(Fisher)=0.0419 in the second stage and indicated a significant association with severe myelosuppression in the combined study (P(Fisher)=0.000237; P(Corrected)=0.036). Although only limited subjects were investigated, our results suggested that a genetic polymorphism in ABCG2 might alter the transport activity for the drug and elevate the systemic circulation level of irinotecan, leading to severe myelosuppression.