Correlation of toxicities and efficacies of pemetrexed with clinical factors and single-nucleotide polymorphisms: a prospective observational study.

BACKGROUND: Pemetrexed is an efficacious multi-targeted antifolate with acceptable toxicity for non-squamous non-small cell lung cancer (non-Sq NSCLC) and malignant pleural mesothelioma. Vitamin B12 and folic acid as premedication can reduce the frequency of severe toxicities of pemetrexed chemotherapy. However, adverse effects are frequent in clinical settings. In this study, we aimed to identify the clinical factors and single-nucleotide polymorphisms (SNPs) associated with the toxicity and efficacy of pemetrexed chemotherapy. METHODS: This observational study was conducted from October 2012 to December 2019; we evaluated the toxicities and efficacies of pemetrexed chemotherapy using multivariate logistic or Cox regression analysis. In total, 106 patients received pemetrexed chemotherapy. SNPs were analyzed for four patients with malignant pleural mesothelioma and 67 with non-Sq NSCLC. RESULTS: The median progression-free survival (PFS) and overall survival of 63 patients with non-Sq NSCLC, excluding four in the adjuvant setting, were 6.8 and 33.3 months, respectively. Per propensity-score-adjusted multivariate Cox analyses, favorable factors for PFS were folic acid level ≥ 9.3 ng/mL before premedication, platinum combination, bevacizumab combination, vitamin B12 level < 1136 pg/mL before chemotherapy, A/A + A/G of BHMT (742 G > A), and A/A + A/C of DHFR (680 C > A). Favorable prognostic factors included good performance status, low smoking index, body mass index ≥ 20.66 kg/m2, folic acid level ≥ 5.55 ng/mL before premedication, higher retinol-binding protein before chemotherapy, and A/G of MTRR (66 A > G). Among the 71 patients who were analyzed for SNPs, the frequencies of hematologic toxicities and non-hematologic toxicities in Grades 3-4 were 38% and 36.6%, respectively. Per propensity-score-adjusted multivariate logistic analyses, risk factors for Grades 3-4 hematologic toxicities were vitamin B12 level < 486 pg/mL before premedication, leucocyte count < 6120 /µL before chemotherapy, folic acid level < 15.8 ng/mL before chemotherapy, status with a reduced dose of chemotherapy, and C/T + T/T of MTHFR (677 C > T). Risk factors for Grades 2-4 non-hematologic toxicities were homocysteine levels ≥ 11.8 nmol/mL before premedication, transthyretin level < 21.5 mg/dL before chemotherapy, C/C + T/T of MTHFR (677 C > T), and A/A + G/G of SLC19A1 [IVS2 (4935) G > A]. CONCLUSION: The information on metabolites and SNPs of the folate and methionine cycle will help predict the toxicities and efficacies of pemetrexed. TRIAL REGISTRATION: This trial was retrospectively registered with the University hospital Medical Information Network (UMIN000009366) on November 20, 2012.

Final report on plasma ctDNA T790M monitoring during EGFR-TKI treatment in patients with EGFR mutant non-small cell lung cancer (JP-CLEAR trial).

Osimertinib is active against T790M-positive epidermal growth factor receptor mutant non-small cell lung cancer. We enrolled 122 sensitive epidermal growth factor receptor mutant non-small cell lung cancer patients who were planned to receive or were receiving first-/second-generation epidermal growth factor receptor tyrosine kinase inhibitors without disease progression and monitored plasma T790M every 1-2 months using the cobas® EGFR Mutation Test v2. We previously reported the concordance between T790M status in plasma and tissue. This is the final report on the sensitivity of plasma T790M and the efficacy of sequential osimertinib. The sensitivity was 21.1% (95% confidence interval: 6.1-45.6%). The best overall response was 25.0% (95% confidence interval: 9.8-46.7) in the plasma T790M-positive group and 28.6% (95% confidence interval: 8.4-58.1) in the plasma T790M-negative but tissue T790M-positive group. Median progression-free survival was 7.9 months (95% confidence interval: 4.7-17.5) for the former and 4.4 months (95% confidence interval: 3.0-N.E.) for the latter, with no statistically significant difference (P = 0.74).

Prolonged SARS-CoV-2 infection associated with long-term corticosteroid use in a patient with impaired B-cell immunity.

Corticosteroids are widely used to treat severe COVID-19, but in immunocompromised individuals, who are susceptible to persistent infection, long term corticosteroid use may delay viral clearance. We present a case of prolonged SARS-CoV-2 infection in a man with significantly impaired B-cell immunity due to non-Hodgkin lymphoma which had been treated with rituximab. SARS-CoV-2 shedding persisted, despite treatment with remdesivir. Viral sequencing confirmed the persistence of the same viral strain, ruling out the possibility of reinfection. Although SARS-CoV-2 IgG, IgA and IgM remained negative throughout the treatment period, after reduction of the corticosteroid dose, PCR became negative. Long-term corticosteroid treatment, especially in immunocompromised individuals, may result in suppression of cell-mediated immunity and prolonged SARS-CoV-2 infection.

Genetic diagnostic features after failure of initial treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors among non-small-cell lung cancer patients harboring EGFR mutations.

BACKGROUND: Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than the first-generation EGFR-TKIs used for first-line treatment, its efficacy with respect to long-term patient survival remains unclear even upon the administration of a complete sequence of EGFR-TKI therapy. Moreover, limited information is available regarding genetic diagnostic approaches after the treatment of EGFR-TKI-naïve patients. This study investigated the clinical characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs, as well as the advantages of rebiopsy and liquid biopsy for these patients. METHODS: The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs, except for osimertinib, single-plexus cobas version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. RESULTS: From April 2016 through May 2019, 113 patients were found to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among whom 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue biopsies and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had a new lesion, and were administered gefitinib as first-line therapy, they were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with coexisting original mutations, brain metastases, tumor enlargement by ≥12 mm, or metastases at minor sites. CONCLUSION: Among patients with positive factors associated with the T790M mutation, repeated tissue or liquid biopsies are useful to maximize the detection rate of the T790M substitution. Furthermore, these biopsies need to be repeated numerous times in order to reduce "detection overlook" among such patients.

Plasma ctDNA monitoring during epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatment in patients with EGFR-mutant non-small cell lung cancer (JP-CLEAR trial).

BACKGROUND: Osimertinib, a third generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), is active against EGFR-mutant non-small cell lung cancer (NSCLC) resistant to first-/second-generation EGFR-TKIs with the T790M mutation. T790M monitoring in plasma circulating tumor DNA (ctDNA) in patients receiving EGFR-TKIs is less invasive than re-biopsy and could provide valuable clinical information. METHODS: Patients with advanced or postoperative recurrent NSCLC with sensitizing EGFR mutations who were planned to receive or were receiving first-/second-generation EGFR-TKI treatment without disease progression were eligible for enrollment. Plasma samples at baseline and every 1-2 months thereafter were analyzed for EGFR mutation status using the cobas®EGFR Mutation Test v2. RESULTS: Between September 2016 and March 2017, 122 patients at 15 Japanese institutions were enrolled. In August 2018, 1291 plasma samples from 121 patients were analyzed for EGFR mutation status. At baseline, a sensitizing EGFR mutation was detected in 29 (23.9%) of 121 patients and T790M mutation was detected in three (2.5%). At follow-up, 66 (54.5%) patients experienced disease progression and 64 (52.9%) discontinued first-line EGFR-TKI treatment. Twenty-two (18.2%) patients showed T790M in plasma ctDNA, of which 15(68.2%) received osimertinib. Although 31 patients received re-biopsy to examine EGFR status at disease progression, T790M was detected in only nine (22.0%) patients, of which 7 (77.8%) received osimertinib. CONCLUSIONS: ctDNA monitoring during EGFR-TKI treatment is useful for detecting T790M mutation. The efficacy of osimertinib treatment based on T790M status in plasma ctDNA remains to be established, warranting further research.

[Efficacy of combination therapy with EGFR-TKI and cytotoxic drug in lung adenocarcinoma already treated with EGFR-TKI].

UNLABELLED: OBJECITVE: To assess the efficacy of combination therapy with EGFR-TKI and a cytotoxic drug in lung adenocarcinoma already being treated with EGFR-TKI. METHODS: Eight patients with adenocarcinoma who were treated with combination therapy of EGFR-TKI and a cytotoxic drug between April 2008 and December 2010 were retrospectively evaluated for response rate, disease-control rate, progression-free survival(PFS), time-to-treatment-failure(TTF)and overall survival(OS). RESULTS: Among the 7 patients with tumor samples available, EGFR-mutations were detected in six.The median number of prior therapy regimens received by the patients was 5.All the patients had been treated before with both gefitinib and erlotinib.Among 8 patients, six showed stable disease, including three patients intolerant because of severe hematological toxicities, and 2 with progressive disease.The disease-control rate was 75%, and median TTF, PFS, and OS were 42 days, 84 days, and 495 days, respectively. CONCLUSION: Combination therapy with EGFR-TKI and a cytotoxic drug after the failure of EGFR-TKI may be a useful therapeutic option for selected patients.

The pharmacokinetics and long-term therapeutic effects of gefitinib in patients with lung adenocarcinoma harboring the epidermal growth factor receptor(EGFR)mutation.

INTRODUCTION: The relationship between the pharmacokinetics and long-term antitumor activity of gefitinib in patients with epidermal growth factor receptor(EGFR)mutation-positive lung adenocarcinoma has not yet been clarified in clinical practice. The present study assessed the correlation between the pharmacokinetics and long-term therapeutic effects of gefitinib in patients with lung adenocarcinoma harboring the EGFR-activating mutation. METHODS: Fifteen patients with lung adenocarcinoma harboring the EGFR mutation were administered 250 mg of gefitinib daily. Blood samples were collected prior to the first administration of gefitinib and after 1, 4, 6, 8, and 24 h. Plasma concentrations of gefitinib were measured via liquid chromatography mass spectrometry, and the peak plasma concentration(Cmax)and area under the plasma concentration time curve from 0 to 24 h(AUC 0-24)of gefitinib were determined. The correlations between these pharmacokinetic variables and the objective responses, including progression-free survival(PFS)and overall survival(OS), were retrospectively analyzed. RESULTS: The Cmax of gefitinib in patients with a partial response(PR)was significantly lower than that of patients with stable disease(SD)(median Cmax: 278 vs 588 ng/mL, p<0.05 ). However, the Cmax of gefitinib did not correlate with longer PFS. Conversely, a significant negative correlation was found between the AUC 0-24 of gefitinib and longer survival(r=-0.545, p<0.05 ). CONCLUSIONS: It may be possible that a high concentration of gefitinib is not necessary to achieve long-term therapeutic effects in patients with lung adenocarcinoma harboring the EGFR mutation.

T790M mutation positive squamous cell carcinoma transformation from EGFR-mutated lung adenocarcinoma after low dose erlotinib: A case report and literature review.

RATIONALE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used for the treatment of EGFR mutation positive advanced nonsmall cell lung cancer (NSCLC); however, acquired resistance is known to develop during these treatments. Among these mechanisms, histological transformation is seldom encountered. Although platinum based chemotherapy has been reported to be effective in the treatment of patients with small cell lung cancer transformation, there is a lack of information on the treatment of patients with squamous cell carcinoma (SQ) transformation. PATIENT CONCERNS AND DIAGNOSIS: An 80-year-old nonsmoking woman was referred to our hospital because of an abnormal shadow on her chest radiograph. Diagnostic bronchoscopy was performed and pathological examination revealed adenocarcinoma. Mutation analysis of the EGFR gene revealed deletion of E746-A750 in exon 19. She refused both surgical treatment and radiation therapy, and preferred periodic radiologic follow-up. Unfortunately, approximately a year and a half after the initial diagnosis, the primary lesion enlarged, and many pleural nodules were newly detected (clinically T4N2M1a, stage IVA). INTERVENTIONS AND OUTCOMES: Based on EGFR mutation analysis, a reduced dose of daily erlotinib was prescribed, which achieved a partial response and 34 months of progression-free survival (PFS). A repeated biopsy with an endobronchial cryoprobe was performed on the enlarged primary lesion. Pathological examination revealed SQ harboring an identical EGFR mutation with a secondary EGFR T790M mutation. Osimertinib 80 mg once a day was started as second line therapy, which resulted in 8 months of PFS and 15 months of survival. LESSON: The literature review and our report suggest that osimertinib is a promising treatment for NSCLC regardless of histology if T790M is present as an acquired mutation.

A rare case of docetaxel-induced myositis in a patient with a lung adenocarcinoma.

Docetaxel is a cytotoxic taxane frequently used to treat patients with various cancers, including non-small cell lung cancer (NSCLC). Docetaxel is known to cause acute myalgias, arthralgias, and neuropathy, but there have been few published case reports of myositis. Here, we describe a rare case of docetaxel-induced myositis diagnosed based on laboratory data, thigh magnetic resonance imaging (MRI), and electromyography (EEG). A 66-year-old male was admitted for thigh pain and fatigue that onset 1 week prior. He had been diagnosed with stage IVA (cT4N0M1a) NSCLC 3 years ago and had been started on docetaxel (60 mg/m2 intravenously every 3 weeks; fourth-line chemotherapy) 1 month earlier. After the second cycle, he developed both thigh pain and fatigue. On admission, his creatinine phosphokinase (CPK) level was elevated, thigh MRI revealed diffuse muscle edema, and EEG showed myogenic changes. We found no plausible cause for myositis except docetaxel. He was diagnosed with myositis and treated with oral prednisolone. His symptoms were relieved and the CPK level declined. Although rare, this case indicates that clinicians should consider the possibility of myositis as a complication in patients on docetaxel.

Efficacy and safety of first-line osimertinib treatment and postprogression patterns of care in patients with epidermal growth factor receptor activating mutation-positive advanced non-small cell lung cancer (Reiwa study): study protocol of a multicentre, real-world observational study.

INTRODUCTION: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is widely used as the first-line treatment for EGFR mutation-positive non-small cell lung cancer (NSCLC). Nevertheless, most cases ultimately acquire resistance to osimertinib, and no effective treatment has been currently established for cases having progressive disease (PD) with osimertinib. In clinical practice, EGFR-TKI therapy could be continued beyond response evaluation criteria in solid tumours (RECIST)-defined PD cases when they are clinically stable. Currently, the progression pattern of osimertinib and criteria for identifying patients who might benefit from osimertinib beyond PD are unknown. In addition, the efficacy and safety of osimertinib as the first-line treatment in real-world clinical practice remain unclear in Japan. This multicentre study was designed to evaluate the real-world data on first-line osimertinib and its post-treatment. METHODS AND ANALYSIS: The study enrols patients with EGFR mutation-positive, advanced or recurrent NSCLC who received EGFR-TKI as the first-line therapy after 1 September 2018, from October 2019 to August 2020, and those started on osimertinib will be followed up until August 2022. We will evaluate the efficacy and safety of the first-line osimertinib treatment, adherence to it, progression patterns on RECIST PD and subsequent treatment. ETHICS AND DISSEMINATION: All participating patients will provide written informed consent before entering the study. The protocol, amendments and patients' informed consent forms will be approved before study commencement by the institutional review board or independent ethics committee at each participation site (Lead Ethics Committee; Japan Red Cross Medical Center (26 April 2019, order number 976)). Patients will be anonymised before registration into the study and their anonymised data will be collected from the case report form. The results of this study will be presented at the national and international conferences and submitted for publication. TRIAL REGISTRATION NUMBER: UMIN000038683.

Endobronchial hamartoma resected via bronchoscopy using high-frequency electrosurgical snare-Preoperative strategies using virtual bronchoscopy.

Pulmonary hamartomas are common benign lung tumors; however, endobronchial hamartomas are relatively rare. We report a case of asymptomatic endobronchial hamartoma in a 51-year-old man. Chest computed tomography revealed a 10-mm protrusion in the right main bronchus. Preoperative virtual bronchoscopy (VBS) was performed; subsequently, minimally invasive bronchoscopic resection was safely performed under local anesthesia. The use of VBS is a useful treatment strategy and follow-up modality.

[Survival-related clinical factors of patients with advanced non-small cell lung cancer after 2000].

PURPOSE: To find new survival-related clinical factors in patients with non-small cell lung cancer (NSCLC) after 2000. PATIENTS AND METHOD: Two hundred one patients were registered with primary NSCLC from years 2000 to 2005. One hundred eighty-six patients were pathologically diagnosed with NSCLC (all patients in the group). These patients were reviewed after wards in order to find any new survival-related clinical factors. RESULTS: One hundred forty-nine patients had adenocarcinoma. Median age was 68 years old, and median performance status (PS) was 1. Fifty-nine patients were treated with gefitinib, which is an epidermal growth factor receptor (EGFR)- tyrosine kinase inhibitor (TKI). In initial treatment, 22 patients were given gefitinib, and 37 patients after secondary treatment. Sixteen patients were managed with the best supportive care, and 12 patients were not allowed to know their precise treatment. These 28 patients were excluded from the all patients group i. e., the treated patients group. In multivariate analysis of this group, the PS, the treatment by gefitinib, the number of metastasized organs, and the serum total bilirubin were independent survival-related clinical factors. The median survival time without use of gefitinib was 46 weeks, and the survival times in first-line or more than first-line were 40 or 105 weeks, respectively (p = 0. 01). CONCLUSION: In addition to PS, the number of metastasized organs, and serum total bilirubin, treatment by gefitinib was considered to be one of the survival-related clinical factors in unselected patients with NSCLC.

Current state and prospect of the perioperative strategy for non-small cell lung cancer.

This paper provides an overview of perioperative treatment for non-small cell lung cancer (NSCLC), including the current widespread use of cytotoxic anticancer agents, promising molecular targeted agents, and immuno-checkpoint inhibitors. Multiple clinical trials have confirmed that postoperative chemotherapy with cytotoxic anticancer agents should be given for stage IIB to III (according to the 8th edition of the TNM classification for NSCLC) if possible, and preoperative treatment also is recommended for patients with N2 or higher stage. However, advances in concurrent chemoradiotherapy are expected to change the significance of neoadjuvant therapy. Perioperative treatment with molecular targeted agents appears to extend disease-free survival, but there is currently no evidence that it can extend overall survival. Perioperative treatment with immune checkpoint inhibitors requires further evidence but is likely to be effective. Although perioperative treatment of NSCLC could be costly it continues to evolve in hopes of a cure.

Diagnosis of miliary nodules as lung adenocarcinoma by cryobiopsy: A case report.

A 62-year-old woman with rheumatoid arthritis and a history of receiving immunosuppressant therapy had a recurrence of lung adenocarcinoma with EGFR L858R mutation. Following 14 months of treatment with erlotinib, computed tomography (CT) findings revealed the presence of small diffuse nodules. Bronchoscopy was performed as metastasis was suspected; however, this was not detected on lung biopsy with forceps. Transbronchial lung cryobiopsy (TBLC) succeeded in detecting metastatic adenocarcinoma, and T790M and L858R gene mutations. Pathological examination revealed a cluster of tumor cells in the intralobular interstitial areas, which was consistent with the CT findings. This report provides important information regarding the role of TBLC in diagnosing metastatic cancer, such as diffuse small miliary nodules, and its genetic mutations.

Usefulness of Jackson mask ventilation during bronchoscopy in patients with acute respiratory failure: A retrospective review.

ABSTRACT: Bronchoscopy is a procedure for diagnosis and treatment decision-making in patients with lung disease, especially those with acute respiratory failure. However, the optimal bronchoscopic method for patients with acute respiratory failure is not known. Therefore, in the real world, we sometimes hesitate to perform bronchoscopy in such patients because of safety and have experienced treating patients without bronchoscopy. To address this problem, we evaluated the usefulness and safety of Jackson mask ventilation, a novel noninvasive method of bronchoscopy performed under mask ventilation using the Jackson Rees circuit, in patients with acute respiratory failure.We retrospectively reviewed patients with acute respiratory failure who underwent bronchoscopy at our institution between January 2015 and May 2018. We compared patients who received Jackson mask ventilation (Jackson group) and those who received conventional oxygen administration (conventional group). Mean percutaneous oxygen saturation (SpO2) and mean oxygen flow rate were compared between the groups by the Wilcoxon signed-rank test. We excluded patients who were intubated and those without acute respiratory failure who received Jackson mask ventilation preventively.Of 1262 patients who underwent bronchoscopy, 12 were classified into the Jackson group and 13 into the conventional group. Proper oxygenation was maintained in the Jackson group, with SpO2 increasing after Jackson mask ventilation (89.4% to 96.8%, P = .03). Mean SpO2 was significantly higher in the Jackson group than in the conventional group (96.8% vs 95.2%, P = .03). Mean oxygen flow rate was significantly lower in the Jackson group (4.0 L/min vs 7.9 L/min, P < .001). There was no significant difference in safety.Our findings suggest that Jackson mask ventilation is safe and effective when performing bronchoscopy in patients with acute respiratory failure. Jackson mask ventilation maintained proper oxygenation and decreased the oxygen flow rate compared with the conventional method. Using Jackson mask ventilation, we could perform bronchoscopy safely and effectively in patients with acute respiratory failure, including some who had unstable respiratory status. (UMIN000038481).

Nivolumab-Induced Periaortitis Demonstrated by FDG PET/CT.

A 66-year-old man with a history of non-small cell lung cancer treated with nivolumab underwent contrast-enhanced CT and FDG PET/CT. No recurrence was demonstrated; however, soft-tissue thickening that showed delayed contrast enhancement and FDG uptake was detected around an abdominal aortic aneurysm. After discontinuation of nivolumab, the periaortic lesion disappeared within 2 months, indicating nivolumab-induced periaortitis. Immune checkpoint inhibitors such as nivolumab can cause vasculitis and periaortitis, a potentially fatal condition, as immune-related adverse events. The underlying aortic aneurysm may have contributed to genesis of periaortitis. FDG PET/CT can be useful for detecting periaortitis and excluding other forms of vasculitis.

Phase I/II Study of Erlotinib to Determine the Optimal Dose in Patients With Non-Small Cell Lung Cancer Harboring Only EGFR Mutations.

The recommended daily dose of erlotinib was determined for patients with all types of non-small cell lung cancer (NSCLC). We determined the optimal dose (OD) in patients with NSCLC harboring only epidermal growth factor receptor (EGFR) sensitizing mutations. EGFR-tyrosine kinase inhibitor-naïve patients with sensitizing mutations were eligible. Clinical OD was determined in a phase I/II study based on the continual re-assessment method (CRM) of both disease control and dose-limiting toxicity, defined as any toxicity of grade 2 (G2) or higher within 8 weeks. We also determined the pharmacologic OD via a pharmacokinetic (PK) study. Thirty-eight patients were enrolled. Clinical OD was 25 mg/day by the CRM. Median progression-free survival (mPFS) was 9.3 months. In receiver operating characteristic (ROC) analysis of mPFS, the trough concentration ( C min ss ) was ≥ 0.30 µg/mL. The area under the curve (AUC) and C min ss were predicted via population PK (PopPK) or a bootstrap of 100 iterations (PopPK100 ). TOX20 was defined as < 20% duration of any toxicity ≥ G2 during the PFS period. In ROC analysis of mPFS and TOX20 in the PopPK100 study, C min ss was ≥ 0.17 and < 0.32 µg/mL, respectively. In ROC analysis of mPFS and TOX20 in the PopPK100 study, C min ss was ≥ 0.15 and < 0.31 µg/mL, AUC was ≥ 14.4 and < 14.5 µg/mL•hour, and the dosage was ≥ 58.4 and < 58.8 mg/day, respectively. Clinical and pharmacologic ODs were 25 by CRM and 50-60 mg/day by PK, respectively. The proposed starting OD is 50-60 mg/day, with personalized adjustment of 0.15-0.31 µg/mL based on C min ss as determined by PopPK monitoring.

Pembrolizumab-related pancreatitis with elevation of pancreatic tumour markers.

Lung cancer immunotherapy is an effective treatment option; however, it can be hampered by adverse events, including pancreatitis, associated with excessive immune activation. Here, we report the case of a 70-year-old patient who presented with recurrent lung squamous carcinoma and was started with pembrolizumab treatment (200 mg every three weeks). The patient developed pembrolizumab-induced pancreatitis. After 14 months of pembrolizumab treatment, positron emission tomography-computed tomography showed a tumour-shaped, highly integrated lesion at the pancreatic head and significantly elevated tumour markers, including carbohydrate antigen 19-9 (149.3 U/mL), s-pancreas antigen-1 (44.7 U/mL), and duke pancreatic monoclonal antigen type 2 (412 U/mL). Pembrolizumab-induced immune-related pancreatitis was effectively treated with prednisolone 90 mg (1 mg/kg/day). Four months later, normal levels of the three specific tumour markers were detected, with improved pancreatic enzymes and radiographic findings. To our knowledge, this is the first reported case of immune-related pancreatitis with elevated pancreatic cancer-specific markers.

IgG4-related disease with elevated adenosine deaminase in pleural effusion diagnosed clinically using thoracoscopy under local anesthesia and FDG-PET-CT.

In general, we have to assume tuberculous pleurisy when a patient presents with pleural effusion and elevated adenosine deaminase (ADA). However, other diseases need to be considered, including immunoglobulin (Ig)G4-related disease (IgG4-RD). This case involved a 65-year-old asymptomatic man with right pleural effusion showing elevated ADA. He had no articular findings or rashes. Results were negative for all autoantibodies. Pleura, mediastinal lymph nodes, and areas around the aorta and vertebra showed high uptake of 18F-fluorodeoxyglucose (FDG) on positron-emission tomography-computed tomography (PET-CT). These findings were specific for IgG4-RD. Based on the results of FDG-PET-CT, we performed thoracoscopy under local anesthesia and bronchoscopy. Pleural biopsy and culture, and other examinations including sputum and blood yielded negative findings for tuberculous pleurisy. A pleural biopsy specimen showed IgG4-positive plasma cells and fibrosis without obliterative phlebitis or storiform fibrosis, and serum IgG4 was also high. The ratio of IgG4-to IgG-positive plasma cells was under 40%, and >10 IgG4-positive cells were seen in high-power fields. This case was classed as 'possible IgG4-RD' on the comprehensive diagnostic criteria for IgG4-RD, but did not meet the diagnostic criteria for IgG4-related respiratory disease. Prednisolone proved effective against the pleural effusion. We therefore clinically diagnosed IgG4-RD with pleural effusion based on the 2019 classification criteria for IgG4-RD in the United States. Although few cases of IgG4-RD with pleural effusion have been reported, this disease needs to be considered among the differential diagnoses for high-ADA pleural effusion. FDG-PET-CT and thoracoscopy under local anesthesia may be helpful for diagnosis.

Cost-effectiveness of bronchial thermoplasty for severe asthmatic patients in Japan.

Bronchial thermoplasty (BT) is an interventional endoscopic treatment for severe bronchial asthma. Some studies have shown the clinical efficacy of this intervention, but its cost-effectiveness is unclear. The aim of this study was to evaluate the cost-effectiveness of BT. We collected data from the medical records of 16 Japanese patients who were treated with BT between February 2015 and April 2017, and compared asthma-related medical expenses between the year preceding and the year following BT. Four patients were Global Initiative for Asthma (GINA) treatment step 4, and 12 were step 5. In 8 patients who had a successful response to BT, the annual asthma-related medical expenses decreased because of a reduction in hospitalization and emergency outpatient visits due to asthma attacks, and termination of the use of biologics. Most patients in the non-responder group had increased asthma-related medical costs postoperatively. The main reason for the increase in medical costs was the add-on treatment of biologics. BT was cost-effective in the responder group. If its effects continue for more than 10 years, BT will be a cost-effective treatment. Medical costs will be reduced if those who respond to BT can be identified prior to commencement of treatment.