Inflammatory myofibroblastic tumor directly invading the right first rib treated with oral steroids: a case report.

BACKGROUND: We present a case of an inflammatory myofibroblastic tumor cured with a short period of steroid administration, a treatment previously unreported for such cases. CASE PRESENTATION: A 49-year-old man had a chief complaint of chest pain for more than 3 days. Computed tomography (CT) revealed a tumoral lesion suspected to have infiltrated into the right first rib and intercostal muscles, with changes in lung parenchymal density around the lesion. The maximal standardized uptake value on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography was high (16.73), consistent with tumor presence. CT-guided biopsy revealed an inflammatory myofibroblastic tumor with no distant metastases. Surgery was indicated based on the disease course. However, he had received an oral steroid before the preoperative contrast-enhanced CT scan due to a history of bronchial asthma, and subsequent CT showed that the tumor shrank in size after administration; he has been recurrence-free for more than a year. CONCLUSIONS: Surgery is still the first choice for inflammatory myofibroblastic tumors, as the disease can metastasize and relapse; however, this condition can also be cured with a short period of steroid therapy.

Transcriptome genetic differences between responders and non-responders before bronchial thermoplasty.

BACKGROUND: Bronchial thermoplasty (BT) is an endoscopic therapy used for the treatment of refractory asthma. Some predictive factors, for example the number of activations and severity of disease at baseline, have been used to determine the effectiveness of BT in treating patients with asthma. The aim of the present study was to comprehensively analyze RNA samples from the airway bronchial tissues of patients with severe asthma treated by BT, and to characterize each patient as a BT responder or non-responder. METHODS: Eight patients with severe asthma scheduled to undergo BT and bronchus biopsies were recruited before the procedures were conducted. Extracted RNA samples from bronchial tissues were sequenced and differential gene expression analysis was carried out.Results/discussion: Subjects with Asthma Quality of Life Questionnaire score changes ≥0.5 for a period of 12 months were considered BT responders. Non-responders had score changes <0.5 for 12 months. Histopathology findings were similar to those reported previously, and no significant differences in the expression of α-smooth muscle actin and protein gene product 9.5 were observed between responders and non-responders. Transcriptome analysis at baseline identified 67 genes that were differentially expressed between responders and non-responders, including SLPI, MMP3, and MUC19, which were upregulated in responders. Although the differentially expressed gene products may have conflicting effects, genes in the airway epithelium and extracellular matrix of patients with severe asthma may determine the BT response. Our results identified possible transcriptomic changes that could be used to identify BT responders.

Activation of murine invariant NKT cells promotes susceptibility to candidiasis by IL-10 induced modulation of phagocyte antifungal activity.

Invariant NKT (iNKT) cells play an important role in a variety of antimicrobial immune responses due to their ability to produce high levels of immune-modulating cytokines. Here, we investigated the role of iNKT cells in host defense against candidiasis using Jα18-deficient mice (Jα18(-/-) ), which lack iNKT cells. Jα18(-/-) mice were more resistant to the development of lethal candidiasis than wild-type (WT) mice. In contrast, treatment of WT mice with the iNKT cell activating ligand α-galactosylceramide markedly enhanced their mortality after infection with Candida albicans. Serum IL-10 levels were significantly elevated in WT mice in response to infection with C. albicans. Futhermore, IL-10 production increased after in vitro coculture of peritoneal macrophages with iNKT cells and C. albicans. The numbers of peritoneal macrophages, the production of IL-1ß and IL-18, and caspase-1 activity were also significantly elevated in Jα18(-/-) mice after infection with C. albicans. The adoptive transfer of iNKT cells or exogenous administration of IL-10 into Jα18(-/-) reversed susceptibility to candidiasis to the level of WT mice. These results suggest that activation of iNKT cells increases the initial severity of C. albicans infection, most likely mediated by IL-10 induced modulation of macrophage antifungal activity.

T-cell-restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung.

Although overexpression of T-bet, a master transcription factor in type-1 helper T lymphocytes, has been reported in several hematologic and immune diseases, its role in their pathogenesis is not fully understood. In the present study, we used transgenic model mice (T-bet(tg/wt) and T-bet(tg/tg)) to investigate the effects of T-bet overexpression selectively in T lymphocytes on the development of hematologic and immune diseases. The results showed that T-bet overexpression in T cells spontaneously induced maturation arrest in the mononuclear phagocyte lineage, as well as spontaneous dermatitis and pulmonary alveolar proteinosis (PAP)-like disease in T-bet(tg/wt) and T-bet(tg/tg) mice, respectively. T-bet(tg/tg) alveoli with the PAP phenotype showed remarkable reorganization of alveolar mononuclear phagocyte subpopulations and impaired function, in addition to augmented T-cell infiltration. In addition, PAP development in T-bet(tg/tg) mice was found to be associated with increased migration of myeloid cells from the bone marrow into the peripheral blood. These findings reveal an unexpected link between T-bet overexpression in T lymphocytes and the development of PAP caused by reorganization of mononuclear phagocytes in the lung, and provide new insight into the molecular pathogenesis of secondary PAP accompanied by hematologic disorders.

[Use of Transdermal Fentanyl in a Hospital].

Recently, the use of transdermal fentanyl (TDF) has been increasing at our hospital owing to its convenience. Furthermore, TDF tends to be increasingly used for patients who have never used opioids. However, the appropriate criteria for indicating TDF have not been established yet. Therefore, we examined how TDF was prescribed in practice and determined its effective dosage. In 43 cases, the reasons, effects, and side effects of TDF were investigated retrospectively. Of the patients, 60% continued using TDF for 30 days. Meanwhile, approximately 25% of them terminated TDF therapy within 8 days. Of those who discontinued TDF therapy, some entirely stopped taking TDF and others chose other opioids instead because of poor pain control. Before receiving TDF therapy, 17 patients (45%) used oxycodone and 14 (37%) never used opioids. In addition, the main reason for starting TDF in opioid-naive patients was gastrointestinal condition. Between opioid-naive and opioid-using groups, no significant differences were observed in usage duration and incidence of side effects. The side effects included somnolence in 6 patients, delirium in 2 patients, and nausea and vomiting, constipation, and breathing restraint in 1 patient each. TDF was considered as an effective treatment regardless of the previous use of opioids. Nonetheless, careful deliberation is necessary because of the slow effects and difficulty with dosage adjustment.

Real Clinical Practice of Combined Atezolizumab Plus Chemotherapy in Patients With Small Cell Lung Cancer.

BACKGROUND/AIM: Atezolizumab, an anti-PD-L1 antibody, has been increasingly administered in combination with chemotherapy to patients with small cell lung cancer (SCLC). This study aimed to determine how patients with extensive disease (ED) -SCLC responded to atezolizumab with chemotherapy and found factors affecting long-term response and survival. PATIENTS AND METHODS: This study focused on patients with SCLC who were treated with a combination of atezolizumab and chemotherapy in Japan between 2019 and 2023. Patient information and tumor response were analyzed, along with adverse events. We compared data and estimated survival probabilities. RESULTS: In our clinical trial, 95 patients with SCLC who received this treatment had a median progression-free survival of 6.0 months and a median overall survival of 15.0 months. Immune-related adverse events were observed in 13.7% of the patients, with grade 3 or higher in 5.3%. The efficacy and immune-related adverse events associated with this treatment regimen were comparable to those reported in previous clinical trials. Progression-free survival >2 years was observed in a small number of patients (5.3%). CONCLUSION: Our research will offer important insights for the future care of patients with extensive-stage SCLC by utilizing atezolizumab in combination with chemotherapy. Accumulation and confirmation of clinical practice results will have important implications for the future implementation of this therapy.

[Effectiveness of switching opioids from fentanyl patch to morphine injection].

Patients endure the switching of opioids from fentanyl patch to morphine injection to improve inadequate pain relief. We retrospectively examined the differences between the maintenance dose of morphine injection after switching, its estimated dose prior to switching, and some other factors. As a result, 8 out of 9 patients had pain control after switching. Also, patients who increased the dose of the fentanyl patch more than twice in a month before switching required a significantly lower maintenance dose for the estimated dose after switching (p < 0.05) than those who took less. In conclusion, switching opioids to morphine injection is very effective, both from the viewpoint of pain control and the reduction of the amount of opioids used for patients with poor pain control, who frequently increase their use of the fentanyl patch.

Patient profiling to predict response to bronchial thermoplasty in patients with severe asthma.

Bronchial thermoplasty is the only device-based nonpharmacological treatment approach for severe asthma. Current guidelines are cautious in recommending bronchial thermoplasty because of unknown patient response prediction. Recent research on bronchial thermoplasty includes up-to-date, state-of-the-art, and recent-advances reviews. However, these reviews provide a broad and general discussion on equipment, technique, patient selection, and patient management, with little evaluation of the predictors of a beneficial response. Predicting an optimal response to bronchial thermoplasty in patients with severe asthma remains elusive. The lack of reliable predictive markers means that bronchial thermoplasty remains a last-line treatment and makes profiling for predicting the response or efficacy a topic of study. Genetic changes are associated with airway remodeling. A gap in the literature exists regarding patient profiling to predict the response to bronchial thermoplasty in patients with severe asthma. Therefore, recently published omics data and genetic associations regarding the response to bronchial thermoplasty therapy should be reviewed. We present an up-to-date review of recent publications profiling the response to bronchial thermoplasty in patients with severe asthma.

A case of epidermal growth factor receptor tyrosine kinase inhibitor effectiveness in epidermal growth factor receptor mutation-positive squamous cell carcinoma.

A 71-year-old non-smoker woman was admitted to our hospital because of left front chest pain. A computed tomography scan showed a large mass of >7.0 cm in the lower left part of the lung and multiple organ metastases in the liver, brain, bone, and left adrenal gland. Pathological analysis of a resected specimen obtained by bronchoscopy revealed keratinization. In addition, p40 was positive and thyroid transcription factor-1, synaptophysin, CD56, and chromogranin A were negative by immunohistochemistry. Programmed cell death ligand 1 expression was 1%-10%, and exon 19 deletion was detected. We diagnosed the patient with stage IVB lung squamous cell carcinoma and administered osimertinib. Osimertinib was later replaced with afatinib because of grade 3 skin rash. Overall, the size of the cancer was decreased. Furthermore, her symptoms, laboratory data, and computer tomographic findings markedly improved. In summary, we experienced a case of epidermal growth factor receptor-positive lung squamous cell carcinoma that was responsive to epidermal growth factor receptor tyrosine kinase inhibitors.

Atezolizumab Monotherapy for Non-small Cell Lung Cancer Patients: An Observational Study in Ibaraki Group (ATTENTION-IBARAKI).

BACKGROUND/AIM: Atezolizumab is a monoclonal antibody that targets programmed death-ligand 1 (PD-L1) expressed on cancer cells derived from various organs and antigen-presenting cells and is currently commonly used in combination with chemotherapy. We conducted a study to clarify the current status of response to atezolizumab monotherapy in clinical practice and clarify the factors that contribute to long-term response and survival. PATIENTS AND METHODS: We conducted a retrospective review of patients with advanced non-small cell lung cancer (NSCLC) treated with atezolizumab monotherapy from April 2018 to March 2023 at 11 Hospitals. RESULTS: The 147 patients evaluated had a progression-free survival (PFS) of 3.0 months and an overall survival of 7.0 months. Immune-related adverse events of any grade were observed in 13 patients (8.8%), grade 3 or higher in nine patients (6.1%), and grade 5 with pulmonary toxicity in one patient (0.7%). Favorable factors related to PFS were 'types of NSCLC other than adenocarcinoma'. Favorable factors for overall survival were 'performance status 0-1' and 'treatment lines up to 3'. There were 16 patients (10.9%) with PFS >1 year. No characteristic clinical findings were found in these 16 patients compared to the remaining 131 patients. CONCLUSION: Efficacy and immune-related adverse events of NSCLC patients associated with atezolizumab monotherapy were comparable to those of previous clinical trial results. Knowledge of characteristics of patients who are most likely to benefit from atezolizumab monotherapy is a crucial step towards implementing appropriate prescribing.

Atezolizumab for EGFR-mutated Non-small Cell Lung Cancer Patients: An Observation Study in Ibaraki Group (ATTENTION-IBARAKI).

BACKGROUND/AIM: Atezolizumab, an anti-programed death-ligand 1 monoclonal antibody, targets programed death-ligand 1 expressed on cancer cells and antigen-presenting cells and is now commonly used in combination with chemotherapy. We conducted a study to clarify the efficacy of atezolizumab in epidermal growth factor receptor (EGFR)-mutated patients who are considered less responsive to immune checkpoint inhibitors. PATIENTS AND METHODS: A retrospective review of patients with advanced non-small cell lung cancer (NSCLC) who received atezolizumab-containing therapy at 11 hospitals from April 2018 to March 2023 was performed. RESULTS: Median progression-free survival and overall survival in 33 EGFR-mutated patients treated with atezolizumab monotherapy were 2.0 and 9.0 months, respectively, and those in 19 patients who received combined atezolizumab plus chemotherapy were 12.0 and 17.0 months, respectively. When comparing EGFR-mutated and EGFR-negative patients after propensity score matching, there were no significant differences in progression-free survival and overall survival between the two groups, whether atezolizumab monotherapy or combined atezolizumab plus chemotherapy. Among EGFR-mutated patients, being male was a significant favorable factor in both atezolizumab treatment groups. None of the EGFR-mutated patients had grade 5 immune-related adverse events. CONCLUSION: Efficacy of atezolizumab in EGFR-mutated NSCLC patients could be comparable to that for EGFR-negative patients. To prolong the survival of EGFR-mutated NSCLC patients, appropriate selection and sequencing of EGFR for tyrosine kinase inhibitors, as well as immune checkpoint inhibitors, anti-tumor agents, and anti-angiogenic agents are important.

[Syndrome of inappropriate secretion of ADH following chemoradiation therapy].

We report a 69-year-old female patient with pulmonary adenocarcinoma complicated by the syndrome of inappropriate secretion of antidiuretic hormone(SIADH)following systemic chemotherapy with cisplatin(CDDP)and vinorelbine(VNR). She was admitted to our hospital for chemo-radiotherapy for advanced lung cancer, and became restless 4 hours after the administration of CDDP and VNR. Symptoms such as restlessness and incontinence were worsening despite the massive infusion that was completed. Laboratory examinations on day 6 after chemotherapy showed severe hyponatremia(107mEq/L)with decreased serum osmolarity(227mOsm/L)and increased urine osmolarity(452mOsm/L). The serum anti-diuretic hormone(ADH)level was elevated to 16. 7 pg/mL despite severe hyponatremia. She was diagnosed with SIADH and was treated with hypertonic saline infusion and fluid restriction. Her restlessness and other psychiatric symptoms were improved. The use of carboplatin and VNR in the subsequent course did not develop SIADH, indicating that the SIADH was induced by CDDP. Although SIADH following CDDP administration is rare, the electrolyte balance should be carefully monitored throughout the clinical course of chemo-radiation therapy, when psychiatric symptoms are found in patients with lung cancer.

Prognostic Implication of PD-L1 Expression on Osimertinib Treatment for EGFR-mutated Non-small Cell Lung Cancer.

BACKGROUND/AIM: Real-world data on the clinical outcomes of first-line osimertinib treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations is lacking. This study aimed to reveal the treatment outcomes and prognostic factors of osimertinib as first-line therapy in clinical practice settings. PATIENTS AND METHODS: We retrospectively evaluated clinical outcomes of patients with EGFR-mutated NSCLC treated with osimertinib as first-line therapy across 12 institutions in Japan between August 2018 and March 2020. RESULTS: Among 158 enrolled patients, the objective response rate (ORR) was 68%, and the estimated median progression-free survival (PFS) was 17.1 months [95% confidence interval (CI)=14.5-19.7]. Subgroup analysis showed that PFS in the group with high programmed death-ligand 1 (PD-L1) expression was significantly shorter than that in groups with low or no PD-L1 expression (10.1 vs. 16.1 vs. 19.0 months; p=0.03). Univariate and multivariate analyses demonstrated that high PD-L1 expression was the only independent adverse prognostic factor of osimertinib outcome related to PFS (hazard ratio=2.71; 95%CI=1.26-5.84; p=0.01). In terms of anti-tumor response, there was no statistically significant correlation between PD-L1 expression and the ORR (67% vs. 76% vs. 65%; p=0.51). No significant correlation was also found between PD-L1 and the incidence of de novo resistance to osimertinib (p=0.39). CONCLUSION: Although PD-L1 expression was not associated with either the ORR or frequency of de novo resistance, high PD-L1 expression could be an independent adverse prognostic factor related to PFS in osimertinib treatment.

Aggravation of bleomycin-induced pulmonary inflammation and fibrosis in mice lacking peroxiredoxin I.

Oxidative stress plays an important role in the pathogenesis of acute lung injury and pulmonary fibrosis. Peroxiredoxin (Prx) I is a cellular antioxidant enzyme induced under stress conditions. In the present study, the protective effects of Prx I on the development of bleomycin-induced acute pulmonary inflammation and pulmonary fibrosis were investigated using Prx I-deficient mice. Survival of Prx I-deficient mice after bleomycin administration was significantly lower than that of wild-type mice, corresponding with enhanced acute pulmonary inflammation and fibrosis. The level of inflammatory cytokines and chemokines, such as TNF-α, macrophage inflammatory protein-2, and monocyte chemotactic protein-1, was significantly elevated in the bronchoalveolar lavage fluid of Prx I-deficient mice after bleomycin administration. Furthermore, the level of 8-isoprostane, an oxidative stress marker, and the concentration and alveolar macrophage expression of macrophage migration inhibitory factor were elevated in the lungs of Prx I-deficient mice after bleomycin administration. The exacerbation of bleomycin-induced pulmonary inflammation and fibrosis in Prx I-deficient mice was inhibited by treatment with N-acetyl-L-cysteine, a radical scavenger, or with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester, a tautomerase inhibitor of macrophage migration inhibitory factor. These findings suggest that mice lacking Prx I are highly susceptible to bleomycin-induced pulmonary inflammation and fibrosis because of increases in pulmonary oxidant levels and macrophage migration inhibitory factor activity in response to bleomycin.

Payao: a community platform for SBML pathway model curation.

SUMMARY: Payao is a community-based, collaborative web service platform for gene-regulatory and biochemical pathway model curation. The system combines Web 2.0 technologies and online model visualization functions to enable a collaborative community to annotate and curate biological models. Payao reads the models in Systems Biology Markup Language format, displays them with CellDesigner, a process diagram editor, which complies with the Systems Biology Graphical Notation, and provides an interface for model enrichment (adding tags and comments to the models) for the access-controlled community members. AVAILABILITY AND IMPLEMENTATION: Freely available for model curation service at http://www.payaologue.org. Web site implemented in Seaser Framework 2.0 with S2Flex2, MySQL 5.0 and Tomcat 5.5, with all major browsers supported. CONTACT: kitano@sbi.jp

Impairment of host defense against disseminated candidiasis in mice overexpressing GATA-3.

Candida species are the most common source of nosocomial invasive fungal infections. Previous studies have indicated that T-helper immune response is the critical host factor for susceptibility to Candida infection. The transcription factor GATA-3 is known as the master regulator for T-helper type 2 (Th2) differentiation. We therefore investigated the role of GATA-3 in the host defense against systemic Candida infection using GATA-3-overexpressing transgenic mice. The survival of GATA-3-overexpressing mice after Candida infection was significantly lower than that of wild-type mice. Candida outgrowth was significantly increased in the kidneys of GATA-3-overexpressing mice, compared with wild-type mice. The levels of various Th2 cytokines, including interleukin-4 (IL-4), IL-5, and IL-13, were significantly higher while the level of Th1 cytokine gamma interferon was significantly lower in the splenocytes of GATA-3-overexpressing mice after Candida infection. Recruitment of macrophages into the peritoneal cavity in response to Candida infection and their phagocytic activity were significantly lower in GATA-3-overexpressing mice than in wild-type mice. Exogenous administration of gamma interferon to GATA-3-overexpressing mice significantly reduced Candida outgrowth in the kidney and thus increased the survival rate. Administration of gamma interferon also increased the recruitment of macrophages into the peritoneal cavity in response to Candida infection. These results indicate that overexpression of GATA-3 modulates macrophage antifungal activity and thus enhances the susceptibility to systemic Candida infection, possibly by reducing the production of gamma interferon in response to Candida infection.

Nrf2 protects against pulmonary fibrosis by regulating the lung oxidant level and Th1/Th2 balance.

BACKGROUND: Pulmonary fibrosis is a progressive and lethal disorder. Although the precise mechanisms of pulmonary fibrosis are not fully understood, oxidant/antioxidant and Th1/Th2 balances may play an important role in many of the processes of inflammation and fibrosis. The transcription factor Nrf2 acts as a critical regulator for various inflammatory and immune responses by controlling oxidative stress. We therefore investigated the protective role of Nrf2 against the development of pulmonary fibrosis. METHODS: To generate pulmonary fibrosis, both wild-type C57BL/6 mice and Nrf2-deficient mice of the same background were administered bleomycin intratracheally. RESULTS: The survival of Nrf2-deficient mice after bleomycin administration was significantly lower than that of wild-type mice. The degree of bleomycin-induced initial pulmonary inflammation and pulmonary fibrosis was much more severe in Nrf2-deficient mice than in wild-type mice. The expression of antioxidant enzymes and phase II detoxifying enzymes was significantly reduced in the lungs of Nrf2-deficient mice, concomitant with an elevation of lung 8-isoprostane level, compared with wild-type mice. The expression of Th2 cytokines, such as interleukin-4 and interleukin-13, was significantly elevated in the lungs of Nrf2-deficient mice with an increase in the number of Th2 cells that express GATA-binding protein 3. CONCLUSIONS: The results indicated that Nrf2 protects against the development of pulmonary fibrosis by regulating the cellular redox level and lung Th1/Th2 balance. Thus, Nrf2 might be an important genetic factor in the determination of susceptibility to pulmonary fibrosis.

Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer.

PURPOSE: NF-E2-related factor 2 (Nrf2), a key transcription regulator for antioxidant and detoxification enzymes, is abundantly expressed in cancer cells. In this study, therefore, the role of Nrf2 in cancer cell proliferation and resistance to anticancer drugs was investigated. EXPERIMENTAL DESIGN: We used three human lung cancer cell lines with different degrees of Nrf2 activation: Nrf2 was highly activated in A549 cells, slightly activated in NCI-H292 cells, and not activated in LC-AI cells under unstimulated conditions. RESULT: A549 cells showed higher resistance to cisplatin compared with NCI-H292 and LC-AI cells. The resistance to cisplatin was significantly inhibited in A549 but not in NCI-H292 or LC-AI cells by knockdown of Nrf2 with its specific small interfering RNA (Nrf2-siRNA). The cell proliferation was also most prominently inhibited in A549 cells by treatment with Nrf2-siRNA. In A549 cells, the expression of self-defense genes, such as antioxidant enzymes, phase II detoxifying enzymes, and drug efflux pumps, was significantly reduced by Nrf2-siRNA concomitant with a reduction of the cellular glutathione level. The degree of DNA crosslink and apoptosis after treatment with cisplatin was significantly elevated in A549 cells by Nrf2-siRNA. Knockdown of Nrf2 arrested the cell cycle at G(1) phase with a reduction of the phosphorylated form of retinoblastoma protein in A549 and NCI-H292 cells but not in LC-AI cells. CONCLUSION: These results indicate that the Nrf2 system is essential for both cancer cell proliferation and resistance to anticancer drugs. Thus, Nrf2 might be a potential target to enhance the effect of anticancer drugs.

[A case of Henoch-Schönlein purpura which was difficult to distinguish from a skin rash associated with gefitinib].

A 52-year-old woman with advanced non-small cell lung cancer was admitted to our hospital with melena and palpable purpura which appeared on her lower legs. She had been taking gefitinib for about 2 months before admission. A skin biopsy revealed leukocytoclastic vasculitis in the superficial dermis and immunofluorescence also showed the presence of C3 depositions within the blood vessel walls, which led to a diagnosis of Henoch-Schönlein purpura. The purpura gradually improved with topical steroids and bed rest; however, gefitinib had to be discontinued because of a growing papulopustular rash with intense itching, and as a result of the discontinuation, both types of skin lesions resolved. Two months later, she resumed gefitinib treatment since her level of CEA began to rise. Even though the papulopustular rash developed after the readministration of gefitinib, there had been no evidence of Henoch-Schönlein purpura recurrence during 2.5 years follow-up. It has been reported that adult onset Henoch-Schönlein purpura is often associated with malignancy. This case, however, suggests that not only drug eruption but also paraneoplastic vasculitis should be considered in the differential diagnosis of palpable purpura in patients with non-small cell lung cancer receiving treatment with gefitinib.

Low-Dose Erlotinib Treatment in Elderly or Frail Patients With EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter Phase 2 Trial.

Importance: Although the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for EGFR gene mutation-positive non-small cell lung cancer is well established, optimal dosing remains to be established, especially in elderly or frail patients. Objective: To investigate the efficacy and safety of low-dose erlotinib in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer. Design, Setting, and Participants: Single-arm phase 2 trial with the Southwest Oncology Group (SWOG) 2-stage design that enrolled frail patients from 21 Japanese institutions after meeting the inclusion criteria. Chemotherapy-naive patients with EGFR-activating mutation-positive non-small cell lung cancer who were considered frail based on age, the Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status were eligible for the study. Interventions: Patients were initially administered 50 mg/d erlotinib for 4 weeks, which was modified based on response or adverse events. Dose increase was permitted for patients with stable disease after 4 weeks. Main Outcomes and Measures: The primary end point was the independent review committee-confirmed objective response rate (ORR) at the dose of 50 mg/d. The study also evaluated the pharmacokinetics of low-dose erlotinib and influence of ABCB1 gene polymorphisms. Results: Eighty patients were enrolled, with a median (range) age of 80 (49-90) years; 54 (68%) were men. An independent review committee confirmed a significant ORR of 60.0% (90% CI, 50.2%-69.2%). The disease control rate was 90.0% (90% CI, 82.7%-94.9%), median progression-free survival was 9.3 months (95% CI, 7.2-11.4 months), and median overall survival was 26.2 months (95% CI, 21.9-30.4 months). Mild adverse events were observed in some participants, with few patients exhibiting grade 3 or greater adverse events. Low-dose erlotinib treatment was temporarily suspended for 10 patients owing to adverse events. Five of 80 patients (6%) had their erlotinib dose reduced to 25 mg because of oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia. Two patients discontinued treatment because of adverse events (cutaneous ulcer and bone infection, and oral mucositis, respectively). There were no cases of interstitial lung disease or treatment-related deaths. The median (range) erlotinib plasma concentration was measured at 685 (153-1950) ng/mL. Seventy-three patients discontinued study treatment owing to disease progression (n = 60), death (n = 3), AEs (n = 4), and patient requests (n = 6). No clear association was observed between the pharmacokinetics of low-dose erlotinib and the treatment outcome. Conclusions and Relevance: Low-dose erlotinib appears to be safe and effective in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer and can be a valid treatment option. Trial Registration: UMIN-CTR Identifier: UMIN000015949.