Clinical characteristics of patients treated with immune checkpoint inhibitors in EGFR-mutant non-small cell lung cancer: CS-Lung-003 prospective observational registry study.

PURPOSE: Immune checkpoint inhibitors (ICIs) are ineffective against epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical characteristics of patients who were treated or not treated with ICIs, and of those who benefit from immunotherapy in EGFR-mutant NSCLC. METHODS: We analyzed patients with unresectable stage III/IV or recurrent NSCLC harboring EGFR mutations using a prospective umbrella-type lung cancer registry (CS-Lung-003). RESULTS: A total of 303 patients who met the eligibility criteria were analyzed. The median age was 69 years; 116 patients were male, 289 had adenocarcinoma, 273 had major mutations, and 67 were treated with ICIs. The duration of EGFR-TKI treatment was longer in the Non-ICI group than in the ICI group (17.1 vs. 12.7 months, p < 0.001). Patients who received ICIs for more than 6 months were categorized into the durable clinical benefit (DCB) group (24 patients), and those who received ICIs for less than 6 months into the Non-DCB group (43 patients). The overall survival in the DCB group exhibited longer than the Non-DCB group (69.3 vs. 47.1 months), and an equivalent compared to that in the Non-ICI group (69.3 vs. 68.9 months). Multivariate analysis for time to next treatment (TTNT) of ICIs showed that a poor PS was associated with a shorter TTNT [hazard ratio (HR) 3.309; p < 0.001]. Patients who were treated with ICIs and chemotherapy combination were associated with a longer TTNT (HR 0.389; p = 0.003). In addition, minor EGFR mutation was associated with a long TTNT (HR 0.450; p = 0.046). CONCLUSION: ICIs were administered to only 22% of patients with EGFR-mutated lung cancer, and they had shorter TTNT of EGFR-TKI compared to other patients. ICI treatment should be avoided in EGFR mutated lung cancer with poor PS but can be considered for lung cancer with EGFR minor mutations. Pathological biomarker to predict long-term responders to ICI are needed.

Clinicogenomic Features and Targetable Mutations in NSCLCs Harboring BRAF Non-V600E Mutations: A Multi-Institutional Genomic Screening Study (LC-SCRUM-Asia).

INTRODUCTION: BRAF non-V600E mutations occur in 1% to 2% of NSCLCs. Because of their rarity, the clinical backgrounds and outcomes of cytotoxic chemotherapy or immunotherapy remain unclear, and no targeted therapies are approved for BRAF non-V600E-mutant NSCLC. METHODS: In this multi-institutional prospective lung cancer genomic screening project (LC-SCRUM-Asia), we evaluated the clinicogenomic characteristics and therapeutic outcomes of BRAF non-V600E-mutant NSCLC. RESULTS: From March 2015 to November 2021, a total of 11,929 patients with NSCLC were enrolled. BRAF mutations were detected in 380 (3.5%), including the V600E (class I) in 119 (31%) and non-V600E in 261; the non-V600E were functionally classified into class II (122, 32%), class III (86, 23%), and non-classes I to III. Smokers and having concurrent RAS gene family or TP53 mutations were more frequently associated with class II or III than with class I. In patients with class III as compared with class I, the progression-free survival in response to platinum-containing chemotherapies (median, 5.3 versus 11.5 mo, p < 0.01) and the overall survival (median, 14.5 versus 34.8 mo, p < 0.02) were significantly shorter. Furthermore, class IIa mutations were significantly more frequent in our Asian cohort than in previously reported cohorts. The clinicogenomic features associated with class IIa were similar to those associated with class I, and one patient with NSCLC with K601E had a good response to dabrafenib plus trametinib. CONCLUSIONS: Patients with NSCLCs with BRAF non-V600E, especially class III, were associated with poorer therapeutic outcomes than those with V600E. Furthermore, patients with NSCLC with class IIa had distinct clinicogenomic features, and further preclinical and clinical studies are needed to evaluate class IIa mutations as a therapeutic target.

A randomized phase II study of afatinib alone or combined with bevacizumab for treating chemo-naïve patients with non-small cell lung cancer harboring EGFR mutations.

BACKGROUND: Adding bevacizumab to first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) prolonged the progression-free survival (PFS), but limited data are available for second-generation EGFR-TKIs. AfaBev-CS is a randomized, phase II trial comparing afatinib plus bevacizumab and afatinib alone as first-line treatment. PATIENTS AND METHODS: Untreated patients with non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations (Del19 or L858R) were enrolled and randomly assigned to receive either afatinib (30 mg) plus bevacizumab (AfaBev group) or afatinib (40 mg) monotherapy (Afa group). The primary endpoint was PFS. The power was >50% under the assumptions of a median PFS of 12 months for the Afa group and hazard ratio (HR) of 0.6 for the AfaBev group. RESULTS: Between August 2017 and September 2019, 100 patients were enrolled. There was no significant difference in PFS between the groups. The median PFS was 16.3 and 16.1 months for the AfaBev and Afa groups, respectively, with an HR of 0.865 (95% confidence interval [CI], 0.539 to 1.388; p = 0.55). In terms of overall survival, there was no significant difference between the groups (HR, 0.84; 95% CI, 0.39 to 1.83; p = 0.67). The overall response rate was 82.6% and 76.6% in the AfaBev and Afa groups, respectively (p = 0.61). Grade ≥ 3 diarrhea, hypertension, acneiform rash, paronychia, and stomatitis were frequently observed in the AfaBev group. CONCLUSIONS: This study failed to show efficacy of AfaBev over Afa for improving PFS in untreated patients with EGFR-mutated NSCLC.

Real-World Data Analysis of Pembrolizumab Monotherapy for NSCLC Using Japanese Postmarketing All-Case Surveillance Data.

Introduction: Pembrolizumab is a programmed death-ligand 1 inhibitor that was initially indicated for monotherapy in patients with advanced lung cancer. The Japanese Lung Cancer Society conducted an observational study on pembrolizumab using confirmative data obtained through postmarketing all-case surveillance (PMACS), which was performed by a pharmaceutical company under the Japanese law in 2017. Methods: This multicenter observational study was conducted by the Japanese Lung Cancer Society using PMACS data with the newly created central registration system regarding patients with NSCLC who received pembrolizumab monotherapy between February 1, 2017 and June 30, 2017; a new database was created by adding the clinical information regarding prognosis for 3 years after therapy to the existing data collected by PMACS. Results: A total of 300 patients from 43 facilities were enrolled in this study. The median overall survival and progression-free survival after pembrolizumab initiation were 558 and 188 days, respectively. Moreover, the 1- and 3-year survival rates were 58.9% and 33.7%, respectively. Results of multivariate analysis revealed performance status (p < 0.0001), histology (p = 0.0118), previous chemotherapy (p = 0.0007), programmed death-ligand 1 expression status (p = 0.0195), and previous steroid use (p = 0.0460) as significant factors that affected overall survival. The toxicity profile was similar to that previously reported. Conclusions: In this first attempt to use PMACS data, we successfully collected clinical information and found the real-world efficacy and safety of pembrolizumab.

Pembrolizumab-induced aseptic meningitis in a patient with non-small cell lung cancer: A case report and literature review of aseptic meningitis as an immune-related adverse event.

Aseptic meningitis is a rare immune-related adverse event (irAE), which occurs during treatment with immune checkpoint inhibitors (ICIs). This condition has non-specific symptoms and exhibits no clear signs on magnetic resonance imaging (MRI). There are only a few reports of aseptic meningitis caused by pembrolizumab treatment for non-small cell lung cancer (NSCLC). The present study includes a report of such a case and a review of the related literature. A 67-year-old Japanese man received first-line pembrolizumab treatment for NSCLC and subsequently developed severe nausea and vomiting. No significant findings were observed following a computed tomography (CT) scan, MRI of the brain and upper gastrointestinal tract, or upper gastrointestinal endoscopy. Cerebrospinal fluid analysis revealed lymphocyte infiltration and elevation of the IgG index, without indications of metastasis or infection, which suggested the presence of aseptic meningitis. The symptoms immediately improved following prednisolone treatment, and aseptic meningitis was diagnosed as an irAE related to pembrolizumab treatment. Given that aseptic meningitis can cause non-specific symptoms, including headache and nausea, the possibility of an irAE should be considered in patients with non-specific symptoms who are receiving ICIs, and a cerebrospinal fluid examination should be performed.

First and repeat rebiopsy for detecting EGFR T790M mutation in non-small-cell lung cancer: CS-Lung-003 prospective observational registry study.

PURPOSE: Osimertinib is still essential for the treatment of epidermal growth factor receptor (EGFR)-T790M-positive non-small-cell lung cancer (NSCLC) even in a relapsed setting, which suggests the importance of rebiopsy. The clinical value of repeat rebiopsy in patients with NSCLC who are T790M-negative on a first rebiopsy remains unclear. In this study, we examined the status of the first rebiopsy and evaluated the frequency of repeat rebiopsy of T790M-negative tumors detected by the first rebiopsy. METHODS: We reviewed 144 patients with NSCLC with major EGFR mutations, but not T790M, who received first- or second-generation EGFR tyrosine kinase inhibitors (TKIs), registered in the prospective, umbrella-type lung cancer patient registry (CS-Lung-003). RESULTS: Overall, 63 patients (44%) underwent the first rebiopsy. In the first rebiopsy, 51 (81%) and 12 (19%) of 63 underwent histological/cytological rebiopsy and liquid biopsy with the blood sampling, respectively. In the repeat rebiopsy, 23 (85%) and 4 (15%) of 27 underwent histological/cytological rebiopsy and liquid biopsy, respectively. The most frequently rebiopsied site was a pulmonary lesion (n = 24, 38.7%). Overall, 29 (46.0%) of 63 patients harbored the T790M mutation. Interestingly, a high detection rate of cancer cells did not necessarily indicate a high detection rate of the T790M mutation (p < 0.01). Among 34 patients with T790M-negative tumors confirmed on the first rebiopsy, 20 (58.8%) underwent repeat rebiopsies following interval therapy, revealing that seven (36.8%) had T790M-positive tumors. Osimertinib yielded median progression-free survival of 11.8 and 16.2 months in patients with the 790M mutation detected by the first rebiopsy and repeat rebiopsy, respectively. CONCLUSION: In our prospective cohort, the T790M mutation was detected in 46% of patients who underwent the first rebiopsy. Repeat rebiopsy may increase the ability to detect the T790M mutation positivity rate.

The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer.

Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer (NSCLC)1. However, such oncogenic drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC2. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1-LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1-LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1-LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1-LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1-LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1-LTK fusion as a target in NSCLC that could be treated with lorlatinib.

Novel prospective umbrella-type lung cancer registry study for clarifying clinical practice patterns: CS-Lung-003 study protocol.

INTRODUCTION: Conventional cancer registries are suitable for simple surveillance of cancer patients, including disease frequency and distribution, demographics, and prognosis; however, the collected data are inadequate to clarify comprehensively diverse clinical questions in daily practice. METHODS: We constructed an umbrella-type lung cancer patient registry (CS-Lung-003) integrating multiple related prospective observational studies (linked studies) that reflect clinical questions about lung cancer treatment. The primary endpoint of this registry is to clarify daily clinical practice patterns in lung cancer treatment; a key inclusion criterion is pathologically diagnosed lung cancer. Under this registry, indispensable clinical items are detected in advance across all active linked studies and gathered prospectively and systematically to avoid excessive or insufficient data collection. Researchers are to input information mutually, irrespective of the relevance to each researcher's own study. Linked studies under the umbrella of the CS-Lung-003 registry will be updated annually with newly raised clinical questions; some linked studies will be newly created, while others will be deleted after the completion of the analysis. Enrollment began in July 2017. DISCUSSION: We successfully launched the umbrella-type CS-Lung-003 registry. Under this single registry, researchers collaborate on patient registration and data provision for their own and other studies. Thus, the registry will produce results for multiple domains of study, providing answers to questions about lung cancer treatment raised by other researchers. Through such analysis of each linked study, this registry will contribute to the comprehensive elucidation of actual daily practice patterns in lung cancer treatment. KEY POINTS: CS-Lung-003 registry directly integrates multiple linked studies created under the umbrella of this cancer registry to solve various clinical questions regarding daily practice patterns of lung cancer treatment.

Nivolumab-induced cholangitis in patients with non-small cell lung cancer: Case series and a review of literature.

Immune checkpoint inhibitors (ICIs), including nivolumab, have exhibited substantial benefits in the treatment of several types of cancers. However, treatment with ICIs is often accompanied by immune-related adverse events (irAEs), and a clear understanding of the precise indications and management of irAEs is important for harnessing the full potential of these agents. While skin- or gastrointestinal-associated irAEs have been relatively well studied, there are few reports regarding nivolumab-induced cholangitis. We retrospectively reviewed data from patients with advanced or recurrent non-small cell lung cancer who were treated with nivolumab between December 2015 and December 2018 at Tottori University in Japan. Among the 59 patients, we identified four patients who experienced nivolumab-induced cholangitis. Of these four patients, stable disease (SD) was observed in two patients (50%), while partial response (PR) was achieved in two patients (50%) under nivolumab treatment. Patients were treated with corticosteroid alone (n=2) or in combination with mycophenolate mofetil (MMF) (n=2); these treatments resulted in improvements in nivolumab-induced cholangitis in three patients. In conclusion, the present retrospective study identified four cases of nivolumab-induced cholangitis. The combination of corticosteroid and MMF was effective in two cases with grade 4 nivolumab-induced cholangitis. Further reports are needed to establish the optimal management of patients with this irAE.

Phase 2 Study of Afatinib Alone or Combined With Bevacizumab in Chemonaive Patients With Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations: AfaBev-CS Study Protocol.

Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), has demonstrated a significant survival benefit over platinum-based chemotherapy in a first-line setting in advanced non-small-cell lung cancer (NSCLC) harboring EGFR exon 19 deletion. In addition, we and other groups have shown there to be favorable progression-free survival (PFS) outcomes, with acceptable toxicity profiles, with bevacizumab and first-generation EGFR-TKI combination therapy. On the basis of the above, we hypothesized that a combination of bevacizumab and afatinib could potentially improve efficacy. In our phase 1 study, a daily 30 mg dose of afatinib and 15 mg/kg intravenous bevacizumab every 3 weeks was well tolerated and was defined as the recommended dose. We have initiated a randomized phase 2 trial comparing afatinib (30 mg daily) and bevacizumab (15 mg/kg every 3 weeks) with afatinib (40 mg daily) alone for nonsquamous NSCLC harboring EGFR common mutations as a first-line therapy. A total of 100 patients will be enrolled onto this study and randomized in a 1:1 ratio. Patients will continue to receive treatment until disease progression or unacceptable toxicity. The primary end point is PFS, and the secondary end points are overall survival, tumor response, and time to treatment failure. The power is greater than 50% under the assumptions of a median PFS of 12 months for the afatinib group and a hazard ratio of 0.6 for the combination group (2-sided α = 0.05). We hypothesize that the combination therapy will be more efficacious than standard therapies for EGFR-mutant NSCLC patients.

Acute-phase reaction induced by zoledronate and its effect on prognosis of patients with advanced non-small cell lung cancer.

OBJECTIVES: Zoledronate (ZOL) is usually used for prevention of skeletal-related events in cancer patients with bone metastases. The first administration of ZOL is occasionally associated with development of acute-phase reaction (APR), which is due to activation of γδ T cells. ZOL-related APR was associated with better overall survival (OS) of patients with non-small cell lung cancer (NSCLC) in our previous retrospective study. However, it remains to be clarified whether γδ T cells are more activated in patients who experienced ZOL-related APR, and whether γδ T cell activation is involved in prolongation of OS. MATERIALS AND METHODS: Twenty-three patients with advanced NSCLC were recruited between 2012 and 2014 in this study. We administered ZOL to participants with standard care. The patient characteristics, change in γδ T cell counts and cytokines, OS, and skeletal-related event-free survival were compared between patients with APR (APR group) and those without APR (non-APR group). RESULTS: Ten patients (43.5%) experienced a ZOL-related APR. The number of γδ T cells at baseline in the APR group was significantly higher than that in the non-APR group. Serum interleukin-6 and tumor necrosis factor-α in the APR group were significantly increased, but no change in the number of γδ T cells was observed after the first administration of ZOL in both groups. OS in the APR group was significantly longer than that in the non-APR group (median survival time: 23.1 vs. 14.5 months, p < 0.01). CONCLUSION: We showed that APR is related to higher numbers of γδ T cells at baseline and increased cytokines after the first ZOL administration, but not to proliferative responses of γδ T cells. In addition, better OS was observed in the APR group. Therefore, the number of γδ T cells might be a prognostic marker in patients with NSCLC.

An onion farmer with a case of hypersensitivity pneumonitis caused by Aspergillus niger.

A 62-year old man was admitted to our hospital with a 2-week complaint of a dry cough, general fatigue, and dyspnea on effort. He has been an onion farmer for several years and developed these symptoms after cleaning up onion peels with air compressors. A chest roentgenogram and computed tomography showed a ground glass shadow in the bilateral upper lung field. Cellular analysis of the bronchoalveolar lavage fluid showed elevated total cell numbers and lymphocytes. Transbronchial lung biopsies revealed a non-caseating granuloma with both epithelioid cells and Langhans giant cells. After the admission, these symptoms and radiological findings gradually improved without any treatment. Then, a returning-home provocation test was positive only when he worked cleaning up onion peels with air compressors. A. niger was cultured from his workplace and black mold from the onion peels. The precipitation antibody and the antigen were both positive for Aspergillus. Therefore, we diagnosed this case as hypersensitivity pneumonitis caused by inhalation of A. niger. Although hypersensitivity pneumonia caused by A. niger is rare, physicians should aware the possibility of this condition in farmers because A niger is ubiquitously present in several vegetables and fruits.

Early Intensive Nutrition Intervention with Dietary Counseling and Oral Nutrition Supplement Prevents Weight Loss in Patients with Advanced Lung Cancer Receiving Chemotherapy: A Clinical Prospective Study.

BACKGROUND: Weight loss in patients with cancer is caused by cancer cachexia and chemotherapy-induced nausea and vomiting (CINV). Recent developments in antiemetic drugs have substantially improved CINV, but nutritional intervention did not improve body weight. This study aimed to investigate the effects of nutrition intervention with appropriate antiemetic treatment in patients with non-small-cell lung cancer during chemotherapy. METHODS: Patients received individualized nutrition counseling by a registered dietitian and were provided with oral supplements for 90 days. Body weight and other parameters were measured at baseline and after 90-day intervention. To evaluate this nutrition intervention, patients were also retrospectively set as control, and then body weight change was compared with inverse probability of treatment weights (IPTW) analysis. RESULTS: Ten patients received individualized nutrition counseling and were provided with oral supplements for 90 days. Of them, 7 patients consumed nutritional supplements, and the mean intake was 130 kcal/day. After 90-day intervention, the patients did not show significant weight and BMI loss during the course of cytotoxic chemotherapy. A total of 38 patients were retrospectively enrolled as controls. The number of the patients who gain the body weight after 90 days in the study cohort was significantly larger than that in the retrospective controls with the IPTW analysis (Odds Ratio (OR) = 8.4; 95% Confidence Interval (CI): 1.6-42; P = 0.01). CONCLUSION: Early intensive nutrition intervention with appropriate antiemetic treatment prevents weight loss. Nutrition interventions might be also beneficial for quality of life, treatment response and survival.

Development of fever following first administration of zoledronate as a prognostic factor in advanced non-small cell lung cancer patients with bone metastases.

Nitrogen-containing bisphosphonates (N-BPs), which are usually used for the treatment of advanced cancer with bone metastasis, occasionally cause fever following the first administration. However, it is unclear as to how the development of fever following the first administration of N-BP is associated with clinical outcome. The aim of the present study was to determine the prognostic value of the development of fever following the first administration of N-BP in advanced non-small cell lung cancer patients with bone metastases. The present study reviewed the data of 46 patients with advanced non-small cell lung cancer who were administered zoledronate (ZOL), an N-BP, for bone metastasis, between March 2009 and March 2011 in the Department of Medical Respirology at Tottori University Hospital. Clinicopathological factors were evaluated using univariate and multivariate analyses, and these factors were compared between the fever and non-fever groups. Of the 46 patients, 15 (32.6%) developed fever following the first administration of ZOL. No significant differences were observed in the clinicopathological characteristics between the two groups. The overall survival in the fever group was significantly longer compared with the non-fever group (median survival time: 33.4 vs. 15.7 months, P=0.04), and the development of fever following the first ZOL administration was independently associated with longer overall survival. The development of fever following the first ZOL administration was an independent prognostic factor in advanced non-small cell lung cancer patients with bone metastases. Thus, ZOL-associated fever may be a predictive factor for an undefined, survival-promoting effect of ZOL.

A case of lung abscess successfully treated by transbronchial drainage using a guide sheath.

A 51-year-old man was diagnosed with colon cancer in September 2011, and a solitary pulmonary nodule was detected by computed tomography (CT) scan. We performed a transbronchial biopsy with endobronchial ultrasonography using a guide sheath (GS) and diagnosed lung metastasis of colon cancer. The patient experienced remittent fever after the biopsy in spite of intravenous antibiotic therapies. Moreover, his CT scan showed a large lung abscess at the biopsy site. We performed transbronchial drainage using a GS as salvage therapy. The bloody pus was successfully aspirated, and chest X-ray following the procedure showed dramatic shrinkage of the abscess.

DNA-PK Inhibition by NU7441 Enhances Chemosensitivity to Topoisomerase Inhibitor in Non-Small Cell Lung Carcinoma Cells by Blocking DNA Damage Repair.

BACKGROUND: DNA double-strand breaks (DSBs) are the most cytotoxic form of DNA damage and are induced by ionizing radiation and specific chemotherapeutic agents, such as topoisomerase inhibitors. Cancer cells acquire resistance to such therapies by repairing DNA DSBs. A major pathway for the repair of DNA DSBs is non-homologous end-joining (NHEJ), which requires DNA-dependent protein kinase (DNA-PK) activity. In this study, we investigated the effect of NU7441, a synthetic small-molecule compound, as a specific inhibitor of DNA-PK on the chemosensitization of non-small cell lung carcinoma (NSCLC) A549 cells. METHODS: The combined effects of chemotherapeutic agents and NU7441 were evaluated by isobologram analysis using Cell Counting Kit-8. DNA DSBs were assessed by immunofluorescence assay. Apoptosis was examined by flow cytometry using an Annexin V apoptosis kit. Activation of DNA-PK was assayed by western blotting. RESULTS: The combination of NU7441 and topoisomerase inhibitors such as amrubicin and irinotecan had a synergistic effect on cell proliferation in A549 cells. NU7441 increased 53BP1 foci and apoptosis induced by topoisomerase inhibitors and decreased phospho-DNA-dependent protein kinase, catalytic subunit (pDNA-PKcs) (S2056) protein expression caused by topoisomerase inhibitors. Interestingly, mitotic inhibitors such as pacritaxel did not cause the pDNA-PKcs (S2056) protein expression and the combination of NU7441 and pacritaxel had an only additive effect. CONCLUSION: NU7441 inhibited the growth of NSCLC cells and enhanced the chemosensitization to topoisomerase inhibitors by blocking DNA repair. A combination of NU7441 and topoisomerase inhibitor may be a promising treatment for NSCLC.

A novel SLC34A2 mutation in a patient with pulmonary alveolar microlithiasis.

Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive disease caused by mutations in SLC34A2 and characterized by intra-alveolar accumulation of microliths. We diagnosed a case of PAM in a 27-year-old Japanese female and identified a novel mutation in SLC34A2 (c.1390 G>C [G464R] in exon 12).

Frequency of Epidermal Growth Factor Receptor Mutation in Smokers with Lung Cancer Without Pulmonary Emphysema.

BACKGROUND: Chronic obstructive pulmonary disease is a smoking-related disease, and is categorized into the emphysema and airway dominant phenotypes. We examined the relationship between emphysematous changes and epidermal growth factor receptor (EGFR) mutation status in patients with lung adenocarcinoma. PATIENTS AND METHODS: The medical records for 250 patients with lung adenocarcinoma were retrospectively reviewed. All patients were categorized into the emphysema or non-emphysema group. RESULTS: Wild-type EGFR was detected in 136 (54%) and mutant EGFR in 48 (19%). Emphysematous changes were observed in 87 (36%) patients. EGFR mutation was highly frequent in the non-emphysema group (p=0.0014). Multivariate logistic regression analysis showed that emphysema was an independent risk factor for reduced frequency of EGFR mutation (Odds Ratio=3.47, p=0.005). CONCLUSION: Our data showed a relationship between emphysematous changes and EGFR mutation status. There might be mutually exclusive genetic risk factors for carcinogenesis and development of emphysematous changes.

Causes of death in patients with asthma and asthma-chronic obstructive pulmonary disease overlap syndrome.

BACKGROUND: The administration of inhaled corticosteroids and worldwide usage of several asthma guidelines have improved asthma mortality. Elderly patients with asthma show high mortality rates, and may have several comorbidities, including overlap with chronic obstructive pulmonary disease (COPD). Among patients showing asthma overlapped with COPD (asthma-COPD overlap syndrome; ACOS), mortality is worse than for asthma alone. Therefore, we investigated comorbidities, malignancies, and causes of death in patients with asthma and ACOS. METHODS: This was a retrospective study. From January 2000 to March 2012, 650 patients were followed up at Tottori University Hospital. Medical records were reviewed to collect data regarding patient characteristics and comorbidities, and causes of death were recorded for patients who died during the study period. RESULTS: Eighty-seven patients died during the study period. The most frequent cause of death was malignancy. The proportion of malignant disease was 21.7% in all patients, 19.4% in patients with asthma alone, and 32.4% in patients with ACOS. One patient died from an asthma attack during this period. CONCLUSION: The most frequent cause of death in patients with asthma and ACOS was malignant disease. It is necessary to control not only asthma but also comorbidities in patients with asthma, especially in those with ACOS.

A novel point-of-care system for high-speed real-time polymerase chain reaction testing for epidermal growth factor receptor mutations in bronchial lavage fluids after transbronchial biopsy in patients with non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) gene mutation testing is essential for choosing appropriate treatment options in patients with advanced non-small cell lung cancer (NSCLC). However, a time delay occurs between histological diagnosis and molecular diagnosis in clinical situations. To minimize this delay, we developed a novel point-of-care test for EGFR mutations, based on a high-speed real-time polymerase chain reaction (PCR) system designated here as ultrarapid PCR combined with highly accurate bronchoscopic sampling. We investigated whether our system for detecting EGFR mutations was valid by comparing test results with those obtained using a commercialized EGFR mutation test. We obtained small amounts of bronchial lavage fluids after transbronchial biopsies (TBBs) were performed on enrolled patients (n=168) who underwent endobronchial ultrasonography using a guide sheath (EBUS-GS). EGFR mutation analysis was performed by ultrarapid PCR immediately after EBUS-GS-TBBs were obtained (on the same day). After pathological diagnoses of NSCLC, EGFR mutation status in formalin-fixed, paraffin- embedded samples was confirmed by the PCR-invader method, and the concordance rates between the PCR methods were compared. The total diagnostic yield of EBUS-GS-TBB was 91.0%. The positive concordance rates for detecting 19del and L858R with the ultrarapid PCR and PCR-invader methods were both 100%. Negative concordance rates were 97.2 and 98.1%, respectively. We also demonstrated a dramatic effect of early erlotinib administration, based on ultrarapid PCR results, for a 52-year-old woman suffering from respiratory failure due to severe intrapulmonary metastases with poor performance status. In conclusion, ultrarapid PCR combined with EBUS-GS-TBB enabled rapid and reliable point-of-care testing for EGFR mutations.