Nobuyuki Koyama

Reliability of the peptide nucleic acid‐locked nucleic acid polymerase chain reaction clamp‐based test for epidermal growth factor receptor mutations integrated into the clinical practice for non‐small cell lung cancers

Gefitinib is an inhibitor of the tyrosine kinase activity of epidermal growth factor receptor (EGFR). Accumulating evidence suggests that gefitinib may provide a survival benefit to EGFR mutation‐positive non‐small lung cancer patients. We have established a clinical test that can detect EGFR mutations from cytological specimens or paraffin‐embedded tissue specimens that are contaminated by normal cells. This test is based on the peptide nucleic acid, locked nucleic acid polymerase chain reaction clamp method that can detect G719S, G719C, L858R, L861Q and seven different exon 19 deletions in the presence of 100–1000‐fold wild‐type alleles. Consequently, using a small aliquot of samples isolated to establish a cancer diagnosis, the EGFR mutation status is determined soon after the diagnosis of cancer is made. We investigated the EGFR mutation status in 86 patients using a variety of cytological specimens (59 bronchoscopy specimens, 16 pleural effusion, 9 sputum, and 2 pericardial effusion) and in 46 patients who had a disease relapse and paraffin‐embedded tissues were available. Forty‐five patients (34%) were positive for mutation (29 exon 19 deletions, 16 L858R and 1 L861Q). The sensitivity and the specificity of this test was 97% and 100%, respectively. EGFR mutation status thereby obtained was used to determine each patients therapeutic regimen. This test is easily integrated into the normal clinical practice for lung cancer, while allowing the medical staff to select therapeutic regimen depending on the EGFR mutation status. (Cancer Sci 2007; 98: 246–252)

Peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp-based detection test for gefitinib-refractory T790M epidermal growth factor receptor mutation

Mutations in the epidermal growth factor receptor (EGFR) are observed in a fraction of non‐small‐cell lung cancers (NSCLS). EGFR mutation‐positive NSCLS responds to gefitinib. Secondary T790M mutation confers gefitinib resistance to NSCLS. A detection test for the T790M mutation was designed based on the peptide nucleic acid–locked nucleic acid polymerase chain reaction clamp method. The specificity and sensitivity of the test were both greater than 0.99. The test revealed that only a small population of the PC‐13 cells carried the T790M mutation. The test also revealed that the T790M mutation was found in none of 151 NSCLC specimens obtained before gefitinib treatment, whereas it was found in four of four specimens obtained from NSCLS that had become refractory to gefitinib. In one patient in whom the L858R‐positive EGFR allele was amplified to multiple copies, an L858R‐T790M double‐mutant allele emerged during the gefitinib therapy. This allele was expressed highly. The T790M mutation detection test based on the peptide nucleic acid–locked nucleic acid polymerase chain reaction clamp method is sensitive and specific, and is applicable to clinical practice. It detects T790M‐positive cells in the course of gefitinib treatment, and thus will help to devise therapies effective for T790M‐positive NSCLS. (Cancer Sci 2008; 99: 595–600)

F-fluorodeoxyglucose positron emission tomography for relapsing polychondritis as a diagnostic approach and evaluation of disease activity.

A 60-year-old man presented with persistent cough and wheezing. The effect of inhaled corticosteroids and β2 agonists was temporary, and low grade fever, malaise and weight loss developed with a C-reactive protein level of 11.59 mg/dl and a white cell count of 10 460 cells/μl, while other manifestations such as otorhinolaryngological involvement were not observed. Tumour markers, anti-nuclear antibody and anti-neutrophil cytoplasmic antibodies were negative except for 780 U/ml of a soluble interleukin 2 receptor. Sputum culture and cytology were also negative. Near circumferentially thickened walls of the trachea and major bronchi were seen on chest radiographs and CT scans. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) was thus performed as an investigation for malignancy; this revealed that 18F-FDG uptake was correspondingly distributed in the cartilages of the thickened airway walls and larynx (fig 1A). During an additional investigation, which was positive for serum anti-type II collagen antibody (>113 ELISA units (EU)/ml), deafness, tinnitus and bilateral ear swellings developed 1 month after 18F-FDG PET. A diagnosis of relapsing polychondritis (RP) was finally established based on clinical manifestations and the histological findings of the biopsy from the patient’s auricle.1 Treatment with systemic corticosteroids eliminated his symptoms and 18F-FDG uptake (fig 1B). Figure 1 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) images of the patient with relapsing polychondritis. 18F-FDG uptake found at relapsing polychondritis (RP) diagnosis (A) was eliminated after the treatment with systemic corticosteroids (B). ... RP is a rare inflammatory chondropathy and may not be readily diagnosed in the absence of specific otorhinolaryngological involvement.2 The characteristic image of 18F-FDG PET helps to establish an early diagnosis of RP and better understand the status and extent of the disease. 18F-FDG PET for RP is a powerful tool for the diagnosis and the evaluation of disease activity.

Distinct Benefit of Overall Survival between Patients with Non-Small-Cell Lung Cancer Harboring EGFR Exon 19 Deletion and Exon 21 L858R Substitution

Background: Exon 19 deletion (Del19) and exon 21 L858R substitution (L858R), which account for 90% of epidermal growth factor receptor (EGFR) mutations as common mutations, are associated with favorable outcomes with EGFR-tyrosine kinase inhibitors (TKIs) compared with other uncommon EGFR mutations in non-small-cell lung cancer (NSCLC). However, whether there are differences in overall survival (OS) between patients with these common EGFR mutations remains controversial. Methods: The subjects studied were 74 NSCLC patients with common EGFR mutations treated with gefitinib or erlotinib. Using univariate and multivariate analyses, we retrospectively compared the clinicopahological characteristics of patients harboring Del19 with those harboring L858R. Results: Compared with patients harboring L858R, EGFR-TKIs provided a significant OS benefit in patients harboring Del19 (p = 0.024), as well as favorable therapeutic responses (p = 0.045) and progression-free survival (PFS) benefits (p = 0.031). In multivariate analyses, Del19 was independently associated with PFS (p = 0.029) and OS (p = 0.009), whereas no parameters other than pleural dissemination at the initial treatment were associated with EGFR mutation types. Conclusion: Del19 and L858R have distinct prognostic implications and may require individual therapeutic strategies.

Advanced Lung Adenocarcinoma with Nivolumab-associated Dermatomyositis

We herein report a 42-year-old man with advanced lung adenocarcinoma and nivolumab-associated dermatomyositis. Nivolumab, an anticancer drug that is classified as an immune checkpoint inhibitor, often induces immune-related adverse events (irAEs). However, there have so far been no reports regarding nivolumab-associated dermatomyositis. This patient was diagnosed with dermatomyositis due to the presence of proximal muscle weakness with abnormal electromyography and magnetic resonance imaging findings; skin lesions, such as heliotrope rash, shawl sign, and periungual erythema; and an elevated serum aldolase level after nivolumab administration. It is important to consider drug-associated dermatomyositis in the differential diagnosis of patients presenting with skin lesions and muscle weakness after nivolumab treatment.

Successful pneumonectomy for invasive pulmonary aspergillosis and advanced non-small cell-lung cancer

Aspergillus spp. is a pathogenic fungus in patients with malignancy, immunosuppression or respiratory diseases, and invasive pulmonary aspergillosis (IPA) caused by its infection is an aggressive and often lethal disorder. We report a case of non-small-cell lung cancer (NSCLC) where pneumonectomy concomitantly enabled radical cure of the underlying disease and IPA against which different antifungal drugs had been ineffective. In a patient with locally advanced NSCLC that progressed despite chemoradiation, radiation pneumonitis and subsequently cavitary disease developed following the administration of corticosteroids. Based upon the isolation of Aspergillus spp. from sputum, a diagnosis of IPA was made and since the latter was refractory to multiple antifungal drugs, pneumonectomy was undertaken which resulted in successful treatment of both NSCLC and IPA. Surgical intervention should be considered as a therapeutic option for IPA complicating NSCLC that is refractory to medical management.

Prognostic Factors and Efficacy of First‐Line Chemotherapy in Patients with Advanced Thymic Carcinoma: A Retrospective Analysis of 286 Patients from NEJ023 Study

BACKGROUND The prognostic factors and the efficacy of first-line chemotherapy remain unclear in patients with advanced thymic carcinoma. MATERIALS AND METHODS We conducted a multi-institutional retrospective study named NEJ023 for patients with advanced thymic carcinoma. All patients without any indication of curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions of the North East Japan Study Group. RESULTS A total of 286 patients with advanced thymic carcinoma were analyzed. First-line chemotherapy included platinum-based doublets in 62.2% of the patients, monotherapy in 3.5%, and other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide [ADOC]) in 34.3%. The median follow-up period was 55.5 months, and the median overall survival (OS) from the start of first-line chemotherapy was 30.7 months (95% confidence interval, 25.9-35.9 months). There was no significant difference in OS among different first-line chemotherapy regimens (e.g., between carboplatin/paclitaxel and ADOC, median OS: 27.8 vs. 29.9 months). Masaoka-Koga stage IVa and volume reduction surgery were favorable prognostic factors for OS in the multivariate analysis using the Cox proportional hazards model. CONCLUSION The efficacy of each first-line chemotherapy regimen for advanced thymic carcinoma did not vary significantly. Our results might support the adequacy of the use of carboplatin/paclitaxel as first-line chemotherapy for these patients. IMPLICATIONS FOR PRACTICE Because of its rarity, there is limited information about prognostic factors and efficacy of chemotherapy in patients with advanced thymic carcinoma. This is the largest data set for those patients treated with chemotherapy. This study suggests there is no significant difference in efficacy between carboplatin/paclitaxel and cisplatin/doxorubicin/vincristine/cyclophosphamide for advanced thymic carcinoma. This result can support the adequacy of the selection of platinum doublets as treatment for those patients, rather than anthracycline-based multidrug regimen.

DLI Induced by Molecular Target Antineoplastic Drug: What Are the Characteristics of DLI in Molecular Target Antineoplastic Drugs?

The standard therapeutic strategy for patients with advanced cancer is treatment with antineoplastic drugs. With the progress in the development of antineoplastic drugs, the prognosis of these patients has improved, despite the difficulty of achieving a complete cure. Molecular target antineoplastic drugs have often provided a paradigm shift in cancer therapy and currently hold a prominent position in cancer therapeutic strategies. While these drugs have clinical benefits, the toxicity profile of these drugs is different from that of conventional cytotoxic chemotherapy. Molecular target antineoplastic drugs consisting of various types of molecules may demonstrate diverse characteristics, although drug-induced lung injury (DLI) is commonly observed in treatment with most of these antineoplastic drugs. In this chapter, reports of DLI associated with molecular target neoplastic drugs were reviewed in order to understand its characteristics and thereby lead to prevention of its occurrence and exacerbation. Diverse patterns of DLI have been commonly observed in patients treated with molecular target antineoplastic drugs, whereas similar DLI patterns have been obtained from various drug types. The incidence and frequency of fatality from DLI also display a wide range. These events were more frequently observed in Japanese patients than in other ethnic groups, suggesting the association of ethnicity with the development and severity of DLI. Clinicians should note the diversity of DLI and the role of ethnicity in DLI in treatment with molecular target antineoplastic drugs.

Effectiveness of nanoparticle albumin-bound paclitaxel plus carboplatin in non-small lung cancer patients with malignant pleural effusion

Malignant pleural effusion (MPE) is a common complication occurring in cancer patients, and its management affects the prognosis of these patients. Preclinical and clinical studies have reported that treatment with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus carboplatin (CBDCA) is effective against intraperitoneal malignant tumors. To investigate the effectiveness of nab-paclitaxel plus CBDCA therapy for MPEs arising in patients with non-small cell lung cancer (NSCLC), we retrospectively analyzed the clinicopathological characteristics of 40 patients with stage IIIb or IV NSCLC who were treated with nab-paclitaxel plus CBDCA from 2013 to 2016. Out of 26 patients with MPEs who were treated with nab-paclitaxel plus CBDCA in this study, 21 patients (80.8%) had effective responses in MPEs; 6 of 21 patients exhibited complete responses (23.1%) and 15 of 21 had partial responses (57.7%). Kaplan-Meier survival curves and log-rank tests to evaluate the effectiveness of nab-paclitaxel plus CBDCA therapy against MPEs showed longer median progression-free survival (323 days vs. 26 days; p=0.009) and overall survival (not reached vs. 199 days; p=0.047) in patients with complete responses compared with those who achieved no response. There were no statistical differences between therapeutic effects on MPEs and those on systemic lesions. Nab-paclitaxel plus CBDCA therapy may be a preferred therapeutic option for patients with NSCLC who experience MPEs, and its effectiveness in treatment of MPEs may need to be evaluated separately from its therapeutic responses in systemic lesions.

A clinicopathological study of surgically resected lung cancer in patients with usual interstitial pneumonia

BACKGROUND The clinicopathological characteristics of lung cancer with concomitant usual interstitial pneumonia (UIP) are insufficiently understood. This study aimed to elucidate a characteristic pathological feature of lung cancer that develops in patients with UIP, with a focus on the location of its onset. METHODS We reviewed surgically obtained specimens, including 547 tumors from 526 patients who underwent lobectomy for lung cancer. Surveyed patients were classified into three groups: patients with UIP (UIP group), patients with lung pathology other than UIP (non-UIP group), and patients without any associated lung pathology (normal group). The histology as well as the lobe and location of the onset of lung cancer were compared among these groups. The peripheral location was subdivided into subpleural, inner and tumor involved centrally secondary to extension. RESULTS The UIP group comprised 82 patients (male, 71 [87%]; mean age, 71 years; smoking rate, 94%), the non-UIP group comprised 334 patients (male, 267 [80%]; mean age, 69 years; smoking rate, 81%), and the normal group comprised 110 patients (male, 33 [30%]; mean age, 63; smoking rate, 29%). No statistical differences were noted in sex, mean age, or smoking index between the UIP and non-UIP groups. Compared with the non-UIP group, the frequency of squamous cell carcinoma (63% vs. 32%), lower lobe origin (76% vs. 32%), and subpleural location (24% vs. 5%) were significantly higher in the UIP group. CONCLUSIONS Lung cancers in patients with UIP show a predilection for the subpleural region, where UIP is also thought to originate.