Masaya Taniwaki

Increases of Amphiregulin and Transforming Growth Factor-{alpha} in Serum as Predictors of Poor Response to Gefitinib among Patients with Advanced Non-Small Cell Lung Cancers

Serum levels of amphiregulin and transforming growth factor-alpha (TGF-alpha), which were identified previously to be expressed at high levels in non-small cell lung cancer (NSCLC) with poor response to gefitinib, were examined by ELISA using blood samples taken from 50 patients with advanced NSCLCs. Of 14 cases that revealed above the cutoff line for amphiregulin in serum, 12 responded poorly to gefitinib, whereas 18 of the 36 cases showing below the cutoff revealed partial response (PR) or stable disease (SD; P = 0.026). Thirteen of 15 patients who were positive for TGF-alpha responded poorly to gefitinib, whereas 18 of the 35 patients with negative TGF-alpha levels turned out to be relatively good responders (P = 0.014). Of 22 patients with positive values for either or both markers, 19 were poor responders. On the other hand, among 28 patients negative for both markers, 17 were classified into the PR or SD groups (P = 0.001). Gefitinib-treated NSCLC patients whose serum amphiregulin or TGF-alpha was positive showed a poorer tumor-specific survival (P = 0.037 and 0.002, respectively, by univariate analysis) compared with those whose serum amphiregulin or TGF-alpha concentrations were negative. Multivariate analysis showed an independent association between positivity for TGF-alpha and shorter survival times among NSCLC patients treated with gefitinib (P = 0.034). Amphiregulin or TGF-alpha positivity in NSCLC tissues was significantly higher in male, nonadenocarcinomas, and smokers. Our data suggest that the status of amphiregulin and TGF-alpha in serum can be an important predictor of the resistance to gefitinib among patients with advanced NSCLC.

Activation of KIF4A as a Prognostic Biomarker and Therapeutic Target for Lung Cancer

Purpose and Experimental Design: To identify molecules that might be useful as diagnostic/prognostic biomarkers and as targets for the development of new molecular therapies, we screened genes that were highly transactivated in a large proportion of 101 lung cancers by means of a cDNA microarray representing 27,648 genes. We found a gene encoding KIF4A, a kinesin family member 4A, as one of such candidates. Tumor tissue microarray was applied to examine the expression of KIF4A protein and its clinicopathologic significance in archival non–small cell lung cancer (NSCLC) samples from 357 patients. A role of KIF4A in cancer cell growth and/or survival was examined by small interfering RNA experiments. Cellular invasive activity of KIF4A on mammalian cells was examined using Matrigel assays. Results: Immunohistochemical staining detected positive KIF4A staining in 127 (36%) of 357 NSCLCs and 19 (66%) of 29 small-cell lung cancers examined. Positive immunostaining of KIF4A protein was associated with male gender (P = 0.0287), nonadenocarcinoma histology (P = 0.0097), and shorter survival for patients with NSCLC (P = 0.0005), and multivariate analysis confirmed its independent prognostic value (P = 0.0012). Treatment of lung cancer cells with small interfering RNAs for KIF4A suppressed growth of the cancer cells. Furthermore, we found that induction of exogenous expression of KIF4A conferred cellular invasive activity on mammalian cells. Conclusions: These data strongly implied that targeting the KIF4A molecule might hold a promise for the development of anticancer drugs and cancer vaccines as well as a prognostic biomarker in clinic.

Characterization of SEZ6L2 cell-surface protein as a novel prognostic marker for lung cancer.

To identify molecules that might serve as biomarkers or targets for development of novel molecular therapies, we have been screening genes encoding transmembrane/secretory proteins that are up‐regulated in lung cancers, using cDNA microarrays coupled with purification of tumor cells by laser microdissection. A gene encoding seizure‐related 6 homolog (mouse)‐like 2 (SEZ6L2) protein, was chosen as a candidate for such molecule. Semi‐quantitative RT‐PCR and western‐blot analyses documented increased expression of SEZ6L2 in the majority of primary lung cancers and lung‐cancer cell lines examined. SEZ6L2 protein was proven to be present on the surface of lung‐cancer cells by flow cytometrical analysis using anti‐SEZ6L2 antibody. Immunohistochemical staining for tumor tissue microarray consisting of 440 archived lung‐cancer specimens detected positive SEZ6L2 staining in 327 (78%) of 420 non‐small cell lung cancers (NSCLCs) and 13 (65%) of 20 small‐cell lung cancers (SCLCs) examined. Moreover, NSCLC patients whose tumors revealed a higher level of SEZ6L2 expression suffered shorter tumor‐specific survival compared to those with no SEZ6L2 expression. These results indicate that SEZ6L2 should be a useful prognostic marker of lung cancers. (Cancer Sci 2006; 97: 737–745)

Putative lung adenocarcinoma with epidermal growth factor receptor mutation presenting as carcinoma of unknown primary site: A case report

Rationale: Only a few cases of putative lung adenocarcinoma presenting as carcinoma of unknown primary site (CUP) with epidermal growth factor receptor (EGFR) mutation have been reported, and the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) for these cases is unclear. Patient concerns and diagnoses: A 67-year-old man complained of paresis of the right lower extremity, dysarthria, and memory disturbance. Computed tomography and magnetic resonance imaging showed multiple brain tumors with brain edema and swelling of the left supraclavicular, mediastinal, and upper abdominal lymph nodes. Moreover, a metastatic duodenal tumor was detected via upper gastrointestinal endoscopy examination. The biopsy specimen of the lesion was examined and was diagnosed as adenocarcinoma with CK7 and TTF-1 positivity. Finally, the case was diagnosed as EGFR mutation-positive putative lung adenocarcinoma presenting as CUP. Interventions and outcomes: Oral erlotinib, an EGFR-TKI, was administered at 150 mg daily. Five weeks later, the brain lesions and several swollen lymph nodes showed marked improvement, and the symptoms of the patient also improved. Three months later, the duodenal lesion was undetected on upper gastrointestinal endoscopy. After an 8-month follow-up, the patient was well with no disease progression. Lessons: Putative lung adenocarcinoma presenting as CUP may have EGFR mutation, and EGFR-TKI therapy may be effective for such malignancy.

Small Cell Lung Cancer with Bizarre Radiographic Findings

A 66-year-old woman with a 36-pack-year smoking history presented to our hospital with dyspnea and a performance status of 2. Chest radiography (Picture 1A) and computed tomography (Picture 1B) revealed thickening of the bronchovascular bundles in the right lung. [F]fluorodeoxyglucose positron emission tomography showed a high uptake in the lesion sites (Picture 1C and D). A bronchoscopic examination showed marked stenosis in the right upper bronchus; however, the bronchial epithelium was retained (Picture 2A). Small-cell lung cancer (SCLC) was confirmed by a histopathological examination of the transbronchial biopsy specimen (Picture 2B). After treatment with carboplatin and etoposide, the patient’s symptoms and radiographic abnormalities improved.

ROS1-rearranged putative lung adenocarcinoma presenting as carcinoma of unknown primary site: a case report

Carcinoma of unknown primary site (CUP) is diagnosed only in 2-9% of all cancer cases. Adenocarcinomas account for approximately 60% of CUP, and some of these are putative lung adenocarcinomas. The frequency of driver oncogene positivity in the putative lung adenocarcinomas is unknown, and the efficacy of targeting therapies for the driver oncogene is also unknown. This is the first case report of C-ros oncogene 1 (ROS1)-rearranged putative lung adenocarcinoma presenting as CUP showing a good response to ROS1 inhibitor therapy. A 55-year-old woman presented with neck lymphadenopathy. Computed tomography and [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) showed swelling of the bilateral supraclavicular, left accessory, mediastinal, and abdominal lymph nodes. The pathological analysis of the lymph node specimen biopsy indicated adenocarcinoma with cytokeratin 7 and thyroid transcription factor-1 positivity. Thus, this case was identified as ROS1- rearranged putative lung adenocarcinoma presenting as CUP. Oral crizotinib, an ROS1 inhibitor, was administered at a dose of 250 mg twice daily. Four weeks later, several swollen nodes showed marked improvement, and eight weeks later, FDG PET showed almost no uptake. In conclusion, putative lung adenocarcinoma presenting as CUP may involve ROS1 rearrangement, and ROS1 inhibitor therapy may be effective.

A Rare Combination of Dermatomyositis, Interstitial Pneumonia, and Lung Cancer in a Patient Treated with Immunosuppressive Therapy and Chemotherapy: A Case Report

We herein report the rare case of co-occurring dermatomyositis (DM), interstitial pneumonia (IP), and lung cancer in a 59-year-old man. Computed tomography (CT) and positron emission tomography-CT showed the presence of a left lung tumor with IP, which was diagnosed as lung adenocarcinoma by a CT-guided tumor biopsy. We diagnosed DM based on the presence of myalgia, Gottrons papules, and anti-aminoacyl-tRNA synthetase antibody positivity in the patient. Co-occurrence of the above-mentioned three diseases is rare, and acute exacerbation of IP is a major cause of death in such cases. These patients can be treated with immunosuppressive therapy followed by chemotherapy.

Intravascular Large B-cell Lymphoma with a Pulmonary [18F]-Fluorodeoxyglucose Uptake

A 58-year-old woman was referred to our hospital with a 3-month history of recurrent fever and weight loss. Computed tomography (CT) revealed normal findings of the bilateral lungs (Picture 1A) and splenomegaly (Picture 1B). Laboratory examinations revealed elevated levels of soluble interleukin-2 receptor (sIL-2R; 6,774 pg/mL). A subsequent examination using [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) showed a high uptake in the spleen, and curiously, the bilateral lungs (Picture 1C and D). A transbronchial lung biopsy specimen (Picture 2A and B) and a partially resected spleen specimen (Picture 2C and D) were examined pathologically, and a definitive diagnosis of intravascular large B-cell lymphoma (IVLBCL) was confirmed. The most common symptom of IVLBCL is a fever, and it often demonstrates a pulmonary FDG uptake even in the absence of chest CT abnormalities (1, 2). For the early diagnosis of IVLBCL, serum sIL-2R and FDG-PET/CT should be examined in patients presenting with a fever of unknown origin.