Tsutomu Tatematsu

APOBEC3B gene overexpression in non‑small-cell lung cancer

Recent study results have demonstrated that a subclass of apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminase may induce mutation clusters in various types of cancer. From the Cancer Genome Altas, an APOBEC mutation pattern was identified in bladder, cervical, breast, head and neck and lung cancers. In the present study, APOBEC3B mRNA expression was investigated using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assay using LightCycler in surgically treated non-small-cell lung cancer (NSCLC) cases. Additionally, 88 surgically removed Japanese NSCLC cases were analyzed for mRNA level. The results showed that APOBEC3B/β-actin mRNA levels were significantly higher in lung cancer (1,598.481±6,465.781) when compared to adjacent normal lung tissues (2,116.639±8,337.331, P=0.5453). The tumor/normal (T/N) ratio of APOBEC3B/β-actin mRNA levels was not different within the gender, age, smoking status and pathological stages. The T/N ratio of APOBEC3B/β-actin mRNA levels was not significantly different in epidermal growth factor receptor (EGFR) or Kras mutation-positive cases as compared to the wild-type cases.

Genetic profiling of thymic carcinoma using targeted next-generation sequencing

OBJECTIVES Thymic carcinoma is a rare mediastinal neoplasm and little is known about its tumorigenesis. There is no effective treatment except for complete resection, and the prognosis of advanced cases is poor. To identify the mutations associated with tumorigenesis, we analyzed genetic profile of thymic carcinoma using targeted next-generation sequencing. MATERIALS AND METHODS We sequenced about 409 cancer-related genes in 12 thymic squamous cell carcinoma tissues including 10 tumor/normal tissue pairs using Ion AmpliSeq Cancer Panel and Ion PGM Sequencer. We filtered the mutations with Ingenuity Variant Analysis, SIFT, PolyPhen-2, and PROVEAN. RESULTS AND CONCLUSION Twenty-five candidate mutations in 24 genes were identified, including five tyrosine kinase genes (KIT, DDR2, PDGFRA, ROS1, IGF1R). There was no recurrent mutation among the samples studied. The KIT exon 11 deletion mutation in 1 patient was an activating mutation and may be an oncogenic driver mutation. Genetic profiling of thymic carcinoma using targeted next-generation sequencing was performed. The mutation status of thymic squamous cell carcinoma is highly heterogeneous.

Prognosis of recurrent non-small cell lung cancer following complete resection

Prognosis following recurrence subsequent to complete resection of non-small-cell lung cancer (NSCLC) is considered a multifactorial process dependent on clinicopathological, biological and treatment characteristics. Gefitinib was approved for lung cancer treatment in Japan in 2002. The aim of the current study was to quantify the prognostic effects of these characteristics on post-recurrence prognosis. In total, 127 NSCLC patients were analyzed who underwent complete resection and subsequently had recurrent cancer. The correlation between characteristics of the initial and recurrent disease with post-recurrence prognosis was investigated. The factors clearly associated with post-recurrence prognosis using Cox proportional hazards models were age at recurrence (those <65 years of age typically had better prognoses) and interval between initial resection and recurrence (intervals of <1 year accompanied a worse prognosis). Epidermal growth factor receptor (EGFR) mutant patients treated with EGFR tyrosine kinase inhibitors (TKIs), exhibited the longest median survival following recurrence (37.4 months) in the sample. Treatment, particularly EGFR TKIs for recurrent NSCLC, was observed to significantly prolong survival. The results of the study highlight that various treatment modalities according to the clinical background of the patient should be considered in patients with postoperative recurrent NSCLC.

Increased BRAF copy number in lung adenocarcinoma.

Point mutation of the BRAF gene is a genetic event that occurs in a subset of lung adenocarcinoma cases. For example, BRAF V600E is a driver mutation that can be effectively targeted using selective BRAF and/or MEK inhibitors. The present study hypothesized that an increase in BRAF copy number may be correlated with certain clinicopathological features of lung adenocarcinoma in Japanese patients. The BRAF gene copy number was analyzed using quantitative polymerase chain reaction amplifications in 29 surgically treated lung adenocarcinoma cases without EGFR or Kras mutations from Nagoya City University Hospital (Nagoya, Japan). Seven BRAF-mutant cases were included. Increased BRAF gene copy number was identified in three lung adenocarcinoma patients (10.3%), all of which exhibited the V600E mutation. Using fluorescence in situ hybridization with BRAF-specific and chromosome 7 centromeric probes, increased copy number status was associated with gene amplification or gain of chromosome 7. Although increased BRAF copy number was correlated with BRAF V600E mutations, numerical changes in BRAF copy number were rare and mild in lung adenocarcinoma, resulting in no significant difference in pathological tumor status or tumor stage.

Blastomatoid pulmonary carcinosarcoma: A rare case report and review of the literature: Blastomatoid pulmonary carcinosarcoma

A 65‐year‐old never‐smoking woman presented to a local hospital, because an abnormal shadow was detected at the right lower lung field by annual chest X‐ray. Computed tomography (CT) revealed a 5‐cm tumor in segment 6 of her right lung and an enlarged subcarinal lymph node, suggesting metastasis. The lung tumor was diagnosed as adenocarcinoma by a CT‐guided percutaneous needle biopsy. She was referred to our hospital and underwent right lower lobectomy with lymph node dissection (ND2a‐2). A histopathological examination of the tumor showed a biphasic proliferation made of carcinomatous and sarcomatous components. The carcinomatous component consisted of glandular structures of atypical cells that possessed chromatin‐rich nuclear and clear cytoplasm, confirming high‐grade fetal adenocarcinoma. The sarcomatous component consisted of immature spindle cells that differentiated into chondrosarcoma. Immunohistochemically, the glandular structures expressed membranous beta‐catenin, and the ultimate diagnosis was blastomatoid variant of pulmonary carcinosarcoma. She received four courses of cisplatin plus vinorelbine as adjuvant chemotherapy and remained alive with neither recurrence nor distant metastasis at two and a half years after the operation. We experienced a rare case of blastomatoid pulmonary carcinoasarcoma.

Thymothymectomy with pulmonary partial resection using the subxiphoid approach: how to do it?

An open approach by sternotomy is still selected for locally advanced anterior mediastinal tumors. Technical and instrumental improvements to video-assisted thoracic surgery (VATS) have enabled the treatment of anterior mediastinal tumor in the last decade, and the indications of VATS for an anterior mediastinal tumor are thus expanding. Recently, a single-port thymectomy procedure using the subxiphoid approach has gained popularity worldwide because of its low invasiveness. Improvements to the thoracoscopic instruments and the development of a single-port device are expanding the adoption of single-port VATS in the thoracic surgical field, including resection of anterior mediastinal tumors. We, herein, report a case of thymothymectomy with pulmonary partial resection using the subxiphoid approach. This approach is useful for extended operation for anterior mediastinal tumors and provides favorable results regarding postoperative pain and cosmetic outcomes.

The relationship between the expression of thymidylate synthase, dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase, excision repair cross‑complementation group 1 and class III β‑tubulin, and the therapeutic effect of S‑1 or carboplatin plus paclitaxel in non‑small‑cell lung cancer

Previous studies have reported that the expressions of specific proteins may predict the efficacy of chemotherapy agents for non-small cell lung cancer (NSCLC) patients. The present study evaluated the expression of proteins hypothesized to be associated with the effect of chemotherapeutic agents in 38 NSCLC patients with pathological stage II and IIIA. The subjects received carboplatin plus paclitaxel (CP) or S-1 as adjuvant chemotherapy following complete resection. The protein expressions evaluated were those of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phsphoribosyltransferase (OPRT), which were suspected to be associated with the effect of S-1 agents, excision repair cross-complementation group 1 (ERCC1), which was suspected to be associated with the effect of platinum-based agents, and class III β-tubulin (TUBB3), which was suspected to be associated with the effect of taxane-based agents. The positive rate of TS was 55.3% (n=21/38), DPD was 57.9% (n=22/38), OPRT was 42.1% (n=16/38), ERCC1 was 47.4% (n=18/38) and TUBB3 was 44.7% (n=17/38). Among the patients who received S-1 adjuvant chemotherapy, TS-negative cases demonstrated a significantly better disease-free survival than positive cases. Thus, TS protein expression may have been a factor that predicted the effect of S-1 agent as adjuvant chemotherapy.

Expression of excision repair cross-complementation group 1 and class III β-tubulin in thymic carcinoma

Thymic carcinoma is a rare mediastinum malignant tumor derived from thymic epithelial cells. With the exception of complete resection, an effective therapy has not been established to date for advanced or relapsed thymic carcinoma. The present study examined the protein expression of excision repair cross-complementation group 1 (ERCC1) and class III β-tubulin (TUBB3), which are consider to be indicators of the anticancer activity of platinum-based and taxane-based chemotherapy, respectively. The expression of ERCC1 and TUBB3 proteins was examined in 40 thymic carcinoma patients who underwent either surgical resection or core-needle biopsy. The present study investigated whether the expression of ERCC1 and TUBB3 proteins was associated with the overall survival and clinicopathological factors of thymic carcinoma patients. The expression of ERCC1 and TUBB3 proteins was also evaluated in 50 patients who underwent curative resection for non-small cell lung cancer (NSCLC). The expression of ERCC1 and TUBB3 proteins was positive in 8 cases (20%) among the thymic carcinoma patients. ERCC1 was expressed in 21 cases (42%), while TUBB3 was expressed in 27 cases (54%), among the 50 NSCLC patients evaluated in the present study. Only complete resection was observed to be associated with a better prognosis than incomplete resection (P=0.0341). Other clinicopathological factors, including expression of ERCC1 and TUBB3 proteins, exhibited no effect on overall survival. The expression of ERCC1 and TUBB3 proteins in the thymic carcinoma cases was lower than that in the NSCLC cases. The present results suggest a possibility for better antitumor effects of platinum-based and taxane-based chemotherapy on thymic carcinoma patients.

S-1 vs. paclitaxel plus carboplatin as adjuvant chemotherapy for completely resected stage II/IIIA non‑small‑cell lung cancer

The majority of patients with completely resected stage II or IIIA non-small-cell lung cancer (NSCLC) require adjuvant chemotherapy to improve survival following surgery. In the present trial, the 2-year disease-free survival (DFS), and the feasibility and safety of S-1 as an adjuvant chemotherapy for advanced lung cancer were evaluated. A total of 40 patients with completely resected stage II or IIIA NSCLC were enrolled and randomized to receive postoperative chemotherapy with either up to 4 cycles of paclitaxel plus carboplatin (arm A) or with up to 1 year of S-1 (arm B). The primary endpoint was 2-year DFS. The secondary endpoints were feasibility and toxicity. A total of 40 patients were enrolled, but 3 were excluded in accordance with the exclusion criteria. The remaining 37 patients were analyzed. The 2-year DFS rate was 54.2% in arm A and 84.2% in arm B. Overall, 15/18 (83.3%) patients completed 4 cycles of paclitaxel plus carboplatin and 13/19 (68.4%) completed 1-year of S-1adjuvant chemotherapy. Of the 18 (16.7%) patients in arm A, 3 experienced grade 3 or 4 adverse events, while none in arm B experienced such events. Therefore, S-1 chemotherapy for patients with completely resected stage II or IIIA NSCLC was a feasible and safe regimen, and it may therefore be considered as a potential adjuvant chemotherapy option for advanced NSCLC.

The detectability of the pretreatment EGFR T790M mutations in lung adenocarcinoma using CAST-PCR and digital PCR

BACKGROUND A gatekeeper T790M mutation is thought to cause resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. The detection of a 2nd mutation is important for planning the next therapy when patients acquire resistance to the first line EGFR-TKI. METHODS We used a competitive allele-specific polymerase chain reaction (CAST-PCR) to analyze the incidence and clinical significance of T790M mutations in 153 lung adenocarcinomas with EGFR-activating mutations. To increase the sensitivity and specificity of the detection of T790M mutations, we subjected 20 of the 153 cases to a digital PCR. The genomic DNAs were extracted from frozen, surgically resected tumor tissue specimens. RESULTS The CAST-PCR detected T790M mutations in 45 (29.4%) of the 153 cases. The analytical sensitivity in the detection T790M mutations was 0.13-2.65% (average 0.27%, median 0.20%). In contrast, the digital PCR, detected T790M mutations in 8 (40%) out of 20 cases. CONCLUSIONS Our study shows that the pretreatment incidence of T790M mutation was less than that reported in previous studies. In order to clinically use pretreatment EGFR T790M mutation identification method, we should clarify the adequate methods and tissue preserved status.