Masashi Takeda

Bio: Masashi Takeda is an academic researcher. The author has contributed to research in topics: Carcinoma & Lung cancer. The author has an hindex of 8, co-authored 34 publications receiving 4344 citations.

Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.

Abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.

Primary signet-ring cell carcinoma of the colon and rectum: report of eight cases and review of 154 Japanese cases.

Abstract: Background/aims Primary signet-ring cell colorectal carcinoma is rare and has been reported to have an extremely poor prognosis. The purpose of the present study was to define the characteristics of this cancer. Methodology Clinicopathological features were analyzed in 154 Japanese patients. Results The mean age at diagnosis was 54.3 years. The most common tumor site was the rectum (32.9%). Frequent type of the tumor was scirrhous in 45.8%, ulcerated in 34.5%. Lymph node metastasis was found in 77.4% and synchronous peritoneal dissemination was seen in 38.7%, while synchronous liver metastasis was only detected in 2.9%. Most patients (78.2%) were in stages III or IV. The overall median survival time was 12.7 months and the 5-year survival rate was 9.4%. For stage II patients, the median survival time and 5-year survival rate were 17.4 months and 14.3%, respectively, while the median survival time was 15.4 months in stage III and 7.9 months in stage IV. The 5-year survival rate of patients with T2 disease was 75.0%, while patients with T3 or T4 had survival rates of 5.1% and 0%, respectively. Conclusions Since the prognosis of primary signet-ring cell colorectal carcinoma is extremely poor, early diagnosis and aggressive treatment strategy are necessary.

Impact of biomarker changes during neoadjuvant chemotherapy for clinical response in patients with residual breast cancers.

Abstract: Residual cancer burden or Ki67 expression levels in residual tumors reportedly provided significant prognostic information for a non-pathological complete response subset after neoadjuvant chemotherapy (NAC). However, the significance of Ki67 reduction for clinical response during chemotherapy in each subtype or menopausal status is yet to be determined. A total of 183 breast cancers surgically removed after chemotherapy were recruited for this study. Expression levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki67 were determined immunohistochemically for semiquantitative measurement and these biomarkers were compared in pre- and post-NAC samples from pathological non-responders (n = 125). Responses to chemotherapy were evaluated both clinically and pathologically. Ki67 expression levels after NAC (median 5 %, range 0–70 %) were significantly reduced compared with before NAC (25, 1–80 %, P < 0.0001), but only in patients who attained clinical response. This significant suppression of Ki67 in clinical responders was consistently observed in breast cancers from the ER-positive subset, but not the ER-negative subset in the total test set (n = 120). These observations were also made in the validation set (n = 63). Among premenopausal, but not postmenopausal patients, a significant decrease in PgR expression levels was detected in breast cancers of patients who attained clinical response (pre-NAC 50, 0–100 %, post-NAC 5, 0–20 %; P = 0.0003). The impact of Ki67 suppression on clinical response seems to be restricted to ER-positive breast cancers. Since PgR expression levels of premenopausal ER-positive cancers were significantly reduced in clinical responders, inhibition of estrogen signaling due to chemotherapy-induced amenorrhea may be involved in this association.

An icteric type hepatocellular carcinoma with no detectable tumor in the liver: report of a case.

Abstract: A 70-year-old man was admitted to our hospital with obstructive jaundice. Computed tomography revealed a tumor in the left intrahepatic bile duct extending to the common bile duct without any significant lesions in the liver. Cholangiography showed a filling defect due to an intraductal tumor. Cytology of the bile juice was negative and tumor markers were carcinoembryonic antigen 5.7 ng/ml, carbohydrate antigen 19-9 49 U/ml, α-fetoprotein 9 ng/dl, and PIVKA-II 19 200 AU/ml. With a preoperative diagnosis of hilar bile duct carcinoma, a laparotomy was performed. The common bile duct was filled with a tumor and it extended into the bilateral intrahepatic bile ducts. The intraductal tumor was removed together with the extrahepatic bile ducts. An intraoperative histological examination of the tumor showed a well-differentiated hepatocellular carcinoma. No lesions were detected in the liver by ultrasonography, palpation during the operation, or a computed tomography scan after the operation. At 1 year postoperatively, no recurrence has been seen in this patient.

Surgical resection of advanced non-small cell lung cancer after a response to EGFR-TKI: presentation of two cases and a literature review.

Abstract: The usefulness of residual tumor resection after epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment remains unclear. We describe two patients who underwent residual tumor resection after responding to EGFR-TKIs for advanced non-small cell lung cancer (NSCLC) harboring EGFR gene mutations, along with a review of the literature. The patient in Case 1 was a 72-year-old female non-smoker who was initially diagnosed with T2aN2M0, stage IIIA adenocarcinoma harboring an EGFR exon 21 L858R mutation. After 8 months of gefitinib therapy, a marked radiologic response was noted, and right upper lobectomy with systemic lymph node dissection was performed. The patient developed brain metastasis despite continuous gefitinib therapy. The patient in Case 2 was a 68-year-old female non-smoker who was initially diagnosed with T3N2M0, stage IIIA adenocarcinoma and an extensive pulmonary thromboembolism. After 3 months of therapy with afatinib and anticoagulants, a marked radiologic response and symptom relief were achieved. We then performed right bilobectomy with systemic lymph node dissection. She developed bone metastasis despite postoperative afatinib therapy. The timing and validity of salvage surgery for residual lesions remain unclear when TKIs are offered as first-line therapy to patients with advanced NSCLC. In our two cases, surgery was performed without any complications. Surgical resection of the residual tumor might contribute to good local control. The accumulation of more clinical data is needed to further investigate the role of surgery in patients with advanced NSCLC harboring EGFR gene mutations.

Oncogenic kinase signalling

Abstract: Protein-tyrosine kinases (PTKs) are important regulators of intracellular signal-transduction pathways mediating development and multicellular communication in metazoans Their activity is normally tightly controlled and regulated Perturbation of PTK signalling by mutations and other genetic alterations results in deregulated kinase activity and malignant transformation The lipid kinase phosphoinositide 3-OH kinase (PI(3)K) and some of its downstream targets, such as the protein-serine/threonine kinases Akt and p70 S6 kinase (p70S6K), are crucial effectors in oncogenic PTK signalling This review emphasizes how oncogenic conversion of protein kinases results from perturbation of the normal autoinhibitory constraints on kinase activity and provides an update on our knowledge about the role of deregulated PI(3)K/Akt and mammalian target of rapamycin/p70S6K signalling in human malignancies

A census of human cancer genes

Abstract: A central aim of cancer research has been to identify the mutated genes that are causally implicated in oncogenesis ('cancer genes'). After two decades of searching, how many have been identified and how do they compare to the complete gene set that has been revealed by the human genome sequence? We have conducted a 'census' of cancer genes that indicates that mutations in more than 1% of genes contribute to human cancer. The census illustrates striking features in the types of sequence alteration, cancer classes in which oncogenic mutations have been identified and protein domains that are encoded by cancer genes.

Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival.

Abstract: ObjectiveTo analyze the outcome of 200 patients with gastrointestinal stromal tumor (GIST) who were treated at a single institution and followed up prospectively.Summary Background DataA GIST is a visceral sarcoma that arises from the gastrointestinal tract. Surgical resection is the mainstay of tre