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Yoshihiro Kakeji

Publications and source records attributed to Yoshihiro Kakeji.

At least 19 recordsLinked to original sources
PubMed2026

A multicenter phase II trial of ramucirumab plus irinotecan for early recurrence of gastric cancer during or after adjuvant chemotherapy with docetaxel plus S-1 therapy: the RAMIEL trial (OGSG1901).

BACKGROUND: There is currently no established chemotherapy regimen for early recurrence of pathological stage III gastric cancer (GC) following adjuvant chemotherapy with docetaxel plus S-1 (DS) after D2 gastrectomy. We aimed to evaluate the efficacy and safety of ramucirumab plus irinotecan in patients with GC who experienced early recurrence during or within 6 months after DS adjuvant chemotherapy. METHODS: This prospective, open-label, multicenter phase II trial enrolled eligible patients treated at 25 centers of the Osaka Gastrointestinal Cancer Chemotherapy Study Group in Japan. Patients received ramucirumab (8 mg/kg) and irinotecan (150 mg/m2) every 2 weeks. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. The sample size was set at 40 based on a threshold median OS of 7 months and an expected median OS of 11 months, with a one-sided alpha error of 0.05 and a power of 0.80. RESULTS: Between November 2019 and July 2023, 43 patients were enrolled, and 39 were included in the analysis after excluding three ineligible patients and one who did not initiate protocol treatment. The median OS was 15.9 months (95% CI: 8.8-42.0; p = 0.003). The median PFS was 5.5 months (95% CI: 3.9-8.1), and the ORR was 38.5%. Grade  ≥ 3 adverse events, including neutropenia (25.6%) and hypertension (25.6%), were observed in more than 20% of patients. CONCLUSION: Ramucirumab plus irinotecan demonstrated promising efficacy and manageable toxicity in patients with early recurrence of GC following adjuvant DS therapy. TRIAL REGISTRATION: This study was prospectively registered in the Japan Registry of Clinical Trials (jRCTs05119071, October 6, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs051190071 ).

Docetaxel↗
PubMed2006

Relationship of hypoxia-inducible factor 1alpha and p21WAF1/CIP1 expression to cell apoptosis and clinical outcome in patients with gastric cancer.

BACKGROUND: Hypoxia-inducible factor-1alpha (HIF-1alpha) plays an essential role in oxygen homeostasis. The expression of HIF-1alpha-inducible genes is associated with tumor progression. p21 mediates cell cycle arrest and is one of the downstream genes targeted by HIF-1. PATIENTS AND METHODS: We examined the relationship between HIF-1alpha and p21 expression, apoptosis and tumor progression using tissue specimens obtained surgically from 126 patients with gastric cancer. RESULTS: Immunohistochemical analysis indicated that loss of p21 expression correlated positively with patient age and tumor size. Lymph node metastasis was significantly more frequent in tumors with loss of p21 expression (P = 0.022). HIF-1alpha-positive/p21-negative tumors had a lower apoptotic index than any other tumor samples, and patients with HIF-1alpha-positive/p21-negative tumors also had a significantly poorer prognosis than the other patient populations. CONCLUSION: These results suggest that loss of HIF-1alpha-dependent p21 expression results in decreased apoptosis, increased cell survival and more aggressive tumors.

Journal Article↗
PubMed2006

Coexistence of the loss of heterozygosity at the PTEN locus and HER2 overexpression enhances the Akt activity thus leading to a negative progesterone receptor expression in breast carcinoma.

Serine/threonine kinase Akt/PKB is known to regulate divergent cellular processes, including apoptosis, proliferation, differentiation, and metabolism. Akt is activated by a variety of stimuli, through such growth factor receptors as HER2, in phosphoinositide-3-OH kinase (PI3K)-dependent manner. A loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function also activates Akt. It has recently been shown that Akt activation is associated with a worse outcome among endocrine treated breast cancer patients and that it also inhibits the progesterone receptor (PR) expression via the PI3K/Akt pathway in breast cancer cells. Therefore, the PI3K/Akt signaling pathway has recently attracted considerable attention as a new target for effective therapeutic strategies. In the present study, we investigated the relationship between Akt activation and either HER2 overexpression or PTEN gene alteration, as well as the PR expression. We analyzed the incidence of LOH at the PTEN locus in 138 breast cancer patients, using our new system for microsatellite analysis, called high-resolution fluorescent microsatellite analysis (HRFMA). We showed Akt activation to significantly correlate with HER2 overexpression or LOH at the PTEN gene locus while inversely correlating with the PR expression. In addition, when LOH at the PTEN gene locus and HER2 overexpression occurred simultaneously, the incidence of Akt activation and reduced PR expression was significant. The association between Akt activation and PR negative expression was observed even in the ER-positive cases. Our results suggest that simultaneous PTEN LOH and HER2 overexpression enhances Akt activation and may thus lead to a negative PR expression.

Breast Neoplasms↗
PubMed2006

Overexpression of hypoxia-inducible factor 1alpha and p53 is a marker for an unfavorable prognosis in gastric cancer.

PURPOSE: To investigate the effects of the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) and p53 on the prognosis of human gastric cancer, the clinicopathologic characteristics of the tumors and the clinical outcome were analyzed. EXPERIMENTAL DESIGN: The expressions of HIF-1alpha and p53 proteins were studied by immunohistochemistry in 216 specimens of primary gastric cancer. RESULTS: HIF-1alpha(+)/p53(+) tumors more frequently showed an undifferentiated type, an infiltrative growth appearance, and an invasive lymphatic involvement compared with HIF-1alpha(-)/p53(-) tumors. HIF-1alpha(+)/p53(+) tumors also had more lymph node metastasis compared with HIF-1alpha(-)/p53(-) tumors. When stratified for HIF-1alpha and p53 positivity, the patients who were p53-negative and HIF-1alpha-negative had the most favorable prognosis, whereas patients who were p53-positive and HIF-1alpha-positive had the worst prognosis (P=0.0018). Using a multivariate Cox regression analysis, the depth of invasion, lymph node metastasis, and HIF-1alpha positivity were all found to be independent prognostic factors in patients with gastric cancer. CONCLUSION: Thus, HIF-1alpha is considered to be a useful independent prognostic factor in gastric cancer, and the combination of a HIF-1alpha protein overexpression with nonfunctional p53 tends to indicate a dismal prognosis.

Adult↗
PubMed2006

Physical activity and colorectal cancer: the Fukuoka Colorectal Cancer Study.

The number of cases of colorectal cancer in Japan has increased over the past few decades, and incidence rates are now among the highest in the world. The present investigation within the Fukuoka Colorectal Cancer Study, including 778 cases and 767 controls aged 20-74 years, examined the association between physical activity and colorectal cancer risk by subsite. Employment-associated and leisure time physical activity was assessed by a questionnaire and interview. Division of sites into the proximal and distal colon, as well as the rectum, revealed clear site-dependent protective effects, with adjustment for smoking, alcohol consumption, BMI and age. In males, greater job-related physical activity was associated with significant reduction of risk in the distal colon and rectum (P = 0.047 and 0.02, respectively), whereas total and moderate or hard non-job physical activity exerted effects limited to the rectum (P = 0.01 and 0.004, respectively). In females, job-related physical activity and moderate or hard non-job physical activity was also protective, but only in the distal colon. Separate assessment of the influence of BMI 10 years previous to the study showed increase in risk with obesity in males but not in females, limited to distal colon and rectum. The results of the present study indicate that physical activity associated with work and leisure-time exerts beneficial effects in Japanese, but not on the proximal colon.

Adult↗
PubMed2006

Clinicopathologic significance of hypoxia-inducible factor 1alpha overexpression in gastric carcinomas.

BACKGROUND: Hypoxia-inducible factor 1alpha (HIF-1alpha) plays a key role in responses to hypoxia and expression of HIF-1alpha downstream genes leads to both an adapted metabolism and increased oxygen supply. We investigated the clinical significance of HIF-1alpha expression in gastric carcinoma. METHODS: We examined HIF-1alpha, vascular endothelial growth factor (VEGF), and insulin-like growth factor-2 (IGF-2) expression patterns immunohistochemically in 126 specimens of gastric carcinoma. CD34 antigen levels were also examined by immunohistochemistry to determine microvessel density (MVD) within tumors and correlations between HIF-1alpha expression, clinicopathological features, and survival were examined. RESULTS: HIF-1alpha expression correlated with tumor size (P<0.005), depth of invasion (P=0.018), VEGF expression (P=0.03), and intra-tumor MVD (P<0.005). IGF-2 expression was more prevalent in HIF-1alpha positive than in HIF-1alpha negative tumors and the 5-year survival rate was 58.4% for HIF-1alpha positive patients and 81.5% for HIF-1alpha negative patients (P=0.009). HIF-1alpha expression is an independent prognostic factor in gastric carcinoma (P=0.032). CONCLUSIONS: Overexpression of HIF-1alpha in gastric carcinomas may upregulate its downstream gene products leading to VEGF-mediated angiogenesis, and resulting in a poor prognosis for patients.

Adult↗
PubMed2006

Aberrant hypermethylation of the promoter region of the CHFR gene is rare in primary breast cancer.

Taxanes are among the most active agents and they are now known to be an indispensable component in chemotherapy for breast cancer. However, some patients are resistant to taxanes and the identification of the molecular characteristics that can predict the sensitivity to taxanes would be useful in selecting the most appropriate patients to receive taxane therapy. Taxanes are antimicrotubular agents that promote microtubular assembly and stabilize microtubules by preventing depolymerization. They interfere with normal mitotic transition and causes cell cycle arrest in the G2-M metaphase. CHFR (checkpoint with forkhead-associated and ring finger) is a recently identified gene, which functions as an important checkpoint protein early in G2-M transition. Its activation delays the cell cycle in prophase and promotes cell survival in response to the mitotic stress induced by either nocodazole or taxane. CHFR is frequently downregulated in human cancers, mostly owing to the hypermethylation of its promoter region. CHFR downregulation has been found in primary cancers or in the established tumor cells of various origins, such as the lung, colon, esophagus, and stomach. The aberrant hypermethylation of CHFR promoter appears to be a good molecular marker to predict sensitivity to taxanes in gastric, lung, and colon cancer. A downregulation of CHFR was observed in breast cancer cells, however, no apparent promoter hypermethylation has yet been reported. In addition, an alteration of the CHFR expression or aberrant promoter hypermethylation in primary breast cancer has not been fully investigated. In this study, we examined the methylation status of the promoter region of CHFR gene in 110 primary breast cancers. We observed the hypermethylation of the CHFR promoter region in only one case (0.9%). We herein show that the aberrant hypermethylation of this region is quite a rare event in primary breast carcinoma.

Breast Neoplasms↗
PubMed2006

The association between Akt activation and resistance to hormone therapy in metastatic breast cancer.

In this retrospective study, the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer was investigated. Thirty-six metastatic breast cancer patients, treated with endocrine therapy, were evaluated for the activation of Akt by an immunohistochemical assessment of the expression of phosphorylated Akt at Ser 473 (pAkt). The relationship between the efficacy of endocrine therapy and Akt activation, HER2 status and hormone receptor expression was also investigated. Of these 36 cases, 12 cases (33.4%) were considered to show a positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated a worse efficacy than in pAkt-negative patients (P<0.01). pAkt positivity was also associated with a poorer objective response (P<0.05). The clinical benefit rate was lower in HER2 positive groups than in HER2 negative group (P<0.05). In addition, the clinical benefit was the smallest in both the HER2 and pAkt-positive patients (P<0.01). Regarding the endocrine agents, the clinical benefit of estrogen deprivation therapy with aromatase inhibitor or luteinising hormone-releasing hormone agosists was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (P<0.05). In addition, there was a tendency for clinical benefit of selective estrogen receptor modulator to be smaller in the pAkt-positive patients (P=0.09). These findings, therefore, suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings suggest that the activation of Akt in the downstream pathway of HER2 plays an important role in the resistance to endocrine therapy for breast cancer. Although our study was small in scope and retrospective in design, our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy.

Antineoplastic Agents, Hormonal↗
PubMed2006

Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients.

Akt/PKB is a serine/threonine kinase that plays an important role in survival when cells are exposed to different apoptotic stimuli. Aberrant activation of Akt/PKB in breast carcinoma is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway currently attracts considerable attention as a new target for effective therapeutic strategies. We therefore investigated the relationship between activation of Akt and clinicopathologic variables including hormone receptor and HER2/neu status. Breast cancer tissues obtained from 252 patients were utilized for this study. We evaluated Akt activation by immunohistochemical assessment of the expression of phosphorylated Akt (pAkt) at Ser-473. Eighty-four cases (33.3%) were diagnosed as positive for pAkt expression. pAkt was significantly associated with HER2/neu overexpression (p < 0.0001). There was an inverse correlation between pAkt and PR expression (p = 0.0321); however, there was no association between pAkt and ER expression. Survival analysis showed that pAkt positivity was associated with poor disease-free survival in cases with postoperative hormone therapy; however, there was no association in cases without hormone therapy. Our results indicate that Akt activation induced poor prognosis in patients who received adjuvant hormone therapy. This finding suggests that inhibition of the Akt signaling pathway may increase the efficacy of hormone therapy and improve the prognosis of patients who receive adjuvant hormone therapy.

Adult↗
PubMed2006

Trastuzumab and breast cancer: developments and current status.

The emergence of trastuzumab has drastically changed therapy for breast cancer. Trastuzumab (Herceptin; Genentech) is a recombinant humanized monoclonal antibody that targets an epitope in the extracellular domain of the human epidermal growth factor receptor 2 (HER2) protein. HER2 is a member of a family of four transmembrane receptor tyrosine kinases that regulate cell growth, survival, and differentiation via multiple signal transduction pathways. Overexpression of HER2 or amplification of the HER2 gene occurs in 20%-30% of human breast cancers. Preclinical models have demonstrated that this antibody has significant antitumor activity as a single agent, and it also has a synergy with certain chemotherapeutic drugs. Phase II and III clinical trials performed in women with metastatic breast cancers that overexpress HER2 have shown trastuzumab to have clinical activity when used as monotherapy, while also improving survival when used as a first-line therapy in combination with chemotherapy. At present, clinical investigations are focusing attention on the efficacy of trastuzumab in both the adjuvant and neoadjuvant setting, as well as in the metastatic setting. In this review, we describe the developments and current status of trastuzumab-based treatment for breast cancer.

Antibodies, Monoclonal↗
PubMed2006

Impact of loss of heterozygosity of encoding phosphate and tensin homolog on the prognosis of gastric cancer.

BACKGROUND AND AIM: Encoding phosphate and tensin homolog (PTEN) is a cancer suppressor gene and it has been assumed that gene mutation and loss of heterozygosity (LOH) occurs frequently in various types of carcinoma. However, the role of LOH of PTEN and its outcome variables in gastric cancer have not been well established. In the present study, we investigated the roles of PTEN, LOH and their outcomes. METHODS: Fresh frozen tumor samples from 119 gastric cancer patients with a primary diagnosis of gastric carcinoma were evaluated for LOH of PTEN using an automated sequencer. Results were compared with pathological parameters. The median follow-up period was 559 days. RESULTS: Loss of heterozygosity of PTEN was observed in 17.1% of patients (13/76) diagnosed with gastric cancer. No particular relationship was found with any clinicopathological factor. However, the prognosis of patients with LOH of PTEN was significantly poor. Multivariate analyses revealed that vascular invasion, invasion depth, LOH of PTEN, histology and lymph node metastasis were correlated with survival of the patient. CONCLUSIONS: Even though mutation of PTEN in gastric cancer has rarely been reported, according to our findings, LOH of PTEN frequently occurs in gastric cancers and is correlated with disease-related deaths. The LOH of PTEN is an independent prognostic factor and PTEN is a candidate as a haploinsufficient tumor suppressor in gastric cancers.

Aged↗
PubMed2006

Wide sleeve resection of lower trachea through anterior approach with omentopexy.

A 61-year-old man with tracheal adenoid cystic carcinoma (case 1) and a 28-year-old woman with benign tracheal stenosis (case 2) were treated with sleeve resection of the lower trachea through a median sternotomy and prophylactic omental wrapping. The resected tracheas were 4.5 cm (case 1) and 4.0 cm (case 2) in length. Both patients had an uneventful course after surgery despite postoperative irradiation in case 1 and preoperative infection with methicillin-resistant Staphylococcus aureus in case 2.

Adult↗
PubMed2006

Activation of PI3K/Akt signaling and hormone resistance in breast cancer.

Akt is a serine/threonine kinase that has been demonstrated to play an important role in survival when cells are exposed to different apoptotic stimuli. Recent studies show that aberrant activation of Akt in breast carcinoma is associated with a poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway is currently attracting considerable attention as a new target for effective therapeutic strategies. We investigated the incidence of Akt activation in 252 primary breast carcinomas and relationships among the activation of Akt, HER2 overexpression, hormone receptor expression, and alteration of the PTEN gene. Eighty-four cases (33.3%) were positive for pAkt expression. pAkt was significantly associated with HER2 overexpression (p<0.0001) and LOH at the PTEN gene locus (p<0.01). There was an inverse correlation between pAkt and PR (p<0.05). We also retrospectively examined the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer. Of these 36 metastatic breast cancer cases, 12 cases (33.4%) were considered to show positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated worse efficacy than in pAkt-negative patients (p<0.01). In addition, the clinical benefit was the smallest in the patients positive both for HER2 and pAkt (p<0.01). The clinical benefit rate of estrogen deprivation therapy with AI or LH-RH agonist was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (p<0.05), and there was a tendency for the clinical benefit of SERM to be smaller in the pAkt-positive patients (p=0.09). These findings therefore suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings indicate that the activation of Akt in the downstream pathway of HER2 plays an important role in resistance to endocrine therapy for breast cancer. Our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy.

Adult↗
PubMed2006

Phase I study of S-1 and biweekly docetaxel combination chemotherapy for advanced and recurrent gastric cancer.

A phase I study of S-1 and biweekly docetaxel (DOC) combination therapy was conducted to determine the maximum tolerated dose (MTD) and pharmacokinetic parameters. Fourteen patients with advanced or recurrent gastric cancer were analyzed. The treatment consisted of S-1 [body surface area (BSA) <1.25 m2:80 mg/day, 1.25<or= BSA <1.50 m2: 100 mg/day, 1.50 m2<or= BSA; 120 mg/day, orally, day 1-14) and DOC (30-40 mg/m2/day, intravenously, day 1 and 15], which were repeated as often as possible every four weeks. Pharmacokinetic analysis was done at DOC 40 mg/m2/day. Initially, patients were administered S-1 and 40 mg/m2/day of DOC, and DOC 40 mg/m2/day was considered as MTD. In detail, one patient developed neutropenia (grade 4, G4), and two other patients had no day 15 DOC administration because of neutropenia (grade 3, G3). When S-1 and 35 mg/m2/day of DOC were administered to three patients, no adverse reactions were noted. In six patients treated with S-1 and 30 mg/m2/day of DOC, one patient developed neutropenia (G4), and another patient developed diarrhea (G3) and anorexia (G3). The rest of this cohort showed no adverse reactions. Although 5-fluorouracil and gimeracil concentrations remained high under impaired renal function, no pharmacokinetic interactions appeared between S-1 and DOC under normal renal function. The dose limiting toxicity of a combination of S-1 and biweekly DOC was leukopenia and neutropenia. The recommended dose for this combination in phase II study is DOC 35 mg/m2/day.

Adult↗
PubMed2006

[Combination chemotherapy of S-1 plus biweekly docetaxel for advanced and recurrent gastric cancer].

The S-1 +biweekly docetaxel (DOC) combination therapy was evaluated for advanced or recurrent gastric cancer patients. This combination therapy was evaluated in vitro using the nude rat-gastric cancer xenograft system. S-1 alone or DOC alone showed antitumor activity, and the antitumor activity was synergistic when two drugs were combined. In clinical settings, the schedule was S-1 80 mg/m2 (day 1-14, orally) and DOC (day 1 and day 15, intravenously) followed by a 2-week rest. In phase I study, the dose of DOC was evaluated, and a recommended dose for phase II was determined as 35 mg/m2. The entry for phase II study was completed, and the preliminary results of 33 patients showed the response rate of 21.2%. The incidence of more than grade 3 adverse effects was 29%(neutropenia, leukocytopenia, anorexia and mucositis). The S-1 +biweekly DOC combination therapy can be a candidate for outpatient chemotherapy for advanced or recurrent gastric cancer.

Animals↗
PubMed2006

[A randomized controlled trial to evaluate the effect of adjuvant oral fluoropyrimidine derivative therapy after curative resection for stage II/III rectal cancer-adjuvant chemotherapy trial of S-1 for rectal cancer (ACTS-RC):].

We are conducting a prospective randomized trial to evaluate the survival benefit of adjuvant chemotherapy with S-1 (tegafur, gimeracil, oteracil potassium) and UFT (uracil-tegafur) after curative surgery for patients with Stage II and III rectal cancer. Patients are randomized to either administration of UFT (control) or S-1. UFT was orally administered for 5 days (400 mg/m2/day) followed by two days rest for a year. S-1 was orally administered for 4 weeks (80 mg/m2/day) followed by two weeks rest for a year. The primary endpoint is relapse-free survival (RFS) rate, and the secondary endpoints are overall survival time (OS) and frequency or level of adverse events. We aim to include 400 patients in each of the treatment groups and assume that the registration period will last until 2009.

Antimetabolites, Antineoplastic↗
PubMed2005

Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer.

Growth factor receptor-mediated signal transduction has been implicated in conferring resistance to conventional chemotherapy on cancer cells. We describe a pathway that involves AKT/PI3K to mediate chemoresistance in gastric cancer patients. Primary gastric carcinoma tissues and corresponding normal mucosa were obtained from 76 gastric cancer patients who underwent surgery in the Department of Surgery II in Kyushu University Hospital from the years 1996-2000. AKT activation was investigated by immunostaining with a phosphorylation-specific antibody, and LOH (loss of heterozygosity) of PTEN was studied in the same samples. AKT was phosphorylated in 22 cases (28.9%) of gastric cancer cases. AKT and phosphorylated AKT were not correlated with any clinicopathological factor. We found that the gastric cancer patients who had higher AKT phosphorylation (activated AKT) seemed to have LOH of PTEN (p = 0.0008). When the chemotherapeutic sensibilities of these patients were studied in an MTT assay, it was found that the activated AKT was associated with increased resistance to multiple chemotherapeutic agents (5-fluorouracil, adriamycin, mitomycin C and cis-platinum). The results of our study indicate that AKT activation and LOH of PTEN plays an important role in conferring a broad-spectrum chemoresistance in gastric cancer patients. It also indicates that AKT may therefore be a novel molecular target for therapies or chemosensitivity tests that improve the outcomes of gastric cancer patients.

Antineoplastic Agents↗