Sadatoshi Sugae

Fluorine-18-labeled 5-fluorouracil is a useful radiotracer for differentiation of malignant tumors from inflammatory lesions.

Objective[18F]-2-fluoro-2-deoxy-d-glucose ([18F]-FDG) is a useful radiotracer to detect malignant tumors. However, inflammatory processes are likely to be mistaken as malignant tumors owing to strong accumulation of [18F]-FDG. The fluorinated nucleoside base 5-fluorouracil has remained an important antimetabolite agent in the treatment of a variety of cancers. The objective of this study was to evaluate the possibility of discriminating between malignant tumors and inflammation by [18F]-5-fluorouracil ([18F]-5-FU).Methods[18F]-5-FU was made with >95% radiochemical purity in our laboratory. BALB/cAJcl-nu/nu mice were subcutaneously inoculated with colon carcinoma cell line, colon 26, into the left side of the back and turpentine oil into the right side of the back to cause chemical inflammation. We examined the biodistribution of [18F]-5-FU in control mice and tumor-inflammation mice. We also examined the biodistribution of [18F]-FDG as a baseline study. Approximately 1 MBq of either [18F]-5-FU or [18F]-FDG was injected into the tail vein of each mouse. The biodistribution study was performed at 1 and 2 h after injection. The radioactivity of each organ was measured by a gamma counter.Results[18F]-5-FU uptakes in the liver and the kidney were especially high. Tumor-to-blood ratios were significantly higher at 2 h than at 1 h (3.69 ± 0.40 vs. 1.81 ± 0.37, P < 0.001). Tumor-to-inflammation ratios at 2 h following injection were significantly higher than those at 1 h (1.94 ± 0.44 vs. 1.26 ± 0.20, P < 0.001). At 2 h after radiotracer injection, the tumor-to-inflammation ratio of [18F]-5-FU was significantly higher than that of [18F]-FDG (1.94 ± 0.44 vs. 1.03 ± 0.23, P = 0.001).ConclusionsOur data suggest that [18F]-5-FU has a diagnostic potential as a positron emission tomography ligand for differentiating malignant tumors from inflammatory lesions.

Evaluation of the Response to Breast Cancer Neoadjuvant Chemotherapy Using 18F-FDG Positron Emission Mammography Compared With Whole-Body 18F-FDG PET: A Prospective Observational Study.

Purpose The aim of this study was to assess therapeutic response to breast cancer neoadjuvant chemotherapy (NAC) by 18F-FDG positron emission mammography (PEM) compared with that to whole-body 18F-FDG PET (WBPET). Methods Twenty patients underwent WBPET and PEM 3 times: the first time was before NAC, the second time was after 2 courses of NAC, and the third time was after all courses of NAC. A pathological complete response (pCR) was defined as no evidence of residual invasive cancer with or without ductal carcinoma in situ. The relationships between each modality’s SUVmax and pathological response were evaluated. Results Nine patients achieved a pCR, whereas the other 11 patients had a non-pCR. The SUVmax of WBPET after 2 courses of NAC was significantly lower in the pCR group than in the non-pCR group (1.4 ± 0.4 vs 2.7 ± 2.1, P = 0.0334). There were no significant differences in the SUVmax of PEM (ie, PEM uptake value [PUV]) between the groups. The SUVmax of WBPET (area under the ROC curve [AUC] = 0.761) was superior to the PUVmax (AUC, 0.648) for predicting non-pCR at the interim time point. After all courses of chemotherapy, there were no significant differences between the groups in the SUVmax of WBPET; however, PUVmax was significantly lower in the pCR group than in the non-pCR group (1.0 ± 0.2 vs 2.5 ± 2.7, P = 0.0351). After NAC, the PUVmax (AUC, 0.796) was superior to the SUVmax of WBPET (AUC, 0.671). Conclusions There proved to be no apparent superiority of PEM in predicting pCR at the interim time point. Positron emission mammography had greater diagnostic capability for detecting residual cancer after all courses of NAC.

Biodistribution and radiation dosimetry of [18F]-5-fluorouracil

PURPOSE To estimate the radiation dose and biodistribution of (18)F-5-fluorouracil ([(18)F]-5-FU) from positron emission tomography/computed tomography (PET/CT) data, and to extrapolate mouse data to human data in order to evaluate cross-species consistency. METHODS Fifteen cancer patients (head and neck cancer (n=11), colon cancer (n=4)) were enrolled. Sequential PET/CT images were acquired for 2h after intravenous administration of [(18)F]-5-FU, and the percent of the injected dose delivered to each organ was derived. For comparison, [(18)F]-5-FU was administered to female BALB/cAJcl-nu/nu nude mice (n=19), and the percent of the injected dose delivered to mouse organs was extrapolated to the human model. Absorbed radiation dose was calculated using OLINDA/EXM 1.0 software. RESULTS In human subjects, high [(18)F]-5-FU uptake was seen in the liver, gallbladder and kidneys. The absorbed dose was highest in the gallbladder wall. In mice, the biodistribution of [(18)F]-5-FU corresponded to that of humans. Estimated absorbed radiation doses for all organs were moderately correlated, and doses to organs (except the gallbladder and urinary bladder) were significantly correlated between mice and humans. The mean effective [(18)F]-5-FU dose was higher in humans (0.0124mSv/MBq) than in mice (0.0058mSv/MBq). CONCLUSION Biodistribution and radiation dosimetry of [(18)F]-5-FU were compared between humans and mice: biodistribution in mice and humans was similar. Data from mice underestimated the effective dose in humans, suggesting that clinical measurements are needed for more detailed dose estimation in order to ensure radiation safety. The observed effective doses suggest the feasibility of [(18)F]-5-FU PET/CT for human studies.

Objection to postoperative radiation therapy in breast cancer with one to three lymph nodes involvements

My arguments regarding postmastectomy radiotherapy (PMRT) for this case are based on the following 4 reasons: (1) high rate of local recurrence in the no PMRT group in the Early Breast Cancer Trialists’ Collaborative Group meta-analysis on which the present guideline is based, (2) stage migration by sentinel node biopsy, (3) possible adverse events of radiotherapy, and (4) problems on extrapolation of data from western countries.

Placebo-Controlled, Double-Blinded Phase III Study Comparing Dexamethasone on Day 1 With Dexamethasone on Days 1 to 3 With Combined Neurokinin-1 Receptor Antagonist and Palonosetron in High-Emetogenic Chemotherapy

Purpose We evaluated the noninferiority of dexamethasone (DEX) on day 1, with sparing on days 2 and 3, combined with neurokinin-1 receptor antagonist (NK1-RA) and palonosetron (Palo) compared with the 3-day use of DEX in highly-emetogenic chemotherapy (HEC). Patients and Methods Patients who were scheduled to receive HEC (cisplatin ≥ 50 mg/m2 or anthracycline plus cyclophosphamide) were randomly assigned to receive either DEX on days 1 to 3 (Arm D3) or DEX on day 1 and placebo on days 2 and 3 (Arm D1) combined with NK1-RA and Palo. The primary end point was complete response (CR), defined as no emesis and no rescue medications during the overall (0 to 120 h) phase. The noninferiority margin was set at -15.0% (Arm D1 - Arm D3). Results A total of 396 patients-196 and 200 patients in Arms D3 and D1, respectively-were evaluated. CR rates during the overall period were 46.9% for Arm D3 and 44.0% for Arm D1 (95% CI, -12.6% to 6.8%; P = .007). CR rates during the acute (0 to 24 h) phase were 63.3% and 64.5% for Arms D3 and D1, respectively (95% CI, -8.1% to 10.6%; P < .001), and they were 56.6% and 51.5%, respectively, during the delayed (24 to 120 h) phase (95% CI, -14.8% to 4.6%; P = .023). Hot flushes and tremors were observed more frequently as DEX-related adverse events on days 4 and 5 in Arm D3, whereas anorexia, depression, and fatigue were observed more frequently on days 2 and 3 in Arm D1. As an indication of quality of life, global health status was similar in both arms. Conclusion Antiemetic DEX administration on days 2 and 3 can be spared when combined with NK1-RA and Palo in HEC.

Abstract P6-07-03: Long non-coding RNA H19 promotes cancer stemness and worsen breast cancer survival

Background : Cancer stem cells (CSC) are good sources of tumor initiation, heterogeneity, progression, and metastasis because of their unique characteristics. Several potential markers for CSCs have been suggested for breast cancer, including CD44 + /CD24 −/low , aldehyde dehydrogenase 1 (ALDH1), and epithelial cell adhesion molecule/epithelial-specific antigen. We previously reported that ALDH1 gene expression is related to aggressive phenotypes and poor prognosis in breast cancers. In this study, we conducted differential analysis of mRNA expression in ALDH1-positive breast cancer to identify genes associated with CSC. Next, we performed basic and clinical studies of one gene. Methods : Messenger RNA was isolated from ALDH1-positive cells and ALDH1-negative cells in 5 ALDH1-positive breast cancers. Microarray analysis revealed that several genes were significantly associated with the ALDH1 gene. Among them, we examined a long non-coding RNA of H19 in this study. We evaluated the effect of H19 on CSCs using RNA interference and a sphere formation assay using two cell lines, HCC1937 and iCSCL10A cells. We also investigated H19 expression in 192 surgical specimens by in situ hybridization and analyzed the relationship between H19 expression and clinic pathological findings in breast cancer patients. Results : Through in vitro experiments, we confirmed that suppression of H19 reduced sphere formation in both HCC1937 and iCSCL10A cells. Among surgical specimens, 48 samples (25%) expressed H19. We verified thatH19 positivity was significantly higher in ALDH1-positive cases than in ALDH1-negative cases (68% vs 9.7%, p Conclusions : H19 is clearly associated with CSCs and correlated with poor prognosis in breast cancer patients, particularly TNBC. Our future studies will investigate the role of H19 in maintaining the nature of CSCs and protein-coding genes associated with H19. Citation Format: Shima H, Kida K, Yamada A, Sugae S, Narui K, Miyagi Y, Ryo A, Ichikawa Y, Ishikawa T, Endo I. Long non-coding RNA H19 promotes cancer stemness and worsen breast cancer survival [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-07-03.

Long-Term Outcomes After Colectomy in Patients With Familial Adenomatous Polyposis

The aim of this study was to evaluate the long-term prognosis of patients who underwent colectomy for familial adenomatous polyposis. The clinical data of 29 familial adenomatous polyposis patients who underwent colectomy were retrospectively reviewed. Five patients died of causes that included colorectal cancer (CRC), desmoid tumor, cancer of the small intestine, and pancreatitis. The 30-year survival rate was 72%. Among the 15 patients who had CRC at primary surgery, the 5-year survival rate was 100% in stages 0, I, and II, and 75% in stage IIIA. Stage I desmoid tumor showed slow or no growth, whereas a stage IV tumor showed rapid growth and was fatal. Extracolonic malignancies were seen in the small intestine, stomach, duodenum, thyroid, kidney, breast, and ovary. Among 8 patients with ileorectal anastomosis, 4 had a second primary rectal cancer and 6 had a salvage reoperation. None of the patients who underwent either stapled or handsewn ileal pouch–anal anastomosis had second primary rectal cancers. ...

Abstract P3-06-27: BRCAness is important to identify TNBC subtype resistant to taxanes

BACKGROUND: Triple negative breast cancer (TNBC) is heterogeneous and consists of tumors associated with basal like, BRCA related and cancer stem cell (CSC) phenotypes. Although anti-cancer agents are substantial for treating TNBC, existing ones do not work in some subpopulation in TNBC at all. However, it has not been reported that subdivision of TNBC is useful for choosing ant-cancer agents. AIM: To examine whether subdividing TNBC is beneficial for tailored chemotherapy and to identify predictive factors for existing anti-cancer agents in TNBC. METHODS: Sixty-six TNBC cases from a randomized phase II trial comparing TCx6 (TC6) with FEC followed by docetaxel (FEC-D) as neoadjuvant chemotherapy for hormone receptor-negative breast cancer (Kanagawa Breast Oncology Group 1101 Study). TNBC was subdivided by 1) IHC of CK 5/6 and EGFR into basal- and non-basal subtypes, and 2) MLPA of BRCA1 into BRCA1 and non-BRCA1 subtypes. The pCR rates were examined according to each regimen and subtype. 3) The association of grade 3 pCR was examined with Ki-67, p53, aldehyde dehydrogenase (ALDH) 1 and topoisomerase 2A (topoIIα) by IHC and TOP2A by FISH for each regimen. RESULTS: 1) In basal subtype, the pCR rate was significantly higher for FEC-D (42.9%) compared with TC6 (13.6%) (p=0.033), but it was equivalent in non-basal subtype (FEC-D vs TC: 25.0% vs 36.4%, p=0.554). 2) In BRCA1 subtype, it was more significant (FEC-D vs TC: 53.8 % vs 13.3%, p=0.022). 3) An association between pCR and low ALDH1 expression was found in both FEC-D and TC6 (OR: 3.75 and 2.73). High topo IIα protein expression was associated with pCR in FEC-D (OR: 3.5). DISCUSSION: TC6 was less effective than FEC-D in basal subtype and BRCA1 subtype, showing that taxanes cannot exert their anticancer role in tumors with BRCA1 dysfunction. Although basal subtype may contain more BRCA1-defective tumors than non-basal subtype, MLPA of BRCA1 was better to identify subtype resistant to taxanes than CK5/6 and EGFR. ALDH1 predicted treatment efficacy, and could therefore represent a marker of resistance to conventional chemotherapy. Citation Format: Takashi Ishikawa, Kazutaka Narui, Kazuhiro Shimada, Kumiko Kida, Mari S Oba, Mikiko Tanabe, Yasushi Ichikawa, Sadatoshi Sugae, Itaru Endo. BRCAness is important to identify TNBC subtype resistant to taxanes [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-27.

Abstract 1899: Predictive factors of anthracycline or taxan based chemotherapy: Analysis from a randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel as neoadjuvant chemotherapy for hormone receptor-negative breast cancer

Background: Taxane-based regimens have been developed and used widely to treat breast cancer. It has therefore become important to identify subgroups of patients in which anthracyclines are indispensable. Thus, we had conducted a randomized phase II NAC study to compare a taxane with and without an anthracycline in hormone receptor (HR) negative breast-cancer subtypes and examined predictive factors for each regimen. Aim: To examine the predictive factors for six cycles of docetaxel and cyclophosphamide (TC6) compared with 5-fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel (FEC-D). Methods: Eligibility criteria were operable HR-negative breast cancer, age younger than 75 years and ECOG PS0-1. According to HER2 status, 103 patients were randomly assigned to TC (75/600 mg/m2) every 3 weeks ×6 or FEC (500/100/500 mg/m2) every 3 weeks ×3 followed by D (100 mg/m2) every 3 weeks ×3. Triple-negative (TN) breast cancer was subdivided by cytokeratin 5/6 and epidermal growth factor receptor into basal- and non-basal subtypes. The association of grade 3 pathological complete response (pCR) was examined with Ki-67, p53, aldehyde dehydrogenase (ALDH) 1 and topoisomerase 2A (TOP2A) by immunohistochemistry and TOP2A by fluorescence in situ hybridization) for each regimen. Results: Ninety-seven of 103 patients were analyzed successfully (50 for FEC-D and 47 for TC6). The pCR rate tended to be higher in FEC-D-treated patients compared with TC6-treated patients (pCR: 36.0 vs. 25.5%, n.s.). FEC-D treatment was significantly more effective than TC6 in basal-type (p=0.033) but not in non-basal and HER2 subtypes. ALDH1 was associated with resistance to both regimens (FEC-D: p=0.047, TC6: p=0.085) Conclusions: TC6 was not more effective than FEC-D in HR negative breast cancer. TC6 was significantly less active than FEC-D in basal subtype, and equivalent to FEC-D in HER2 and non-basal subtypes. ALDH1 could provide a marker for novel strategies such as stem cell-based therapies for breast cancer. The association of BRCAness with pCR is being investigated and will be presented at the meeting. Citation Format: Takashi Ishikawa, Kazutaka Narui, Kazuhiro Shimada, Kumiko Kida, Sadatoshi Sugae, Yasushi Ichikawa, Mikiko Tanabe, Itaru Endo, Mari S. Oba. Predictive factors of anthracycline or taxan based chemotherapy: Analysis from a randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel as neoadjuvant chemotherapy for hormone receptor-negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1899. doi:10.1158/1538-7445.AM2014-1899

Abstract 263: Identification of subgroup of triple negative breast cancer by cancer stem cell markers.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC [Background] Anti-cancer agents are essential for treating triple negative breast cancer (TNBC). The cases resistant to them showed unfavorable clinical courses and thus may require novel agents. It is crucial to predict the efficacy of existing agents in TNBC. Recently, cancer stem cell (CSC) theory has drawn an attention in relation to TNBC and chemoresistance. Aldehyde dehydrogenase 1 (ALDH1) is a biomarker of breast cancer stem cell. [Aims] In order to subdivide TNBC and finally find subgroup resistant to existing anti-cancer agents and better markers for stem cell phenotype. [Methods] 1)The expression of ALDH1 was examined immunohistochemically in each subtype of 447 breast cancer patients. 2)The expression of ALDH1 and its association with Ki-67,P53, CK5/6 or EGFR were examined in TNBC. 3)Correlation between ALDH1 and pathological response by neoadjuvant chemotherapy was examined. 4)ALDH1 positive and negative cells were collected by microdissection from 5 ALDH1 positive breast cancer cases. The expression profile was assessed by Affymetrix cDNA microarray. The difference of profile between ALDH-1 positive and negative cells was assessed. [Results] 1)The expression rate of ALDH1 was 4.5% in Luminal type, 11.1% in Luminal-HER2 type, 23.8% in HER2-enriched type and 33.6% in triple negative type. ALDH1 was expressed highly in TNBC. 2)In 79 TNBC with neoadjuvant chemotherapy, 29 cases(36.7%) was positive for ALDH1.The averages of NG, Ki67 and p53 were 2.7, 37.8% and 37.7% respectively in ALDH1 positive TNBC. 80% of them were positive for CK5/6 or EGFR. There was no significant correlation between ALDH1 and these pathological markers. 3) Poorly responsiveness to NAC (0-1b) was found in 17 cases (21.5%). Only ALDH1 was associated with chemoresistance to NAC (P=0.033), suggesting ALDH1 positive TNBC were resistant to anticancer agents. 4)63 and 41 genes were up- and down-regulated respectively in ALDH1 positive cells. These potential related genes are now under investigation. [Conclusions] ALDH1 could be a marker for chemoresistance in TNBC. As ALDH1 identifies some specific subpopulation of breast cancer, further studies will provide important information on subdividing TNBC and individualizing treatment of this intractable subtype. Citation Format: Kumiko Kida, Takashi Ishikawa, Akimitsu Yamada, Kazuhiro Shimada, Kazutaka Narui, Sadatoshi Sugae, Daisuke Shimizu, Mikiko Tanabe, Takeshi Sasaki, Yasushi Ichikawa, Itaru Endo. Identification of subgroup of triple negative breast cancer by cancer stem cell markers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 263. doi:10.1158/1538-7445.AM2013-263