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Background The Safari study (UMIN000015168) was a retrospective, multicenter study in which 1072 consecutive cases of estrogen receptor-positive advanced breast cancer treated using 500 mg fulvestrant were registered. We previously reported the relationship between the patient factors and overall survival after the diagnosis using the same cases and the same factors for the analysis of time to treatment failure in patients with estrogen receptor-positive advanced breast cancer. The current study is an ad hoc analysis that focused on the relationship between the patient factors and overall survival after recurrence by adding factors generally associated with overall survival after recurrence. Methods The overall survival after recurrence in patients with estrogen receptor-positive human epidermal growth factor receptor 2 negative recurrent breast cancer was analyzed via univariate and multivariate analyses with a Cox proportional hazards model. Results A total of 598 cases were used for the analysis of overall survival after recurrence. Multivariate analysis revealed that favorable overall survival (median, 6.4 years) was significantly correlated with long time from recurrence to fulvestrant use (≥3 years), low nuclear or histological grade (G3 vs. G1), long time to treatment failure of initial palliative endocrine therapy (≥12 months) and long time to initial palliative chemotherapy (≥2 years). Conclusion The results of this study indicate that sequential endocrine monotherapy may be a useful treatment option for patients with estrogen receptor-positive/human epidermal growth factor receptor 2 negative recurrent breast cancer who have been successfully treated with initial long-term palliative endocrine therapy.

Background: Only old evidence exist to back up the use of medroxyprogesterone acetate (MPA) in endocrine therapy. Therefore, this study aimed to explore the factors that influence the time to treatment failure (TTF) of MPA in real world settings as late-line treatment following aromatase inhibitors and fulvestrant. Methods: This was a cohort study that used the database of the Safari study, on estrogen receptor-positive (ER+) post-menopausal advanced breast cancer previously treated with fulvestrant (UMIN000015168). We created Kaplan-Meier curves for TTF treated with MPA. Further, univariate and multivariate analyses were performed using a Cox hazard model of the clinicopathological factors involved in the TTF of MPA. Results: Fist, we made Kaplan-Meier curves by treatment line for MPA in TTF analysis population 1 (n = 244), excluding HER2+ and HER2 with unknown status. The median TTF for MPA was 8.2 months (95% CI 5.1–14.9) for first- and second-line treatments, 3.0 months (95% CI 2.5–3.9) for third-line treatment, and 4.1 months (95% CI 3.5–5.0) for fourth or later treatment lines. The first- and second-line treatments had significantly longer TTF than the third-line treatment (P < 0.001) and fourth-line or later treatments (P < 0.001). No difference in TTF was observed between the third and fourth or later treatment lines. Similar results were obtained in the analysis population 2 (n = 203) for TTF, excluding cases in which MPA was considered to have been used in palliative care. The median TTF for MPA was 7.9 months (95% CI, 5.1-16.0) for first- and second-line treatments, 3.0 months (95% CI 2.8–4.6) for third-line treatment, and 4.3 months (95% CI 3.7–5.6) for fourth or later treatment lines. The first- and second-line treatments had significantly longer TTF than the third-line treatment (P < 0.001) and the fourth-line or later treatments (P < 0.001). No difference in TTF was observed between the third and fourth or later treatment lines. Second, Table 1 shows the clinicopathological factors involved in the TTF of MPA. In univariate analysis, long DFI (≥ 6 years), small nuclear or histological grade, and the presence of visceral metastases correlated with significantly long TTF (P < 0.05). Whereas PgR, adjuvant chemotherapy, and adjuvant endocrine therapy did not affect the TTF of patients treated with MPA. However, in the multivariate regression analysis, only longer DFI (≥ 6 years) was correlated with a significantly longer TTF. Third, we compared the clinicopathologic factors in the groups that received MPA as the fourth or later treatment lines and achieved a TTF of more than 1 year with those that did not. There were no characteristic clinicopathological factors distinct between the two groups. Conclusion: In actual clinical practice, patients treated with MPA alone as the fourth or subsequent treatment lines showed a TTF of 4 months, suggesting that there is merit in using MPA even in late treatment lines, especially in patients with long DFI and those who are difficult to treat with other antineoplastic agents. Table 1. Univariate and Multivariate analyses to investigate association between clinicopathological factors and TTF of MPA (n=170) Citation Format: Kaho Utsunomiya, Hidetoshi Kawaguchi, Yutaka Yamamoto, Shigehira Saji, Norikazu Masuda, Takahiro Nakayama, Kenjiro Aogi, Keisei Anan, Shoichiro Ohtani, Nobuaki Sato, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Satoshi Morita, Miki Yamaguchi, Toshinari Yamashita, Daisuke Yotsumoto, Masakazu Toi, Shinji Ohno. Retrospective study using database for the effectiveness of medroxyprogesterone acetate in patients with ER-positive/HER2-negative postmenopausal advanced breast cancer: An additional analysis of the JBCRG-C06 Safari study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-15.

BackgroundOnly old evidence exists to back up the use of medroxyprogesterone acetate. Therefore, this study aimed to explore the factors that influence the time to treatment failure of medroxyprogesterone acetate in real-world settings as late-line treatment.MethodsThis was a cohort study that used the database of the Safari study on oestrogen receptor-positive post-menopausal advanced breast cancer (UMIN000015168). We created Kaplan–Meier curves for time to treatment failure with medroxyprogesterone acetate. Further, univariate and multivariate analyses were performed using a Cox hazard model of the clinicopathological factors involved in the time to treatment failure of medroxyprogesterone acetate.ResultsFrom the 1031 patients in the Safari study, 279 patients were selected as the population for the analysis of effectiveness of medroxyprogesterone acetate monotherapy. In the analysis of medroxyprogesterone acetate by treatment line, the median time to treatment failure was 3.0 months for third-line treatment and 4.1 months for fourth and subsequent treatment lines. In cases where medroxyprogesterone acetate was used as a third-line or later endocrine treatment, multivariate analysis showed that the length of the disease-free interval was correlated with the length of time to treatment failure of medroxyprogesterone acetate (P = 0.004). With medroxyprogesterone acetate monotherapy as the fourth-line or later treatment, 20% of the patients achieved a time to treatment failure of 12 months or longer.ConclusionIn actual clinical practice, patients treated with medroxyprogesterone acetate alone as the fourth or subsequent treatment lines showed a time to treatment failure of 4 months, suggesting that there is merit in using medroxyprogesterone acetate even in late treatment lines, especially in patients with long disease-free interval and those who are difficult to treat using other antineoplastic agents.

Aim To assess the utility of the perioperative use of direct oral anticoagulants for patients with hepatocellular carcinoma (HCC) with cancer-associated thrombosis. Case report An 83-year-old woman was admitted with a solitary HCC (10-cm diameter), as well as with multiple sites of venous thromboembolism and macroscopic portal vein tumor thrombosis. She had appropriate liver function without viral hepatitis, triple-positive tumor markers, and secondary polycythemia. Edoxaban at 30 mg was initiated 10 days before surgery to remove HCC. Complete remission of the pulmonary embolism and stability of the deep vein thrombosis and massive superior mesenteric vein thrombosis were recognized preoperatively. An extended left hepatectomy was successfully performed. To avoid hemorrhage complications, we used intravenous administration of nafamostat mesylate for 2 days, thereafter we restarted edoxaban. Superior mesenteric vein thrombosis resolved 5 months after surgery. Conclusion Perioperative oral administration of edoxaban was useful in multidisciplinary treatment for a patient with advanced HCC with cancer-associated thrombosis.

SummaryPurpose To date, it is not clear which anticancer agent is useful in combination with trastuzumab and pertuzumab As the first and second selective regimens for advanced or metastatic breast cancer (AMBC), this multicenter, open-label, phase II trial (JBCRG-M03: UMIN000012232) presents a prespecified analysis of eribulin in combination with pertuzumab and trastuzumab. Methods We enrolled 50 patients with no or single prior chemotherapy for HER2-positive AMBC during November 2013–April 2016. All patients received adjuvant or first-line chemotherapy with trastuzumab and a taxane. The treatment comprised eribulin on days 1 and 8 of a 21-day cycle and trastuzumabplus pertuzumab once every 3 weeks, all administered intravenously. While the primary endpoint was the progression-free survival (PFS), secondary endpoints were the response rate and safety. Results Of 50 patients, 49 were eligible for safety analysis, and the full analysis set (FAS) included 46 patients. We treated 8 (16%) and 41 (84%) patients in first- and second-line settings, respectively. While 11 patients (23.9%) had advanced disease, 35 (76.1%) had metastatic disease. The median PFS was 9.2 months for all patients [95% confidence interval (CI): 7.0–11.4]. In the FAS, 44 patients had the measurable lesions and the complete response rate (CR) was 17.4%, and partial response rate (PR) was 43.5%. The grade 3/4 adverse events were neutropenia (5 patients, 10.2%), including febrile neutropenia (2 patients, 4.1%), hypertension (3 patients, 6.1%), and other (1 patient). The average of the left ventricular ejection fraction did not decline markedly. No symptomatic left ventricular systolic dysfunction was observed. Conclusions In patients with HER2-positive AMBC, eribulin, pertuzumab, and trastuzumab combination therapy exhibited substantial antitumor activity with an acceptable safety profile. Hence, we have started a randomized phase III study comparing eribulin and a taxane in combination with pertuzumab and trastuzumab for the treatment of HER2-positive AMBC. Trial registration ID: UMIN-CTR: UMIN000012232.

Purpose To investigate the effectiveness and safety of bevacizumab–paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice. Methods In this prospective multicenter observational study, bevacizumab–paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors. Results Between November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8–23.6) months in eligible patients; 25.2 (22.4–27.4) months and 13.2 (11.3–16.6) months in cohorts A and B, respectively; and 24.4 (21.9–27.2) months and 17.6 (15.2–20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44–2.14), second-line therapy (1.35, 1.13–1.63), ECOG performance status ≥ 1 (1.28, 1.04–1.57), taxane-based chemotherapy (0.65, 0.49–0.86), cancer-related symptoms (0.56, 0.46–0.68), and visceral metastasis (0.52, 0.40–0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively. Conclusions In Japanese clinical practice, combined bevacizumab–paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously. Trial registration Trial no. UMIN000009086.

Background: There are now many treatment options for estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). However, there are few reports indicating the optimal treatment sequence for this disease. Information to predict response to treatment is vital for personalized therapy and determining the most beneficial approach for individual patients. In this study, we attempted to determine predictive factors of response to hormonal therapy and survival outcomes using the large-scale databases constructed in the Safari study (UMIN000015168), a retrospective, multicenter cohort study involving 1,072 Japanese patients receiving fulvestrant 500mg for ER+ ABC. We examined the association between clinicopathological factors and time to failure (TTF) of fulvestrant in Japanese ABC patients. Methods: Among 1072 patients, 247 patients were selected for this study. Inclusion criteria was as follows: 1) patients treated with either SERM or AI in the adjuvant setting (AS) with known starting and finishing date of the treatment (patients relapsed on adjuvant treatment were excluded), 2) patients treated with SERM, AI and SERD in the metastatic setting (MS) as the first and the second line treatment. Influence of the adjuvant hormonal therapy on the TTF of the first line and the second line treatment and overall survival (OS) was assessed. Cox proportional hazards model was used for this analysis. Results: Patients treated with SERM in AS had significantly longer TTF of 1st line and 1st+2nd line of hormonal therapy in MS (1st line: HR 1.519, 95% CI 1.04-2.218, p=0.0307, 1st+2nd line: HR 2.372, 95% CI 1.584-3.551, p Conclusions: Interestingly, once AI-treated patients in AS have relapsed, their hormone sensitivity is lower and survival outcomes are worse compared with SERM-treated patients in AS in this cohort. Our results have consistency with the results of ABCSG-12 trial showing a pronounced higher risk of death for anastrozole-treated patients (Annals of Oncology 26: 313–320, 2015). Since it is a cohort of selected patients who were successfully treated with fulvestrant, prospective analysis would be therefore warranted. Citation Format: Takahiro Nakayama, Hidetoshi Kawaguchi, Norikazu Masuda, Kenjiro Aogi, Keisei Anan, Yoshinori Ito, Shoichiro Ohtani, Nobuaki Sato, Shigehira Saji, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Satoshi Morita, Miki Yamaguchi, Hiroko Yamashita, Toshinari Yamashita, Yutaka Yamamoto, Daisuke Yotsumoto, Masakazu Toi, Shinji Ohno. Influence of the adjuvant hormonal therapy on hormone sensitivity and survival outcomes in ER+ and HER2−advanced breast cancer: A subgroup analysis of the JBCRG-C06 Safari study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-11.

Background: After the CONFIRM trial, fulvestrant 500 mg (F500) became a standard treatment for patients with estrogen receptor positive (ER+) advanced/metastatic breast cancer (AMBC). The JBCRG-C06 Safari study (UMIN 000015168) showed that earlier F500 use, a longer time from diagnosis to F500 use, and no prior chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with ER+ and HER2-negative AMBC (Kawaguchi H, et al. Breast Cancer Res Treat, 2017; Kawaguchi H, et al. Curr Med Res Opin, 2018). We had carried out subgroup analyses on real world data from the Safari study focusing on ER+ and HER2+ AMBC with the objective to examine further on potential interactions between TTF and the following: F500 single treatment or F500 with anti-HER2 therapy; presence or absence of visceral metastasis; progesterone receptor (PgR) status; and prior chemotherapy for AMBC. Material & methods: The Safari study was a retrospective, multicenter cohort study, conducted in 1072 patients at 16 sites in Japan for ER+ AMBC. Patients starting treatment with F500 between Nov 2011 and Dec 2014 were registered. After the data cleaning through the central review, 94 patients (9.6%) has been included in this sub-analysis among the 978 patients in which HER2 status was confirmed by the documentation. The relationship between baseline clinical/pathological factors, treatment line, and TTF (time from start to cessation of F500 treatment for any reason, including toxicity and death) were analyzed using Kaplan-Meier methods. Univariate analysis of TTF data was performed by Cox hazards model using: age, histological type, histological/nuclear grade, visceral-metastases, stage, PgR, period from AMBC diagnosis to F500 use, treatment line of F500, prior chemotherapy. Results: Median age at diagnosis of AMBC was 57.5yrs (33-85); 59(33-85) and 56.5(39-75) for F500 with/ without anti-HER2 therapy. Median age of fulvestrant start was 61yrs (35-96). 21.3% had de novo metastatic disease; 78.7% recurrent disease; 37.2% visceral metastases. All patients’ ER status was positive, and PgR status was positive in 65.9%, negative 25.5% respectively. HER2 IHC 3+ patients accounted for 44.7%, IHC 2+/1+ for 38.3%. In the case of IHC 2+/1+, HER2-positivity was confirmed by FISH. F500 alone was administered in 52 patients, while F500 with anti-HER2 therapy in 42 patients. At median follow up of 3.9 years, median TTF was 4.4m (95% CI: 3.3-5.7); 3.7m (95% CI: 2.9-5.9), 5.1m(95% CI: 3.6-6.4) for the F500 alone group, F500 with anti-HER2 therapy group respectively (p = 0.5973). F500 with/ without anti-HER2 therapy was administered in 1stor 2nd-line in 20 (21.3%), and ≥3rd-line in 74(78.7%) patients. Median TTF was 6.6m (95% CI: 4.6-8.5) and 3.7m (95% CI: 2.8-5.2) in the 1stor 2nd-line and ≥3rd-line respectively (p value:0.0145). Although no statistically significant difference was found, TTF tended to be shorter in the group receiving chemotherapy prior to F500 (median TTF: 3.7m vs 5.5m). No other clinical parameters including age, PgR status, metastatic sites were associated with the effectiveness. The median OS was 7.8-years (95% CI: 5.9-9.5), which had not been influenced by with/ without anti-HER2 therapy. The toxicity profile we observed was similar to that in the registration trial. Conclusions: Our findings suggest that F500 with/without anti-HER2 therapy appears to be effective also in the ER+ and HER2-positive ABMC setting which is consistent with the limited results previously published. Earlier line use of F500 use may be useful in HER2-positive patients as well as HER2-negative patients. Citation Format: Misato Hagi, Hidetoshi Kawaguchi, Norikazu Masuda, Shigehira Saji, Yutaka Yamamoto, Takahiro Nakayama, Kenjiro Aogi, Keisei Anan, Yoshinori Ito, Shoichiro Ohtani, Nobuaki Sato, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Miki Yamaguchi, Hiroko Yamashita, Toshinari Yamashita, Daisuke Yotsumoto, Satoshi Morita, Masakazu Toi, Shinji Ohno. Outcomes of fulvestrant therapy among Japanese women with ER-positive HER2-positive advanced or metastatic breast cancer: A subgroup analysis of the JBCRG-C06 safari study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-13.

Background: To evaluate the survival risk is an important factor to decide or treatment options for recurrent breast cancer patients with estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2−), though there are not enough supporting reports from large-scale databases. The Safari study (UMIN000015168) is a newly conducted retrospective, multicenter cohort study including 1072 ER+ advanced breast cancer Japanese patients treated with fulvestrant 500 mg mostly as a second or later line hormonal therapy. The follow-up data of Safari study is evaluated to focus on any relationship between clinicopathological factors and post-recurrence survival (PRS) in ER+ HER2− recurrent breast cancer patients. Methods: PRS was defined as the duration from the date of initial treatment for recurrent breast cancer to death. The Cox hazards model was used to evaluate the relationship between the clinical factors and PRS. We also performed multivariate analysis on PRS using factors that showed a statistical difference (p < 0.15) in univariate analysis. Hazard ratios (HRs) with 95% confidence intervals (CIs) and p-values are described. All tests were two-sided and p Citation Format: Kenjiro Aogi, Hidetoshi Kawaguchi, Norikazu Masuda, Takahiro Nakayama, Keisei Anan, Yoshinori Ito, Shoichiro Ohtani, Nobuaki Sato, Shigehira Saji, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Satoshi Morita, Miki Yamaguchi, Hiroko Yamashita, Toshinari Yamashita, Yutaka Yamamoto, Daisuke Yotsumoto, Masakazu Toi, Shinji Ohno. Factors associated with prolonged post-recurrence survival in patients with postmenopausal estrogen receptor-positive breast cancer taking fulvestrant: A follow-up data of the JBCRG-C06 Safari study factors associated with prolonged post-recurrence survival in patients with postmenopausal estrogen receptor-positive breast cancer taking fulvestrant: A follow-up data of the JBCRG-C06 Safari study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-55.

Background Assessing survival risk is important for discussing treatment options with estrogen receptor-positive (ER+) advanced breast cancer (ABC) patients. However, there are few reports from large-scale databases on the survival risk factors in ER+ ABC. The Safari study (UMIN000015168) was a retrospective, multicenter cohort study involving 1072 Japanese patients receiving fulvestrant 500 mg mostly as a second- or later-line endocrine therapy for ER+ ABC. The follow-up data after the Safari study were examined, focusing on any relationship between clinicopathological factors and overall survival (OS) in ER+ ABC patients. Methods OS in patients with ER+ ABC was analyzed by univariate and multivariate analyses with a Cox proportional hazards model in this study. Results A total of 1031 cases were evaluable for OS analysis. Multivariate analysis showed that younger age ( Conclusions In ER+ ABC patients whose treatment history included fulvestrant, younger age, longer time from ABC diagnosis to fulvestrant use, no prior palliative chemotherapy use, PgR−, and lower histological or nuclear grade correlated positively with prolonged OS.

Applications in which multiple users share the states in real-time over a network have been rapidly spreading, but network latency degrades their quality of service (QoS) and quality of experience (QoE). Although Fog computing effectively mitigates this problem, user allocation methods suitable for these applications with strict latency requirements have not yet been studied. Therefore, this paper proposes both offline and online methods that assume state sharing for user allocation in Fog environments. These methods not only reduce the mean of delays within each group composed of users who share the same states but also guarantee fairness among the users. The simulations demonstrate that our methods complete the allocation in a realistic time and outperform the baseline methods and architectures.

Background The Safari study (UMIN 000015168) was a retrospective, multicenter study in which 1072 consecutive cases of estrogen receptor-positive (ER+) advanced breast cancer (ABC) treated using 500 mg fulvestrant were registered. We previously reported the relationship between the patient factors and overall survival (OS) after the diagnosis using the same cases and the same factors for the analysis of time to treatment failure (TTF) in patients with ER + ABC. The current study is an ad-hoc analysis that focused on the relationship between the patient factors and OS after recurrence by adding factors generally associated with OS after recurrence. Methods The OS after recurrence in patients with ER + human epidermal growth factor receptor 2 negative (HER2−) recurrent breast cancer was analyzed via univariate and multivariate analyses with a Cox proportional hazards model. Results A total of 598 cases were used for the analysis of OS after recurrence. Multivariate analysis revealed that favorable OS (median, 6.4 years) was significantly correlated with long time from recurrence to fulvestrant use (≥ 3 years), low nuclear or histological grade (G3 vs. G1), long TTF of initial palliative endocrine therapy (≥ 12 months), and long time to initial palliative chemotherapy (≥ 2 years). Conclusion In patients with ER + HER2 − recurrent breast cancer who received endocrine therapy as the primary palliative treatment, the low proliferation activity of the tumor at the first diagnosis, sensitivity to initial endocrine therapy after the recurrence, and long time to the initiation of chemotherapy might be correlated with the favorable OS after recurrence. Trial registration: University Hospital Medical Information Network: UMIN 000015168, 2014/09/16

Background This study aimed to investigate whether schedule modification is safe and effective in patients intolerant to the standard eribulin dose and schedule. Methods Patients with metastatic breast cancer (MBC) treated with both anthracycline and taxane and ≤ 3 prior regimens of chemotherapy for MBC received eribulin at the standard dose and schedule (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) in the first cycle; change of dosing schedule (1.4 mg/m2 on days 1 and 15 of a 28-day cycle) was determined by change in neutrophil count, platelet count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum creatinine, and non-hematological toxicity on day 8 of the first cycle or day 1 of the second cycle. Clinical benefit rate (CBR; primary endpoint), time to treatment failure (TTF), overall survival (OS), and safety were evaluated. Results Of the 88 patients who were enrolled and received standard eribulin therapy in the first cycle, 42 patients were moved to the bi-weekly therapy group and 40 continued standard therapy. In the bi-weekly and standard therapy groups, mean relative dose intensity was 62.7 and 90.9%, CBR was 31.0 and 25.0%, median TTF was 81.5 and 75 days, and OS was 523 and 412 days, respectively. Neither group reported severe adverse events. Conclusion This is the first study to show that a bi-weekly eribulin schedule is tolerable and has comparable efficacy in patients intolerant to the standard eribulin schedule. Clinical trial registration University Hospital Medical Information Network (UMIN) Center (ID: UMIN 000008491). Electronic supplementary material The online version of this article (10.1007/s12282-018-0843-y) contains supplementary material, which is available to authorized users.

Background: Pertuzumab provided overall and progression-free survival (PFS) benefits in HER2-positive metastatic breast cancer patients (pts) in the CLEOPATRA (Clinical evaluation of docetaxel, pertuzumab and trastuzumab) study. However, few studies have described the efficacy of other drugs in combination with pertuzumab plus trastuzumab. Here, we present a pre-specified analysis of eribulin in combination with pertuzumab plus trastuzumab as first- and second-line therapy for advanced or metastatic breast cancer (AMBC) in a multicenter, open-label phase II study (UMIN000012232, JBCRG-M03). Methods: HER2-positive AMBC with no or single prior chemotherapy for AMBC were enrolled. All pts were administered trastuzumab and taxane as adjuvant or first-line chemotherapy. Treatment consisted of eribulin 1.4 mg/m2 on days 1 and 8 of a 21-day cycle and trastuzumab (8 mg/kg loading dose, then 6 mg/kg) plus pertuzumab (840 mg/body loading dose, then 420 mg/ body) once every 3 weeks, all administered intravenously. The primary endpoint was PFS, and secondary endpoints included overall response rate (ORR) and safety. PFS was determined using Kaplan–Meier analysis. Tumor response was assessed according to RECIST ver. 1.1. Results: Fifty pts were enrolled from November 2013 to April 2016. Forty-nine pts were eligible for safety analysis and the full analysis set (FAS) included 46 pts. The median age was 56 years (23–70), and 8 (16%) and 41 (84%) pts were treated in first- and second-line settings, respectively. Eleven pts (23.9%) were de-novo Stage 4, and 35 pts (76.1%) had progressed in metastatic disease after completion of local therapy. Median PFS was 9.3 months (M) (95% confidence interval [CI]: 6.4–12.3). Table 1 shows the efficacy data for each treatment line and includes ORR, complete response rate (CR), partial response rate (PR), stable disease rate (SD), progressive disease rate (PD), not evaluable rate (NE) and PFS in the FAS. The median relative dose intensities of eribulin, trastuzumab, and pertuzumab were 93.3% (77.0%–100%), 100% (96.0%–100%), and 100% (89.7%–100%), respectively, in the FAS. The grade 3/4 adverse events (AE) were neutropenia in 5 pts (10.2%), including 2 pts (4.1%) with febrile neutropenia; hypertension in 3 pts (6.1%), and other AEs in only one patient. The average of the ejection fraction did not decrease significantly. Symptomatic left ventricular systolic dysfunction was not observed. Conclusion: In pts with HER2-positive AMBC, first- and second-line therapy of eribulin in combination with pertuzumab plus trastuzumab demonstrated substantial antitumor activity with an acceptable safety profile. We are planning a phase III study comparing eribulin with taxanes in combination with pertuzumab plus trastuzumab for the treatment of HER2-positive AMBC. Efficacy data for each treatment lineTreatment LineTotal (n=46)First line (n=8)Second line (n=38)PFS (95% CI), months9.3 (6.4-12.3)20.8 (2.8-38.7)8.7 (7.2-10.2)ORR (%)28 (60.9)7 (87.5)21 (55.3)CR (%)8 (17.4)3 (37.5)5 (13.2)PR (%)20 (43.5)4 (50.0)16 (42.1)SD (%)11 (23.9)1 (12.5)10 (26.3)PD (%)5 (10.9)05 (13.2)NE (%)2 (4.3)02 (5.3) Citation Format: Kawaguchi H, Yamashita T, Masuda N, Kitada M, Narui K, Hattori M, Yoshinami T, Matsunami N, Yanagihara K, Kawasoe T, Nagashima T, Bando H, Yano H, Hasegawa Y, Nakamura R, Kashiwaba M, Morita S, Ohno S, Toi M. Phase II study of eribulin in combination with pertuzumab plus trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer [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 P5-21-07.

The JBCRG-C06 Safari study showed that earlier fulvestrant 500 mg (F500) use, a longer time from diagnosis to F500 use, and no prior palliative chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC). The objective of this sub-group analysis was to further examine data from the Safari study, focusing on ER + and human epidermal growth factor receptor-negative (HER2-) cases.The Safari study (UMIN000015168) was a retrospective, multi-center cohort study, conducted in 1,072 patients in Japan taking F500 for ER + ABC. The sub-analysis included only patients administered F500 as second-line or later therapy (n = 960). Of these, 828 patients were HER2-. Results Multivariate analysis showed that advanced age (≥65 years; p = .035), longer time (≥3 years) from ABC diagnosis to F500 use (p .001), no prior chemotherapy (p .001), and F500 treatment line (p .001) were correlated with prolonged TTF (median = 5.39 months).In ER+/HER2- patients receiving F500 as a second-line or later therapy, treatment line, advanced age, no prior palliative chemotherapy use, and a longer period from ABC diagnosis to F500 use were associated with longer TTF.

In the original publication, the name of the fourth author should be: Takafumi Sangai and his affiliation should be.

Personalised breast cancer therapy requires pathological characterisation of tumours. The proliferative index, based on Ki67, is pivotal, but a standard method has not been established. Here we look for an easy and practical way to evaluate Ki67.Immunohistochemical staining of estrogen receptors, progesterone receptors, HER2 and Ki67 (MIB-1) was performed on resected specimens from 406 primary invasive ductal carcinomas. Ki67 labelling index (LI) from manual counting was compared with visual assessment using a 5-grade scale (Eye-5). Next, 10 pathologists evaluated 100 samples with marked hot spots by using Eye-5. Another 100 samples without marking were also assessed by eight pathologists. One year later, two pathologists reviewed 222 cases with Eye-5. Prognosis was analysed among estrogen receptor-positive cases with postoperative endocrine therapy.Eye-5 showed good correlation to LI. All 136 cases of score 4-5 had LI20% and all 56 cases of score 1 had LI20%, which means that manual counting was not necessary for about half of the cases. Interobserver and intraobserver variability was low even when a hot spot was not fixed. Eye-5 also correlated with histological grade and lymph node metastasis. Combining Eye-5 and histological grade created a new algorism to predict LI, which allows 80% of all cases (74% of luminal cases) without manual counting. Cases of Eye-5 score 1-2 had significantly better survival than score 3-5.Visual assessment of Ki67 by a 5-grade scale (Eye-5) is fast, easy, and reliable with acceptably low interobserver and intraobserver variability. Eye-5 can replace LI in many luminal tumours, and is a strong candidate as a standard method of evaluating Ki67.

The Ki67 labeling index (LI) reflects the proliferative activity of breast cancers and defines luminal A and B tumors; however, no detailed method to measure Ki67 has been standardized. Here, we propose a fast and easy way to evaluate Ki67.Immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PgR), HER2 and Ki67 (MIB-1) was performed on 235 primary invasive ductal carcinomas. For each sample, a hot spot with many Ki67+ cells was identified using a low-power field (40×, 4× objective). Three independent areas in high-power field (400×) were selected at the hot spot, and all cancer cells in the 3 areas were manually counted to calculate LI (% Ki67+ cells). Alternatively, micrographs taken at 100× and 200× fields including the hot spot were shown to 2 pathologists, who visually assessed percentages of Ki67+ cells in 10 % intervals at a glance (Eye-10).Eye-10 and LI were strongly correlated (r = 0.9412, P 0.0001). All cases of Eye-10 ≥ 30 % had LI 14 %; most of those10 % had LI 14 %. Of 170 ER+/HER2- tumors, Eye-10-based subtypes matched 87 % of LI-driven subtypes, and interobserver agreement was good (κ = 0.705).Eye-10 is far easier than counting many cancer cells and useful for classifying breast cancers. Eye-10 can exclude obviously high and low Ki67 cases, leaving a "gray zone" around a cutoff point. Combining Eye-10 and manual counting is a good candidate for a standard method to evaluate Ki67.

Background Decisions of systemic treatment for recurrent breast cancer are usually based on the estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor status of the primary tumor. Recently, discordance in receptor status between primary and recurrent tumors has been reported. The objective of this study was to compare receptor status between the primary and recurrent tumor, and to evaluate overall survival (OS) after the diagnosis of recurrence between patients with discordant and concordant receptor status. Material and Methods Patients with recurrent breast cancer treated at National Kyushu Cancer Center between January 2004 and May 2011 were reviewed retrospectively. Primary and recurrent lesions were analyzed for ER and PR by immunohistochemistry (IHC) and HER2 by IHC or fluorescence in situ hybridization (FISH). OS in discordant and concordant groups for each receptor was estimated by Kaplan-Meier method and compared by log-rank test. Results Among 283 recurrent breast cancer patients both primary and recurrent tumor information for ER, PR, and HER2 was available in 69. Among these, recurrent biopsy specimens were obtained from locoregional recurrence in 72.5% and from distant metastases in 27.5%. Discordant rate in receptor status between the primary and recurrent tumor was 36.2%. Discordant rate in ER, PR, and HER2 was 14.4%, 23.1%, and 4.3%, respectively. Two-year OS after the diagnosis of recurrence in discordant and concordant ER group was 66.7% and 84.7%, respectively. The discordant ER group had significantly worse OS than the concordant ER group (P = 0.040). There was no significant difference in OS between the discordant and concordant PR group (P = 0.950). Conclusions Because discordance of receptor status between primary and recurrent tumors may exist, tissue confirmation of receptor status of recurrent tumor should be considered. Japanese patients with discordant ER between primary and recurrent tumor had a poorer outcome. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-21.

Unlike early stage breast cancer, metastatic breast cancer (MBC) is generally considered incurable except for a small number of patients with oligometastatic disease. The goal of treatment of MBC should be the prolongation of life and improvement of symptoms and quality of life. The prognoses of patients with MBC, however, have been improved with the introduction of newer, more effective agents. Therefore, the clinical question arises whether MBC patients can be cured with these new therapeutic agents. However, there are a couple of problems in tackling this question, including the duration of follow-up and the presence of strong adjuvant therapy. Firstly, most trials in MBC have a relatively short follow-up; long-term surveillance (>3–5 years) is exceptional, so little is known about the definitive outcome and the exact proportion of long-term survivors. Secondly, most of the patients have received pre- or postoperative adjuvant therapy. The cancer cells at metastatic sites are considered to be relatively resistant to the agents used in metastatic settings. Promisingly, a number of novel therapeutic agents including antibody–drug conjugates, irreversible small molecule HER2-tyrosine inhibitors, and HER2 dimerization inhibitors show promise in the treatment of HER2-overexpressing MBC, as well as PARP-1 [poly(ADP-ribose) polymerase-1] inhibitors for triple-negative breast cancer.

Background: The necessity of adjuvant trastuzumab therapy for patients with T1N0M0 tumors remains controversial. The objective of this study is to determine the risk of recurrence in Japanese women with T1N0 HER2- positive tumors compared with HER2-negative tumors. Methods: Among 1,180 patients with breast cancers diagnosed at our institution between 2001 and 2007, we reviewed 464 T1N0M0 diseases in which HER2 status was evaluated by IHC or gene amplification, who had not received trastuzumab in the adjuvant setting. Recurrence free survival (RFS) was estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards models were used to determine the association of each group with the risk of recurrence. Results: Seventy-nine (17%) of 464 patients had HER2-positive tumors and remaining 385 (83%) were HER2-negative diseases. Patients who had HER2-positive tumors tended to be younger (P=0.015), have more hormone receptor-negative tumors (P Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-12.

Y-box binding protein-1 (YB-1) plays pivotal roles in acquisition of global drug resistance and cell growth promotion through transcriptional activation of genes for both drug resistance and growth factor receptors. In this study, we investigated whether YB-1 is involved in regulation of the cell cycle and cell proliferation of human cancer cells. Treatment with YB-1 siRNA caused a marked suppression of cell proliferation and expression of a cell cycle related gene, CDC6 by cancer cells. Of cell cycle of cancer cells, S phase content was specifically reduced by knockdown of YB-1. The overexpression of CDC6 abrogated this inhibition of both cell proliferation and S phase entry. ChIP assay demonstrated that YB-1 binds to a Y-box located in the promoter region of the CDC6 gene. Expression of cyclin D1, CDK1 and CDK2 was also reduced with increased expression of p21(Cip1) and p16(INK4A) when treated with YB-1 siRNA. Furthermore, the nuclear YB-1 expression was significantly associated with the level of CDC6 nuclear expression in patients with breast cancer. In conclusion, YB-1 plays an important role in cell cycle progression at G1/S of human cancer cells. YB-1 thus could be a potent biomarker for tumour growth and cell cycle in its close association with CDC6.

Purpose Oral leukoplakia (OPL) is a heterogeneous oral lesion with an increased oral cancer risk. Current clinical parameters cannot predict the potential of malignant transformation in patients with OPL. We have shown that podoplanin, a lymphatic endothelial marker, is highly expressed in oral cancer and some oral premalignancies. The purpose of this study is to determine a role of podoplanin in predicting oral cancer development in patients with OPL. Patients and Methods Podoplanin expression was determined in 150 OPL patients with long-term follow-up using immunohistochemistry. Association between the protein expression patterns and clinicopathologic parameters including oral cancer development during the follow-up were analyzed. Results Fifty-six (37%) of the 150 OPL patients exhibited podoplanin expression in the basal and suprabasal layers and were classified as podoplanin positive. Podoplanin positivity was more frequent in older patients (P = .016), females (P = .020), and dysplastic lesions (P = .040). Patients with OPL that was podoplanin positive had significantly higher incidence of oral cancer than did those whose OPL was podoplanin negative (P = .0002). In the multivariate analysis using histology and podoplanin as cofactors, podoplanin was the only independent factor for oral cancer development (hazard ratio = 3.087; 95% CI, 1.530 to 6.231; P = .002). Importantly, oral cancer risk can be further stratified by considering both histology and podoplanin information. Conclusion Podoplanin is frequently expressed in OPL. Together with histology, podoplanin may serve as a powerful biomarker to predict the risk for oral cancer development in patients with OPL.

PurposeOverexpression of epidermal growth factor receptor (EGFR) is common in head and neck squamous cell carcinoma (HNSCC). Recent studies showed that EGFR inhibitors are effective for patients with HNSCC. This study analyzed the genetic nature of EGFR gene in HNSCC and its clinical correlations.Patients and MethodsThe EGFR gene copy numbers in 134 HNSCC tumors were determined using quantitative real-time polymerase chain reaction. The status of EGFR gene copy numbers was analyzed with clinical parameters including clinical outcome. Mutation status of EGFR exons 18, 19, and 21 was determined in the HNSCC tumors.ResultsAberrant EGFR copy numbers were found in 32 (24%) of 134 tumors, including 22 (17%) with increased copy number and 10 (7%) with decreased copy number. Patients whose tumors had EGFR copy number alterations (particularly patients with increased copy numbers) had significantly poorer overall, cancer-specific, and disease-free survivals compared with patients with normal copy numbers (P < .0001). At 5 years after initial diagnosis, 20 (91%) of the 22 patients with increased copy numbers died of disease compared with 30 (29%) of the 102 patients with normal copy number. No mutations on EGFR exons 18, 19, and 21 were detected in any of the tumors.ConclusionA subset of HNSCC manifests EGFR copy number alterations, and this is associated with a poor clinical outcome, suggesting a biologic role of the alterations. The rare mutation or small deletion at EGFR exons 18 to 21 indicates a minimal role of these events in HNSCC.

Drug cost is considered an important factor in treatment compliance for cancer patients. However, it is difficult to calculate individual drug costs. We were previously unable to provide sufficient information on costs to cancer patients starting drug therapy. Therefore, we developed a tool, in the form of a spreadsheet, which calculates drug costs for breast cancer treatment. This software tool runs on every terminal for electronic medical charts in our hospital. To evaluate the tool, we created 10 fictional breast cancer patient sets. Five pharmacists calculated the drug costs for a single regimen using method A (without software) and method B (with software). The pharmacists then calculated the drug costs for 3 regimens in the same way. We compared the time taken to calculate costs using method A and method B. For the single regimen, the mean time for method B (22.6±6.9 s) was 6.4-times shorter than that for method A (145.2±28.3 s, p0.0001). For the 3 regimens, the mean time for method B (35.5±5.0 s) was 8.9-times shorter than that for method A (315.8±43.1 s, p0.0001). The differences observed were statistically significant. By using the software, we were able to shorten the calculation time for drug costs, and therefore, alleviate the burden on medical staff.

BACKGROUND Endoscopic mucosal resection (EMR) is a less invasive localized treatment for patients with esophageal carcinoma. However, indications for EMR use in cases of superficial esophageal carcinoma are controversial. The authors evaluated histopathologic risk factors for lymph node metastasis and recurrence. METHODS In the specimens resected, the authors examined depth, the superficial area and the area attached to or infiltrating the lamina muscularis mucosa. RESULTS The authors found that the superficial area and the attached or infiltrated area reflected the depth of the tumor. However, there was a recurrence of esophageal carcinoma even in m3 cases attached only to the lamina muscularis mucosa. CONCLUSIONS The authors concluded that m1 and m2 esophageal carcinoma had almost no risk of lymph node metastasis and recurrence no matter how extensive the superficial area. In addition, sm2 and sm3 carcinoma have a high frequency of lymph node metastasis and recurrence. M3 and sm1 carcinoma run the risk of lymph node metastasis and recurrence however small the superficial area and the area attached to or infiltrating the lamina muscularis mucosa. Treatment strategies for patients with superficial esophageal carcinoma, including EMR, should take the above findings into account. Cancer 2002;94:570–5. © 2002 American Cancer Society.

To clarify mechanisms involved in the carcinogenesis of multiple oesophageal squamous cell carcinoma, the expression of p53 protein in 46 lesions surgically excised from 13 Japanese patients was investigated immunohistochemically and the relation of p53 protein accumulation to the patient’s history of alcohol consumption and cigarette smoking was analyzed. p53 protein accumulation was observed in 13 main lesions, that is in 6 (85.7%) of 7 subjects with a history of heavy drinking and smoking, but only in 1 (16.7%) of 6 with no such history (Fisher’s exact test, p = 0.025). As regards the 46 lesions, p53 protein accumulation was evident in 22 (88.0%) of 25 lesions of the high-risk patients, but in 7 (33.3%) of 21 lesions of the other subjects (Fisher’s exact test, p < 0.001). p53 protein accumulation was similarly recognized in all oesophageal lesions in 5 of 7 high-risk patients. Thus, use of both alcohol and cigarettes is clearly associated with a high frequency of p53 protein accumulation in multiple oesophageal squamous cell carcinoma present at the same time. These findings are considered to support the concept of field carcinogenesis of the oesophagus.

Granulomatous mastitis (GM) is a rare chronic inflammatory breast disease that can be mistaken for a variety of inflammatory and neoplastic disorders of the breast. Erythema nodosum (EN) is a common panniculitis, and is often associated with a variety of diseases, yet coexistence of EN and GM is very rare. In this paper, we present a young Japanese woman with EN associated with GM probably due to Corynebacterium infection. Both lesions of EN and GM were successfully treated with oral minocycline and surgical drainage. To the best of our knowledge, this is the first case of EN associated with GM due to Corynebacterium infection in the English-language published work.

Disruption of the APC/β-catenin/Tcf pathway has been proposed as an important step in the development of cancer. The Tcf-4 transcription factor gene was reported to be one of the targets of microsatellite instability (MSI) in colorectal cancers in with MSI. We carried out a sequencing analysis of the Tcf-4 gene in 41 Japanese patients with gastrointestinal tumors with MSI as well as in cancer cell lines. Three of 21 (14.3%) colorectal tumors with MSI contained a mutant Tcf-4 gene encoding 1-bp deletion in an (A)9 repeat, leading to carboxyl terminal truncation of Tcf-4 protein. No Tcf-4 mutations were detected in 20 gastric tumors with MSI, or in gastric cancer cell lines. Additionally, we found a novel transcript of the Tcf-4 gene which contained a segment of 73 bp in front of the (A)9 repeat of the Tcf-4 coding sequence. Sequencing analysis revealed that the inserted fragment was 60% homologous to that of exon IXA of the Tcf-1 gene. It is of interest that this insertion resulted in truncation of Tcf-4, similar to the 1-bp deletion in the (A)9 repeat. Therefore, in part of the Japanese colorectal tumors with MSI, frameshift mutations in Tcf-4 may be of functional significance. Functional alterations in the Tcf-4 signaling network in gastrointestinal tumorigenesis require further investigations.

BACKGROUND While there are reports that CYFRA 21-1 is a useful tumor marker, to our knowledge the clinical utility of this marker to detect recurrences for squamous cell carcinoma of the esophagus has not been addressed. METHODS By immunoradiometric assay, human serum levels of CYFRA 21-1, SCC antigen and CEA were measured in esophageal squamous cell carcinoma patients prior to their initial treatment. Monthly follow-ups of these tumor markers was done after surgery. RESULTS The diagnostic sensitivity of CYFRA 21-1 was 43.9% (18 of 41), a value superior to that for SCC antigen (26.8%) and CEA (17.0%) (P < 0.05). The positive rates of CYFRA 21-1 increased with progression of the disease, 22.2% of pTNM Stage 0-IIA and 77.8% of pTNM Stage IIB/III (P = 0.013), whereas SCC antigen and CEA rates were not related to pTNM stage. Among 13 patients with clinical evidence of a recurrence, 76.9% (10 of 13) exhibited an increase in CYFRA 21-1, and this increase was evident before clinical detection of the recurrence in 9 of these 13 patients (69.2%). Consequently, postoperative elevations of serum CYFRA 21-1 levels were indicative of a tumor recurrence 1–13 months before acquisition of clinical and radiological data. CONCLUSIONS The assay of CYFRA 21-1 is useful not only for diagnosis but also for close monitoring of patients with esophageal squamous cell carcinoma. Cancer 2000;89:1413–7. © 2000 American Cancer Society.

To clarify the prognostic factors in patients with submucosal carcinoma of the oesophagus, we examined the results of surgical treatment for 78 cases over the last decade. The clinicopathological factors including age, sex, location of the tumour, length of the tumour, histological differentiation, subclassification of depth, lymphatic or blood vessel invasion, intramural metastasis and lymph node metastasis were all analysed. Then the correlation between these factors and prognosis was investigated. As a result, significant differences were observed in the survival rates between the groups regarding lymphatic vessel invasion (P = 0.0003), intramural metastasis (P = 0.0051) and lymph node metastasis (P = 0.0026). According to a multivariate analysis, intramural metastasis (P = 0.0038, relative risk 9.17), vessel invasion (P = 0.0033, relative risk 6.25) and lymph node metastasis (P = 0.0187, relative risk 3.62) were found to be independent prognostic factors. The prognosis of the patients with at least one of these factors was significantly poorer than that without. The five-year survival rate of the patients without these factors was as good as that with mucosal carcinoma of the oesophagus. Based on our findings, vessel invasion, intramural metastasis and lymph node metastasis are thus considered to be significant prognostic factors in patients with submucosal carcinoma of the oesophagus. © 2000 Cancer Research Campaign

We have previously reported the association of tumor cell invasion with expression of growth factor receptor-bound protein 7 (Grb7). This molecule contains a Src homology 2 (SH2) domain and shares structural homology with a cell migration molecule designated Mig-10 found in Caenorhabditis elegans. In the present study, Grb7 expression was analyzed in human esophageal carcinomas with or without metastatic spread. The Grb7 protein was overexpressed in 14 of 31 esophageal carcinomas as compared to the adjacent normal mucosa (45%) and this finding was significantly correlated with the presence of lymph node metastases. We also identified that Grb7 protein in esophageal carcinoma cells was phosphorylated on tyrosine by epidermal growth factor as well as attachment to extracellular matrix proteins including fibronectin. Such fibronectin-dependent phosphorylation of Grb7 was regulated by integrin signaling that leads to the interaction with focal adhesion kinase protein. Furthermore, ectopic expression of a Grb7-SH2 dominant-negative fragment inhibited the fibronectin-dependent phosphorylation of endogenous Grb7, and reduced migration of esophageal carcinoma cells into fibronectin. Our results suggest a role of Grb7 mediated signal transduction in generation of an invasive cell phenotype against extracellular matrix, and thus contributes to metastatic progression of human esophageal carcinoma.

Some esophageal diseases such as carcinoma, esophagitis, and collagen diseases have often been reported to show a diffusely thickened esophageal wall in the roentogenogram findings. In the current report, a preoperative upper gastrointestinal series and an endoscopic examination showed a diffusely infiltrative type carcinoma, but other examinations did not suggest any diseases such as esophagitis or collagen diseases which might cause a thickening of the esophageal wall or a constriction, of the esophagus. A postoperative histological examination revealed the primary carcinoma to remain only within the mucosal layer, while a large degree of lymphatic vessel permeation reached the adventitia over a wide area. An extraordinary degree of lymphatic permeation spread through the esophageal wall, and stromal fibrosis developed as a result of such lymphatic permeation. These histological phenomena might thus have led to the macroscopic appearance of infiltrative type esophageal carcinoma.

Intraepithelial carcinoma contiguous with invasive squamous-cell carcinoma is a conspicuous feature of esophageal cancer. However, whether the mechanism of intraepithelial spreading is due to cell proliferation or field carcinogenesis has yet to be clarified. This study investigated the mechanism of intraepithelial spreading by measuring the cell proliferative activity using argyrophilic nucleolar organizer region (AgNOR) and proliferating cell nuclear antigen (PCNA)-positive cell counting. We examined the AgNOR number and PCNA-positive ratio (PCNA ratio) in the center and outer edge of intraepithelial carcinoma and in the center and deep margin of invasive squamous-cell carcinoma of the esophagus in 50 specimens from 18 cases of esophageal squamous-cell carcinoma concomitant with contiguous intraepithelial carcinoma. The proliferative activity was thus found to differ between the normal epithelium and cancerous lesions (p < 0.001), between intraepithelial carcinoma and invasive cancer (p < 0.001) and between deep margin and center areas of invasive cancer (p < 0.005). On the other hand, such activity was observed to be similar in the center and outer edge of the intraepithelial spread. These findings suggest that cell proliferation is the main mechanism of tumor progression at the invasive site of cancer, whereas in intraepithelial carcinomatous areas, "field carcinogenesis" or a paracrine mechanism, and not cell proliferation, is thought to be the cause of intraepithelial spread of esophageal cancer. These results therefore support the concept of field carcinogenesis.

The role of family history in the multiple occurrence of cancer in the upper aerodigestive tract (UADT) remains unclear. The family histories of close relatives were examined in 167 patients with either hypopharyngeal or cervical esophageal cancer (PhCe cancer) and in 167 control subjects with benign diseases. The odds ratio for PhCe cancer was 2.6 in relation to family history of UADT cancers. Based on the family histories of close relatives, 167 cases with PhCe cancer were divided into 3 groups (Group I, 18 cases with a family history of UADT cancer; Group II, 37 cases with a family history of other cancers; Group III, 112 cases with no family history of any cancers). The mean age of the cases in group I was 59.4, which was younger than in group III (64.2). Second primary squamous-cell carcinomas in the UADT were more frequently recognized in group I (39%) than in group III (11%). However, no differences were observed in the smoking and drinking habits of male patients between each group. These results thus suggest that a family history of UADT cancers appears to be associated with the multiple occurrence of UADT cancers as well as the development of PhCe cancer.

Oral mucositis is a frequent complication, but is poorly studied among patients with solid tumors. The purpose of this study is to clarify the incidence rate of oral mucositis in Japanese breast cancer patients receiving anthracycline-based chemotherapy(FEC100).From June 2007 to July 2008, 61 breast cancer patients eligible for this study received anthracycline-based chemotherapy(FEC100: 5-FU 500mg/m / / 2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2)at National Kyushu Cancer Center and Iwate Medical University Hospital. The incidence rate and grade of oral mucositis were evaluated in these patients.The cumulative incidence of oral mucositis was about 50%. Episodes of oral mucositis were more common during courses with febrile neutropenia than during courses without it(75. 0% vs 44. 9%, p=0. 12). The reduction of oral mucositis was only 13. 6% after administering the steroidal ointment and/or mouthwash, including sodium azulene sulfonate.New methods are needed to prevent and treat oral mucositis in patients receiving anthracycline- based chemotherapy(FEC100).

p21(WAF1/CIP1) is a potent inhibitor of various cyclin-dependent kinases, the expression of which is transcriptionally regulated by tumor suppressor gene product p53. We immunohistochemically examined the expression of p53 and p21(WAF1/CIP1) in 61 esophageal squamous cell carcinomas. p53 protein was expressed in 37 (61%) of 61 carcinomas. p21(WAF1/CIP1) was consistently expressed in the normal stratified esophageal mucosa. In the carcinomas, the expression of p21(WAF1/CIP1) protein was markedly reduced or not expressed in 33 (54%) cases. Clinicopathologic analyses revealed that no significant correlation exists either between p53-positive and -negative cases or between p21(WAF1)/(CIP1)-positive and -negative cases. Twenty-four cases were p53-positive/p21(WAF1/CIP1) negative, 15 were p53-negative/p21(WAF1/CIP1)-positive, 13 were positive for both and 9 were negative for both, and these findings thus showed an inverse correlation of the positivity between p53 and p21(WAF1/CIP1) (p