National Kyushu Cancer Center Research Articles

A Multicenter Analysis of Short-term and Long-term Outcomes Following Laparoscopic Multivisceral Resection for Advanced Colorectal Cancer.

Recent research has demonstrated that laparoscopic multivisceral resection (MVR) for advanced colorectal cancer is safe, practicable, and yields satisfactory oncological results, which is in line with the growing usage of laparoscopic surgery. The effectiveness of laparoscopic MVR is still debatable, though. The goal of this study was to compare the short- and long-term results of patients with advanced colorectal cancer treated with open MVR with laparoscopic procedures. Data on 3,571 consecutive patients hospitalized at the Kyushu University National Kyushu Cancer Center for colorectal cancer surgery between 2004 and 2020 were gathered retrospectively. In the end, 84 individuals with advanced colorectal cancer who had a colectomy with MVR were examined. We evaluated invasiveness in terms of complications, blood loss, and operating time. Recurrence-free survival rates and overall 5-year survival were among the oncological outcomes. Of the 84 patients examined, 29 underwent laparoscopic treatment, and 55 underwent open treatment. The laparoscopic surgery group experienced shorter hospital stays (15 vs. 18 days, p<0.05) and much less blood loss (median volume: 167 vs. 1,058 g, p<0.005) than the open surgery group. Following the exclusion of patients with stage IV colorectal cancer from the study (groups undergoing laparoscopic surgery, n=25; open surgery, n=38), the groups displayed comparable pathologic results and no discernible variations in either the 5-year overall survival (p=0.87) or recurrence-free survival (p=0.86). In certain individuals with advanced colorectal cancer, a laparoscopic method of manipulation with MVR may be less invasive than an open method without compromising the prognosis.

Risk factors for de novo hepatitis B during solid cancer treatment.

BACKGROUNDReactivation of hepatitis B virus (HBV) during anticancer treatment is a critical issue. When treating patients with solid tumors, it is unclear whether specific cancer types or treatments affect HBV reactivation in hepatitis B surface antigen (HBsAg)-negative and hepatitis B core antibody (HBcAb)-positive patients, so-called de novo hepatitis B patients. The risk of de novo hepatitis B may vary based on different background factors.AIMTo determine the frequency and risk factors for de novo hepatitis B during solid tumor treatment.METHODSThis retrospective cohort study comprised 1040 patients without HBsAgs and with HBcAbs and/or hepatitis B surface antibodies (HBsAbs). The patients were treated for solid cancer from 2008 to 2018 at the National Kyushu Cancer Center and underwent HBV DNA measurements. Patient characteristics and disease and treatment information were investigated. HBV DNA measurements were performed using TaqMan polymerase chain reaction (PCR). To identify the risk factors associated with HBV DNA expression, the age, sex, original disease, pathology, treatment method, presence or absence of hepatitis C virus (HCV), and HBsAb and/or HBcAb titers of all subjects were investigated. In patients with HBV DNA, the time of appearance, presence of HBsAgs and HBsAbs at the time of appearance, and course of the subsequent fluctuations in virus levels were also investigated.RESULTSAmong the 1040 patients, 938 were HBcAb positive, and 102 were HBcAb negative and HBsAb positive. HBV DNA expression was observed before the onset of treatment in nine patients (0.9%) and after treatment in 35 patients (3.7%), all of whom were HBcAb positive. The HBV reactivation group showed significantly higher median HBcAb values [9.00 (8.12-9.89) vs 7.22 (7.02-7.43), P = 0.0001] and significantly lower HBsAb values (14 vs 46, P = 0.0342) than the group without reactivation. Notably, the reactivated group showed a significantly higher proportion of cancers in organs related to digestion and absorption (79.0% vs 58.7%, P = 0.0051). A high HBcAb titer and cancers in organs involved in digestion and absorption were identified as independent factors for HBV reactivation (multivariate analysis, P = 0.0002 and P = 0.0095). The group without HBsAbs tended to have a shorter time to reactivation (day 43 vs day 193), and the frequency of reactivation within 6 mo was significantly higher in this group (P = 0.0459) than in the other group.CONCLUSIONA high HBcAb titer and cancers in organs involved in digestion and absorption are independent factors that contribute to HBV reactivation during solid tumor treatment.

The C-Reactive Protein/Albumin Ratio is a Novel Significant Prognostic Factor in Patients with Malignant Pleural Mesothelioma: A Retrospective Multi-institutional Study.

Malignant pleural mesothelioma (MPM), a devastating neoplasm, is traditionally considered to be resistant to antitumor therapy. Identification of clinical prognostic indicators is therefore needed. Although the C-reactive protein/albumin ratio (CAR) has been used to predict the prognosis of many types of malignancy, its utility in patients with MPM is unknown. The data of 100 patients diagnosed as having MPM from 1995 to 2015 at the National Kyushu Cancer Center and Kyushu University were analyzed. The CAR was calculated as serum C-reactive protein concentration divided by albumin concentration. A cutoff for CAR was set at 0.58 according to a receiver operating characteristics curve for 1-year survival. Thirty-five of the 100 (35.0%) patients were classified as having a high CAR. A high CAR was significantly associated with advanced clinical stage (p<0.001) and chemotherapy alone (p=0.002). Patients with a high CAR had significantly shorter overall survival (OS) (p<0.001) and disease- or progression-free survival (DFS/PFS) (p<0.001). These associations between CAR and prognosis remained significant after propensity score-matching. In multivariate analysis, a high CAR was an independent predictor of shorter OS and DFS/PFS (p=0.003 and p=0.008, respectively). Multivariate analyses of the subgroups of patients who had received chemotherapy and of patients who had undergone surgery also showed that a high CAR was an independent predictor of shorter OS and DFS/PFS. CAR is an independent predictor of prognosis in MPM patients. This prognostic index contributes to clinicians' ability to predict benefit from treatment. Further larger, prospective studies are necessary to validate these findings.

Renal function and urological complications after radical hysterectomy with postoperative radiotherapy and platinum-based chemotherapy for cervical cancer.

We aimed to clarify renal functional changes long term and serious urological complications in women with cervical cancer who undergo radical hysterectomy followed by pelvic radiotherapy and/or platinum-based chemotherapy to treat the initial disease. Data on 380 women who underwent radical hysterectomy at the National Kyushu Cancer Center from January 1997 to December 2013 were reviewed. Main outcome measures were the estimated glomerular filtration rate (eGFR) and monitored abnormal urological findings. Postoperative eGFR was significantly lower than preoperative eGFR in 179 women with surgery alone and in 201 women with additional pelvic radiotherapy and/or chemotherapy (both P < 0.01). Two types of univariate analyses for eGFR reduction in women after treatment showed that older age, advanced stage, pelvic radiotherapy, and platinum-based chemotherapy were significant variables on both analyses. Two types of multivariate analyses showed that platinum-based chemotherapy or pelvic radiotherapy were associated with impaired renal function (odds ratio 1.96, 95% confidence interval 1.08-3.54 and odds ratio 2.85, 95% confidence interval 1.12-7.24, for the respective analyses). There was a higher rate of bladder wall thickening in women with pelvic radiotherapy had than those without it (17.4% vs. 2.7%, P < 0.01). One serious urological complication (intraperitoneal rupture of the bladder) occurred among women who underwent pelvic radiotherapy (0.6% vs. 0%). Surgeons should be aware that eGFR is reduced after platinum-based chemotherapy and/or postoperative pelvic radiotherapy. Serious and life-threatening urological complications are rare, but surgeons should be aware of the possibility during the long follow-up.

The combination of paclitaxel and carboplatin as second-line chemotherapy can be a preferred regimen for patients with urothelial carcinoma after the failure of gemcitabine and cisplatin chemotherapy.

There is no established standard second-line chemotherapy after the failure of the first-line cisplatin-based chemotherapy for patients with advanced or metastatic urothelial carcinoma. With regards to second-line chemotherapy, methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) was used from July 2009 onwards, and paclitaxel and carboplatin (TC) was introduced in April 2014 at the National Kyushu Cancer Center. The present study aimed to assess the prognostic factors for overall survival (OS) in second-line treatment that included best supportive care (BSC), and the tolerability and efficacy of TC chemotherapy. In total, 52 patients who were confirmed to have disease progression with first-line gemcitabine and cisplatin (GC) between June 2009 and November 2016 were enrolled in the current study. In addition, 28 patients selected BSC as second-line treatment, while 24 patients received second-line chemotherapy (MVAC, n=8; TC, n=16). The median OS for BSC, MVAC and TC was 2.8, 5.4, and 12.7 months, respectively. The difference between BSC and MVAC was not statistically significant (P=0.596). However, the difference between BSC and TC was statistically significant after Bonferroni correction (P=0.002). Multivariate analyses revealed that anemia [hazard ratio (HR), 7.047; 95% confidence interval (CI), 1.553-35.636; P=0.011], the presence of visceral metastasis (HR, 4.174; 95% CI, 1.506-13.429; P=0.005) and second-line treatment (TC HR, 0.296; 95% CI, 0.124-0.636; P=0.003) were independent prognostic factors. TC achieved an 18.7% overall response rate and a 56.2% disease control rate. Myelosuppression was the most common grade ≥3 toxicity, but no treatment-associated mortalities occurred during the study period. TC was associated with favorable benefits and safety, and may be considered a preferred regimen after the failure of GC.

Determination of adequate pelvic lymph node dissection range for Japanese males undergoing radical prostatectomy.

The present study aimed to determine the adequate pelvic lymph node dissection (PLND) range for Japanese males undergoing radical prostatectomy. A total of 467 Japanese patients who underwent antegrade radical prostatectomy at the National Kyushu Cancer Center (Fukuoka, Japan) were retrospectively reviewed. The patients were divided into two groups according to the PLND extent: The standard (obturator + internal iliac nodes) group and the expanded (standard + additional nodes) group, which accounted for 64.5% (301/467) and 35.5% (166/467) of the patients, respectively. No differences were observed in the preoperative and postoperative characteristics of the two groups. In addition, there was no difference in PSA recurrence between the two groups. There were no differences between the standard and expanded groups in the low-, intermediate- and high-risk groups (P=0.1456, P=0.1581, P=0.2125, respectively). The median number of lymph node dissection was 13 and 19, in the standard and expanded groups respectively (P<0.0001). However, regarding the number of lymph node metastases and the rate of patients with lymph node metastasis, no significant difference was observed between the standard and expanded groups (P=0.4219 and P=0.4257, respectively). According to multivariate analysis, a significant difference in the presence of lymph node metastasis (hazard ratio 3.547; P=0.0247), but not in the PLND extent, was detected in patients with prostate specific antigen failure (P=0.0655). When expanding the dissection extent, the number of dissected lymph nodes increases, but is not associated with the number or rate of positive lymph nodes. Thus, the current dissection range is considered to be appropriate for Japanese men undergoing radical prostatectomy.

Abstract P5-13-05: The relationship between the expression of FOXA1 and GATA3 and the efficacy of neoadjuvant endocrine therapy

Abstract Background. The estrogen receptor (ER)/ GATA3/ Forkhead box A1 (FOXA1) network is necessary for the ERα functional signature specific to luminal type breast cancers. High expression of FOXA1 indicates a good prognosis in ER-positive breast cancer. However, little is known about the association between the expression of FOXA1 and GATA3, and the efficacy of neoadjuvant endocrine therapy (NAE). This study investigated their predictive potential for NAE and the changes of their expression after NAE. Methods. The expression of ER, progesterone receptor (PgR), Ki67, FOXA1, and GATA3 were analyzed by immunohistochemistry in 66 patients with hormone receptor-positive/ human epidermal growth factor receptor 2 (HER2)-negative breast cancer who had been treated with NAE between March 2003 and December 2012 at Kyushu University Hospital, National Kyushu Cancer Center, and Sagara Hospital. The association between the expression of biological marker and the efficacy of NAE, and their expression changes after NAE were evaluated. Results. The median age of the patients was 60 years (range, 30–84 years). Pre- and post-menopausal patients were 24 (36.4%) and 42 (63.6%). Endocrine agents that were administered are as follows: aromatase inhibitors (AIs) for 42 patients (63.6%), luteinizing hormone-releasing hormone (LHRH) agonist plus AI for 10 patients (15.2%), LHRH agonist plus tamoxifen for 13 patients (19.7%). NAE yielded a partial response (PR) in 21 patients (31.8%) and stable disease (SD) in 45 patients (68.2%). Breast conserving surgery was performed in 56 patients (84.8%) and mastectomy was performed in 10 patients (15.2%). Preoperative Endocrine Prognostic Index (PEPI) score was 0 in 10 patients (15.2%) and 1 or greater (score 1 ≤) in 56 patients (84.8%). Pre-treatment FOXA1 expression was positively correlated with GATA3 (P = 0.0003) and PgR (P = 0.0138). Post-treatment Ki67 expression was significantly lower in tumors, which achieved PR compared with those with SD (P = 0.0007). The expression of PgR, Ki67, and FOXA1 was significantly lower in post-treatment tumors compared with those in pre-treatment samples (p &amp;lt; 0.0001, p &amp;lt; 0.0001 and p &amp;lt; 0.0001, respectively). The expression of PgR, Ki67, and FOXA1 was significantly reduced in both tumors with PR and those with SD (PR: P = 0.0004, P &amp;lt; 0.0001, and P = 0.0417, respectively; SD: P &amp;lt; 0.0001, P = 0.0001, and P &amp;lt; 0.0001, respectively). The expression of PgR, Ki67, and FOXA1 was significantly decreased in post-treatment tumors in both patients with the PEPI score 0 and those with score 1 ≤ (score 0: P = 0.0078, P = 0.0059, and P = 0.0098, respectively; score 1 ≤: P &amp;lt; 0.0001, P &amp;lt; 0.0001, and P = 0.0002, respectively). In tumors with PgR &amp;gt; 20%, the expression of Ki67 and FOXA1 were significantly lower in post-treatment tumors (P &amp;lt; 0.0001 and P &amp;lt; 0.0001, respectively). Conclusions. FOXA1 expression correlated with PgR expression, and was reduced significantly after NAE. These results suggest that blocking the effect of estrogen might reduce FOXA1 expression. Citation Format: Tanaka K, Tokunaga E, Inoue Y, Ueo H, Yamashita N, Sagara Y, Ohi Y, Taguchi K, Ohno S, Okano S, Kitao H, Oki E, Oda Y, Maehara Y. The relationship between the expression of FOXA1 and GATA3 and the efficacy of neoadjuvant endocrine therapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-13-05.

Early Identification of Asymptomatic Pulmonary Embolism Proximal to the Subsegmental Arteries After Gynecologic Surgery.

Few studies have assessed whether cases of asymptomatic pulmonary embolism (PE) in the early postoperative phase are subsegmental versus more proximal. In this study, we investigated whether asymptomatic PE occurring just after gynecologic surgery was subsegmental, and we examined the background characteristics of patients who experienced PE within 2 months postoperatively. All hospital records were reviewed, yielding a total of 2052 women who had undergone surgeries performed by the gynecologic oncology team between 2003 and 2013 in the National Kyushu Cancer Center. Asymptomatic and symptomatic postoperative PE cases diagnosed by multidetector computed tomography angiography or lung scan were identified; after excluding 2 cases of preoperative PE, there were 15 (0.73%) cases of postoperative PE among 2050 women. Of the 15 cases, 9 (60%) were diagnosed on postoperative day 1 or 2. Of the 9 women, 4 had no or minor symptoms/signs other than decreased oxygen saturation as measured by pulse oximetry (Spo 2), and PE was segmental or more proximal in 3 cases. Only 1 of the 9 cases showed dyspnea. The remaining 4 cases showed dizziness or perspiration, suggesting PE. Univariate analysis showed age, operation time, hypertension, and preoperative d-dimer elevation to be associated with postoperative PE. Multivariate analysis demonstrated that a high (≥ 1 µg/mL) preoperative d-dimer level was associated with postoperative PE (odds ratio, 6.331; 95% confidence interval, 1.567-25.589). Most asymptomatic PE cases occurring within 2 days postoperatively were segmental or more proximal. Identification of early, asymptomatic postoperative PE may be clinically significant because most of these emboli are proximal to the subsegmental arteries.

Feasibility of cisplatin/pemetrexed with 15 mg/kg bevacizumab for the treatment of patients with advanced non-squamous non-small cell lung cancer.

The aim of the present study was to retrospectively evaluate the feasibility of cisplatin/pemetrexed/bevacizumab (CPB) therapy at a bevacizumab (BEV) dose of 15 mg/kg as a first-line chemotherapeutic strategy for patients with advanced non-squamous non-small cell lung cancer (NSCLC). A total of 31 consecutive patients with non-squamous NSCLC were treated with first-line chemotherapy of CPB at a BEV dose of 15 mg/kg at the National Kyushu Cancer Center (Fukuoka, Japan) between November 2009 and December 2011. Clinical characteristics, response rate (RR), progression-free survival (PFS) time, overall survival (OS) time and adverse events were retrospectively analyzed. The 31 patients exhibited a male:female ratio of 21:10 and a median age of 60 years (range, 38-76 years). In total, 5 patients were of clinical stage III and 26 patients were of stage IV, 15 had a performance status of 0 and 16 had a performance status of 1, and 29 patients were diagnosed with adenocarcinoma and 2 were diagnosed with adenosquamous carcinoma. The EGFR mutation status was positive (exon 19 deletion), wild-type and unknown in 3, 21 and 7 patients, respectively. A total of 28 patients (90.3%) received a minimum of four courses of CPB therapy. Hematological toxicities classified as grade III or higher included neutropenia (29.0%), anemia (3.2%) and thrombocytopenia (3.2%), however, no severe non-hematological toxicities were observed. Additionally, 22 patients (71.0%) exhibited a partial response and 9 (29.0%) exhibited stable disease, resulting in a RR of 71.0% [95% confidence interval (CI), 41-74]. The median PFS and OS times were 8.4 months (95% CI, 7.9-9.0) and 28.5 months (95% CI, 26.4-30.6), respectively. Therefore, CPB therapy at a BEV dose of 15 mg/kg appears to be a feasible treatment strategy for patients with advanced non-squamous NSCLC.

P026 Mechanical ventilation promotes lung metastasis in 4T1 breast cancer lung-metastasized models

Goals: Recent evidence suggests that general anaesthesia and perioperative factors significantly increased risk of cancer recurrence compared to locoregional anaesthesia in patients undergoing surgery, however, their effects on behavior of cancer cells are not yet known. The endothelial cell and epithelial disruption was observed during mechanical ventilation, general anaesthesia in animalmodels. This studywas to test the hypothesis thatmechanical ventilation during cancer surgery induces lung stroma/tissue milieu changes, creating a favorable microenvironment for postoperative lung metastatic tumor establishment. Methods: Female BALB/c mice were anesthetized by intraperitoneal pentobarbital administration and divided into a mechanical ventilation group [mice ventilated with low pressures and low tidal volumes, 60min; n =8) and a control group (no ventilation; n =8). All the mice were subjected to intravenous injection of murine mammary adenocarcinoma 4T1-green fluorescent protein (GFP) 10 cells during anaesthesia. 24 hr later, sections from the lung tissue were examined and 4T1 celler were counted by direct GFP fluorescence observation, hematoxylineosin histology and Ep-CAM immunohistochemistry. To closely mimic human cancer surgical and anaesthetic manipulation, A clinically relevant animal model of spontaneous breast cancer lung metastasis with surgical resection of primary tumor was used to investigate the purified mechanical ventilation event that dictate lung metastasis post-operation. Female BALB/c mice were inoculated with metastatic murine mammary adenocarcinoma 4T1 cells in the mammary fat pad (3×105/mouse). After 14 day growth, mice were anesthetized by intraperitoneal pentobarbital administration and divided into a mechanical ventilation group [mice ventilated with low pressures and low tidal volumes, 60min; n =6) and a control group (no ventilation; n =6). All the mice were subjected to flank tumor resection during anaesthesia. Two weeks later, Metastatic tumor burden was assessed by both macroscopic metastatic nodule count and hematoxylin-eosin histology. Results: Mechanical ventilation was associated with increased circulating breast tumor cells arrest at microvasculature of lung (P = 0.01). The histology analysis data indicated that mechanical ventilation induced endothelial-epithelium abnormalities, inflammatory reaction and significantly upregulated the expression of epithelial adhesion molecules (Ep-CAM). Postoperative metastases exhibited significantly increase in mechanical ventilated groups in comparison with those in non-ventilated group (P < 0.05). Conclusion: Mechanical ventilation led to a progressive phenotype of lung metastases that exhibited a microenvironment for cancer cell adhesion, invasion, survive and growth within lungs. Disclosure of Interest: No significant relationships. P027 The analysis of cytogenetic intra-tumoral heterogeneity in squamous cell carcinoma of the breast M. Oikawa *, A. Igawa, M. Ishida, Y. Nakamura, S. Nishimura, C. Koga, S. Akiyoshi, Y. Koi, K. Taguchi, S. Ohno. Breast Oncology, National Kyushu Cancer Center, Fukuoka, Japan, Pathology, National Kyushu Cancer Center, Fukuoka, Japan

Clinical Significance of Extracapsular Invasion at Sentinel Lymph Nodes in Breast Cancer Patients with Sentinel Lymph Node Involvement.

A certain number of patients have extracapsular invasion (ECI) at the sentinel lymph node (SLN), but only a few reports describe its clinical significance. This study aimed to determine the clinical significance of ECI at SLN in breast cancer patients with involved SLN. This study evaluated ECI at SLN in 131 consecutive SLN-positive patients who underwent axillary lymph node dissection between 2003 and 2008 at the National Kyushu Cancer Center with regard to their long-term prognosis and non-SLN metastasis. Of the 131 patients, 46 (35 %) tested positive for ECI at SLN. Of these 46 patients, 61 % (28/46) had non-SLN metastasis compared with 28 % (24/85) in ECI-negative group (χ (2) test; P < 0.001). Multivariate analysis showed that ECI at SLN is significantly predictive for non-SLN metastasis [hazard ratio (HR) 3.2; 95 % confidence interval (CI) 1.4-7.1; P = 0.005]. The 5-year recurrence-free survival (RFS) rates were 71.3 % in the ECI-positive group and 89.9 %in the ECI-negative group (P = 0.001, log-rank test). Cox-regression analysis showed that ECI at SLN independently predicts lower RFS (HR 4.5; 95 % CI 1.8-11.7; P = 0.002). The findings show that ECI at SLN is an independent predictor of both non-SLN metastasis and poor prognosis for breast cancer patients with involved SLN. The clinical significance of ECI at SLN in operable-stage breast cancer warrants further study.

Palliative effects and adverse events of strontium-89 for prostate cancer patients with bone metastasis.

The aim of the present study was to evaluate the palliative effects and adverse events of strontium-89 (Sr-89) in patients with bone metastasis from prostate cancer. A total of 18 patients with prostate cancer and painful bone metastases, as diagnosed on bone scintigraphy, who were treated with Sr-89 at the National Kyushu Cancer Center between February, 2008 and April, 2014 were reviewed. Of the 18 subjects, 13 (72.2%) achieved a pain response, whereas 5 were classified as pain non-responders (27.8%). According to a logistic regression analysis, the pre-administration characteristics, including age, prostate-specific antigen (PSA), alkaline phosphatase (ALP), history of bone-modifying agent administration, opioid use or palliative radiation therapy, time after the combined androgen blockade nadir and time since the pain onset, were not found to be significant predictors of the pain response. Similarly, the post-administration characteristics, including pain flares and the PSA and ALP response, were not found to be significant predictors of the pain response. Although no patients exhibited leukocyte toxicities, 2 patients experienced myelosuppression, involving anemia and thrombocytopenia, requiring transfusion of red cell or platelet concentrate following Sr-89 treatment. Of the 18 patients, 5 (27.8%) reported pain flares, all of whom were successfully treated with rescue drugs alone. According to the logistic regression analysis, of the pre-administration characteristics, only ALP was identified as a significant predictor of bone marrow suppression in the univariate and multivariate analyses (P=0.006). Therefore, Sr-89 treatment was found to be effective in ameliorating bone pain associated with metastasis from prostate cancer. Although it is difficult to identify the patients who will receive pain relief prior to Sr-89 administration, this drug should be administered during the early stages due to the potential for bone marrow suppression in patients with high ALP levels.

P1-17-3 - Chemotherapy with Cisplatin and Pemetrexed for Non-Small Cell Lung Cancer Patients: a Retrospective Single Center Study

Background: Cisplatin and pemetrexed combination regimen (CP) is one of the promising therapies for non-squamous NSCLC patients. The PARAMOUT trial demonstarated the survival benefits of continuation maintenance chemotherapy with pemetrexed (PEM) after four cycles of CP. In Japan, only one phase II study showed feasibility and effectiveness of CP therapy.Methods: Japanese advanced NSCLC patients who were administered CP in National Kyushu Cancer Center from 2009 to 2014 were enrolled in this retrospective study. The drugs were administered day1 every three weeks as a cycle. Treatment was repeated four to six cycles until disease progression or unacceptable toxicities. Non-PD patients received maintenance chemotherapy with pemetrexed until disease progression. The response rate of CP was evaluated retrospectively.Results: One hundred and six patients received CP treatment. Sixty six patients were male and 40 were female. Median age was 63 years (range 34-77). Pathological diagnosis was adenocarcinoma in 104, large cell carcinoma in 1 and NSCLC in 2. The clinical stage of patients was IIIA in 1, IIIB in 3, IV in 86 and postoperative recurrence was 16. ECOG performance status was 0 in 58 patients, 1 in 46 patients and 2 in 2 patients. EGFR mutation is positive in 31, negative in 68, and unknown in 7, respectively. The median cycles of induction chemotherapy were 4. Thirty nine patients (36.8%) had partial response, 44 patients (41.5%) had stable disease. The median progression-free survival from the initiation of induction chemotherapy was 163 days.Conclusions: CP combination therapy for Japanese non-squamous NSCLC patients is feasible. Effectiveness of this regimen in current study is equivalent to previous clinical trials. Further prospective studies are warranted.

Positive resection margins may not reflect the true margin in patients undergoing radical prostatectomy

The aim of the present study was to evaluate the hypothesis that a positive resection margin (RM1) of an excised specimen may not reflect the true margin in patients that have undergone radical prostatectomy (RP). Between September 2003 and March 2011, 370 Japanese patients underwent an antegrade RP at the National Kyushu Cancer Center (Fukuoka, Japan), however, 95 of these patients were excluded from the study due to a history of receiving hormonal therapy or insufficient preoperative clinical data. The incidence of biochemical failure (BCF) was evaluated using multivariate analysis, which revealed that the preoperative prostate-specific antigen (PSA) level, pathological tumor stage, RP Gleason score and a PSA nadir <0.008 ng/ml were significant predictors (P=0.0065, 0.0006, 0.0002 and <0.0001, respectively). By contrast, an RM1 was not found to be a significant predictor of BCF, while the parameter with the highest hazard ratio (HR) was a PSA nadir <0.008 ng/ml (HR, 10.055; 95% confidence interval, 5.005–20.200). From the 56 cases that were RM1, 41 cases (73.2%) exhibited a PSA nadir <0.008 ng/ml. There were 42 cases (75.0%) in which only one site was identified to be RM1; among these cases, no significant difference was observed between a PSA level <0.008 ng/ml and a PSA level ≥0.008 ng/ml at the RM1 site (apex, P=0.1460; base, P=0.1384; anterior, P=0.3870; and posterolateral, P=0.5040). There were 14 cases (25.0%) in which multiple sites were RM1; these cases were classified by the number of sites that were RM1 (one vs. multiple) and no significant difference was observed between a PSA level <0.008 ng/ml and a PSA level ≥0.008 ng/ml (P=0.6090). Based on these results, an RM1 of an excised specimen may not reflect the true margin in patients that are treated with RP, specifically in cases where the PSA level is identified to decrease to below the postoperative measurement threshold value (PSA nadir <0.008 ng/ml).

Treatment and prognosis of breast cancer patients with brain metastases according to intrinsic subtype.

How breast cancer subtypes should affect treatment decisions for breast cancer patients with brain metastases is unclear. We analyzed local brain metastases treatments and their outcomes according to subtype in patients with breast cancer and brain metastases. We reviewed records and database information for women treated at the National Kyushu Cancer Center between 2001 and 2010. Patients were divided into three breast cancer subtype groups: Luminal (estrogen receptor positive and/or progesterone receptor positive, but human epidermal growth factor receptor 2 negative); human epidermal growth factor receptor 2 positive and triple negative (estrogen receptor negative, progesterone receptor negative and human epidermal growth factor receptor 2 negative). Of 524 advanced breast cancer patients, we reviewed 65 (12%) with brain metastases and records showing estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status, as well as outcome data; there were 26 (40%) Luminal, 26 (40%) had human epidermal growth factor receptor 2 and 13 (20%) had triple negative subtypes. There was no statistical difference in the number of brain metastases among subtypes; however, rates of stereotactic radiosurgery or surgery for brain metastases differed significantly by subtype (human epidermal growth factor receptor 2: 81%, Luminal: 42% and triple negative: 47%; P = 0.03). Patients having the human epidermal growth factor receptor 2 subtype, a performance status of ≤1 and ≤4 brain metastases, who underwent systemic therapy after brain metastases and underwent stereotactic radiosurgery or surgery, were predicted to have longer overall survival after brain metastases. Multivariate analysis demonstrated that not having systemic therapy and not having the human epidermal growth factor receptor 2 subtype were independent factors associated with an increased risk of death (hazard ratio 2.4, 95% confidence interval 1.01-5.6; P = 0.05 and hazard ratio 2.9, 95% confidence interval 1.5-5.8; P = 0.003, respectively). Our study showed that local brain treatments and prognosis differed by subtype in breast cancer patients with brain metastases.

Persistence and discontinuation of adjuvant endocrine therapy in women with breast cancer.

Although 8-73 % of breast cancer patients who receive adjuvant endocrine therapy discontinue it, discontinuation is little studied in Asian breast cancer patients. To determine frequency and reasons for discontinuation at a single institution, we reviewed records and database information for women with hormone receptor-positive breast cancer who were treated at the National Kyushu Cancer Center 2001-2006, defining "persistence" as continued endocrine treatment (even when physicians decided to stop because of recurrent disease or severe adverse effects), and "discontinuation" as ending therapy due to patient's wishes. Among 686 patients who started adjuvant endocrine therapy, 607 patients (88 %) persisted, 79 patients (12 %) discontinued. Of the 79 patients who discontinued, 37 (46 %) did so because of side effects, 26 (33 %) stopped appointments, 11 (14 %) stopped for "no particular reason", 4 (5 %) to get pregnant, and 1 (1 %) for economic reasons. The rate of persistence was higher in patients with lymph node involvement than in those without lymph node involvement (92 vs. 87 %; P = 0.03). Clinicians should discuss side effects with patients, both as part of informed consent and to prepare them to continue therapy, and should be aware that over time, patients' reasons for discontinuation change.

Allogeneic BMT in ATL: whom to transplant and which modality to use

Allogeneic hematopoietic stem cell transplantation (HSCT) has been used for treatment of ATL in Japan since 90’s, mainly for the patients with acute or lymphoma types of ATL after chemotherapies. The 3-year overall survival of HSCT in ATL is 31-39%, and many of the survivals live without disease for a long time. However, the treatment-related mortality (TRM) of HSCT is also high. Graft-versus-host (GVH) response is likely involved in both anti-tumor effects and TRM. Immunological study indicates the potential involvement of Tax-specific CTL in long-lasting anti-tumor surveillance after HSCT as well, suggesting that a tumor-vaccine to activate these CTL might partly reproduce the long-lasting effects of HSCT and could be an alternative choice of therapy following other initial therapies. The clinical trial of immunotherapy with Tax-peptide pulsed dendritic cells, currently undergoing in collaboration of National Kyushu Cancer Center, Kyushu University, and Tokyo Medical and Dental University, will find the answer.

Abstract P5-14-18: Indication of post-mastectomy radiation associated with risk of local recurrence in breast cancer patients with 1-3 lymph node metastasis

Abstract Objective: Post-mastectomy radiotherapy (PMRT) is strongly recommended for breast cancer patients with 1 to 3 axillary lymph node metastasis (N1-3) in NCCN guidelines Version 3.2013 (category 1), whereas the indication of that treatment should be considered individually according to the risk of local recurrence (St Gallen Consensus Meeting 2013). In order to support decision making of PMRT, we evaluated the risk factors of local recurrence after mastectomy. Patients and methods: We reviewed retrospectively 2422 cases with Stage I – III primary breast cancer receiving surgery at National Kyushu Cancer Center between 2000 and 2009. Seven hundred seventy six of them underwent mastectomy, and 547 of them received no PMRT. We analyzed the risk of local recurrence in relation to clinicopathologial factors, the status of hormone receptor and HER2, especially in cases with N1-3. Results: Among 547 cases with no PMRT, there were 364 cases with no LN metastasis (N0), 146 N1-3, and 37 N≥4, and 5-year local disease free survival (DFS) rates were 97.0%, 91.2%, and 73.4%, respectively. In N1-3 (146) cases who underwent no post-operative regional radiotherapies, the 5-year DFS in extent of lymph vessel infiltration (ly) were: ly0 was 97.9% (50) and ly1-3 was 87.9% (92) (ly unknown were 4). In the ly0 cases, the 5-year local DFSs were 100% in grade 2 and 85.7% in grade 3; 100% in ER positive and 90.0% in ER negative; 90.9% in HER2 positive and 100% in HER2 negative. Those in the cases of ly1-3 were 94.5% and 73.4%, 88.7% and 76.6%, and 91.0% and 64.3%, respectively. Conclusion: In patients with N1-3 breast cancer, the risk of local recurrence after mastectomy was significantly related to grade, extent of lymph vessel infiltration, ER and HER2. PMRT could be omitted in case with ly0,additionaly with grade 1-2, ER positive and HER2 negative. The remaining cases have the risk of local recurrence over 10%, if they don't receive PMRT, in which the indication of PMRT should be considered. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-18.

Abstract P1-13-15: Risk of late recurrence of hormone receptor positive breast cancer in cases with no recurrent disease at five years after surgery

Abstract Background: Among women who take 2-5 years of adjuvant endocrine therapy, more than half of all recurrences of hormone receptor (HR) positive breast cancer occur after the first 5 years. Data from large clinical trials including ATLAS, aTTom,MA17 and NSABP B-30 support extending tamoxifen or aromatase inhibitor beyond 5 year for women with HR positive breast cancer. For decision making according to extending endocrine therapy, the information of the risk of late recurrence is quietly important. Patients and methods: In order to determine ten year disease free survival (DFS) rates, we reviewed medical records and database of patients who were treated at National Kyushu Cancer Center between 1990 and 2001. Among seven hundred fifty seven patients with HR positive breast cancer, 550 received tamoxifen for 2-5 years. Eighty eight patients had recurrence within five years after surgery, and 13 were not followed, with 83.5% of 5-year DFS after surgery. Remaining four hundred twenty six had no recurrence at the time of 5 years after surgery. To evaluate the risk of late recurrence, we analyzed the long-term results in association with clinicopathological factors for these 426 patients. Results: Four hundred twenty six patients had 87.1% of 10-year DFS rate. According to lymph node metastasis (N), ten year DFS rates were 91.4% for 275 N-negative and 80.0% for 155 N-positive cases (P = 0.0037). As for the number of lymph node metastasis, 10-year DFS rates were 82.5%, 74.2%, and 79.1% for N1-3, N4-9, N&amp;gt;9, respectively. Tumor size was correlated with the prognosis, and 10-year DFS rates were 91.5% for 167 T1 (≤2 cm), 86.9% for T2 (2-5 cm), and 67.9% for T3 (&amp;gt;5cm) (P = 0.0334). There were no significant differences between grade and prognosis, and 10-year DFS rates of grade 1, 2 and 3 were 88.9%, 89.8%, and 96.8%, respectively (p = 0.3914). Considering the age at 5 years after surgery, no significant differences were observed as for late recurrence. Ten-year DFS rates of 96 cases of age under 50, 227 between 50 and 65, 113 over 65 was 89.4%, 85.1%, and 86.0%, respectively. Ten-year DFS rates of N-negative and N-positive were 94.3% and 81.2%, 88.1% and 80.1%, and 90.4% and 76.7% for these age criteria, respectively. Conclusion: Patients with HR positive breast cancer require optimal information for decision making whether to receive extending endocrine therapy or not. Our data demonstrated the risk of late recurrence in relation to clinic-pathological factors, which may support the consideration about extending endocrine therapy. Relatively high risks of late recurrence with over 10% of 10 year DFS rates are there in cases with N-positive or T2-3 HR positive breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-15.

The impact of obesity on the use of a totally laparoscopic distal gastrectomy in patients with gastric cancer.

PurposeSince a patient's obesity can affect the mortality and morbidity of the surgery, less drastic surgeries may have a major benefit for obese individuals. This study evaluated the feasibility of performing a totally laparoscopic distal gastrectomy, with intracorporeal anastomosis, in obese patients suffering from gastric cancer.Materials and MethodsThis was a retrospective analysis of the 138 patients, who underwent a totally laparoscopic distal gastrectomy from April 2005 to March 2009, at the National Kyushu Cancer Center. The body mass index of 20 patients was ≥25, and in 118 patients, it was <25 kg/m2.ResultsThe mean values of body mass index in the 2 groups were 27.3±2.2 and 21.4±2.3. Hypertension was significantly more frequent in the obese patients than in the non-obese patients. The intraoperative blood loss, duration of surgery, post-operative complication rate, post-operative hospital stay, and a number of retrieved lymph nodes were not significantly different between the two groups.ConclusionsIntracorporeal anastomosis seemed to have a benefit for obese individuals. Totally laparoscopic gastrectomy is, therefore, considered to be a safe and an effective modality for obese patients.