Search

Background Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors. Materials and Methods We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel—which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)—to patients with advanced or recurrent solid tumors before its approval in Japan. Results A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21–126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death–ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy. Conclusion The FoundationOne CDx assay was performed with formalin‐fixed, paraffin‐embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs. Implications for Practice This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy., Comprehensive genomic profiling assays can identify multiple actionable genetic alterations that may inform treatment recommendations for patients with solid tumors. This article evaluates the feasibility of the application of the FoundationOne CDx panel to patients with advanced or recurrent solid tumors.

Extramammary Paget disease (EMPD) is a rare cutaneous adenocarcinoma that usually is of epidermal origin and shows glandular differentiation and that is treated by wide local excision depending on the disease extent. For widely metastatic disease, however, a standard treatment remains to be established. Similar to breast cancer, EMPD has been found to overexpress human epidermal growth factor receptor 2 (HER2) or hormone receptors (HRs). Whereas HER2-directed therapy was recently shown to be effective for HER2-positive EMPD, the potential role of endocrine therapy for HR-positive EMPD has remained unknown. We here report a case of metastatic EMPD with HR positivity that was successfully treated with the selective estrogen receptor modulator tamoxifen. This first-line treatment of systemic metastasis resulted in durable tumor regression for > 20 months without any treatment-related toxicities. This is the first report to reveal the promise of tamoxifen as a safe and effective treatment for HR-positive metastatic EMPD.

HER2‐targeted therapy, especially the anti‐HER2 antibody trastuzumab, is standard for HER2‐positive breast cancer; however, its efficacy is limited in a subpopulation of patients. HER3 ligand (heregulin)‐dependent HER2‐HER3 interactions play a critical role in the evasion of apoptosis and are therefore a target for oncotherapy to treat HER2‐positive breast cancer. The anti‐HER2 antibody pertuzumab and anti‐HER3 antibody patritumab both target this heregulin–HER3‐HER2 complex in different ways. This study examined the anticancer efficacy of dual HER2 and HER3 blockade in trastuzumab‐resistant HER2‐positive breast cancer. HER2‐positive SKBR3 or BT474 cells overexpressing heregulin (SKBR3‐HRG, BT474‐HRG) were used to evaluate the efficacy of trastuzumab, pertuzumab, and patritumab in vitro by performing cell viability, immunoblotting, and clonogenic assays. The effects of these agents were then evaluated in vivo using BT474‐HRG and an intrinsic heregulin‐expressing and HER2‐positive JIMT‐1 xenograft models. SKBR3‐HRG and BT474‐HRG cells lost sensitivity to trastuzumab, which was accompanied by Akt activation. Unexpectedly, trastuzumab in combination with pertuzumab or patritumab also showed limited efficacy toward these cells. In contrast, trastuzumab/pertuzumab/patritumab triple treatment demonstrated potent anticancer efficacy, concomitant with strong repression of Akt. Finally, in heregulin‐expressing BT474‐HRG and JIMT‐1 xenograft models, the addition of pertuzumab and patritumab to trastuzumab also enhanced antitumor efficacy leading to tumor regression. The current study found that triple blockade of HER2 and HER3 using trastuzumab, pertuzumab, and patritumab could overcome resistance to trastuzumab therapy in heregulin‐expressing and HER2‐positive breast cancer, which could be exploited clinically.

The high prevalence of obesity is a global concern. However, obesity and inflammatory bowel disease have similarities in epidemiology, diet, and gut microbial dysbiosis. An omnivorous (westernized) diet replacement with a plant-based diet in inflammatory bowel disease achieved better outcomes in both the induction and quiescent phases. Educational hospitalization providing a plant-based diet was found effective in suppressing flare-up in ulcerative colitis. This case report was designed to assess whether a plant-based diet can reduce body weight in patients with obesity during educational hospitalization for a short period of two weeks. Three men with metabolic syndrome (55, 61, and 65 years old) were included in the study with body mass index ranging from 27.0 to 31.2 kg/m2 and visceral fat area between 94.7 and 128 cm2. In Japan, a body mass index of ≥25 is defined as obesity. A lacto-ovo-vegetarian diet with brown rice (1400 or 1100 kcal/day), a plant-based diet, was provided during hospitalization for around two weeks. Patients walked for about 1 h in a park daily during the hospitalization. All three patients showed weight loss: 2.9%, 6.1%, and 6.6% at discharge. A decrease in body mass index, waist circumference, and the visceral fat area was also observed. Restriction in total calories in the form of a plant-based diet and daily 1-hour walks through an educational hospitalization for two weeks effectively reduced body weight and improved obesity-related parameters. Thus, a plant-based diet could be an effective weight-loss diet.

PURPOSE Cancer treatment can alter patient appearance, leading to psychological, social, and behavioral issues. This study aimed to investigate distress and difficulties related to appearance concerns in Japanese cancer patients and to identify information and support needs among them. METHODS We conducted a questionnaire survey using the Derriford Appearance Scale 59 (DAS59) among cancer patients with a prior history of chemotherapy, molecular targeted therapy, or immunotherapy, who were recruited from the Departments of Medical Oncology and Psychosomatic Medicine, Kindai University Hospital. RESULTS Participants were 114 patients with a mean age of 62.9 years; 70.2% were female, 86.0% had metastatic or locally advanced unresectable cancer, and 78.1% had concerns about some aspect of their appearance. Mean DAS59 full-scale score was 77.7 ± 36.4. Younger and female participants were found to have higher full-scale scores in univariate analysis (P

Introduction Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show marked therapeutic efficacy in patients with non–small cell lung cancer (NSCLC) harboring the echinoderm microtubule-associated protein-like 4– ALK fusion gene. The effect on overall survival (OS) of sequential treatment with the first- and second-generation ALK-TKIs crizotinib and alectinib, respectively, has remained unknown. We have examined the clinical outcome of such sequential treatment in a retrospective analysis of patients with ALK -rearranged NSCLC. Materials and Methods Eleven patients with ALK -rearranged NSCLC treated with crizotinib followed by alectinib were identified. The progression-free survival (PFS) and OS for these patients were determined from a retrospective review of their medical records. Results The median PFS on crizotinib or alectinib was 6.1 months (range, 1.0-15.4 months) and 15.2 months (range, 1.0-28.3 months), respectively. The median combined PFS for both crizotinib and alectinib was 18.2 months (range, 10.4-43.7 months). Crizotinib was continued beyond radiographic evidence of progressive disease in 6 of the 11 patients, with a median duration of postprogression crizotinib treatment of 9.4 months (range, 0-20.5 months). The OS period from the diagnosis of metastatic disease or the initiation of crizotinib treatment was 51.1 months (range, 20.9-69.5 months) and 48.6 months (range, 19.8-50.1 months), respectively. Conclusion Our retrospective study has revealed durable survival for alectinib treatment after crizotinib failure in patients with ALK -rearranged NSCLC.

Background We previously reported the synergistic effect of S-1 and eribulin in preclinical models. In addition, our phase I study revealed the recommended dose for the phase II study of the combination therapy in advanced breast cancer (ABC) patients pre-treated with anthracycline and taxane. Our current study reports on the efficacy and safety of the combined use of eribulin and S-1 in patients with ABC and poor prognosis. Methods Patients with breast cancer who received prior anthracycline- and/or taxane-based therapy were assigned to receive a combination therapy of eribulin (1.4 mg/m2 on days 1 and 8, every 21 days) and S-1 (65 mg/m2, on days 1 to 14, every 21 days) for advanced/metastatic disease. All patients had at least one clinicopathological factor such as being oestrogen receptor negative, Human Epidermal Growth Factor Receptor 2 (HER2) receptor negative, presence of visceral involvement, presence of three or more metastatic sites, or having a disease-free interval shorter than 2 years. The primary endpoint was the independent-reviewer assessed objective response rate (ORR). Secondary endpoints were clinical benefit rate, disease control rate, progression-free survival (PFS), and overall survival (OS). Results This study enrolled 33 patients. Confirmed ORR was 33.3% (95% CI: 17.3 to 52.8). Median PFS was 7.5 months (95% CI: 4.0 to 14.3). Median OS time was not reached during the current experimental periods. The most common grade 3/4 adverse event was neutropenia (68.8%). Conclusions The combination of eribulin and S-1 is safe and effective for treatment in patients with ABC and poor prognosis. Trial registration Current Controlled Trials UMIN000015049, date of registration: September 5th 2014.

Medical oncologists are challenged to personalize medicine with scientific evidence, drug approvals, and treatment guidelines based on sequencing of clinical samples using next generation sequencer (NGS). Knowledge-based curation systems have the potential to help address this challenge. We report here the results of examining the level of evidence regarding treatment approval and clinical trials between recommendations made by Watson for Genomics (WfG), QIAGEN Clinical Insight Interpret (QCII), and Oncomine knowledge-based reporter (OKR). The tumor samples obtained from the solid cancer patients between May to June 2018 at Kindai University Hospital. The formalin-fixed paraffin-embedded tumor samples (n = 31) were sequenced using Oncomine Comprehensive Assay v3. Variants including copy number alteration and gene fusions identified by the Ion reporter software were used commonly on three curation systems. Curation process of data were provided for 25 solid cancers using three curation systems independently. Concordance and distribution of curated evidence levels of variants were analyzed. As a result of sequencing analysis, nonsynonymous mutation (n = 58), gene fusion (n = 2) or copy number variants (n = 12) were detected in 25 cases, and subsequently subjected to knowledge-based curation systems (WfG, OKR, and QCII). The number of curated information in any systems was 51/72 variants. Concordance of evidence levels was 65.3% between WfG and OKR, 56.9% between WfG and QCII, and 66.7% between OKR and QCII. WfG provided great number of clinical trials for the variants. The annotation of resistance information was also observed. Larger differences were observed in clinical trial matching which could be due to differences in the filtering process among three curation systems. This study demonstrates knowledge-based curation systems (WfG, OKR, and QCII) could be helpful tool for solid cancer treatment decision making. Difference in non-concordant evidence levels was observed between three curation systems, especially in the information of clinical trials. This point will be improved by standardized filtering procedure and enriched database of clinical trials in Japan.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC). Preclinically, HER3 ligand heregulin induces resistance to EGFR-TKIs, whereas the pan-human EGFR family inhibitor afatinib remains effective. Here, we examined whether soluble heregulin levels have clinical implications for EGFR-mutant NSCLC treated with EGFR-TKIs. Soluble heregulin was immunologically measured in plasma from EGFR-mutant NSCLC patients. Cutoff values were determined by 1-year PFS ROC curve. The relationship between soluble heregulin and PFS following EGFR-TKI therapy was analyzed by Cox proportional hazards model. Seventy-three patients were enrolled: 44 were treated with 1st-generation and 29 with 2nd-generation EGFR-TKIs. Soluble heregulin levels varied (range: 274–7,138 pg/mL, median: 739 pg/mL). Among patients treated with 1st-generation EGFR-TKIs, those with high heregulin (n = 20, >800 pg/mL) had a tendency for shorter PFS than those with low heregulin (n = 24, st-generation EGFR-TKIs (HR: 1.825, 95% CI: 0.865–4.318) but not against 2nd-generation EGFR-TKIs. Soluble heregulin potentially correlates with resistance to EGFR-TKIs but not 2nd-generation EGFR-TKIs in patients with EGFR-mutant NSCLC.

// Naoki Takegawa 1 , Kimio Yonesaka 1 , Kazuko Sakai 2 , Hiroto Ueda 1 , Satomi Watanabe 1 , Yoshikane Nonagase 1 , Tatsuya Okuno 1 , Masayuki Takeda 1 , Osamu Maenishi 3 , Junji Tsurutani 1 , Taroh Satoh 4 , Isamu Okamoto 5 , Kazuto Nishio 2 , Takao Tamura 1 , and Kazuhiko Nakagawa 1 1 Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan 2 Department of Genome Biology, Kinki University School of Medicine, Osaka, Japan 3 Department of Pathology, Kinki University School of Medicine, Osaka, Japan 4 Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, Japan 5 Center for Clinical and Translational Research, Kyushu University, Kyushu, Japan Correspondence to: Kimio Yonesaka, e-mail: yonesaka@sakai.med.kindai.ac.jp Keywords: colorectal cancer, cetuximab, acquired resistance, human epidermal growth factor receptor 2, ctDNA Received: August 21, 2015 Accepted: November 21, 2015 Published: December 02, 2015 ABSTRACT Background: Patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS benefit from epidermal growth factor receptor (EGFR)-targeted therapy. However, patients who are treated with anti-EGFR antibodies will eventually develop the resistance to those agents. HER2 amplification is one of the mechanisms conferring resistance to anti-EGFR antibody therapy and could therefore be a potential therapeutic target. The aim of this study was to detect HER2 amplification in circulating tumor DNA (ctDNA) from patients with CRC and acquired resistance to anti-EGFR antibody therapy. Results: Our data showed that 22% (4/18) of patients in the cohort exhibited HER2 amplification. One of these patients was found to be positive for HER2 amplification in matched tumor specimens collected after cetuximab therapy, at which point the patient had acquired cetuximab resistance, despite being negative for HER2 amplification prior to therapy. Methods: We analyzed plasma ctDNA using digital polymerase chain reaction (PCR) from 18 patients with CRC, who had been treated with anti-EGFR antibody-based therapy (cetuximab) and subsequently acquired resistant cetuximab. HER2 gene copy number was analyzed using fluorescence in situ hybridization in tumor samples before and after acquisition of resistance to cetuximab-based therapy. Conclusion: Analysis of plasma ctDNA by digital PCR could be useful for detecting HER2 amplification in patients with CRC who were resistant to anti-EGFR antibody therapy.

Background: Activating RET gene fusions have been reported in diverse solid tumors but Case summary: A 46-year-old Japanese woman presented with FDG-avid right axillary, right neck and mediastinal lymphadenopathy on PET-CT imaging. Ultrasound identified a hypoechoic nodule in the right breast; biopsy revealed malignant cells, ER(+), PgR(-), and HER2(-). She was diagnosed with stage IV adenocarcinoma of the right breast. Genomic testing results of a lymph node specimen identified a CCDC6-RET fusion with no other reported alterations, including none in BRCA1 or BRCA2. Consistent with local standard of care, she received treatment with tamoxifen plus goserelin from March through June 2019, but these were discontinued for progression in the right breast and new lesions in the left lower lung. Re-biopsy revealed that the molecular biology changed into triple-negative at the time of progression. On 10-Jul-19 she started treatment with selpercatinib at the recommended Phase 2 dose of 160 mg twice daily in the ongoing Phase 1/2 trial of selpercatinib. She experienced rapid clinical improvement, with resolution of right breast and neck pain and erythema. Spiral CT imaging on 31-Jul-2019 and 4-Sep-2019 demonstrated a partial response by RECIST 1.1 (tumor reductions -30% and -30%), with reduction in multiple right breast masses, axillary, neck and mediastinal lymphadenopathy and left lung metastases; repeat imaging on 30-Oct-19 demonstrated a complete response. At the time of this writing, she remains in response and on treatment for >150 days, with all adverse events grades 1-2, and most recovered and none requiring dose interruption or modification. Conclusion: Selpercatinib demonstrated anti-tumor activity in a patient with RET fusion-positive breast cancer. To our knowledge, this is the first report of a breast cancer patient with a sustained response to selective, RET-targeted therapy and adds to the diversity of RET fusion-positive tumor types that may benefit from selective RET inhibition. Citation Format: Masayuki Takeda, Satomi Watanabe, S. Michael Rothenberg, Jennifer Kherani, Pearl P. French, Elizabeth Olek. Complete response to selpercatinib (LOXO-292), a highly selective RET inhibitor, in a patient with RET fusion-positive breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5236.

Background Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) improve the prognosis of EGFR-mutant non-small cell lung cancer (NSCLC). However, other human epidermal growth factor receptor (HER) families contribute to EGFR-TKI resistance. The HER3 ligand heregulin is aberrantly expressed in NSCLC. Previously, heregulin genomic induction in an EGFR-mutant NSCLC cell line caused EGFR-TKI resistance, except against 2nd-generation EGFR-TKIs, which uniquely blocked the pan-HER family. However, the clinical relevance of heregulin is unclear in EGFR-mutant NSCLC. Here, we aimed to explore the implication of heregulin in patients with EGFR-mutant NSCLC treated with EGFR-TKIs. Methods Soluble heregulin was immunologically measured in the plasma of patients with EGFR-mutant NSCLC. Cut-off values were determined via 1-year progression-free survival (PFS) receiver operating characteristic curve. Relationship between soluble heregulin and PFS, after EGFR-TKI therapy, was analyzed using a Cox proportional hazards model. Results Seventy-six patients were enrolled, of which 44 were treated with 1st-generation, 29 with 2nd-generation, and 3 with 3rd-generation EGFR-TKIs. Soluble heregulin levels were found to vary (range: 274–7,138 pg/mL, median: 741.5 pg/mL). Among patients treated with 1st- and 3rd-generation EGFR-TKIs, those with high heregulin (n = 22, > 800 pg/mL) had a shorter PFS than those with low heregulin (n = 25, Conclusions Results showed soluble heregulin to potentially correlate with EGFR-TKI resistance, though not so for 2nd-generation EGFR-TKIs, in patients with EGFR-mutant NSCLC. Therefore, 2nd-generation EGFR-TKIs warrant comparative clinical examination regarding their anti-cancer efficacy in heregulin-expressing NSCLC. Legal entity responsible for the study The authors. Funding Boehringer Ingelheim. Disclosure K. Yonesaka: Honoraria (self), Research grant / Funding (institution): Boehringer ingelheim. E. Iwama: Research grant / Funding (institution): Boehringer Ingelheim. H. Hayashi: Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. S. Suzuki: Research grant / Funding (institution): Boehringer Ingelheim. R. Kato: Research grant / Funding (institution): Boehringer Ingelheim. S. Watanabe: Research grant / Funding (institution): Boehringer Ingelheim. T. Takahama: Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. J. Tanizaki: Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. K. Tanaka: Research grant / Funding (institution): Boehringer Ingelheim. M. Takeda: Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. K. Sakai: Research grant / Funding (institution): Boehringer Ingelheim. K. Azuma: Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. Y. Chiba: Research grant / Funding (institution): Boehringer Ingelheim. S. Atagi: Honoraria (self): Boehringer Ingelheim. K. Nishio: Research grant / Funding (self), Research grant / Funding (institution): Boehringer Ingelheim. I. Okamoto: Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca. K. Nakagawa: Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Boehringer ingelheim; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Bristol-Myers Squibb.

9038 Background: Previous clinical trials demonstrated that alectinib (ALEC) had a longer time-to-progression than crizotinib (CRZ) in 1st-line settings. Information on long-term overall survival (OS), however, is still limited with a few studies having reported that the sequential strategy of “CRZ followed by other ALK-inhibitor” can provide extended OS. In Japan, ALEC was approved for a 1st-line setting earlier than in other countries. Methods: We reviewed the clinical data of ALK-rearranged NSCLC patients who received CRZ or ALEC between May 2012 and Dec 2016. Patients were divided into two groups according to the first-administered ALK inhibitor, the CRZ or ALEC group. In order to evaluate the efficacy of the sequential strategy of “CRZ followed by ALEC”, the combined time to treatment failure (TTF) was calculated in the CRZ group as defined by the sum of the “TTF of CRZ” plus the “TTF of ALEC” if patients were treated with ALEC followed by CRZ. In the ALEC group, the “TTF of ALEC” was calculated. The primary endpoint is the comparison between the combined TTF in the CRZ group with the TTF in the ALEC group. Results: Of 864 patients enrolled from 61 institutions, 840 patients were analyzed. Median age was 61 (range, 20-94); 56% were female; and 95% had adenocarcinoma. There were 535/305 patients in the CRZ/ALEC group. In the CRZ group, 282 patients received ALEC after CRZ failure. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group; median, 34.4 vs 27.2 months (mo); hazard ratio (HR), 0.709 [95%CI;0.559- 0.899]; P= 0.0044. However, there was no significant difference in OS between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group; median, 88.4 months vs. not reached; HR 1.048 [95%CI;0.758-1.451]; P= 0.7770. In the whole population, the CRZ group had a significantly shorter OS than the ALEC group; median, 53.6 mo vs not reached HR, 1.821 [95%CI;1.372-2.415]; P< 0.0001. Conclusions: The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group, however, OS benefit of sequential therapy of CRZ followed by ALEC was not shown. Clinical trial information: UMIN000028605.

Metastatic spread to the brain is common in patients with non-small cell lung cancer (NSCLC), but these patients are generally excluded from prospective clinical trials. The studies, phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations (LUX-Lung 3) and a randomized, open-label, phase III study of BIBW 2992 versus chemotherapy as first-line treatment for patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR activating mutation (LUX-Lung 6) investigated first-line afatinib versus platinum-based chemotherapy in epidermal growth factor receptor gene (EGFR) mutation-positive patients with NSCLC and included patients with brain metastases; prespecified subgroup analyses are assessed in this article.For both LUX-Lung 3 and LUX-Lung 6, prespecified subgroup analyses of progression-free survival (PFS), overall survival, and objective response rate were undertaken in patients with asymptomatic brain metastases at baseline (n = 35 and n = 46, respectively). Post hoc analyses of clinical outcomes was undertaken in the combined data set (n = 81).In both studies, there was a trend toward improved PFS with afatinib versus chemotherapy in patients with brain metastases (LUX-Lung 3: 11.1 versus 5.4 months, hazard ratio [HR] = 0.54, p = 0.1378; LUX-Lung 6: 8.2 versus 4.7 months, HR = 0.47, p = 0.1060). The magnitude of PFS improvement with afatinib was similar to that observed in patients without brain metastases. In combined analysis, PFS was significantly improved with afatinib versus with chemotherapy in patients with brain metastases (8.2 versus 5.4 months; HR, 0.50; p = 0.0297). Afatinib significantly improved the objective response rate versus chemotherapy in patients with brain metastases. Safety findings were consistent with previous reports.These findings lend support to the clinical activity of afatinib in EGFR mutation-positive patients with NSCLC and asymptomatic brain metastases.

// Yoshikane Nonagase 1 , Kimio Yonesaka 1 , Hisato Kawakami 1 , Satomi Watanabe 1 , Koji Haratani 1 , Takayuki Takahama 1 , Naoki Takegawa 1 , Hiroto Ueda 1 , Junko Tanizaki 1 , Hidetoshi Hayashi 1 , Takeshi Yoshida 1 , Masayuki Takeda 1 , Yasutaka Chiba 2 , Takao Tamura 1 , Kazuhiko Nakagawa 1 , Junji Tsurutani 1 1 Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan 2 Clinical Research Center, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan Correspondence to: Junji Tsurutani, email: tsurutani_j@dotd.med.kindai.ac.jp Keywords: HER2, T-DM1, resistance, heregulin, breast cancer Received: March 28, 2016 Accepted: October 01, 2016 Published: October 19, 2016 ABSTRACT Background: Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer. Results: Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel. The heregulin mRNA level of one of 10 patients was up-regulated after the acquisition of resistance to trastuzumab-based therapy. Materials and Methods: SK-BR-3, NCI-N87, BT-474, MDA-MB-453, HCC1954, SNU-216 and 4-1ST cells were pharmacologically treated with recombinant heregulin or transfected with the heregulin gene. We also assessed the expression of heregulin mRNA in HER2-positive breast or gastric cancer samples before and after trastuzumab-based therapy using a RT-PCR-based method. Conclusions: mRNA up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo.

Extramammary Paget's disease is a malignant intraepithelial carcinoma, which constitutes less than 1 % of all vulvar malignancies. Surgical resection is the first treatment of choice and standard chemotherapy has not been established for advanced or recurrent disease. Experimental and clinical studies have identified human epidermal growth receptor 2 as a potential therapeutic target. A 63-year-old male was referred for recurrent extramammary Paget's disease after surgery. Human epidermal growth receptor 2 was shown to be overexpressed and amplified by immunohistochemical analysis and fluorescence in situ hybridization analysis, respectively. After two cycles of trastuzumab monotherapy, all lymph node metastases decreased in size. However, he experienced recurrence in the lymph nodes during the seven courses of trastuzumab. As a subsequent treatment, trastuzumab was administered in combination with docetaxel and pertuzumab; clinical response was sustained for 12 months without significant adverse events.

A public open space is an urban facility which has significant influence on a community's formation. This study has two purposes. 1. To clarify the significance of community formation via resident's management of public open spaces. 2. To clarify the support of local government and activity of local residents for the improvement of a community. The study area is greenway Imaigawa Ikoi-no Mizube in Yokohama city. This study consists of the questionnaire investigation of the members of the Imaigawa Ikoi-no Mizube care organization which is a voluntary organization of local residents, the questionnaire investigation of the other residents of Imai-cho, and the fieldwork at the greenway. The results of these investigations were viewed according to five factors of community formation and two indexes of community value. Through these examinations, we came to two conclusions. 1. Management by the local residents contributes to a community's formation by synthesizing the image of future, deepening the attachment to the area, and deepening and widening communication. 2. For the improvement of a community, local government support and public relations is essential to not only lead the residents to autonomous activity, but also to join the care organization.

The farmlands located in urban fringe areas have been segmented and abandoned under high urbanization pressure. However, there was little knowledge about quantitative tendency of farmland, which located in outer suburbs where large-scale farmland complex were dominated. By clarifying the feature of the distribution of abandoned farmlands and its occurring process in large-scale farmland complex, it was revealed that although the quantitative aspect of farmland was maintained, the quality of agricultural management was declined in these areas.

In order to find the idea and impression about the urban water related area to utilize for urban landscape designing, we conducted questionnaire surveys of junior high school students and their parents who live in urban area (Bunkyo-ku, Tokyo), asking their consciousness of water related area around them and way of using of them (frequency/activity) and analyzed by a statistic method. As a result, the following three facts have been found. 1) Students have relatively less dissatisfaction compared to their parents, which is partly related to their lower interest. 2) Parents have strong dissatisfaction in terms of the access and use of water related landscape. 3) The chances and activities of students and parents differ to each other; parents positively enjoy water landscape more than students and make the most of opportunities. These indicate that the way of facilitating the water related area needs to be the high accessibility, better usability, and with better design for parents, which also enhance and attract students’ attention.

高齢化社会に向けた緑地政策に資する基礎的知見を得ることを目的に, 総理府実施の世論調査の結果を分析し, 1) 高齢者では自然に強い関心を持つ者が多いが, 関心のない者も少なくないこと, 2) 居住地周辺の自然に非常に恵まれていると答える者が多いこと, 3) 自然との触れ合いの機会では高齢になるほど恵まれていると答える者が多くなること, 4) 自然保護の賛成理由では資源確保・災害防止への反応が高く, 近年の潮流である動植物の生態系の保護に対する反応が低いこと, 5) 自然公園内での開発はすべきでないとする意見が強いが, 開発容認派では利便性向上への期待が大きいこと, 6) 自然保護活動への参加意向が近年高まりつつあることなどをみた。

総理府が1983から95年にかけて実施した緑に関する世論調査の結果からつぎの点をみた。調査は選択肢を呈示し, 該当事項を選ばせ, 回答させている。1) “快適な生活環境における重要な要素” として回答量を増やしてきた “豊かな緑” が, 91年調査から95年調査にかけて回答量を減らしている。2) 緑への回答量が全体的に増えるなかで都市的・施設的な緑で減少するものがあり, 91年調査から自然指向への動きが顕著にみられるようになる。ただし, 3) “大都市” では自然指向への動きは “守り増やしたい緑” で顕著に現れるが, 日頃よく “見受けられる緑” でははっきり現れていない。そして, 2) ～3) の知見をもとに, 1) の原因についての考察を行った。

Background HER2-targeted therapies have been shown clinical benefits in patients with HER2 positive breast and gastric cancers. However, resistance against such targeted therapies eventually develops in most cases. Overexpression of heregulin, a ligand for HER3, has been reported as one of the resistant mechanism against HER2-targeted therapies. Upregulation of heregulin activates HER3-PI3K-AKT signaling, leading to the resistance against HER2-targeted therapies. We investigated the effects of heregulin in cell lines and evaluate its clinical impacts in HER2 positive breast and gastric cancers. Materials and methods We utilized transfected or recombinant heregulin to investigate the effect of heregulin on proliferation and apoptosis of SK-BR-3 and NCI-N87 cell lines treated with lapatinib, trastuzumab, trastuzumab-emtansine and paclitaxel. Clinical data and specimens were obtained from patients with HER2 positive breast and gastric cancers, evaluating their heregulin value from both serum and tissues using ELISA and RT-PCR, respectively. Results Heregulin transfection and recombinant heregulin conferred resistance against treatment with lapatinib, trastuzumab, and weak resistance against trastuzumab-emtansine, but no resistance against paclitaxel in HER2 positive cell lines. Clinical data of heregulin among patients treated with HER2-targeted therapies revealed that patients with relatively high heregulin value tended to have worse prognosis. Conclusions Together these data, overexpression of heregulin may at least in part play a role in resistance against HER2-targeted therapies in HER2 positive cancer patients. Further investigation is warranted to elucidate the relevance of treatments targeting heregulin-HER3-PI3K signaling. Citation Format: Yoshikane Nonagase, Kimio Yonesaka, Satomi Watanabe, Koji Haratani, Takayuki Takahama, Naoki Takegawa, Hiroto Ueda, Hisato Kawakami, Hidetoshi Hayashi, Masayuki Takeda, Haruka Sakamoto, Takao Tamura, Kazuhiko Nakagawa, Junji Tsurutani. Heregulin-induced resistance against HER2-targeted therapies in HER2 positive breast and gastric cancer in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2939.

This paper proposes a new reinforcement learning approach for acquiring conflict avoidance behaviors in multi-agent systems. Multi-agent systems are able to construct orderly systems autonomously through interactions with autonomous agents. We expect to be able to construct flexible and robust systems for the environmental changes by multi-agent system approaches. However, it is difficult for designers to preliminarily embed appropriate behaviors to avoid conflict because complex dynamics emerge by interactions with many agents. We demonstrate the effectivity of the proposed method in narrow road problems that many agents go by each other in narrow roads. In narrow road problems, it is the optimal strategy that agents select behaviors different from other agents. However, agents are faced with a dilemma because they cannot predict other agents' behaviors beforehand. The proposed method can differentiate into agents preferring to pass through a road and agents preferring to give way, by Q-learning that can adjust discount rates. We show that agents differentiate into two type of agents, and acquire stable conflict avoidance behaviors with higher probability than conventional Q-learning algorithms, through experimental results.

総理府実施の『緑化推進に関する世論調査』(1983) および『都市緑化に関する世論調査』(1991) の回答者属性別集計表をもとに多次元尺度法 (MDS) による解析を行い, 1)「みどりのイメージ」に関する項目間でのバラつきが1983年と比較して1991年に少なくなる傾向がみられること, 2)「よく見受けられるみどり」と「守り増やしたいみどり」との関係が都市規模の違いによって分類されること, 3)「みどり」に関する全質問の選択肢を説明因子とする回答者属性の類型化の結果から, 都市規模・年齢において, 大都市から小都市・若年から老年への序列化の傾向がみられることが明らかになった.

緑化政策と自治体属性との関係把握を目的に首都圏各市区を対象にアンケートを行い、各自治体の緑化政策への反応パターン等から政策実施数が人口や産業別就業者構造などに規定されること、“人口規模”や“都市化の進展度”、および田園性が十分に保持されているか都市化の進展により招来される“緑化不要・困難”軸等が政策実施の構造を支配していること等が明らかとなり、自治体の緑化政策実施態様への理解が深められた。

本研究では, 建築, 上木を念頭におきながら, それらとの比較における造園学術の特質・性格, 独自性を抽出し, フィジカルな空間の計画設計・構成施工に係わる分野における造園学の占める位置づけを明らかにし, そこから, 現状の活動内容を説明すると考えられる造園学の定義づけを試み, 学を大きく規定していると考えられる “自然性”“機能性”“快適性” の諸契機の意義内容について考察した。

文部省指定の名勝の実態については, その内容的な複雑さもあって, 必ずしも一般に周知されているとはいえない現状にある。筆者らは名勝の文化財における位置づけについて考察するとともに, 文化庁編集の「史跡名勝天然記念物指定目録」をもとに, 多少の補足的な調査を加えながら, 指定されている全ての名勝について, その地域, 種類, 指定内容, 指定年別の実態の要因にかかわる数嫉的な把握を行った.

This is a study of the Square in the ancient ages.Firstly, the existence of the two types Squares concerning to Agrargemeinde, and the Hausgemeinde which grows obvious in Kofun-jidai are presumed.And secondly their instances are studied. They are as follows:1. The Square in Hausgerneinde2. The mythological meeting place3. The place Utagaks4. The market place5. The Shinto shrine

In this study, I try to explain the process of the formation and the development of town square in the Germanic feudal age.In part II, it is perceived that the Cathedral Place is formed from the Narthex, Churchyard, and the Parvis, and the Market Place is formed from the broadened main street.In part III, the developmental process is inquired into, and the result is following:1st stage; The socio-economic need of the square is contented with the Narthex and the main road2nd stage; The socio-economic need of the square forms the square itself3rd stage; The square develops typically4th stage; The square changes in qulity.