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The utilization of biomarkers has become increasingly active to enhance efficiency of clinical development. This study evaluated the current situation and quantitative impact of co-development of companion diagnostics (CDx) on the oncology drug development in Japan. Based on publicly available information about the oncology drugs and CDx approved in Japan in 2010–2020, we evaluated the approval lag time between drugs and CDx, and the duration between the pivotal study start date and the new drug application submission date (the time to application). Influences of multiple factors including the use of CDx on the time to application were also analyzed. A diagnostic test was mostly used from an early development phase such as phase1/2 study, and the median approval lag has tended to decrease when approved CDx were used (− 507 vs. − 25 days for newly developed CDx). The shorter median times to application were observed in Drugs with CDx (1204 days) compared to Targeted therapies without CDx (1423 days) or Other drugs without CDx (1853 days), although both the cancer types and the implementation of multi-regional clinical trials have a larger impact on the time to application compared to the use of CDx. The use of CDx from the early development phase and the global development strategy could have a positive contribution on the development period of oncology drugs, which will facilitate patients’ earlier access to the optimal treatment.

The utilization of biomarkers has become increasingly active to enhance efficiency of clinical development. This study evaluated the current situation and quantitative impact of co-development of companion diagnostics (CDx) on the oncology drug development in Japan.Based on publicly available information about the oncology drugs and CDx approved in Japan in 2010-2020, we evaluated the approval lag time between drugs and CDx, and the duration between the pivotal study start date and the new drug application submission date (the time to application). Influences of multiple factors including the use of CDx on the time to application were also analyzed.A diagnostic test was mostly used from an early development phase such as phase1/2 study, and the median approval lag has tended to decrease when approved CDx were used (- 507 vs. - 25 days for newly developed CDx). The shorter median times to application were observed in Drugs with CDx (1204 days) compared to Targeted therapies without CDx (1423 days) or Other drugs without CDx (1853 days), although both the cancer types and the implementation of multi-regional clinical trials have a larger impact on the time to application compared to the use of CDx.The use of CDx from the early development phase and the global development strategy could have a positive contribution on the development period of oncology drugs, which will facilitate patients' earlier access to the optimal treatment.

Purpose The objective of this study is to specify the most reported adverse events as preferred terms (PTs) and to compare the reported adverse events about some properties including the number of report and time-to-onset (TTO) distribution of the originator of filgrastim Neupogen® and its biosimilars in Europe, using VigiBase®. Methods We identified the biosimilar which was reported as the suspected drug in more than 100 individual case safety reports in Europe. Then, we specified the top ranking 10 PTs in the cases reported with Neupogen® or each biosimilar as the suspected drug. We also compared the TTO of the most reported PTs using the data about the onset date of the PT and the start date of filgrastim. We used Kolmogorov–Smirnov method to detect significant difference. Results The total ICSR numbers with Neupogen® and 3 biosimilars, Zarzio®, Nivestim®, and Tevagrastim® were 1,301, 295, 156, and 127, respectively, in Europe. The most reported PTs with Neupogen® were bone pain, pyrexia, and dyspnoea. The TTO of bone pain and pyrexia with Zarzio® (N: 22 and 16, median: 1 and 0.5 days) were significantly shorter than those with Neupogen® (P < 0.01, N: 72 and 33, median: 3.5 and 3 days), respectively. The most reported PTs with biosimilars were drug ineffective and neutropenia. Conclusion The difference in the TTO was identified between originator filgrastim Neupogen and its biosimilar regarding some PTs, which may suggest the difference in their safety profile. Copyright © 2017 John Wiley & Sons, Ltd.

A significant number of inquiries are issued during the review of pharmaceutical products developed using the quality-by-design (QbD) approach in Japan. The purpose of this article was to identify key elements specific to QbD development that should be described in the Quality Overall Summary (QOS) dossier.The review reports of the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) were investigated to identify review points for QbD products. Based on the results, key considerations for preparing the QOS of QbD products were determined.The primary review points for QbD products were control strategy (∼30%), design space (∼15%), and real-time release (∼15%). Additionally, the market authorization application form (AF) was discussed more frequently for QbD products than for products developed using a traditional approach. Based on the results, a "QOS checklist for QbD products" was developed to highlight key elements of QbD products that should be included in the QOS.It is important to explain the scientific rationale for the control strategy, design space, and real-time release in the QOS and how "regulatory flexibility" is expressed in the AF. The QOS checklist enables applicants to prepare an appropriately detailed QOS that should satisfy the PMDA's critical review points. The following are recommended for further discussion topics to enable efficient and consistent review by the PMDA for QbD products: (1) Clear guidance on how to express "regulatory flexibility" in the AF and (2) a "QOS checklist for QbD products" that is agreed upon by both regulatory agencies and pharmaceutical companies.

It is considered important that the applicants and reviewers communicate well from the development stage and that both mutually understand the development strategy and application contents in conducting the review efficiently after the application is submitted. Therefore, we focus on Pharmaceuticals and Medical Devices Agency (PMDA) consultations from the viewpoint of communication before the application and clarify the issues to consider in the challenge to reduce the review time in terms of the relationship between the review time and various PMDA consultations. We investigated the relationship between the review time and various PMDA consultations for the drugs with new active ingredients approved in Japan using public information from the PMDA. Review times tended to be shorter as more PMDA consultations were conducted. In standard review products, statistically significant differences were noted in the review times (median). When looking at the results of the cases of each category of PMDA consultations, variations in the review times were greater as the consultations were conducted in the later stages of clinical development. Review times tended to be shorter when prior assessment consultations were conducted. In standard review products, significant reductions were noted with the review time (median). It was suggested that conducting more PMDA consultations might lead to shorter review times. Regarding the review times, variations from the standard review time could possibly be smaller by conducting PMDA consultations from the early stage of clinical development in Japan. It was suggested that review times could possibly be further reduced by conducting prior assessment consultations.

The aim of this study was to investigate the validity of the management strategy for intraductal papillary mucinous neoplasms (IPMNs) advocated by the international consensus guidelines 2012 (ICG2012). The medical records of 49 patients who underwent pancreatectomy for IPMN were retrospectively reviewed. According to preoperative imaging, 10 patients (20 %) had main-duct IPMNs, 20 (41 %) had mixed IPMNs, and 19 (39 %) had branch-duct IPMNs, with malignancy frequencies of 80, 15, and 37 %, respectively. Twenty-seven patients had high-risk stigmata and 21 had worrisome features, with malignancy frequencies of 59 and 10 %, respectively. The sensitivity, specificity, and positive and negative predictive values of high-risk stigmata for malignancy were 88, 65, 59, and 91 %, respectively. Lesions were malignant in 88 % of patients with an enhanced solid component, which was significantly correlated with the prevalence of malignancy (P

Introduction Endoscopic surgery is reportedly associated with smaller scars and greater patient satisfaction. Herein we evaluate the early results of endoscopy-assisted breast-conserving surgery(E-BCS). Methods Between May 2009 and October 2010, 61 women with breast cancer underwent E-BCS. We performed E-BCS on patients with tumors measuring less than 2 cm, without skin or pectoralis muscles invasion. Any patients with microcalcified lesions or axillary lymph node metastasis were excluded. We used an endoscopic vein retractor to dissect the dorsal layer of the mammary gland from a small axillar incision. We dissected the subcutaneous layer and cut the mammary gland vertically from a periareolar incision. We evaluated the clinicopathological characteristics, the surgical outcomes, and early cosmetic results. Results The mean age of the patients was 58.5 years, and the mean tumor size was 1.4 cm. Sentinel node biopsy was positive in seven patients, all of whom underwent axillary node dissection. An additional intraoperative resection of the breast was performed in 12 patients. The mean length of the operation was 167 min, and the mean blood loss was 27 mL. Eight patients received a boost to the tumor bed. The cosmetic results were satisfactory, and the wound scar was inconspicuous in most patients. Conclusion Herein we demonstrate that E-BCS is a feasible and safe procedure for patients with early breast cancer. It allows for a better cosmetic scar location and offers patients favorable aesthetic results in the short-term follow-up results.

Objective: The aim of this study was to investigate the correlation between human epidermal growth factor receptor 2 (HER2)-related biomarkers and the treatment outcomes using lapatinib plus capecitabine (LC) and to evaluate the influence of the estrogen receptor (ER) status in trastuzumab-refractory HER2-positive advanced breast cancer. Method: Eighty patients were enrolled in this study. Total HER2, p95HER2, and total HER3 expression were quantified using the VeraTag assays. PTEN (phosphatase and tensin homolog) and p95 expression was evaluated using immunohistochemistry and PIK3CA mutation using direct sequencing. Results: The response rate to LC was 30%, clinical benefit rate was 51.3%, and the median progression-free survival (PFS) was 174.5 days. ER negativity significantly correlated with higher HER2 and p95HER2. The lower HER2 and PIK3CA mutations were often observed in the nonresponders. A high p95HER2 expression correlated with longer PFS especially in the high HER2- and ER-positive cases. Patients without the PIK3CA mutation showed longer PFS in the same subset. Overall survival after LC significantly correlated with the number of recurrence organs. Conclusion: LC therapy is effective in trastuzumab-refractory HER2-positive breast cancer. Moreover, the biomarker expression differed depending on ER status, and a high p95HER2 expression and wild-type PIK3CA gene correlated with longer PFS especially in the ER-positive cases.

The objective of this study is to specify the most reported adverse events as preferred terms (PTs) and to compare the reported adverse events about some properties including the number of report and time-to-onset (TTO) distribution of the originator of filgrastim Neupogen® and its biosimilars in Europe, using VigiBase®.We identified the biosimilar which was reported as the suspected drug in more than 100 individual case safety reports in Europe. Then, we specified the top ranking 10 PTs in the cases reported with Neupogen® or each biosimilar as the suspected drug. We also compared the TTO of the most reported PTs using the data about the onset date of the PT and the start date of filgrastim. We used Kolmogorov-Smirnov method to detect significant difference.The total ICSR numbers with Neupogen® and 3 biosimilars, Zarzio®, Nivestim®, and Tevagrastim® were 1,301, 295, 156, and 127, respectively, in Europe. The most reported PTs with Neupogen® were bone pain, pyrexia, and dyspnoea. The TTO of bone pain and pyrexia with Zarzio® (N: 22 and 16, median: 1 and 0.5 days) were significantly shorter than those with Neupogen® (P0.01, N: 72 and 33, median: 3.5 and 3 days), respectively. The most reported PTs with biosimilars were drug ineffective and neutropenia.The difference in the TTO was identified between originator filgrastim Neupogen and its biosimilar regarding some PTs, which may suggest the difference in their safety profile. Copyright © 2017 John WileySons, Ltd.

Trastuzumab (T) has contributed to improving the prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Although some patients have been unresponsive or resistant to T. Loss of phosphatase and tensin homolog (PTEN) deleted on chromosome 10, PIK3CA mutation and p95HER2 expression have been reported to potentially be responsible for the poor response to T. This is a small-scale pilot study to be followed by a large-scale investigation examining the association between the biomarkers and clinical response. Based on the response to T, patients were divided into 3 groups in terms of progression-free survival (PFS): PFS >8 months (group A, n=15), 3–8 months (group B, n=7) and PFS

We herein report a rare case of primary angiosarcoma of the breast. A 31-year-old pregnant woman noted a progressing mass in her left breast, and it was suspected to be a phyllodes tumor on the basis of images acquired after the delivery. The histological diagnosis by excisional biopsy was well-differentiated angiosarcoma, so she was referred to our hospital for further treatment. CT and MRI suggested that there was a residual lesion in the remnant breast and multiple bone metastases. She underwent a simple mastectomy, and chemotherapy was performed postoperatively. Four months after surgery, liver, ovary, and mandibular gingival metastases became apparent, although these metastatic lesions had not been distinguished at first. They rapidly progressed, and the regimen of chemotherapy was changed from weekly paclitaxel, MAID (mesna/ifosfamide/doxorubicin/dacarbazine) combination therapy, to docetaxel. Radiation therapy to the gingival tumor was relatively effective. However, the liver and ovary metastases continued to progress under chemotherapy and caused a fatal hemorrhage. Early diagnosis is very important in this highly aggressive disease, and a novel strategy for treatment is needed to prolong the survival and maintain the quality of life of such patients.

Sixty-four cases of malignant lymphoma involving the liver were examined. Of these, 20 cases were histologically confirmed to be primary hepatic B-cell lymphoma. Twelve of these 20 cases were diffuse large B-cell lymphoma (DLBCL) and eight cases were mucosa-associated lymphoid tissue (MALT) lymphoma. Of the 12 cases of DLBCL, six were immunohistologically positive for CD10 and/or Bcl6 (indicating a germinal center phenotype), six were positive for Bcl2, and five were positive for CD25. Eight of the 12 DLBCL cases (66.7%) and two of the eight MALT lymphoma cases (25%) had serum anti-hepatitis C virus (HCV) antibodies and HCV RNA. The incidence of HCV infection was significantly higher in the hepatic DLBCL cases than in systemic intravascular large B-cell cases with liver involvement (one of 11 cases, 9.1%) and T/NK-cell lymphoma cases (one of 19 cases, 5.3%) (p

症例1:74歳女性，上行結腸癌に対し右半結腸切除術を施行し，術後14カ月目に下部消化管内視鏡検査で吻合部再発を認めた．症例2:71歳女性，下行結腸癌に対し左半結腸切除術を施行し，術後42カ月目に下部消化管内視鏡検査で吻合部再発を認めた．共に進行癌で，吻合部を含めた腸管切除術を施行し，いまだ再発を認めていない．開腹し再建を手縫い吻合で行っているが，同吻合が主である当科における過去10年間の結腸癌吻合部再発は当2例であり，再発率は0.92％で文献的統計と差はない．近年器械吻合の機会が増え，吻合部再発の報告が増えている．当科では吻合前腸管洗浄や吻合部へのポビドンヨード塗布は行っていなかったが，implantationが原因である可能性が高いことから，一般的な予防法の確立が望まれる．

In recent years, drug development has become dramatically globalized, and global clinical trials (GCTs) are being conducted in both International Conference on Harmonisation (ICH) and non-ICH regions.1 To ensure the success of global drug development, ethnicity-related factors must be taken into consideration. In this article, the experiences and initiatives of the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan are described, and the contours of an effective global drug development strategy are discussed. Clinical Pharmacology & Therapeutics (2010) 87 3, 362–366. doi:10.1038/clpt.2009.285

肉眼的腹膜播種のない腹腔内洗浄細胞診陽性（P0cy1）ss以深胃癌の予後因子について検討した．腹腔内細胞診陽性率はP0 5.4％，P1 67％，ss 10％ se 40％ si 29％であった．ss以深胃癌987例のうちP0cy1胃癌は86例で，P0cy0，P0cy1，P1のMST（生存期間中央値），1年，2年，3年，4年，5年生存率は1678日，83％，70％，58％，51％，48％，446日，56％，30％，21％，14％，9.6％，244日，36％，18％，11％，3％，2％であった．P0cy1の予後はP0cy0とP1との中間に位置している．P0cy1胃癌の予後因子は単変量解析では肉眼分類，肝転移，リンパ節転移度，転移リンパ節個数，リンパ節郭清度，PM，DM，間質，INF，リンパ管侵襲，細胞診の細胞数，細胞診の細胞の大きさ，術後化学療法，化学療法の14因子であったが，多変量解析ではDM，リンパ節郭清度，術後化学療法の3因子であった．P0cy1ss以深胃癌の予後は不良だが，切除断端を陰性にし，D2以上のリンパ節郭清を行い，術後化学療法を行うことができれば予後が良好なことが期待される．

The main missions of the Pharmaceuticals and Medical Devices Agency (PMDA) are the review of drug applications and also being in charge of the electronic common technical document (eCTD) regulations in the review process. However, we believe that we should consider enhancing eCTD implementation with other activities in electronic standardization of clinical trials. With this sense, the Ministry of Health, Labor and Welfare (MHLW) and PMDA are cooperating to enhance eCTD and e-clinical trials in Japan. This article introduces eCTD implementation in Japan, and also our concept for enhancing eCTD submissions in view of the Japanese government initiative for supporting the development of new drugs by the electronic standardization of clinical trials. PMDA is keen to have eCTD submissions and hopes these activities for eCTD will enhance the understanding of our concepts and support the activities of developing drugs in Japan.

The therapeutic advances in breast cancer have improved the survival of patients with early disease; however, survival improvement of patients with recurrent disease remains ambiguous. In this retrospective study, we examined whether disparities in survival improvement exist in patients with recurrent breast cancer with distant metastasis.The survival time of 126 patients who experienced recurrence at distant sites from 1990 through 1996 was compared to that of 195 patients who did from 1997 through 2003.A significant survival improvement was observed in the patients who experienced recurrence in the period of 1997-2003 in comparison to the other period in the subsets with estrogen receptor (ER)-positive disease, those who received adjuvant hormonal therapy, and those with a disease-free interval (DFI) of 24 months or more. However, no significant survival improvement was observed in each counterpart. The median survival time (MST) from the first relapse of patients with ER-positive disease in the recurrence period of 1997-2003 was 18.8 months longer than that in the recurrence period of 1990-1996 (46.6 months vs. 27.8 months). The MST of patients with a DFI of 24 months or more in 1997-2003 was 20.3 months longer than that in the other time period (47.2 months vs. 26.9 months).The survival of recurrent breast cancer has improved with disparities. The ER status and the DFI are associated with a survival improvement of women with recurrent breast cancer with distant metastases.

We assessed interinstitutional and interobserver consistency of human epidermal growth factor receptor type-2 (HER2) testing using immunohistochemical analysis and fluorescence in situ hybridization (FISH) in a set of 20 breast cancer samples among 10 institutions in Japan and a Herceptin adjuvant study participating laboratory in Germany and identified factors that may lead to discordant results.We found a good agreement in immunohistochemical HER2 scoring between the coordinating institution and 10 participating laboratories (kappa = 0.718) and excellent agreement for FISH (kappa = 0.900). The results of a comparison between 10 Japanese laboratories and the German laboratory was good for immunohistochemical studies (kappa = 0.713) and excellent for FISH (kappa = 0.887). FISH retesting of equivocal samples (2+ immunohistochemically) improved agreement. Discrepancies between results were attributed to the evaluation process in 33.0% of the samples, staining procedures in 25.0%, and a combination of the two in 41.7%. Evaluation of samples according to the American Society of Clinical Oncology/College of American Pathologists guideline increased the number of 2+ immunohistochemical scores. By performing FISH retesting for these samples, consistency among multiple institutions could be archived. The quality of the staining procedures performed and the consistency of evaluations require regular assessment.

Pharmacogenomics (PGx) has the potential impact to improve drug-development efficiencies and proper usages of drugs in clinical practice. However, in order to translate PGx into practical applications, multidisciplinary challenges, such as cost and time in development, processes of genomic biomarker qualification, PGx test availabilities and reimbursements, and education on PGx, still remain in clinical, pharmaceutical and regulatory settings. Japanese regulatory bodies for drug approval (i.e., Ministry of Health, Labour and Welfare and Pharmaceutical and Medical Devices Agency) have been taking proactive actions, both internally and internationally, toward translating PGx from bench to bedside. In this article, we summarize the current situations and projects in regulatory implementations of PGx in drug administrations in Japan, including activities to promote PGx-based drug/device developments and therapies. Moreover, we also discuss the future tasks for utilization of PGx in drug evaluations and clinical practices.

The current situation of chiral drug development in Japan was investigated. The trend in the Japanese pharmaceutical development is increasingly moving towards the development of single isomers rather than racemates. The development of single-enantiomer drugs was made possible by the current technologies of asymmetric synthesis and chiral separation, and encouraged by the guidelines on the development of chiral drugs worldwide. Japan has not issued specific guidelines on the development of chiral drugs, however, the chiral drug development approached in Japan were essentially consistent with the approaches recommended by the U.S.A. and EU guidelines.

目的：マンモグラフィ（MMG）で微小円形または淡く不明瞭な石灰化のみを呈した乳癌の超音波検査による石灰化巣の描出能とその病理学的所見の関係を検討する．方法：術前MMGで微小円形または淡く不明瞭な石灰化のみを示した非浸潤性乳管癌あるいは微小浸潤癌14例を対象に，超音波像での高エコースポットの明瞭さを3段階に分類した．組織亜型をcomedo typeとnon-comedo typeに分類，さらに組織学的因子として石灰化径，管腔拡張の程度，管腔密度，管腔内細胞量を3段階に分類した．結果：組織亜型では，comedo typeを有するものは8例中7例で高エコースポットが描出されたが，non-comedo typeのみの病変では6例中5例で描出は不能であり，comedo typeを有するものは有意に高エコースポットの描出が明瞭であった（P＝0.007）．組織学的所見では，石灰化径の大きいもの（P＝0.02），管腔拡張程度が大きいもの（P＝0.003），管腔密度が高いもの（P＝0.01）が有意に高エコースポットの描出が明瞭であったが，管腔内細胞量と高エコースポットの描出に有意な相関は認めなかった（P＝0.58）．結論：comedo typeでは高エコースポットが良好に描出された．組織学的所見として，石灰化径が大きい，管腔が拡張している，管腔密度が高いほど高エコースポットの描出が明瞭であった．

症例は40歳，女性．1996年4月繰り返す黒色便を主訴に当院を受診した．血液検査にてHb5.3g/dlと著名な貧血を認めた．出血シンチグラフィーにて右下腹部にRIの血管外漏出およびテクネシウムシンチグラフィーにて骨盤内右側に異常集積を認めたためMeckel憩室からの出血を疑い緊急開腹術を施行した．開腹所見ではMeckel憩室は存在せず，回腸末端より160cmの小腸腸間膜対側に径7cmの管外性に発育した腫瘍を認め，小腸部分切除術を施行した．病理組織学的にGISTと診断された．その後，約7年間に3回の肝転移を認め，肝切除術を施行した．2003年8月より2年間メシル酸イマチニブ（以下グリベック）の投薬を行った．その間再発は認めなかった．グリベック休薬11カ月後，残肝に転移が出現し，4回目の肝切除を施行した．診断から10年以上経過した現在生存中である．

Angiomyofibroblastoma-like tumor is a rare mesenchymal tumor involving the male genital tract. We report a case of an angiomyofibroblastoma-like tumor that arose in the subcutaneous tissue of the left inguinal region in a 50-year-old man. Ultrasonography of the region demonstrated a well-circumscribed subcutaneous mass. Intralesional fat was revealed on magnetic resonance images. Although these imaging features are nonspecific, radiological findings enable considering the diagnosis of angiomyofibroblastoma-like tumor.

一般に予後不良とされているAFP産生のS状結腸癌の1例を経験したので報告する. 症例は61歳の女性で, 前医にてS状結腸癌に対しS状結腸切除術を施行された. 術後8か月目に肝S5を主体に右葉を占居する長径9cmの肝転移を認めたため, 当院へ入院し拡大肝右葉切除術を施行した. 術前の腫瘍マーカーは, CEAが6.6ng/ml, CA19-9が239.4U/mlと上昇し, さらに血清AFP値は1,463.7ng/mlと異常高値を示していた. 病理組織学的検査においては, 原発巣および肝転移巣ともに, 中分化型腺癌でAFP の免疫染色が陽性であった. Hepatoid differentiationは肝転移巣で認められた. これらより, AFP産生大腸癌の肝転移と診断した. AFP産生大腸癌の報告は極めてまれである. また, 免疫組織学的検査所見において, chromogranin A染色陽性部分は原発巣およびリンパ節転移巣に比べ, 肝転移巣でより広範囲に認められた. このことは腫瘍が分化・増殖に伴い, 神経内分泌性分化を呈していった可能性を示唆するものであった. AFP産生腫瘍で, かつ神経内分泌性分化を伴った大腸癌の症例はさらにまれである.

肝細胞癌に対する経皮的ラジオ波焼灼術（RFA）後に発症した右横隔膜ヘルニアの2症例を経験した．横隔膜の欠損は治療部位に接して生じており，ラジオ波焼灼術による合併症と判断した．RFA治療から発症までの期間は症例1で78週，症例2で112週であった．しかし，横隔膜の断裂は症例1では65週の時点で，症例2では42週の時点でCT上明らかになっていた．横隔膜断裂に加え，肝委縮・腹水貯留・腹圧上昇などにより腸管が横隔膜下腔に入り込むことがヘルニア発症の誘引と考えられた．右葉横隔膜直下の腫瘍に対するラジオ波焼灼術においては，十分量の人工腹水注入や腹腔鏡あるいは開腹下などの横隔膜を損傷しない工夫と治療後の経過観察が重要であると考えられた．

In Japan, five new drug applications (NDAs) of triptans have been approved through a bridging strategy. They constituted the largest target disease field among 26 NDAs which had been approved through the strategy between 1999 and 2003. The bridging strategies of the drugs were classified into two major categories to be described below. One was to conduct a placebo-controlled dose-response study as a bridging study in an attempt to extrapolate the data from the pivotal foreign Phase III studies including a repeated dose study (i.e., zolmitriptan, sumatriptan succinate, and eletriptan hydrobromide). Another was to conduct a placebo-controlled Phase III study in Japan in an attempt to extrapolate the data for efficacy from a repeated dose study (i.e., sumatriptan and rizatriptan benzoate). The extrinsic ethnic factors relating to triptans did not interfere with the extrapolation of foreign clinical data in the five applications. A bridging strategy reduced the number of clinical trials and/or sample size. The accumulation of these bridging experiences indicated that foreign clinical data could be used to support the approval of triptans in Japan.

症例は50 歳の女性で, 全身倦怠感を主訴に近医を受診した. 腹部超音波検査で膵体部に径1cm の腫瘍を認め, 当院紹介となった. 腹部CT では膵体部に造影効果のある径1cm の腫瘍を認め膵内分泌腫瘍が疑われたが, 腹部MRI ではT1, T2強調像ともに低信号であり, 膵内分泌腫瘍としては非典型的な所見であった. 血清CA19-9が1,459.2U/ml と高値であり, 膵管癌の可能性も否定できず, 外科的切除を施行した. 病理組織検査で腫瘍細胞は膵島類似の索状配列をなし, 一部に腫瘍細胞と連続して腺管構造を伴っていた. また, 間質が高度に線維化しており, これがMRI T2強調像で腫瘍が低信号を示した原因と考えられた. 免疫染色では内分泌細胞の部分がグルカゴンに陽性, 腺管構造の部分がCA19-9染色に陽性を示し, 非機能性膵内分泌腫瘍と診断した. 膵内分泌腫瘍の起源に関しては諸説有るが, 内分泌腫瘍細胞と腺管組織が連続性を持つことより膵内分泌腫瘍の起源として多分化能を持つ膵管上皮が考えられた.

症例は60歳,女性.右腎細胞癌(clear cell type)の根治術術後4年で,左内下部に腫瘤を自覚し,徐々に増大のため当科紹介. 2.6cmの腫瘤に対し, core needle biopsy (CNB)施行し,腎細胞癌からの転移が強く疑われた.他部位に転移はみられず,乳房円状部分切除とセンチネルリンパ節生検(SNB)を施行した.病理診断は腎細胞癌からの転移でリンパ節転移はみられなかった.術後無治療で経過観察中である.腎細胞癌からの乳腺転移は非常に稀のため,文献的考察を加える.

症例は初診時64歳の女性. 1990年2月右乳癌(潜在癌)の診断で拡大乳房切除術施行した(Stage III,充実腺管癌).術後はタモキシフェン, UFT®を5年間内服.1998年5月(71歳)性器出血から子宮体癌と診断,同年7月準広汎子宮全摘術施行され,組織検査では小細胞癌(Stage IIIc)であった.術後補助化学療法としてカルボプラチン+エトポシドを6コース施行. 1998年12月(72歳)子宮癌の経過観察中腹部超音波検査で膵体部癌を発見され, 1999年3月膵体尾部切除術,術中放射線照射25Gy施行された(Stage II,高分化腺癌).膵癌術後5年10カ月経過したが,無再発生存中である.本症例では子宮体癌術後の経過観察中に膵癌を比較的早期に発見できたことが長期生存の大きな要因と考えた.

The authors reviewed the computed tomographic (CT) scans and pathologic specimens of 57 histologically proved bronchogenic carcinomas (35 squamous cell carcinomas, 12 small cell carcinomas, and 10 adenocarcinomas) in 47 patients with diffuse pulmonary fibrosis. The patients ranged in age from 61 to 87 years (mean age, 72 years; 42 men and 5 women). On radiography and CT, most tumors (82%) were located in peripheral areas of honeycomb lung. In 50 of the 57 lesions, the tumors were round or lobulated with sharp margins. In seven tumors, including six squamous cell carcinomas and one small cell carcinoma, the tumor invaded the adjacent honeycomb lung and lacked distinct margins. Intratumor lucency was seen in 13 tumors (five solitary and eight multiple). The CT findings, including high-resolution CT scans, were compared with the histologic findings in a subgroup of 29 lesions in 25 patients with available surgical or autopsy specimens. Invasive growth of tumors with unclear margins (four lesions), septal thickening of the contiguous/surrounding honeycombed areas (16 lesions), and discrete masses (nine lesions) with solitary (four of nine) or multiple (five of nine) intratumor lucencies. The lucencies in six of nine patients (67%) with intratumor lucencies were found to represent engulfed cystic airspaces histologically. CT revealed that bronchogenic carcinoma associated with diffuse pulmonary fibrosis has distinct morphologic characteristics that correlate histologically with a specific pattern of tumor growth.

Background and Objectives Although studies have focused on modulating the bioavailability of 5-FU through inhibition of dihydropyrimidine dehydrogenase (DPD) to improve efficacy of the drug, activity of this enzyme in breast cancer has not been thoroughly examined. We measured DPD activity in primary and metastatic lesions and benign breast tumors to evaluate the clinical significance of this enzyme in the treatment of breast cancer. Methods DPD activity was measured by catalytic assay and compared in 100 primary tumors (95 invasive carcinomas, 5 intraductal carcinomas), 26 uninvolved adjacent breast tissue specimens, 6 metastatic sites, and 7 intraductal papillomas. Results The enzyme level in the carcinomas was 4-fold that of adjacent uninvolved breast tissues (101 vs 23 pmol/min/mg protein, P

乳腺穿刺吸引細胞診において, 常に乳癌との鑑別が問題となるのが線維腺腫や良性乳頭状病変である. 今回, 線維腺腫のなかで特に乳頭腺管癌との鑑別が問題となる乳腺症型線維腺腫について, その細胞像および良悪の鑑別点を乳癌例と対比しながら細胞学的検討を行った. 乳腺症型線維腺腫の細胞像は, 一般的な線維腺腫の細胞像に加え, 乳腺症に出現する細胞集団 (乳頭重積状・節状・充実重積状・クサビ状) が認められる. よって増殖の強い細胞集団を散見する場合, 全体像をよく把握したうえで, 各細胞出現様式について詳細な細胞の観察を行い, 総合的に判断することが重要である.

The in vitro effects of various chemicals, such as styrene dimers, styrene trimers, alkylphenols, phthalate esters, phytoestrogens, and organotin compounds, on the production of interferon-gamma (IFN-γ), a type 1 helper T-cells (Th1) specific cytokine, and interleukin-4 (IL-4), a type 2 helper T-cells (Th2) specific cytokine, which are secreted from anti CD3-stimulated mouse spleen cells, were examined. These chemicals suspected of having an endocrine disruptor function and to which humans may become exposed via ingestion through food, food containers, and food packaging. It was found the organotin compounds bis(tributyltin) oxide, tributyltin chloride, and dibutyltin dichloride at concentrations which did not elicit any cytotoxicity inhibited secretion of the Th1 and Th2 specific cytokines IFN-γ and IL-4 at concentrations (0.01–0.03, 0.07–0.1, and 0.096–0.132 μM for IC50, respectively) that were much lower than those of the other chemicals. However, these butyltin compounds exhibited similar degrees of inhibitory effects on IFN-γ and IL-4 secretion and did not selectively inhibit the secretion of one or the other cytokine. However, diphenyltin dichloride and phenyltin trichloride enhanced the secretion of IL-4 at the comparatively low concentrations of 0.3 μM and 1.0 μM, respectively, although these compounds significantly inhibited IFN-γ secretion at the same concentrations. In addition, 4-t-pentylphenol enhanced IL-4 secretion although it inhibited IFN-γ secretion at the comparatively high concentration of 30 μM. It was also found that some styrene trimers, phthalate esters and flavonoids as well as the alkyl phenols octylphenols and nonylphenol among others, inhibited the secretion of both cytokines at comparatively high concentrations (< 30 μM).

The actin-binding protein p57, a member of the coronin protein family, is expressed in a variety of immune cells. It has five WD repeats and a coiled-coil motif containing a leucine zipper, both of which are known to mediate protein-protein interactions. In order to identify the precise actin-binding regions in p57, and to assess the contribution of these structural motifs, we prepared various truncated p57 as fusion proteins with glutathione S-transferase (GST) and examined their actin-binding activity. A co-sedimentation assay demonstrated that p57(1-371) (C-terminal truncated p57) had the ability to bind F-actin, but p57(372-461) (a fragment containing the coiled-coil motif) did not. A segment consisting of the N-terminal 34 amino acids of p57 (p57(1-34)) was found to bind to F-actin in the co-sedimentation assay. Furthermore, fluorescence microscopic observation showed that p57(1-34) was co-localized with F-actin in COS-1 cells after the transfection with the p57(1-34) construct. Deletion of (10)KFRHVF(15), a sequence conserved among coronin-related proteins, from p57(1-34) abolished its actin-binding activity, suggesting that this sequence with basic and hydrophobic amino acids is crucial for p57 to bind to F-actin. However, the N-terminal deletion mutant p57(63-461) retained the binding ability to F-actin. This result suggests the presence of a second actin-binding region. Further deletion analysis revealed that p57(111-204), which includes the second and third WD repeats, also exhibited weak actin-binding activity in the co-sedimentation assay. Taken together, these data strongly suggest that at least two regions within Met-1 to Asp-34 and Ile-111 to Glu-204 of p57 are responsible for its binding to the actin cytoskeleton.

This study examined the pathological complete response (pCR )rate and safety of induction chemotherapy with 12 cycles of weekly paclitaxel (80 mg/m²) followed by 4 cycles of 5-fluorouracil (500 mg/m²), epirubicin (100 mg/m²), and cyclo- phosphamide (500 mg/m²). The study medication was administered to female patients (n=31)with a mean age of 51 years, diagnosed with stage II A (n=18), II B (n=11) and III A (n=2) disease and with an estrogen receptor positive rate of 65% (20/31). No patient was HER2-IHC [human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC)](3+) or HER2-FISH (fluorescence in situ hybridization) positive. Twenty-eight patients completed the treatment regimen. Treatment was halted in 2/31 patients due to progression of disease in one patient and a Grade 3 non-hematological adverse effect of skin eruption and itching in the other patient. A third patient died of causes unrelated to the study medication. Central review ascertained a pCR in 6 patients. In patients with triple-negative disease we observed a pCR rate of 67% (6/9). In patients with the Luminal (A+B) subtype, 0% (0/19) had a pCR. Grade 3/4 toxicity included leucopenia (58%), neutropenia (58%), febrile neutropenia (26%), fatigue (10%), and ALT elevation (7%). In terms of pCR, patients presenting with triple-negative disease and manageable safety profiles appear to respond well to this treatment regimen, while only a modest response was observed in patients with Luminal subtype disease.

Inhibitory effects of flavonoid phytochemicals, flavones, flavonols and isoflavones on cortisol production were examined in human adrenal H295R cells stimulated with di-buthylyl cAMP. In addition, the inhibitory effects of these chemicals on the activity of P450scc, 3beta-HSD type II (3beta-HSD II), P450c17, P450c21 and P45011beta, steroidogenic enzymes involved in cortisol biosynthesis, were examined in the same cells. Exposure to 12.5 microM of the flavonoids 6-hydroxyflavone, 4'-hydroxyflavone, apigenin, daidzein, genistein and formononetin significantly decreased cortisol production (by 6.3, 69.6, 47.5, 26.6, 13.8 and 11.3%, respectively), and biochanin A significantly decreased cortisol production (by 47.3%) at a concentration of 25 microM without any significant cytotoxic effects or changes in cell number. Daidzin, the 7-glucoside of daidzein, did not alter cortisol production by H295R cells at concentrations over 10 microg/ml (24 microM). Daidzein-induced reduction of cortisol production by H295R cells was not inhibited by the estrogen receptor antagonist ICI 182,780. The flavonoids 6-hydroxyflavone, daidzein, genistein, biochanin A and formononetin strongly and significantly inhibited microsomal 3beta-HSD II activity at concentrations from 1 to 25 microM, and I(50) values were estimated to be 1.3, 2, 1, 0.5 and 2.7 microM, respectively. In addition, these flavonoids significantly inhibited microsomal P450c21 activity at 12.5 and/or 25 microM. In addition, 6-hydroxyflavone inhibited activity of microsomal P450c17 and mitochondrial P45011beta at 12.5 and/or 25 microM. Results of Lineweaver-Burk's plot analysis indicate that daidzein is a competitive inhibitor of the activity of 3beta-HSD II and P450c21. K(m) and V(max) values of 3beta-HSD II for DHEA were estimated to be 6.6 microM and 328pmol/minmg protein, respectively. K(m) and V(max) values of P450c21 for progesterone were estimated to be 2.8 microM and 16pmol/minmg protein, respectively. K(i) values of 3beta-HSD II and P450c21 for daidzein were estimated to be 2.9 and 33.3 microM, respectively.