Design and control of noise-induced synchronization patterns

We propose a method for controlling synchronization patterns of limit-cycle oscillators by common noisy inputs, i.e., by utilizing noise-induced synchronization. Various synchronization patterns, including fully synchronized and clustered states, can be realized by using linear filters that generate appropriate common noisy signals from given noise. The optimal linear filter can be determined from the linear phase response property of the oscillators and the power spectrum of the given noise. The validity of the proposed method is confirmed by numerical simulations.Comment: 6 pages, 4 figure

Analysis of Clinical Outcome of Patients with Poorly Differentiated Thyroid Carcinoma

Background. We retrospectively analyzed whether poor differentiation is the independent prognostic factor for thyroid carcinoma or not. Methods. The subjects were 29 patients with PDTC who were treated between April 1996 and March 2006 to compare with those of well-differentiated papillary carcinoma patients (n = 227). Results. The relapse free (RFS), distant relapse-free survival and cause-specific survival, rates were significantly lower in patients with PDTC (P < .0001, P < .001, and P < .05). After classification into focal (<10%) and diffuse type (over 10%) of PDTC, there were no significant differences in RFS and cause-specific survival due to component type or proportion of poorly differentiated component. On multivariate analysis, poor differentiation (P < .0005, RR = 4.456, 95% CI; 1.953–10.167) and extrathyroidal infiltration (P < .05, RR = 2.898, 95% CI; 1.278–6.572) showed a significant impact on DFS, and poor differentiation (P < .05, RR = 9.343, 1.314–66.453) and age (P < .005, RR = 1.306, 1.103–1.547) significantly impacted cause-specific survival. Conclusion. Poor differentiation was an independent factor for survival. Distant relapse was significantly more common among PDTC patients, and systemic therapy might be warranted

Anti-cancer stem cell activity of the Src inhibitor dasatinib in thyroid cancer cells

Although the prognosis of differentiated thyroid cancer (DTC) is good, those of poorly-differentiated and undifferentiated thyroid cancers (PDTC and UDTC) are poor. Recent preclinical studies have suggested that the Src inhibitor dasatinib is active in thyroid cancer cell lines. We conducted the present study in an attempt to clarify the antitumor activity of dasatinib in PDTC and UDTC. The expression levels of c-Src, phosphorylated Srcs (p-SrcY416 and p-SrcY527), focal adhesion kinase (FAK), and phosphorylated FAK (p-FAKY861) were immunohistochemically investigated in a case-control series (15 cases of PDTC or UDTC vs. 29 control cases of DTC). The PDTC cell line KTC-1 and UDTC cell line KTC-2 were used to investigate the anticell growth and anti-cancer stem cell (CSC) activities of dasatinib. The combined effects of dasatinib and the taxane paclitaxel on anti-cell growth and anti-CSC activities were also tested. c-Src and p-FAKY861 expression levels were significantly higher, while those of p-SrcY416 were slightly higher in PDTC and UDTC than in DTC. Dasatinib inhibited cell growth in association with G1-S cell cycle retardation and increased apoptosis in both cell lines. Dasatinib significantly decreased the proportion of CSCs and more than additively enhanced the anti-cell growth activity of paclitaxel. The results of this study suggest that the Src signaling pathway is activated more in PDTC and UDTC than in DTC. The Src inhibitor dasatinib exhibited anti-cell growth and anti-CSC activities. Furthermore, it more than additively enhanced the anti-cell growth activity of paclitaxel

A Case of Adenomatous Goiter Involving Diffuse, Acute, and Painful Thyroid Enlargement after Fine-Needle Aspiration Cytology

The patient was a 44-year-old woman who exhibited a diffuse goiter during health screening. Her medical history did not include any significant medication-based treatment. An echographic examination detected a solid cystic tumor, which measured 21 × 14 × 10 mm, in her right thyroid lobe; however, she displayed normal thyroid function. After fine-needle aspiration cytology had been performed with a 22 G injection needle, the patient immediately complained of compression and pain extending from the front of her neck to her lower chin, which was not accompanied by dyspnea. A second echographic examination revealed diffuse and edematous enlargement and increased internal blood flow in the bilateral thyroid lobes as well as a thyroid nodule. We immediately iced the patient’s neck and administered 125 mg methylprednisolone via an intravenous infusion. Within one hour, her symptoms had markedly improved, but acute pain remained. Thus, we continued the steroid (prednisone) treatment, but the dose was gradually reduced from 10 mg/day to 5 mg/day at 1 week after the patient’s symptoms disappeared. The mechanism responsible for the patient’s condition remains unclear

甲状腺低分化・未分化癌細胞に対するヘッジホッグ阻害薬GANT61の抗腫瘍効果と癌幹細胞制御作用

　甲状腺分化癌は予後良好であるが低分化・未分化癌は予後不良であり，新規治療薬の開発が急務である．多くの悪性腫瘍でヘッジホッグ（Hh）経路の異常な活性化が起こっており，Hh 経路を標的とした治療戦略が有望視されている．Hh 経路の活性化は，腫瘍の生存・増殖・血管新生の促進ばかりでなく，癌幹細胞の制御との関与が示されている．我々は，甲状腺癌細胞を用いてHh経路を阻害するGANT61の抗腫瘍効果並びに癌幹細胞に与える影響を検討した．また，進行甲状腺癌の治療薬として用いられているタキサン系抗癌化学療法薬パクリタキセルとの併用効果も検討した．当教室で樹立された甲状腺低分化癌細胞株KTC-1及び甲状腺未分化細胞株KTC-2，KTC-3を用いてGANT61の細胞増殖，細胞周期，アポトーシス，癌幹細胞比率に与える影響を検討した．また，Hh 経路のeffector であるglioma-associated oncogene （Gli） 1，その下流にある癌幹細胞制御因子（aldehyde dehydrogenase [ALDH], Snail, Slug）や抗アポトーシス分子（survivin,Bcl-2）発現に与えるGANT61の効果を調べた．GANT61は，すべての甲状腺癌細胞株で細胞増殖を用量依存性に抑制した（50% 阻止濃度の平均値: KTC-1細胞は17.2 μM; KTC-2細胞は13.6 μM;KTC-3細胞は13.3 μM）．GANT61は，KTC-1及びKTC-2細胞のsub-G1分画を増加したが，G1-Sブロックは起こさなかった．GANT61は，全ての細胞株において用量依存性にアポトーシス分画を増加し，survivin やBcl-2の発現を低下させた．GANT61は，すべての細胞株でGli1, ALDH, Slugの発現を低下し，癌幹細胞比率を低下させた．以上の結果は，GANT61が甲状腺低分化・未分化癌細胞のsurvivin やBcl-2発現低下を介してアポトーシス誘導し，細胞増殖を抑制し，さらに，Hhシグナル標的因子Gli1, ALDH, Slug の発現低下により癌幹細胞の自己再生能を抑制することを示唆している．さらにGANT61は，すべての甲状腺癌細胞株においてパクリタキセルの細胞増殖抑制効果を増強した．これらの基礎研究の結果は，GANT61が甲状腺低分化・未分化癌の新規治療薬として有望なことを示唆している．　Patients with differentiated thyroid cancer have a good prognosis, but those with poorly-differentiated or undifferentiated thyroid cancer (PDTC or UDTC) do not. Thus, new therapeutics are urgently needed for PDTC and UDTC. As abnormal activation of the hedgehog (Hh) signaling pathway is observed in several malignancies, it is a promising therapeutic target. Activation of the Hh pathway is suggested to promote not only tumor survival, growth and angiogenesis, but also the growth of cancer stem cells (CSC). Therefore, we investigated the anti-cell growth and anti-CSC effects of the Hh inhibitor GANT61 in thyroid cancer cells. In addition, the combined anti-cell growth activity of GANT61 with an anti-thyroid cancer agent, paclitaxel, was evaluated. The effects of GANT61 on cell growth, cell cycle progression, apoptosis and CSC proportion using the Aldefluor and Thyrosphere assays were measured in the KTC-1 PDTC cell line, and KTC-2 and KTC-3 UDTC cell lines. All cell lines were established at our institute. We also examined the influence of GANT61 on the expression levels of the Hh effector glioma-associated oncogene (Gli) 1, its down-stream CSC-related molecules, aldehyde dehydrogenase (ALDH), Snail and Slug, and anti-apoptotic molecules, Bcl-2 and survivin. GANT61 dose-dependently inhibited the growth of all cell lines (mean 50% inhibitory concentrations: 17.2 μM for KTC-1 cells, 13.6 μM for KTC-2 cells and 13.3 μM for KTC-3 cells) in association with increased apoptosis, and decreased expression of survivin and Bcl-2. Furthermore, the proportion of surviving CSC cells decreased with decreased expression of Gli1, ALDH and Slug. These results demonstrate that GANT61 induced apoptosis via decreased expression levels of survivin and Bcl-2, and inhibited cell growth in thyroid cancer cells. Moreover, GANT61 reduced the expression levels of Hh target genes, such as Gli1, ALDH and Slug, and inhibited CSC self-renewal. GANT61 also enhanced the anti-cell growth effects of paclitaxel in all three thyroid cancer cell lines. Therefore, GANT61 may be a promising antitumor therapy for patients with PDTC or UTC

ベバシズマブ併用化学療法中に消化管穿孔をきたした再発乳癌の１例

　ベバシズマブはパクリタキセルとの併用でHER2陰性の進行・再発乳癌に対する有効性が示されており，無増悪生存期間を有意に延長させる．しかし，ベバシズマブ特有の有害事象も報告されており，投与の際には注意を要する．今回，再発乳癌に対しベバシズマブを使用し，腸管穿孔を起こした１例を経験した．症例は72歳女性．右乳癌術後５年目に多発リンパ節，肺転移を認め，化学療法で治療中に８次治療としてベバシズマブとパクリタキセル（BP）療法を開始した．１年ほど奏効したが，突然，腹痛を訴え受診した．CT で腹腔内にfree air を認めたため緊急開腹術を施行した．小腸に１か所の穿孔部位を認めた．病理組織検査では，穿孔部に乳癌の転移巣が認められた．乳癌に対するベバシズマブ併用化学療法中の消化管穿孔は報告が少ない．腹膜播種を認める症例やベバシズマブ投与期間の長い患者では，腹部膨満感や腹痛を訴えた際は消化管穿孔を念頭におく必要がある．　Combination therapy with bevacizumab and paclitaxel (BP therapy) has been reported to be effective for the treatment of HER2-negative metastatic breast cancer and to significantly prolong progression-free survival. However, there are specific adverse effects induced by bevacizumab that physicians should pay attention to. We report a recent case of metastatic breast cancer with gastrointestinal perforation during bevacizumab therapy. A 72-year-old female patient had metastases into multiple lymph nodes and lungs five years after surgery for primary breast cancer, and was treated with several chemotherapies. The patient received BP therapy as the eighth treatment regimen. Although the therapy led to stable disease for approximately one year, the patient suddenly developed abdominal pain. Emergency laparotomy was performed because computed tomography revealed free air in the peritoneal cavity. A perforated lesion was found in her small intestine. On pathological examination, breast cancer metastasis was noted around the perforated site. There are few reports of gastrointestinal perforation during bevacizumab therapy for patients with metastatic breast cancer. When a patient has peritoneal dissemination, long-term BP therapy and abdominal pain, physicians should keep in mind the possibility of gastrointestinal perforation during BP therapy. (187 words

術後化学療法後に持続性無月経であったが高エストロゲン血症を呈した閉経前乳癌の1症例

ホルモン感受性乳癌患者においては,内分泌療法を選択する上で,閉経状況が重要である.また,先行する化学療法によって無月経になることがあり,閉経前・後の判断は難しい.今回,我々は化学療法後に無月経状態であったにも関わらず,高エストロゲン血症を呈した1症例を経験したので報告する.症例は診断時42歳の女性.左乳癌に対して左乳房切除及び腋窩リンパ節郭清術を施行した.病理検査結果は硬癌,核グレードIII,エストロゲン受容体陽性,プロゲステロン受容体陽性,HER2陰性,リンパ節転移2個であり,術後補助療法として複合化学療法施行後にタモキシフェンを内服していた.化学療法中より無月経であったが,化学療法開始後2年4ヶ月後にホルモン状態を確認したところ血清エストラジオール(E2)は567.2 pg/mlと高値であった.化学療法後に1年以上無月経であっても,卵巣機能は保持されている症例があり,定期的な血清中のE2およびFSH を測定し,閉経状況を評価する必要がある.In patients with endocrine-sensitive breast cancer, the menopausal status is important for the selection of endocrine therapy. When chemotherapy is administered prior to endocrine therapy, it becomes more difficult to judge the menopausal status. We report a premenopausal breast cancer patient who developed amenorrhea after postoperative adjuvant chemotherapy despite a high serum estrogen level. The patient was a 42-year-old woman diagnosed with left breast cancer. She underwent left mastectomy and axillary lymph node dissection. The pathological findings revealed scirrhous carcinoma, which was estrogen receptor-positive, progesterone receptor-positive, and HER2-negative, with two positive lymph nodes. She received tamoxifen after combined cytotoxic chemotherapy as postoperative adjuvant therapy. She developed amenorrhea during the chemotherapy, which continued for two years and four months. Her serum estradiol (E2) level was very high (562.2 pg/ml). After further examinations, she was diagnosed with hypothalamuspituitary gland-related amenorrhea. Even if amenorrhea persists over a year after chemotherapy, the ovarian function might be preserved, as in this case. Therefore, serum levels of E2 and FSH should be periodically measured during endocrine therapy

当院における進行・再発乳癌に対するベバシズマブ・パクリタキセル併用療法の有用性の検討

　抗血管内皮増殖因子（vascular endothelial growth factor, VEGF）モノクローナル抗体ベバシズマブが進行・再発乳癌の治療薬として日本においても2011年から使用されている．日本乳癌学会乳癌診療ガイドライン2018年においてHER2陰性転移・再発乳癌に対する１次・２次の化学療法にベバシズマブを併用することが推奨されている．今回，当院における進行・転移再発乳癌に対するベバシズマブとパクリタキセル同時併用療法（BP 療法）の有用性の検討を行った．対象患者は2011年９月～2018年10月に当科でBP 療法を導入した79症例で，電子カルテを参照して後方視的検討を行った．年齢の中央値は58歳．ホルモン受容体（hormone receptor, HR）陽性humanepidermal growth factor receptor（HER）２陰性サブタイプが45例，HR 陽性HER2陽性サブタイプが２例，HR 陰性HER2陽性サブタイプが５例，HR 陰性HER2陰性（triple negative）サブタイプが27例であった．Stage Ⅳが24例，再発が55例であり，主な転移部位（重複あり）は骨が45例，肝が34例，肺が29例，胸膜が21例であった．前化学療法レジメン数の中央値は２レジメン（範囲：0-8）であった．奏効率は63.3%，無増悪生存期間（PFS）の中央値は5.4か月であり，全生存期間（OS）の中央値は9.4か月であった．HER2陰性症例における多変量解析の結果，performance status 2以上がOS を悪化させる因子であり（ハザード比 [HR] が2.85， p=0.002），triple negative サブタイプ（HR が2.44，p=0.025）と中枢神経転移あり（HR が3.24，p=0.045）がPFS を悪化させる因子であった．重篤な有害事象としては，消化管穿孔と皮膚・軟部組織潰瘍形成，縦隔気管瘻，肺膿瘍，脳出血，上部消化管出血，血尿，鼻出血が認められた．本研究対象は２次治療以降で使用された症例が多いため，既報の臨床試験の結果と比較するとPFS は短かったが，奏効率は同等であった．一方，重篤な有害事象も10% 以上の頻度で認められ，BP 療法施行時には慎重な観察が必要である．　The humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab has been used to treat advanced or metastatic breast cancer since 2011 in Japan. According to the Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer 2018, the addition of bevacizumab to first- or second-line chemotherapy is recommended for patients with human epidermal growth factor receptor (HER) 2-negative advanced or metastatic breast cancer. We investigated the clinical utility of combined bevacizumab and paclitaxel therapy (BP therapy) for patients with advanced or metastatic breast cancer at our hospital. The study subjects were 79 breast cancer patients who received BP therapy at our hospital between September 2011 and October 2018, and their medical records were retrospectively reviewed. The median age of the subjects was 58 years old. Their primary tumors were categorized as follows: the hormone receptor (HR)-positive, HER2- negative subtype in 45 patients, the HR-positive, HER2-positive subtype in 2 patients, the HR-negative, HER2-positive subtype in 5 patients, and the HR-negative, HER2-negative (socalled triple-negative) subtype in 27 patients. Twenty-four patients had stage IV disease and 55 had recurrent disease. The main metastatic lesions were in bone in 45 patients, in the liver in 34 patients, in the lungs in 29 patients, and in pleura in 21 patients. The median number of previous chemotherapeutic regimens was 2 (range: 0-8). The objective response rate was 63.3%, the median progression-free survival (PFS) time was 5.4 months, and the median overall survival (OS) time was 9.4 months. Multivariate analyses of predictive factors for PFS or OS in HER2-negative subjects revealed a performance status of 2 or higher to be a significant predictor of poor OS (hazard ratio [HR]=2.85, p=0.002), and the triple-negative subtype and metastasis to the central nervous system to be predictors of poor PFS (HR=2.44，p=0.025 for the former and HR=3.24，p=0.045 for the latter). Serious adverse events, such as perforation of the gastrointestinal tract, ulcer formation in the skin and soft tissue, fistula formation between the trachea and mediastinum, pulmonary abscess, intracranial hemorrhage, gastrointestinal bleeding, macro-hematuria, and nasal bleeding, were observed during BP therapy. Most patients in this study received BP therapy as greater than second-line therapy; therefore, the PFS was slightly shorter, but the ORR was similar to that previously reported. As serious adverse events were observed in more than 10% of the study subjects, physicians should pay close attention during BP therapy