Serum High-density Lipoprotein Cholesterol Level and Lifestyle Habits among Japanese Junior High School Students

Article信州医学雑誌 61(4):205-215(2013)journal articl

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

Longitudinal change of postoperative serum anti-thyroglobulin antibody levels in patients without total thyroidectomy and remnant ablation

　Backgroud: There is little information regarding postoperative anti-thyroglobulin antibody (TgAb) changes in patients without a total thyroidectomy and ablation. This study aimed to analyze the longitudinal change of TgAb levels in patients with remnant thyroid.　Methods: The study group were patients who had undergone a non-total thyroidectomy for papillary thyroid carcinoma from 1996 to 2018. The median follow-up period of measurement serum Tg and Tg Ab was 3.5 years (1-7.5 years). Eligible patients had a combined serum Tg and TgAb measurement at least three times biannually. We excluded patients with thyroid dysfunction at the initial diagnosis or with papillary carcinoma who had persistent or any recurrence of disease.　Results: A total of 209 patients were enrolled. In the preoperative analysis, 41 (31%) patients had positive TgAb values, and 91 were negative (69%). Seventeen years after the operation, a TgAb value over 800 IU/ml was not seen. The positive TgAb ratio was stable for 12 years (20%-30%); however, its positivity gradually increased from 13 years onward to 45.5%. The number of patients with consistently negative and positive TgAb values was 140 (67.0%) and 47 (22.5%), respectively. The number of patients with a mixture of positive and negative TgAb values was 10 (4.8%). The number of patients who changed from positive to negative values was six (2.9%) and, inversely, six (3.9%).　Conclusions: We found positivity of TgAb after surgery gradually increases up to 45.5% over about 10 years in patients with normal remnant thyroid. We might continue to measure both serum Tg and TgAb values concurrently for the patients with remnant thyroid tissue throughout

パルボシクリブ併用内分泌治療が著効した閉経前再発乳癌の１例

　パルボシクリブ併用内分泌療法が著効した閉経前再発乳癌の１例を報告する．８年前に乳房温存手術を受け，残存乳房への放射線治療後に化学内分泌補助療法（シクロフォスファミド＋エピルビシン（CE 90）を４サイクル後に毎週パクリタキセルを４サイクル施行．化学療法終了後からLH-RH アゴニスト２年間とタモキシフェン５年間）を行った．治療継続中も含め定期で外来受診を継続しており，年１回の画像検査（肺，肝，骨を標的）と３か月ごとの腫瘍マーカー測定では再発の兆候はなく経過していた．しかし，補助治療終了後約３年で発熱と肝機能障害をきっかけに多発遠隔再発（肺・骨・肝・子宮体部）を発見した．ホルモン感受性は残存している可能性はあったが，急速な再発であるために，再発後初回治療としてドセタキセルおよびデノスマブの投与を開始した．有効ではあったが投与後約半年でマーカーの再上昇と体動時呼吸困難（在宅酸素療法導入）および疲労・倦怠感の増強が出現した．有害事象と病勢進行のため再発後の二次治療としてパルボシクリブ，フルベストラント，LH-RH アゴニストを導入した．導入後１か月で体動時呼吸困難が消失し，３か月で在宅酸素療法が中止できた．半年後のPET/CT で集積が消失しており画像上は著効と判断できた．有害事象は白血球・好中球減少が出現した以外に認めなかった．再発治療としてパルボシクリブ併用内分泌治療が有用であった．　We have a case of pre-menopausal patient with recurrent breast cancer showing an excellent response to endocrine therapy with palbociclib. Eight years ago, she underwent breast conserving operation followed by adjuvant chemo-endocrine therapy (4 cycles of cyclophosphamide and doxorubicin, 4 cycles of paclitaxel and tamoxifen adding LHRH agonist). The administration of tamoxifen continued for 5 years as an adjuvant therapy. After 3 years of discontinuation of adjuvant medication, fever and liver dysfunction led to find the recurrence of breast cancer in lung, bone, liver and uterus. We chose to treat with chemotherapy as the first line, because the recurrence was rash and multiple. After 6 months of treatment of docetaxel and denosumab, serum decreased tumor markers elevated gradually and dyspnea and general fatigue worsened. She recieved palbociclib, fluvestrant and LH-RH agonist as a second endocrine therapy. Six months after the treatment, PET/CT revealed an excellent effect on each metastatic lesion. Adverse event was only seen in neutropenia to make one-level reduction of dose. Palbociclib and endocrine therapy appeared to be useful as a second-line treatment for recurrent breast patient

ダイガクセイ ニ オケル キョウイン ト シテ ノ シシツ ノウリョク コウジョウ ノ トリクミ ニ ミトメラレル アクティブ ラーニング ノ ヨウソ ニ カンスル ケントウ : チテキ ショウガイジ オ タイショウ ト シタ イベント ノ キカク ウンエイ オ トオシテ

教員養成課程を有する大学においては、学校インターンシップ等の教員の資質能力向上に関する取組の拡充が進んでいる。これらの取組がアクティブ・ラーニングの観点でどのような有効性を持つものであるのか、必ずしも十分な検討がなされていない。筆者らは、教員志望の学生が主体となり、知的障害に関する理解啓発を目的としたアートイベントを企画・運営する機会を得た。参加学生を対象として、教員の資質能力に関する学びの内容について事後アンケートを実施した。その結果、子どもへの愛情に関して、他の項目より高く評価される傾向が見られた。自由記述においては、深い学びの軸となる｢考察する力」｢構想する力」｢説明する力」｢議論する力」という4つの視点に関連する回答が得られたことから、今回の取組は、アクティブ・ラーニングの視点からも有効性が示された。また、4つの視点を学生に伝えることで、知識と経験の連関が促されることが示唆された

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

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

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