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

Novel prospective umbrella-type lung cancer registry study for clarifying clinical practice patterns: CS-Lung-003 study protocol

Introduction Conventional cancer registries are suitable for simple surveillance of cancer patients, including disease frequency and distribution, demographics, and prognosis; however, the collected data are inadequate to clarify comprehensively diverse clinical questions in daily practice. Methods We constructed an umbrella‐type lung cancer patient registry (CS‐Lung‐003) integrating multiple related prospective observational studies (linked studies) that reflect clinical questions about lung cancer treatment. The primary endpoint of this registry is to clarify daily clinical practice patterns in lung cancer treatment; a key inclusion criterion is pathologically diagnosed lung cancer. Under this registry, indispensable clinical items are detected in advance across all active linked studies and gathered prospectively and systematically to avoid excessive or insufficient data collection. Researchers are to input information mutually, irrespective of the relevance to each researcher's own study. Linked studies under the umbrella of the CS‐Lung‐003 registry will be updated annually with newly raised clinical questions; some linked studies will be newly created, while others will be deleted after the completion of the analysis. Enrollment began in July 2017. Discussion We successfully launched the umbrella‐type CS‐Lung‐003 registry. Under this single registry, researchers collaborate on patient registration and data provision for their own and other studies. Thus, the registry will produce results for multiple domains of study, providing answers to questions about lung cancer treatment raised by other researchers. Through such analysis of each linked study, this registry will contribute to the comprehensive elucidation of actual daily practice patterns in lung cancer treatment. Key points CS‐Lung‐003 registry directly integrates multiple linked studies created under the umbrella of this cancer registry to solve various clinical questions regarding daily practice patterns of lung cancer treatment

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

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

A case of isolated thyroid metastasis that was diagnosed 24 years after renal cancer surgery

　転移性甲状腺癌において原発部位は腎癌が最も多いとされているが，今回腎癌術後24年と長期間経過後に孤立性甲状腺転移の症例を経験したので報告する．症例は68歳，女性．既往歴に右乳癌，両側肺癌，左腎癌あり．右乳癌温存術後の放射線治療目的に前医より当院放射線治療部に紹介．位置決め CT で甲状腺右葉腫瘤を指摘され当科紹介．頸部超音波で甲状腺右葉に約３㎝大の被膜を有する低エコー腫瘤を認めた．穿刺吸引細胞診で良性との結果で経過観察としていた．その後，腫瘤の増大を認めたため，手術を勧め，甲状腺右葉切除術を行った．術後病理検査で腎癌（淡明細胞癌）の転移との診断であった．その後当院泌尿器科に紹介し，全身精査するも明らかな遠隔転移なく経過観察となっている．腎癌術後に甲状腺腫瘤を認める場合は転移の可能性を考慮する必要性があると考える．　Renal cancer is the most common primary site of metastatic thyroid cancer. We report a case of solitary thyroid metastasis 24 years after renal cancer surgery. The patient was a 68-year-old woman. She had a history of right breast cancer, bilateral lung cancer, and left kidney cancer. She was referred to our radiotherapy department by her previous doctor for radiotherapy after right breast-conserving surgery as a positioning CT scan revealed a mass in the right lobe of the thyroid gland. Cervical ultrasound showed a hypoechoic mass with a capsule about 3 cm in size in the right lobe of the thyroid gland. Puncture aspiration cytology revealed that the mass was benign, and the patient was followed up for observation. Subsequently, the mass was found to be enlarged and surgery was recommended. Right lobe thyroidectomy was performed. Postoperative pathological examination revealed metastasis of renal cancer (clear cell carcinoma). The patient was referred to the Department of Urology at our hospital for a full-body examination, but there was no obvious distant metastasis, and the patient was under observation. When a thyroid mass is found after renal cancer surgery, the possibility of metastasis should be considered

転移・再発乳癌患者に対するエリブリン療法の有用性

　エリブリンはタキサンとは異なる作用機序をもつ微小管阻害剤である．海外の第Ⅲ相試験 では，エリブリンの転移・再発乳癌に対する延命効果が示されている．今回，エリブリンの臨床 的な有用性を検討するため，2011年９月から2017年８月に当科でエリブリン療法を行った進行・ 再発乳癌97症例を対象として後方視的に調査した．対象患者の年齢は35 － 81歳（中央値58）， performance status は１が最多で64例，Stage Ⅳが５例，再発が92例であった．原発腫瘍のエス トロゲン受容体は陽性が64例，プロゲステロン受容体は陽性が48例，human epidermal growth factor receptor 2は陰性が78例であった．前化学療法のレジメン数は0 － 9（中央値２）, 臓器転 移ありが69例，肝転移ありが40例，エリブリン療法の実施サイクル数は1 － 12回（中央値3.5）， 観察期間は1 － 55か月（中央値10），有害事象による中止例は10例であった．最大治療効果は，完 全奏効が０例，部分奏効が１例，長期安定が27例，安定が16例，進行が42例，不明・評価不能が 11例であった． 臨床的有効率（奏効率＋長期安定率）は29% であった．Time-to-treatment failure (TTF) は0 － 178週間（中央値13），治療開始後全生存期間は0 － 55か月（中央値15.5）であった． 好中球減少症はグレード１が最多で61例，非血液毒性は嘔気が７例，肝機能障害が６例，末梢神 経障害が５例，間質性肺炎が3例などであった．良好なTTF の予測因子は，単変量解析で「臓器転 移なし」（P = 0.0356）が同定された．良好な治療開始後生存の予測因子は，多変量解析にて「臨 床的有効性あり」（P = 0.0008）と「PS が０か１」（P < 0.0001）が同定された．エリブリン療法は， 奏効率は低かったが，本療法は，約30% の症例に臨床的有効性をもたらし，生存期間の延長に寄 与する可能性がある．　Eribulin is an anti-microtubule agent that uses a different mechanism of action to taxanes. Phase 3 clinical trials have shown that eribulin exerts life-prolonging effects in patients with metastatic or recurrent breast cancer. In order to investigate the utility of eribulin, we conducted a retrospective and observational study on 97 patients with metastatic and recurrent breast cancer who were treated in our institute between September 2011 and August 2017. The median age of the patients was 58 years (range: 35 － 81). The performance status was 1 in 64 patients. Five patients had stage IV disease, while 92 had recurrent disease. Sixtyfour patients had estrogen receptor-positive tumors, 48 had progesterone receptor-positive tumors, and 78 had human epidermal growth factor receptor 2-negative tumors. The median number of regimens of previous chemotherapies was 2 (range: 0 － 9). Sixty-nine patients had visceral metastases, while 40 had liver metastases. The median number of cycles of eribulin therapy was 3.5 (range: 1 － 12). The median follow-up period was 10 months (range: 1 － 55). The best responses to therapy were a complete response in 0 patients, a partial response in 1, long-term stable disease in 27, stable disease in 16, progressive disease in 42, and unevaluable in 11. The clinical benefit rate (objective response rate + long-term stable disease rate) was 32%. The median time-to-treatment failure (TTF) was 13 weeks (range: 0 － 178). Median overall survival (OS) after the initiation of therapy was 15.5 months (range 0 － 55). The most frequent grade of neutropenia was 1, which was observed in 61 patients. Major non-hematological toxicities were nausea in 7 patients, liver dysfunction in 6, peripheral neuropathy in 5, and interstitial pneumonitis in 3. Univariate and multivariate analyses identified “no visceral metastasis” as the only predictive factor for TTF (P = 0.0356 for the multivariate analysis). The multivariate analysis revealed that“ the presence of a clinical benefit by the therapy” (P = 0.0008) and “a performance status of 0 or 1” (P < 0.0001) were independent predictive factors for OS. Eribulin therapy for patients with metastatic or recurrent diseases provided clinical benefits for approximately 30% of patients. These results suggest that this therapy prolongs the OS of patients

Characteristics and prognosis of adolescent and young adult (AYA) breast cancers at Kawasaki Medical School Hospital, Okayama

　Adolescent and young adults（AYA）世代の癌は一般成人の癌に比べ，頻度は低いものの妊孕性の維持など複雑な問題を抱えている．AYA 世代の後半30から39歳では，乳癌の発生頻度が最も高い．今回我々は，AYA 世代の乳癌患者を後方視的に調査し，予後因子を解析した．　対象は2010年１月～2018年12月に川崎医科大学附属病院乳腺甲状腺外科で治療を行った40歳未満の AYA 世代乳癌患者123名（AYA 群）．また同期間に治療を受けた40歳以上の非若年乳癌患者1,541名（非若年群）と予後の比較を行った．無病生存率（DFS），全生存率（OS）の予後因子は，単変量解析及び多変量解析で分析した．　両側性乳癌，非浸潤癌，データ不足例を除外した1,322名（AYA 群が99名，非若年群が1,223名）の乳癌患者が予後解析の対象となった．５年 DFS は AYA 群で81.5％，非若年群は91.3％であり，AYA 群で有意に不良であった（P = 0.0007）．臨床病期を揃えると，病期Ⅱのみで両群間に有意差が認められた（P = 0.0319）．５年 OS は AYA 群，非若年群ともに96.7% であり，差は認められなかった．AYA 群の DFS 予測因子は，単変量解析では，臨床病期Ⅱ期以上，腫瘍浸潤径２cm 超，血管侵襲陽性が有意の予後不良因子であった．多変量解析では，臨床病期Ⅱ期以上，血管侵襲陽性が独立した予後不良因子であった．OS では，単変量解析では血管侵襲因子のみが OS の有意の予測因子として抽出された．多変量解析では，血管侵襲因子とトリプルネガティブサブタイプが，独立した予後不良因子であった．妊娠関連乳癌は，DFS, OS ともに有意の予後因子とならなかった．　AYA 群は非若年群に比べて５年 DFS が有意に悪かった．AYA 群の予後因子として，血管侵襲因子が重要なことが示唆された．　Adolescent and young adult (AYA) cancers are infrequent compared with common cancers but have complicated problems such as fertility preservation. Breast cancer is the most common cancer in women aged between 30 and 39. In the present study, we conducted a retrospective cohort study to characterize AYA breast cancers and to analyze predictive factors for prognosis.　A total of 123 AYA breast cancer patients under 40 years-old treated in our department in Kawasaki Medical School Hospital, Okayama, between January 2010 and December 2018 (AYA group) were the study subject group. Prognostic data of 1,541 breast cancer patients older than 39 years of age treated in the same department and period (elder group) was obtained to compare with that of the AYA group. Possible prognostic factors for disease-free survival (DFS) and overall survival (OS) were investigated using either univariate or multivariate analyses.　After excluding patients with bilateral breast cancers, non-invasive breast cancers and/or insufficient clinicopathological data, a total of 1,332 patients (99 for the AYA group and 1,223 for the elder group) were the subjects for analysis of prognosis. Five-year DFS for the AYA group was significantly worse than that for the elder group (81.5% for the former, 91.3% for the latter, P = 0.0007). This was significantly worse in the AYA group at stageⅡ(P = 0.0319) but not at the other stages. Five-year OS was almost identical between the two groups (P = 0.5532). Univariate analysis for DFS in the AYA group showed that later stage (stageⅡor Ⅲ), invasive tumor size of over 2 cm and positive vascular invasion were significantly worse prognostic factors. Multivariate analysis showed that later stage and positive vascular invasion were independent prognostic factors. With regard to OS, univariate analysis revealed that only positive vascular invasion was a worse prognostic factor. Multivariate analysis revealed that positive vascular invasion and triple negative subtype were independent worse prognostic factors. Pregnancy-associated breast cancer was not a significant prognostic factor for either DFS or OS.　In conclusion, five-year DFS was significantly worse in the AYA group than in the elder group. Presence of vascular invasion was suggested to be an important worse prognostic factor for either DFS or OS

進行・再発乳癌患者に対するフルベストラントの有用性

　ホルモン受容体陽性の閉経後進行・再発乳癌患者に対する内分泌療法として，フルベストラントが本邦で臨床導入されて６年余りが経過した．本剤の有用性を検討するため，2012年１月〜2016年10月に川崎医科大学附属病院乳腺甲状腺外科において，フルベストラントが単独使用され，治療評価が可能であった51症例の電子カルテを後方視的に調査した．対象患者の年齢の中央値は70歳．進行例が９例，再発例が42例．臓器転移ありが23例．観察期間の中央値は18か月．前内分泌療法数の中央値は２．前化学療法歴ありは21例．治療効果は，完全奏効が３例，部分奏効が６例，安定が25 例（うち長期安定は20例），進行が16例であった．客観的奏効は９例（17.6%），臨床的有用は29例（56.9%）であった．無増悪生存（PFS）期間の中央値は８か月，全生存（OS）期間の中央値は34か月であった．治療効果の予測因子を調べるため，サブグループに分けてPFS及びOS を解析した．肝転移の有無では，PFS 期間の中央値は，なしが9.5か月，ありが５か月（P= 0.0386），OS 期間の中央値は，なしが41か月，ありが15か月（P = 0.0036）であった．前化学療法の有無では，PFS 期間の中央値は，なしが12.5か月，ありが3.5か月（P < 0.0001），OS 期間の中央値は，なしが41か月，ありが24か月（P = 0.0208）．多変量解析では，前化学療法歴の有無が唯一のPFS の有意な予測因子であった．また，肝転移の有無が唯一のOS の有意な予測因子であった．有害事象は６例（11.7%）に認めたが，いずれも軽微であり治療が中断されることはなかった．要約すると，ホルモン受容体陽性の進行・再発乳癌の治療薬として，フルベストラントは17.6% の客観的奏効率，56.9% の臨床的有用性が認められ，既知の報告と同等の治療効果であった．フルベストラントは，化学療法歴のある症例，肝転移のある症例では，有用性が低いと考えられた．　Fulvestrant has been used for the treatment of postmenopausal patients with advanced or recurrent breast cancer in Japan for over six years. To investigate the utility of fulvestrant, we retrospectively reviewed electronic medical records and evaluated the responses of 51 patients with advanced or recurrent breast cancer treated with fulvestrant alone at the Department of Breast and Thyroid Surgery, Kawasaki Medical School Hospital between January 2001 and December 2016. The median age of the subjects was 70 years old. Nine had stage IV diseases and 42 had recurrent diseases. Twenty-three patients had visceral metastases. The median follow-up time after the start of fulvestrant treatment was 18 months. The median number of previous endocrine therapies was 2. Twenty-one patients received chemotherapy previously. Three patients had a complete response, six had a partial response, 25 had a stable disease including 20 patients with a long-term stable disease, and 16 had progressive disease. The objective response rate was 17.6% (9 out of 51), and the clinical benefit rate was 56.9% (29 out of 51). The median progression-free survival (PFS) time was 8 months. The median overall survival (OS) time was 34 months. To investigate predictive factors for response to fulvestrant, subgroup analyses were performed. For liver metastasis, the median PFS and OS time were 9.5 and 41.0 months, respectively, in patients without liver metastasis but 5.0 and 15.0 months, respectively, in those with liver metastasis (P = 0.0386 and P = 0.0036, respectively). For previous chemotherapy, the median PFS and OS time were 12.5 and 41.0 months, respectively, in patients without previous chemotherapy but 3.5 and 24.0 months, respectively, in those with previous chemotherapy (P < 0.0001 and P = 0.0208, respectively). In addition, the Cox’s proportional hazards model revealed that previous chemotherapy was only an independent predictive factor for PFS and that liver metastasis was only an independent predictive factor for worse OS. Although toxicities were recorded in 6 of 51 patients (11.7%), all instances were slight and no patient stopped fulvestrant therapy because of toxicities. In summary, fulvestrant therapy at our hospital provided a 17.6% objective response rate and 56.9% clinical benefit rate in patients with advanced or recurrent breast cancer. These results were similar to those reported previously. According to our subgroup analyses, fulvestrant was unlikely to be effective in patients who received previous chemotherapy or had liver metastasis

センチネルリンパ節生検を施行した腋窩リンパ節微小転移乳癌症例の検討

N0乳癌において症例を選べば，センチネルリンパ節転移陽性例であっても，腋窩リンパ節郭清（ALND）の省略が可能であると報告されている．微小転移（pN1mi）乳癌においても，同様の結果が得られている．当科でセンチネルリンパ節生検（SLNB）を施行し，pN1mi であった66例を研究対象とした．SLNB の方法は，99mTc-フチン酸を用いたRI 法とインドシアニングリーンを用いた色素法の併用法で行った．SLNB 群52例とSLNB → ALND 群14例に分け，予後を中心に検討し，ALND 省略の可能性について検討した．結果は，１）SLNB 群とSLNB → ALND 群で無病生存率および全生存率に有意差を認めなかった．２）乳房切除症例でも同様の結果であった．３）スキップ症例や術後にpN1mi と判明する症例が存在する．pN1mi 症例では乳房の術式にかかわらずALND の省略が可能である．It has been reported that axillary lymph node dissection (ALND) can be safely omitted if we carefully select breast cancer patients with sentinel lymph node metastases, including breast cancer patients with micrometastases (pN1mi). The subjects were 66 breast cancer patients with pN1mi who underwent sentinel lymph node biopsy (SLNB) in our department. SLNB was performed by the dual method using 99mTc-phytate and indocyanine green. We divided the subjects into the SLNB group (n=52) and SLNB → ALND group (n=14). Clinico-pathological factors, in particular prognosis of the patients were retrospectively studied. 1) No significant difference in disease-free survival and overall survival between the SLNB → ALND group and the SLNB group. 2) The similar findings were observed in patients who underwent mastectomy. 3) The pN1mi patients consisted of patients with so-called skip metastases and patients whose micrometastases were found in permanent sections after surgery. The omission of ALND is possible regardless of surgical methods, i.e., mastectomy or breast-conserving surgery, in pN1mi patients