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

エストロゲン受容体陽性乳癌細胞における抗エストロゲン薬とmTOR阻害薬エベロリムスの細胞増殖及び癌幹細胞制御に対する効果

乳癌を含め多くの固形腫瘍において,癌幹細胞(CSC)が治療抵抗性や再発の原因となることが示唆されている.一方, エストロゲン感受性乳癌におけるCSCの制御機構に関する研究は少ない.そこで,エストロゲン受容体(ER)陽性乳癌細胞におけるエストロゲンや抗エストロゲン薬(抗E薬)の細胞増殖やCSC制御に与える影響について検討した.さらに,内分泌療法抵抗性乳癌に有効性が期待されているmTOR阻害薬エベロリムス(EVE)と抗E薬との併用効果も検討した.ER陽性乳癌の実験モデルとして,エストロゲン高感受性(HS)のMCF-7,T-47D乳癌細胞株,エストロゲン低感受性(LS)のKPL-1,KPL-3C乳癌細胞株を用いた.薬剤は,17β-estradiol(E2),4-hydroxytamoxifen(4-OHT),fulvestrant(FUL),EVEを用い,細胞増殖,細胞周期,アポトーシス,CSC比率に与える影響を検討した.CSCの同定には,CD44/CD24/EpCAM抗体を用いたフローサイトメトリー法及びmammosphere assayを用いた.ER-α,PgRおよびER関連転写因子(GATA3等)の発現は免疫細胞化学的に検討した.結果として(1)LS細胞株では,PgRの発現が認められなかった.それ以外のER関連因子は,HS細胞株,LS細胞株ともに高発現が認められた.(2)HS細胞株はLS細胞株に比べ,E2による細胞増殖の促進効果,CSC比率の増加効果が,ともにより顕著であった.(3)HS細胞株はLS細胞株に比べ,抗E薬による細胞増殖の抑制効果,CSC比率の低下効果がより顕著であった.(4)EVEと抗E薬の併用は,LS細胞株において相加的な細胞増殖抑制効果を示した.両薬の併用により,一部の細胞株ではCSC比率の減少効果が増強された.以上の結果は,LS乳癌において,抗E薬の増殖抑制効果ばかりでなく,CSC比率の低下効果も減弱していることを示唆している.抗E薬抵抗性獲得のメカニズムの一つとして,CSC制御機構の異常が関わっている可能性がある.また,一部の乳癌細胞株において,抗E薬とEVE併用の結果から,内分泌抵抗性乳癌におけるEVEの有用性が示唆された.Recent studies have revealed the existence of cancer stem cells (CSCs) in breast cancer. CSCs may play critical roles in resistance to anticancer agents and radiation, and in the development of metastases. However, the roles of CSCs in estrogen-responsive breast cancer remain to be elucidated. In this study, we investigated the effects of estrogen and antiestrogens (AEs) as well as an inhibitor of mammalian target of rapamycin (mTOR), everolimus (EVE) on the cell growth and regulation of the CSC population in estrogen-responsive breast cancer cell lines (BCCLs). Two high estrogen-sensitivity (HS) BCCLs, MCF-7 and T-47D, and two low estrogen-sensitivity (LS) BCCLs, KPL-1 and KPL-3C, were used. 4-hydroxytamoxifen (4-OHT) and a steroidal AE fulvestrant (FUL) and EVE were studied. Expression levels of ER-related proteins, ER-α, progesterone receptor (PgR), GATA3, FOXA1 and XBP1 were immunocytochemically investigated. The effects of the agents on the cell growth, cell cycle progression, apoptosis and regulation of the CSC population, defined as EpCAM-positive, CD44-high, CD24-low or negative cells using flow cytometery or mammosphere assay, were examined. Experimental results are as follows: (1) The LS BCCLs were negative for PgR but positive for the other ER-related proteins examined. The HS BCCLs were positive for all the ER-related proteins. The LS BCCLs were tumorigenic in female nude mice without estrogen supplementation, but the HS BCCLs were not. (2) The increase in cell growth induced by 17β-estradiol (E2) was more pronounced in the HS BCCLs. The decrease in cell growth induced by 4-OHT or FUL was more pronounced in the HS BCCLs. The AEs inhibited the G1-S cell cycle progression and induced a slight apoptosis. (3) E2 significantly increased the proportion of CSCs in all the cell lines tested. The increase in the CSC proportion by E2 was more pronounced in the HS BCCLs. The decrease in the CSC proportion by both 4-OHT and FUL was more pronounced in the HS BCCLs. (4) The decrease in the cell growth by EVE was more pronounced in LS BCCLs. Combined treatment of 4-OHT or FUL with EVE showed an additive effect in the LS BCCLs but not in the HS BCCLs. (5) Although EVE alone slightly increased the proportion of CSCs, the combined treatment of 4-OHT or FUL with EVE did not increased it. In conclusions, the HS BCCLs were more sensitive to estrogen and AEs than the LS BCCLs with regard to the cell growth response and CSC regulation. Thus, the LS BCCLs were more resistant to AE. It should be noted that EVE was more active in the LS BCCLs. These findings suggest that the combined use of EVE with AEs may be more useful in patients with breast cancer resistant to AEs

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

乳腺神経内分泌癌の一例

稀な癌である乳腺神経内分泌癌(neuroendocrine carcinoma:以下NEC)を経験したので報告する.患者は35歳の女性で,右乳頭直下に腫瘤を自覚し当科を受診した.画像診断で乳癌を疑い,細胞診では乳頭腺管癌あるいは硬癌が推定された.針生検で浸潤性乳管癌と診断し,乳房温存術とセンチネルリンパ節生検を施行した.腫瘍は乳腺原発であり,組織像は,小細胞癌などの神経内分泌癌に類似していた.免疫組織化学的検査では,chromogranin A, synaptophysin, neuronspecific enolase陽性細胞が大部分を占めていたためWHO分類に従い神経内分泌癌の診断に至った.リンパ節転移は認めなかった.乳腺NECは稀な癌であり,臨床病理学的な特徴,予後,治療法についての定まった見解はない.本症例では,通常の乳癌同様に臨床病理学的予後因子に基づき術後補助化学療法を行った.術後8年5カ月の時点で無再発生存中である.We are reporting a rare case of breast neuroendocrine carcinoma (NEC). A 35-year- old woman noticed a breast lump underneath her right nipple, and she consulted our hospital. The mass was suspected of being breast cancer by mammography, ultrasonography and MRI. Cytological diagnosis was papillotubular or scirrhous carcinoma. Finally, it was diagnosed as invasive ductal carcinoma by a core needle biopsy. We performed breastconserving surgery and sentinel lymph node biopsy. There was no metastasis in the sentinel lymph node. Pathological findings suggested that it was a small cell carcinoma or a neuroendocrine carcinoma. Chromogranin A, synaptophysin, neuron-specific enolase were positively stained in most of the cancer cells by immunohistochemistry. Therefore, it was diagnosed as breast NEC according to the WHO classification. Because breast NEC is a relatively rare cancer, its clinicopathological significance, prognosis and appropriate treatment has not been evaluated. We chose the adjuvant systemic therapy based on recommendations from the St.Gallen Consensus Conference in this case. 101 months after the operation, she has no recurrence and is alive

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target