悪性褐色細胞腫患者の生存と化学療法の効果

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A Case of Corticotroph Carcinoma that Caused Multiple Cranial Nerve Palsies, Destructive Petrosal Bone Invasion, and Liver Metastasis

A 52-year-old woman experienced sudden onset of double vision due to a right abducens nerve palsy and was diagnosed as having a pituitary macroadenoma that invaded into the right cavernous sinus. Otherwise, she was asymptomatic despite marked elevation of ACTH (293 pg/ml) and cortisol (24.6 μg/dl) levels. The patient underwent transsphenoidal surgery followed by γ-knife radiosurgery (GKR), which healed the diplopia and ameliorated the hypercortisolemia. The excised tumor was diffusely stained for ACTH with a high (15%) Ki-67 labeling index. Early tumor recurrence occurred twice thereafter, producing right lower cranial nerve palsies with petrosal bone destruction at 8 months and an ipsilateral oculomotor nerve palsy at 12 months after GKR; all palsies resolved completely with the second and third GKRs. Hypercortisolemia worsened rapidly soon after the third GKR, and the patient developed marked weight gain, hypokalemia, and hypertension. Multiple liver lesions were incidentally detected with computer tomography and identified as metastatic pituitary tumor on immunohistochemistry. An ACTH-producing adenoma should be followed carefully for early recurrence and/or metastatic spread when the tumor is an invasive macroadenoma with a high proliferation marker level. The unique aggressive behavior and high potential for malignant transformation of this case are discussed

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

家族性バセドウ病の臨床的特徴 : 東京女子医科大学病院での検討

バセドウ病を含む自己免疫性甲状腺疾患には家族集積が認められ,遺伝性因子がその発症や進展に関与している可能性が示唆されている.今回当院に通院中の家族性バセドウ病患者と家族歴のない患者とを比較し,家族性バセドウ病の特徴について臨床的検討を行った.対象は,当院に受診中のバセドウ病患者で兄弟姉妹,親,子にバセドウ病を発症していることが確認された28名を家族性バセドウ病とした.また,2000年に当科初診のバセドウ病患者のうち家族歴を有しないものより43名を受診日より無作為に抽出してコントロールとした.男性の割合は家族性で有意に高く,発症年齢は家族性で有意に低かった.発症時の遊離甲状腺ホルモン,甲状腺受容体抗体は有意差を認めなかった.今回の検討では,若年発症者は遺伝性因子の関与が強く,高齢発症者では環境因子の関与も大きい可能性が示唆された.また,疾患の活動性と遺伝性因子が直接関与しない可能性が示唆された.To characterize the influence of genetic factors on clinical features of Graves\u27 disease (GD), we investigated 28 patients with familial GD, which were patients who had at least one family member with GD within the proband\u27s first-degree relatives. We compared 43 non-familial cases of GD that were selected randomly from patients referred to the Endocrine Clinic of our hospital. The male-to-female ratio was significantly higher in familial than non-familial GD. The age of onset of the disease was significantly lower in familial GD, but we could not detect any statistically significant differences in thyroid hormone concentrations or the levels of thyrotropin receptor-related antibodies. These data suggest that the influences of chromosome X-linked genes or estrogen products may be less important than susceptibility genes for the onset of familial than non-familial GD, and nongenetic factors may have a stronger influence in older patients. The results also suggested that genetic factors may not influence the disease activities by themselves, but further studies are necessary to clarify these issues

家族性バセドウ病の臨床的特徴 : 東京女子医科大学病院での検討

バセドウ病を含む自己免疫性甲状腺疾患には家族集積が認められ,遺伝性因子がその発症や進展に関与している可能性が示唆されている.今回当院に通院中の家族性バセドウ病患者と家族歴のない患者とを比較し,家族性バセドウ病の特徴について臨床的検討を行った.対象は,当院に受診中のバセドウ病患者で兄弟姉妹,親,子にバセドウ病を発症していることが確認された28名を家族性バセドウ病とした.また,2000年に当科初診のバセドウ病患者のうち家族歴を有しないものより43名を受診日より無作為に抽出してコントロールとした.男性の割合は家族性で有意に高く,発症年齢は家族性で有意に低かった.発症時の遊離甲状腺ホルモン,甲状腺受容体抗体は有意差を認めなかった.今回の検討では,若年発症者は遺伝性因子の関与が強く,高齢発症者では環境因子の関与も大きい可能性が示唆された.また,疾患の活動性と遺伝性因子が直接関与しない可能性が示唆された.To characterize the influence of genetic factors on clinical features of Graves' disease (GD), we investigated 28 patients with familial GD, which were patients who had at least one family member with GD within the proband's first-degree relatives. We compared 43 non-familial cases of GD that were selected randomly from patients referred to the Endocrine Clinic of our hospital. The male-to-female ratio was significantly higher in familial than non-familial GD. The age of onset of the disease was significantly lower in familial GD, but we could not detect any statistically significant differences in thyroid hormone concentrations or the levels of thyrotropin receptor-related antibodies. These data suggest that the influences of chromosome X-linked genes or estrogen products may be less important than susceptibility genes for the onset of familial than non-familial GD, and nongenetic factors may have a stronger influence in older patients. The results also suggested that genetic factors may not influence the disease activities by themselves, but further studies are necessary to clarify these issues