An Immunohistochemical Study of Tumor Vascularity and Proliferation Activity in Cholangiocellular Carcinoma: Relationship to Clinicopathologic Factors and Prognosis after Hepatic Resection

This study was designed to provide an immunohistochemical analysis of tumor biological factors in 28 patients who underwent hepatectomy for cholangiocellular carcinoma (CCC). Analyzed factors were microvessel counts (stained by CD34) and proliferating cell nuclear antigen (PCNA). PCNA L.I. was correlated with serum level of CA19-9, which was correlated with a higher recurrence rate and shorter patient survivals. Microvessel counts were negatively correlated with tumor size. Furthermore, the microvessel count in CCC with mass-forming (MF) plus periductal infiltrating (PI) type associated with poorer survivals, was significantly lower compared to that of CCC with MF type or PI type. Neither microvessel counts nor PCNA L.I. were associated with any other clinicopathologic factors or cancer recurrence. The five-year overall and cancer-free survival rates were 26% and 13%, respectively. Patients with MF plus PI type, poorer differentiated carcinoma, stage 4A and higher CA19-9 level had shorter cancer-free and overall survivals after hepatectomy (p<0.05). Cancer-free and overall survivals in patients with lower microvessel counts tended to be slightly worse but were not significantly different. Although tumor microvessel count and proliferating activity were correlated with prognostic clinicopathologic parameters, both factors might not be prognostic markers for predicting CCC recurrence and patient survival

CCL2 as a potential therapeutic target for clear cell renal cell carcinoma

We previously reported that the pVHL-atypical PKC-JunB pathway contributed to promotion of cell invasiveness and angiogenesis in clear cell renal cell carcinoma (ccRCC), and we detected chemokine (C-C motif) ligand-2 (CCL2) as one of downstream effectors of JunB. CCL2 plays a critical role in tumorigenesis in other types of cancer, but its role in ccRCC remains unclear. In this study, we investigated the roles and therapeutic potential of CCL2 in ccRCC. Immunohistochemical analysis of CCL2 expression for ccRCC specimens showed that upregulation of CCL2 expression correlated with clinical stage, overall survival, and macrophage infiltration. For functional analysis of CCL2 in ccRCC cells, we generated subclones of WT8 cells that overexpressed CCL2 and subclones 786-O cells in which CCL2 expression was knocked down. Although CCL2 expression did not affect cell proliferation in vitro, CCL2 overexpression enhanced and CCL2 knockdown suppressed tumor growth, angiogenesis, and macrophage infiltration in vivo. We then depleted macrophages from tumor xenografts by administration of clodronate liposomes to confirm the role of macrophages in ccRCC. Depletion of macrophages suppressed tumor growth and angiogenesis. To examine the effect of inhibiting CCL2 activity in ccRCC, we administered CCL2 neutralizing antibody to primary RCC xenografts established from patient surgical specimens. Inhibition of CCL2 activity resulted in significant suppression of tumor growth, angiogenesis, and macrophage infiltration. These results suggest that CCL2 is involved in angiogenesis and macrophage infiltration in ccRCC, and that CCL2 could be a potential therapeutic target for ccRCC

Functional and genomic characterization of patient‐derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma

Resistance to the mechanistic target of rapamycin (mTOR) inhibitors, which are a standard treatment for advanced clear cell renal cell carcinoma (ccRCC), eventually develops in most cases. In this study, we established a patient-derived xenograft (PDX) model which acquired resistance to the mTOR inhibitor temsirolimus, and explored the underlying mechanisms of resistance acquisition. Temsirolimus was administered to PDX model mice, and one cohort of PDX models acquired resistance after repeated passages. PDX tumors were genetically analyzed by whole-exome sequencing and detected several genetic alterations specific to resistant tumors. Among them, mutations in ANKRD12 and DNMT1 were already identified in the early passage of a resistant PDX model, and we focused on a DNMT1 mutation as a potential candidate for developing the resistant phenotype. While DNMT1 expression in temsirolimus-resistant tumors was comparable with the control tumors, DNMT enzyme activity was decreased in resistant tumors compared with controls. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated heterozygous knockdown of DNMT1 in the temsirolimus-sensitive ccRCC (786-O) cell line was shown to result in a temsirolimus-resistant phenotype in vitro and in vivo. Integrated gene profiles using methylation and microarray analyses of PDX tumors suggested a global shift for the hypomethylation status including promotor regions, and showed the upregulation of several molecules that regulate the mTOR pathway in temsirolimus-resistant tumors. Present study showed the feasibility of PDX model to explore the mechanisms of mTOR resistance acquisition and suggested that genetic alterations, including that of DNMT1, which alter the methylation status in cancer cells, are one of the potential mechanisms of developing resistance to temsirolimus

Resected or Remnant Liver Volume and Standard Liver Volume Ratio in Patients with Major Hepatectomy

To clarify the relationship between resected (RSV) or remnant hepatic volume (RMV) in major hepatectomy, and standard liver volume (SLV) and its clinical significance, the RSV/SLV, RMV/SLV and the volume of regeneration (RGV)/RMV were examined in 41 patients including 19 with chronic hepatitis and 5 with obstructive jaundice who underwent lobectomy or extended lobectomy. The hepatic function was maintained in all patients. SLV was calculated by the body-surface area using Urata\u27s formula. RGV was calculated by subtracting the RMV from the remnant liver volume at day 28 after hemi-hepatectomy. Measurement of the hepatic volume was performed by computed tomography. The means of RSV, RMV, RGV and SLV were 591 ﾂｱ 173, 459 ﾂｱ 119, 667 ﾂｱ 129 and 1128 ﾂｱ 129cm3, respectively. The means of RSV/SLV, RMV/SLV and RGV/RMV were 0.52 ﾂｱ 0.14, 0.41 ﾂｱ 0.12 and 1.54 ﾂｱ 0.47, respectively. RGV was inversely correlated with RMV/SLV (p<0.001) but not with the other parameters. RSV/SLV and RMV/SLV were not associated with long-term ascites and hepatic failure. The tendency of these results was similar in each patient with a normal liver, obstructive jaundice and chronic viral hepatitis. If the hepatic functional reserve is maintained, a liver with lower hepatic volume has potentially sufficient regeneration even in patients with an injured liver

IL13RA2は、淡明型腎細胞癌のスニチニブ抵抗性獲得に関与する。

京都大学0048新制・課程博士博士(医学)甲第19888号医博第4137号新制||医||1016(附属図書館)32965京都大学大学院医学研究科医学専攻(主査)教授 清水 章, 教授 柳田 素子, 教授 武藤 学学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

前立腺全摘後における尿道カテーテル早期抜去とその後の排尿状態についての臨床的検討

前立腺全摘術後35例に対し, 6日目または7日目に膀胱造影施行し, 漏れがなければ尿道カテーテルを抜去した.そして, Uroflowmetryをカテーテル抜去直後と外来follow時(4～20ヵ月)に施行した.その結果, 1)1例を除き尿道カテーテルを早期抜去できたが, 抜去直後3例に尿閉を認め尿道カテーテルを再留置した.2)尿失禁に関してはexcellent(pad必要なし)が25例(71.4%), good(padが1枚以下)が7例(20%)であった.3)抜去直後uroflowmetryのmaximum flow nomogramでは12例に排尿困難を認めたが, 外来follow時では8例に減少していた.しかし, そのうち3例に吻合部狭窄, 1例に尿道狭窄が認められた.以上, これらのことからも, 尿道カテーテル早期抜去は安全に施行できると考えられたが, 抜去直後に排尿困難や尿閉を来す症例もあり, おそらく吻合部の浮腫が原因と考えられた.一方, 術後しばらくしてから排尿困難を訴える場合は吻合部狭窄や尿道狭窄を念頭に置く必要があると思われたCystography was performed on 35 patients 6 to 7 days after retropubic radical prostatectomy (RRP), to determine the feasibility of early removal of the urinary catheter. The urethral catheter was removed the same day if no extravasation was evident on cystography. Uroflowmetry was also performed both immediately after early catheter removal and at follow-up 4 to 20 months later. The urethral catheter could be removed on postoperative day 6 or 7 from all but one patient. Three patients developed acute urinary retention after catheter removal, requiring reinsertion of a Foly catheter. During a mean follow-up of 8.3 months (range 4 to 20 months), 25 patients (71.4%) reported excellent continence (requiring no pad) and seven patients (20%) good continence (requiring a single pad). Immediately after early catheter removal, 12 patients (34%) showed obstruction on a maximum flow nomogram. The number of patients with obstruction decreased to eight during follow-up, three of whom suffered anastomotic stricture and one anterior urethral stricture, all of which required urethrotomy. Our results show that early catheter removal can be accomplished safely, although some patients may have difficulty with urination or develop acute urinary retention immediately after catheter removal, probably due to anastomotic edema. On the other hand, if the patients develop difficulty in urination some time after the operation, the possibility of anastomotic or urethral stricture should be considered. Therefore we recommend uroflowmetry within one year after RRP to identify anastomotic or urethral stricture