進行性尿路上皮腫瘍に対するM-VAC(methotrexate, vinblastine, doxorubicin and cisplatin)療法と治療強度に基づいた効果

41人の患者を術後補助化学療法24人, 術前補助化学療法5人, 救済化学療法12人の3グループに分け, 各群について調査した.平均の治療強度は術後補助化学療法群77±11%, 術前補助化学療法群73±4%, 救済化学療法群74±12%であった.他因死を除いた5年生存率は補助化学療法では69%であった.術前補助化学療法の5例中2例は治療開始より23ヵ月で癌なし生存, 救済化学療法の全例は33ヵ月以内に癌死或いは副作用で死亡した.生存期間の中央値は術後補助化学療法群で38ヵ月, 術前補助化学療法群で21ヵ月, 救済化学療法群で7ヵ月であった.75%以上の治療強度は各群において生存率を改善しなかったThe effects of the M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) regimen, which has been reported to improve the outcome of patients with urothelial cancers, were studied on 41 patients treated at our hospital. The patients were divided into adjuvant (24 patients), neoadjuvant (5 patients), and salvage (12 patients) groups. We investigated the dose intensity, the cause-specific survival, response rate and toxicities in the three groups. Although 36 patients received > or = 95% of the initial doses projected, the mean dose intensity (+/-standard deviation) in the adjuvant, neoadjuvant, and the salvage groups was 77 (+/-11), 73 (+/-4), and 74 (+/-12)%, respectively. The five-year cause-specific survival in the adjuvant group was 69% (95% confidence limit: 50-88%). Only 2 of the 5 patients (40%) in the neoadjuvant group survived 23 months after the initiation of the treatment, and all patients in the salvage group died of cancer or treatment-related toxicity within 33 months. The median survival was 38 months in the adjuvant group, 21 months in the neoadjuvant group, and 7 months in the salvage group. A dose intensity > or = 75% did not improve survival in any group. The overall response rate was 33% in 15 patients with evaluable lesions. A complete response was noted in 1 patient and a partial response was noted in 1 patients. Two patients died of treatment-related complications. Nausea and vomiting were observed in all patients. Leukopenia, thrombocytopenia and anemia > or = WHO grade 3 were observed in 25 (61%), 4 (10%), and 7 (17%) patients, respectively. Thrombocytopenia, anemia, and pyrexia > or = grade 3 were seen relatively more often in the patients receiving a dose intensity or = grade 3 appeared to be more frequent in the patients receiving a dose intensity > or = 75%. Adjuvant M-VAC might be beneficial, while its efficacy was limited in the neoadjuvant and salvage settings. Although dose intensity is considered to be important, it did not appear to be related to survival, the response rate, or the toxicity of M-VAC

鶏卵尿漿膜上に異種移植されたヒト腫瘍の増殖動態

腎細胞癌の78.6%, 尿路上皮癌の77.8%, 精巣腫瘍の66.7%, 結腸腺癌, 及び卵巣腺癌は移植に成功したが, 前立腺癌は全て失敗した。組織学的に膜上で生存している細胞は, 構造が良く保たれている類器官を形成していた。しかし, 癌巣の生存力は壊死組織周囲の炎症性変化の影響を受けなかった。腎細胞癌は生存し, 瀰漫性に顕著に血管を形成していた。膜上の癌細胞の%BrdU(ブロモデオキシウリジン)標識指数と元の腫瘍の%Ki-67指数との間には強い相関が認められた。癌巣の大小によっては%BrdU指数に差異がなかった。接種後8日間成長状態は一定に留まっていた。生存している癌巣の成長能力はインキュベーション中不変We evaluated the success rates of transplantation and growth conditions of 33 human tumor xenografts transplanted on the chorioallantoic membrane of chick embryos. Eleven out of 14 renal cell carcinomas (78.6%), 7 out of 9 urothelial carcinomas (77.8%), 2 out of 3 testicular tumors (66.7%), an adenocarcinoma of the colon and an adenocarcinoma of the ovary but none of the 5 prostatic carcinomas were transplanted successfully. Histologically, carcinoma cells survived on the chorioallantoic membrane forming organoids the structure of which was well preserved. Several regions of the grafts frequently became necrotized. However, the viability of carcinoma nests was not influenced by the inflammatory changes surrounding necrotic tissues. Renal cell carcinomas survived diffusely with prominent angiogenesis. Immunostaining with anti-bromodeoxyuridine (BrdU) and Ki-67 monoclonal antibodies demonstrated a strong correlation between the %BrdU labeling index of the cancer cells on the chorioallantoic membrane and %Ki-67 index of the original tumors. No difference in %BrdU indexes was found between small and large cancer nests. Growth conditions remained constant for 8 days after inoculation. The growth potential of cancer nests surviving on the chorioallantoic membrane, which was identical to that of the original carcinomas, appeared to be unchanged during incubation. However, it might be difficult to exploit the chorioallantoic membrane for anticancer chemosensitivity tests except for renal cell carcinoma since few cancer cell nests were produced in spite of the high transplantation success rates

腹膜外的骨盤リンパ節郭清後のリンパ漏に対するミノサイクリン注入療法

腹膜外的骨盤リンパ節郭清後発生したリンパ漏の4症例に対し, ドレーンからミノサイクリンを注入し治療した。4症例のうち2症例は同時に膀胱全摘術を, 1症例は前立腺全摘術を施行した。4症例すべてにおいてリンパ漏は著明に改善し, 以後のドレーン留置期間を短縮できた。副作用は生じなかったWe managed four cases of lymphorrhea after extraperitoneal pelvic lymphadenectomy by means of minocycline instillation into the cavity around the drainage tube. Two patients had concomitantly undergone cystectomy and one prostatectomy via the extraperitoneal approach. In all four cases, the lymphorrhea markedly subsided, which dramatically shortened the duration of drainage. No side effects occurred. These findings indicate that minocycline instillation is an efficacious treatment for lymphorrhea

Interleukin-1beta (IL-1β)-induced Notch ligand Jagged1 suppresses mitogenic action of IL-1β on human dystrophic myogenic cells

<div><p>Duchenne muscular dystrophy (DMD) is a severe X-linked recessive muscle disorder caused by mutations in the dystrophin gene. Nonetheless, secondary processes involving perturbation of muscle regeneration probably exacerbate disease progression, resulting in the fatal loss of muscle in DMD patients. A dysfunction of undifferentiated myogenic cells is the most likely cause for the reduction of regenerative capacity of muscle. To clarify molecular mechanisms in perturbation of the regenerative capacity of DMD muscle, we have established several NCAM (CD56)-positive immortalized human dystrophic and non-dystrophic myogenic cell lines from DMD and healthy muscles. A pro-inflammatory cytokine, IL-1β, promoted cell cycle progression of non-dystrophic myogenic cells but not DMD myogenic cells. In contrast, IL-1β upregulated the Notch ligand Jagged1 gene in DMD myogenic cells but not in non-dystrophic myogenic cells. Knockdown of Jagged1 in DMD myogenic cells restored the IL-1β-promoted cell cycle progression. Conversely, enforced expression of Jagged1-blocked IL-1β promoted proliferation of non-dystrophic myogenic cells. In addition, IL-1β prevented myogenic differentiation of DMD myogenic cells depending on Jagged1 but not of non-dystrophic myogenic cells. These results demonstrate that Jagged1 induced by IL-1β in DMD myogenic cells modified the action of IL-1β and reduced the ability to proliferate and differentiate. IL-1β induced Jagged1 gene expression may be a feedback response to excess stimulation with this cytokine because high IL-1β (200–1000 pg/ml) induced Jagged1 gene expression even in non-dystrophic myogenic cells. DMD myogenic cells are likely to acquire the susceptibility of the Jagged1 gene to IL-1β under the microcircumstances in DMD muscles. The present results suggest that Jagged1 induced by IL-1β plays a crucial role in the loss of muscle regeneration capacity of DMD muscles. The IL-1β/Jagged1 pathway may be a new therapeutic target to ameliorate exacerbation of muscular dystrophy in a dystrophin-independent manner.</p></div

IL-1β inhibited myogenesis of dystrophic myogenic cells in a Jagged1-dependent manner.

<p>(A-R) Human non-dystrophic (Hu37KD5, A-C) and dystrophic (D4P4, D-F) myogenic cell clones and derivatives of D4P4 were stimulated with (B, C, E, F, H, I, K, and L) or without (A, D, G, and J) IL-1β (500 pg/ml) under the differentiation-inducing condition for 3 d. D4P4 cells were transduced by a lentivirus encoding random shRNA (D4shCTR, G-I) or shJagged1 (D4shJ1, J-L). Myosin heavy chain and troponin T were visualized using an inverted microscope (red). Nuclei were stained with DAPI (blue). Scale bar, 100 μm. (M) Hu37KD5, D4P4, and derivatives of D4P4 were cultured for up to 3 or 4 d under the differentiation-inducing condition with (+) or without (-) IL-1β (500 pg/ml). Twenty micrograms of total proteins was subjected to immunoblot analysis with antibodies against MyHC and β-tubulin.</p