Yonson Ku

A phase I/II study of gemcitabine-concurrent proton radiotherapy for locally advanced pancreatic cancer without distant metastasis

PURPOSE We conducted the study to assess the feasibility and efficacy of gemcitabine-concurrent proton radiotherapy (GPT) for locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS Of all 50 patients who participated in the study, 5 patients with gastrointestinal (GI)-adjacent LAPC were enrolled in P-1 (50 Gy equivalent [GyE] in 25 fractions) and 5 patients with non-GI-adjacent LAPC in P-2 (70.2 GyE in 26 fractions), and 40 patients with LAPC regardless of GI-adjacency in P-3 (67.5 GyE in 25 fractions using the field-within-a-field technique). In every protocol, gemcitabine (800 mg/m(2)/week for 3 weeks) was administered concurrently. Every patient received adjuvant chemotherapy including gemcitabine after GPT within the tolerable limit. RESULTS The median follow-up period was 12.5 months. The scheduled GPT was feasible for all except 6 patients (12%) due to acute hematologic or GI toxicities. Grade 3 or greater late gastric ulcer and hemorrhage were seen in 5 patients (10%) in P-2 and P-3. The one-year freedom from local-progression, progression-free, and overall survival rates were 81.7%, 64.3%, and 76.8%, respectively. CONCLUSION GPT was feasible and showed high efficacy. Although the number of patients and the follow-up periods are insufficient, the clinical results seem very encouraging.

Abstract 449: Hypoxia induces tumor aggressiveness by an acquired stem-like phenotype in pancreatic cancer through HIF-1α signaling

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: Intratumoral hypoxia is a negative prognostic indicator, as it has been associated with increased aggressiveness and distant metastasis. Although hypoxia can drive the metastatic phenotype secondary to genetic instability and clonal selection of aggressive tumor cells, the interplay underlying them is to be unanswered. We hypothesized that mature cancer cells might acquire the stem-like phenotype under hypoxia, consequently leading to aggressive phenotype. Methods: Under normoxia (20% O2) or hypoxia (1% O2) condition, the expression of CD133 (cancer stem cell marker), CXCR4 (chemokine receptor), HIF-1α, and pimonidazole (hypoxic probe) were examined by quantitative RT-PCR and imuunohistochemistry using human pancreatic cancer cell lines. Moreover, we evaluated the expression of CD133 and hypoxia markers (pimonidazole, HIF-1α, and CA) in xenograft and human pancreatic cancer specimen. Furthermore, we transfected dominant active HIF-1α (HIF-1α ΔODD) by the retroviral gene transfer and examined the effects both in vitro and in vivo. Results: We demonstrated that hypoxia induces tumor aggressive phenotype in pancreatic cancer, including invasiveness and CXCR4 expression. Furthermore, this phenotype is followed distinctively by the subpopulation of CD133+ pancreatic cancer cells, which themselves show hypoxic and invasive properties, indicating that mature cancer cells might reacquire an undifferentiated stem-like phenotype. In addition, both acquired stem-like phenotype and invasiveness under hypoxia are predominantly in a HIF-1α/CXCR4-dependent manner, and dominant active HIF-1αΔODD transfected cells promoted their tumorigenic ability. Surprisingly, orthotopic engraftment of these cells showed liver metastasis, while the engraftment of mock transfected cells did not occur any liver metastasis. Conclusion: We demonstrated that mature cancer cells acquired the stem-like phenotype under hypoxia and showed aggressive phenotype including invasiveness and metastasis through HIF-1α signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 449.

Use of veno-venous bypass combined with direct hemoperfusion during intraarterial chemotherapy of the liver in dogs.

制癌剤肝動注療法に際して静脈間バイパスにより肝静脈系を分離し活性炭吸着する方法を考案し,全身への薬剤溢流防止効果を実験的に検討した.雑種犬でI群:肝動注のみ(n=4),II群:下大静脈血の部分的吸着(n=5),III群:肝静脈血の選択的吸着(n=8)の3群に分け,Adriamycin (ADR, 3mg/kg), Mitomycin C (MMC, 1mg/kg)を1分間で肝動注し薬剤血中濃度(μg/ml)を比較した.さらにIII群では動注時間を変えて吸着効果の違いを検討した.1分動注時の末梢血中ADR, MMCの最高値はI群で6.61±2,44, 2.20±1.05, II群で1.25±1.02, 0.79±0.52, III群で0.41±0.15, 0.13±0.07となり,III群ではI群に比べて各々,6.2%, 5.9%と著しく低値(p<0.01)であった,吸着除去率は動注時間が長い方が高い傾向にあった.以上より本法は制癌剤を全身循環に流入する手前で効果的に除去し,副作用を最小限に抑え,さらに大量投与を可能にする新しい肝動注療法として有用と思われた.