Device to Improve Treatment of Colorectal CA using O2 Dependent Phosphorescence

描述（由申请人提供）：直肠癌手术切除的护理标准是低位前切除术（LAR）的表现。切除癌段后，外科吻合器通过在分离的肠两端之间建立吻合来恢复连续性。吻合口瘘是结直肠手术中最可怕的并发症之一，由于粪便污染腹腔而引起发病率和死亡率。据报道，直肠癌LAR术后吻合口漏发生率高达14%；是其他肠道切除术的三倍。吻合口漏的后遗症包括局部脓肿形成、衰弱性疼痛、排便功能障碍、压倒性细菌性败血症和死亡。其后果是如此严重，以至于外科医生主观地选择将粪便流从愈合吻合口转移到造口；几个月后，患者需要再做一次手术以恢复正常排便。虽然转移造口术可以减轻吻合口漏的影响，但它并不能预防吻合口漏，而且会带来额外并发症的高风险，同时显著影响康复患者的生活方式。临床上既没有一种实用的方法来预测哪些患者会出现吻合口漏，也没有一套客观的标准，外科医生可以根据这些标准来选择那些将从造口术中受益的患者。本研究的长期目标是通过建立一种客观的、可重复的方法来筛查术中患者，从而减少吻合口漏的发生率和不必要的造口转移。低风险的患者将避免不必要的造口手术。尽管努力提高组织活力，但对于有高泄漏风险的患者来说，永久性造口术可能比失败、痛苦的修复手术更好。直肠癌切除术后瘘发生率增加的假设机制都可能导致愈合吻合处供氧不足；这些在手术时都存在。吻合器生存能力评估（SAVE）系统通过用传感砧代替市售的圆形吻合器砧，集成到手术工作流程中。SAVE Anvil使用一组多模态传感器，使外科医生能够以标准化的方式执行手术，同时在整个缝合过程中评估吻合术的可行性。传感器数据被传输到基站，在那里可操作的信息被显示给外科团队。第一阶段证明了通过局部注射荧光粉，通过氧依赖猝灭磷光来测量吻合部位间质氧合水平的可行性。该探针的初步毒性研究表明，在剂量-反应水平上无毒性。本研究的第二期将通过动物模型的生存研究，建立间质氧水平与吻合完整性之间的关系。同时，候选荧光粉要经过必要的筛选和药代动力学评估，为新药开发前的讨论做准备。

DESCRIPTION (provided by applicant): Standard of care for surgical resection of rectal cancer is the performance of low anterior resection (LAR). After removal of the cancerous segment, a surgical stapler is used to restore continuity by creating an anastomosis between the resulting ends of disjointed bowel. Anastomotic leak is one of the most dreaded complications of colorectal surgery due to the morbidity and mortality caused by fecal contamination of the abdominal cavity. Anastomotic leak, after LAR for rectal cancer, has been reported to occur in as many as 14% of patients; three times more frequently than with other bowel resections. The sequela of anastomotic leak can include local abscess formation, debilitating pain, dysfunctional defecation, overwhelming bacterial sepsis, and death. The consequences are so severe that surgeons subjectively opt to divert the fecal stream away from the healing anastomosis to an ostomy; many months later the patient is then subject to an additional operation to restore normal defecation. While creation of a diverting ostomy can lessen the impact of anastomotic leak, it does not prevent the leak, and poses a high risk for additional complications while significantly compromising the lifestyle of the recovering patient. There is neither a clinically practical method available for predicting which patients will experience an anastomotic leak, nor an objective set of criteria by which a surgeon can select those patients that would benefit from an ostomy. The long term goal of the proposed research is to reduce the rate of anastomotic leak and unnecessary ostomy diversion through the creation of an objective, repeatable means by which to screen patients intra-operatively. Patients at low risk will avoid an unnecessary ostomy. Patients at high risk of leak, despite efforts to improve tissue viability, would likely be better served by a permanent ostomy instead of a failed, painful attempt at a restorative procedure. Postulated mechanisms for the increased incidence of leak after resection of rectal cancer can each contribute to inadequate oxygen delivery to the healing anastomosis; each of which are present at the time of surgery. The Stapled Anastomosis Viability Evaluation (SAVE) System integrates into the surgical workflow by replacing the anvil of commercially available, circular staplers with a sensing anvil. The SAVE Anvil uses an array of multi-modality sensors to enable the surgeon to perform the procedure in a standardized manner while assessing the viability of the anastomosis at the staple line throughout its formation. Sensor data is transmitted to a base station where actionable information is displayed to the surgical team. Phase I demonstrated the feasibility of measuring interstitial oxygenation levels at the anastomotic site using oxygen dependent quenching of phosphorescence via a locally injected phosphor. Initial toxicity studies of the probe indicate non-toxicity at dose-response levels. Phase II of this study will establish the relationship between interstitial oxygen level and integrity of the anastomosis through survival studies in animal models. Concurrently the candidate phosphor with undergo requisite screening, and pharmacokinetic evaluation in preparation for pre-IND discussion.