Device to Improve Treatment of Colorectal CA using O2 Dependent Phosphorescence

描述（由申请人提供）：直肠癌手术切除的标准治疗是进行低位前切除术（LAR）。在切除癌性肠段后，使用外科吻合器通过在所产生的脱节肠端之间建立吻合来恢复连续性。吻合口漏是结直肠手术最可怕的并发症之一，因为腹腔粪便污染导致的发病率和死亡率很高。据报道，直肠癌LAR术后发生吻合口漏的患者高达14%，是其他肠切除术的三倍。吻合口漏的后遗症可能包括局部脓肿形成、使人虚弱的疼痛、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的吻合口转移到造口术;许多个月后，患者需要接受额外的手术以恢复正常排便。虽然建立转向造口术可以减轻吻合口瘘的影响，但它不能防止吻合口瘘，并且会造成额外并发症的高风险，同时显著损害恢复患者的生活方式。目前既没有一种临床实用的方法可用于预测哪些患者会发生吻合口瘘，也没有一套客观的标准，外科医生可以根据这些标准选择那些将从造口术中受益的患者。拟议研究的长期目标是通过创建一种客观、可重复的方法在术中筛查患者，降低吻合口瘘和不必要的造口分流的发生率。低风险患者将避免不必要的造口术。尽管努力提高组织活力，但高泄漏风险的患者可能更好地接受永久性造口术，而不是失败的，痛苦的修复手术。直肠癌切除术后渗漏发生率增加的假设机制均可能导致愈合吻合口的氧气输送不足;每种机制均存在于手术时。吻合器吻合活力评价（SAVE）系统通过将市售圆形吻合器的钉砧替换为传感钉砧而集成到手术工作流程中。SAVE钉砧使用多模态传感器阵列，使外科医生能够以标准化方式执行手术，同时在整个吻合口形成过程中评估缝钉线处吻合的可行性。传感器数据被传输到基站，在基站中可操作的信息被显示给手术团队。阶段I证明了通过局部注射磷光体使用磷光的氧依赖性淬灭测量吻合部位的间质氧合水平的可行性。探针的初始毒性研究表明在剂量反应水平下无毒性。本研究的第II阶段将通过动物模型中的存活研究确定间质氧水平与吻合完整性之间的关系。同时，候选磷光体进行必要的筛选和药代动力学评价，为IND前讨论做准备。

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.