Li Zihao, Hannan Md Nafiz, Sharma Ashwani K, Baran Timothy M
medRxiv. 2023 Nov 6:2023.10.23.23297420. doi: 10.1101/2023.10.23.23297420.
Photodynamic therapy (PDT) is an effective antimicrobial therapy that we used to treat human abscess cavities in a recently completed Phase 1 clinical trial. This trial included pre-PDT measurements of abscess optical properties, which affect the expected light dose to the abscess wall and eventual PDT response.
The objective of this study was to simulate PDT treatment planning for the 13 subjects that received optical spectroscopy prior to clinical abscess PDT. Our goal was to determine the impact of these measured optical properties on our ability to achieve fluence rate targets in 95% of the abscess wall.
During a Phase 1 clinical trial, 13 subjects received diffuse reflectance spectroscopy prior to PDT in order to determine the optical properties of their abscess wall. Retrospective treatment plans seeking to achieve fluence rate targets in 95% of the abscess wall were evaluated for all subjects for 3 conditions: (1) at the laser power delivered clinically with assumed optical properties, (2) at the laser power delivered clinically with measured optical properties, and (3) with patient-specific treatment planning using these measured optical properties. Factors modified in treatment planning included delivered laser power and intra-cavity Intralipid (scatterer) concentration. The effects of laser fiber type were also simulated.
Using a flat-cleaved laser fiber, the proportion of subjects that achieved 95% abscess wall coverage decreased significantly when incorporating measured optical properties for both the 4 mW/cm (92% vs. 38%, p=0.01) and 20 mW/cm (62% vs. 15%, p=0.04) fluence rate thresholds. However, when measured optical properties were incorporated into treatment planning, a fluence rate of 4 mW/cm was achieved in 95% of the abscess wall for all cases. In treatment planning, the optimal Intralipid concentration across subjects was found to be 0.14 ± 0.09% and the optimal laser power varied from that delivered clinically but with no clear trend (p=0.79). The required laser power to achieve 4 mW/cm in 95% of the abscess wall was significantly correlated with measured µ at the abscess wall (ρ=0.7, p=0.008), but not abscess surface area (ρ=0.2, p=0.53). When using spherical diffuser fibers as the illumination source, the optimal intralipid concentration decreased to 0.028 ± 0.026% (p=0.0005), and the required laser power decreased also (p=0.0002), compared to flat cleaved fibers. If the intra-cavity lipid emulsion (Intralipid) was replaced with a non-scattering fluid, all subjects could achieve the 4 mW/cm fluence rate threshold in 95% of the abscess wall using a spherical diffuser, while only 69% of subjects could reach the same criterion using a flat cleaved fiber.
The range of optical properties measured in human abscesses reduced coverage of the abscess wall at desirable fluence rates. Patient-specific treatment planning including these measured optical properties could bring the coverage back to desirable levels by altering the Intralipid concentration and delivered optical power. These results motivate a future Phase 2 clinical trial to directly compare the efficacy of patient-specific-treatment planning with fixed doses of Intralipid and light. The parent clinical trial from which these data were acquired is registered on ClinicalTrials.gov as "Safety and Feasibility Study of Methylene Blue Photodynamic Therapy to Sterilize Deep Tissue Abscess Cavities," with ClinicalTrials.gov identifier NCT02240498 .
光动力疗法（PDT）是一种有效的抗菌疗法，我们在最近完成的一项1期临床试验中用于治疗人体脓肿腔。该试验包括在PDT前对脓肿光学特性进行测量，这些特性会影响到达脓肿壁的预期光剂量以及最终的PDT反应。
本研究的目的是为13名在临床脓肿PDT前接受光谱学检查的受试者模拟PDT治疗计划。我们的目标是确定这些测量的光学特性对我们在95%的脓肿壁实现注量率目标能力的影响。
在一项1期临床试验中，13名受试者在PDT前接受了漫反射光谱检查，以确定其脓肿壁的光学特性。针对所有受试者，评估了在3种情况下旨在实现95%脓肿壁注量率目标的回顾性治疗计划：（1）在假设光学特性下以临床输送的激光功率进行；（2）在以测量的光学特性下以临床输送的激光功率进行；（3）使用这些测量的光学特性进行患者特异性治疗计划。治疗计划中修改的因素包括输送的激光功率和腔内脂质体（散射体）浓度。还模拟了激光光纤类型的影响。
使用平切激光光纤时，纳入测量的光学特性后，在4 mW/cm²（92%对38%；p = 0.01）和20 mW/cm²（62%对15%；p = 0.04）注量率阈值下，实现95%脓肿壁覆盖的受试者比例显著降低。然而，当将测量的光学特性纳入治疗计划时，所有病例在95%的脓肿壁中均实现了4 mW/cm²的注量率。在治疗计划中，发现所有受试者的最佳脂质体浓度为0.14±0.09%，最佳激光功率与临床输送的不同，但无明显趋势（p = 0.79）。在95%的脓肿壁中实现4 mW/cm²所需的激光功率与脓肿壁处测量的μ显著相关（ρ = 0.7，p = 0.008），但与脓肿表面积无关（ρ = 0.2，p = 0.53）。当使用球形扩散光纤作为照明源时，与平切光纤相比，最佳脂质体浓度降至0.028±0.026%（p = 0.0005），所需激光功率也降低（p = 0.0002）。如果用非散射液替代腔内脂质乳剂（脂质体），使用球形扩散器时所有受试者在95%的脓肿壁中均可达到4 mW/cm²的注量率阈值，而使用平切光纤时只有69%的受试者能达到相同标准。
在人体脓肿中测量的光学特性范围在理想注量率下降低了脓肿壁的覆盖范围。包括这些测量的光学特性的患者特异性治疗计划可通过改变脂质体浓度和输送的光功率将覆盖范围恢复到理想水平。这些结果促使开展一项未来的2期临床试验，以直接比较患者特异性治疗计划与固定剂量脂质体和光的疗效。获取这些数据的母临床试验已在ClinicalTrials.gov上注册为“亚甲蓝光动力疗法对深部组织脓肿腔进行消毒的安全性和可行性研究”，ClinicalTrials.gov标识符为NCT02240498。
