Beta Camera and Laparoscopic Probe for Surgical Cancer Removal.

描述（由申请人提供）：唯一确定的癌症治愈方法是通过手术完全切除恶性组织。完全切除可以防止肿瘤的再生长，并消除第二次手术的需要。手术过程中的困难之一是确定是否所有的癌组织都已从肿瘤边缘切除。目前，外科医生依赖于手术腔的目视检查和边缘的随机组织取样，或手术结束后通常准备好的切除组织的病理结果。放射性标记的肿瘤标志物在癌细胞中优先具有高摄取，并为边缘处的隐匿性肿瘤的检测提供了独特的机会。背景：β射线在组织中的射程为几毫米。β射线探测器，结合β放射性同位素是理想的边缘上的隐匿性肿瘤的检测，因为背景辐射不会干扰边缘的识别。以前，我们已经开发了一个β探头和β相机探测器，并证明他们是选择性敏感的β射线。具有成像能力的仪器将进一步帮助外科医生快速准确地定位任何阳性肿瘤边缘。Beta相机在过去已经被提出，但从未在临床上使用，因为设计一个敏感的相机，同时在手术期间使用电气安全的问题。新奇：在本次提交中，我们提出了一种基于固态光电倍增管（SSPM）的新型beta相机设计。SSPM是一种相对较新的光电传感器，其性能接近传统PMT，但仅需要在数十伏而不是PMT所需的kV下工作。因此，使用SSPM将显著减轻术中使用β摄像头的电气安全性问题。还将测试多个探测器模块，以提高对β射线的灵敏度，降低对γ射线的灵敏度。初步研究：最近，我们进行了一项试点研究，涉及7例接受乳房肿瘤切除术的患者。在手术过程中，用β探头测量手术腔和切除的组织。我们发现，由β-探针检测到的手术腔中的背景仅为12 - 18 cps，而5 mg产生3518 cps，表明γ背景足够低，以允许检测小体积组织中的摄取。这项研究的另一个结论是，需要一种成像设备来更快速、更准确地调查手术腔。我们已经建立了一个原型的SSPM为基础的测试相机在一个小规模，并证明了其可行性。研究计划（第一阶段）：我们将用一片塑料闪烁体和一个新的陶瓷安装SSPM的5x 5阵列来构建相机。我们将实验用Peltier冷却器来降低SSPM阵列的温度。我们将优化相机的灵敏度，并进行表征，以及使用Phantom的检测限测试。我们将测试符合鉴别的新概念，以减少SSPM的电子噪声，并增加相机对低能β射线的灵敏度。我们将测试双探测器模块设计，以降低背景伽马灵敏度。我们将测试具有一层SSPM和2层不同衰减器的相机模块，这些衰减器通过衰减时间常数和光敏开关电路来区分。研发和临床试验计划（第二阶段）：将选择最好的探测器模块概念，用于构建用于临床试验的beta相机。摄像机的电子器件、机械外壳和软件以及腹腔镜版本的摄像机将在第二阶段的第一部分进行构建和测试。这些摄像机的原型设计将通过手术器械的电气和环境标准，并将被发送到CSA以获得UL安全证书。我们将向FDA提交新器械豁免（NDE）申请，以测试乳腺和前列腺摄像机。在第二阶段的后期，我们将与我们的长期合作者Armando Giuliano博士进行临床试验，使用FDG检测肿块切除术中的边缘。本研究将入组30例患者，将修订现有的β探头IRB方案，以纳入β摄像头。与康奈尔大学的Bander和Tewari博士一起，我们将在机器人腹腔镜手术中测试腹腔镜beta相机，并结合一种名为J591的单克隆抗体，针对用Lu-177（一种β发射体）标记的PSMA。将对正在进行的IRB批准的Lu-177-J591 Mab研究进行修订，以纳入腹腔镜下的β摄像机探查。统计分析：这两项研究旨在确定β相机在切除边缘肿瘤检测中的有效性、灵敏度和特异性。通过外科医生的视觉检测对beta相机进行ROC分析，将显示添加的beta相机是否有助于提高切缘检测率。

DESCRIPTION (provided by applicant): The only certain cure of cancer is the complete removal of the malignant tissue by surgery. A complete removal would prevent the re-growth of the tumor and eliminate the need for a second operation. One of the difficulties during the operation is to determine if all of the cancerous tissue has been removed from the tumor margin. Currently surgeons rely on visual inspection of the surgical cavity and random tissue sampling of the margins, or pathology results on the excised tissue that is often ready after the surgery is concluded. Radiolabeled tumor markers have preferentially high uptake in cancerous cells and offer a unique opportunity for detection of occult tumors at the margin. Background: Beta rays have a range of a few millimeters in tissue. Beta ray detectors, in conjunction with beta emitting isotopes are ideal for detection of occult tumors on the margin since background radiation would not interfere with identification of margins. Previously we have developed a beta probe and beta camera detector and demonstrated that they are selectively sensitive to beta rays. An instrument with imaging capability would further aid the surgeon to quickly and accurately localize any positive tumor margins. Beta cameras have been proposed in the past, but have never been used clinically, because of problems designing a camera that is sensitive and at the same time electrically safe to use during surgeries. Novelty: In this submission, we are proposing a novel beta-camera design based on the use of Solid State Photomultipliers (SSPMs). SSPMs is a relatively new class of photo-sensors that have been shown to have a performance close to that of conventional PMTs, but only requiring operating at tens of volts instead of kV needed for PMTs. Thus, the use of SSPM would significantly alleviate the electrical safety aspect of using the beta-camera intra-operatively. Multiple detector modules will also be tested to increase sensitivity to beta and decrease sensitivity for gamma rays. Preliminary Studies: Recently we performed a pilot study that involved 7 patients that underwent lumpectomy. During the procedure, the surgical cavity and excised tissues were surveyed with a beta-probe. We found that the background in the surgical cavity detected by the beta-probe was only a 12 18 cps, while a 5 mg generated 3518 cps, showing that the gamma background is low enough to allow detection of uptake in small volumes of tissues. Another conclusion from this study was that an imaging device is needed to allow a more rapid and accurate survey of the surgical cavity. We have built a prototype of the SSPM-based beta camera in an small scale and demonstrated its feasibility. Research Plan (Phase I): We will build the camera with a sheet of plastic scintillator and a 5x5 array of new ceramic-mounted SSPMs. We will experiment with Peltier coolers to lower the temperature of the SSPM array. We will optimize the sensitivity of the camera, and perform characterization, and limit of detection tests with phantoms. We will test the novel concept of coincidence discrimination to reduce the electronic noise of SSPMs and increase the sensitivity of the camera to low energy beta rays. We will test a dual detector module design to reduce the background gamma sensitivity. We will test a module for the camera with one layer of SSPMs and 2 layers of different scintillators that are differentiated by decay-time constants and phoswitch circuitry. R&D and Clinical Trials Plan (Phase II): The best detector module concept will be selected for building a beta camera for clinical trial. The electronics, mechanical housing, and software for the camera, as well as a Laparoscopic version of the camera will be built and tested during the first part of the Phase II. The prototypes of these cameras will be designed to pass electrical and environmental standards of surgical instruments, and will be sent to CSA in order to obtain UL safety certificates. We will submit a New Device Exemption (NDE) application to FDA for testing the cameras in breast and prostate. During the later part of Phase II we will conduct clinical trials with our long term collaborator Dr. Armando Giuliano on detection of margins in lumpectomy using FDG. Thirty patients will enroll is this study and the existing IRB protocol for beta probe will be amended to include beta camera. Together with Drs. Bander and Tewari at Cornell we will test the laparoscopic beta camera in robotic prostatectomies, in conjunction with a monoclonal antibody, called J591, against PSMA that is labeled with Lu-177 (a beta emitter). The on going IRB approved studies of Lu-177-J591 Mab will be amended to include beta camera exploration laparoscopically. Statistical Analysis: Both studies are designed to determine the efficacy, sensitivity, and specificity of the beta cameras in detection of tumors on the margins of resection. The ROC analysis of the beta camera with visual detection of the surgeons will show if beta cameras added can help increase the rate of margin detection.