Beta Camera and Laparoscopic Probe for Surgical Cancer Removal.

描述（由申请人提供）：唯一确定的治愈癌症的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次生长，并消除第二次手术的需要。手术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，外科医生依靠手术腔的目视检查和边缘的随机组织抽样，或手术结束后切除组织的病理结果。放射标记的肿瘤标志物在癌细胞中具有优先的高摄取性，并为边缘隐匿性肿瘤的检测提供了独特的机会。背景：β射线在组织中的范围为几毫米。射线探测器，结合发射同位素是理想的检测隐匿肿瘤边缘，因为背景辐射不会干扰边缘的识别。之前我们已经开发了一种β探针和β相机探测器，并证明它们对β射线有选择性地敏感。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。过去曾有人提出Beta相机，但从未在临床上使用过，因为在设计灵敏的相机的同时，在手术中使用的电气安全存在问题。新颖性：在本次提交中，我们提出了一种基于使用固态光电倍增管（SSPMs）的新型beta相机设计。sspm是一种相对较新的光电传感器，其性能已被证明接近传统的pmt，但只需要在几十伏而不是pmt所需的千伏下工作。因此，使用SSPM将显著减轻术中使用β -相机的电气安全性。还将测试多个探测器模块，以提高对β射线的灵敏度，降低对伽马射线的灵敏度。初步研究：最近我们进行了一项涉及7名接受乳房肿瘤切除术的患者的初步研究。在手术过程中，用β探针检查手术腔和切除的组织。我们发现，β探针在手术腔中检测到的背景仅为12 18 cps，而5 mg产生的背景为3518 cps，表明伽马背景足够低，可以在小体积组织中检测到摄取。本研究的另一个结论是，需要一种成像设备，以便对手术腔进行更快速和准确的调查。我们已经建立了一个基于sspm的小尺寸测试版相机的原型，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5x5的新型陶瓷安装的sspm阵列来构建相机。我们将尝试用珀尔帖冷却器来降低SSPM阵列的温度。我们将优化相机的灵敏度，并进行表征，并与幽灵的检测极限测试。我们将测试符合辨别的新概念，以减少sspm的电子噪声，并提高相机对低能射线的灵敏度。我们将测试双探测器模块设计，以降低背景伽马灵敏度。我们将用一层SSPMs和两层不同的闪烁体来测试相机模块，这些闪烁体通过衰减时间常数和光开关电路来区分。研发及临床试验计划（二期）：选择最佳的探测器模块概念，构建beta相机进行临床试验。相机的电子设备、机械外壳和软件以及腹腔镜版本的相机将在第二阶段的第一部分进行制造和测试。这些相机的原型将被设计为通过手术器械的电气和环境标准，并将被送到CSA以获得UL安全证书。我们将向FDA提交新设备豁免（NDE）申请，以测试乳房和前列腺的相机。在第二阶段的后期，我们将与长期合作伙伴阿曼多·朱利亚诺博士一起进行临床试验，使用FDG检测乳房肿瘤切除术的边缘。本研究将招募30名患者，现有的β探针IRB方案将被修改为包括β相机。与博士一起。康奈尔大学的Bander和Tewari将在机器人前列腺切除术中测试腹腔镜β相机，并结合一种名为J591的单克隆抗体，对抗PSMA，该抗体被标记为Lu-177 （β发射器）。正在进行的IRB批准的Lu-177-J591 Mab研究将进行修改，包括腹腔镜下的β相机探查。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、敏感性和特异性。对外科医生的视觉检测的β相机的ROC分析将显示β相机的添加是否有助于提高边缘检测率。

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.