Beta Camera and Laparoscopic Probe for Surgical Cancer Removal.

描述(申请人提供)：癌症唯一确定的治愈方法是通过手术完全切除恶性组织。彻底切除将防止肿瘤再次生长，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，外科医生依靠对手术腔的肉眼检查和对边缘的随机组织采样，或者对切除的组织进行病理检查，这些结果通常是在手术结束后准备好的。放射性标记的肿瘤标志物在癌细胞中具有较高的摄取率，为发现边缘的隐匿性肿瘤提供了独特的机会。背景：贝塔射线在组织中的射程为几毫米。由于背景辐射不会干扰边缘的识别，贝塔射线探测器与贝塔发射的同位素相结合是检测边缘隐匿性肿瘤的理想选择。此前，我们已经开发了一种β探测器和β相机探测器，并证明了它们对贝塔射线具有选择性的敏感性。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相机过去曾被提出，但从未用于临床，因为在设计一种在手术期间使用时既灵敏又电气安全的相机时存在问题。新颖性：在这份意见书中，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，其性能已被证明接近于传统的PMT，但只需要在数十伏的电压下工作，而不是PMT所需的千伏。因此，SSPM的使用将显著减轻术中使用Beta相机的电气安全方面的问题。还将测试多个探测器模块，以提高对贝塔的灵敏度，降低对伽马射线的灵敏度。初步研究：最近，我们进行了一项初步研究，涉及7名接受肿瘤切除术的患者。在手术过程中，用贝塔探头测量了手术腔和切除的组织。我们发现，贝塔探头在外科手术腔中检测到的本底只有12 18cps，而5 mg的本底产生了3518 cps，这表明伽马本底足够低，可以检测到少量组织的摄取。这项研究的另一个结论是，需要一种成像设备来更快、更准确地检查手术腔。我们已经在小范围内构建了基于SSPM的Beta相机的原型，并论证了其可行性。研究计划(第一阶段)：我们将用一片塑料闪烁体和一组5x5的新型陶瓷安装SSPM来制造相机。我们将试验使用Peltier冷却器来降低SSPM阵列的温度。我们将优化相机的灵敏度，并使用模体进行表征和检测极限测试。我们将测试符合鉴别的新概念，以降低SSPM的电子噪声，并提高相机对低能量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。我们将使用一层SSPM和两层不同的闪烁体来测试相机的模块，这些闪烁体由衰减时间常数和磷光开关电路来区分。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来构建用于临床试验的Beta相机。摄像机的电子设备、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制造和测试。这些摄像机的原型将设计为通过手术器械的电气和环境标准，并将被送往CSA以获得UL安全认证。我们将向FDA提交新设备豁免(NDE)申请，以测试乳房和前列腺中的摄像头。在第二阶段的后期，我们将与我们的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检测肿块切除术的边缘。30名患者将参加这项研究，现有的贝塔探头IRB方案将被修改为包括贝塔相机。我们将与康奈尔大学的班德和特瓦里博士一起，在机器人前列腺切除术中测试腹腔镜贝塔相机，并结合一种名为J591的单抗，对抗标记有Lu-177(贝塔发射体)的PSMA。IRB批准的Lu-177-J591单抗正在进行的研究将被修改，以包括腹腔镜下的Beta相机探查。统计分析：这两项研究都旨在确定Beta相机在检测切除边缘肿瘤方面的有效性、敏感性和特异性。对带有外科医生视觉检测的Beta摄像头的ROC分析将表明，添加Beta摄像头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.