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1.发明授权Diagnostic method and apparatus for cervical squamous intraepithelial lesions in vitro and in vivo using fluorescence spectroscopy 失效使用荧光光谱法在体外和体内宫颈鳞状上皮内病变的诊断方法和装置公开(公告)号：US06258576B1
公开(公告)日：2001-07-10
申请号：US08666021
申请日：1996-06-19
IPC分类号： G01N2164
CPC分类号： G01N21/6486 , A61B5/0059 , A61B5/7264 , G01N21/645 , G01N2021/6419 , G01N2021/6484
摘要： The present invention involves the use of fluorescence spectroscopy in the diagnosis of cervical cancer and precancer. Using multiple illumination wavelengths, it is possible to (i) differentiate normal or inflamed tissue from squamous intraepithelial lesions (SILs) and (ii) to differentiate high grade SILs from non-high grade SILs. The detection may be performed in vitro or in vivo. Multivariate statistical analysis was employed to reduce the number of fluorescence excitation-emission wavelength pairs needed to re-develop algorithms that demonstrate a minimum decrease in classification accuracy. Fluorescence at excitation-emission wavelength pairs was used to redevelop and test screening and diagnostic algorithms that have a similar classification accuracy to those that employ fluorescence emission spectra at three excitation wavelengths. Both the full-parameter and reduced-parameter screening algorithms discriminate between SILs and non-SILs with a similar specificity and a substantially improved sensitivity relative to Pap smear screening and differentiate high grade SILs from non-high grade SILs.
摘要翻译： 本发明涉及在宫颈癌和癌前期诊断中使用荧光光谱。 使用多个照明波长，可以（i）区分正常或发炎的组织与鳞状上皮内病变（SIL）和（ii）区分高等级SIL和非高等级SILs。 检测可以在体外或体内进行。 采用多元统计分析方法，减少重新开发算法所需的荧光激发 - 发射波长对数，证明其分类精度最小。 激发 - 发射波长对的荧光被用来重建和测试筛选和诊断算法，它们具有与在三个激发波长下采用荧光发射光谱相似的分类精度。 全参数和简化参数筛选算法都区分SILs和非SILs，具有相似的特异性，并且相对于Pap涂片筛选具有显着提高的敏感性，并区分高等级SIL和非高级SILs。
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2.发明授权Near-infrared raman spectroscopy for in vitro and in vivo detection of cervical precancers 失效近红外拉曼光谱法用于宫颈预处理的体外和体内检测
公开(公告)号：US5991653A
公开(公告)日：1999-11-23
申请号：US667993
申请日：1996-06-19
CPC分类号： G01N21/6486 , A61B5/0059 , A61B5/0071 , A61B5/0075 , A61B5/0084 , A61B5/4331 , G01N21/65 , A61B5/0086 , A61B5/7264 , G01N2021/656
摘要： Early diagnosis of cervical precancer is an important clinical goal. Optical spectroscopy has been suggested as a new technique to overcome limitations of current clinical practice. Herein, NIR Raman spectroscopy is applied to the diagnosis of cervical precancers. Using algorithms based on empirically selected peak intensities, ratios of peak intensities and a combination of Principal Component Analysis (PCA) for data reduction and Fisher Discriminant Analysis (FDA), normal tissues, inflammation and metaplasia were distinguishable from low grade and high grade precancers. The primary contributors to the tissue spectra appear to be collagen, nucleic acids, phospholipids and glucose 1-phosphate. These results suggest that near infrared Raman spectroscopy can be used effectively for cervical precancer diagnosis.
摘要翻译： 子宫颈癌的早期诊断是一个重要的临床目标。 光谱学被认为是克服当前临床实践的局限性的新技术。 在这里，NIR拉曼光谱法被应用于子宫颈预处理的诊断。 使用基于经验选择的峰值强度的算法，峰值强度的比率和用于数据降低的主成分分析（PCA）和Fisher判别分析（FDA），正常组织，炎症和化生的组合与低等级和高级别的预处理可以区分开。 组织光谱的主要贡献者似乎是胶原，核酸，磷脂和葡萄糖1-磷酸。 这些结果表明，近红外拉曼光谱可以有效地用于子宫颈癌前期诊断。
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3.发明授权Spectroscopic method and apparatus for optically detecting abnormal mammalian epithelial tissue 失效用于光学检测异常哺乳动物上皮组织的光谱法和装置
公开(公告)号：US6095982A
公开(公告)日：2000-08-01
申请号：US988840
申请日：1997-12-11
CPC分类号： G01N21/6486 , A61B5/0071 , A61B5/0075 , A61B5/0084 , A61B5/4331 , A61B5/7264 , G01N21/65 , A61B5/0086 , G01N2021/656
摘要： A method and apparatus for detecting tissue abnormality, particularly precancerous cervical tissue, through fluorescence or Raman spectroscopy, or a combination of fluorescence and Raman spectroscopy. In vivo fluorescence measurements were followed by in vitro NIR Raman measurements on human cervical biopsies. Fluorescence spectra collected at 337, 380 and 460 nm excitation were used to develop a diagnostic method to differentiate between normal and dysplastic tissues. Using a fluorescence diagnostic method, a sensitivity and specificity of 80% and 67% were observed for differentiating squamous intraepithelial lesions (SILs) from all other tissues. In accordance with another aspect of the invention, using Raman scattering peaks observed at selected wavenumbers, SILs were separated from other tissues with a sensitivity and specificity of 88% and 100%. In addition, inflammation and metaplasia samples are correctly separated from the SILs.
摘要翻译： 一种用于通过荧光或拉曼光谱法或荧光和拉曼光谱的组合检测组织异常，特别是癌前期宫颈组织的方法和装置。 体内荧光测量之后是人体宫颈活检的体外NIR拉曼测量。 使用在337,380和460nm激发下收集的荧光光谱来开发用于区分正常组织和发育不良组织的诊断方法。 使用荧光诊断方法，从所有其他组织中鉴别出鳞状上皮内病变（SILs）的灵敏度和特异度为80％和67％。 根据本发明的另一方面，使用在选定波数处观察到的拉曼散射峰，将SIL与其他组织分离，灵敏度和特异性为88％和100％。 此外，炎症和化生样本正确地从SILs分离。
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4.发明授权Optical method and apparatus for the diagnosis of cervical precancers using raman and fluorescence spectroscopies 失效用于使用拉曼和荧光光谱诊断子宫颈预处理的光学方法和装置
公开(公告)号：US5697373A
公开(公告)日：1997-12-16
申请号：US403446
申请日：1995-03-14
CPC分类号： G01N21/6486 , A61B5/0071 , A61B5/0075 , A61B5/0084 , A61B5/4331 , A61B5/7264 , G01N21/65 , A61B5/0086 , G01N2021/656
摘要： A method and apparatus for detecting tissue abnormality, particularly precancerous cervical tissue, through fluorescence or Raman spectroscopy, or a combination of fluorescence and Raman spectroscopy. In vivo fluorescence measurements were followed by in vitro NIR Raman measurements on human cervical biopsies. Fluorescence spectra collected at 337, 380 and 460 nm excitation were used to develop a diagnostic method to differentiate between normal and dysplastic tissues. Using a fluorescence diagnostic method, a sensitivity and specificity of 80% and 67% were observed for differentiating squamous intraepithelial lesions (SILs) from all other tissues. In accordance with another aspect of the invention, using Raman scattering peaks observed at selected wavenumbers, SILs were separated from other tissues with a sensitivity and specificity of 88% and 100%. In addition, inflammation and metaplasia samples are correctly separated from the SILs.
摘要翻译： 一种用于通过荧光或拉曼光谱法或荧光和拉曼光谱的组合检测组织异常，特别是癌前期宫颈组织的方法和装置。 体内荧光测量之后是人体宫颈活检的体外NIR拉曼测量。 使用在337,380和460nm激发下收集的荧光光谱来开发用于区分正常组织和发育不良组织的诊断方法。 使用荧光诊断方法，从所有其他组织中鉴别出鳞状上皮内病变（SILs）的灵敏度和特异度为80％和67％。 根据本发明的另一方面，使用在选定波数处观察到的拉曼散射峰，将SIL与其他组织分离，灵敏度和特异性为88％和100％。 此外，炎症和化生样本正确地从SILs分离。
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公开(公告)号：US5842995A
公开(公告)日：1998-12-01
申请号：US672623
申请日：1996-06-28
CPC分类号： A61B5/444 , A61B5/0071 , A61B5/0075 , A61B5/0086 , A61B5/4331 , A61B5/445 , G01N21/65
摘要： An optical probe is disclosed which is suitable for rapidly measuring Raman spectra in vivo. The probe is designed to minimize interfering Raman and fluorescence signals generated within the probe itself. In addition, the probe design is compact, making it particularly suited for use in confined spaces such as body cavities. In one embodiment, the probe is employed to detect tissue abnormalities such as cervical cancers and precancers.
摘要翻译： 公开了适用于在体内快速测量拉曼光谱的光学探针。 探头设计用于最小化探针本身内产生的干扰拉曼和荧光信号。 此外，探头设计紧凑，使其特别适用于诸如体腔的密闭空间。 在一个实施方案中，探针用于检测组织异常，例如宫颈癌和胃癌。
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6.发明授权Method for probabilistically classifying tissue in vitro and in vivo using fluorescence spectroscopy 有权使用荧光光谱法在体外和体内概率分类组织的方法公开(公告)号：US07236815B2
公开(公告)日：2007-06-26
申请号：US10688152
申请日：2003-10-17
申请人： Rebecca Richards-Kortum , Nirmala Ramanujam , Anita Mahadevan-Jansen , Michele Follen , Urs Utzinger
发明人： Rebecca Richards-Kortum , Nirmala Ramanujam , Anita Mahadevan-Jansen , Michele Follen , Urs Utzinger
IPC分类号： A61B6/00
CPC分类号： G01N21/274 , A61B5/0071 , A61B5/0075 , A61B5/0084 , A61B5/4331 , A61B5/7264 , G01N21/6486 , G01N2021/6417 , G01N2021/6419 , G01N2021/6484 , G06F19/00 , Y10S436/813
摘要： Fluorescence spectral data acquired from tissues in vivo or in vitro is processed in accordance with a multivariate statistical method to achieve the ability to probabilistically classify tissue in a diagnostically useful manner, such as by histopathological classification. The apparatus includes a controllable illumination device for emitting electromagnetic radiation selected to cause tissue to produce a fluorescence intensity spectrum. Also included are an optical system for applying the plurality of radiation wavelengths to a tissue sample, and a fluorescence intensity spectrum detecting device for detecting an intensity of fluorescence spectra emitted by the sample as a result of illumination by the controllable illumination device. The system also include a data processor, connected to the detecting device, for analyzing detected fluorescence spectra to calculate a probability that the sample belongs in a particular classification. The data processor analyzes the detected fluorescence spectra using a multivariate statistical method. The five primary steps involved in the multivariate statistical method are (i) preprocessing of spectral data from each patient to account for inter-patient variation, (ii) partitioning of the preprocessed spectral data from all patients into calibration and prediction sets, (iii) dimension reduction of the preprocessed spectra in the calibration set using principal component analysis, (iv) selection of the diagnostically most useful principal components using a two-sided unpaired student's t-test and (v) development of an optimal classification scheme based on logistic discrimination using the diagnostically useful principal component scores of the calibration set as inputs.
摘要翻译： 根据多变量统计学方法处理从体内或体外组织获得的荧光光谱数据，以实现以诊断有用的方式（例如通过组织病理学分类）对组织进行概率分类的能力。 该装置包括用于发射被选择使得组织产生荧光强度光谱的电磁辐射的可控照明装置。 还包括用于将多个辐射波长施加到组织样本的光学系统和用于通过可控照明装置的照明来检测由样品发射的荧光光谱的强度的荧光强度光谱检测装置。 该系统还包括连接到检测装置的数据处理器，用于分析检测到的荧光光谱以计算样品属于特定分类的概率。 数据处理器使用多变量统计方法分析检测到的荧光光谱。 多变量统计方法涉及的五个主要步骤是（i）从每个患者预处理光谱数据以考虑患者间变异，（ii）将预处理的光谱数据从所有患者划分为校准和预测组，（iii） 使用主成分分析对校准集中的预处理光谱进行维数减少，（iv）使用双侧不配对的学生的t检验来选择诊断上最有用的主成分，以及（v）基于物流歧视开发最优分类方案 使用校准集的诊断上有用的主成分分数作为输入。
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公开(公告)号：US06697666B1
公开(公告)日：2004-02-24
申请号：US09519153
申请日：2000-03-06
IPC分类号： A61B500
CPC分类号： A61B5/0071 , A61B5/0075 , A61B5/0084 , A61B5/4331
摘要： A method and apparatus for characterizing tissue of epithelial lined viscus in vivo including, for example, the endocervical canal. The method comprises illuminating an interior surface of the viscus with electromagnetic radiation wavelengths to produce a plurality of fluorescence intensity spectra, detecting a plurality of emission wavelengths from the fluorescence intensity spectra, and characterizing the epithelial viscus tissue as a function of the emission wavelengths. The apparatus includes a light source of emitting a plurality of electromagnetic radiation wavelengths, an optical probe connected to the light source, the probe being adapted to apply the plurality of electromagnetic radiation wavelengths to an interior surface of epithelial viscus tissue under test and to gather fluorescence emitted from the tissue, a detector connected to the probe for detecting at least one fluorescence spectrum emitted from the tissue under test and a programmed computer connected to the detector for processing the at least one fluorescence spectrum according to a predetermined algorithm to characterize the tissue under test.
摘要翻译： 用于表征体内上皮内衬粘液的组织的方法和装置，包括例如子宫颈管。 该方法包括用电磁辐射波长照射粘液的内表面以产生多个荧光强度光谱，从荧光强度光谱检测多个发射波长，以及表征上皮粘液组织作为发射波长的函数。 该装置包括发射多个电磁辐射波长的光源，连接到光源的光学探针，该探针适于将多个电磁辐射波长施加到被测上皮粘液组织的内表面并收集荧光 从所述组织发射的检测器，连接到所述探针的检测器，用于检测从被检测组织发射的至少一个荧光光谱;以及编程计算机，连接到所述检测器，用于根据预定算法处理所述至少一个荧光光谱， 测试。
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8.发明授权公开(公告)号：US06241662B1
公开(公告)日：2001-06-05
申请号：US09175232
申请日：1998-10-20
申请人： Rebecca Richards-Kortum , Anant Agrawal , Costas Pitris , Urs Utzinger , Carrie Brookner , Michele Follen Mitchell
发明人： Rebecca Richards-Kortum , Anant Agrawal , Costas Pitris , Urs Utzinger , Carrie Brookner , Michele Follen Mitchell
IPC分类号： A61B500
CPC分类号： G01N33/52 , A61B5/0071 , A61B5/4331 , G01N1/30 , G01N2015/1488
摘要： A method for using acetic acid as a signal enhancing contrast agent during fluorescence spectroscopy of normal and neoplastic tissue, particularly epithelium. In one aspect, the invention includes a method of detecting tissue abnormality in a diagnostic tissue sample in a patient, comprising the steps of obtaining a first fluorescence intensity spectrum from the diagnostic tissue sample; thereafter, applying acetic acid to the diagnostic tissue sample in sufficient concentration to alter the response of such diagnostic tissue sample to electromagnetic radiation for at least an effective period of time; during the effective period of time, obtaining a second fluorescence intensity spectrum from the diagnostic tissue sample; determining a parameter indicative of a change between the first and second fluorescence emission intensity spectra; and analyzing the determined parameter to determine a probability that the diagnostic tissue sample is normal or abnormal.
摘要翻译： 在正常和肿瘤组织，特别是上皮的荧光光谱学过程中使用乙酸作为信号增强造影剂的方法。 一方面，本发明包括检测患者的诊断性组织样本中的组织异常的方法，包括以下步骤：从所述诊断组织样品获得第一荧光强度光谱; 此后，以足够的浓度将乙酸施用于诊断组织样品，以将这种诊断性组织样品的响应改变为电磁辐射至少有效的一段时间; 在有效时间段内，从诊断组织样品获得第二荧光强度光谱; 确定指示所述第一和第二荧光发射强度光谱之间的变化的参数; 并分析确定的参数以确定诊断组织样本正常或异常的概率。
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9.发明授权Optical probe for the detection of cervical neoplasia using fluorescence spectroscopy and apparatus incorporating same 失效用于使用荧光光谱检测子宫颈瘤形成的光学探针和结合其的装置
公开(公告)号：US5699795A
公开(公告)日：1997-12-23
申请号：US415356
申请日：1995-03-31
CPC分类号： A61B5/0084 , A61B5/0071 , A61B5/4331 , A61B5/0075
摘要： A probe, and an apparatus incorporating the probe, for detecting tissue abnormality, particularly precancerous cervical tissue, through fluorescence spectroscopy are disclosed. In vivo fluorescence excitation and detection can be accomplished easily and accurately using a probe whose tip conforms to the surface of the cervix. In addition, a higher number of fiber pairs provides more information and, therefore, more accurate diagnosis.
摘要翻译： 公开了一种用于通过荧光光谱法检测组织异常，特别是癌前期宫颈组织的探针和结合有探针的装置。 可以使用尖端符合子宫颈表面的探针，容易且准确地实现体内荧光激发和检测。 此外，更多数量的光纤对提供更多信息，因此提供更准确的诊断。
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10.发明授权Spectroscopic detection of cervical pre-cancer using radial basis function networks 失效使用径向基函数网络进行子宫颈癌的光谱检测
公开(公告)号：US6135965A
公开(公告)日：2000-10-24
申请号：US757116
申请日：1996-12-02
CPC分类号： A61B5/0084 , A61B5/0071 , A61B5/7267 , A61B5/0075 , G01J2003/2866 , Y10S128/925
摘要： An apparatus and methods for spectroscopic detection of tissue abnormality, particularly precancerous cervical tissue, using neural networks to analyze in vivo measurements of fluorescence spectra. The invention excites fluorescence intensity spectra in both normal and abnormal tissue. This fluorescence spectroscopy data is used to train a group (ensemble) of neural networks, preferably radial basis function (RBF) neural networks. Once trained, fluorescence spectroscopy data from unknown tissue samples is classified by the trained neural networks. This process is used to differentiate pre-cancers from normal tissues, and can also be used to differentiate high grade pre-cancers from low grade pre-cancers. One embodiment of the invention is able to distinguish pre-cancerous tissue from both normal squamous tissue (NS) and normal columnar (NC) tissue in a single-stage of analysis. The invention demonstrates significantly smaller variability in classification accuracy, resulting in more reliable classification, with superior sensitivity. Moreover, the single-stage embodiment of the invention simplifies the decision-making process as compared to a two-stage embodiment.
摘要翻译： 用于分光检测组织异常的装置和方法，特别是癌前宫颈组织，使用神经网络分析荧光光谱的体内测量。 本发明激发正常组织和异常组织中的荧光强度谱。 该荧光光谱数据用于训练神经网络的组（集合），优选径向基函数（RBF）神经网络。 一旦训练，来自未知组织样本的荧光光谱数据被训练的神经网络分类。 该过程用于区分癌前病变与正常组织，也可用于区分高级别前期癌症与低级别前期癌症。 本发明的一个实施方案能够在单阶段分析中区分癌前组织与正常鳞状组织（NS）和正常柱状（NC）组织。 本发明在分类精度方面显示出较小的可变性，导致更可靠的分类，具有优异的灵敏度。 此外，与两级实施例相比，本发明的单级实施例简化了决策过程。
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