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    • 专利摘要:
    The invention relates to a device and a method for cancer detection and screening, based on analysis of Volatile Organic Compounds emitted by certain cancerous tumors. The device and method provide high sensitivity and specificity analyses. The sample to be analysed may be e.g. blood or blood plasma. In one aspect, the invention is directed towards detection of or screening for gynaecological cancers, e.g. ovarian cancer. Particularly, the device comprises the following parts:a sample holder for a fluid or solid body sample;an air inlet which is reversed T shaped. Both tubes have the same diameter a detector tube comprising 4 x 4 - 16 x 4 sensors each with adjustable heating voltage individually estimated load resistors are connected to each sensor;an individual potentiometer connected to each sensor of the detector tube;an analogue to digital signal converter;four control cardsa computer-based program for the registration and statistical calculation of results; an electricity source;
    公开号:SE1630165A1
    申请号:SE1630165
    申请日:2016-06-27
    公开日:2017-12-28
    发明作者:Horvath György
    申请人:Voc Diagnostics Ab；
    IPC主号:
    专利说明:

    Olfactory detector for early diagnosis of ovarian cancer Technical field The present invention relates to a device and method for cancer detection and diagnosis, andin particular to such device and method for ovarian cancer detection and diagnosis. Moreover,the invention provides efficient cancer screening possibilities.
    Background Most cancers can be fatal if detected late. Cancers develop relatively slowly. From the firstcancer cell in the body until first symptoms, and clinical diagnosis, usually several yearselapse. Cancer diagnosed in the early stages has a much better chance of being cured. For thisreason, screening was introduced for several known forms of cancers. The methods availablemay not always be reliable, whereby only a few screening programs have been set up.
    When it comes to gynecological cancers, cervical screening contributes to early diagnosis ofcervical cancer and is working well and uterine and vulvar cancers produce symptoms earlyon. Only for ovarian cancer would there be a need for general screening.
    Ovarian cancer is the eighth most common cancer among women worldwide. In Swedenalone, ovarian cancer represents an annual incidence of just under 800 cases. Early discovered(ca. 30% of newly diagnosed ovarian cancers) belong to clinical stages l-ll. Patients with suchearly discovered cancers have relatively good survival prospects. ln Contrast, about 70% of allnewly diagnosed cases belong to stage lll-IV, which means that the survival rate for thepatients is low. The overall five-year survival rate is just below 50% (47-48% in Sweden).The latter fact means that more than 400 women die annually from ovarian cancer in Swedenalone.
    The survival rate for ovarian cancer patients during the last 10 years has not been improved atall. Biggest problem is the lack of a reliable screening method for early diagnosis. The knownand used diagnostic methods such as ultrasound, X-ray, CA-l25 analysis (as a tumor marker)all have too low sensitivity and specificity to be used for mass-screening, Due to the highmortality rates of ovarian cancer the disease is highly suitable for screening of healthypopulations,. A method with sufficient sensitivity and specificity could save hundreds of liveseach year in Sweden alone.
    The discovery of the specific Volatile Organic Compounds (VOCs) emitted by variouscancerous tumors resulted in trials with trained dogs (l), and later with "electronic noses", toevaluate said dogs and electronic noses as possible diagnostic methods for different cancers.The present inventor demonstrated in several studies that also ovarian cancer cells emitspecific VOCs (3). These VOCs can be detected in the patient's blood plasma (4, 5).
    The development of so-called nano sensors could possibly be used for the diagnosis of lungcancer through analysis of eXhaled air (2). Most substance found in circulating blood can befound also in the breath, albeit in lower concentrations. However, an analysis of exhaled airmay be disturbed by various undiagnosed chemical reactions of the oral cavity or pharynx,and/or extemal agents such as environmental agents and cosmetic preparations.
    Small tissue samples were examined by the inventor using a traditional "electronic nose",based on four TGS sensors. The results showed only very weak signals (6). Consequently, themethod using traditional electronic noses is not useful in practice for early diagnosis and screening. That is because the sensitivity of these traditionally built electronic noses in thecontext of cancer diagnosis is very low. As an example, these noses may not detect VOCs from plasma or blood. Hence, there is a need for improved devices and methods for cancerdiagnosis based on VOCs.
    Short Description of the Figures Figure l; shows a schematic representation of by the inventor developed "olfactory detector".Calculated volume of the detector tube is 36l.0 cm3. The inlet manifold with air filter markedby l/a, while the location of the sample holder and air inlet during the "sensor recovery time"is marked with l /b. The diameter, length and volume of the two air inlets may be the same.Air filter (2), sensors (3) and the fan (4) are in place. The rear tube with fan on may have thesame diameter, length and volume as two air inlets have.
    Figure 2; shows the sample holder, with room for e.g. blood plasma, with a plasma surfacearea of 6,6 cmz.
    Short Description of the Invention The invention relates to a device and a method for cancer detection and screening, based onanalysis of Volatile Organic Compounds emitted by certain cancerous cells. The device andmethod provide high sensitivity and specificity analyses. The sample to be analysed may bee. g. blood or blood plasma. In one aspect, the invention is directed towards detection of orscreening for gynaecological cancers, e. g. ovarian cancer. Particularly, the device comprisesthe following parts:l. Device for cancer detection comprisinga sample holder for a fluid or solid body sample, said sample holder having a cavitywith a surface of 6.6 cmz;an air inlet with a horizontal and a vertical shaft, diameter, length and volume of thetwo air inlets may be the same;an air filter fitted in at least one of the shafts, device may be provided a rear tube witha fan on, which rear tube may have the same diameter, length and volume as two airinlet shafts have;a detector tube having a volume of 36l.0 cm3, said detector tube comprising 4 X 4 - l6X 4 sensors, whereby the sensors comprise or consist of TGS 2602, TGS 2603, TGS2620, and TGS 2600, all in quadruplicate, each sensor having adjustable heatingvoltage and adjustable circuit voltage, and each with set sensor resistance interval, fordetecting volatile organic compounds from a sample;an individual potentiometer and load resistor with individually calculated resistance ,respectively, connected to each sensor of the detector tube;an analogue to digital signal converter connected to each sensor;a computer-based analysis program operably connected to each individual sensor ofthe detector tube, through the analog to digital signal converter, for registration ofsignals and analysis of results;and an electricity source.
    Detailed Description of the Invention The present invention provides a device for early cancer diagnosis or screening, e. g. forgynecological cancers, lung cancer, breast cancer, cancer of the urinary tract, prostate cancer,head and neck cancer. In one aspect, the cancer to be diagnosed or screened for is ovariancancer.
    The device comprises the following parts: a sample holder for a fluid or solid body sample, said sample holder having a cavitywith a surface of 6.6 cmz; an air inlet with a horizontal and a vertical shaft each with same volume; an air filter fitted in at least one of the shafts, device may be provided a rear tube witha fan on, which rear tube may have the same diameter, length and volume as two airinlet shafts have; a detector tube having a volume of 361.0 cm3, said detector tube comprising 4 X 4 - 16X 4 sensors, whereby the sensors comprise or consist of TGS 2602, TGS 2603, TGS2620, and TGS 2600, all in quadruplicate, each sensor having adjustable heatingvoltage, and adjustable circuit voltage, and each with set sensor resistance interval, fordetecting volatile organic compounds from a sample; an individual potentiometer connected to each sensor of the detector tube; a load resistor with individually calculated resistance connected to each sensor; an analogue to digital signal converter connected to each sensor through control cards;four control cards may be used of which each card is on the one side connected to eachsensor on the same side of the detector tube, and on the other side the cards areconnected to the analogue to digital converter. These cards Work by individualpotentiometers and load resistors, and have other resistors and amplifiers mounted onthe cards; a computer-based program which is used for the registration and statistical calculationof results. The computer is operably connected to each individual sensor of thedetector tube, through the analog to digital signal converter and control cards.
    The sample holder may have different shapes. It may have a round, oval or rectangularcircumference. The sample holder has a cavity, wherein the sample is placed. The sample tobe placed in the sample holder may be a body fluid, e.g. blood, blood plasma cyst fluid orurine, or a solid sample, e.g. a biopsy or apiece of a solid tumor.
    The size of the cavity of the sample holder is correlated to the air flow through the device, i.e.the detector tube dimensions, so that the VOCs may reach the detector tube in an efficientfashion. The choice of parameters in the respect of sample holder cavity surface and detectortube volume is not a trivial task. VOCs need to be accumulated in the detector tube in highenough concentration, for the invention to Work at all. To further improve evaporation ofVOCs, heating of the sample holder may be made use of. Another possibility is the use of afan to draw VOCs from the sample in the sample holder into the detector tube. The fan speedmay need to be adjusted depending on whether an air filter is used in the air inlet. Heating ofthe sample holder may also be combined with the use of a fan.
    The air inlet may be single (as defined by a horizontal and vertical shaft in combination), oralternatively several air inlets may be made use of, to facilitate an efficient analysis process.
    At least one inlet is provided With air filters, to ensure that the VOCs to be analyzed do indeedemanate from the sample. The air filter(s) may be simple activated coal filters. The personskilled in the art is Well equipped to find and choose adequate air filter(s).
    The detector tube may have various cross section geometries. Even though the term tube isused throughout herein for the sake of clarity, circular, elliptical or rectangular cross sectionsare all contemplated. The detector tube is advantageously made of a material minimizingturbulence in the tube. This is especially important if a fan is provided in the device. Thedetector tube may be made of stainless steel, and/or have an inner surface coated With e. g.Teflon.
    The detector tube has 4 X 4 - l6 X 4 sensors mounted through the detector tube Wall, With thesensing element facing inWards, towards the tube lumen. The number of sensors, and theindividual sensor types, depends on the type of cancer to be detected.
    In one aspect, the number of sensors is 4 X 4 - l2 X 4. In another aspect, the number ofsensors is 4 X 4 - 8 X 4 sensors.
    The designation “4 X 4” above should be construed as 4 sensors being placed on each side of arectangular cross section of the tube, along the length of the tube. l6 X 4 should similarly beconstrued as meaning l6 sensors placed on each side of a rectangular cross section of thetube. If a circular cross section is used, the sensors Would advantageously be evenlydistributed throughout the circumference and length of the tube. “4 X 4” should also beconstrued as meaning that 4 types of sensors are present in quadruplicate, Whereby the voltageused through each individual sensor of a quadruplicate is advantageously different. HoWever,it is very important that the sensors of the same type are calibrated to different heating voltageWithin the above range, so that the program can distinguish signals coming from differentVOC's.
    The output signal from the sensors is converted to a digital signal by a signal converter. Saidsignal converter may be connected to each sensor, through circuit cards. Circuit cardsadvantageously have integrated protection for over voltage. The potentiometers, the loadresistors for each individual sensor and amplifiers may be mounted on the circuit card.
    In one embodiment, a Measurement card by National Instruments, USB 6218 is used asanalogue to digital signal converter. Its 32 inputs, l6 bit may be connected to each sensorseparately via the circuit voltage. The digital signal may be fed into a computer via a USBconnection.
    An amplifier may be connected to one or more of the sensors. Amplifiers are used to amplifysignals and enables the signal strength does not drop through Wires that connect different partsof the apparatus.
    The sensing material in TGS gas sensors is metal oXide, most typically SnO2. When a metaloXide crystal such as SnO2 is heated at a certain high temperature in air, oXygen is adsorbedon the crystal surface With a negative charge. Then donor electrons in the crystal surface aretransferred to the adsorbed oXygen, resulting in leaving positive charges in a space chargelayer. Thus, surface potential is formed to serve as a potential barrier against electron flow.Inside the sensor, electric current floWs through the conjunction parts (grain boundary) ofSnO2 micro crystals. At grain boundaries, adsorbed oXygen forms a potential barrier Whichprevents carriers from moving freely. The electrical resistance of the sensor is attributed to this potential barrier. In the presence of a deoXidizing gas, the surface density of thenegatively charged oXygen decreases, so the barrier height in the grain boundary is reduced.The reduced barrier height decreases sensor resistance.
    The sensors used may be metal oXide sensors, which are suitable for detecting VOCs.According to one aspect, the sensors are SnO2 sensors. These sensors can detect botharomatic and other hydrocarbons with good results.
    The sensor requires two voltage inputs: heater voltage and circuit voltage. The heater voltageis applied to the integrated heater in order to maintain the sensing element at a specifictemperature which is optimal for sensing. Circuit voltage is applied to allow measurement ofvoltage across a load resistor which is connected in series with the sensor. DC voltage isrequired for the circuit voltage since the sensor has a polarity.
    According to the invention, a separate potentiometer is connected to each sensor to enableindividual selection of required temperature to maximize each sensor”s sensitivity. Circuitvoltage is applied to allow measurement of voltage across a load resistor, which is connectedin series with the sensor. Sensors' resistance to deoxidizing gas concentration (VOCs) islinear on a logarithmic scale within a range from several ppm to several thousand ppm.
    A common power supply circuit can be used for both the circuit voltage and the heatervoltage to fulfil the sensor's electrical requirements.
    As regards the electricity source for the whole device as such (absent computer) a unit thatconverts 220V AC power to two separate outputs of between 3 and 15 V DC may be used.
    The device according to the invention may consists of or comprise the sensors TGS 2602,TGS 2603, TGS 2620, and TGS 2600, all of which are present in quadruplicate. Use of thesefour Taguchi Gas Sensor (TGS) is the lowest number in a detector to detect ovarian cancer.The TGS 2602 has high sensitivity to low concentrations of odorous gases such as ammoniaand H2S generated from waste materials. The sensor also has high sensitivity to lowconcentrations of VOCs such as toluene, an aromatic hydrocarbon.
    The TGS 2603 has high sensitivity to low concentrations of odorous gases such as amine-series such as Trimethyl-amin and sulphurous such as Methyl mercaptan odors. Both arepresent in human metabolism, often derived from dead cells.
    The TGS 2620 has high sensitivity to the vapours of organic solvents as well as other volatilevapours such as hydrocarbons.
    The TGS 2600 has high sensitivity to low concentrations of gaseous air contan1inants such ashydrogen and carbon monoXide, methane and alcohol, occurring in human metabolism Alternatively, the device according to the invention may consists of or comprises the sensorsTGS 2602, TGS 2603, TGS 2620, TGS 26l l-E00, TGS 2600, and TGS 2444, all of which arepresent in quadruplicate. Completion of the above mentioned four sensors with TGS26l l-EOO and TGS2444 improves the sensitivity of the device for the diagnosis of ovarian cancer.TGS26l l-E00 uses filter material in its housing which eliminates the influence of interferencegases such as alcohol, resulting in highly selective response to methane gas. TGS 2444displays good selectivity to ammonia. Both substance present low concentrations in thecancerous tumors, usually originates from dead cells As yet an alternative, the device according to the invention may consists of or comprises thesensors TGS 2602, TGS 2603, TGS 2620, TGS 26l l-E00, TGS 2600, TGS 26l l-C00, TGS2444, and TGS 26l0, all of which are present in quadruplicate. TGS26l l-C00 detects thehydrocarbons that TGS26l l-EOO but their selectivity is different since it has no built-in filtermaterials, which facilitates differentiation between different VOCs. TGS26l0 has high sensitivity for various hydrocarbons. With the addition of the two latter sensors, the device iscapable of detecting VOCs not only ovarian cancer but also from other gynecological cancers.
    In accordance with the invention, the heating voltage to each sensor is regulated between 2.5- 5.5 V. Experiences from the inventor's investigations show that one can get the best signalquality for VOC's en1itted from the plasma of ovarian cancer patients if the heating voltage isbetween those limits. However, it is necessary to fine-tune the voltage of each individualsensor to detect VOCs from ovarian and other gynecological cancers from blood plasma.(Table 4).
    The correct selection of load resistance for each individual (or group of) sensor enables thesensor to provide uniform characteristics The inventor designed a well functioning system to use for the selection of load resistors.Calculating the desired resistance is achieved by use forms: sensor resistance (in ohms)divided by resistance of the load resistor (in ohms) must be = / <0.5. The method used for thefirst time in this invention. (Table l). In the calculations for detection of ovarian cancer, theminimum values of the sensors” internal resistance have been used.
    Table lSensors Range of sensor Range of loadresistance possible resistancepossibleTGS 2602 10-100 kOhm 20-200 kOhmTGS 2603 20- 200 kOhm 40-400 kOhmTGS 2620 1-5 kOhm 2-10 kOhmTGS 2611-E00 0,68- 6,8 kOhm 1,5-14 kOhmTGS 2600 13,3- 133 kOhm 27-270 kOhmTGS 2611 -C00 0,68- 6,8 kOhm 1,5-14 kOhmTGS 2444 3,6-36,3kOhm 8-75 kOhmTGS 2610 0,68- 6,8 kOhm 1,5-14 kOhm The device and method according to the invention is suitable for detecting any oftriethylamine, pyridine, toluene, p-Xylene, E,Z-8,l0-dodecadien-l-ol, trifluoromethylbenzene,heXadecanoic acid, docosane, 3-methylhexadecane, tetracosane, and heptadecane, asevidenced by comparative gas chromatography and mass spectrometry (GC-MS) studies. Theabove substances have been shown to be markers of cancer, e. g. gynaecological cancers.
    The results of GC-MS studies showed significant differences, namely 10 out of ll differentcompounds (VOCs) present in cancer cells "headspace" are either only in minimal amounts, or not at all in control tissues. The exception is E,Z-8,l0-dodecadien-l-ol, Which is apheromone that healthy tissues emit more of than cancer tissues do. Whereas individualcompounds of the above list have been shown to be markers of cancer, the panel disclosed hasbeen shown to give an especially high statistical significance for ovarian cancer, as comparedwith control tissues.
    In one embodiment of the invention, the set time for sample analysis is divided into 5separate, subsequent parts, for improved statistical significance during statistical analysis.The breakdown into 5 separate, subsequent parts of the set time for sample analysis is basedon the sensors' signal recording and sensors recovery time, i.e. rising and falling of the signalcurve during the analysis. Calculating statistics in this way may further improve thesensitivity and specificity of the device. For statistical analysis, five shorter intervals wereused to achieve more accurate calculation possibilities than analyzing the entire signal for 600sec.
    Computer software is used for the statistical analyses. In Excel changes in the sensor circuitvoltage are registered, in volts, ten times per second. The registrations may be 6000 individualvalues per sensor, for each analysis. These values are used in statistical calculations.
    Upon completion of the statistical analysis a value between 0 and lmay be obtained. Valuesabove 0.5 indicate cancer.
    The invention shall now be described with reference to a specific embodiment, which shallhowever not be seen as limiting the scope invention claimed in any way whatsoever.
    Detailed description of an embodimentThe apparatus consists of 4 different parts.
    A detector tube is provided as a stainless steel tube with a square cross section (Figure l).Eight holes are drilled on each side. The size of each hole corresponds to the sensor diameter,and a small rubber ring ensures air tightness between each sensor and the detector tube. A fewmillimeters of the sensor top for air inlet is located inside of the tube for better uptake ofimportant gases (VOCs). Corresponding sensors are placed in corresponding, numberedlocations on each side of the square cross section tube, 4 X 8 sensors for a total of 32 sensors(Table 3). The detector tube is extended forward with a upside down "T" shaped tube (Figurel)The two pipes of the entire air inlet (vertical and horizontal; T-shaped) have the samediameter and length .
    The vertical part of the air inlet is through an air filter with activated coal (Sundström,Sweden) to minimize or elin1inate the influence of examination room contaminants on signalsduring the first 360 seconds i.e. sensors active time of measurement. Airflow from the verticalpart goes over the horizontal part. In the latter section the sample holder is located, so the tubediameter of the air intake is cut in half. This causes the air to move faster over the sample andincreases the concentration of VOCs in the detector tube. The detector tube with sensors has aconsiderably larger diameter than the air inlet, which leads to a slower flow of air, thus givingbetter ability for the sensors to detect entrapped VOCs. The horizontal tube is provided forplacement of the sample holder (Figure 2). After removal of the sample holder with thesample (after the 360th second of the total of 600 seconds analysis time), the air goes throughthe horizontal tube, with the flow of air having a higher speeds. A system with two separateair inlets shortens and improves the sensor recovery time. Using a horizontal tube without theresistance of an air filter mounted on the vertical tube improves the second part of the analysisby increasing the airflow through the detector tube. This means that the sensors are cleared faster and regain original resistance more rapidly before the next analysis, whereby the unitbecomes more efficient. A similar horizontal tube eXtends the square head tube alsobackward. At the end of the tube a fan is fitted (Micro Nell Ltd., Switzerland) to draw airthrough the detector tube provided with sensors. This rear tube with fan on may have the samediameter, length and volume as two air inlets have. The fan has a separate power supply. Theused voltage for the fan was chosen based on the air resistance from the air filter used.
    The sample holder has been custom made to fit exactly in the horizontal air inlet part, and hasbeen designed to ensure that a sufficiently large surface of e. g. blood plasma (or other liquidsample) can form, for sufficient emission of VOCs (Figure 2). The sample holder dimensionsare: 60mm in length, llmm in width and 8mm in depth. The surface of the liquid samplesurface is 6,6cm2 .
    Sensor selection was based on results from previous investigations carried out with gaschromatography. The results showed that predominantly hydrocarbons dominate the VOC ofovarian cancer (Table 2). Aromatic hydrocarbons and other hydrocarbons may be derivedfrom dead cells in the tumor mass. Up to 90% of the cancer tumor mass may consist of deador dying cells. Thus, these substances are present in much higher concentration in the blood ofcancer patients than they do in blood of healthy people. The choice of sensors was TGS metaloXide sensors (SnO2) from Figaro Engineering Inc., Japan. These sensors can detect botharomatic and other hydrocarbons with good results. These sensors are relatively ineXpensiveand have a long lifetime.
    Table 2 1, Triethylamine 2,Pyridine 3,Toluene 4, p-Xylene 5, E,Z-8,10-Dodecadien-1-ol *6, Trifluoromethylbenzene 7, Hexadecanoic acid 8, Docosane 9, 3-Methylhexadecane10,Tetracosane11,Heptadecane Eight different sensors were built into each side of the detector tube, sensor positions called l-8 (Table 3). In each position an identical sensor is placed in each detector tube wall, giving atotal of 32 sensors in the sensor tube (Figure l). Since each sensor has a different heatingvoltage thus working at a different temperature from its peers, the signals from each sensor ina sensor set quadruple differs. The temperature differences enable four identical sensors todetect far more substances than four identical sensors working at the same temperature may.
    Table 3 Position/sensor nameTGS2602TGS2603TGS2620TGS2611{00TGS2600TGS2611-C00TGS2444TGS2610 w w w w w _y w m_p h w N H For detection of ovarian carcinoma sensors No. l, 2, 3 and 5 are of great importance but alsosensors No 4 and 7 provide important contributions to the diagnosis. The other two sensorsare potentially important in the diagnosis of other carcinomas such as gynecological cancers,except of ovarian carcinomas.
    Each group of eight sensors placed on the same side of the detector tube is controlled by aseparate circuit card, making a total of four identical cards used in the device. On each circuitcard is mounted a potentiometer to the heater voltage circuit of each sensor, to be able toindividually set the optimal temperature for maximum sensor sensitivity. It was found that fordetection of VOCs from ovarian cancer a voltage between 2,5V and 5,5V is required. Foreach group of four identical sensors, the heater voltage for each individual sensor is set so thatthe temperature differences between the 4 (or more) identical sensors (one on each side of thedetector tube) enables the detection of wide range of gases (Table 4).
    Table 4. The digits represent voltage. H = heating circuit; S = sensor circuit. A, B, C and D,respectively, represent the four different sides of the sensor tube with rectangular crosssection.
    TGS TGS TGS TGS TGS TGS TGS TGS2602 2603 2620 2611- 2620 2611- 2444 2610E00 C00H 17 40 10 13 10 10 13 45A S 49 49 48 49 49 49 49 48H 40 44 15 16 45 45 10 40B S 49 49 48 49 49 49 49 49H 45 47 40 19 15 10 48 15C S 48 49 49 49 49 49 49 49H 48 10 45 42 10 18 46 10D S 49 49 48 49 49 49 49 48 Signal output is obtained through the load resistors. Various load resistances were testedwithin the range of Table 2, to determine which load resistances provide the best signalquality for VOCs from plasma of patients with ovarian cancer. As to the sensor resistances, itwas found that the minimum values of sensor resistance are the most suitable for ovariancancer detection. For diagnosis of other cancers, other values of sensor resistance may bemore useful. The integrated resistors are shown below (Table 5).
    Table 5 Position/sensor name Load resistors1 TGS 2602 20 kOhm2, TGS 2603 30 kOhm3, TGS 2620 2 kOhm4, TGS 2611-E00 10 kOhm5, TGS 2600 24 kOhm6, TGS 2611 -C00 2 kOhm7, TGS 2444 20 kOhm8, TGS 2610 2 kOhm The analogue to digital converter used was a Measurement card by National Instruments,USB 6218 with 32 inputs, l6 bit, which was connected to each sensor separately via thecontrol cards” circuit voltage. The digital signal was fed to a computer through a USB port A computer-based analysis unit part of the device for cancer detection. The computer-basedanalyze unit comprises software and hardware. Measurement software has been developed inthe development environment Labview. The purpose of the measurement software is tocollect and present data from the gas sensors and to store the information in graphical and textform (in Excel). The measurement software is running on a computer that has Windows 7.The measurement program is flexible and modular. The measurement software collects l0measured data signals per second. The files are then statistically analyzed of the computerstats program.
    For the statistical analysis, the signals are divided in 5 separate time intervals. These intervalsare important characteristics of the invention. By comparing statistically the relatively shorttime intervals of the signals, an opportunity for a more sensitive discrimination of signalsarises. The following time periods were chosen and were the basis for statistical analyses: tl =0-20sec; t2 = 20-l20sec; t3 = l20-200sec; t4 = 200-360sec; t5 = 360-500sec. The programcalculates the maximum-minimum / minimum values in Volt for each time interval of eachsignal from each individual sensor. Thereupon, the data is analyzed with logistic regression using the lasso method and cross-validation. Final results are displayed as a value between 0and l.Values above 0.5 represent VOCs from ovarian cancer.
    Power supply to the device absent the computer is by way of a UNI-T DC power supply (0-32V; 0-3A). Two separate input voltages are taken from the power supply: the heating voltageis 9.0V while the sensor circuit voltage is 5.0V.
    Use of a device according to the embodiment described above The device for cancer detection needs to be "conditioned" for one hour before use, for thesensors to reach the proper operating temperature. The temperature in the examination roomneeds to be between 20-21 degrees and relative humidity (RH) between 25-30% for optimumresults. In the sample holder's cavity, 0, 8-lml of plasma is placed. It is important that theplasma covers the bottom of the cavity evenly, to ensure a large and equal surface area in allmeasurements. The analysis process is started via the measurement program Labview, on thecomputer, but without the fan on. The program runs for 20 sec for establishing a "base line"for each sensor signal, whereupon the sample holder with plasma in its cavity is inserted intothe detector tube. The computer records the signals for a further 20 sec without the fan on.After 2 X 20 sec of measurements, the fan is switched on. Registration is made of theascending signal curves, for 360 second (including the 2 X 20 sec initial baselinemeasurements). Thereupon, the sample holder is removed from the detector tube and theprogram runs up to a total of 600 sec. The latter period is the "sensor recovery" time, i.e.signals from individual sensors decrease and return to the "base line" again. New tests runscan be made immediately after the signal has reached base line.
    The last test on l50 plasma samples from ovarian cancer patients and healthy controls showed92% sensitivity and 92% specificity. This is a result that no currently available medicalanalysis equipment or method can even come close to.
    Blood plasma from l2 endometrial, 8 vulva, and l0 cervical cancer (all gynecologicalcancers) patients was analyzed, and compared with blood plasma from 65 ovarian cancerpatients. The device was able to distinguish, at close to 100%, ovarian cancers from theothers.
    权利要求:
    Claims (26)
    [1] 1. Device for cancer detection comprising a sample holder for a fluid or solid body sample, said sample holder having a cavityWith a surface of 6.6 cmz (Figure 2); an air inlet With a horizontal and a vertical shaft, both With the same volume ; an air filter fitted in at least one of the shafts (Figure 1); a detector tube having a volume of 361.0 cm3, said detector tube comprising 4 X 4 - 16X 4 sensors, Whereby the sensors comprise or consist of TGS 2602, TGS 2603, TGS2620, and TGS 2600, all in quadruplicate, each sensor having adjustable heatingvoltage and adjustable circuit voltage, and each With a set sensor resistance interval,for detecting volatile organic compounds from a sample; an individual potentiometer and load resistor With individually calculated resistance,respectively, connected to each sensor of the detector tube; an analogue to digital signal converter connected to each sensor; a computer-based analysis program operably connected to each individual sensor ofthe detector tube, through the analog to digital signal converter, for registration ofsignals and analysis of results; and an electricity source.
    [2] 2. Device according to claim 1, Wherein the sample holder is heated to facilitate transportof the volatile organic compounds from the sample holder to the detector tube
    [3] 3. Device according to claim 1 or claim 2, Wherein a fan draWs the volatile organiccompounds from the sample holder into the detector tube.
    [4] 4. Device according to any of the preceding claims, Wherein the detector tube has acircular, elliptical, or rectangular cross section.
    [5] 5. Device according to any of the preceding claims, Wherein the detector tube comprises4 X 4 - 12 X 4 sensors.
    [6] 6. Device according to any of the preceding claims, Wherein the detector tube comprises4 X 4 - 8 X 4 sensors.
    [7] 7. Device according to any of the preceding claims, Wherein the sensors are metal oXidesensors.
    [8] 8. Device according to any of the preceding claims, Wherein a group of sensors areconnected to and controlled by a common circuit card, and the common circuit card is connected to the analogue to digital signal converter.
    [9] 9. Device according to any of the preceding claims, Wherein an amplifier is connected toone or more sensor(s), and to one or more circuit card(s).
    [10] 10. Device according to claim 7, Wherein the sensors are SnOZ sensors.
    [11] 11. Device according to any of the preceding claims, Wherein the detector tube consists ofor comprises the sensors TGS 2602, TGS 2603, TGS 2620, TGS 2611-E00, TGS2600, and TGS 2444, all of Which are present in quadruplicate.
    [12] 12. Device according to any of the preceding claims, Wherein the detector tube consists ofor comprises the sensors TGS 2602, TGS 2603, TGS 2620, TGS 2611-E00, TGS2600, TGS 2611-C00, TGS 2444, and TGS 2610, all of Which are present inquadruplicate.
    [13] 13. Device according to any of the preceding claims, Wherein the heating voltage to eachsensor is regulated between 2.5 - 5.5 V.
    [14] 14. Device according to any of the preceding claims, Wherein the resistance ratio betweenthe sensor resistor and the load resistor is equal to or less than 0.5.
    [15] 15. Device according to any of the preceding claims, Wherein the device has beenprovided With an additional air inlet.
    [16] 16. Device according to any of the preceding claims, Wherein an air filter is located in theair in1et(s).
    [17] 17. Device according to any of the preceding claims, Wherein the air filter is an activatedcoal filter.
    [18] 18. Device according to any of the preceding claims, Which is suitable for detecting any oftriethylamine, pyridine, toluene, p-Xylene, E,Z-8,10-dodecadien-1-ol,trifluoromethylbenzene, heXadecanoic acid, docosane, 3-methylheXadecane,tetracosane, and heptadecane.
    [19] 19. Use of a device according to any of the preceding claims for detection or screening ofgynaecological cancers, lung cancer, breast cancer, cancer of the urinary tract, prostatecancer, head and neck cancer.
    [20] 20. Use according to claim 19, Wherein the gynaecological cancer is ovarian cancer.
    [21] 21. Use of a device according to any of the preceding claims, Wherein the resistance ofthe individual load resistors is chosen to be as 1oW as possible in relation to theinternal resistance of each sensor.
    [22] 22. Method of detecting or screening for cancer in vitro, comprising providing a samplein the forrn of blood, blood plasma, cyst fluid, urine, or tumor tissue, using the deviceaccording to any of claims 1 - 21 to analyse said sample during a set time, andstatistically analysing the sensor values.
    [23] 23. Method according to claim 22, Wherein during the set time for sample analysis isdivided into 5 separate parts, for improved statistical significance during statisticalanalysis.
    [24] 24. Method according to claim 23, Wherein the cancer is a gynaecological cancers, lungcancer, breast cancer, cancer of the urinary tract, prostate cancer, or head and neckcancer.
    [25] 25. Method according to clairn 24, Wherein the gynaecological cancer is ovarian cancer.
    [26] 26. Method according to any of claims 22 - 25, Wherein the presence in a sample of any oftriethylamine, pyridine, toluene, p-Xylene, E,Z-8,10-dodecadien-1-ol,trifluoromethylbenzene, heXadecanoic acid, docosane, 3-rnethy1heXadecane,tetracosane, and heptadecane is analysed.
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    同族专利:
    公开号 | 公开日
    DK3474736T3|2022-02-28|
    SE540171C2|2018-04-17|
    EP3474736B1|2021-12-01|
    EP3474736A4|2020-02-12|
    EP3474736A1|2019-05-01|
    US20190317073A1|2019-10-17|
    WO2018004414A1|2018-01-04|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US6631333B1|1999-05-10|2003-10-07|California Institute Of Technology|Methods for remote characterization of an odor|
    WO2001013087A2|1999-08-18|2001-02-22|California Institute Of Technology|Sensors and sensor arrays of conducting and insulating composites and methods of use thereof|
    ES2173048B1|2001-03-26|2003-12-16|Univ Barcelona|INSTRUMENT AND METHOD FOR ANALYSIS, IDENTIFICATION AND QUANTIFICATION OF GASES OR LIQUIDS.|
    US9664661B2|2014-05-08|2017-05-30|Active-Semi, Inc.|Olfactory application controller integrated circuit|
    WO2016036950A1|2014-09-05|2016-03-10|The Trustees Of The University Of Pennsylvania|Volatile organic compound-based diagnostic systems and methods|
    CN104634776B|2015-02-15|2017-12-19|河北百强医用设备制造有限公司|The detection method and its sensor special array of a kind of gas|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    SE1630165A|SE540171C2|2016-06-27|2016-06-27|Olfactory detector for early diagnosis of ovarian cancer|SE1630165A| SE540171C2|2016-06-27|2016-06-27|Olfactory detector for early diagnosis of ovarian cancer|
    DK17820633.0T| DK3474736T3|2016-06-27|2017-06-26|OLFACTORY DETECTOR FOR EARLY DIAGNOSIS OF OVARIAN CANCER|
    PCT/SE2017/000029| WO2018004414A1|2016-06-27|2017-06-26|Olfactory detector for early diagnosis of ovarian cancer|
    US16/313,465| US11275077B2|2016-06-27|2017-06-26|Olfactory detector for early diagnosis of ovarian cancer|
    EP17820633.0A| EP3474736B1|2016-06-27|2017-06-26|Olfactory detector for early diagnosis of ovarian cancer|
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