Clinical Study ISSN: 2435-1210 Volume 6
Blood-Test Based Targeted Visualization Enables Early Detection of Premalignant
and Malignant Tumors in Asymptomatic Individuals
Department of Oral and Maxillofacial Surgery,
University Medical Center Hamburg-Eppendorf
(UKE), Martinistr. 52, 20246 Hamburg, Germany,
Received: 02 May 2022
Accepted: 16 May 2022
Published: 20 May 2022
J Short Name: JCMI
©2022 Simon Burg, This is an open access article distrib-
uted under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and
build upon your work non-commercially.
Simon Burg, Blood-Test Based Targeted Visualization
Enables Early Detection of Premalignant and Malignant
Tumors in Asymptomatic Individuals.
J Clin Med Img.
2022; V6(9): 1-12
Journal of Clinical and
Simon Burg1*, Audrey Laure Céline Grust1,2, Oliver Feyen3, Katja Failing4, Gamal-André Banat5, Johannes F Coy3, Martin
Grimm6, Martin Gosau1 and Ralf Smeets1,2
1Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf (UKE), Martinistr. 52, 20246 Hamburg,
2Department of Oral and Maxillofacial Surgery, Division of “Regenerative Orofacial Medicine”, University Medical Center Ham-
burg-Eppendorf (UKE), Martinistr. 52, 20246 Hamburg, Germany
3Zyagnum AG, Graefenhaeuser Str. 26, 64293 Darmstadt, Germany
4Precura Center, Heidelberger Str. 44, 64285 Darmstadt, Germany
5Internal Medicine, Hematology and Oncology, Chaumontplatz 1, 61231 Bad Nauheim, Germany
6Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstr. 2-8, 72076, Tuebingen, Germany
Apo10; TKTL1; Blood-test; Early cancer
Imaging is a powerful tool for the early detection of cancer and the
concomitant increase of patient survival time. The low incidence
of cancer in asymptomatic individuals hampers the use of imaging
techniques, as the vast majority of imaging results show the ab-
sence of cancer. In a prospective, non-interventional study, 5.114
asymptomatic individuals between 50 to 70 years of age who had
no personal history of cancer within the last eight years were ana-
lyzed with the so called PanTum Detect blood test, which is based
on phagocytosis and elimination of tumor cells by CD14 and CD16
positive macrophages. A ow cytometry analysis of blood samples
was used to detect macrophages with intracellularly tumor cell
derived epitopes of biomarkers DNaseX/Apo10 and TKTL1. The
increased presence of these biomarkers in macrophages allowed
the identication of asymptomatic individuals eligible for further
imaging. On subsequent imaging, a high proportion of this pre-se-
lected subgroup showed abnormal tissue structures which are in-
dicative of early cancer stages or pre-malignant structures at high
risk for malignancy development. Therefore, the PanTum Detect
blood test enables the identication of asymptomatic individuals
eligible for imaging.
The implementation of regular screening regimen that is based on
the detection of premalignant cells resulted in a dramatic 60-70%
reduction in the incidence of cervical cancer [1, 2]. According to
data from 2014, without any screening measures, about 3-5% of
women in Germany develop cervical cancer, whereas this is the
case in less than 1% of women with early detection measures .
Early detection of tissue alterations that are not yet malignant but
are at high risk for malignancy provides the possibility of remo-
ving or monitoring them until removal is indicated, potentially
preventing the onset of cancer and signicantly reducing mortality
Regular screening measures have been established in Germany
also for tumors of the colon, skin, breast, and prostate, with which
about 45% of new cancer cases per year can be detected - assu-
ming widespread and consistent adherence [6, 7]. Conversely, this
means that about 55% of new cancer cases per year cannot be de-
Volume 6 Issue 9-2022 Clinical Study
tected with the currently established screening programs. Further
developments in cancer screening should therefore aim to extend
the success of cervical cancer screening to other tumor types, thus
closing this «screening gap».
Our department of Oral and Maxillofacial Surgery, at the Univer-
sity Medical Center Hamburg-Eppendorf (UKE), is specialized in
surgery of tumors of the oral cavity, tongue and neck, which are
not yet covered by any early detection programs. However, early
detection programs would be valuable for these tumors in particu-
lar, as they are often characterized by aggressive growth and tis-
sue-preserving surgery, therefore carrying a high risk of recurrence
. In addition to the psychological burden of the life-threatening
disease, patients often suer from the consequences of the ope-
ration, which can lead to facial disgurement and restrictions in
eating and speaking. Our department is therefore particularly in-
terested in early detection measures that would ideally allow the
detection of oral cavity carcinomas at such an early stage that tis-
sue-sparing surgery can still be performed.
In order to close the aforementioned «screening gap», an early
detection procedure would be required that fullls the following
1. detection of many dierent tumor entities, since for the majority
of tumor entities no established screening measures are available
so far [6, 7].
2. detection of pre-malignant tumors in addition to malignant tu-
mors - similar to the screening for cervical carcinoma. However,
since the incidence of premalignant tumors increases with age [9-
12], the procedure should ideally only detect tumors with a high
risk of malignant transformation or at the onset of malignant trans-
3. applicable in the eld of health screening to detect tumors in
premalignant or early malignant stages prior to the onset of symp-
toms. This requires the detection of as many malignant and pre-
malignant tumors as possible with a high risk of transition to mali-
gnancy without generating many false positive results at the same
The use of imaging techniques such as ultrasound, Magnetic Re-
sonance Imaging (MRI), Computed Tomography (CT), or positron
emission tomography with the glucose analog 2-[18F] uoro-2-
deoxy-D-glucose (FDG-PET) in combination with computed to-
mography (FDG-PET/CT) already allows the detection of prema-
lignant and malignant tumors. They have proven to be powerful
tools for localizing and evaluating a wide variety of tumors and are
widely accepted in clinical practice as the gold standard for tumor
detection and localization in cases with sucient tumor suspicion
[13-15]. Their use in health screening, however, does not seem
justied due to the associated costs, limited availability, and risk
of radiation exposure for certain procedures.
Therefore, in order to close the «screening gap» via imaging tech-
niques, an additional selection procedure is needed so that patients
with increased suspicion of premalignant or malignant tumors can
be identied easily, cost-eectively, and without signicant bur-
den, and these patients are eligible to undergo appropriate imaging
to conrm or eliminate the suspicion.
A screening program based on a blood test (PanTum Detect) en-
ables a stratication for targeted imaging procedures and could
fulll all three requirements.
The PanTum Detect blood test exploits the technique of Epitope
Detection in Monocytes (EDIM) utilizing the fact that activated
monocytes/macrophages (CD14+/CD16+) phagocytose tumor
cells and contain tumor proteins intracellularly [16-20]. These
can be detected by ow cytometry from peripheral blood samples
using specic antibodies. The PanTum Detect blood test screens
for the presence of two biomarkers, Apo10 (epitope of DNaseX =
DNase1L1) and TKTL1 (epitope of the enzyme transketolase-like
1 (TKTL1)) in CD14+/CD16+ activated monocytes (macro-
phages) by ow cytometry [19-22]. Apo10 is an epitope of the
endonuclease DNaseX, accumulating in the nucleus of abnormal
proliferating cells. The presence of the Apo10 epitope in these
cells is indicative of an inhibited apoptosis. The accumulation of
the Apo10 epitope is being used as a marker of inhibited apoptosis
and thereby enables the detection of cells with abnormal prolife-
ration – the rst and general step towards tumor formation and
growth. Apo10 epitope accumulation can be seen in all types of
solid and nonsolid tumor cells [19, 20, 23, 24]. TKTL1 is a bio-
marker for activated cell division, increased ribose-5-phosphate
formation, high proliferation, increased glucose uptake and lactic
acid production even in the presence of oxygen (aerobic glycoly-
sis / Warburg eect), invasive growth and metastasis [25-30] and
tumors executing immunosuppression [31-33].
A pilot study with 1976 subjects (Ethics Committee of the Medi-
cal Association of Hessen, Frankfurt, Germany, approval number:
2020-1981-evBO) was conducted to determine the proportion of
PanTum Detect test positives under realistic conditions in a popu-
lation of asymptomatic subjects between 50 and 70 years of age
without known cancer within the last eight years. In case of a posi-
tive blood test result, participants were recommended to follow up
with FDG-PET/CT imaging (not part of the study), revealing clear
evidence of malignant tumors in many cases. Particularly impres-
sive was the case of a 53-year-old female patient (former smoker)
with no complaints or symptoms and a positive blood test result.
FDG-PET/CT showed an urgent suspicion of lung carcinoma pa-
rahilar in the right upper lobe. Surgical resection and subsequent
histologic examination revealed a typical stage I A2 carcinoid of
the right upper lobe, which was completely excised, and no further
therapy was required.
Aim of the present prospective, interventional study was to verify
the ndings of the preliminary study and to investigate the suitabi-
lity of the PanTum Detect blood test for pre-selecting such asymp-
Volume 6 Issue 9-2022 Clinical Study
tomatic individuals with a high probability of malignant tumors in
subsequent imaging. In contrast to the pilot study, MRI was addi-
tionally used as an imaging modality in the PanTum Detect study.
3. Material and Methods
3.1 Patients and Study Design
Prospective, multicenter, interventional study (ZYA-IVD-20202)
conducted since 13 July 2021 under scientic direction of R.S.,
University Medical Center Hamburg-Eppendorf. Goal was to en-
roll 5000 healthy subjects, between 50 and 70 years of age with
no personal history of cancer within the last eight years. Age- and
gender-distribution, health condition and family history of cancer
were evaluated to characterize the population. The participants
were enrolled through the Precura Center, Darmstadt, Germany,
and the University Medical Center Hamburg-Eppendorf, Ger-
many. After being informed of the scope and potential outcome
of the study, all applicants were required to provide written infor-
med consent. Exclusion criteria were, due to their inuence on im-
mune competence: current cancer indications or suspected cancer;
treatment with immunostimulants like granulocyte-macrophage
colony-stimulating factor, corticosteroids; acute febrile or herpes
zoster diseases; vaccinations or intake of contrast agents within the
last four weeks prior to blood draw; amygdalin intake, surgeries,
or serious injuries within the last eight weeks prior to blood draw.
3.2 Blood Collection and Conduct of the Blood Test
Blood collection had to take place at the earliest 60 minutes af-
ter the last meal. At least 2 ml of EDTA whole blood per subject
was collected in a sterile manner by venipuncture using a Sarstedt
Monovette 2.7 ml EDTA. Shipping to the laboratory was under-
taken by a transport service provider specialized in shipping blood
samples, and the samples were stored at room temperature (15-25
°C). Staining was performed with antibodies CD14 (OFC-14D),
CD16 (Hi-16a), Apo10 (clone JFC 19X63) and TKTL1 (clone JF-
C12T10), and ow cytometry analysis took place within 36 hours
after blood collection at PreMed Labor GmbH, Pfungstadt, Ger-
many with a BD FACSCantoTM II Flow Cytometry (Canto) opera-
ting software BD FACSDivaTM software version 8.0.3 and version
9.0.1. Test results were considered positive if the sum of the two
individual scores for Apo10 and TKTL1 reached or exceeded the
threshold of 260 and, in addition, the Apo10 individual score was
≥ 140 (hereafter total score). Subjects with a positive test result
and a Prostate Specic Antigen (PSA) level in the normal range
underwent subsequent MRI examination and FDG-PET/CT exa-
mination. Subjects with an elevated PSA level were referred to
a specic Prostate MRI. Subjects with a negative test result were
followed up after 12 months to obtain information on possible
cancer diagnoses (e.g., in the context of other cancer screening
measures and due to symptoms) within this period to assess the
sensitivity of the procedure.
For MRI examination, subjects were instructed to fast for at least 4
hours prior to the examination and to remove all metallic objects.
An MRI of the abdomen was performed, followed directly by an
MRI of the head and neck (native without contrast) in the same
device after repositioning. As a standard, a 3 Tesla device with the
highest resolution was used, for patients over 130 kg body weight
and/or severe claustrophobia, it was possible to switch to a 1.5 Tes-
la device with a larger diameter in the same practice. At Die Ra-
diologen Weiterstadt, a GE Nr 750 (3T) or a Siemens Aera (1.5T)
was used. The following sequences were created: Abdomen: T2
axial single shot 5 mm 2-3 blocks; T2 coronal FS propeller; T2 sa-
gittal single shot; T1 axial 5 mm 2-3- blocks; axial DWI 2 blocks /
Head: Flair axial; T2 sagittal; T1 coronal; DWI axial / Neck: STIR
coronal; T2 FS axial; T2 sagittal; T1 coronal. At Radiologie am
Rathausmarkt Hamburg, a Siemens-Skyra (3T) or Sola (1.5 T) is
used; analog sequences were acquired. Additional contrast agent
administration was not required.
FDG-PET/CT was performed at the Nuclear Medicine / PET-CT
Center, DKD HELIOS Clinic Wiesbaden and Radiologische Al-
For FDG-PET/CT assessments subjects were instructed to fast for
at least 6 hours prior to the scan and to avoid strenuous exercise
48 hours in advance. Subjects with diabetes were also instructed
about taking medication before the scan. Blood glucose levels
were controlled before intravenous administration of F18-FDG
(1-2 MBq/kg BW, maximum 200 MBq) with a cut-o of ≤200
mg/dL. Following an uptake-phase (60 to 90 minutes) a low-dose
CT was performed from the base of the skull to the thighs without
iodinated contrast. CT images were obtained with 1-2 mm slice
thickness, 100-120 kV and variable mAs based on weight (quality
reference 50-80 mAs, iterative reconstruction). Subsequent PET
images were acquired in 3D mode and obtained from the base of
the skull to mid-thigh (8 to 10 bed positions, 2 to 3 minutes per
bed position depending on weight, or by continuous acquisition
over 20 minutes (‘FlowMotion’). The PET data were reconstruc-
ted using «time of ight» and «point spread function modeling».
Weakness correction was performed by the CT data set. Multipla-
nar (axial, coronal and sagittal) reconstructions and a MIP were
generated, in addition axial CT and PET images were fused.
3.4 Evaluation and Categorization of the Findings
Blood test, MRI and PET/CT data were evaluated by a multidis-
ciplinary review committee consisting of experienced radiologist
and oncologist (K.F., A.B., A.W., J.H., A.G., S.B., M.O.), who
were led by the principal investigators. Test ndings were cate-
gorized by the tumor board with respect to anamnesis and family
history as follows: 1. no suspicion of tumor, 2. situation unclear,
3. suspicion of malignant tumor. A closer look at the cases in the
Volume 6 Issue 9-2022 Clinical Study
category «unclear situation» revealed that a dierentiated classi-
cation regarding the risk potential for malignancy seemed reaso-
nable. Therefore, the cases within the category «situation unclear»
were additionally assigned to the following subcategories: a. be-
nign tumor, b. morphologically conspicuous without glucose up-
take, and c. morphologically conspicuous with glucose uptake.
3.5 Statistical Analysis
Statistical analyses have been performed using SAS software
(Version 9.4; SAS Institute; Cary NC, USA). This Interim analysis
followed pre-specied principles, outlined in a Statistical Analy-
sis Plan (SAP). Data has been descriptively evaluated, presenting
means, standard deviations, medians, quartiles, minima and maxi-
ma for continuously scaled data, or absolute and relative (percen-
tage) frequencies for categorically scaled data, respectively.
Overall, 5114 subjects were included in the study. In 50 cases,
blood samples could not be analyzed due to transport damage or an
insucient macrophage count. The study analysis included data
of 5064 participants with a valid PanTum Detect blood test re-
sults, with 57% of participants being female and 43% male. Parti-
cipants were in mean (SD) 56.8 ± 5 years, with about 72.6% being
between 50 and 59 years and 27.4% between 60 and 70 years.
3921 of 5048 (77.7%) of participants reported a family history
of tumor diseases. The age adjusted Charlson Comorbidity Index
(CCI) was moderate (1-2) in the vast majority (92.2%) of partici-
pants, 7.5% had severe CCI scores of 3-4 and 0.3% of participants
had a CCI Score of ≥ 5.
Based on the cut-o value of ≥ 260 for the combined PanTum
score and, in addition, an Apo10 score ≥ 140, the proportion of test
positive subjects (n=186) was 3.67%. The proportion of test posi-
tives increased from 3.55% (CCI 1-2) to 5.34% (CCI ≥ 3).
For 151 patients with positive PanTum test results, imaging results
and tumor board assessment were available. Reasons for drop-out
were patients refusing MRI or PET/CT or postponing of imaging
to a later date due to illness, vacation, etc. For these test positives,
imaging and tumor board evaluation revealed „no suspicion of tu-
mor“ in 9 subjects, „suspicion of tumor“ in 27 subjects, and „situa-
tion unclear“ in 115 subjects. A more dierentiated categorization
of this last group revealed evidence of a) benign tumor in 18 sub-
jects, b) morphologically conspicuous premalignant tumor without
glucose uptake in 17 subjects, and a morphologically conspicuous
premalignant tumor with glucose uptake in 80 subjects. In total,
premalignant and malignant tumors were detected in 32 localiza-
tions (Figures 1 to 4). In case of subjects with more than one pre-
malignant or malignant tumor detected in dierent locations, these
were included in the respective graphs.
Figure 1: Localization of malignant tumors detected with PanTum Detect and subsequent imaging.
Volume 6 Issue 9-2022 Clinical Study
Figure 2: Localization of morphologically conspicuous premalignant tumors without glucose uptake detected with PanTum Detect and subsequent
Figure 3: Localization of morphologically conspicuous premalignant tumors with glucose uptake detected with PanTum Detect and subsequent
Figure 4: Localization of benign tumors detected with PanTum Detect and subsequent imaging.
Volume 6 Issue 9-2022 Clinical Study
The aim of the study was to investigate the suitability of the Pan-
Tum Detect blood test for pre-selection of asymptomatic indivi-
duals with a high probability of the presence of a malignant tumor
on subsequent imaging. For that purpose, it was intended to eva-
luate whether the proportion of individuals testing positive with
malignant tumor on subsequent imaging is high enough to justify
the use of these procedures.
The presented results demonstrate that the combination of the
PanTum Detect blood test and subsequent imaging (in case of test
positives) is capable of indicating a suspected malignant tumor.
Additionally, in other subjects with positive PanTum Detect re-
sults, evidence of premalignant tumor was detected on subsequent
imaging. A more detailed analysis of this group demonstrated that,
based on FDG-PET/CT ndings, a dierentiation regarding their
risk of tumor progression appears to be feasible. In our opinion,
these ndings are groundbreaking, therefore we decided to present
them in this publication prior to the completion of the study.
With regard to the detection of malignant tumors, in this study,
27 of the 151 subjects with a positive PanTum Detect result had
evidence of a malignant tumor in subsequent imaging and tumor
board evaluation, corresponding to a detection rate for malignant
tumors of 0.66%. Of a total of 5064 subjects, 186 showed positive
PanTum Detect scores. Of these, results from PET/CT and MRI
examinations were available for 81.18% (n=151) of subjects. The-
refore, the calculation of the detection rate was based on 81.18%
of 5064 subjects, i.e., 4111 subjects. Chan et al. determined a
malignant tumor detection rate of 1.1% when FDG-PET/CT was
used directly (without preselection) in an asymptomatic Asian po-
pulation . Detection rates of 0.7-1.5% have been reported from
other cancer screening studies with more than 1000 participants
using PET or PET/CT within Asian symptomatic populations [35-
38]. The dierent detection rates are not directly comparable due
to dierent study populations, age distributions and study design.
In our study design, the detection of advanced tumor disease was
largely ruled out, as subjects with symptoms and a suspicion of
tumor disease were excluded. In addition, 98.8% of 5048 in our
study reported attendance at established screening examinations.
Thus, subjects in whom a tumor was detected during an establi-
shed screening examination within the last 12 months could not
participate in our study. Accordingly, due to the study design and
the selected inclusion and exclusion criteria, it was expected that
the incidence for the presence of malignant disease in the subject
group would be lower than the incidence of new cancer cases in
the overall population.
Calculations taking into account the gender and age distribution
suggest an incidence of new cancer cases of 0.75 in the study
group . RKI incidence data were available for the age range of
50 to 69 years. Considering the sex and age distribution, the detec-
tion rate of 0.66% determined in this study thus corresponds to the
statistically expected detection rate. It can therefore be assumed
that the actual study objective will be achieved.
Overall, the data suggest that the detection rate which was deter-
mined in our study is within the expected range. It should be noted
that in our study, due to the upstream use of the PanTum Detect
test for pre-selection, only the 186 test-positive subjects required
an FDG PET/CT scan to screen the study population of 5064 sub-
jects, whereas in the study by Chan et al. all 3700 asymptomatic
subjects received an FDG PET/CT scan. In addition, indications
of malignant tumors of various origins were detected in dierent
organs, including tumors for which no established early detection
measures are yet available (Figure 1: Localization of malignant
tumors), such as oral cavity carcinoma. The detection of tumors of
various origins with the PanTum Detect blood test in combination
with radiological imaging is attributable to the biomarker Apo10,
which detects an epitope of DNaseX. This endonuclease executes
the nal step of apoptosis (programmed cell death), namely the de-
gradation of nuclear DNA in 300 base pair fragments [39, 40]. In
contrast to this, the Apo10 epitope of DNaseX accumulates in the
nucleus of abnormally proliferating cells without achieving endo-
nucleatic degradation of nuclear DNA [21, 41]. Accumulation of
the Apo10 epitope in the nucleus of abnormally proliferating cells
thus represents a very early event during malignant transformation
of normal cells into tumor cells [20, 23, 24], and has also been
demonstrated in Cervical Intraepithelial Neoplasia (CIN), cervi-
cal cancer, and Oral Squamous Cell Carcinoma (OSCC) as well
[20, 21, 41]. The detection of Apo10 in macrophages as a result
of phagocytosis of cells with an abnormally increased prolifera-
tion is being exploited as a Pan marker for all types of cells with
abnormal proliferation. The presence of a such a biomarker for all
types of cells with an abnormally increased proliferation is a pre-
requisite of a Pan tumor marker, therefore enabling the detection
of all types of tumors. In addition to the detection of the epitope
DNaseX (Apo10), an epitope of TKTL1 is also detected in macro-
phages in the blood. Accordingly, the PanTum Detect blood test is
exploiting the detection of two dierent biomarkers – the Apo10
and the TKTL1 epitopes, respectively. This allows the detection of
phagocytosed cells with an abnormally increased proliferation rate
and phagocytosed cells with TKTL1 associated metabolic changes
(metabolic transformation), which are indicative and crucial for
the presence of malignant tumors. Several studies have shown that
the overexpression of TKTL1 occurs in numerous cancers such as
breast, lung, colon, urothelial, esophageal, liver, gastric, laryngeal,
oral squamous cell carcinoma and melanoma, and is associated
with a poor prognosis, invasiveness, and metastasis in many of
these tumor entities [21, 28, 42-57], and as well as tumors execu-
ting immunosuppression [31-33].
Volume 6 Issue 9-2022 Clinical Study
In addition to the detection of malignant tumors, the detection of
precancerous lesions is even more essential in terms of cancer
screening, as this oers the possibility of preventing the occur-
rence of cancer [4, 5]. However, with increasing age, the presence
of such premalignant growths [9-12] that will never progress into
carcinomas also increases – accompanied by a risk of overdiagno-
sis or even overtherapy, which could jeopardize the benet of a
screening program. In this regard, the observation made in our stu-
dy that the group of precancerous lesions can be divided into die-
rent subgroups depending on the expected risk of degeneration is
groundbreaking. In this context, the biomarker TKTL1 is of parti-
cular importance, as the metabolic changes (metabolic transforma-
tion) associated with TKTL1 expression becomes measurable [26,
48, 58]. This is crucial for the transition from a premalignant to a
malignant cell and correlates with an increased glucose uptake on
The importance of TKTL1 for cell division was impressively des-
cribed for the rst time by Li et al. . With the onset of cell
division, cells require additional glucose to provide energy and
precursor materials for new cellular components, resulting in an
increased glucose demand. The transformation of a premalignant
to a malignant cell is therefore characterized by an increased
glucose uptake [13, 19, 42, 59-61]. The transformation process to
malignancy does not start in all cells simultaneously, but in dis-
crete cell areas with increased TKTL1 expression. This increase in
TKTL1 expression can be detected with the PanTum Detect blood
test and is visible in PET/CT imaging by diuse FDG accumu-
lation. Feyen et al. have shown that the TKTL1 marker can be
used to detect upregulation of glucose metabolism in tumor cells,
which correlates with FDG PET/CT results . Thus, there is
a direct rationale between elevated levels of TKTL1 as a marker
of metabolic transformation and transition to malignancy and the
accumulation of radiolabeled glucose in tumor cells. For cervical
carcinoma, it has already been shown that the level of TKTL1
expression correlates with progression from premalignant stages
(cervical neoplasms) to advanced stages . Research by Chiari-
ni et al. shows that there is a highly signicant association between
increasing levels of TKTL1 in double-positive (HR-HPV – high
oncogenic risk human papillomaviruses and Pap smear – Papa-
nicolaou smear) cervical smears and the risk of HR-HPV-related
oncoprogression and suggests that TKTL1 is a robust predictive
biomarker for the risk of progression of premalignant precursors
Accordingly, in the present study, premalignant lesions were divi-
ded into the following three subgroups according to their expec-
ted risk of degeneration based on morphological and metabolic
parameters: a) benign tumors, b) morphologically conspicuous
without glucose uptake, and c) morphologically conspicuous with
glucose uptake. A total of 251 premalignant lesions were found
in dierent organs (Figure 2-4). Since the risk of progression for
benign tumors is considered to be very low, no further follow-up
was recommended, and these cases were considered false-positive.
Consistent observations on the presence of asymmetries were des-
cribed as the most common clinical manifestations for head and
neck malignancies [64-68]. Based on these ndings, within the
group of morphologically conspicuous tumors without glucose up-
take, the risk of progression was considered by the tumor board to
be so high that further investigations by specialists were strongly
recommended. In morphologically conspicuous tumors that simul-
taneously showed increased glucose uptake on FDG-PET/CT, the
risk of progression was judged even higher. Detection of tumors
belonging to the two subgroups «morphologically conspicuous»
(without or with glucose uptake) thus provides the opportunity to
prevent the occurrence of cancer by regularly monitoring them and
removing them promptly in the event of a transition to malignancy
[4,5]. For both groups, imaging provided valuable information for
the subjects, that positive PanTum Detect ndings were conside-
red true-positive. In particular, identication of premalignant le-
sions with increased glucose uptake on FDG-PET/CT appears to
potentially allow detection of precisely those precursors that are
in transition to malignancy. In this context, diuse FDG enrich-
ments in FDG-PET/CT examinations seem to reect a coexistence
of TKTL1-positive and TKTL1-negative cell areas, indicating the
process of malignant transformation. This is impressively demons-
trated by the case of a patient with a positive PanTum Detect result,
who presented with a diuse FDG accumulation in the prostate on
the FDG-PET/CT (Figure 5a). Due to slightly elevated PSA level
(5.31 ng/ml) and CA19.9 level (58.4 U/ml), a 3T high-resolution
MRI scan of the prostate was subsequently performed, revealing
a PI-RADS stage 5 and thus a high-grade suspicion for a mali-
gnant tumor. Also, in the case of a patient with a positive PanTum
Detect result, FDG-PET/CT showed a focal FDG enhancement at
the edge of an ovarian cyst, where the histological evaluation of
the excised cyst conrmed the suspicion of a malignant precursor
Overall, the combination of the two markers Apo10 (impaired
apoptosis; transition from healthy cell to tumor cell) and TKTL1
(metabolic transformation, transition to malignancy, tumors exe-
cuting immunosuppression) aims to detect malignant and immune
escaping tumors in the whole body. The determination of Apo10
as well as TKTL1 in macrophages (single score) as well as the
combined value of Apo10 and TKTL1 can be further used to iden-
tify those among the group of premalignant tumors, in which a
metabolic transformation and progression to malignant and immu-
nosuppressive tumors has already begun (Figure 6). In addition to
the localization of the tumor, the subsequent FDG-PET/CT ima-
ging fullls another important function, as it enables a dierentia-
tion between premalignant stages with and without an increased
glucose uptake as a surrogate marker for high risk of switching to
Volume 6 Issue 9-2022 Clinical Study
Figure 5a: FDG PET/CT image of a patient with positive PanTum Test and a slightly elevated PSA level of 5.31 ng/ml. A diuse FDG accumulation
in the prostate is visible (marked with arrows).
Figure 5b: FDG-PET/CT image of a patient with positive PanTum Test result showing focal FDG accumulation in the area of an ovarian cyst (marked
by an arrow). Histology after excision revealed a premalignant stage.
Figure 6: The PanTum Detect test is eectively used annually for cancer prevention. N- Negative test result, P- Positive test result. Top: Expression
of the biomarkers Apo10 and TKTL1 with time as a function of tumorigenesis. Bottom: Schematic representation of the tissue alteration during tum-
origenesis from normal tissue to proliferative disorders to cancer with matrix degeneration and metastasis. Phase A represents the critical PanTum de-
tection area. In this phase the disease is called a “tumor”, which grows locally. In this phase, the disease is still easy to treat successfully, and the tumor
can usually be removed by surgery. In phase B the disease is called “cancer”. In this phase the tumor grows more aggressively and forms metastases.
Volume 6 Issue 9-2022 Clinical Study
5.1 Potential of the PanTum Detect Blood Test for use in Health
In general, the use of blood tests in health screening is conside-
red critical because the proportion of false-positive cases resul-
ting in unnecessary patient burden is considered too high [69, 70].
However, unlike other blood tests that detect biomarker concen-
trations directly within the blood, PanTum Detect is based on
EDIM technology, which utilizes the ability of the innate immune
system, developed over billions of years of evolution, to phago-
cytose and eliminate premalignant and malignant cells from the
body by CD14+/CD16+ activated monocytes/macrophages [19,
20, 22]. These can be isolated from the blood allowing the de-
tection of such premalignant or malignant cells that are not easily
accessible via skin or mucosa. Phagocytosis of premalignant and
malignant cells throughout the body including cells in solid tis-
sue types by macrophages, thus accounting for an immunological
biopsy that opens up the entire proteome of a phagocytosed cell
for analysis and characterization by detecting respective epitopes
that are present intracellularly in macrophages by ow cytometry.
Accordingly, the biomarkers Apo10 and TKTL1 are not detected
diluted in the blood, but rather concentrated in the cell volumes
of the macrophages. This process has a direct positive impact on
the sensitivity of the PanTum Detect blood test. At the same time,
phagocytosis of cells generally occurs if they are also reliably re-
cognized as premalignant or malignant cells by the macrophages.
This endogenous process must be highly specic to prevent the
elimination of healthy cells.
However, the PanTum Detect test does not provide information
on tumor identity and tumor localization. Therefore, the test must
always be used in combination with imaging procedures in the
eld of health care. This was taken into account when setting the
additional threshold for the Apo10 marker to ≥ 140, so that in the
case of a positive test result, a possible tumor has already reached
a size that allows detection and evaluation in imaging. The Apo10
threshold is therefore not optimized for maximum sensitivity,
which automatically contributes to an increase in specicity. It can
be assumed that the selection of the cut-o value and the detection
of the markers Apo10 and TKTL1 in macrophages by ow cyto-
metry should translate to the performance of the assay.
Since imaging cannot be used independently for health screening,
the key question is whether the PanTum Detect blood test can
identify those with reasonable suspicion of malignancy or tumor
at high progression risk in an asymptomatic population so that the
use of imaging is justied. This was impressively demonstrated
with the data of the present study: of a total of 186 subjects with
a positive PanTum Detect result, imaging results and tumor board
assessment were available for 151 of those 124 subjects showed
evidence of a malignant tumor or a premalignant lesion with a high
progression risk in the subsequent imaging. Thus, a PPV (positive
predictive value) for the PanTum Detect blood test for a suspec-
ted malignant or dangerous premalignant lesion on imaging of
82.12% is calculated. This calculation is based on 151 subjects
with imaging results (PP2 population with PET/CT and MRI re-
sults). Consequently, the number of true positives considerably
outweighs the number of false positives. 82.12% of subjects tes-
ting positive for the PanTum Detect test hence benet from the use
of imaging modalities such as MRI and PET/CT. In our opinion,
this substantial benet justies the limited risks associated with a
With regard to patients, it is important that the imaging procedures
following a false positive PanTum Detect blood test can reliably
exclude a dangerous tumor, so that the psychological stress caused
by a false positive test nding can be limited to a certain period
until imaging results are available. Our results indicate that the
PanTum Detect blood test could be used as a screening tool and,
in combination with PET/CT and MRI, enables the detection of
malignant tumors and pre-malignant lesions at a stage where, in
many cases, there is a good chance for a cure.
Based on the United States Preventive Services Task Force
(USPSTF) recommendations on the use of low dose computed to-
mography for early detection of lung cancer , the number of
detected early-stage lung cancer increased, and so did patient sur-
vival. This strongly conrms that imaging techniques such as low
dose computed tomography are important tools for an early cancer
detection. Additionally, a study published by Potter et al. showed
an increase in diagnosed stage I Non-Small Cell Lung Carcinoma
(NSCLC) from 30.2% to 35.5% (2014 to 2018) associated with an
increase in the median all cause survival of 11.9% per year within
the same period .
The annual use of the PanTum Detect blood test could enable the
identication of asymptomatic persons eligible for visualization
and early detection of tumors leading to increased survival times
of cancer patients. The detection of premalignant lesions could
increase the survival times even more because the absence of in-
vasive growth and immunosuppression will strongly contribute to
improve the survival of patients.
The high PPV of 82.12% can be explained by the high speci-
city of the PanTum Detect blood test. With only 27 false positive
ndings from imaging (groups: no suspicion of tumor/benign tu-
mors), a specicity of 99.3% is calculated. As described above,
4111 subjects (i.e., 81.18% of 5064 subjects) were also used as the
reference value for calculating specicity, because PET/CT and
MRI examinations were available for 81.18% (n=151) of the 186
subjects with positive PanTum Detect scores.
Regarding sensitivity, only an approximate estimate based on sta-
tistical data is currently feasible prior to completion of the study.
A comparison of the detected suspected cases with the incidence
for the annual new cancer cases indicates that most of the existing
tumors were detected. It is important to emphasize that the use of
Volume 6 Issue 9-2022 Clinical Study
the PanTum blood test in combination with imaging modalities is
intended as a complement to, and not a replacement of, existing
screening methods. Thus, tumors can be detected via the establi-
shed screening methods. In addition, tumors for which no scree-
ning procedures exist can be detected, which in turn consequently
reduces the existing screening gap.
5.2 Limitations of the Blood Test
Like any diagnostic test, the PanTum Detect blood test has certain
limitations. The number of false positives is low at (27) 0.66%.
In combination with imaging, the false positive PanTum Detect
ndings can be classied into the given categories. If many small
events contribute to an elevated Apo10, imaging will not reveal
evidence of premalignant lesions. If an elevated Apo10 is caused
by a larger premalignant event and accompanied by an elevated
TKTL1, PET/CT imaging will reveal whether the events overlap
or are separate events. Separate events also lead to false positive
5.3 Integration into a Screening Program
Overall, the study results show that the PanTum Detect blood
test (in the case of test positives) should always be performed in
combination with subsequent imaging, since only imaging allows
the localization of possible tumors and dierentiation of premali-
gnant stages with high and low progression risk. From our point
of view, it therefore seems reasonable to integrate the blood test
into a screening program that ensures rapid imaging examinations
within a dened network in the event of a positive test result. This
also helps to keep the phase of uncertainty for patients as short as
possible and to quickly guide all subjects with positive PanTum
Detect results to further, goal-oriented and structured diagnostics.
The study results presented here demonstrate that the PanTum
Detect blood test is able to identify asymptomatic individuals eli-
gible for imaging. This targeted imaging detected abnormal tissue
structures covering the whole range of malignant transformation
from benign, to premalignant and to malignant structures. By
choosing certain cut-o levels for single and combined scores for
the biomarkers Apo10 and TKTL1 in macrophages in the blood,
it was possible to select a window of detection with low amounts
of structures indicative of premalignant structures and a high
percentage of structures indicative of premalignant and malignant
structures. Within the detected group of premalignant structures, a
subgroup could be identied by increased glucose uptake in FDG-
PET/CT indicating a metabolic switch which may reect the statu
nascendi development of malignancy and therefore could be in-
dicative for high risk of progression. In the future, a follow up of
benign and premalignant structures and their possible transition to
malignant structures can be used to optimize the cut-o levels for
the single and combined scores for Apo10 and TKTL1. Similar to
the successful reduction of cervical cancer based on premalignant
cells (CIN), the detection of premalignant tissue on imaging after
a positive Pantum Score can also contribute to a massive reduction
in cancer-related deaths. The observed distribution of images indi-
cative of benign, premalignant and malignant structures conrms
that the applied cut-o values for the PanTum Detect blood test
is suitable for pre-selecting such asymptomatic individuals with a
high probability of malignant tumors in subsequent imaging.
7. Conict of Intrest
Johannes F Coy is founder and shareholder of Zyagnum AG,
Darmstadt, Germany as well as owner of patents granting the use
of DNaseX and TKTL1 for diagnosis of cancer. Oliver Feyen is an
employee of Zyagnum AG. Authors Simon Burg, Ralf Smeets, Ka-
tja Failing, Gamal-Andreé Banat, Martin Gosau and Audrey Laure
Céline Grust declare nancial funding from Zyagnum AG. Martin
Grimm declares no conict of interest
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