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Clinical Study Blood-Test Based Targeted Visualization Enables Early Detection of Premalignant and Malignant Tumors in Asymptomatic Individuals Citation: Journal of Clinical and Medical Images


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1. Abstract 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 absence 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 analyzed 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 flow 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 identification of asymptomatic individuals eligible for further imaging. On subsequent imaging, a high proportion of this pre-selected subgroup showed abnormal tissue structures which are indicative of early cancer stages or pre-malignant structures at high risk for malignancy development. Therefore, the PanTum Detect blood test enables the identification of asymptomatic individuals eligible for imaging.
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Clinical Study ISSN: 2435-1210 Volume 6
Blood-Test Based Targeted Visualization Enables Early Detection of Premalignant
and Malignant Tumors in Asymptomatic Individuals
*Corresponding author:
Simon Burg,
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
Medical Images 1
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
screening; FDG-PET/CT
1. Abstract
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 identication 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 identication of asymptomatic individuals
eligible for imaging.
2. Introduction
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 [3].
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 signicantly reducing mortality
[4, 5].
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- 2
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
[8]. In addition to the psychological burden of the life-threatening
disease, patients often suer from the consequences of the ope-
ration, which can lead to facial disgurement 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 fullls the following
three requirements:
1. detection of many dierent 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 sucient tumor suspicion
[13-15]. Their use in health screening, however, does not seem
justied 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 identied easily, cost-eectively, and without signicant bur-
den, and these patients are eligible to undergo appropriate imaging
to conrm or eliminate the suspicion.
A screening program based on a blood test (PanTum Detect) en-
ables a stratication for targeted imaging procedures and could
fulll 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 specic 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 eect), 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- 3
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 scientic 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 inuence 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 Specic 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 specic 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.
3.3 Imaging
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-
lianz Hamburg.
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 4
Volume 6 Issue 9-2022 Clinical Study
category «unclear situation» revealed that a dierentiated 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-specied 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.
4. Results
Overall, 5114 subjects were included in the study. In 50 cases,
blood samples could not be analyzed due to transport damage or an
insucient 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 dierentiated 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 dierent locations, these
were included in the respective graphs.
Figure 1: Localization of malignant tumors detected with PanTum Detect and subsequent imaging. 5
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. 6
Volume 6 Issue 9-2022 Clinical Study
5. Discussion
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 dierentiation 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 [15]. 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 dierent detection rates are not directly comparable due
to dierent 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 [6]. 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 dierent
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 dierent 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]. 7
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 oers 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 benet of a
screening program. In this regard, the observation made in our stu-
dy that the group of precancerous lesions can be divided into die-
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
FDG-PET/CT [19].
The importance of TKTL1 for cell division was impressively des-
cribed for the rst time by Li et al. [30]. 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 diuse 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 [19]. 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 [62]. Research by Chiari-
ni et al. shows that there is a highly signicant 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 dierent 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, identication 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, diuse FDG enrich-
ments in FDG-PET/CT examinations seem to reect 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 diuse 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 conrmed the suspicion of a malignant precursor
(Figure 5b).
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 fullls another important function, as it enables a dierentia-
tion between premalignant stages with and without an increased
glucose uptake as a surrogate marker for high risk of switching to
malignant tumors. 8
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 diuse 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 eectively 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. 9
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 specic 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 specicity. 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 justied. 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 benet from the use
of imaging modalities such as MRI and PET/CT. In our opinion,
this substantial benet justies the limited risks associated with a
PET/CT examination.
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 [71], the number of
detected early-stage lung cancer increased, and so did patient sur-
vival. This strongly conrms 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 [72].
The annual use of the PanTum Detect blood test could enable the
identication 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 specicity 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 specicity, 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 10
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 classied 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 dierentiation 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 dened 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.
6. Conclusion
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 identied by increased glucose uptake in FDG-
PET/CT indicating a metabolic switch which may reect 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 conrms
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. Conict 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 conict of interest
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si-experimental study. BMJ. 2022; 376: e069008.
... However, due to the cost and risk of radiation exposure, whole-body FDG-PET/CT does not yet appear suitable for general cancer screening in asymptomatic populations (4,9). In contrast, a blood test that detects a variety of tumor types at early, asymptomatic stages can be used to pre-select subjects with a high likelihood of (pre)cancerous lesions on subsequent imaging (10). The PanTum Detect blood test is based on the unique technique of epitope detection in monocytes (EDIM) utilizing the fact that activated monocytes/macrophages (CD14+/CD16+), belonging to the group of circulating cancer-associated macrophage-like cells (CAMLs), phagocytose tumor cells and contain tumor proteins intracellularly (11)(12)(13)(14)(15). ...
... using imaging procedures to screen these preselected asymptomatic individuals for possible tumors -also under suitable cost and radiation aspects (10). Since TKTL1 expression is linked to increased glucose uptake into the cell, an increased glucose uptake is a clear indication of transformation of a benign to a malignant tumor. ...
... Moreover, this blood test offers the advantage of exploiting the specific elimination of tumor cells by the innate immune system without dilution effects, as antigens are detected directly in macrophages. In addition, the two biomarkers Apo10 and TKTL1 allow the detection of many different tumor entities -including those for which tumor markers are not yet available (10). ...
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We present the case of a 53-year-old woman who was diagnosed with early-stage lung cancer by targeted cancer screening consisting of an immunological biopsy-based blood test followed by radiological imaging. The PanTum Detect blood test detects the biomarkers Apo10/DNaseX and Transketolase-like 1 (TKTL1) in circulating macrophage-like cells from peripheral blood samples to identify asymptomatic individuals with a high risk for malignancy. The elevated blood test values initiated an 18 F-FDG PET/CT visualization for further clarification. In this case, imaging indicated a lung carcinoma in the right upper lobe. A biopsy confirmed the presence of a lung carcinoma, which was removed surgically. Histologic examination revealed a typical I A2 carcinoid, which was completely removed, making further therapy obsolete. KEYWORDS early cancer screening, Apo10/DNaseX, TKTL1, immunological biopsy, blood test, FDG-PET/CT
The detection of biomarkers in blood macrophages is a new non-invasive cancer screening method, but its performance in early stage lung cancer screening remains undetermined. We evaluated the Apo10 and TKTL1 levels in blood macrophages of 156 early-stage lung cancer patients and 153 controls. APT (combination of Apo10 and TKTL1) level was significantly higher in the lung cancer group than that in the control group (P < 0.001). AUROC analysis showed that APT has high diagnostic value in differentiating early-stage lung cancer (AUC = 0.9132) and can be considered a biomarker for screening lung cancer patients from individuals with lung nodules.
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Cancer remains a leading cause of death worldwide, partly owing to late detection which entails limited and often ineffective therapeutic options. Most cancers lack validated screening procedures, and the ones available disclose several drawbacks, leading to low patient compliance and unnecessary workups, adding up the costs to healthcare systems. Hence, there is a great need for innovative, accurate, and minimally invasive tools for early cancer detection. In recent years, multi-cancer early detection (MCED) tests emerged as a promising screening tool, combining molecular analysis of tumor-related markers present in body fluids with artificial intelligence to simultaneously detect a variety of cancers and further discriminate the underlying cancer type. Herein, we aim to provide a highlight of the variety of strategies currently under development concerning MCED, as well as the major factors which are preventing clinical implementation. Although MCED tests depict great potential for clinical application, large-scale clinical validation studies are still lacking.
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Objective To determine the effect of the introduction of low dose computed tomography screening in 2013 on lung cancer stage shift, survival, and disparities in the stage of lung cancer diagnosed in the United States. Design Quasi-experimental study using Joinpoint modeling, multivariable ordinal logistic regression, and multivariable Cox proportional hazards modeling. Setting US National Cancer Database and Surveillance Epidemiology End Results program database. Participants Patients aged 45-80 years diagnosed as having non-small cell lung cancer (NSCLC) between 1 January 2010 and 31 December 2018. Main outcome measures Annual per cent change in percentage of stage I NSCLC diagnosed among patients aged 45-54 (ineligible for screening) and 55-80 (potentially eligible for screening), median all cause survival, and incidence of NSCLC; multivariable adjusted odds ratios for year-to-year changes in likelihood of having earlier stages of disease at diagnosis and multivariable adjusted hazard ratios for changes in hazard of death before versus after introduction of screening. Results The percentage of stage I NSCLC diagnosed among patients aged 55-80 did not significantly increase from 2010 to 2013 (from 27.8% to 29.4%) and then increased at 3.9% (95% confidence interval 3.0% to 4.8%) per year from 2014 to 2018 (from 30.2% to 35.5%). In multivariable adjusted analysis, the increase in the odds per year of a patient having one lung cancer stage lower at diagnosis during the time period from 2014 to 2018 was 6.2% (multivariable adjusted odds ratio 1.062, 95% confidence interval 1.048 to 1.077; P<0.001) higher than the increase in the odds per year from 2010 to 2013. Similarly, the median all cause survival of patients aged 55-80 did not significantly increase from 2010 to 2013 (from 15.8 to 18.1 months), and then increased at 11.9% (8.9% to 15.0%) per year from 2014 to 2018 (from 19.7 to 28.2 months). In multivariable adjusted analysis, the hazard of death decreased significantly faster after 2014 compared with before 2014 (P<0.001). By 2018, stage I NSCLC was the predominant diagnosis among non-Hispanic white people and people living in the highest income or best educated regions. Non-white people and those living in lower income or less educated regions remained more likely to have stage IV disease at diagnosis. Increases in the detection of early stage disease in the US from 2014 to 2018 led to an estimated 10 100 averted deaths. Conclusions A recent stage shift toward stage I NSCLC coincides with improved survival and the introduction of lung cancer screening. Non-white patients and those living in areas of greater deprivation had lower rates of stage I disease identified, highlighting the need for efforts to increase access to screening in the US.
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Background: Colon adenocarcinoma (COAD) is a common gastrointestinal tumor and often occurs in the left colon with a poor prognosis. The progression of COAD is closely related to the tumor microenvironment, especially the hypoxia. Currently, few studies have reported the correlation between hypoxia-related genes and the prognosis of COAD patients. Furthermore, we constructed a prognostic model using four hypoxia-related genes to predict the prognosis of COAD patients. Methods: The mRNA expression profiles and corresponding clinicopathological data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The string online analysis tool was used to construct a protein-protein interaction network (PPI) of hypoxia-related genes. Kaplan-Meier curve was used to analyze the relationship of hypoxia risk score and the overall survival of COAD patients, and the receiver operating characteristic (ROC) curve was used to assess the reliability. Results: We screened out four hypoxia genes, including TKTL1 (transketolase like 1), SLC2A3 (solute carrier family 2 member 3), ALDOB (aldolase, fructose-bisphosphate B) and ENO3 (enolase 3), which were used to construct a hypoxia risk model to predict the overall survival of COAD patients. Besides, we also found that the hypoxia risk score was correlated with the immunosuppression of tumor microenvironment. Conclusion: The model we constructed with four survival-related hypoxia genes, including TKTL1, SLC2A3, ALDOB and ENO3, could be used to predict the overall survival of COAD patients with high stability.
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Many studies have reported an increase in the level of circulating cell-free DNA (cfDNA) in the blood of patients with cancer. СfDNA mainly comes from tumor cells and, therefore, carries features of its genomic profile. Moreover, tumor-derived cfDNA can act like oncoviruses, entering the cells of vulnerable organs, transforming them and forming metastatic nodes. Another source of cfDNA is immune cells, including neutrophils that generate neutrophil extracellular traps (NETs). Despite the potential eliminative effect of NETs on tumors, in some cases, their excessive generation provokes tumor growth as well as invasion. Considering both possible pathological contributions of cfDNA, as an agent of oncotransformation and the main component of NETs, the study of deoxyribonucleases (DNases) as anticancer and antimetastatic agents is important and promising. This review considers the pathological role of cfDNA in cancer development and the role of DNases as agents to prevent and/or prohibit tumor progression and the development of metastases.
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Lung cancer is a leading cause of cancer-related deaths, contributing to 18.4% of cancer deaths globally. Treatment of non-small cell lung carcinoma has seen rapid progression with targeted therapies tailored to specific genetic drivers. However, identifying genetic alterations can be difficult due to lack of tissue, inaccessible tumors and the risk of complications for the patient with serial tissue sampling. The liquid biopsy provides a minimally invasive method which can obtain circulating biomarkers shed from the tumor and could be a safer alternative to tissue biopsy. While tissue biopsy remains the gold standard, liquid biopsies could be very beneficial where serial sampling is required, such as monitoring disease progression or development of resistance mutations to current targeted therapies. Liquid biopsies also have a potential role in identifying patients at risk of relapse post treatment and as a component of future lung cancer screening protocols. Rapid developments have led to multiple platforms for isolating circulating tumor cells (CTCs) and detecting circulating tumor DNA (ctDNA); however, standardization is lacking, especially in lung carcinoma. Additionally, clonal hematopoiesis of uncertain clinical significance must be taken into consideration in genetic sequencing, as it introduces the potential for false positives. Various biomarkers have been investigated in liquid biopsies; however, in this review, we will concentrate on the current use of ctDNA and CTCs, focusing on the clinical relevance, current and possible future applications and limitations of each.
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Objective: The EDIM (Epitope detection in monocytes) blood test is based on two biomarkers Apo10 and TKTL1. Apo10 is responsible for cell proliferation and resistance to apoptosis. TKTL1 plays a major role in anaerobic glycolysis of tumor cells, leading to destruction of the basal membrane and metastasis as well as in controlling cell cycle. For the first time we analyzed Apo10 and TKLT1 in patients with cholangiocellular (CCC), pancreatic (PC), and colorectal carcinoma (CRC). Methods: Blood samples of 62 patients with CCC, PC, and CRC were measured and compared to 29 control patients. We also investigated 13 patients with inflammatory conditions, because elevated TKTL1 and Apo10 have been previously described in affected individuals. Flow cytometry was used to detect surface antigens CD14+/CD16+ (activated monocytes/macrophages). Percentages of macrophages harboring TKTL1 and Apo10 were determined. A combined EDIM score (EDIM-CS: TKTL1 plus Apo10) was calculated. Results were correlated with serum tumor markers CEA and CA19-9. Results: Patients with CCC had 100% positive EDIM-CS but CEA and CA19-9 were positive in only 22.2% and 70%, respectively. Patients with PC had 100% positive EDIM-CS but positive tumor markers in only 37.5% (CEA) and 72.7% (CA19-9). Patients with CRC had 100% positive EDIM-CS but only 50% positive CEA. EDIM-CS was positive in 100% (62/62) of all cancer patients and in 0% of healthy individuals. Of the individuals with inflammation, 7.7% had a positive EDIM-CS. Conclusion: The sensitivity of the EDIM blood test and the comparison with traditional tumor markers indicate that this new test might improve the detection of carcinomas (CCC, PC and, CRC) and might be relevant for the diagnosis of all tumor entities.
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Accumulation of nucleotide building blocks prior to and during S phase facilitates DNA duplication. Herein, we find that the anaphase-promoting complex/cyclosome (APC/C) synchronizes ribose-5-phosphate levels and DNA synthesis during the cell cycle. In late G1 and S phases, transketolase-like 1 (TKTL1) is overexpressed and forms stable TKTL1-transketolase heterodimers that accumulate ribose-5-phosphate. This accumulation occurs by asymmetric production of ribose-5-phosphate from the non-oxidative pentose phosphate pathway and prevention of ribose-5-phosphate removal by depleting transketolase homodimers. In the G2 and M phases after DNA synthesis, expression of the APC/C adaptor CDH1 allows APC/CCDH1 to degrade D-box-containing TKTL1, abrogating ribose-5-phosphate accumulation by TKTL1. TKTL1-overexpressing cancer cells exhibit elevated ribose-5-phosphate levels. The low CDH1 or high TKTL1-induced accumulation of ribose-5-phosphate facilitates nucleotide and DNA synthesis as well as cell cycle progression in a ribose-5-phosphate-saturable manner. Here we reveal that the cell cycle control machinery regulates DNA synthesis by mediating ribose-5-phosphate sufficiency. Ribose-5-phosphate (R5P) is required for DNA synthesis, but how this is regulated during cell cycle progression is unclear. Here the authors report that the cell cycle regulator APC/C-CDH1 synchronizes cell cycle progression with R5P-derived DNA synthesis by controlling TKTL1 stability
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High oncogenic risk human papillomaviruses (HR-HPVs) promote cervical carcinoma development, the fourth most common feminine cancer. A slow oncodevelopmental phase—defined histopathologically as Cervical Intraepithelial Neoplasia (CIN) grades 1–3, or cytologically as Low- or High-grade Squamous Intraepithelial Lesions (LSIL or HSIL)—precedes the malignancy. Cervical carcinoma screenings through HR-HPV genotyping and Pap smears are regularly performed in Western countries. Faulty cytology screening or genotyping or patients' non-compliance with follow-ups can let slip an oncoprogression diagnosis. Novel biomarker tests flanking HR-HPV genotyping and cytology could objectively predict the risk of disease progression thus helping triage LSIL/ASCUS patients. Here, anonymized leftovers of fresh cervical epithelium scrapings from twice (LSIL/ASCUS and HR-HPV DNA)-positive and twice (Pap smear- and HR-HPV DNA)-negative (control) patients in a proteome-preserving solution served to assess the biomarker worth of three cervical carcinoma-related proteins, i.e., B-MYB (or MYBL2), Cancerous Inhibitor of PP2A (CIP-2a), and transketolase-like1 (TKTL1). Leftovers anonymity was strictly kept and storage at −80°C, protein extraction, immunoblotting, and band densitometry were blindly performed. Only after tests completion, the anonymous yet code-corresponding HR-HPV-genotyping and cytology data allowed to assign each sample to the twice-positive or twice-negative group. Descriptive statistics showed that the three proteins levels significantly increased in the twice-positive vs. twice-negative scrapings. Diagnostic ROC curve analysis identified each protein's Optimal Decision Threshold (OTD) showing that TKTL1 and CIP-2a are stronger risk predictive biomarkers (Sensitivity, 0.91–0.93; Specificity, 0.77–0.83) than B-MYB. Logistic Regression coupled with Likelihood-Ratio Tests confirmed that a highly significant relation links increasing TKTL1/CIP-2a/B-MYB protein levels in twice-positive cervical scrapings to the risk of HR-HPV-driven oncoprogression. Finally, a 3 year clinical follow-up showed that 13 patients (50% of total) of the twice-positive group with biomarker values over OTDs compliantly underwent scheduled colposcopy and biopsy. Of these, 11 (i.e., 84.7%) received a positive histological diagnosis, i.e., CIN1 (n = 5; 38.5%) or CIN2/CIN2+ (n = 6; 46,2%). Therefore, TKTL1/CIP-2a/B-MYB protein levels could objectively predict oncoprogression risk in twice (HR-HPV- and Pap smear)-positive women. Further studies will assess the translatability of these findings into clinical settings.
Lymphoma is the most common childhood malignancy in the head and neck. The most common clinical manifestations of lymphoma in palatine tonsil are the tonsils asymmetry, alteration in the appearance of the mucous and cervical lymphadenopathy. The unilateral tonsillar hypertrophy must be differentiated with infectious processes, with chronic processes, other tumors or benign tonsillar hyperplasia. The monitoring of tonsillar hypertrophy is strict, because early diagnosis and treatment are of great importance in the prognosis of tonsillar lymphoma patients. A 14 year-old girl presents unilateral tonsillar enlargement and odynophagia. After 21 days of antibiotic treatment, she has not clinical improvement. The diagnosis is Burkitt's lymphoma. One year after diagnosis, she presents complete remission of the disease.
Importance Lung cancer is the second most common cancer and the leading cause of cancer death in the US. In 2020, an estimated 228 820 persons were diagnosed with lung cancer, and 135 720 persons died of the disease. The most important risk factor for lung cancer is smoking. Increasing age is also a risk factor for lung cancer. Lung cancer has a generally poor prognosis, with an overall 5-year survival rate of 20.5%. However, early-stage lung cancer has a better prognosis and is more amenable to treatment. Objective To update its 2013 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on the accuracy of screening for lung cancer with low-dose computed tomography (LDCT) and on the benefits and harms of screening for lung cancer and commissioned a collaborative modeling study to provide information about the optimum age at which to begin and end screening, the optimal screening interval, and the relative benefits and harms of different screening strategies compared with modified versions of multivariate risk prediction models. Population This recommendation statement applies to adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. Evidence Assessment The USPSTF concludes with moderate certainty that annual screening for lung cancer with LDCT has a moderate net benefit in persons at high risk of lung cancer based on age, total cumulative exposure to tobacco smoke, and years since quitting smoking. Recommendation The USPSTF recommends annual screening for lung cancer with LDCT in adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. (B recommendation) This recommendation replaces the 2013 USPSTF statement that recommended annual screening for lung cancer with LDCT in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.
Background/Aim: Whole-body positron-emission tomography/computed tomography with the glucose analog 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG-PET/CT) has been used to screen examinees for underlying malignancy in many countries. The aim of this study was to compare the potential value of FDG-PET/CT application in asymptomatic individuals with those with suspected malignancy. Patients and Methods: A total of 9,408 examinees underwent whole-body FDG-PET/CT at our hospital from July 2006 to August 2013. Three thousand and seven hundred asymptomatic individuals and 848 individuals with laboratory and clinical/radiologicaI suspicion of malignancy who had undergone FDG-PET/CT for cancer screening were recruited. The final confirmation of cancer and outcomes were based on a pathological report and continuous follow-up. Results: Forty-five out of 3,700 asymptomatic individuals (1.2%) had proven malignancy, and 42 of them (93.3%) were found by FDG-PET/CT. Two hundred and twelve out of 848 with suspected malignancy (25%) had proven malignancy, and 196 of them (92.5%) were detected by FDG-PET/CT. Most of these cancers in asymptomatic individuals were clinically at an early stage. The discovery rate in asymptomatic individuals and those with suspected malignancy was 1.1% and 23.1%, respectively. The overall survival of patients with cancer diagnosed with PET/CT was higher than those with suspected malignancy (78.6% vs. 48.5%, p<0.001). Patients with a resectable lesion, early-stage disease, and lower maximal standardized uptake value had significantly better survival than those without. Conclusion: FDG-PET/CT is useful in the early diagnosis of cancer and thus might improve the survival rates of these patients. Considering the costs and risk of radiation exposure, it would be better used as a priority in patients with laboratory and clinical/radiologic suspicion of malignancy.