Book Volume 1
Molecular Imaging in the Development of Antibody-Drug Conjugates
Page: 1-14 (14)
Author: Clare Senko, Sze-Ting Lee*, Hui K. Gan, Umbreen Hafeez, Sagun Parakh and Andrew M. Scott
PDF Price: $30
Abstract
Antibody-drug conjugates (ADCs) are novel drugs that deliver a potent
cytotoxic payload to the tumor site, by exploiting the specificity of a monoclonal
antibody (mAb) to tumor antigens expressed on cancer cells. ADCs allow the delivery
of drugs to tumor cells or microenvironment while minimizing toxicity to normal
tissue. More than 80 ADCs worldwide are currently under clinical development, of
which nine have already received FDA approval. Molecular imaging can play a vital
role in evaluating the biodistribution and pharmacokinetics of ADCs for optimal patient
selection and early clinical trial development. This chapter provides an overview of
ADC structure and design, outlines approved ADCs, discusses the role of molecular
imaging in drug development, and highlights clinical and pre-clinical experience with
radiolabelled ADCs [1].
Preclinical Applications with Phage Displayderived Peptides
Page: 15-18 (4)
Author: Erkki Koivunen*
PDF Price: $30
Abstract
A lot of effort has been devoted to convert phage display-derived peptides to
more stable peptidomimetics and only a few such peptides have been examined in
preclinical trials. The applications of short peptides include radio-isotope labelling for
imaging purposes and targeting a virus or nanoparticle to specific tissue or cell.
Perspectives in 11C and 18F Radiochemistry
Page: 19-31 (13)
Author: Hugo Helbert, Gert Luurtsema, Rudi A.J.O. Dierckx*, Wiktor Szymanski, Ben L. Feringa and Philip H. Elsinga
PDF Price: $30
Abstract
The state-of-the-art of carbon-11 and fluorine-18 radiochemistry for positron
emission tomography (PET) is presented. From the latest developments in labelling
methodology, a picture of future challenges is drawn. The exploration of novel
reactivity to allow 11C-labelling, alongside a particular focus in making such reaction
compatible for clinical production, is presented to be key in 11C-tracer discovery. 18F is
envisioned to be at the heart of further development in PET. Broadening imaging
strategies towards pre-targeting approaches, together with the use of modified
antibodies or peptides, constantly challenges the field of radiofluorination for new and
efficient labelling methods applicable to complex molecules. Translation of
biorthogonal reactions into radiolabelling methods appears as a valuable option to
address these issues and is expected to be a significant advance in upcoming 18F-tracer
developments.
Introduction to Radionanotargeting in the 1990's: Dosimetry and Optimization of Antisense Oligonucleotide Radiotherapy in Vivo
Page: 32-39 (8)
Author: Antti Jekunen*, Mikko Tenhunen and Kalevi Kairemo
PDF Price: $30
Abstract
Radiolabeled oligodeoxynucleotides (ODNs) have the potential of having
both direct antisense inhibition and radiation effects being derived against the most
specific target, a DNA/RNA sequence. Nuclear DNA is the primary target for ionizing
radiation, and low-energy electrons with short ranges are responsible for the
radiotoxicity of Auger electron emitters. Antisense technology has begun to provide an
alternative approach for manipulating the expression of specific genes. Here, we
optimize the label of ODNs with Auger-emitting radionuclides by calculating
subcellular dose distribution. We show that for subcellular targeting, internal labels 35S
and 32P give the lowest variation in estimated absorbed nuclear dose in our cell model
with defined dimensions (nuclear diameter, 6-16 μm ; cellular diameter, 12-20 μm).
Role of SPECT/CT Imaging with Gamma-emitted Radionuclides in Personalized Treatment of Cancer Patients
Page: 40-78 (39)
Author: Sonya Sergieva*
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Abstract
Radiopharmaceuticals are a well-known form of ionizing radiation, emitting
gamma photons. They are used in clinical routine for cancer patients; nuclear medicine
utilizes oncotropic cationic complexes such as 99mTc-Sestamibi/Tetrofosmin
(MIBI/TF); radioiodine 123I /131I; radiolabeled somatostatin (SST) derivatives 111In-
Octreoscan/99mTc- Tektrotyd; diphosphonates 99mTc-MDP /HEDP; nanoparticles 99mTc-
Nanocoll and etc. The tracer accumulation to tumor cells is dependent on blood
perfusion, biodistribution, cellular proliferation, oxygen consumption, receptor status,
and other factors in different tumors. Besides multiple imaging methods for evaluating
malignant diseases, new hybrid SPECT/CT imaging can provide accurate diagnostic
information about the presence and staging of neoplastic diseases as well as unique
biological characteristic information, such as quantification of cellular proliferation or
SST-receptor status. The SPECT component of the hybrid SPECT/CT images provides
information about the functional activity of the primary neoplastic tumor and the
secondary metastatic lesions, whereas the CT component is needed for the anatomy of
the “hot” lesions seen in the nuclear medicine modality. This may result in a reduced
number of false-positive and false-negative results and increased sensitivity and
specificity of the nuclear medicine studies. The SPECT/CT examinations may find a
different clinical value in oncology. Combined SPECT/CT images enable discovering
primary occult tumors, visualizing local or distant metastases for accurate NM-staging,
and evaluating therapy response. SPECT/CT images can be used for radiotherapy
planning to delineate target and functional gross tumor volumes.
Radionanotargeting and Precision Radiotherapy Planning in Patients with Breast Cancer
Page: 79-90 (12)
Author: Pavel Krzhivitskiy*, Sergey Novikov, Sergey Kanaev and Petr Krivorotko
PDF Price: $30
Abstract
Purpose:Through this work dedicated to the study of molecular imaging
capabilities for radiotherapy planning in patients with breast cancer, we would like to
acknowledge our gratitude and pay respect to one of the most prominent world-class
researchers in nuclear medicine, Kalevi Kairemo. Materials and Methods: In this
retrospective study, we present our experience of molecular imaging in more than
1,800 women with breast cancer. Participants underwent Mammoscintigraphy/Breast
molecular imaging with 99mTc-MIBI for detection of multicentric (MC) breast cancer
and SPECT-CT imaging for the diagnosis of multiple (>2) metastatic axillary lymph
nodes involvement. In order to evaluate the variability of SLNs localisation and
determine how this data may influence the efficacy of the above-mentioned therapeutic
strategy, we retrospectively analysed the results of SPECT-CT examinations with
99mTc labelled nanocolloids. All of these findings were evaluated according to impact
for subsequent individual radiotherapy planning. Results: We found out that
sensitivity, specificity and accuracy of Scintimammo-graphy/Molecular breast imaging
(SMG/MBI) with 99mTc -MIBI in the diagnosis of multicentric breast cancer (MC)
was 84.3%, 98% and 96.3%, respectively. More of that, the sensitivity of SMG was
significantly superior to ultrasound (52.3%) and mammography (54.0%). This
advantage was more evident in women with dense breasts. Nowadays, we routinely use
SMG/MBI for selecting the best candidates for conservative surgery and postoperative
partial breast irradiation. An accurate diagnosis of metastases in regional lymph nodes
(LN) can significantly affect the radiotherapy strategy. The prospective evaluation of
SPECT-CT with 99mTc -MIBI in 184 primary patients with early breast cancer
indicates high sensitivity (94%-96%) of SPECT-CT in the diagnosis of extensive (more
than 2 metastases) axillary LN invasion. In these patients, additional SPECT-CT
visualisation of individual lymph flow pattern with 99mTc-nannocolloids can be
effectively used for 3D planning of simultaneous whole breast and sentinel lymph
nodes irradiation. Conclusion: Our accumulated experience in using SMG/MBI and SPECT-CT imaging
with tumor-seeking and nanocolloids radiopharmaceuticals 99mTc labelled provides a
high informative value and broad usability perspectives in developing cutting-edge
radiotherapeutic methods in patients with early and regional breast cancer.
The Diagnostic Potential of Radiolabelled Neurotensin in PET Imaging of Patients with Pancreatic Cancer: Results from In Vivo, Animal And Human Studies
Page: 91-100 (10)
Author: Marina Hodolic*
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Abstract
In nuclear medicine, multiple peptide receptors are recognized as potential
diagnostic and therapeutic targets. 68Ga-NT-20.3 radiopharmaceutical has been
developed for diagnosis of neurotensin receptors. Three neurotensin receptors subtypes
have been cloned: NTR-1, NTR-2 and NTR-3. NTR-1 is the most commonly expressed
neurotensin receptor. High NTR-1 expression has been observed in various tumours
including pancreatic ductal adenocarcinoma. 68Ga-labelled NT ligand was successfully
applied in in vitro, animal model as well as in human. The results on humans
demonstrated that PET radiopharmaceutical 68Ga-NT-20.3 is safe and well tolerated.
Based on the published data, NTR-1 is promising target for the development of
radioactive analogues for both imaging and therapy in patients with primary and
metastatic pancreatic ductal adenocarcinoma.
Dr. Saul Hertz (1905–1950) Discovers the Medical Uses of Radioactive Iodine: The First Targeted Cancer Therapy
Page: 101-110 (10)
Author: Barbara Hertz*
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Abstract
Dr. Saul Hertz (1905-1950) conceived and brought from bench to bedside
the medical uses of Radioiodine (RAI). Dr. Hertz established the use of
radiopharmaceuticals to diagnose and treat disease. He spontaneously posed the
question “Could iodine be made radioactive artificially?” to MIT President Karl
Compton on November 12, 1936. MGH's Dr. Hertz and his MIT collaborator, Arthur
Roberts, Ph. D., were the first and the foremost to develop the experimental data for the
medical uses of radioiodine (RAI) and apply RAI in the clinical setting. Dr. Hertz
successfully used RAI in diagnosing and treating hyperthyroidism and thyroid cancer,
believing that the targeted precision approach held the key to the larger problem of
cancer in general. RAI is the first and gold standard of targeted cancer therapies.
Hertz established the Radioactive Isotope Research Institute and The Massachusetts
Women’s Hospital’s their first Nuclear Medicine Department reported as,” Opening a
new division where radioactive isotopes will be used to study and treat disease.”
Dosimetric Approach to Radioactive Iodine Therapy of Differentiated Thyroid Cancer
Page: 111-118 (8)
Author: Hee-Seung Henry Bom*
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Abstract
My personal memory with Prof. Kalevi Kairemo is related to our coworking
for biokinetics of radioactive iodine (RAI), and a couple of international conferences
organized by him. I presented my data on the dosimetric approach of RAI treatment for
differentiated thyroid cancer (DTC) at the conference in Helsinki. We analyzed the data
of our work and published a paper. Here I summarize my experience of working with
him. In summary, maximum permissible dose (MPD) therapy with dosimetry is
effective for a selected group ofhigh-risk DTC patients. Calculation of MPD is feasible
either by tracer and therapeutic doses and either by blood clearance method and
metaphase analysis of peripheral blood lymphocytes. The use of recombinant thyroidstimulating
hormone (rhTSH) changes the biokinetics of RAI. It needs further
investigation whether rhTSH can be used for MPD therapy of DTC.
Extent of Surgery and Following Treatment Depending on The Risk Evaluation of Thyroid Cancer
Page: 119-134 (16)
Author: Ilya V. Sleptsov*
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Abstract
The experience gained in North-West Center for Endocrinology and
Endocrine Surgery (St.Petersburg, Russia), performing about 6000 endocrine surgeries
annually, shows that in a significant part of patients presenting with differentiated
thyroid cancer, it is possible to perform organ-preserving surgeries and to avoid using
radioactive iodine therapy. Such tactic are possible only in the settings of the presence
of high-quality preoperational cytological diagnostics, thorough following the preoperative
examination protocol (ultrasound examination of the neck area performed by
the operating surgeon and by the Head of the clinics, further computed tomography of
the chest in all the patients with cytological diagnosis of Bethesda 6, screening of
medullary carcinoma using calcitonin blood tests), performing radical resection of the
primary tumor with a wide use of preventive central cervical lymph node dissection
controlled by intra-operative neuro-monitoring, as well as in the settings of long-term
follow-up by the operating surgeons employed in the clinic. Radioactive iodine therapy
is an integral phase of therapy for locally advanced tumors and tumors with the
presence of distant metastases or high risk of the distant metastatic activity. Making the
decision on the necessity of radioactive iodine therapy is possible both based on the
evaluation of primary tumor characteristics and the evaluation of blood levels of
thyroglobulin and antibodies to thyroglobulin.
The Rise of Biopharmaceuticals and Immuno-PET: Where Pharmacy and Radiopharmacy Meet
Page: 135-145 (11)
Author: Guus A.M.S. van Dongen*
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Abstract
The identification of molecular drivers of disease and the compelling rise of
biotherapeutics such as peptides, monoclonal antibodies, antibody fragments and nontraditional
binding scaffolds, activatable antibodies, bispecific antibodies,
immunocytokines, antibody-drug conjugates, enzymes, polynucleotides, therapeutic
cells as well as alternative drug carriers like nanoparticles have impacted clinical care
but also came with challenges. Drug development is expensive, attrition rates are high,
and efficacy rates are lower than desired. Nowadays, almost all these drugs, which
generally have a long residence time in the body, can be stably labeled with 89Zr for
whole body PET imaging and quantification. Although not restricted to monoclonal
antibodies, this approach is called 89Zr-immuno-PET. This contribution summarizes at
a high level the historical background, the technical aspects, and the future perspectives
of 89Zr-immuno-PET.
In the Wake of European Winds and Head and Neck Radioisotope Imaging
Page: 146-151 (6)
Author: Erkki Hopsu*
PDF Price: $30
Abstract
The first reported imaging studies with radio-labelled antibodies of head and
neck cancer patients were published at the halfway of 1980s. Started with polyclonal
anti-CEA antibody, the anti-CEA monoclonal antibody was followed shortly thereafter
in the radioimmunoscintigraphy imaging of head and neck tumor patients. Despite a
promising platform, the pilot-antibody studies in the latter part of the last millennium
have in the end, not yielded a clear advantage or benefit to support clinical decisionmaking
by RIS imaging method in head and neck tumors, neither in terms of diagnostic
imaging nor in terms of treatments. The investigated antibodies have not been shown to
be sufficiently selective in identifying head and neck tumors.
Radionuclide Management of Prostate Cancer: Molecular Targeting of Tumour; Strategic Targeting of Patients
Page: 152-163 (12)
Author: J. Harvey Turner*
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Abstract
The 2020 American Society of Clinical Oncology (ASCO) Guideline for
optimum imaging strategies for advanced prostate cancer [1] encompasses patients
with newly diagnosed clinical high risk disease, suspected or confirmed metastatic
disease, recurrent disease or progressive disease while under treatment. It is
recommended that “imaging studies that will not impact or inform treatment decisions
should be minimized.” It is admitted that “studies have generally shown the superior
diagnostic performance of 68Ga-PSMA, 18F-DCFPyL and 18F-PSMA-1007 over other
relevant radiotracers in the clinical settings of intermediate to high-risk primary cancer,
biochemical recurrence after definitive therapy, and delineation of the extent of
metastatic disease and patient eligibility for PSMA-targeted radioligand therapy.” “The
major impact of PSMA-PET imaging on the management of patients with prostate
cancer” is acknowledged. Nevertheless, there will be no ASCO guideline
recommendation for PSMA radionuclide theragnostic diagnosis or therapy until the
perceived “need to define the potential influence on outcome has been satisfied by
additional investigations.”
The immediate challenge for nuclear physicians is to design and execute the
prospective controlled clinical studies in large representative populations of defined
advanced prostate cancer patients. These real-world patients, treated on harmonized
standard protocols, in accordance with European Association of Nuclear Medicine
(EANM) Guidelines, with primary outcomes of overall survival (OS) and quality of life
(QOL), may provide acceptable evidence of efficiency leading to regulatory approval
and eventual reimbursement and oncologist acceptance into routine clinical practice.
How this desirable outcome may be achieved is the subject of this review of 68Ga/18FPSMA
PET imaging and 177Lu/225Ac-PSMA therapy in which the current status of
theragnostics of advanced prostate cancer is explored by reference to scientific
communications published in 2020.
Ga-PSMA PET/CT for Patients with Prostate Cancer with PSA Relapse
Page: 164-178 (15)
Author: Finn Edler von Eyben*
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Abstract
In Danish guidelines for imaging of patients with prostate cancer and PSA
relapse, PSMA PET/CT is the recommended restaging modality. A multicenter study
has been initiated to analyze findings of 68Ga-PSMA PET/CT scans for patients with
prostate cancer with PSA relapse. This report details preliminary findings of 779
patients in six cohorts from three continents. At the time of the restaging, the PSA
values were grossly similar between the six cohorts, with an important subgroup of the
patients having PSA values < 1 ng/ml. Patients who initially underwent radical
prostatectomy had lower PSA values at the restaging than patients who were initially
treated with external beam radiation therapy or brachytherapy. Even for patients with
restaging PSA values < 0.5 ng/ml, some patients had positive sites in extra pelvic
lymph nodes and bones. Patients were followed up to 7 years after the restaging PSMA
PET/CT. In multiple Cox regression analysis of 196 patients, only the number of
positive sites on 68Ga-PSMA PET/CT significantly predicted overall survival (p =
0.0001). The findings illustrate why restaging PSMA PET/CT change salvage
treatment for up to half of the patients with PSA relapse compared with planned
salvage treatment based on only conventional imaging modalities like CT and bone
scans.
Imaging Bladder Cancer
Page: 179-208 (30)
Author: Manisha Kumari, Sushil Tripathi and Mathew Thakur*
PDF Price: $30
Abstract
Imaging plays an important role in the management of bladder cancer (BCa).
Cystoscopy, ultrasound, computed tomography (CT) and magnetic resonance imaging
(MRI) are the commonly used imaging modalities. Introduction of positron emission
tomography (PET), a molecular imaging modality, with CT or MRI offers precise
anatomical reference. Certain molecules labeled with radiotracers such as Fluorine-18
and Carbon-11 have been evaluated for their potential applicability in PET imaging.
However, urinary excretion of Fluorine-18 and the very short half-life of Carbon-11
restrict their use. Copper-64 labeled peptide TP3805 (64Cu-TP3805) targeted to BCa
cell-specific receptors demonstrated promising results in detecting BCa and its
metastasis by PET imaging. A description of all these imaging modalities and their
recent advances, together with their potential advantages and limitations, are presented.
Radiomolecular Therapy of Neuroendocrine Character, Positive for sst2 Receptor Hepatocellular Malignancies
Page: 209-220 (12)
Author: G.S. Limouris*
PDF Price: $30
Abstract
In 1996, Krenning et al. injected the radiopeptide for the first time
intravenously.111In-Octreotide as a new treatment approach, today, worldwide known as
Peptide Receptor Radionuclide Therapy (PRRT) to confront unresectable
neuroendocrine tumors. We started treating this rare category of neoplasms in our
Institution in 1997, exclusively injecting intra-arterially, initially 111In Octreotide, in
high doses, focused our interest on multiple liver metastases (particularly, less than 20
mm, in diameter) after catheterization of the hepatic artery [“Aretaieion Protocol”]. The
radiopeptide was infused in repeated high activity, ranging per session from 4.070 GBq
(110 mCi) to 5.920 GBq (160 mCi) with a time interval between sessions of 6-8 weeks,
seeking to achieve a tumor absorbed dose according to the dosimetry followed, over 70
Gy (tumor mass 10 gr). When 90Y DOTA-TOC was used (3 folds in total, in bi-monthly
intervals between sessions), the infused activity was 4.1± 0.2 GBq per patient, per
session, whereas when n.c.a. 177Lu-TOTA-TOC was injected (6 folds in total, in bimonthly
intervals between sessions), the activity was 7.0 ± 0.4 GBq per patient, per
session. Follow-up at tri-monthly intervals was performed by means of ultrasonography
(US) and every six months, by contrast, material-enhanced computed tomography (CT)
and / or magnetic resonance tomography (MRI). This therapeutic procedure is
described in detail, based on the experience in more than 800 hundred catheterizations,
analyzing its advantages and limitations as a first-line treatment scheme for the
management of this rare category of tumors.
Abstract
Frankly, Japan is at the end of the line of current clinical theranostics such as
PRRT and PSMA. Many patients go abroad for PRRT and PSMA treatment. This
lamentable situation has been caused mainly by the strict regulations as well as the
limited number of isolation rooms available for these purposes in this country. But
despite this, Japanese scientists are developing several unique activities in theranostics,
including 211At[NaAt] for 131I radioiodine refractory thyroid cancer and meta-211Atastato-
benzyl guanidine (211At-MABG) for 131I-MIBG refractory pheochromocytoma/
paraganglioma, which are currently ready for investigator-initiated trial. There are
several other developments in this field. Such information is described in this short
article.
Abstract
Over the past decades, Professor Kalevi Kairemo has been a well-known and
dear colleague with whom we have excellently cooperated, especially via the
international organisations IAEA (International Atomic Energy Agency) and The
WARMTH (World Association of Radiopharmaceutical and Molecular Therapy). The
work resulted in the construction of radiotracers using different modal systems,
including a variety of radiolabelled peptide analogues such as somatostatin,
cholecystokinin (CCK-2/gastrin), or prostate-specific membrane antigen (PSMA)
ligand for specific tumour targeting. Radiopharmaceuticals are produced at clinical
grade in dedicated laboratories for use in SPECT/CT or PET/CT studies. Patients
evaluated by SPECT/CT dosimetry studies are treated with high dose thera(g)nostics.
Radioiodine ablation therapy of thyroid cancer remnants, peptide receptor radionuclide
therapy (PRRT) of NET patients, and peptide ligand radionuclide therapy (PLRT) of
PC patients are today the most important therapeutic tools.
Precision Oncology Through Radiating Bullets: What All We Have Conquered and What All We Have To
Page: 246-254 (9)
Author: Partha S Choudhury* and Manoj Gupta
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Abstract
Precision oncology refers to personalized or precise oncological care for
each patient based on their biomarkers, gene sequencing profile, and disease /receptorspecific
imaging status. Precision oncology through theranostics is derived from a
diagnostic tool that helps identify a therapeutic tool for a specific disease. In Nuclear
Medicine, a radioisotope with suitable imaging characteristics or a tracer labeled ligand
is fired to a particular target on a cancer cell. After identification of the target, it is
labeled with a tracer having therapeutic characteristics labeled with the same ligand to
target the disease. The theragnostic concept was first used in 1964 to treat thyroid
cancer with radioiodine I-131 (RAI). With the passage of time, this concept has been
refined, and more theragnostic pairs have been added successfully for clinical use.
The growth of the theragnostic in India is parallel to the west with the availability of
indigenous radiotracers like Lu-177 and others, available from the reactors of Bhabha
Atomic Research Centre (BARC). The peptides like DOTATATE and PSMA are also
available in a ready-to-use labeled form with an excellent tradesmanship by BARC and
Board of Radiation and Isotope Technology (BRIT) We, in India, perform radionuclide
therapies for neuroendocrine tumors (NET) and metastatic castration-resistant prostate
cancer (mCRPC) regularly. The main constraints about this concept are the cost of
treatment and awareness among the clinicians. These are gradually being taken care of
by the private health insurance and our participation in disease management group and
tumor board meetings. The theragnostic concept has become quite popular over the
years and has the potential for further and rapid sustained growth. This article is a
living tribute to Prof Kalevi Kairemo, who has a tremendous research interest in radiotargeting
and molecular radiotherapy.
Current Status of PSMA Targeted Alpha Therapy in Prostate Cancer Patients
Page: 255-264 (10)
Author: Thabo Lengana* and Mike Sathekge
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Abstract
Despite multiple new agents having been available routinely for men with
metastatic castration-resistant prostate cancer (mCRPC), the diagnosis remains fatal,
with these agents contributing minimally to over-all survival. Targeting the prostatespecific
membrane antigen (PSMA) has been attractive because it is overly expressed
in prostate cancer cells with upregulation of the over-expression related to tumour
grade, castration status and metastatic disease. To this end novel agents have been
developed targeting the PSMA antigen not only for imaging but also for therapy.
Actinium-225 (225Ac), an alpha emitter, has been labelled to PSMA ligands as 225Ac-
PSMA for targeted alpha therapy (TAT). 225Ac deposits high energy, resulting in
irreparable double strand DNA destruction while sparing surrounding normal tissue,
making it an attractive anti-tumour agent. Clinical application of 225Ac-PSMA TAT as
the last line of therapy in patients with mCRPC has demonstrated an excellent
response, especially in the setting of chemotherapy-naive patients. Widespread
application of 225Ac-PSMA TAT, though remains hampered by its salivary gland
toxicity.
Nanotheranostics: A Dream Coming True
Page: 265-271 (7)
Author: Oula Penate Medina* and Tuula Penate Medina
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Abstract
This chapter discusses how nanoparticles and multimodal nano-imaging are
bringing closer to the moment where imaging and therapy converge. This means that
the diagnosed illnesses can be treated in situ based on the imaging result allowing
personalized Nano-medicine. There are already theranostic nano-medicines that can do
precise drug delivery only to the targets that are seen and approved by radiology and
nuclear medicine tools. In this chapter, we also discuss the already existing emerging
techniques and their challenges and implications on the traditional pharma industry and
startup-driven biobusiness.
“Fit for Purpose” 64Cu Labeled Liposome Formulations Specialized for Enriched Targeting to 1) Bone Marrow Spleen; 2) lymph Nodes; or 3) Tumor
Page: 272-276 (5)
Author: Sang-Gyu Lee*, Kishore Pillarsetty and Steven M. Larson
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Abstract
Upon intravenous injection, liposomal particles are rapidly cleared from the
blood by fixed macrophages in the liver, spleen, bone marrow and lymph nodes i.e.
specialized cells of the innate immune system. By reducing the affinity for these fixed
macrophages, therapeutic liposomes containing drugs have been used to target tumor
by the Enhanced Permeability and Retention (EPR) effect. In this communication, we
report minor modifications of lipid compositions that result in the production of 3
classes of liposomes, each suitable for enhanced selectivity of uptake in 1) Bone
Marrow/Spleen (SBMT Lipo); 2) Lymph Nodes (LNT Lipo); and 3) Tumor (TT Lipo).
Theranostics at the Crossroads of Precision Health and Precision Medicine
Page: 277-281 (5)
Author: Hossein Jadvar*
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Abstract
There have been major recent advances in multiple disciplines that have
culminated into the underpinnings of precision health and precision medicine. The
advances include but are not limited to new insights into human biology in health and
disease, innovations in computation technology capable of storing and processing
massive amounts of multidimensional data (big data), improvements in imaging
technology, and developments such as sophisticated radiomics, and incorporation of
artificial intelligence and deep learning. Theranostics, which is an integration of
targeted diagnostics and therapeutics, is emerging rapidly and is positioned
strategically to link precision health and precision medicine.
Oncolytic Immunotherapy: From Spontaneous Regression to Development of Armed Gene Modified Viruses
Page: 282-294 (13)
Author: Akseli Hemminki* and Joao M. Santos
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Abstract
Spontaneous regression of tumors, meaning the disappearance of clinically
diagnosed tumors without treatment, is a relatively rare but well-established
phenomenon. Many explanatory theories have been proposed, but currently, the
strongest data support a role for microbial infection in inducing antitumor immunity,
which then eradicates the tumor. For at least 4600 years, physicians have been
attempting to take advantage of this phenomenon. Initially, bacteria or bacterial
products were used for infecting tumors or cancer patients. Then, about a hundred years
ago, the focus shifted to viruses. Initially, virulent wild-type (unmodified) viruses were
used, but these caused many side effects. In the late 20th century, the generation of
modified (recombinant) viruses became possible. Oncolytic viruses are replicationcompetent
only in tumors. Initial modifications of the respective wild-type viruses
focused on making them safer for clinical use, and the next step was increasing efficacy
by arming with transgenes. The field of immunotherapy evolved to take advantage of
immune cells directly in approaches such as dendritic cell therapy and adoptive T-cell
therapy. It was also discovered that many T-cells are inhibited by tumors, and that they
could be reactivated with checkpoint inhibitors. An unexpected finding relating to the
gut microbiome ties together microbes, diet and the immune system. Cancer
immunotherapy can already cure some patients, and rapid steps forward are expected to
continue. Learnings from attempts of recreation of spontaneous regression have
contributed to these developments in an important manner.
Boron Neutron Capture Therapy and Targeted Alpha Therapy for Intractable Cancers Combined with Positron Emission Tomography/Computed Tomography
Page: 295-308 (14)
Author: Jun Hatazawa*
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Abstract
The boron neutron capture therapy (BNCT) is based on the cell-killing effect
of α-particle and lithium-particle produced in the body by 10B (n, α) 7Li nuclear
transmutation reaction after 10B delivery to target cancer cells and local irradiation of
neutron. Neutron source was initially a nuclear reactor, and recently in-house
accelerator. 10B delivery molecule was 10B-boronophenylalanine (10B-BPA), which was
transported into cancer cells through L-type amino acid transporter 1 (LAT1)
predominantly expressed on the membrane of cancer cells. 18F-fluor-
-boronophenylalanine (18F-FBPA) was a PET probe to estimate 10B-BPA accumulation
in the target tumor and surrounding normal tissue. The BNCT was recently approved as
a treatment of head and neck cancer in Japan. The targeted α therapy (TAT) employed
α-particle emitting radioisotopes mainly to metastatic cancers. The element 85, 211At
with physical half-life of 7.2 hours, belongs to halogen family in the Periodic Table. Its
distribution was similar to 131I. We are now trying to apply 211At to treat intractable
thyroid cancers and other types of advanced cancers. Preclinical studies with 211At
labeled LAT1 compounds including 211At-phenylalanine (211At-Phe) and 211At-α-methyl
tyrosine (211At-AAMT) demonstrated their tumor growth suppression effect on the
xenograft model of glioblastoma and pancreatic cancer in rats, respectively. 18F-fluor-
-phenylalanine (18F-FPhe) and 18F-fluoro-α-methyl-tyrosine (18F-FAMT) are PET
probes to study their accumulation to cancers, respectively. The BNCT and the TAT
combined with PET/CT imaging may provide effective treatment of intractable and/or
metastatic cancers.
Targeting Imaging Brain Lesions with PET/CT: F18-CH and F-18-FLT
Page: 309-316 (8)
Author: Alexandra Nikaki*
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Abstract
Passing to the era of molecular imaging and precision oncology, the
radiopharmaceuticals may play an incremental role in further revealing the nature of
the evaluated lesion. FLT, a radiolabeled thymidine analogue, and FCH, a radiolabeled
substance of the cell membrane phospholipids, have been more or less investigated in
the imaging, identification, and evaluation of brain tumor lesions. In our study, using a
Siemens Biograph LSO PET/CT 16 slices device, a Siemens multimodality workplace
(MMWP) system for brain analysis, and qualitative and semiquantitative analysis
(SUVmax, SUVpeak, T/B ratio), we investigated the role of these two
radiopharmaceuticals in primary and metastatic brain lesions, lymphomas as well as in
investigating neurological symptoms with inconclusive/indefinite evidence in the
conducted MRI. Using F-18-CH for PET/CT imaging, we found that there was FCH
uptake by active tumor sites, with no statistical significance in SUVmax, SUVpeak and
T/B ratio for the discrimination of the lesions between primary, metastatic and
lymphomas, (p > 0.05). However, recurrent primary lesions exhibited lower T/B and
SUVmax compared to the respective mean values of the metastatic ones. With the
utilization of F-18-FLT we concluded that it could discriminate between active from
non-active foci, while mean values of T/B and SUVmax were statistically significantly
higher for NHL compared to primary and metastatic tumors (p<0,001). There was a
tendency for significance for SUVmax and T/B between low and high-grade recurrent
primary tumors (p=0.08 and p=0.06, respectively) when excluding the outliers.
However, further investigation is required for definite conclusions.
FDG Uptake by Brown Adipose Tissue in Paediatric and Adolescent Hodgkin Lymphoma, Visualised on PET/CT Performed at Diagnosis
Page: 319-328 (10)
Author: Linda Jorgov*, Anne-Ségolène Cottereau, Sona Balogova, Françoise Montravers and Jean-Noël Talbot
PDF Price: $30
Abstract
We aimed to shed some light on the relation between brown adipose tissue
(BAT) visualisation on FDG PET/CT at diagnosis in children with Hodgkin lymphoma
(HL) and the main determinants reported in adult HL, outside temperature, gender, age,
but also with the metabolic activity of HL lesions and of some organs that did not look
to be invaded by HL.
Pre therapeutic FDG PET/CT was performed in 135 children or adolescents suffering
from HL and was centrally blind read, in search for BAT visualisation, determination
of SUVmax of the liver, the bone marrow at the iliac crest and the spinal cord at Th12,
providing those sites did not show focal uptake evocative of HL. The maximum
SUVmax, total metabolic tumour volume, and total lesion glycolysis of HL were also
determined.
The visualisation of BAT as foci of FDG uptake in those patients with paediatric HL
was not significantly associated with gender, age, the outside temperature on the day of
PET/CT, the intensity of FDG in non-invaded organs and maximum SUVmax of HL
tumours. There was a trend for an association with lower tumour volume and lower
total lesion glycolysis of HL that did not reach the statistical significance level.
Our study confirms, in 135 paediatric HL patients at diagnosis, i.e. a homogeneous
clinical status, previous evidence derived from heterogeneous conditions, that the
epidemiology of BAT activation is quite different between paediatric patients and
adults. In relation to HL, BAT activation was not linked with the metabolic activation
of the liver, the bone marrow, and the spinal cord, which may be observed as a consequence of HL presence in the patient. Nevertheless, our results suggest that BAT
visualisation could be associated with a lower HL tumour mass.
[99mTc]Tc – MIBI as Oncologic Radiotracer
Page: 329-340 (12)
Author: Raluca Mititelu*
PDF Price: $30
Abstract
Latest advances in PET imaging, the growing importance of the theragnostic
approach and the inclusion of 18F-FDG in the staging guidelines of many oncological
situations put in shadow the research on SPECT radiopharmaceuticals, including those
considered classic as having oncological tropism. However, there are studies, some of
them very recent, that highlight an important role of MIBI in cancer imaging and
management. The dynamics of uptake and the wash-out process differ depending on
the cellular metabolism and can be used for various indications, one of them being
differentiation of malignant processes or predict chemotherapy resistance. In this paper,
we will review the literature and present most important actual and potential
application of 99m-Tc-MIBI scan in oncologic diseases.
The Actual Role of Nuclear Molecular Imaging in the Follow-up of Chemotherapy-Induced Cardiac Dysfunction
Page: 341-358 (18)
Author: Taner Erselcan*
PDF Price: $30
Abstract
The increase in life expectancy due to the increase in cancer treatment
success has made the follow-up of the acute, short and long-term cardiac side effects of
chemotherapeutic drugs more important today. Although chemotherapy-induced
cardiac dysfunction is one of the major problems, there is still a need for an accurate
and readily available non-invasive monitoring technique. In the present article, we tried
to evaluate past and present nuclear molecular imaging techniques from the perspective
of chemotherapy-induced cardiotoxicity monitoring.
Today neither nuclear imaging methods nor other techniques are sufficiently
accurate/readily available to use in clinical routine to show cardiotoxic effects of
chemotherapeutics at an early stage. However, nuclear molecular imaging can detect
biological processes at the molecular level that precede the structural changes and
pathological consequences of chemotherapy-induced cardiotoxicity.
Until today, many molecules to use with a conventional gamma camera or positron
emission tomography have been tried for this clinic pathology. Many of them have
been shown to have prognostic value in the early stages of the disease, but relatively in
small patient groups. However, sometimes due to difficulty in procuring, the lack of
comparative studies seems to prevent their value from coming to light. There is a need
for additional studies to clarify the role of nuclear imaging of cardiac damage in
chemotherapy-induced carditoxicity.
Quantitation of Myocardial Perfusion using 15OWater PET: From a Research Tool to Clinical Routine
Page: 359-367 (9)
Author: Juhani Knuuti*
PDF Price: $30
Abstract
The application of 15O-water for cardiac PET perfusion imaging was one of
the main goals when this tracer was developed. However, the development of a method
from basic research to routine tool in clinical work takes a long time. With the case of
cardiac 15O-water PET it took 22-27 years from the initial plans to clinically accepted
tool. This is likely not unusual as the validation of new method and demonstrating the
clinical impact requires many studies and a long time. Eventually, the method has been
now included in the European clinical guidelines of chronic coronary syndromes as an
accepted clinical tool. This paper illustrates the development of the cardiac 15O-water
PET at Turku PET Centre, one of the pioneers in developing the method from bench to
bedside. Despite the current success, there are still many open issues, which warrant
further development and studies.
Bone Targeted Radionuclide Therapy in Russia From Beta- to Alpha- Emitters
Page: 368-383 (16)
Author: V.V. Krylov*, T.Yu. Kochetova and N.G. Seleva
PDF Price: $30
Abstract
Treatment of patients with painful multiple bone metastases is a complicated
clinical task. Radionuclide therapy is one of the solutions, which is used to achieve the
long reduction of pain syndrome and to significantly improve the quality of life.
However, the mechanism of action of bone-seeking radiopharmaceuticals suggests not
only pain control but the antitumor effect as well. In early clinical studies of safety and
efficacy, single administrations of the most common bone-seeking
radiopharmaceuticals did not demonstrate any benefit in overall survival, but individual
extraordinary tumor regressions were reported. Repeated administrations and
combination with other treatment modalities can help to gain a statistically significant
increase in overall survival. In this chapter, the history of bone-targeted radionuclide
therapy in Russia is reviewed.
Role of Beta-Emitter Sm-153 in Combined and Complex Therapy of Skeletal Metastases
Page: 384-394 (11)
Author: Nigora Rasulova*
PDF Price: $30
Abstract
In spite of significant progress in the diagnosis and management of solid
tumors, the incidence of bone metastasis is still high, and the use of bone-targeted
agents does not prevent the development of their complications such a skeletal related
events. While the most current bone targeting medications act on the bone microenvironment
and the osteolytic bone metastasis. The beta-emitters radiopharmaceuticals
such as Samarium-153-ethylene diamine tetramethylene phosphonate and
Sm-153 oxabifore target osteoblastic bone lesions by irradiating nerve fibers that
innervate the skeleton and cancer cells which may lead to the termination of growth
factorsthat stimulates cancer cell dissemination to the skeleton.
However, their role usually is limited by palliative treatment for painful bone
metastases. Recently it is demonstrated that the combination of radionuclide therapy
with bisphosphonates or chemotherapy is potentially more effective as compared to use
in isolation. The synergetic approach of bone metastasis therapy is perspective;
however, chemotherapy is generally contraindicated in combination with radionuclide
therapy due to possible synergetic myelotoxicity. Vertebral fracture and impending
cord compression are other contraindications for radionuclide therapy.
In this book chapter, we presented possible combined/complex therapy approach
including best timing of radionuclide/bisphosphonate administration, combined therapy
with monoclonal antibody Denosumab its effectiveness and metabolic response,
radionuclide therapy in combination with percutaneous vertebroplasty, possibility to
use Sm-153 therapy in combination with bisphosphonates, hormonal therapy,
chemotherapy and targeted therapy in breast cancer patients, side effects, survival rate
and incidence of SRE in patients who received combined/complex therapy and the
possibility to use of lactate dehydrogenase level as an indicator of disease progression.
Molecular Radiobiology and Radionuclides Therapy Concepts
Page: 395-408 (14)
Author: Aisyah Elliyanti*
PDF Price: $30
Abstract
Radionuclides therapy (RNT) development is a multidisciplinary endeavor.
It requires expertise in radiochemistry, radiobiology, oncology, pharmacology, medical
physics, and nuclear medicine. Many pharmaceutical companies are not familiar with
the aspects of radiation and radionuclide therapy, and the deployment of RNT agents
for cancer therapy is also unfamiliar to the oncology community. When compared with
almost all other systemic cancer treatment options, RNT has shown efficacy with
minimal toxicity. Moreover, molecular radiobiology needs to be further explored to
gain knowledge of the bystander's radiation effect. It can lead to updating for systemic
radionuclide therapy concept. This paper aims to review radiation biology and
radionuclides concepts to better understand the importance of basic concepts of
ionizing radiation, particularly for a systemic cancer treatment option.
War and Peace Inside - imaging Immune Attack in Blood Vessels
Page: 409-417 (9)
Author: Seppo Meri*
PDF Price: $30
Abstract
During evolution, immunity has been developed to protect against invading
organisms and remove unwanted structures, like malignant cells. Yet, in extreme cases
the organisms, like bacteria or parasites, find their way through tissues and can survive
even in blood, which contains most elements of the immune system. A drastic example
is parasitic Schistosoma mansoni worms that can live within blood vessels for years.
Imaging studies have helped us to visualize ways how Schistosoma parasites can
escape immune attacks inside circulation. Parasites often escape the immune system by
hijacking soluble inhibitors of the blood complement inhibitors. By molecular
radioimaging it is also possible to trace the accumulation of these inhibitors to their
targets. Specifically, our collaborative work has been able to demonstrate the
acquisition of immunoglobulins by adult S. mansoni worms and show the distribution
of the complement inhibitor factor H in live animals. Radioimaging can thus be applied
not only to detection of tumors and their metastases but to analysis of immune
reactions against endogenous and exogenous targets in vivo.
Observations on Russia’s COVID-19 Politics
Page: 418-423 (6)
Author: Markku Kangaspuro*
PDF Price: $30
Abstract
Russia’s Sputnik V vaccine has become for various reasons, a topic of
geopolitical struggle, a source of vaccine nationalism and Russia’s soft power, and
conversely, a source of Western vaccine nationalism also. Global competition over the
souls and minds of low-resource countries will continue since 80 percent of their
population will not receive a vaccine this year. In this context, Sputnik V is not only a
medical achievement and a step towards overcoming the pandemic, but it has also
interpreted a political victory for the Russian regime. Politicization and suspicions over
the vaccine, the lack of transparency and deep distrust of the Russian authorities’
actions against COVID-19, and the impact of the pandemic, as well as several factors
related to Russian political culture, have caused problems for the regime. The general
lack of trust and the public belief in conspiracy theories, as well as widespread vaccine
skepticism, have had a significant influence on Russians’ attitude towards vaccination
and restrictions. A significant portion of populace is skeptical about COVID-19, and
the vaccine and vaccinations have not progressed very well so far. The biggest
challenge of regime seems to be gain the trust of the population to achieve adequate
vaccine coverage and herd immunity.
Radiomics Analysis of 177Lu-PSMA I&T Radioligand Therapy Dosimetry in a Castration Resistant Metastatic Prostate Cancer Patient
Page: 424-429 (6)
Author: Eve Kelk*
PDF Price: $30
Abstract
177Lu-DOTAGA-(l-y)fk(Sub-KuE) (177Lu-PSMA I&T) is currently used for
radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC)
in several centers in Europe. It was launched in Tallinn, Estonia, in December 2018. As
an additional project, a model of dosimetric analysis was created, utilizing voxel-based
dosimetry and intra-lesion radiomics to assess their practicality in routine dosimetry
[1]. This was a successful project, and the work is summarized in this chapter.
Dancing in the Rain. Cancer as a Personal Experience
Page: 430-439 (10)
Author: J.P. Roos*
PDF Price: $30
Abstract
A discussion on the experience of cancer and how it affects one's personal
life Many authors think that cancer is in the last instance a positive learning experience.
At least it is seen as necessary to emphasize the positive attitudes towards cancer when
trying to overcome its effects and recover. Hope is seen as the essential ingredient of
adapting to cancer. Or fighting it. I also compare having cancer to corona or getting to
know of your spouse's unfaithfulness.
The Flat Earth: Working with Patients and Patient Advocates in our Connected World
Page: 440-443 (4)
Author: Josh Mailman*
PDF Price: $30
Abstract
This is a patient´s journey after a diagnosis of rare cancer in the
US and multiple treatments in Europe who became active in the cancer support
community, communicating and networking with each other, patient to patient,
provider to provider, and provider to patient. In addition of being active in their patient
networks, this is a prime example of how patients can contribute to the scientific
community by actively participating in social networks and global scientific
conferences.
Introduction
The Evolution of Radionanotargeting towards Clinical Precision Oncology is a remarkable book honoring Professor Kalevi Kairemo, who is known among academic and medical circles as a pioneer in novel radiolabeled therapeutics. This festschrift provides an overview of key advances in the field of radionanotargeting, and the directions for future development in patient care. Prof Kairemo's research is based on multiomics, which involves multiple elements: genomics, transcriptomics, proteomics, metabolomics, microbiomics, epigenomics, exposome, imaging, and precision medicine, which is reflected by the unique collection of articles presented. The articles start from the angle of radionanotargeting and theragnostics leading to imaging and therapy, which includes sections for thyroid cancer, head and neck cancer, genitourinary cancers and neuroendocrine neoplasms. Theragnostics, nanoparticles and precision oncology have also been covered in their own segments, while also giving a glimpse of research in metabolic imaging, cardiovascular radionuclide imaging, and bone therapies. The sequence of chapters demonstrates how, through Professor Kairemo's efforts, radionanotargeting has evolved to a practice changing therapeutic approach in the clinic, particularly in oncology. Finally, Professor Kairemo's own memoir, Seven decades in health care and memoirs from colleagues including a personal introduction to him with a photographic cavalcade reveals the world of a multitasking person with a multidisciplinary approach to science, that ushered his development of significant expertise across the fields of chemistry, biology, engineering, physics and clinical medicine. This book is excellent for medical historians, trainees and specialists in clinical and radiological oncology in expanding their understanding of the role of radionuclide imaging over the years, making it an ideal tribute that belongs in the library of anyone involved in the field.
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