Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Wounds and Injuries

Symptoms and General Pathology

Musculoskeletal Diseases

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Fractures, Bone

Disease Progression

Bone Neoplasms

Fractures, Spontaneous

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Disease Attributes

All patients referred to the Hematology clinic for diagnosis and treatment of active multiple myeloma will be asked to participate in the study and undergo 3 consecutive low-dose CT scans over a period of 12 months. For non-consenting patients only minimal demographic data will be documented.

Eligible consenting patients will sign informed consent.

CTFEA is a computerized analysis of CT-scans which simulates stress testing of finite element models of various bones (in this study - femurs and vertebrae).

No intervention is planned - the study is observational. CT scans are performed for follow-up as an accepted standard of care. Secondary use of CT scans for CTFEA is in addition to the standard of care.

In a case when CTFEA analysis detects a high risk of pathologic fracture, the treating hematologist will be informed and will refer the patient for evaluation at the National Unit of Orthopedic Oncology.

CT-based finite element analysis

Amir Sternheim, MD

Haggai Schermann, MD

Patients with Multiple Myeloma are monitored for disease progression and for response to treatment by the treating hematologist or oncologist. Laboratory tests are usually utilized for these purposes. The role of imaging is confined to follow-up the progression of visible bone lesions. We suggest that microscopic bone lesions impair bone structure well before they grow enough to be visible on a CT scan. This impairment of bone strength can probably be captured by application of CT-based finite element analysis to the CT scans that were performed for monitoring of progression of the disease.

Background

Multiple myeloma (MM) is the most common primary bone malignancy, caused by proliferation of plasma cells secreting immunoglobulins. Active MM (aMM) is characterized in many patients by multiple lytic bone lesions, presenting with pain in the involved bones (e.g. pelvis, spine, etc.). In a recent publication, key-opinion leaders of multiple-myeloma state "MM-induced bone disease is a hallmark of MM; up to 80% of patients present with osteolytic bone lesions at diagnosis and have an increased risk of skeletal-related events (SREs) associated with increased morbidity and mortality" (Terpos et al, 2018). Approximately 60% of myeloma patients will develop a fracture during the disease course" (Terpos et al, 2018). Current CT scans provide qualitative measures of bone involvement detected only after irreversible damage has occurred and which cannot predict disease evolution so to optimize treatment and enhance life quality and longevity.

Medical treatment modalities, including multi-agent chemotherapy and bone marrow transplantation, may stop progression of MM, and prevent further bone lesions. Myeloma response to therapy is usually monitored by measurement of the monocloncal protein which is secreted by the malignant plasma cells into the blood and urine. This protein includes an intact immunoglobulin - M-SPIKE - which is measured by serum protein electrophoresis (SPEP) and, Circulating free light chains - kappa and lambda. Usually one of the chains is "involved" in the disease; The level of M-SPIKE and the ratio of the "involved" to "uninvolved" chains is used to monitor disease progression. The role of imaging technologies in monitoring progression of the disease is less defined. Low-dose total body CT scans are recommended as second-line imaging (total body MRI is first-line) during the initial diagnostic workup of MM by the most current guidelines of National Institute for Healthcare Excellence (NICE, 2016). The guidelines encourage further research of the role of various imaging modalities in treatment of MM:

"Newer imaging techniques are replacing skeletal surveys for assessing myeloma related bone disease in people with newly diagnosed myeloma. However, the most effective tech-nique is not known. Outcomes of interest are lesion detection, sensitivity and specificity for myeloma related bone disease, patient acceptability, incremental upstaging, radiation exposure, risk of second primary cancer, the impact of additional information on predicting progression-free survival, overall survival and skeletal related events." (NICE, 2016) As previously stated, current imaging modalities visualize bone lesions but do not quantify their progression, any response to therapy or their impact on bone strength. A novel scientific tool that describes bone's response by mathematical equations and is based on CT scans of MM patients, allows to construct a 3-D model of patient's femurs and vertebrae including the inhomogeneous material properties, virtually loads the bones by physiological loads associated with patient's weight and determine the deformations and strains by a computer simulation. This technology, termed CTFEA, allows a quantitative evaluation of bone's strength and risk of fracture, was double-blinded validated ex-vivo, and clinically validated in a retrospective clinical trial on a cohort of 50 patients with metastatic tumors to their femurs (Sternheim et al, 2018).

Combining the engineering and scientific expertise with the clinical knowledge and database of MM patients accumulated during the past ten years, may identify by monitoring femurs' and vertebrae' strength the evolution of MM, and trigger the need of prophylactic surgeries. Such CTFEA has the potential to revolutionize MM treatment by providing the MDs quantitative scientific measures to monitor and change treatment options so to optimize medication prescription and enhance life-quality and longevity of MM patients on one hand, and determine with high level of accuracy the risk of impending fracture due to metastatic tumors to the femurs and vertebrae.

Preliminary results on a cohort of seven MM patients (Cohen et al, 2017), has recently been presented in Dec 2017 at the ASH conference in the USA. These results showed the potential of assisting MDs to determine disease evolution and treatment. Since the vertebrae are prone to MM involvement, we plan to validate the CTFEA methods for such vertebrae with MM involvement by comparing experiments performed on cadaveric human vertebrae with the computational simulation. In addition, we propose to in-vivo validate the accuracy and predictability of patient specific CTFEA of vertebrae and femurs by a clinical trial on a cohort of MM patients treated at Sourasky medical center.

Rationale CTFEA may add efficacy to CT scans used for follow-up of disease progression. This analysis can detect differences of as little as 10% in bone strength. It has the ability to detect changes even in normal looking bone on CT and not just in lytic lesions. In addition, CTFEA characterises the effect of each myeloma lesion on bone structure and calculates the risk of a pathologic fracture.

Study hypothesis:

We hypothesize that CTFEA analysis of LDTBCT will detect changes over time in patients with a dynamic disease, even when these changes in CT are undetectable to the human eye.

Study objectives:

Primary objective:

To observe CTFEA-determined bone strength changes over time in patients with Active MM.

Secondary objectives

1. To measure CTFEA changes over a period of 12 months in lumbar vertebrae and femurs of patients with AMM.
2. To determine correlation between CTFEA and clinical indicators of response to treatment (e.g. light chains, clinical staging of bone lesions).
3. To compare CTFEA changes over time between patients responding to AMM treatment and those who do not respond to treatment.

Methods Study design This is a prospective study with one patient group. All patients will undergo three Low-Dose Total Body CT (LDTBCT) scans as part of diagnostic workup for MM, which represents our current common practice: at 0, 6 and 12 months into treatment (or 3 CT scans at least 6 months apart).

All three scans will be sent for CTFEA, which is not part of the common practice. The CTFEA results will be compared to clinical assessments as per patient files and light chain values on blood work. Changes in lesion size will be compared to changes that the lesion inflicts in bone structure and changes in the risk of fracture.

Bone strength in both femurs and lower lumbar vertebra will be analyzed even where there are no lytic lesions for changes in bone strength.

Results will be correlated with Myeloma clinical variables including baseline demographic and disease charateristics, therapy details and response to treatment over time.

Patients will continue followup, for recording of skeletal related events (fratures or new lytic lesions)

Measured parameters

1. Primary and secondary disease diagnoses and their ICD-9 codes.
2. Patient ambulatory status at time of MM diagnosis: independent walker; cane ambulator; walker ambulator; wheel chair bound.
3. Time since patient was independent walker, ECOG performance status (Oken et al, 1982)(Appendix A).
4. Treatment for osteoporosis and duration.
5. Date of diagnosis of active MM (and preceding plasma cell dyscrasia if relevant)
6. Myeloma treatment details (dose \& dates) and response to therapy according to IMWG criteria (IMWG, 2010)(Appendix B)
7. CT scans (used for CTFEA) dates.
8. Last patient follow-up date.

10) Medical center at which the patient received their oncology treatment before the hematology referral.

11) Laboratory results, specifically: Myeloma paraprotein measures including SPEP, quantitative immunoglobulins and free light chain values; kidney function; CBC; LDH; B2MG; FISH cytogenetics; BM PC% at diagnosis 12) active myeloma clinical presentation: CRAB criteria (hypercalcemia / renal / anemia / bone lesions); and or SLIM-CRAB criteria (FLC ratio\>100; focal lesions on MRI or PETCT; BM PC\>60%); 13) clinical status at time of CT scan (newly diagnosed MM (NDMM); relapsed refractory MM \[RRMM\]) 14) VAS (Visual Analogue Scale) for pain and Harris Hip Score

CTFEA Myeloma Study

Prospective Application of CTFEA for Monitoring Disease Progression in Active Multiple Myeloma

Identification of changes in bone strength on CT-based FE analysis on three consecutive CT scans that are not apparent to the human eye

Quantification of changes in bone strength in normal looking bone and areas of lytic lesions

Pathological fracture during 12 months of follow up - a diagnosis of fracture that occurred in a bone with a myeloma lesion, without significant trauma. Diagnosis by a primary care physician or a hospital diagnosis will count towards the outcome.

Becoming bed-ridden due to inability to ambulate - the patient will be contacted and asked regarding the ability to bear weight with or without a walking support. Patients who were able to walk independently at the time of study beginning and became dependent on chair or bed for transportation will count towards the outcome

Tel Aviv University

Tel-Aviv Sourasky Medical Center

Nervous System Diseases

Neoplasm Metastasis

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

All Drugs and Chemicals

Dihydroxyphenylalanine

patients with PBT (Glioblastoma, Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Anaplastic Oligoastrocytoma), before treatment with radiation and chemotherapy.will be followed with PET MRI

patients with lung or breast metastasis to brain treated by SRS in which at least one lesion showed deterioration by MR performed after treatment.

will be followed with PET MRI

patients with lung or breast metastasis to brain where the SRS treatment was postponed for clinical reasons (getting mutation information for targeted treatment) the lesion size measures 5-40 mm.

will be followed with PET MRI

PET MR with 18 Fluorodopa (\[18F\]-DOPA) will be performed on patient at set intervals

PET MR

Michal Guindy, MD

Judith Luckman, MD

Judith LuKman, MD

PET-MRI scanning regarding amino acid metabolic profile, functional and morphological details will be performed on set intervals to patients with brain tumor \& brain metastases in order to try to optimize the study protocol, distinguish between pseudo-response to anti-angiogenic therapy and tumor progression, and most importantly try to distinguish between progressive tumor and treatment related effects.3 cohort of patients will be included in the study.

The multimodality approach for management of primary and secondary brain tumors includes surgery, radiotherapy and chemotherapy. Determination of an objective response to treatment relies on imaging findings (e.g. CT, MRI, PET).During the course of the disease patients with brain tumors often develop new or worsening contrast-enhancing lesions on routine follow-up imaging.These lesions may reflect tumor recurrence, treatment effect, or a combination of both. Discerning between tumor recurrence and treatment effect is clinically significant issue and a major challenge in neuro-oncology. Treatment-related effects exist within a spectrum, with "pseudoprogression" reflecting subacute and often transient injury, and "radiation necrosis" reflecting later and more permanent damage.The difficulty in differentiating tumor progression from treatment-related effects has serious implications for individual patient treatment decisions and prognosis as well as for clinical trial design and interpretation of results.

A contemporary hybrid scanner technology is capable of acquiring both metabolic information from PET and morphological and functional details from MRI. This new integrated technique opens new horizons for clinical and research evaluation of brain tumors and the associated treatment effects.

The aim of the current study is to use the combined data obtained by PET-MRI scanning regarding amino acid metabolic profile, functional and morphological details in order to:

1. Distinguish between progressive tumor and treatment related effects
2. To identify pseudo-response to antiangiogenic therapy from tumor progression
3. To optimize the study protocol of PET-MRI for future routine clinical application.

The study will include three cohorts of patients with brain tumors:

1. Primary brain tumors:

   A cohort of 60 adult patients (age: 18-70) with newly diagnosed high grade gliomas (Glioblastoma, Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Anaplastic Oligoastrocytoma) scheduled for a combined treatment with chemotherapy and radiotherapy. Patients will be eligible for the study immediately after receiving the pathological diagnosis and prior to any further treatment. These patients will undergo the PET-MRI scanning at 4 time points as follows:
   * 1st scan: after surgery or biopsy and before any further treatment
   * 2nd scan: will be performed up to 4 weeks after completing the combined radiotherapy and chemotherapy regimen.
   * 3rd and 4th scans: will follow with interval of 3 months between studies.
   * Additional scans will be performed by the decision of the investigators or when the patient is scheduled for antiangiogenic therapy
2. Brain metastases treated with stereotactic radiosurgery (SRS):

   A cohort of 60 adult patients (age: 18-75) who are being followed after SRS treatment for brain metastases secondary to breast or lung cancer whose recent imaging showed signs of progression in at list one of the previously treated lesion. Progression will be determined by Response Assessment in Neuro-Oncology Criteria (RANO criteria) for brain metastases. Number of target lesions should not exceed 4 with size of lesions ranging between 5-40 mm. These patients will undergo the PET-MRI scanning at three time points as follows:
   * 1st scan: Following determination of progression of SRS treated lesion based on standard surveillance MRI
   * 2nd and 3rd scans: will be performed every 2 months after the first scan
   * Additional scans will be performed by the decision of the investigators
3. Brain metastases not treated with SRS/radiotherapy

A cohort of 20 adult patients (age: 18-75) with a diagnosis of brain metastases secondary to human epidermal growth factor receptor 2 (HER2) positive breast cancer or anaplastic lymphoma kinase (ALK) or Epidermal Growth Factor Receptor (EGFR) gene mutant lung cancer who might be candidate for SRS treatment and in whom targeted therapy is selected instead. The size of the lesions should range between 5-40 mm. These patients will undergo the PET-MRI scanning at three time points as follows:

* 1st scan: after the first documentation of brain metastases on standard MRI
* 2nd and 3rd scans: will be performed every 2 months after the first scan
* In case of progression and SRS treatment follow-up scanning will be performed every 2 months
* Additional scans will be performed by the decision of the investigators

to use the combined data obtained by PET-MRI scanning regarding amino acid metabolic profile, functional and morphological details in order to:

1. Distinguish between progressive tumor and treatment related effects
2. To identify pseudoresponse to antiangiogenic therapy from tumor progression
3. To optimize the study protocol of PET-MRI for future routine clinical application.

Can Hybrid PET-MRI Differentiate Between Radiation Effects and Disease Progression?

Imaging After Stereotactic Radiosurgery for Brain Metastases or Primary Tumor Can Hybrid PET-MRI Differentiate Between Radiation Effects and Disease ?

finding PET-MRI difference between progression and treatment effect correlating with clinical out come

Rabin Medical Center

Assuta Medical Center

Medical Director of Imaging Services

Skin and Connective Tissue Diseases

Breast Neoplasms

Cardiac Complexes, Premature

Breast Diseases

Skin Diseases

Conventional treatment protocols of breast cancer

Anne-Cécile PHILIPPE, Dr

Emmanuelle JACQUET, Dr

Anne-Cécile PHILIPPE, Pr

Emmanuelle JACQUET

Mireille MOUSSEAU, Pr

Candidate markers have been identified thanks to an original approach developed by our research team aiming at detecting ectopic gene expression using public pan-genomic breast cancer data. The same approach had already been used and validated in lung tumors, leukemias and lymphomas. The main objective of the present research is to use tumor samples from patients in a retrospective and prospective cohort to test and validate the relevance of these prognostic markers in breast cancer.

Following a diagnosis of breast cancer, the most immediate challenges in patient management are the determination of prognosis and the identification of the most appropriate neoadjuvant and adjuvant systemic therapy. Indicators to assess the risk of relapse or metastasis during treatment are still largely insufficient, a situation which does not allow to precisely adjust the treatment, often leading to heavy side effects. In order to minimize the side effects and risks of therapies, it is therefore necessary to discover new markers which would enable us to reliably assess the prognosis of patients diagnosed with breast cancer.

The approach used here for discovering new prognostic markers is based on an original strategy developed by the researchers associated with this project and published in the respective contexts of lung cancer, acute lymphoblastic leukemia and lymphoma. Indeed, genetic abnormalities and deregulation of the systems controlling the expression of specific gene programs not only lead to the abnormal extinction of normally active genes, but is also responsible for the aberrant activation of genes that normally should remain silent. The investigators have recently demonstrated that any type of malignancy is associated with the ectopic expression of these normally silent genes, including genes of the male germline. The in-depth study of these aberrant gene expressions and the search for correlations and associations with the clinical and biological data of the tumors show that the expression of some of these genes and the presence of their products are good indicators of tumor aggressiveness.

The investigators propose here to apply the same approach for the search for new prognostic markers in the case of breast cancer. A prior analysis of breast tumors, of which transcriptome data are publicly available, has identified a number of tissue-specific genes, including the germline and placenta genes, frequently activated in breast cancer. Based on our past observations, our hypothesis is that some of them may directly reflect the level of tumor aggressiveness and could therefore be used as prognostic biomarkers.

The objective of this work will be to look for the prognostic value of these genes by using the samples collected in this cohort of patients to detect their activation and to correlate these aberrant activations with the anatomopathological data of the tumor, as well as to the clinico-biological data and patient follow-up.

The research uses blood samples and biopsies made at diagnosis or during surgical resection of the tumor for gene or protein expression analysis (RNA and protein extraction).

Identification of New Prognostic Markers for Breast Cancer.

Identification de Nouveaux Marqueurs Pronostiques Des Cancers du Sein

The overall survival and disease-free survival of patient with breast cancers will be analyzed in terms of gene expression change in order to identify new prognostic biomarkers.

Evaluation of a response rate after neoadjuvant chemotherapy according to RECIST criteria

University Hospital, Grenoble

Recurrence

Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

Amino Acids

Angiogenesis Inhibitors

Tyrosine

Recurrent GBM patients receiving Avastin, imaged twice with 18F-FET PET before and approximately 8 weeks after receiving Avastin

Radiotracer, surrogate marker for protein synthesis

18F-FET

Raymond L Huang, MD

Hypothesis: The central hypothesis underlying the proposed research study is that FET-PET will predict durable benefit in patients receiving anti-angiogenic benefit for presumed recurrent GBM (i.e. progression-free survival and overall survival). We have defined one primary specific aim, for which we expect to obtain definitive results, and two secondary aims, under which we plan to generate preliminary data to support a future, larger project.

The PET radiotracer FET provides a measure of large, neutral amino acid transport. This transport is significantly upregulated in malignant brain tumors. FET rarely gives false positive findings in the setting of inflammation seen after high dose chemotherapy or radiotherapy. FET labels low-grade as well as high-grade gliomas, in contrast to FDG, which almost exclusively labels only high-grade gliomas. FET imaging may prove to be particularly useful in the setting of infiltrative tumor, which is not contrast-enhancing on MRI and therefore not detectable with FDG. Management of glioblastoma patients with stable contrast-enhancing disease on MRI but increased signs of edema is difficult. This is because it is difficult to distinguish simple edema from infiltrative tumor. The former is managed with steroids and the latter is managed with chemotherapy, and anti-angiogenic drugs.

FET may be particularly useful in assessing changes after GBM patients receive anti-vascular agents such as Avastin. Avastin is very commonly used in patients after failure of first-line treatment in GBM. Not only is Avastin costly, but it also can have serious side effects such as internal bleeding and gastric perforation, severe hypertension, poor wound healing, and renal toxicity. It is important to know when a patient is failing Avastin treatment so that the drug can be discontinued. Preliminary data in Europe (see figures below) suggests that FET-PET can accurately distinguish Avastin responders from non-responders.

Inclusion Criteria:

1. GBM patients with changes on MRI suggestive of recurrence who have not yet initiated antiangiogenic therapy.
2. Age ≥ 18
3. Anticipated survival \>3 months
4. Able to give informed consent
5. Capable of undergoing scan without the need for sedation or general anesthesia.

Exclusion Criteria:

1. Active intracranial infection or nonglial brain mass.
2. Recent large intracranial hemorrhage (\<1 month; size to be determined by principal investigator)
3. Pregnant or nursing. Quantitative serum hCG testing will be performed prior to the initial and each -subsequent FET- PET scan on all females of childbearing potential. Our BWH Radiation Safety Committee and Partners IRB requires stat serum ß-hcG pregnancy tests.
4. Patient lives too far from BWH and/or is unwilling/ unable to return for scheduled imaging visits.

FET-PET for Evaluation of Response of Recurrent GBM to Avastin

Assessment of the Utility of the Radiotracer "FET"in PET Imaging of Recurrent Glioblastoma Multiforme (GBM): Monitoring Early Response to Antiangiogenic Therapy

The primary objective is to assess the utility of FET-PET imaging for prediction of progression-free survival in recurrent glioblastoma.

The secondary objective is to assess the utility of FET-PET imaging for prediction of overall survival in recurrent glioblastoma.

Marcelo F. Di Carli, MD, FACC

Chief of Nuclear Medicine/PET

Recurrent GBM patients receiving Avastin, imaged twice with 18F-FET PET before and approximately 8 weeks after receiving Avastin

18F-FET: Radiotracer, surrogate marker for protein synthesis

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
CTFEA Myeloma Study	NCT04364724	Myeloma Multipl... Metastatic Bone...	CT-based finite...	18 Years - 95 Years	Tel-Aviv Sourasky Medical Center
Can Hybrid PET-MRI Differentiate Between Radiation Effects and Disease Progression?	NCT03068520	Brain Tumor	PET MR	18 Years - 70 Years	Assuta Medical Center
CTFEA Myeloma Study	NCT04364724	Myeloma Multipl... Metastatic Bone...	CT-based finite...	18 Years - 95 Years	Tel-Aviv Sourasky Medical Center
Identification of New Prognostic Markers for Breast Cancer.	NCT03436069	Breast Cancer	Conventional tr...	18 Years -	University Hospital, Grenoble
FET-PET for Evaluation of Response of Recurrent GBM to Avastin	NCT01756352	Glioblastoma Mu... GBM	18F-FET	18 Years - 85 Years	Brigham and Women's Hospital

Spots Global Cancer Trial Database for response to treatment