Non-invasive MRI spectroscopy at 7 Tesla in lymphoma

Metabolites like lactate and phospholipds are associated with tumor
aggressiveness, response to therapy and prognosis of several cancers. With 7
Tesla 1H and 31P magnetic resonance imaging (MRI) spectroscopy these
metabolites can be detected non-invasively. The lymphomas comprise a
heterogeneous group of tumors with a very variable biology and prognosis,
ranging from very indolent to highly aggressive. If MRI spectroscopy can
differentiate between aggressive and indolent lymphoma non-invasively, this
could have an important impact on patient management. For instance, MRI
spectroscopy findings suggestive for aggressive lymphoma in a patient with
biopsy- proven indolent lymphoma, will indicate either a redirected biopsy or a
more intensive treatment. This would also support the development of a
full-body MRI spectroscopy set-up at 7T to realize multiple "metabolic
biopsies" in different organs in one scan session. Advantages of this method
compared to biopsy and pathological examination are its non-invasiveness, its
repeatability (making it suitable for follow-up examinations) and the provision
of spatial information via MRI spectroscopic imaging (thereby taking into
account tumor hetereogeneity amongst lymph nodes). The second objective of this
study is to assess interscan agreement (i.e. test-retest variability) of 7T
spectroscopy for the quantification of lactate and fosfolipids. Therefore, in
the first 30 patients, the scan performed before treatment will be repeated to
assess the degree of correlation with the previous assessment of the same lymph
node. Tumor heterogeneity amongst lymph nodes in lymphomas is not uncommon. In
the present study difference in concentration of lactate and phospholipids
between lymph nodes will be assessed. Therefore the last 30 patients will be
scanned twice before therapy and concentrations of lactate and phospholipids in
two different lymph nodes will be assessed. The final object of the present
study is to assess changes in lactate and phospholipid concentrations shortly
after the start of treatment compared to pretreatment values to analyse the
feasibility of this technique for early therapy response assessment in patients
with various pathological subtypes of lymphoma. Previous animal experiments
showed that the concentration of lactate and phospholipids changed
significantly after start of treatment. This suggests MRI spectroscopy can be
used as a tool for early response assessment. Patients who are unlikely to
respond to therapy can consequently be directed to another therapy. In order to
determine the feasibility of MRI spectroscopy for early response assessment,
patients with various pathological subtypes of lymphoma will be scanned before
and shortly after start of therapy. In all patients, changes in concentration
of lactate and phospholipids relative to pretreatment values will be determined
to analyse feasibility of MRS for the assessment of early therapy response in
various pathological subtypes of lymphoma. A positive outcome of this
feasibility study will justify the execution of future large-scale studies in
specific lymphoma subtypes that are treated with more homogeneous therapies.

The primary objective of this project is to investigate whether 7T MRI
spectroscopy biomarkers lactate and phospholipids can differentiate between
aggressive and indolent lymphoma non-invasively.
The secondary objective of this study is to assess interscan agreement (i.e.
test-retest variability) of 7T MRI spectroscopy for the quantification of
lactate an phospholipids.
The tertiary objective is to assess degree of dissimilarity in lactate and
phospholipid concentrations between two different lymphomatous lymph nodes in
the same patient.
The fourth objective is to assess changes in levels of lactate and
phospholipids shortly after the start of treatment in order to establish the
feasibility of this technique for early therapy response assessment. A positive
outcome of this feasibility study will justify the execution of future
large-scale studies.

Patients eligible for enrolment in this, prospective, diagnostic cohort study
are adults aged >= 18 years under high suspicion of or with histologically
proven, newly diagnosed or relapsed Hodgkin or non-Hodgkin lymphoma with an
enlarged (i.e. 2 >= diameter) lymphomatous lymph node in a superficial region
(e.g. head/neck, axial or inguinal in order to fit in the MRI spectroscopy
field of view). The hematologist will identify eligible participants, will
inform them about the ongoing research and ask for their participation. All
patients will undergo 1H and 31P MRI spectroscopy at 7T twice before and once
within the first week after the start of treatment by using the 7T MRI located
in the UMC Utrecht. In the first 30 patients MRI spectroscopy of the same lymph
node will be performed twice before therapy to assess the interscan agreement.
In the last 30 patients, MRI spectroscopy before therapy will be performed
twice to assess lactate and phospholipids concentrations in two different lymph
nodes to analyse tumor heterogeneity. 18F-FDG PET will be performed as part of
standard clinical care. The tissue specimen that was acquired by
excision/biopsy for diagnosis as part of standard clinical care will be
additionally stained for Ki-67 in order to determine the proportion of dividing
cells within the tumor. In order to determine the presence of early
therapy-induced changes in the levels of lactate and phospholipids all patients
will also undergo a 7T MRI spectroscopy scan within the first week after the
start of treatment. Five-year follow-up data will be acquired of all patients
in order to explore any potential correlation between levels of lactate and
phospholipids and the progression free survival/overall survival.

The risk associated with the (radiation-free) MRI spectroscopy examinations is
negligible and the burden can be considered minimal (no contrast agents will be
applied and the patient just has to lie still in the scanner for approximately
40 minutes for each scan). To reduce the amount of anxiety and discomfort
caused by scanning as much as possible, patients will be informed about the
procedure.