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E. Tamm, B.J.Barron, L.M. Lamki , M. Roarke, J. Bull, P. Holoye, E. Roquinez, K. Stroehlein, B. Fang and V. Ephron

The University of Texas-Houston Medical School Departments of Radiology and Internal Medicine, Divisions of Nuclear Medicine and Medical Oncology, and Hermann Hospital, Houston, Texas

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INTRODUCTION

PURPOSE OF STUDY

PATIENTS

PROTOCOL

RESULTS

CONCLUSIONS

INCLUSION CRITERIA

PRIMARY OBJECTIVES

CASES

EXCLUSION CRITERIA

SECONDARY OBJECTIVES

INTRODUCTION
Non-Hodgkin's Lymphomas (NHL) are the most common group of neoplasms affecting the immune system and are characterized by a monoclonal expansion of T or B cells. Overall, lymphomas account for 8% of the deaths from cancer in the U.S. NHL is a subtype of B-Cell lymphoma with an estimated 5-year survival of 50%. However, the initial development of NHL is characteristically asymptomatic and thus, often delays patient presentation with disease well into Ann Arbor Stage III or IV.
The diagnosis is based on clinical, laboratory and immunohistochemical testing and radiographic findings. Staging is dependent to a high degree on bone marrow analysis and current diagnostic modalities (CDM's) such as CT, MRI, bone scans and often gallium scans. Despite all of the modalities available, initial staging is not always accurate. Restaging of recurrence has a sensitivity of between only 21 and 55%. (Weeks, 1991) Early diagnosis of lymphoma or its recurrence can optimize the effectiveness of currently available therapies, and understandably, a better method of diagnosis is needed. Current diagnostic modalities have difficulty detecting early disease, as lymph node size is a key determinant of scan abnormality. On post-therapy evaluation, CDM's cannot distinguish scar tissue from recurrence. Chemotherapy may be stopped early based on CT findings. However, more accurate determination of disease activity may allow for more effective treatment. Our study utilized a radiolabeled monoclonal antibody against the cellular membrane of the Raji cell component of B cell lymphoma for diagnostic evaluation in the initial staging and restaging of patients with non-Hodgkin's B-cell lymphoma.

   INCLUSION CRITERIA:

• Male or female patients, over 21 years of age, with histologically proven non-Hodgkin's B-cell lymphoma, low, intermediate or high grade categories.
• Include relapsed and newly diagnosed patients (LL2-05) or previously treated with chemotherapy and/or radiotherapy with evidence of minimal residual disease by conventional diagnostic modalities (CDM's).
• Non-lactating Females of child-bearing potential need a negative pregnancy test.
• Must be off all investigational therapy for at least one month prior to entry.

  EXCLUSION CRITERIA:

• Renal insufficiency: BUN > 1.5 X upper limit of normal.
• Prior exposure to mouse antibodies or known allergies to mouse proteins.
• Second primary malignancy within 5 years before study entry other than adequately treated in situ carcinoma of the cervix or uterus or basal or squamous cell carcinoma of the skin.
• Concurrent participation in another research protocol involving medical devices or administration of investigational agents.

PURPOSE OF STUDY

Protocols IM-D-LL2-05 and ­p;06 were designed to assess the implication and potential role of LL-2 imaging to clinical management plans in initial assessment (LL2-05) and post-chemotherapy assessment (LL2-06). The following are the objectives of this study:

  PRIMARY OBJECTIVES:

• Determine the detection performance of Lymphoscan in low, intermediate and high-grade B-cell non-Hodgkins Lymphoma.
• Demonstrate the addition of Lymphoscan to CDM's can differentiate between tumor and residual scarring.
• Evaluate safety of an initial administration.
• Evaluate safety of one or two repeat injections.

  SECONDARY OBJECTIVES:

• Demonstrate that Lymphoscan can correctly stage all grades of NHL similarly to non-invasive CDM's (CT and bone scan).   
• Demonstrate that Lymphoscan is at least as sensitive for detecting disease in various body sites as any other standard diagnostic imaging method.
• Determine the diagnostic operating characteristics of Lymphoscan to detect residual tumor in patients with radiologically detectable masses.
• Compare patient management plans based on CDM's alone, Lymphoscan alone and the combination.

PATIENTS

• Eleven patients were recruited from the oncology services at Hermann Hospital.
• Six patients were enrolled in the initial staging arm of the study and the other five were enrolled in the follow-up staging. All patients had recent bone marrow biopsies, and abdominal and chest CT scans. Three patients also underwent a gallium scan.

• Recruitment and enrollment.
• Informed consent for this study approved by the Committee for the Protection of Human Subjects was obtained.
• Baseline blood sampling Injection of 30 mCi Tc-99m-LL2 (Lymphoscan ) intravenously 4, 6 and 24 hour planar imaging using a dual headed LFOV gamma camera (BIAD, Trionix).
• 4-6 hour SPECT images of the chest, abdomen and pelvis.
• Repeat SPECT images in some patients were obtained at approximately 24 hours.
• Anterior and Posterior 1000K, 4h planar images were obtained over the chest, abdomen, pelvis, in addition to right and left laterals of the head.
• 500K planar images were obtained at 18-24 hours.

RESULTS

• 11 Patients enrolled, 6 for initial staging and 5 for restaging.
•   6 patients had a second imaging set after therapy.
• 43 lesions were detected by LL-2 imaging.
• 29 lesions were detected by CDM's or physical exam.
• 24/29 confirmed lesions were detected by LL-2 (Sensitivty 83%).
• 19 new lesions (occult) were identified by LL-2. In several of the LL-2 positive sites lymph nodes were seen on CT, but were not diagnostic.
• Physiologic Distribution of tracer included blood pool, liver, spleen, kidneys, bowel, testes, and minimally in the salivary glands. The following ratios were noted and early and late values were compared for both the early and delayed SPECT image sets:

• Six patients had repeat imaging after completion of therapy and 5/6 had residual disease, unsuspected by CDM's. In 2 patients, new lesions were seen. In 3 others residual disease was still present. In one case (FIG_____) tibial uptake was improved but new abnormal uptake in the femur was noted. It was not clear whether or not this was a result of GCSF administration.
• Three patients also had gallium imaging performed. In one case gallium and LL-2 images showed concordant, mild uptake. In the 2nd patient, the LL-2 was grossly positive, but the gallium scan was negative. In the final patient, the LL-2 was negative, but a gallium scan performed one month later was grossly abnormal.
• 2/11 patients, were upstaged on the basis of the LL-2 study.
• Several Potential Pitfalls were noticed:
  • A.   An area of decreased activity was noted between the kidneys on SPECT images. This was due to a reconstruction artifact secondary to the high kidney activity. This artifact can be reduced by a technique of "clamping" which assigns a value to the highest level of counts.
  • B.   Lymph node uptake generally was more marked on LL-2 images than suspected by normal sized nodes seen on other CDM's. However, physical exam usually demonstrated some small nodes. One patient( FIG___) was thought to have inguinal lymph node involvement and this was determined to be a retracted testicle in the inguinal canal. Another patient (FIG____) had inguinal lymphadenopathy for most of his adult life. This was not demonstrated on Gallium imaging but was active on LL-2 imaging.
  • C.   In 2 patients, FIG_____, abnormal bone marrow activity was also noted. This could help localize an appropriate site for biopsy.

CASES

       The following cases represent an interesting mix of findings and areas of potential error in interpretation:

	Figure 1:
		Figure 1:  41 y.o. showing relatively normal distribution of tracer.
		A) Nasopharynx
		B) Heart
		C) Liver, Spleen, and Kidney
		D) Testicles, Bladder and Bone Marrow

Figure 2:
	Figure 2 PB: 69 y.o. with right tonsillar lymphoma and multiple positive nodes. (A) 4-h 3D reprojection images (Ant., Post, Lat.) and (B) Comparable 24-hour images.

Figure 3:
	Figure 3: 69 y.o. with right tonsillar lymphoma. 3-D reprojection images demonstrating the findings on (A) Study #1 and (B) Study #2, 4 months apart. A focal area of increased activity is seen in the region of the left lip on the first study and has resolved by Study #2.

Figure 4:
	Figure 4 CW: 64 y.o. with primary lymphoma of the thyroid. (A) Bone scan showing abnormal pelvic uptake secondary to Paget's disease (Arrow) and (B) 4-hour LL-2 image showing no abnormal pelvic uptake.

Figure 5:
	Figure 5 RT: 4-hour (A) and 24-hour (B) planar images of the skull, groin, and right knee demonstrating abnormal uptake in the left parietal and temporal regions, inguinal lymph nodes and right proximal tibia. Mild uptake in the distal right femur and left femoral bone marrow is also noted.
	The right distal femur became positive on the follow-up study. It was thought that this represented bone marrow stimulation after GCSF therapy.
	(C) CT of the skull showing parietal and temporal bone destruction
	(D) MRI of the tibia showing intermediate signal on proton density weighted images in the proximal tibia.

Figure 6:
	Figure 6 RT: 24 y.o. with primary lymphoma of the right tibia and skull. Pre and post-clamped coronal SPECT images demonstrate the effect of clamping on bladder activity. This allows surrounding areas to be better visualized.

Figure 7:
	Figure 7: 55 y.o. with post-therapy for mediastinal lymphoma and thought to be in remission.
	A) Negative gallium images.
	B) Multiple focal areas of increased uptake suggesting active disease.

Figure 8:
	Figure 8 RM: 3-D reprojection of the pelvis on LL-2 study (A) vs. (B) gallium. Inguinal nodes are not noted on the gallium scan.

Figure 9:
	Figure 9 RM: Coronal SPECT slices showing marked mediastinal uptake. Note uptake in splenic remnant.

Figure 10:
	Figure 10 PC: (A) 4-hour LL-2 planar images showing focal uptake in the region of the right groin (arrow) and physiologic uptake in the testicles. Gallium scan was normal. (B) CT scan showing right testicle high in inguinal canal.

Figure 11:
	Figure 11 KK: 67 y.o. with lymphoma of the neck (arrow). (A) 4-hour coronal slices before "clamping" and (B) after clamping. Note the effect of the clamping on high count regions. Increased bone marrow activity is also noted in the right humerus. (C) Demonstrating prominent nodes in the left neck.

CONCLUSIONS:

• Tc-99-LL2 imaging in B-cell lymphoma is fairly accurate in identifying focal areas of involvement, especially in lymph nodes.
• Based on baseline scan findings, 2 patients were upstaged.
• Based on follow-up imaging sets, 5/6 patients were upstaged.
• Lymph node positivity on LL2 and negativity on gallium imaging may be related to the grade of the tumor. Further investigation into this occurrence is needed.
  • One can see from the above that relative spleen counts decrease with time, while kidney counts increase. The lesion to background ratios for focal lesions increases with time. Planar ratios were variable, and in many cases, lesions could not be seen on planar images.
• Relative spleen counts decrease with time while kidney counts increase.
• Lesion to background ratios for focal lesions increase with time. Therefore, delayed imaging at 24 hours may be helpful in confirming questionable abnormalities on the earlier scans. Planar ratios were variable and in many cases lesions could not be seen on planar images.
• LL-2 may prove useful in identifying patients who would be candidates for RadioImmunoTherapy with radioiIodine labeled antibody.
• LL2 is a useful adjunct for evaluation of patients with B-cell Lymphoma, and probably has its greatest role in determining when to stop chemotherapy. As patient demise is usually due to unrecognized recurrences, early detection of recurrence or residual disease could allow for earlier treatment and potentially lengthen life span.

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