Effect of microdistribution of alpha and beta-emitters in targeted radionuclide therapies on delivered absorbed dose in a GATE model of bone marrow.

Acute hematologic toxicity is a frequent adverse effect of beta-emitter targeted radionuclide therapies (TRTs). Alpha emitters have the potential of delivering high linear energy transfer (LET) radiation to the tumor attributed to its shorter range. Antibody-based TRTs have increased blood-pool half-lives, and therefore increased marrow toxicity, which is a particular concern with alpha emitters. Accurate 3D absorbed dose calculations focusing on the interface region of blood vessels and bone can elucidate energy deposition patterns. Firstly, a cylindrical geometry model with a central blood vessel embedded in the trabecular tissue was modeled. Monte Carlo simulations in GATE were performed considering beta (177Lu, 90Y) and alpha emitters (211At, 225Ac) as sources restricted to the blood pool. Subsequently, the radioactive sources were added in the trabecular bone compartment in order to model bone marrow metastases infiltration (BMMI). Radial profiles, dose-volume histograms and voxel relative differences were used to evaluate the absorbed dose results. We demonstrated that alpha emitters have a higher localized energy deposition compared to beta emitters. In the cylindrical geometry model, when the sources are confined to the blood pool, the dose to the trabecular bone is greater for beta emitting radionuclides, as alpha emitters deposit the majority of their energy within 70 µm of the vessel wall. In the BMMI model, alpha emitters have a lower dose to untargeted trabecular bone. Our results suggest that when alpha emitters are restricted to the blood pool, as when labeled to antibodies, hematologic toxicities may be lower than expected due to differences in the microdistribution of delivered absorbed dose.

Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification.

The purpose of this work was to modernize recommendations for evaluation, staging, and response assessment of patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). A workshop was held at the 11th International Conference on Malignant Lymphoma in Lugano, Switzerland, in June 2011, that included leading hematologists, oncologists, radiation oncologists, pathologists, radiologists, and nuclear medicine physicians, representing major international lymphoma clinical trials groups and cancer centers. Clinical and imaging subcommittees presented their conclusions at a subsequent workshop at the 12th International Conference on Malignant Lymphoma, leading to revised criteria for staging and of the International Working Group Guidelines of 2007 for response. As a result, fluorodeoxyglucose (FDG) positron emission tomography (PET)­computed tomography (CT) was formally incorporated into standard staging for FDG-avid lymphomas. A modification of the Ann Arbor descriptive terminology will be used for anatomic distribution of disease extent, but the suffixes A or B for symptoms will only be included for HL. A bone marrow biopsy is no longer indicated for the routine staging of HL and most diffuse large B-cell lymphomas. However, regardless of stage, general practice is to treat patients based on limited (stages I and II, nonbulky) or advanced (stage III or IV) disease, with stage II bulky disease considered as limited or advanced disease based on histology and a number of prognostic factors. PET-CT will be used to assess response in FDG-avid histologies using the 5-point scale. The product of the perpendicular diameters of a single node can be used to identify progressive disease. Routine surveillance scans are discouraged. These recommendations should improve evaluation of patients with lymphoma and enhance the ability to compare outcomes of clinical trials.

Isolation of disseminated neuroblastoma cells from bone marrow aspirates for pretreatment risk assessment by array comparative genomic hybridization.

In neuroblastoma, tumor biopsies are used for prognostic evaluation and risk assessment by molecular genetic analyses such as fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (array CGH). Analysis of primary tumors by array CGH can be hampered by the lack of sufficient tumor cells due to small biopsy size or availability of invaded bone marrow only. Given the importance of accurate assessment of genetic alterations in the diagnostic work-up of patients with neuroblastoma, we evaluated the possibility to analyze bone marrow metastases in patients with disseminated disease. Disseminated neuroblastoma cells were isolated from bone marrow aspirates by using either laser capture microdissection (LCM) or magnetic activated cell sorting (MACS). The array CGH profiles of these isolated metastases were compared to array CGH profiles and/or FISH data of the corresponding primary tumor. Here, we show that the major recurrent DNA copy number alterations detected in primary neuroblastoma tumors (i.e., 1p, 3p and 11q deletion, 17q gain and MYCN amplification) can be detected, with high sensitivity and specificity, in the disseminated neuroblastoma cells isolated from the bone marrow aspirates, using an array platform with high coverage for these regions. Moreover, we demonstrate that for archived material, for example, for retrospective studies, LCM is the method of choice, while for fresh bone marrow aspirates, acquired at the time of diagnosis, MACS is superior.

Tc-99m labelled anti CD 66 antigranulocyte antibody imaging for assessment of bone marrow reserve.

Patients with metastatic disease to the bone marrow are at risk of significant hematologic toxicity, if they undergo myelotoxic chemotherapy. Tc-99m labelled Anti CD 66 monoclonal antibody imaging is a useful, noninvasive approach to the assessment of bone marrow reserve under such circumstances.

Can MIBG scan replace the need for bone marrow assessment at diagnosis and reassessment in stage 4 neuroblastomas?

UNLABELLED: Complete staging (extensive marrow investigation and meta-iodo benzylguanine (MIBG) scan) is considered as mandatory both at diagnosis and after chemotherapy for assessment of metastases in neuroblastomas. However the correlation between bone marrow invasion and uptake of MIBG at metastatic sites remains unclear. This study investigates whether MIBG alone is sufficiently sensitive to make these procedures redundant. PATIENTS AND METHODS: 20 children over one year of age, with histologically proven metastatic neuroblastoma were studied. Extensive bone marrow assessment and MIBG bone scan performed both at diagnosis and after completion of induction chemotherapy were reviewed. RESULTS: At diagnosis metastases were detected by marrow investigation alone in 2, MIBG alone in 2 and both procedures in 16. After induction chemotherapy metastases were detected by only marrow investigation in 2, by only MIBG in 3, by both procedures in 6 patients, and by none in 9. CONCLUSIONS: Whether marrow investigations and MIBG scan explore the same phenomenon remains unclear. However it appears that marrow disease that is histologically detectable may remain MIBG negative both at diagnosis and after treatment. Both procedures are still justified at time of diagnosis and evaluation of response.

Micrometastasis in the bone marrow of patients with lung cancer associated with a reduced expression of E-cadherin and beta-catenin: risk assessment by immunohistochemistry.

BACKGROUND: The presence of disseminated tumor cells in bone marrow is considered to be a premetastatic state, which is called micrometastasis. To evaluate the relationship between micrometastasis and cellular adhesion molecules in the primary lesion, E-cadherin and beta-catenin were immunohistochemically investigated. Methods. Fifty-eight patients with non-small cell lung cancer who underwent a complete resection were entered into this study. Tumor cells in bone marrow aspirates were detected by immunohistochemistry using cytokeratin (CK) 18. Immunohistochemical studies of E-cadherin and beta-catenin were performed in the corresponding primary tumor. RESULTS: CK-positive cells were detected in the bone marrow aspirates from 27 of 58 patients. A reduced expression of the E-cadherin and beta-catenin was found in 16 (27.6%) and in 22 (37.9%) of 58 patients, respectively. In 26 cases with a reduced expression of E-cadherin and/or beta-catenin, 16 cases had CK-positive cells, whereas 11 of 32 cases with normal expression of both factors had CK-positive cells (P=.0392). The patients with micrometastasis demonstrated an earlier recurrence (P =.0642) and a significantly poorer survival (P =.0437) than those without such cells. CONCLUSIONS: Micrometastasis in the bone marrow might be a significant predictor of poor prognosis, and a reduced expression of E-cadherin and beta-catenin are important determinants for the metastatic capability of individual cancer cells.

Bone marrow and lymph node assessment for minimal residual disease in patients with breast cancer.

The immunocytological detection of disseminated epithelial cells in bone marrow in patients with breast cancer has been performed at many hospitals and institutes since the early 1980s. Despite numerous publications in this field, it has not been possible to standardize the method and establish the 'ideal' antibody, either nationally or internationally. Molecular biological methods using PCR technology could extend the diagnostic spectrum. However, one of the major problems in breast cancer is the lack of a disease-specific marker gene. As a result, immunocytology is still the standard procedure for tumour cell detection. The detection of disseminated single cells in bone marrow in primary breast cancer (also known as minimal residual disease) is a new prognostic factor for disease-free and overall survival. This has been demonstrated in two large (N > 300) groups and several small to medium groups (N = 50-300). As a marker of dissemination in a target organ for metastasis this prognostic factor corresponds much more closely to the tendency of breast cancer to early haematogenic spread. Tumour cell detection may predict the course of the disease better than the axillary lymph node status. Bone marrow aspiration and detection of disseminated cells might replace lymph node dissection, at least in those patients with small tumours and no clinical signs of lymph node involvement. This strategy will soon be investigated in appropriate studies. Another possible clinical use might be in deciding on whether or not to give adjuvant systemic therapy to node-negative patients. Patients with positive tumour cell detection are at a higher risk of subsequent metastasis, even if the axillary nodes are histologically normal. The immunohistological or molecular biological detection of tumour cells in axillary lymph nodes might also be very useful, now that it has been shown that a considerable subset of patients determined to be node-negative by means of conventional methods, are positive according to these new techniques. These methods could be a useful supplement to sentinel node biopsy. A further potential use of this method is in monitoring therapy with new treatment modalities such as gene therapy and immunotherapy. Repeated bone marrow aspiration can provide information on the success of therapy in minimal residual disease (cytoreduction). Immunocytochemical investigation of individual cells may be useful in studying the pathogenesis of metastasis, in particular in the skeleton. Phenotyping of cells might allow statements to be made on the metastatic potential of cells and the question of cell dormancy. It remains to be hoped that this aspect of minimal residual disease will be granted more attention in future.

Comparative immunocytochemical assessment of isolated carcinoma cells in lymph nodes and bone marrow of patients with clinically localized prostate cancer.

After radical prostatectomy for clinically localized prostate cancer, biochemical progression is seen in up to 40% of the patients due to persistent local and/or systemic remnants. Isolated disseminated carcinoma cells, undetectable by current staging methods, are of special interest as potential precursors of subsequent overt metastases. In the present study, immunohistochemistry (IHC) was performed to evaluate simultaneously the frequency of occult carcinoma cells in both lymph nodes (LNs) and bone marrow (BM) obtained from the iliac crests of 45 prostate cancer patients with untreated stage T(1-3) pN0 M0 prostatic carcinoma. IHC using monoclonal antibodies (MAbs) against epithelial cytokeratins was performed on 521 paraffin-embedded LNs histopathologically classified as tumorfree (pN0), as well as on BM cytospin preparations. To confirm the prostatic origin of positive cells in LNs, additional IHCs for prostate-specific antigen (PSA) and epithelial glycoproteins were performed. In total, isolated tumor cells in LNs and/or BM were detected in 17 of the 45 patients. Parameters such as tumor stage, grade and volume of the primary tumor as well as blood serum PSA levels could not detect patients harboring disseminated single tumor cells in LNs or BM. Following a median observation time of 24.9 months, no significant correlation between IHC positivity and PSA progression as a measure of early relapse was observed. Although the overall incidence of occult tumor cell spread corresponds to similar incidence of relapses after radical prostatectomy as reported by others, the fate of these cells needs to be evaluated in longer follow-up studies.

Ferumoxides-enhanced quantitative magnetic resonance imaging of the normal and abnormal bone marrow: preliminary assessment.

The purpose of our study was to assess the effects of intravenous administration of ferumoxides on normal and abnormal vertebral bone marrow T1 and T2 relaxation times. Changes in bulk T1 and T2 relaxation times induced by intravenous administration of ferumoxides were determined in the normal vertebral marrow of two healthy subjects and four patients. In the four patients, changes in bulk T1 and T2 values induced by furomoxides injection were also determined in 12 vertebral metastases. Relative to precontrast relaxation time values, bulk T1 and T2 values of normal bone marrow had declined by a mean of 24% and 19%, respectively, in the two subjects and the four patients 45 minutes after ferumoxides administration. Relative to precontrast values, bulk T1 and T2 values of abnormal bone marrow had decreased by a mean of 16% and 2%, respectively. Decreases in bulk T1 and T2 values in normal bone marrow and in bulk T1 values in metastases were statistically significant (P<0.001). Changes in bulk T2 values observed in metastases were not statistically significant. Quantitative MRI demonstrates that ferumoxides infusion induces a decrease in bulk T1 and T2 relaxation times of normal bone marrow. It also suggests a lack of T2 shortening in bone metastases.

[Bone marrow involvement in ovarian cancer by immunohistochemical assessment]. / Immunohistochemiczna analiza szpiku kostnego chorych z rakiem jajnika.

In the study below we introduced certain conclusions from bone marrow analysis in patient with ovarian cancer in the presence of epithelial cells. The study included cytological bone marrow slides taken from 31 patients. We analyzed the cellular antigen expression using immuno-histological chemistry technic with NCL-CA 125, NCL-EMA and NCL-C11 antibodies. In the material drived from 3 patients with advanced neoplastic changes, we detected the presence of cells that were stained positively. In order to define the actual frequency of cell presence with tested antigen expression in bone marrow as well as to signify the diagnostic and prognostic value of their detection requires a larger study group as well as using other examination technics such as PCR or transluscent photometry.

[The morphological assessment of bone marrow infiltration in neuroblastoma]. / Valutazione morfologica dell'infiltrazione midollare nel neuroblastoma.

Bone marrow biopsy is very important in diagnosis and follow-up of children affected by neuroblastoma (NB). Between June 1995 and May 1997 we studied 55 patients with NB stage 4. Specimens were obtained at the diagnosis (in 8 patients) and after chemotherapy (in 55 patients) in order to evaluate the effects of treatment on bone marrow disease. 88% of 343 biopsies were representative versus 99% of 639 aspirates. Of 8 stage 4 patients evaluated at diagnosis, 15/16 biopsies versus 9/15 aspirates were positive. Following chemotherapy, out of 298 evaluable sites examined, 111 biopsies versus 30 aspirates (37 versus 10%) were positive. Of 111 positive biopsies 53 showed a focal pattern (35 differentiated, 18 undifferentiated), while 51 showed a diffuse pattern (18 differentiated, 40 undifferentiated). Our results confirm previous literature data indicating a better efficacy of histology versus morphology in detecting residual bone marrow disease (especially in case of focal differentiated pattern). The recent introduction of a specific monoclonal antibody, called anti-GD2, has improved our capacity to detect minimal residual disease in patients' bone marrow. The inclusion of anti-GD2 immunohistochemistry in our evaluation will possibly increase our overall sensitivity to detect minimal residual disease and may provide information capable to direct the physician's decision into a more rational patient's treatment.