PubMed · 13347252
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G RAGALYI, G GONDA. 1956. [Bone reticulum cell sarcoma simulating multiple myeloma].. https://pubmed.ncbi.nlm.nih.gov/13347252/
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BACKGROUND: Therapeutic decisions in cancer are generally guided by molecular biomarkers or, for some newer therapeutics, primary tumor genotype. However, because biomarkers or genotypes may change as new metastases emerge, circulating tumor cells (CTCs) from blood are being investigated for a role in guiding real-time drug selection during disease progression, expecting that CTCs will comprehensively represent the full spectrum of genomic changes in metastases. However, information is limited regarding mutational heterogeneity among CTCs and metastases in breast cancer as discerned by single cell analysis. The presence of disseminated tumor cells (DTCs) in bone marrow also carry prognostic significance in breast cancer, but with variability between CTC and DTC detection. Here we analyze a series of single tumor cells, CTCs, and DTCs for PIK3CA mutations and report CTC and corresponding metastatic genotypes. METHODS: We used the MagSweeper, an immunomagnetic separation device, to capture live single tumor cells from breast cancer patients' primary and metastatic tissues, blood, and bone marrow. Single cells were screened for mutations in exons 9 and 20 of the PIK3CA gene. Captured DTCs grown in cell culture were also sequenced for PIK3CA mutations. RESULTS: Among 242 individual tumor cells isolated from 17 patients and tested for mutations, 48 mutated tumor cells were identified in three patients. Single cell analyses revealed mutational heterogeneity among CTCs and tumor cells in tissues. In a patient followed serially, there was mutational discordance between CTCs, DTCs, and metastases, and among CTCs isolated at different time points. DTCs from this patient propagated in vitro contained a PIK3CA mutation, which was maintained despite morphological changes during 21 days of cell culture. CONCLUSIONS: Single cell analysis of CTCs can demonstrate genotypic heterogeneity, changes over time, and discordance from DTCs and distant metastases. We present a cautionary case showing that CTCs from any single blood draw do not always reflect metastatic genotype, and that CTC and DTC analyses may provide independent clinical information. Isolated DTCs remain viable and can be propagated in culture while maintaining their original mutational status, potentially serving as a future resource for investigating new drug therapies.
BACKGROUND: The prognostic significance of isolated tumor cells (ITCs) in bone marrow (BM) from patients with breast carcinoma at the time of their primary diagnosis recently was been confirmed by a large pooled analysis. If the persistence of ITCs after adjuvant therapy confers a similar risk for recurrence, then it would be an indication to consider secondary adjuvant therapy. METHODS: The authors analyzed BM aspirates from 228 patients during recurrence-free follow-up at a median interval +/- standard deviation (SD) of 21.3 +/- 29.1 months after a primary diagnosis of breast carcinoma (pathologic T1 [pT1]-pT2, pN0-pN3, pM0). Carcinoma cells were detected using a standardized immunoassay with monoclonal antibody A45-B/B3 directed against cytokeratin (CK). Patients were followed for a median +/- SD of 49.8 +/- 32.1 months after their primary diagnosis. RESULTS: Persistent ITCs in BM were detected in 12.7% of patients (n=29 patients). Positive BM status was more frequent (15.7%) within the first 21 months after primary diagnosis than after a follow-up > 21 months (9.7%). The Kaplan-Meier estimate for mean recurrence-free survival was 149.7 months (95% confidence interval [95% CI], 139.6-159.8 months) in patients with negative BM status and 86.5 months (95% CI, 65.7-107.4 months; P=0.0003) in patients with positive BM status at the time patients underwent follow-up BM aspiration. Patients who were without evidence of persistent ITCs had a significantly longer overall survival (162.1 months; 95% CI, 152.1-172.0 months) compared with patients who had positive BM status (overall survival, 98.7 months; 95% CI, 79.7-117.9 months; P=0.0008). In multivariate Cox regression analysis that included BM status, tumor size, lymph node status, and histopathologic grade, evidence of ITCs was an independent significant predictor for reduced disease-free survival (relative risk [RR], 4.57; P <0.0001) and overall survival (RR, 5.57; P=0.002). Persistent ITCs had the greatest prognostic relevance when they were detected between 25 months and 42 months after primary diagnosis (RR, 7.68). CONCLUSIONS: Evidence of persistent ITCs in BM from patients with breast carcinoma indicated an increased risk for subsequent recurrence. Prospective trials should investigate the benefit of secondary adjuvant treatment on the basis of BM marrow status.
PURPOSE: We developed an intensity-modulated arc therapy (IMAT) technique for the treatment of women with high-risk endometrial malignancies. In the context of multimodality therapy, nodal and tumor bed irradiation was delivered while respecting tolerance doses for critical structures. METHODS AND MATERIALS: Five patients were planned and treated with the IMAT technique after hysterectomy. Computed tomographic (CT) scans for treatment planning were acquired with the tumor bed contoured as the clinical target volume (CTV(tumor_bed)) and the iliac and presacral vessels contoured as the gross tumor volume (GTV). In 2 patients the lower para-aortic nodes were included into the GTV. The small bowel, iliac crests, femoral heads, bladder, and rectum were contoured as critical organs. For the nodes, a CTV(nodes) was generated with a 7-10-mm margin around the vessels, and the planning target volume (PTV(nodes)) was generated by a further 5-mm expansion. For the tumor bed, the PTV(tumor_bed) was generated with a margin of 7-10 mm around CTV(tumor_bed). Planning constraints included adequate coverage of the tumor bed (>95% receiving > or =45 Gy) and nodes (> or =95% receiving > or =40 Gy). Arc combinations with different extents were tested, and the final plan was generated based on the balance between complexity (number of arcs), PTV coverage, and critical structure sparing. Conventional and 8-field intensity-modulated radiation therapy (IMRT) plans were generated for each patient for comparison purposes. All patients were treated with IMAT. RESULTS: We found that two anterior intensity-modulated arcs (300 degrees to 30 degrees and 330 degrees to 60 degrees ) adequately treated the PTVs. Furthermore, this IMAT technique allowed sparing of small bowel and the iliac crests (marrow space) to a similar degree as the 8-field IMRT. The 8-field IMRT yielded better dose uniformity than IMAT in the target volumes; however, neither technique was as uniform as the conventional plan. In the 5 patients, IMAT treatment was well tolerated and completed as planned. CONCLUSIONS: We successfully piloted an optimized intensity-modulated arc technique to treat 5 high-risk endometrial cancer patients undergoing multimodality treatment. This allowed a significant reduction in dose to bone marrow and small bowel compared with conventional techniques and was simpler to deliver than multifield IMRT.