Presence Of Bone Marrow Metastases Research Articles

Analysis of the incidence, characteristics, and risk factors of complications during induction chemotherapy in children with high-risk neuroblastoma.

The presence of bone marrow involved and increased VMA were high-risk factors for infection, while NSE ≥ 200µg/L and LDH ≥ 1000 U/L were high-risk factors for hemorrhage. For those children who had experienced severe myelosuppression, the presence of bone marrow metastases, increased VMA, and LDH ≥ 1000 U/L were their risk factors. The presence of bone involvement was a high-risk factor for children to have non-myelosuppressive adverse effects. Complications that arise during induction chemotherapy could negatively impact the children's prognosis and overall quality of life. • The high-risk neuroblastoma (HR-NB) had a worse prognosis; there was a general international preference for high-intensity chemotherapeutic regimens in the induction phase to these children. • We analyzed the incidence and risk factors of complications during induction chemotherapy in children with HR-NB and tried to help clinicians predict such complications and adopt optimized therapeutic strategy.

Effectiveness of autologous hematopoietic stem cell transplantation in the treatment of high-risk neuroblastoma in children: a single-center clinical study

To investigate the effectiveness of high-dose chemotherapy combined with autologous hematopoietic stem cell transplantation (ASCT) in the treatment of children with high-risk neuroblastoma (NB). A retrospective analysis was performed on 29 children with high-risk NB who were admitted to Shanghai Children's Hospital and were treated with high-dose chemotherapy combined with ASCT from January 2013 to December 2021, and their clinical features and prognosis were analyzed. Among the 29 children treated by high-dose chemotherapy combined with ASCT, there were 18 boys (62%) and 11 girls (38%), with a median age of onset of 36 (27, 59) months. According to the International Neuroblastoma Staging System, 6 children (21%) had stage III NB and 23 children (79%) had stage IV NB, and the common metastatic sites at initial diagnosis were bone in 22 children (76%), bone marrow in 21 children (72%), and intracalvarium in 4 children (14%). All 29 children achieved reconstruction of hematopoietic function after ASCT. After being followed up for a median time of 25 (17, 45) months, 21 children (72%) had continuous complete remission and 8 (28%) experienced recurrence. The 3-year overall survival rate and event-free survival rate were 68.9%±16.1% and 61.4%±14.4%, respectively. Presence of bone marrow metastasis, neuron-specific enolase ≥370 ng/mL and positive bone marrow immunophenotyping might reduce the 3-year event-free survival rate (P<0.05). Children with high-risk NB who have bone marrow metastasis at initial diagnosis tend to have a poor prognosis. ASCT combined with high-dose chemotherapy can effectively improve the prognosis of children with NB with a favorable safety profile.

Pro-metastatic and mesenchymal gene expression signatures characterize circulating tumor cells of neuroblastoma patients with bone marrow metastases and relapse.

Existing marker-based methods of minimal residual disease (MRD) determination in neuroblastoma do not effectively enrich for the circulating disease cell population. Given the relative size differential of neuroblastoma tumor cells over normal hematogenous cells, we hypothesized that cell size-based separation could enrich circulating tumor cells (CTCs) from blood samples and disseminated tumor cells (DTCs) from bone marrow aspirates (BMA) of neuroblastoma patients, and that their gene expression profiles could vary dynamically with various disease states over the course of treatment. Using a spiral microfluidic chip, peripheral blood of 17 neuroblastoma patients at 3 serial treatment timepoints (diagnosis, n=17; post-chemotherapy, n=11; and relapse, n=3), and bone marrow samples at diagnosis were enriched for large intact circulating cells. Profiling the resulting enriched samples with immunohistochemistry and mRNA expression of 1490 cancer-related genes via NanoString, 13 of 17 samples contained CTCs displaying cytologic atypia, TH and PHOX2B expression and/or upregulation of cancer-associated genes. Gene signatures reflecting pro-metastatic processes and the neuroblastoma mesenchymal super-enhancer state were consistently upregulated in 7 of 13 samples, 6 of which also had metastatic high-risk disease. Expression of 8 genes associated with PI3K and GCPR signaling were significantly upregulated in CTCs of patients with bone marrow metastases versus patients without. Correspondingly, in patients with marrow metastases, differentially-expressed gene signatures reflected upregulation of immune regulation in bone marrow DTCs versus paired CTCs samples. In patients who later developed disease relapse, 5 genes involved in immune cell regulation, JAK/STAT signaling and the neuroblastoma mesenchymal super-enhancer state (OLFML2B, STAT1, ARHGDIB, STAB1, TLR2) were upregulated in serial CTC samples over their disease course, despite urinary catecholamines and bone marrow aspirates not indicating the disease recurrences. In summary, using a label-free cell size-based separation method, we enriched and characterized intact circulating cells in peripheral blood indicative of neuroblastoma CTCs, as well as their DTC counterparts in the bone marrow. Expression profiles of pro-metastatic genes in CTCs correlated with the presence of bone marrow metastases at diagnosis, while longitudinal profiling identified persistently elevated expression of genes in CTCs that may serve as novel predictive markers of hematogenous MRD in neuroblastoma patients that subsequently relapse.

Haematological and biochemical predictors of bone marrow metastases in non-haematological malignancies: A clinico-pathological analysis

Background: Bone marrow metastasis is an uncommon yet significant presentation of many non haematological malignancies. Aims: The present study was conducted with the aim of analysing the clinical, haematological and biochemical parameters of the patients with bone marrow metastases and determines the parameters which could possibly indicate the presence of bone marrow metastases. Patients and Methods: Bone marrow aspirate, imprint and biopsy slides of 22 cases with bone marrow metastases were reviewed and the haematological and biochemical data of all these cases were compared with that of 20 controls without any evidence of metastases. Results: The mean values of mean platelet volume (MPV), neutrophil to lymphocyte ratio (NLR) and serum lactate dehydrogenase (LDH) were found to be significantly different (P < 0.001) between the cases and controls. MPV <8.1 fL, NLR >3.5 and LDH >452 U/L showed a high likelihood ratio in predicting bone marrow metastases. Conclusion: Parameters such as MPV, NLR and LDH can be used as efficient and easily available methods to predict bone marrow metastasis for a rapid diagnosis.

A nomogram of clinical and biologic factors to predict survival in children newly diagnosed with high-risk neuroblastoma: An International Neuroblastoma Risk Group project.

Long-term outcome remains poor for children with high-risk neuroblastoma (five-year overall survival [OS] ∼50%). Our objectives were to (a) identify prognostic biomarkers and apply them in a nomogram to identify the subgroup of ultra-high-risk patients at highest risk of disease progression/death, for whom novel frontline therapy is urgently needed; and (b) validate the nomogram in an independent cohort. A total of 1820 high-risk patients (≥18 months old with metastatic neuroblastoma), diagnosed 1998-2015, from the International Neuroblastoma Risk Groups (INRG) Data Commons were analyzed in a retrospective cohort study. Using multivariable Cox regression of OS from diagnosis, a nomogram was created from prognostic biomarkers to predict three-year OS. External validation was performed using the SIOPEN HR-NBL1 trial cohort (n=521), evidenced by receiver operating characteristic curves. The nomogram, including MYCN status (P<0.0001), lactate dehydrogenase (LDH) (P=0.0007), and presence of bone marrow metastases (P=0.004), had robust performance and was validated. Applying the nomogram at diagnosis (a) gives prognosis of an individual patient and (b) identifies patients predicted to have poor outcome (three-year OS was 30% ± 5% for patients with a nomogram score of>82 points; 58% ± 1% for those ≤82 points). Median follow-up time was 5.5 years (range, 0-14.1). In high-risk neuroblastoma, a novel, publicly available nomogram using prognostic biomarkers (MYCN status, LDH, presence of bone marrow metastases; https://neuroblastoma.shinyapps.io/High-Risk-Neuroblastoma-Nomogram/) has the flexibility to apply a clinically suitable and context-specific cutoff to identify patients at highest risk of death. This will facilitate testing urgently needed new frontline treatment options to improve outcome for these children.

A RARE SITE OF METASTASIS IN LUNG CANCER: SILENT OR LOQUACIOUS?

Lung cancer is the most common cause of cancer-related deaths worldwide. Most of the lung cancer patients present at an advanced or metastatic stage (84%). Common sites of lung cancer metastasis are the liver, bone, brain, and adrenals. In our index case, we describe a rare site of metastasis in a 59-year-old gentleman that presented to us with cough and easy fatigability. On examination, he was pale and had crepitation’s in the left infrascapular region. The chest radiograph revealed a right hilar mass, which was confirmed on computed tomography. Bronchoscopy-guided biopsy revealed squamous cell lung cancer. Among significant baseline investigations, his hemoglobin was low (6.2 g/dl) with an elevated leukocyte and platelet count. Serum iron profile revealed a picture suggestive of anemia of chronic disease. Bone marrow examination was done, which revealed the presence of bone marrow metastasis with squamous cells. A diagnosis of Stage IVB squamous cell lung cancer with bone marrow metastasis was made and the patient was started on chemotherapy (carboplatin and paclitaxel). After the fourth cycle of chemotherapy, it was seen that the overall tumor was showing partial remission, and hemoglobin had also increased which was suggestive of bone marrow recovery. This demonstrates that bone marrow metastasis, though rare, needs not be silent overall.

Automatic Bone Segmentation in Pelvis Area with Bone Marrow Metastases; Applications in Breast Cancer Treatment Monitoring

Background: In bone marrow metastatic cancers, therapy goals are delay skeletal-related events, reduce symptoms, improve patients life quality and increase their survival. Correct knowledge about patients bone state in shortest possible time is the key to achieve therapy goals. Therefore, several quantitative analyses of MR images have been used, in which accurate segmentation of the bone plays a vital role. Due to heterogeneous nature of tumors and presence of cystic or necrotic areas, correct separation of the overall border of bone is difficult, creating source of error for the quantitative analysis results. Diffusion-weighted (DW) MR images are capable of revealing information of bone status, showing applications in skeletal related diseases. The poor anatomy available in these images gears them toward anatomical MR images such as T1-wighted (T1-w) images. However, boundary distortion created by bone metastasis hierarchically affects information extracted from DW-MR images. Commonly used bone segmentation methods are applicable on healthy bone structures, while they partly fail in presence of bone metastasis, especially in advanced situations. Objectives: In this study, we proposed an automatic method to extract pelvis bone from T1-w images in the presence of bone marrow metastasis. This method eliminates manual segmentation variability, resulting reproducible quantitative analysis independent of human error. We also investigated clinical quantitative analyses variations caused by miss-segmentation of the bone due to the bone marrow metastasis, and how our proposed method eliminates such errors. Patients and Methods: Pelvis images of ten female patients, with metastatic bone marrow breast cancer under treatment, were carried out on 1.5T MR with the following specifications: TR/TE = 171/4.76 ms, FOV = 430 430, slice thickness = 5 mm, spaces between slices = 5.5 mm. Whole-body DW images acquired using GE-EPI sequence with the following specifications: TR/TE = 5540/102 ms, percent phase FOV =430430, slice thickness=5 mm, spaces between slices = 5.5 mm, at b-value = 50, 900 sec/mm2. ADC-maps were then calculated from DW images. Image processing and analysis: Image processing consisted of the following steps: 1) automatic non-rigid registration of T1w MR images with the ADC-maps with SPM8 software; 2) segmentation of bone in each T1-w image using local level-set with prior information algorithm, implemented in MATLAB; 3) using result of step 2 as a mask, for bone extraction from corresponding DW-MR images such as ADC-map. In order to show the applicability of the automatic segmentation-based analysis, its performance in ADC-map analysis was compared to manual-based analysis methods. Results: An example of bone structure was illustrated which was diminished due to bone marrow metastasis. Registration and segmentation procedure leads to bone structure extraction regardless of the disease, providing an efficient and accurate bone study. In order to exhibit the variation of information extracted from DW-MR images based on ROI selection, three common parameters extracted from ADC-map based on manual segmentation (performed by 10 different unbiased observers) against parameters extracted based on proposed automatic segmentation method, suggesting significant differences in analysis results. Automatic segmentation accuracy has been evaluated using boundary-based (Hausdorff parameter, result: 5.55 + 1.4) and volume-based (Dice, result: 83% + 0.06 and sensitivity parameter, result: 81% + 0.08) measures. Performance of proposed method was quantitatively evaluated, comparing its performance with two commonly used different methods, in terms of segmentation accuracy. The proposed method is superior to the other two methods with Dice values of 76% and 67%, respectively. Conclusions: In conclusion, the proposed automatic algorithm has promising results in bone segmentation and in the presence of bone marrow metastasis. This method is accurate and robust, which improves the design of the patients treatment plan and provides the opportunity for accurate high profile analyses. This segmentation is a significant step towards accurate information extraction and therefore, applicable usage of DW-MRI images in bone marrow metastatic cancers, bringing consistency and reproducibility to the extracted information.

Abstract P2-03-01: Identification of cancer stem cells (CD44+CD24−/lo) in bone marrow as a prognostic factor in early breast cancer patients

Abstract Background: Cancer stem cells (CSCs) in bone marrow (BM) are epithelial tumor cells that express CD44+CD24−/lo. CSCs can be further divided into those that have ALDH activity (Aldefluor+) and those that do not. We hypothesized that if CSCs are responsible for tumor dissemination, their presence in BM would be prognostic in early stages of breast cancer (EBC) patients. Therefore, using multiparameter flow cytometry (FACS), we assessed epithelial cells for expression of CD44+CD24−/low and Aldefluor in BM of EBC patients and correlated these findings with circulating tumor cells (CTC), disseminated tumor cells (DTC) and clinical outcome. Methods: This is a prospective laboratory study (Protocol 04–0657) conducted in the Departments of Surgical Oncology and Hematopathology, at The University of Texas MD Anderson Cancer Center in Houston, TX, USA, and was approved by the institutional review board. BM aspirates were collected at the time of surgery from 108 patients with EBC. BM was analyzed for CSCs and ALDH activity by FACS analysis. Ten cytospin slides of the bone marrow mononuclear cells were prepared from each BM aspirate and reacted with a cocktail of antibodies, including AE1/AE3, CAM5.2, MNF116, CK8 and CK18, to identify epithelial cells (DTC) by immunohistochemistry (IHC). In addition, the CellSearch system (Veridex, Raritan, NJ) was used to enumerate CTCs in each of 3 tubes of 7.5 mL of peripheral blood per patient. Overall survival (OS) and disease-free survival (DFS) were calculated from the date of diagnosis and analyzed with Kaplan-Meier survival plots. Cox multivariate proportional hazards model was also performed. Results: Of the 103 evaluable patients, 45 patients received neoadjuvant chemotherapy, 35 adjuvant chemotherapy and 23 no chemotherapy. The median follow-up was 40 months (range 7–66 months). Patients with CSCs in BM had a hazard ratio (HR) of 8.8 for DFS (p = 0.002); patients with Aldefluor+ CSCs had a HR of 5.9 (p = 0.052) for DFS. Seven patients have expired and all of them had CSCs in BM. Moreover, we evaluated the presence of DTCs by FACS (CD326+CD45−) in 104 patients. Sixty-one (75%) of patients had positive BM samples for DTC (CD326+CD45- BM cells ≥ 0.53%). No association was shown between DTC in BM as determined by FACS and CTCs in PB. In a multivariate model, after adjusting for age (&amp;lt; 45 years old), clinical T stage, N stage, ER, PR, HER2 status, and nuclear grading, the presence of CSCs was found to be an independent predictor of DFS (HR = 15.8, P = 0.017) as was the presence of CTCs (HR = 13.9, P = 0.007). In this subset of patients, the presence of Aldefluor+ CSCs and DTCs was not found to be predictive of DFS in the multivariate model including the same factors as listed above. Conclusions: Our data indicate that the presence of BM metastasis is correlated to CSCs, and CSCs irrespective of ALDH activity are independent adverse prognostic factors in EBC patients. Moreover, the presence of CTCs was a strong independent predictor of DFS. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-03-01.

Early bone marrow metastasis detection: The additional value of FDG-PET/CT vs. CT imaging

ObjectiveTo assess the addition value of 18F-Fluorodeoxyglucose (FDG) PET/computed tomography (FDG-PET/CT) vs. CT in detecting early metastatic deposits in bone marrow (BM). MethodsFrom January 2009 to December 2010, 198 consecutive patients (88 male, 110 female; median age: 64 years) were retrospectively examined. All patients underwent 18F-FDG-PET/CT for disease evaluation: 65 for lung cancer, 66 for breast cancer, 57 for lymphoma and 10 for multiple myeloma. All scans were reviewed by a radiologist and a specialist in nuclear medicine for the identification of bone lesions. The presence of BM metastases was confirmed by biopsy, sequential PET/CT scan or magnetic resonance imaging when available. A patient-based analysis was performed. ResultsInvestigating the presence of skeletal metastasis, 94 (48%) patients had positive and 104 (52%) negative CT scan whereas 110 (56%) had positive and 88 (44%) negative FDG-PET/CT scan (P<0.001). The two imaging modalities were concordant in 178 (90%) patients for bone lesions; on the contrary 20 (10%) patients had discordant results (P<0.001). In 21 out of 178 concordant patients BM lesions were identified both in CT and FDG-PET, whereas nine out of the 20 discordant patients showed BM involvement at PET/CT only. Overall, PET/CT was able to identify 30 (15%) patients with BM lesions. In these latter patients, the maximum standardized uptake value (SUVmax) for BM metastases was 7.9±4.5 (range: 3.1–19.0), resulting slightly higher in patients with negative than positive CT scan (8.3±5.1 vs. 7.8±4.3, respectively; P=0.79). ConclusionsFDG-PET/CT resulted more accurate than CT in early detection of BM metastases. The FDG-PET/CT images improve the staging of about 15% of our study population. PET/CT detected BM lesions mainly on the basis of their increased metabolic activity rather than on anatomical alterations. Moreover, it provided an accurate identification of tumour viability that was useful for treatment planning and follow-up.

The role of bone marrow evaluation in the staging of patients with otherwise localized, low‐risk neuroblastoma

Bone marrow aspirations and biopsies are standard staging procedures for neuroblastoma because the tumor frequently metastasizes to the bone marrow. The presence of bone marrow metastases indicates stage 4 or 4S neuroblastoma by International Neuroblastoma Staging System (INSS) criteria; these stages are also associated with other metastatic sites of disease. We questioned whether bone marrow studies changed the staging or treatment of children with localized, completely resected tumors if there was no other evidence of metastatic spread. If stage of disease rarely changed with bone marrow results, it might be possible to avoid this procedure in a subset of patients with neuroblastoma. The staging studies of patients with INSS stage 1 (n = 29), 4 (n = 60), and 4S (n = 13) neuroblastoma from two institutions were reviewed. There were no patients upstaged from stage 1 to 4 or 4S by bone marrow metastases alone. Fifty-nine of 60 stage 4 patients had other sites of metastases on imaging studies, the remaining patient had an unresectable primary tumor and marrow disease. All subjects with stage 4S disease had liver metastases. Bone marrow studies did not contribute data that changed the stage of patients who had surgically resectable tumors and no evidence of metastatic spread on imaging studies. When present, metastatic spread to the marrow was associated with advanced local tumors or other sites of metastatic disease. Given the relatively small size of our study population, further studies are warranted that investigate the utility of bone marrow studies for patients who otherwise have INSS stage 1 neuroblastoma.

Magnetic resonance imaging in suspected metastatic spinal cord compression

This study describes high field magnetic resonance imaging (MRI), in 55 patients with suspected metastatic spinal cord compression. MRI, principally using T1-weighted sagittal surface coil images, showed evidence of cord compression in 29 patients, and intramedullary masses in three patients. MRI clearly showed the site, nature and extent of the cord compression and gave useful additional information about the presence of bone marrow metastases and paravertebral soft-tissue masses. Comparison with conventional myelography was possible in 21 patients and MRI was superior or equivalent to myelography in 18 patients and inferior in three patients. MRI is the method of choice for the investigation of patients with suspected metastatic spinal cord compression.

Small Cell Carcinoma of the Lung: Relation of Calcitonin to Bone Marrow Metastases, Parathormone and Gastrin

The relations of calcitonin concentrations to the presence of bone marrow metastases and to the concentrations of calcium, parathormone and gastrin in serum were investigated in 74 untreated patients with small cell carcinoma of the lung. Calcitonin concentrations were enhanced in two thirds of the patients, while serum calcium concentrations were normal in all. In 19 of 57 patients parathormone concentrations were slightly above the normal range, but the concentrations of parathormone and calcitonin were not correlated. Bone marrow metastases had no influence on the concentration of serum calcitonin. Finally, a small inverse correlation between the concentrations of gastrin and calcitonin in serum was observed. The results resemble those of the calcitonin-producing medullary carcinoma of the thyroid, supporting the suggestion of an ectopic source of hypercalcitoninemia in small cell carcinoma of the lung.