Optimization of cardiovascular risk factor management in patients with BCR::ABL1 negative chronic myeloproliferative neoplasms, current knowledge, and perspectives.

The exact prognostic role of cardiovascular (CV) risk factors in patients with BCR::ABL1 negative chronic myeloproliferative neoplasms (MPNs) remains unknown as it is often masked by other MPN-related features that bear strong prognostic impact on thrombotic risk. Therefore, current MPN treatment is not primarily guided by presence of CV risk factors. Treatment of CV risk factors in MPN patients usually mirrors that from the general population, despite the fact that CV risk factors in MPNs have their own specificities. Moreover, the optimal target levels for different metabolic deflections in MPNs (i.e., low-density lipoprotein, serum uric acid, or glycated hemoglobin levels) have not been defined. In the current review, we separately discuss the most important aspects of every individual CV risk factor (arterial hypertension, hyperlipidemia, chronic kidney disease, smoking, diabetes mellitus, hyperuricemia, and obesity and cachexia) in MPNs, summarize recent advances in the field, and propose future directions and research areas which may be needed to appropriately manage CV risk factors in MPNs.

Comprehensive review of solid tumor bone marrow metastasis.

Bone marrow metastasis (BMM) of solid tumors refers to a group of diseases that originate from non-hematopoietic malignant tumor cells invading the bone marrow (BM) through complex metastatic patterns. If BMM identification is delayed, the disease will rapidly develop into disseminated carcinogenesis of the BM, which manifests as a series of hematological disorders and microangiopathic hemolytic anemia, leading to serious life-threatening conditions. Although the study of solid tumor BMM is receiving increasing attention, study remains limited, and most descriptions are derived from case reports. Currently, clinicians have insufficient understanding of BMM, and BMM occurrence is often not recognized early or treated effectively, resulting in high mortality rates. In this article, we review the epidemiology, molecular mechanisms, clinical diagnosis, treatment, and prognosis of solid tumor BMM.

Antigen density quantification of cell-surface immunotherapy targets by flow cytometry: Multi-antigen assay of neuroblastoma bone marrow metastasis.

The central role of target antigen density on chimeric antigen receptor T cell potency highlights the need for accurate measurement of antigen levels on clinical tumor samples. Here, we present a protocol for quantifying antigen density for six cell-surface antigens on neuroblastoma cells metastatic to bone marrow. We describe steps for patient sample acquisition, flow cytometry panel development, instrument setup, and compensation and detail procedures for running clinical samples and data analysis. For complete details on the use and execution of this protocol, please refer to Heitzeneder et al. (2022).1.

Systematic review of isolated disseminated carcinomatosis of bone marrow from colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) metastasis commonly occurs in the liver and lungs with bone metastasis rarely occurring in isolation. Disseminated carcinomatosis of bone marrow (DCBM) is extremely rare in CRC. We conducted a systematic review to provide more information on the diagnosis, treatment options, and prognosis of the condition. METHODS: Studies were identified by performing searches on MEDLINE and EMBASE electronic databases according to the PRISMA statement standards. We included a single patient whom we treated for metastatic CRC presenting with DCBM in our study. Statistical analysis was performed using SPSS software version 23.0. RESULTS: A search through 5502 unique studies yielded 14 studies that were eventually included. There was a total of 17 cases of DCBM in CRC with back pain and constitutional symptoms as the most common presenting complaints. DCBM in CRC was associated with markedly elevated CEA of 275.57 (95% CI 17.13-534.00). There was no predilection for site of primary tumour. Overall median survival was 120 days (95% CI 64.43-175.58). The median survival for patients who received chemotherapy was 240 days (95% CI 71.11-408.89), as compared to 9 days (95% CI 1.80-16.20) for patients who received best supportive treatment. CONCLUSION: DCBM from CRC is extremely rare. Bone marrow examination remains the gold standard for diagnosis. Colonic stenting or surgical diversion may be more appropriate than primary resection in obstructed CRC in view of the poor prognosis. Systemic chemotherapy shows promise in increasing median survival.

Bone marrow metastasis/carcinomatosis in head and neck squamous cell carcinoma.

BACKGROUND: Literature on bone marrow carcinomatosis in head and neck squamous cell carcinoma (HNSCC) is sparse. This work aims to augment understanding on its characteristic features, clinical presentation, investigations, treatment and outcomes. METHODS: Comprehensive literature review of all published cases of metastasis of HNSCC to the bone marrow with regard to clinical presentation, diagnosis, treatment and survival outcomes of this disease. Each of these factors is discussed forming an up-to-date review on the subject. RESULTS: Eight case reports were identified, seven males and one female with an age range of 35-64 years. Primary sites were from the oral cavity (n = 4), oropharynx (n = 3) and supraglottis (n = 1). Six were stage four disease with nodal involvement, one case stage two and one case with unknown staging. Two of the oropharyngeal cancers were p16 positive, and one p16 status was not documented. Five patients presented with back pain, two patients had ecchymoses with bleeding, and one presented with sepsis and thrombocytopaenia. Three patients had proven disseminated intravascular coagulation. Four patients were treated with palliative chemoradiotherapy, one had palliative radiotherapy, one had radiotherapy and dendritic cell vaccine immunotherapy, and two died from the disease prior to any treatment. Various facets of presentation and management are discussed. CONCLUSION: Bone marrow carcinomatosis from HNSCC is rare. It can present with a variety of non-specific symptoms, and a high index of suspicion is required to be able to diagnose the condition promptly. Aggressive chemotherapy is the treatment of choice but prognosis remains poor.

Magnetic resonance imaging for assessing treatment response in bone marrow metastases.

Cancer metastasis to bone is a frequent observation in malignancy that may result in complications such as pathological fractures and spinal cord compression. Monitoring treatment effects is the main concern in oncology; however, the evaluation of treatment response in bone is particularly challenging as it lacks well-established criteria. In addition, bone metastases have traditionally been considered non-measurable manifestations of cancer. Magnetic resonance imaging (MRI) is one of the most specific and sensitive methods for imaging skeletal metastases. The aim of this article is to highlight the diagnostic performance of MRI in the treatment monitoring of bone metastases, to review the current literature, and to provide an overview of recommendations for the evaluation of treatment response in bone.

Chimeric antigen receptor T-cell therapy for marrow and extramedullary relapse of infant acute lymphoblastic leukemia.

Chimeric antigen receptor (CAR) T-cells, engineered autologous T-cells that target antigens found in leukemia, have shown durable remissions in relapsed acute lymphoblastic leukemia (ALL). Infant ALL with KMT2A rearrangements (KMT2Ar) is a rare, aggressive form of leukemia associated with extramedullary disease both at diagnosis and at relapse, and overall outcomes for these patients are dismal. Here we report the successful use of tisagenlecleucel, a CAR T-cell product approved for relapsed/refractory ALL, in a patient with KMT2Ar infant ALL who was treated for combined marrow and extramedullary (renal) relapse.

Pictorial review of whole body MRI in myeloma: emphasis on diffusion-weighted imaging.

There have been major advances in myeloma imaging over the past few years with focal lesions on imaging now forming part of the disease defining criteria. Whole body diffusion-weighted MRI (WB-MRI) is considered the most sensitive technique for the detection of focal active lesions. This pictorial review will focus on imaging the spectrum of myelomatous disorders on WB-MRI including diffusion and Dixon sequences. The typical imaging patterns of disease are demonstrated including in the contexts of staging, presumed solitary plasmacytoma, smouldering myeloma and examples of paramedullary and extramedullary disease. The utility of diffusion-weighted imaging in response assessment is a major advantage and this will be exemplified here.

Successful treatment of pyrotinib for bone marrow metastasis induced pancytopenia in a patient with non-small-cell lung cancer and ERBB2 mutation.

ERBB2 mutations are found in about 2% of patients with non-small cell lung cancer (NSCLC). A recent study reported that pyrotinib (an irreversible pan ErbB inhibitor) had superior antitumor effect compared to other tyrosine kinase inhibitor therapies in patients with ERBB2 mutations. Bone marrow metastasis is rare in lung adenocarcinoma, and has been reported to be associated with poor prognosis. Here, we report the case of a 62-year-old female diagnosed with lung adenocarcinoma and bone marrow metastasis. ERBB2 exon 20 insertion mutation was confirmed by next-generation sequencing (NGS) of lung tissue as well as bone marrow. The patient achieved stable disease and recovery of pancytopenia after two months of pyrotinib therapy. This is the first report of homogenous mutations of ERBB2 detected in bone marrow, as well as a good response of bone marrow to pyrotinib therapy. KEY POINTS: This is the first report of a homogenous mutation of ERBB2 detected in the bone marrow of an NSCLC patient with bone marrow metastasis. Our patient with NSCLC ERBB2 mutation and bone marrow metastasis responded well to pyrotinib therapy.

Chimeric antigen receptor-modified T-cell therapy for bone marrow and skin relapse Philadelphia chromosome-like acute lymphoblastic leukemia: A case report.

RATIONALE: Chimeric antigen receptor-modified T-cell (CART) therapy has revolutionized the treatment of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). However, the capacity of CART therapy has not yet been fully elucidated. PATIENT CONCERNS: An 18-year-old Chinese male patient presented with multiple firm masses on the skin all over his body following regular chemotherapy. DIAGNOSES: Bone marrow smear and skin biopsy confirmed that it was a bone marrow and skin relapse from the initial B-cell ALL. INTERVENTIONS: CD19 CART-cell therapy was performed to manage the bone marrow and skin of the relapsed B-cell ALL. OUTCOMES: During CART-cell therapy, cytokine release syndrome and central nervous encephalopathy occurred. Eventually, the lesions disappeared, and the bone marrow and skin tested minimal residual disease (MRD) negative. The patient achieved complete remission (CR). Fourteen days after testing MRD negative, he received allogeneic hematopoietic stem-cell transplantation and has remained disease free to date. LESSONS: The CR of this patient with leukemia cutis demonstrated that CART exhibited efficacy in this case. While further research is still required, this treatment could potentially be used as a therapy for skin leukemia, lymphoma, and other primary skin cancers.

Pediatric rhabdomyosarcoma with bone marrow metastasis.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of adolescence and childhood. Although most patients with localized RMS are cured, outcome of those with metastatic disease remains unsatisfactory. RMS with bone marrow (BM) metastasis accounts for approximately 6% of all cases with RMS and has a 3-year event-free survival of 14%. Our study aims to describe our institution's experience of patients with metastatic RMS with BM involvement. METHODS: This was a single-institution retrospective study from Memorial Sloan Kettering Kids, a tertiary pediatric oncology center. Patients with RMS who were diagnosed with BM metastasis between 1998 and 2018 were identified from pathology reports. RESULTS: For patients with RMS and BM positivity at diagnosis (N = 27), the median survival was 1.5 years. The 1-, 2-, and 3-year overall survival (OS) were 81%, 32%, and 20%, respectively. There is one long-term (defined as >4 year) survivor who is still alive 14.9 years after diagnosis despite two metastatic recurrences. An Oberlin status of 4 that included BM metastasis portended a 3-year OS of 0%. CONCLUSIONS: Although most patients will respond to initial therapy, BM metastasis at the time of diagnosis lends a near-fatal diagnosis in pediatric patients with RMS. Novel therapies are desperately needed to consolidate their initial remission.

Diagnostic performance of 18F-2-fluoro-2-deoxy-D-glucose PET/computerized tomography in identifying bone marrow infiltration in new patients with diffuse large B-cell lymphoma and Hodgkin lymphoma.

OBJECTIVE: To compare between F-2-fluoro-2-deoxy-D-glucose PET/computerized tomography (F-FDG PET/CT) and routine iliac bone marrow biopsy (BMB) in assessment of bone marrow infiltration (BMI) in Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL) patients at initial presentation. PATIENTS AND METHODS: A retrospective analysis of 138 patients (50 Hodgkin lymphomas, 88 DLBCLs). The study included 70 males and 68 females with median age of 43 years. All patients underwent F-FDG PET/CT and iliac crest BMB before treatment. Any focal or patchy FDG uptake in the bone marrow, superior-to hepatic uptake was interpreted as abnormal with or without corresponding CT changes. Treatment response was evaluated clinically with each cycle of chemotherapy, radiologically after three cycles and at the end of treatment. RESULTS: The overall diagnostic performance showed significant higher sensitivity of F-FDG PET/CT than that of BMB (73.9 versus 62.5%, P = 0.046), while the specificity was higher in BMB than in F-FDG PET/CT (100% in BMB versus 93.5% in F-FDG PET/CT). In Hodgkin lymphoma, sensitivity, negative predictive value (NPV) and accuracy were significantly higher in F-FDG PET/CT compared with BMB, being 87.5, 94.4 and 96% versus 50, 81 and 84% (P = 0.02, 0.03, 0.04, respectively). However, for DLBCL patients, almost comparable results were found between both tests in terms of sensitivity, NPV and accuracy (66.7, 83.9 and 81.8% versus 68.8, 84.9 and 88.6%, respectively). After PET/CT scan, 12 patients (8.6%) were upstaged to stage IV, eight of them were negative by BMB. CONCLUSION: F-FDG PET/CT seemed to be an excellent diagnostic test in assessment of BMI at initial assessment and staging of Hodgkin lymphoma and DLBCL patients.

Comprehensive evaluation of context dependence of the prognostic impact of MYCN amplification in neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project.

BACKGROUND: MYCN amplification (MYCN-A) is an established adverse prognostic factor in neuroblastoma. The extent to which the prognostic impact of MYCN-A depends on other factors has not been fully characterized. PATIENTS AND METHODS: Using the International Neuroblastoma Risk Group database, we constructed Cox models of overall survival (OS) to obtain hazard ratios of the effect of MYCN-A within subgroups defined by other prognostic factors. Cox models assessed the degree to which the prognostic impact of MYCN-A was modulated by each other covariate. We used absolute hazard ratio (HR) differences to construct classification trees to identify subgroups with greatest differential prognostic effect of MYCN-A. RESULTS: In a cohort of 6223 patients with known MYCN status, the OS hazard ratio associated with MYCN-A was 6.3 (95% confidence interval 5.7-7.0, P < .001). Age at diagnosis conferred the largest HR absolute difference for MYCN-A between subgroups (HR absolute difference 16.6; HRs for MYCN-A of 19.6 for <18 months, 3.0 for ≥18 months). MYCN-A remained significantly prognostic of OS after controlling for other factors, abrogating their prognostic strength. Patients whose outcome was most impacted by MYCN status were those who were <18 months, had high mitosis karrhyohexis index (MKI) and low ferritin. CONCLUSION: The prognostic strength of MYCN-A varies depending on which patient subgroup defined by other neuroblastoma risk factors is examined, with greatest strength in patients with otherwise favorable features. MYCN-A has little effect within some subgroups, aiding clinical decision-making if MYCN status cannot be assessed. Subgroups where MYCN-A has large effect may be prioritized for agents targeting Myc family proteins.

[Bone Marrow Metastases of Breast Cancer Treated with Endocrine Therapy-A Case Report].

We report a case of bone marrowmetastases of breast cancer treated with endocrine therapy. A 54-year-old woman underwent right partial mastectomy and sentinel lymph node biopsy, followed by adjuvant chemotherapy and radiotherapy. She declined the endocrine therapy and was lost to follow-up after 3 postoperative years. After 9 postoperative years, she visited our hospital because of backache and an axillary lump. FDG-PET scan, incisional biopsy of the axillary lump, and bone marrowbiopsy revealed multiple bone and bone marrowmetastases of the breast cancer. She was treated with endocrine therapy(fulvestrant: FUL), which effectively decreased the FDG uptake in the metastatic lesions after 6 months. However, tumor markers elevated after 1 year and 6 months, and she is currently under combination therapy with aromatase inhibitors and CDK4/6 inhibitors.

Azacitidine for Relapse After Allogeneic Stem Cell Transplantation-Single-Center Study.

BACKGROUND: Relapse is the leading cause of treatment failure for myeloid malignancies treated with allogeneic hematopoietic stem cell transplantation. Treatment options are very limited and use of azacitidine is one of the available options. METHODS: This was a retrospective, single-institution study. Of 28 evaluated patients, 18 were males, and the median age was 60 years (range, 15-78). There were 15 patients with acute myeloid leukemia, 8 with myelodysplastic syndrome, 4 with chronic myelomonocytic leukemia, and 1 with primary myelofibrosis. Ten patients received azacitidine for overt relapse, 14 received it as a preemptive therapy, and 4 others received it as maintenance treatment after allo-hematopoietic cell transplant (HSCT). Eleven patients received a donor lymphocyte infusion (DLI). RESULTS: The patients received median 5 (1-9) cycles of azacitidine in preemptive and maintenance therapy and median 2.5 (1-9) cycles in patients with relapse. Thirty-nine percent of patients received DLIs. Median overall survival was 6.1 months (95% CI, 0.7-13) for relapse therapy vs 21.2 months (95% CI, 8.4-inf) for preemptive therapy. Among patients treated for relapse, 30% achieved temporary disease control and underwent the second allo-HSCT. A complete, cytogenetic remission was achieved in 50% of patients and stable minimal residual disease in 14% of patients in a group with preemptive therapy. Toxicity was considerable; neutropenia (71%), anemia (14%), thrombocytopenia (36%), and serious infections (36%) were observed in the preemptive setting. CONCLUSIONS: These data support the notion that azacitidine is best used as a preemptive therapy against relapse for patients after allo-HSCT performed for myeloid malignancy. Applying azacitidine as therapy for ongoing relapse after allo-HSCT may lead to stable disease and allow for better performance of the second allo-HSCT.

Histiocytic cell neoplasms involving the bone marrow: summary of the workshop cases submitted to the 18th Meeting of the European Association for Haematopathology (EAHP) organized by the European Bone Marrow Working Group, Basel 2016.

The bone marrow is a preferential site for both reactive and neoplastic histiocytic proliferations. The differential diagnosis ranges from reactive histiocyte hyperplasia in systemic infections, vaccinations, storage diseases, post myeloablative therapy, due to increased cell turnover, and in hemophagocytic lymphohistiocytosis, through extranodal Rosai-Dorfman disease to neoplasms derived from histiocytes, including histiocytic sarcomas (HS), Langerhans cell histiocytoses (LCH), Erdheim-Chester disease (ECD), and disseminated juvenile xanthogranuloma (JXG). One of the most important recent developments in understanding the biology of histiocytic neoplasms and in contributing to diagnosis was the detection of recurrent mutations of genes of the Ras/Raf/MEK/ERK signaling pathway, in particular the BRAFV600E mutation, in LCH and ECD. Here, we summarize clinical and pathological findings of 17 histiocytic neoplasms that were presented during the bone marrow symposium and workshop of the 18th European Association for Haematopathology (EAHP) meeting held in Basel, Switzerland, in 2016. A substantial proportion of these histiocytic neoplasms was combined with clonally related lymphoid (n = 2) or myeloid diseases (n = 5, all ECD). Based on the latter observation, we suggest excluding co-existent myeloid neoplasms at initial staging of elderly ECD patients. The recurrent nature of Ras/Raf/MEK/ERK signaling pathway mutations in histiocytic neoplasms was confirmed in 6 of the 17 workshop cases, illustrating their diagnostic significance and suggesting apotential target for tailored treatments.

Clinical outcome of 30 patients with bone marrow metastases.

OBJECTIVE: Cancer patients with bone marrow metastases are rare and dismal. The study was to identify the clinical features and prognostic factors in cancer patients with bone marrow metastases. PATIENTS AND METHODS: A total of 30 patients with bone marrow metastases were reviewed between September 2007 and September 2013. Bone marrow metastases were identified by bone marrow aspiration. RESULTS: The median age was 56.5 years (range, 8-85 years). The two most common primary tumor sites were the stomach (7, 23.3%), breast (5, 16.7%). Bone metastases (27, 90.0%) were the most common concurrent metastases. The most common cause for bone marrow aspiration was anemia and thrombocytopenia (10, 33.3%). The median survival time was 3 months (range, 0.5-82 months). Patients with good performance status (n = 19) had a longer median survival time than patients with poor performance status (n = 11) (8 months vs. 1 months, P = 0.041). Patients with primary unknown origin (n = 5) had a significantly shorter overall survival time than patients with known origin (n = 25) (1 month vs. 6 months = 0.010). The median survival time was 9 months in the systemic therapy group (n = 21) and 1 month in the best supportive care group (n = 9) (P = 0.000). CONCLUSION: To make primary origin clear and start systemic antitumor therapy is beneficial for patients with bone marrow metastases.