Extensive Bone Marrow Research Articles

2669 Mucosa-Associated Lymphoid Tissue Lymphoma: Crossing the Borders!

INTRODUCTION: Mucosa-associated lymphoid tissue (MALT) lymphoma or MALTomas are responsible for half of the primary gastric lymphomas and up to 8% of B-cell lymphomas. It mostly affects patients in their 5th or 6th decade of life. MALT lymphoma is well known to remain localized in the stomach and to follow a benign course. Despite that gastric MALToma is well defined in the literature, it is rather uncommon to present as a peri-pancreatic mass. Herein, we present the case of a patient with an incidental peri-pancreatic mass diagnosed as an aggressive form of MALT lymphoma. CASE DESCRIPTION/METHODS: A 76-year-old male with hypertension presented to the gastroenterology clinic for the evaluation of peri-pancreatic mass incidentally found during computed tomography (CT) scan performed for renal colic. Physical examination was remarkable for an epigastric fullness with no tenderness. Laboratory tests were remarkable for iron deficiency anemia. CT showed a 7 cm ill-defined soft tissue mass within the pancreaticoduodenal groove abutting the pancreatic head and encasing the gastroduodenal artery suspicious for a pancreatic neoplasm (Figure 1). Endoscopic ultrasound (EUS) showed a hypoechoic heterogeneous mass arising from the gastric wall in close proximity to the pancreas (Figure 2). EUS-guided biopsies were consistent with extra-nodal marginal zone lymphoma of MALT (Figure 3). Gastric biopsies confirmed the presence of MALToma and revealed positive Helicobacter Pylori (HP) infection. Staging workup confirmed extensive bone marrow as well as para-aortic, mediastinal and paratracheal lymph node involvement. The patient received curative HP treatment and was started on bendamustine and rituximab. DISCUSSION: The stomach is the most commonly affected organ by MALT lymphoma. Helicobacter Pylori is a major precursor for the development of gastric MALT lymphoma as up to 90% of affected patients show H.Pylori on stomach biopsies. Chronic HP infection leads to lymphoid tissue proliferation within the stomach and progression towards lymphoma. In this setting, the course is usually indolent with the disease usually confined to the stomach but aggressive tumor behavior has been reported. HP antibiotic eradication remains the first line therapy for early-stage HP positive gastric MALT lymphoma. In other instances, a patient-tailored approach is recommended based on the stage, involved site, HP status and clinical characteristics. Therapeutic options include radiation therapy, chemotherapy and surgery accordingly.

Intra-articular osteoid osteoma accompanied by extensive bone marrow edema. A clinical and micro-morphological analysis

Osteoid osteoma (OO) is a benign bone tumor producing non-mineralized bone matrix (i.e., osteoid). While peritumoral edema is commonly found in OO, extensive bone marrow edema has been reported less frequently. Furthermore, the micro-morphological characteristics of the nidus and its central calcification remain unclear. In this study, a consecutive series of four patients suffering from extensive bone marrow edema triggered by intra-articular osteoid osteoma underwent clinical examination, magnetic resonance imaging (MRI) and computed tomography (CT) as well as dual-energy X-ray absorptiometry (DXA) and laboratory bone turnover analyses. The obtained resection specimens were processed by undecalcified histology and were subsequently analyzed by light microscopy and quantitative backscattered electron imaging (qBEI). We report an entity of intra-articular osteoid osteoma in the knee and foot, in which an extensive and persistent bone marrow edema syndrome masked the correct diagnosis. While metabolic bone diseases were excluded in all cases, the reassessment of the patients’ clinical history including pain characteristics (nocturnal, aspirin sensitivity) led us to perform additional CT, where the tumor was diagnosed. The micro-morphological analysis of the OO biopsies revealed that the nidus was surrounded by hyperosteoidosis, while central mineralization was detected in all cases. This mineralized area showed a significantly higher mineralization heterogeneity than the surrounding trabecular bone and more disorganized collagen fibers detected by qBEI and polarized light microscopy, respectively. Taken together, our results indicate that osteoid osteoma should be considered when persistent and extensive, peri-articular bone marrow edema is diagnosed. The central calcification that is found inside the nidus in conventional imaging was mirrored by bone matrix with a heterogeneous mineralization pattern.

Osteomyelitis After Deadlifting Injury- A Rare Case Of A Burst Abscess

HISTORY: 68-yr old male weightlifter presented with 1 mo. L buttock pain, acute onset of popping mid-lift during a deadlift, with radiating vague pain in L buttock. He continued to exercise through pain and 1 wk later pain progressed to severe deep buttock pain and difficulty ambulating. Denied low back pain, radiating thigh/leg symptoms, numbness/tingling, weakness, or bowel/bladder changes. Past hx positive for melanoma (treated in remote past), social hx negative for smoking, drug/alcohol abuse. He initially went to outside facility (only lumbar x-rays taken) without improvement, came in for another opinion with progressive symptoms. PHYSICAL EXAMINATION: Skin normal without warmth, erythema. Vague tenderness in region of L buttock and SI joint. Full lumbar spine and hip ROM. Negative SLR. Mild nonspecific back discomfort with FABER. Normal lower limb neurovascular exam. DIFFERENTIAL DIAGNOSIS: 1. SI Joint Dysfunction 2. Lumbar Radiculopathy 3. Piriformis Syndrome 4. Lumbar or Sacral Compression Fracture 5. Metastatic Cancer 6. Sacroiliitis TEST AND RESULTS: Outside lumbar x-rays negative for fracture, showed minimal degenerative disc changes. We obtained hip/pelvis radiographs showing significant erosions and destructive changes of L SI joint. An urgent MRI showed fluid-filled and widened SI joint, severe inflammatory sacroiliitis with extensive erosions and bone marrow edema, widespread reactive muscle edema (iliacus showing fluid collection/early abscess at SI joint); SI joint aspirate was obtained. FINAL WORKING DIAGNOSIS: septic sacroiliac arthritis with iliacus abscess and secondary osteomyelitis; aspirate grew staphylococcus aureus (MSSA). TREATMENT AND OUTCOMES: The patient had a unique etiology of osteomyelitis not commonly reported. Orthopedics and ID determined he had pre-existing asymptomatic abscess that ruptured. Under the extreme abdominal pressures of deadlifting, they felt abscess burst leading to local spread and secondary osteomyelitis. This case highlights the rapidity and widespread destruction of infectious arthritis and need for awareness and prompt workup. Patient was treated with 6 wks of oxacillin and responded well. He returned to baseline physical activity at follow up; repeat x-rays showed SI joint sclerosis and patient was counseled on SI joint arthritis.

Leukoerythroblastosis in castration-resistant prostate cancer: A clue to diffuse bone marrow carcinomatosis.

A 66-year-old man with a previous history of advanced prostate cancer failing complete androgen blockade, docetaxel chemotherapy, denosumab, and abiraterone acetate as judged by persistent high serum levels of prostate specific antigen presented with exertional dyspnea, normocytic anemia, and thrombocytopenia. Leukoery - throblastosis was noted in his peripheral blood. Bone marrow examination disclosed diffuse bone marrow carcinomatosis from prostate cancer. Prolonged activated partial thromboplastin time, prothrombin time, and an extremely elevated serum level of Ddimer led to a diagnosis of disseminated intravascular coagulation. Magnetic resonance imaging of spine revealed extensive bone marrow involvement but bone scan showed only scanty bony metastasis. We like to call attention to the importance of prompt bone marrow examination once recognizing leukoerythroblastosis in patients with advanced prostate cancer. Survey of a possible coexistent disseminated intravascular coagulation is as well strongly recommended in this condition.

The PAF1c Subunit CDC73 Is Required for Mouse Hematopoietic Stem Cell Maintenance but Displays Leukemia-Specific Gene Regulation.

SummaryThe Polymerase Associated Factor 1 complex (PAF1c) functions at the interface of epigenetics and gene transcription. The PAF1c is required for MLL fusion-driven acute myeloid leukemia (AML) through direct regulation of pro-leukemic target genes such as Hoxa9 and Meis1. However, the role of the PAF1c in normal hematopoiesis is unknown. Here, we discovered that the PAF1c subunit, CDC73, is required for both fetal and adult hematopoiesis. Loss of Cdc73 in hematopoietic cells is lethal because of extensive bone marrow failure. Cdc73 has an essential cell-autonomous role for adult hematopoietic stem cell function in vivo, and deletion of Cdc73 results in cell-cycle defects in hematopoietic progenitors. Gene expression profiling indicated a differential regulation of Hoxa9/Meis1 gene programs by CDC73 in progenitors compared with AML cells, suggesting disease-specific functions. Thus, the PAF1c subunit, CDC73 is essential for hematopoietic stem cell function but exhibits leukemia-specific regulation of self-renewal gene programs in AML cells.

Microangiopathy in Cancer: Causes, Consequences, and Management.

Thrombotic microangiopathy (TMA) is a syndrome involving fragmentation haemolysis, thrombocytopenia, and thrombosis. A range of disorders including cancer may have TMA as a clinical manifestation. TMA in cancer may be caused by several mechanisms, including systemic microvascular metastases,but may also be due to extensive bone marrow involvement with cancer or secondary necrosis. Chemotherapeutic agents may also cause associated TMA through a range of different mechanisms. Gemcitabine, platinum-based drugs, mitomycin C, and proteasome inhibitors are known to cause TMA in cancer patients. Transplant-associated TMA (TA-TMA) may affect either solid organ or HSCT patients. TA-TMA remains a difficult complication to address due to its high mortality rate, lack of standard diagnostic criteria, and limited therapeutic options. The challenge of cancer-associated TMA is furthered by the fact that plasma exchange is ineffectivein its management.

The PAF1c Subunit Cdc73 Is Essential for Hematopoiesis and Displays Differential Gene Regulation in MLL-AF9 Driven Leukemia

The Polymerase Associated Factor 1 complex (PAF1c) functions at the interface of epigenetics and gene transcription. The PAF1c is a multi-protein complex composed of Paf1, Cdc73, Leo1, Ctr9, Rtf1 and WDR61, which have all been shown to play a role in disease progression and different types of cancer. Previous reports demonstrated that the PAF1c is required for MLL-fusion driven acute myeloid leukemia. This is due, in part, to a direct interaction between the PAF1c and wild type MLL or MLL fusion proteins. Importantly, targeted disruption of the PAF1c-MLL interaction impairs the growth of MLL-fusion leukemic cells but is tolerated by normal hematopoietic stem cells. These data point to differential functions for the PAF1c in normal and malignant hematopoietic cells that may be exploited for therapeutic purposes. However, a detailed exploration of the PAF1c in normal hematopoiesis is currently lacking.Here, we utilize a mouse genetic model to interrogate the role of the PAF1c subunit, Cdc73, in the development and sustenance of normal hematopoiesis. Using hematopoietic-specific constitutive and conditional drivers to express Cre recombinase, we efficiently excise floxed alleles of Cdc73 in hematopoietic cells. VavCre mediated excision of Cdc73 results in embryonic lethality due to hematopoietic failure. Characterization of the hematopoietic system demonstrated that cKit+ hematopoietic stem and progenitor cells (HSPC) are depleted due to Cdc73 knockout.We next investigated the role of Cdc73 in adult hematopoiesis using Mx1Cre mediated excision. Conditional knockout of Cdc73 in the adult hematopoietic system leads to lethality within 15 days of Cdc73 excision while no phenotype was observed in heterozygous Cdc73fl/wt controls. Pathological examination of bones in these mice showed extensive bone marrow failure. Flow cytometry analysis revealed that cKit+ HSPCs in adult mice are ablated following loss of Cdc73. Bone marrow transplantation assays demonstrated a cell autonomous requirement of Cdc73 for HSC function in vivo.To perform cellular characterization of HSPCs upon Cdc73 KO, we optimized excision conditions to capture cKit+ HSPCs with excised Cdc73 but before their exhaustion. Flow cytometry analysis demonstrated that Cdc73 KO leads to a cell cycle defect. Cdc73 excision leads to a 2.5 fold increase in the accumulation of HSPCs in the G0 phase of cell cycle with a reduction in the proliferative phases. This is accompanied with an increase in cellular death as indicated by Annexin V staining. Together, these data indicate that Cdc73 is required for cell cycle progression and HSPC survival.To understand the molecular function of Cdc73, we performed RNAseq analysis to identify genes regulated by Cdc73 in HSPCs. We observed 390 genes are upregulated and 433 genes are downregulated upon loss of Cdc73. Specifically, Cdc73 excision results in upregulation of cell cycle inhibitor genes such as p21 and p57, consistent with the cell cycle defect observed following Cdc73 excision.Further, when comparing our results to leukemic cells, we uncovered key differences in Cdc73 gene program regulation between ckit+ hematopoietic cells and MLL-AF9 AML cells. Loss of Cdc73 in leukemic cells leads to downregulation of genes associated with early hematopoietic progenitors and upregulation of myeloid differentiation genes consistent with previous studies. Interestingly, we observed a more even distribution of expression changes (non-directional) within these gene programs following Cdc73 inactivation in HSPCs. Most importantly, while loss of Cdc73 in MLL-AF9 AML cells leads to a profound downregulation of the Hoxa9/Meis1 gene program, excision of Cdc73 in HSPCs results in a modest non-directional change in expression of the Hoxa9/Meis1 gene program. This was attributed to no change in Hoxa9 and Meis1 expression in HSPCs following excision of Cdc73, in contrast to MLL-AF9 cells where these pro leukemic targets are significantly downregulated. Together, these data indicate an essential role for the PAF1c subunit Cdc73 in normal hematopoiesis but differential roles and context specific functions in normal and malignant hematopoiesis, which may be of therapeutic value for patients with AMLs expressing Hoxa9/Meis1 gene programs. DisclosuresNo relevant conflicts of interest to declare.

A Phase I First-in-Human Clinical Trial of CD19-Targeted 19-28z/4-1BBL “Armored” CAR T Cells in Patients with Relapsed or Refractory NHL and CLL Including Richter's Transformation

A Phase I First-in-Human Clinical Trial of CD19-Targeted 19-28z/4-1BBL “Armored” CAR T Cells in Patients with Relapsed or Refractory NHL and CLL Including Richter's Transformation

Ex Vivo Evidence for the Combination of Immune Checkpoint Inhibition with TGF-β Blockade to Enhance Anti-Tumor T Cell Responses in Multiple Myeloma

Immunosuppressive milieu of multiple myeloma is associated with various cellular and non-cellular factors that foster immune escape leading to tumor progression. While immune checkpoint inhibitors have achieved significant clinical success in many types of solid tumors, recent clinical trials of immune checkpoint blockade performed in patients with multiple myeloma failed to demonstrate significant anti-tumor efficacy. To enhance the clinical efficacy of immune checkpoint blockade in multiple myeloma, elaborate characterization of tumor antigen-specific T cells is an essential prerequisite. In the present study, we investigated the immunophenotypic and functional characteristics of tumor antigen-specific T cells in patients with multiple myeloma. In addition, using direct ex vivo experimental techniques, we tried to examine how to manipulate the immunosuppressive microenvironment to maximize anti-myeloma responses of the tumor-specific T cells.We first tried to define and characterize CD8+ T cell population capable of specifically recognizing and reacting to myeloma cells in bone marrow of myeloma patients using MHC multimer technique. In selected patients, we could successfully define CD8+ T cell population specifically recognizing the HLA-A*0201-restricted epitopes (either “SLLMWITQC” or “LLLGIGILV”), included in myeloma tumor antigens NY-ESO-1 and HM1.24. The vast majority of myeloma-antigen specific CD8+ T cells expressed high level of PD-1 and also co-expressed other types T cell inhibitory receptors. More strikingly, PD-1+ myeloma-specific CD8+ T cells had a distinct pattern of transcriptional factor expression, high level of Eomes and low level of T-bet (EomeshiT-betlo), indicating that they were profoundly exhausted functionally and that a simple blockade of PD-1/PD-L1 binding might not be enough to reinvigorate their anti-myeloma activity.Consistent with the immunophenotypes of myeloma-specific CD8+ T cells, malignant plasma cells in bone marrow of myeloma patients, defined as CD14-CD19-CD138+CS1+CD56hi, also expressed PD-L1 abundantly, compared to normal plasma cells, suggesting that PD-1/PD-L1 axis plays a major role in making myeloma-recognizing T cells unresponsive to TCR stimulation. Interestingly, in addition to tumor cells, various types of immune cells comprising myeloma microenvironment also highly express PD-L1. Indeed, in response to ex vivo TCR stimulation with anti-CD3, CD8+ T cells from myeloma bone marrow showed lower proliferation and reduced production of anti-tumor effector cytokines (INF-γ and TNF-α), compared to marrow-infiltrating CD8+ T cells of diffuse large B cell lymphoma and Hodgkin lymphoma patients with extensive bone marrow involvement. However, even in the presence of anti-PD-1, myeloma-specific responses of marrow-infiltrating CD8+ T cells was only modestly improved in terms of proliferation and cytokine production.Next, we investigated whether blocking TGF-β signaling in combination with PD-1/PD-L1 axis blockade could restore the function of marrow-infiltrating CD8+ T cells of myeloma patients, since TGF-β produced by clonal plasma cells and bone marrow stromal cells is critical in immunosuppressive microenvironment of multiple myeloma. To this end, we found that combination of TGF-β signaling blockade (either anti-TGF-β1 or Galunisertib, a small molecule inhibitor of TGF-β receptor I) with anti-PD-1 significantly increased the frequencies of IFN-γ- and/or TNF-α-producing CD8+ T cells in response to ex vivo TCR stimulation, compared to a single PD-1 or a single TGF-β blockade. Likewise, myeloma antigen-specific proliferation of CD8+ T cells was significantly enhanced with addition of TGF-β signaling blockade.Taken together, although PD-1/PD-L1 axis acts as a major component of immunosuppressive milieu in multiple myeloma, the efficacy of PD-1 blockades in multiple myeloma might be hampered by complicated microenvironment consisting of T cell-intrinsic and -extrinsic factors. Our results provide an ex vivo evidence of incorporating TGF- β signaling blockade to immune checkpoint inhibition to enhance anti-tumor T cell responses in multiple myeloma DisclosuresNo relevant conflicts of interest to declare.

Reactive plasmacytosis mimicking multiple myeloma associated with SFTS virus infection: a report of two cases and literature review

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel bunyavirus named SFTS virus (SFTSV), which is classified into the genus Phlebovirus and family Phenuiviridae. Reactive plasmacytosis mimicking multiple myeloma is a very rare condition in association with SFTS. Here, we describe two SFTS cases who presented with hyperimmunoglobulinemia, as well as extensive bone marrow and peripheral blood plasmacytosis, which mimicked multiple myeloma (MM).Case presentationWe report two cases who presented with fever and blood routine abnormity which were conformed as SFTS eventually. They were performed bone marrow aspiration and were admitted to the department of hematology with a preliminary diagnosis of MM. They all had hyperimmunoglobulinemia, extensive bone marrow and peripheral blood plasma cells, prolonged activated partial thromboplastin time (APTT), elevated hepatic enzyme. The two patients recovered with treatment of doxycycline, human immunoglobulins, plasma transfusion, and other supporting treatments. But case 1 occurred lymphoma 8 months later and died.ConclusionSFTS might be one of differential diagnosis of MM in certain endemic area. We also conclude that SFTSV is a pantropic virus that could injure most tissues and cells of the human body.

An Unusual Cause of Obscure Gastrointestinal Bleeding Unmasked by Video Capsule Endoscopy

Follicular lymphoma (FL) is the most common type of non-Hodgkin's lymphoma in the West, usually detected in lymph nodes. Gastrointestinal tract (GIT) is a common site of extra-nodal disease. We report a case of atypical GI-FL diagnosed as a consequence of investigations for microcytic anemia. A 73-year-old gentleman was referred for evaluation of iron-deficiency anemia, presumed GI source. Physical examination was grossly normal. Initial age-appropriate colonoscopy revealed a cecal hyperplastic polyp and non-bleeding internal hemorrhoids. Six weeks later, upper endoscopy for new-onset melena revealed grade C esophagitis, erosive gastritis, and single small angioectasia in anterior duodenal bulb, unlikely to account for the severity of blood loss. Duodenal biopsy was negative for celiac disease. Video capsule endoscopy (VCE) was performed for worsening anemia necessitating blood transfusion. Active oozing spot amongst an area of erythema, erosions, small ulcers and likely luminal narrowing and stricture was evident in the distal jejunum/proximal ileum. The capsule did not reach the cecum. Due to retained capsule and luminal stricture, CT enterography was performed. This revealed large anterior mediastinal, retroperitoneal, pelvic masses and extensive severe small bowel wall thickening, compatible with possible nodal and extra-nodal metastatic lymphoma. The capsule has since passed. Subsequent pelvic mass biopsy showed low-grade FL. Further staging including PET confirmed atypical involvement with most intense uptake in the mesentery, omentum and pleura, and extensive nodal and bone marrow involvement. GI-FL is a rare entity, generally affecting the small intestines. It is not always possible to determine the primary site of origin of GI-FL. It could either arise from extra-intestinal regions and present in the GIT at an advanced stage, or arise primarily in the GIT and disseminate to involve lymph nodes or other extra-intestinal sites. Optimal work-up and treatment plan is not well established. Endoscopic evaluation of the entire GIT and whole body PET are required for accurate staging. Based on the stage, treatment options include watch and wait approach, surgery, chemotherapy, radiotherapy, immune-radiotherapy or a multi-modal approach. Chemotherapy with rCHOP was initiated on our patient. Initially he responded to the regimen. Unfortunately, the disease turned aggressive shortly afterwards, and he subsequently transitioned to palliative care.1935_A Figure 1. Capsule endoscopy demonstrating edema, erosion, luminal narrowing and oozing in distal jejunum/proximal ileum.1935_B Figure 2. Active oozing from the erythematous, inflamed area with luminal narrowing narrowing in the distal jejunum/proximal ileum noted on capsule endoscopy.1935_C Figure 3. Capsule endoscopy demonstrating edematous, inflamed area in distal jejunum

225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study

BackgroundA remarkable therapeutic efficacy has been demonstrated with 225Ac-prostate-specific membrane antigen (PSMA)-617 in heavily pre-treated metastatic castration-resistant prostate cancer (mCRPC) patients. We report our experience with 225Ac-PSMA-617 therapy in chemotherapy-naïve patients with advanced metastatic prostate carcinoma.MethodsSeventeen patients with advanced prostate cancer were selected for treatment with 225Ac-PSMA-617 in 2-month intervals, with initial activity of 8 MBq, then de-escalation to 7 MBq, 6 MBq or 4 MBq in cases of good response. In one patient, activity was escalated to 13 MBq in the third cycle. Fourteen patients had three treatment cycles administered, while in three patients treatment was discontinued after two cycles due to good response. Six out of 17 patients received additional treatments after the third cycle. Prostate-specific antigen (PSA) was measured every 4 weeks for PSA response assessment. 68Ga-PSMA-PET/CT was used for functional response assessment before each subsequent treatment cycle. Serial full blood count, renal function test, and liver function were obtained to determine treatment-related side effects.ResultsGood antitumor activity assessed by serum PSA level and 68Ga-PSMA-PET/CT was seen in 16/17 patients. In 14/17 patients, PSA decline ≥90% was seen after treatment, including seven patients with undetectable serum PSA following two (2/7) or three cycles (5/7) cycles of 225Ac-PSMA-617. Fifteen of 17 patients had a > 50% decline in lesions avidity for tracer on 68Ga-PSMA-PET/CT including 11 patients with complete resolution (PET-negative and either stable sclerosis on CT for bone or resolution of lymph node metastases) of all metastatic lesions. Grade 1/2 xerostomia was seen in all patients, and none was severe enough to lead to discontinuation of treatment. One patient had with extensive bone marrow metastases and a background anemia developed a grade 3 anemia while another patient with solitary kidney and pre-treatment grade 3 renal failure developed grade 4 renal toxicity following treatment. The group presented with significant palliation of bone pain and reduced toxicity to salivary glands due to de-escalation.Conclusions225Ac-PSMA-617 RLT of chemotherapy-naïve patients with advanced metastatic prostate carcinoma led to a ≥ 90% decline in serum PSA in 82% of patients including 41% of patients with undetectable serum PSA who remained in remission 12 months after therapy. The remarkable therapeutic efficacy reported in this study could be achieved with reduced toxicity to salivary glands due to de-escalation of administered activities in subsequent treatment cycles. This necessitates further exploration for informing clinical practice and clinical trial design.

T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma.

Purpose Therapies with novel mechanisms of action are needed for multiple myeloma (MM). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are artificial proteins that target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells but not normal essential cells. We conducted the first-in-humans clinical trial, to our knowledge, of T cells expressing a CAR targeting BCMA (CAR-BCMA). Patients and Methods Sixteen patients received 9 × 106 CAR-BCMA T cells/kg at the highest dose level of the trial; we are reporting results of these 16 patients. The patients had a median of 9.5 prior lines of MM therapy. Sixty-three percent of patients had MM refractory to the last treatment regimen before protocol enrollment. T cells were transduced with a γ-retroviral vector encoding CAR-BCMA. Patients received CAR-BCMA T cells after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Results The overall response rate was 81%, with 63% very good partial response or complete response. Median event-free survival was 31 weeks. Responses included eradication of extensive bone marrow myeloma and resolution of soft-tissue plasmacytomas. All 11 patients who obtained an anti-MM response of partial response or better and had MM evaluable for minimal residual disease obtained bone marrow minimal residual disease-negative status. High peak blood CAR+ cell levels were associated with anti-MM responses. Cytokine-release syndrome toxicities were severe in some cases but were reversible. Blood CAR-BCMA T cells were predominantly highly differentiated CD8+ T cells 6 to 9 days after infusion. BCMA antigen loss from MM was observed. Conclusion CAR-BCMA T cells had substantial activity against heavily treated relapsed/refractory MM. Our results should encourage additional development of CAR T-cell therapies for MM.

Lu-177-PSMA treatment for metastatic prostate cancer: case examples of major responses

Prostate-specific membrane antigen (PSMA) is expressed in high-risk prostate cancer (PCa). PSMA has potential as a basis for new diagnostics and theragnostics. 177Lu-PSMA radioligand therapy is mainly used for patients with end-stage prostate cancer. This report describes seven PCa patients: one patient with extensive metastatic bone and bone marrow disease during the first visit, one patient with his fifth recurrence during 15 years, one patient with extensive metastatic disease in liver, one patient with multiple lung metastases, one patient with metastatic disease where 177Lu-PSMA was used as first-line treatment and one patient with extensive metastatic disease in the lymphatics and skeleton. All these patients were treated with 177Lu-PSMA radioligand therapy with major response, i.e. major (up to complete) response by imaging and substantial (> 90%) reduction of PSA. 177Lu-PSMA radioligand therapy gave only mild adverse effects. In conclusion, in patients with metastatic prostate cancer, 177Lu-PSMA radioligand therapy had an attractive therapeutic profile, showing efficacy in the prostate, in lymph nodes, in lungs, in the liver and also in bones. The therapy had to be adjusted according to the patients’ needs.

Pediatric acute lymphoblastic leukemia presenting with bone and joint pain

We report on three cases of pediatric acute lymphoblastic leukemia presenting with bone pain and arthralgia as initial symptoms. At the first visit, their primary signs were recurrent bone pain and arthralgia, without significant peripheral blood abnormalities. It took 2-4 months to confirm the diagnosis from the onset of arthralgia due to this atypical presentation of the disease. Definitive diagnosis was obtained by bone marrow examination, and in all cases, complete remission was achieved by chemotherapy. As a feature of imaging, MRI exhibited diffuse bone marrow signal changes in T1-weighted images, and FDG-PET showed extensive abnormal bone marrow uptakes. In cases 2 and 3, it was difficult to diagnose by bone marrow aspiration from the iliac bone, but definitive diagnosis was obtained by bone marrow aspiration from the tibia, in which FDG-PET showed increased uptake. FDG-PET was therefore considered useful for the selection of bone marrow aspiration sites. In cases presenting with recurrent migratory bone pain and arthralgia, we need to consider performing bone marrow aspiration and imaging, such as MRI and FDG-PET, for early diagnosis and treatment of leukemia.

Primary lymphoma of bone, myeloma mimicker: a case report and review of literature

Primary lymphoma of the bone (PLB) primarily arising from the medullary cavity is an extremely rare entity, with only limited number of studies and sporadic cases reported in the literature. The current study presents one case of PLB presented with unique presentation and treated with chemotherapy only. A 66 year old male presented with severe pain in the left hip that persisted for two months. Initial laboratory work up showed anemia, hypercalcemia and increase in free light chains kappa to lambda ratio, a diagnosis of multiple myeloma was suspected, magnetic reso¬nance imaging of the vertebral spine extensive involvement of bone marrow of the vertebrae. An 18F fluorodeoxyglucose positron emission tomography computed tomography (FDG PET CT) scan showed widely scattered moderate to intense uptake in multiple lytic of skeleton, Impression was : Image compatible with extensive multiple myeloma, No extra osseous involvement was found. Bone marrow examination was performed confirmed a diagnosis of extensive bone marrow involvement by High grade B-cell neoplasm with areas of bone marrow necrosis. The patient received six cycles of R-CHOP regimen (Rituximab, cyclo-phosphamide, Anthracycline, vincristine and prednisone) and achieved a complete response, as confirmed by FDG PET CT. At present, the patient is in a good condi¬tion.so this patient presentation mimicking multiple myeloma, which represent diagnostic dilemma. Primary lymphoma of the bone is rare disease entity, there is no strong evidence supporting some diagnostic and therapeutic decisions, and therefore, case presentation of the rare disease may facilitate treatment of similar diseases. A review of the literature to elucidate the clinical, radiological, pathological phenotype and optimal treatment of PLB done.

Can FDG-PET/CT replace blind bone marrow biopsy of the posterior iliac crest in Ewing sarcoma?

ObjectiveTo determine and compare the value of 18F–fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT) to blind bone marrow biopsy (BMB) of the posterior iliac crest in detecting metastatic bone marrow involvement in newly diagnosed Ewing sarcoma.Materials and methodsThis retrospective study included 20 patients with newly diagnosed Ewing sarcoma who underwent pretreatment FDG-PET/CT and a total of 38 blind BMBs (two unilateral and 18 bilateral) of the posterior iliac crest. FDG-PET/CT scans were evaluated for bone marrow involvement, both in the posterior iliac crest and other sites, and compared to blind BMB results.ResultsFDG-PET/CT was positive for bone marrow involvement in 7/38 posterior iliac crests, whereas BMB was positive in 5/38 posterior iliac crests. FDG-PET/CT and BMB results in the posterior iliac crest agreed in 36/38 cases (94.7%, 95% confidence interval [CI]: 82.7–98.5%). On a patient level, FDG-PET/CT was positive for bone marrow involvement in 4/20 patients, whereas BMB of the posterior iliac crest was positive in 3/20 patients. On a patient level, FDG-PET/CT and BMB results agreed in 19/20 patients (95.0%, 95% CI: 76.4–99.1%). The only discrepancies between FDG-PET/CT and BMB were observed in two BMBs of one patient. Both BMBs in this patient were negative, whereas FDG-PET/CT indicated bilateral posterior iliac crest involvement and also extensive bone marrow involvement elsewhere.ConclusionsFDG-PET/CT appears to be a valuable method for metastatic bone marrow assessment in newly diagnosed Ewing sarcoma. The routine use of blind BMB of the posterior iliac crest should be reconsidered when FDG-PET/CT is available.

Current strategies for the management of autologous peripheral blood stem cell mobilization failures in patients with multiple myeloma.

Multiple myeloma (MM) is the leading indication of autologous hematopoietic stem cell transplantation (AHSCT) worldwide. The collection of PBSCs is the essential step for AHSCT. The limits for minimum and optimum CD34+ cells collected have been accepted as 2 × 106 /kg and ≥4 × 106 /kg for single AHSCT; 4 × 106 /kg and ≥8-10 × 106 /kg for double AHSCT. Despite the success of conventional methods for PBSC mobilization in MM, mobilization failure is still a concern depending on patient age, duration of disease, and the type of induction therapy. By definition, "proven poor mobilizer" is the occurrence of mobilization failure (CD34+ cell peak <20/µL peripheral blood) after adequate preparation (after 6 days of G-CSF 10 µg/kg body weight alone or after 20 days of G-CSF >5 µg/kg body weight following chemotherapy) or a CD34+ cell yield of <2.0 × 106 /kg body weight after three consecutive apheresis. "Predicted poor mobilizer" involves (1) a failure of a previous collection attempt OR (2) a previous history of extensive radiotherapy or full courses of therapy affecting mobilization OR (3) the presence of at least two of the following features: advanced disease (>2 lines of chemotherapy), refractory disease, extensive bone marrow involvement or cellularity of 30% at the time of mobilization or age >65 years. This article aims at discussing the risk factors for mobilization failure in the era of novel antimyeloma drugs, defining the poor mobilizer concept and summarizing the current and future strategies for the prevention and management of mobilization failures in MM.

Region specific Raman spectroscopy analysis of the femoral head reveals that trabecular bone is unlikely to contribute to non-traumatic osteonecrosis

Non-traumatic osteonecrosis (ON) of the femoral head is a common disease affecting a young population as the peak age of diagnosis is in the 40 s. The natural history of non-traumatic ON leads to a collapse of the femoral head requiring prosthetic replacement in a 60% of cases. Although trabecular bone involvement in the collapse is suspected, the underlying modifications induced at a molecular level have not been explored in humans. Here, we examine changes in the molecular composition and structure of bone as evaluated by Raman spectroscopy in human end-stage ON. Comparing samples from femoral heads harvested from 11 patients and 11 cadaveric controls, we show that the mineral and organic chemical composition of trabecular bone in ON is not modified apart from age-related differences. We also show that the molecular composition in the necrotic part of the femoral head is not different from the composition of the remaining ‘healthy’ trabecular bone of the femoral head. These findings support that quality of trabecular bone is not modified during ON despite extensive bone marrow necrosis and osteocyte death observed even in the ‘healthy’ zones on histological examination.

A Concise Review of Autoimmune Cytopenias in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is frequently associated with autoimmune complications such as autoimmune hemolytic anemia, immune thrombocytopenia, pure red cell aplasia, and autoimmune granulocytopenia. It is critical to diagnose cytopenias from these secondary complications of CLL accurately, since prognosis and therapy are substantially different from patients who have cytopenias due to extensive bone marrow infiltration by CLL. The pathogenesis of autoimmune cytopenias in CLL is complex; and it involves antigen presentation by CLL cells to polyclonal B cells resulting in production of autoantibody, and alteration of the T cell milieu tilting the balance in favor of an autoimmune response. Traditional therapy of autoimmune complications in CLL consists of immunosuppression with corticosteroids and/or anti-CD20 monoclonal antibodies. In patients who have a suboptimal response, treating the underlying CLL is generally effective in ameliorating secondary cytopenias. Although novel oral therapies such as ibrutinib, idelalisib, and venetoclax have been shown to be extremely effective in the management of CLL, prospective data from larger numbers of patients with longer follow-up are needed prior to recommending their routine use in the management of autoimmune cytopenias in CLL.