The emergence of non-secretory multiple myeloma during the non-cytotoxic treatment of essential thrombocythemia: A case report

Introduction. The emergence of multiple myeloma as a second malignancy in patients with essential thrombocythemia is extremely rare. Several cases have been published so far, pointing out the impact of a cytotoxic effect during treatment of essential thrombocythemia on the development of multiple myeloma. Case presentation. We report the case of a 52-year-old Caucasian man who presented to our hospital because of leukocytosis, a slightly decreased hemoglobin level and thrombocytosis. After a complete hematological work-up, essential thrombocythemia was diagnosed. The patient was included in a multicenter clinical study, treated with anagrelide and his platelet counts were maintained in the normal range for more than 3 years. A sudden drop in his hemoglobin level with normal leukocyte and platelet count occurred at the same time as a back pain. Magnetic resonance imaging of his spine revealed the existence of a pathological fracture of Th4, the collapse of the upper edge of Th7 and osteolytic lesions of multiple thoracic vertebrae. Repeated hematological examinations, including bone biopsy with immunohistochemistry, disclosed diagnosis of multiple myeloma of the non-secretory type. Conclusions: To the best of our knowledge this is the first published case in which multiple myeloma developed during the treatment of essential thrombocythemia with the non-cytotoxic drug anagrelide. Our attempts to find a common origin for the coexistence of multiple myeloma and essential thrombocythemia have not confirmed the genetic basis of their appearance. Further studies are needed to determine the biological impact of this coexistence

Metabolic Syndrome and Cardiovascular Disease after Hematopoietic Cell Transplantation: Screening and Preventive Practice Recommendations from the CIBMTR and EBMT

Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus, and all-cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with an estimated prevalence of MetS of 31% to 49% among HCT recipients. Although MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to review literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors

Primary small cell carcinoma of the esophagus: clinicopathological and immunohistochemical features of 21 cases

BACKGROUND: Primary small cell carcinoma (SCC) of the esophagus is a rare and aggressive tumor with poor prognosis. In this study, we report the clinicopathological characteristics of 21 cases of small cell carcinoma of the esophagus treated at the Cancer Center of Sun Yat-Sen University, with particular focus on the histologic and immunohistochemical findings. METHODS: Twenty-one patient records were reviewed including presenting symptoms, demographics, disease stage, treatment, and follow-up. Histologic features were observed and immunohistochemical detection of cytokeratin (CK), epithelial membrane antigen (EMA), neuron specific enolase (NSE), synaptophysin (Syn), chromogranin A (CgA), neuronal cell adhesion molecules (CD56), thyroid transcriptional factor-1 (TTF-1) and S100 protein (S100) was performed. RESULTS: The median age of patients in the study was 56 years, with a male-to-female ratio of 3.2:1. Histologically, there were 19 "homogenous" SCC esophageal samples and 2 samples comprised of SCC and well-differentiated squamous cell carcinoma. The percentages of SCC samples with positive immunoreactivity were Syn 95.2%, CD56 76.2%, TTF-1 71.4%, NSE 61.9%, CgA 61.9%, CK 57.1%, EMA 61.9%, and S100 19.0%, respectively. The median patient survival time was 18.3 months after diagnosis. The 2-year survival rate was 28.6%. CONCLUSION: Our study suggests that esophageal SCC has similar histology to SCC that arises in the lung compartment, and Chinese patients have a poor prognosis. Higher proportion of positive labeling of Syn, CD56, CgA, NSE, and TTF-1 in esophageal SCC implicate that they are valuably applied in differential diagnosis of the malignancy

Expansion of Cord Blood CD34+ Cells in Presence of zVADfmk and zLLYfmk Improved Their In Vitro Functionality and In Vivo Engraftment in NOD/SCID Mouse

BACKGROUND: Cord blood (CB) is a promising source for hematopoietic stem cell transplantations. The limitation of cell dose associated with this source has prompted the ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs). However, the expansion procedure is known to exhaust the stem cell pool causing cellular defects that promote apoptosis and disrupt homing to the bone marrow. The role of apoptotic machinery in the regulation of stem cell compartment has been speculated in mouse hematopoietic and embryonic systems. We have consistently observed an increase in apoptosis in the cord blood derived CD34(+) cells cultured with cytokines compared to their freshly isolated counterpart. The present study was undertaken to assess whether pharmacological inhibition of apoptosis could improve the outcome of expansion. METHODOLOGY/PRINCIPAL FINDINGS: CB CD34(+) cells were expanded with cytokines in the presence or absence of cell permeable inhibitors of caspases and calpains; zVADfmk and zLLYfmk respectively. A novel role of apoptotic protease inhibitors was observed in increasing the CD34(+) cell content of the graft during ex vivo expansion. This was further reflected in improved in vitro functional aspects of the HSPCs; a higher clonogenicity and long term culture initiating potential. These cells sustained superior long term engraftment and an efficient regeneration of major lympho-myeloid lineages in the bone marrow of NOD/SCID mouse compared to the cells expanded with growth factors alone. CONCLUSION/SIGNIFICANCE: Our data show that, use of either zVADfmk or zLLYfmk in the culture medium improves expansion of CD34(+) cells. The strategy protects stem cell pool and committed progenitors, and improves their in vitro functionality and in vivo engraftment. This observation may complement the existing protocols used in the manipulation of hematopoietic cells for therapeutic purposes. These findings may have an impact in the CB transplant procedures involving a combined infusion of unmanipulated and expanded grafts

Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis

<p>Abstract</p> <p>Purpose</p> <p>to investigate the factors affecting survival and toxicity in patients treated with stereotactic radiosurgery (SRS), with special attention to volumes of brain receiving a specific dose (V10 - V16 Gy) as predictors for brain radionecrosis.</p> <p>Patients and Methods</p> <p>Two hundred six consecutive patients with 310 cerebral metastases less than 3.5 cm were treated with SRS as primary treatment and followed prospectively at University of Rome La Sapienza Sant'Andrea Hospital. Overall survival, brain control, and local control were estimated using the Kaplan-Meier method calculated from the time of SRS. Univariate and multivariate analysis using a Cox proportional hazards regression model were performed to determine the predictive value of prognostic factors for treatment outcome and SRS-related complications.</p> <p>Results</p> <p>Median overall survival and brain control were 14.1 months and 10 months, respectively. The 1-year and 2-year survival rates were 58% and 24%, and respective brain control were 43% and 22%. Sixteen patients recurred locally after SRS, with 1-year and 2-year local control rates of 92% and 84%, respectively. On multivariate analysis, stable extracranial disease and KPS >70 were associated with the most significant survival benefit. Neurological complications were recorded in 27 (13%) patients. Severe neurological complications (RTOG Grade 3 and 4) occurred in 5.8% of patients. Brain radionecrosis occurred in 24% of treated lesions, being symptomatic in 10% and asymptomatic in 14%. On multivariate analysis, V10 through V16 Gy were independent risk factors for radionecrosis, with V10 Gy and V12 Gy being the most predictive (p = 0.0001). For V10 Gy >12.6 cm³and V12 Gy >10.9 cm³the risk of radionecrosis was 47%.</p> <p>Conclusions</p> <p>SRS alone represents a feasible option as initial treatment for patients with brain metastases, however a significant subset of patients may develop neurological complications. Lesions with V12 Gy >8.5 cm³carries a risk of radionecrosis >10% and should be considered for hypofractionated stereotactic radiotherapy especially when located in/near eloquent areas.</p

High-dose ifosfamide and mitoxantrone (HDIM) in patients with relapsed or refractory Hodgkin’s lymphoma

Relapsed/refractory Hodgkin's lymphoma (HL) is treated with salvage chemotherapy and autologous stem cell transplantation (ASCT). Optimal chemotherapy is unknown. We retrospectively analyzed outcomes of 58 patients treated with 2 cycles of high-dose ifosfamide and mitoxantrone (HDIM). HDIM consisted of ifosfamide 5 g/m(2)/day and MESNA 5 g/m(2)/day in continuous 24-h infusion (days 1 and 2), MESNA 2.5 g/m(2) over 12 h (day 3), and mitoxantrone 20 mg/m(2) (day 1) administered every 2 weeks. Stem cells were collected after the first cycle. Responding patients proceeded to ASCT. Toxicity was acceptable. Stem cell mobilization was successful in 96 % of patients. Overall response rate was 74 % (89 % in relapsing and 45 % in refractory patients) with 31 % complete remissions. After a median follow-up of 54 months, 5-year event-free survival was 56 % (69 % for relapsing and 35 % for refractory patients), and 5-year overall survival was 67 % (73 % for relapsing and 55 % for refractory patients). Significant adverse prognostic factors were refractoriness to previous therapy and HDIM failure. No differences in outcomes were noted between patients with early and late relapses or between complete and partial responders. HDIM is a well-tolerated and effective regimen for relapsed and refractory HL with excellent stem cell mobilizing properties. Patients failing HDIM may still benefit from other salvage options

Busulphan-Cyclophosphamide Cause Endothelial Injury, Remodeling of Resistance Arteries and Enhanced Expression of Endothelial Nitric Oxide Synthase

Stem cell transplantation (SCT) is a curative treatment for malignant and non malignant diseases. However, transplantation-related complications including cardiovascular disease deteriorate the clinical outcome and quality of life. We have investigated the acute effects of conditioning regimen on the pharmacology, physiology and structure of large elastic arteries and small resistance-sized arteries in a SCT mouse model. Mesenteric resistance arteries and aorta were dissected from Balb/c mice conditioned with busulphan (Bu) and cyclophosphamide (Cy). In vitro isometric force development and pharmacology, in combination with RT-PCR, Western blotting and electron microscopy were used to study vascular properties. Compared with controls, mesenteric resistance arteries from the Bu-Cy group had larger internal circumference, showed enhanced endothelium mediated relaxation and increased expression of endothelial nitric oxide synthase (eNOS). Bu-Cy treated animals had lower mean blood pressure and signs of endothelial injury. Aortas of treated animals had a higher reactivity to noradrenaline. We conclude that short-term consequences of Bu-Cy treatment divergently affect large and small arteries of the cardiovascular system. The increased noradrenaline reactivity of large elastic arteries was not associated with increased blood pressure at rest. Instead, Bu-Cy treatment lowered blood pressure via augmented microvascular endothelial dependent relaxation, increased expression of vascular eNOS and remodeling toward a larger lumen. The changes in the properties of resistance arteries can be associated with direct effects of the compounds on vascular wall or possibly indirectly induced via altered translational activity associated with the reduced hematocrit and shear stress. This study contributes to understanding the mechanisms that underlie the early effects of conditioning regimen on resistance arteries and may help in designing further investigations to understand the late effects on vascular system

Uncovering the multifaceted roles played by neutrophils in allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a life-saving procedure used for the treatment of selected hematological malignancies, inborn errors of metabolism, and bone marrow failures. The role of neutrophils in alloHSCT has been traditionally evaluated only in the context of their ability to act as a first line of defense against infection. However, recent evidence has highlighted neutrophils as key effectors of innate and adaptive immune responses through a wide array of newly discovered functions. Accordingly, neutrophils are emerging as highly versatile cells that are able to acquire different, often opposite, functional capacities depending on the microenvironment and their differentiation status. Herein, we review the current knowledge on the multiple functions that neutrophils exhibit through the different stages of alloHSCT, from the hematopoietic stem cell (HSC) mobilization in the donor to the immunological reconstitution that occurs in the recipient following HSC infusion. We also discuss the influence exerted on neutrophils by the immunosuppressive drugs delivered in the course of alloHSCT as part of graft-versus-host disease (GVHD) prophylaxis. Finally, the potential involvement of neutrophils in alloHSCT-related complications, such as transplant-associated thrombotic microangiopathy (TA-TMA), acute and chronic GVHD, and cytomegalovirus (CMV) reactivation, is also discussed. Based on the data reviewed herein, the role played by neutrophils in alloHSCT is far greater than a simple antimicrobial role. However, much remains to be investigated in terms of the potential functions that neutrophils might exert during a highly complex procedure such as alloHSCT