Sood P, Seth T, Kapil A, et al.
Emergence of multidrug resistant acinetobacter blood stream infections in febrile neutropenia patients with haematological cancers and bone marrow failure syndromes.
J Indian Med Assoc. 2012; 110(7):439-44 [PubMed]

Acinetobacter infections are fast emerging as a major nosocomial threat across the globe. With a predilection for blood stream infections in critically ill, immunocompromised patients, their presence is now being felt in febrile neutropenics with underlying malignancies and marrow failure. We aimed through this study to ascertain the current circulating pathogens and levels of antimicrobial resistance in blood stream infections in febrile neutropenia patients, with specific emphasis on elucidating acinetobacter and pseudomonas infections. Clinical and laboratory records of all consecutive neutropenic patients with underlying haematological malignancies and marrow failure, admitted to our AIIMS, New Delhi from April 2009 to March 2010 were analysed for blood stream infections, pathogen profiles and antimicrobial resistance. All clinical and microbiological variables were statistically analysed to elucidate potential risk factors, infection patterns and drug resistance trends. Of the 1,165 blood cultures investigated, 105 episodes of blood stream infections were microbiologically confirmed in febrile neutropenia patients. Gram-negative infections (n = 78, 72.9%) dominated with acinetobacter spp (n = 20, 18.7%) emerging as the most common pathogen. Acinetobacter and pseudomonas together were responsible for 42.9% of all blood stream infections. Both acinetobacter and pseudomonas displayed very high resistance to all five major classes of antibiotics, including multidrug resistance (90.0% and 76.9%) and ESBL production (90.0% and 84.6%), respectively. Comparison of infection patterns and resistance levels with reports over the past decade from this centre and other centres across the globe, revealed a striking increase in multidrug resistant acinetobacter blood stream infections in these patients. Multidrug resistant acinetobacter Infections are a fast emerging threat in febrile neutropenia patients and at this centre in general. Similar early trends from some Indian centres and neighbouring developing countries suggest grave concern. These emerging circulating pathogens and drug resistance patterns demand to systematically evaluate antibiotic and hospital infection policies and to sensitise all clinicians to curb this pathogen capable of rapid nosocomial spread.

Nowicka J, Nahaczewska W, Owczarek H, Woźniak M
The decrease in prolidase activity in myeloproliferative neoplasms.
Adv Clin Exp Med. 2012 Nov-Dec; 21(6):767-71 [PubMed]

BACKGROUND: The development of bone marrow fibrosis is a severe complication in hematological diseases. The progress of bone marrow myelofibrosis is evaluated by a trephine examination and may be characterized by the biochemical markers of collagen turnover determination.
OBJECTIVES: Investigation of serum prolidase activity and biochemical markers of collagen metabolism in order to establish its role in the development of bone marrow fibrosis.
MATERIAL AND METHODS: The group of 37 patients with myeloproliferative neoplasms (MPN) before treatment, consisted of 16 patients with chronic myeloid leukemia (CML), 7 with primary myelofibrosis (PMF), 8 with essential thrombocythopenia (ET), and 6 with polycythemia vera (PV).
RESULTS: It was found that the plasma activity of prolidase (Pro) was reduced to almost half together with the serum level of osteocalcin (BGL), and hydroxyproline (H-PRO) in the serum and urine of patients with MPN in comparison to the control group. In the MPN group of patients, the levels of N-terminal procollagen III peptide (PIIINP), type I procollagen (PICP) and the C-terminal telopeptide of type I collagen (ICTP) were significantly higher.
CONCLUSIONS: The alteration of collagen turnover markers in the MPN patient group (the elevation of synthesis and inhibition of collagen catabolism rate) has suggested that a diminished prolidase activity may contribute to such alteration of collagen metabolism and should be consider a biomarker of MPN progress.

Roccaro AM, Sacco A, Maiso P, et al.
BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression.
J Clin Invest. 2013; 123(4):1542-55 [PubMed] Free Access to Full Article

BM mesenchymal stromal cells (BM-MSCs) support multiple myeloma (MM) cell growth, but little is known about the putative mechanisms by which the BM microenvironment plays an oncogenic role in this disease. Cell-cell communication is mediated by exosomes. In this study, we showed that MM BM-MSCs release exosomes that are transferred to MM cells, thereby resulting in modulation of tumor growth in vivo. Exosomal microRNA (miR) content differed between MM and normal BM-MSCs, with a lower content of the tumor suppressor miR-15a. In addition, MM BM-MSC-derived exosomes had higher levels of oncogenic proteins, cytokines, and adhesion molecules compared with exosomes from the cells of origin. Importantly, whereas MM BM-MSC-derived exosomes promoted MM tumor growth, normal BM-MSC exosomes inhibited the growth of MM cells. In summary, these in vitro and in vivo studies demonstrated that exosome transfer from BM-MSCs to clonal plasma cells represents a previously undescribed and unique mechanism that highlights the contribution of BM-MSCs to MM disease progression.

Driul L, Londero AP, Papadakis C, et al.
Fertility in women survivors of hematological malignancies: what is the real role of GnRH analogue treatment?
Clin Exp Obstet Gynecol. 2012; 39(4):504-8 [PubMed]

PURPOSE OF INVESTIGATION: The aim of this study was to evaluate the ovarian function in women who received or not gonadotropin-releasing hormone (GnRH) analogue co-treatment compared to the control group that did not receive it.
MATERIALS AND METHODS: This study analyzed 124 patients affected by hematological diseases between 1998 and 2007. The data were analyzed using R (v 2.9.1).
RESULTS: In the women treated with GnRH analogue, the authors found 33% post-treatment secondary amenorrhea and 6% had a pregnancy post-treatment, while in the other group the prevalence were respectively 49% and 4% (p n.s.). Moreover, in multivariate analysis the authors found bone marrow transplantation to be a risk factor for secondary amenorrhea, while the association of chemotherapy with radiotherapy was a protective factor (p < 0.05). Finally, none of the considered factors were predictive of pregnancy achievement post-treatment.
CONCLUSIONS: The authors found no statistical evidence to support that Gn-RH analogue treatment preserves ovarian follicular reserve during hematologic cancer treatment, but more evidence must be obtained.

Wang SA, Hutchinson L, Tang G, et al.
Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease: clinical significance and comparison of chomosomal abnormalities in SM and AHNMD components.
Am J Hematol. 2013; 88(3):219-24 [PubMed]

Some patients with systemic mastocytosis have concurrent hematological neoplasms, designated in the World Health Organization (WHO) classification as systemic mastocytosis with associated clonal hematological non-mast cell lineage disease (SM-AHNMD). In this study, we analyzed 29 patients with SM-AHNMD and compared them to 40 patients with pure SM. The AHNMDs were classified as chronic myelomonocytic leukemia (CMML) (n = 10), myelodysplastic syndrome (MDS) (n = 7), myeloproliferative neoplasms (n = 4), B-cell lymphoma/leukemia/plasma cell neoplasms (n = 7), and acute myeloid leukemia (n = 1). Patients with SM-AHNMD were older, more frequently had constitutional symptoms and hematological abnormalities, less often had skin lesions, and had an inferior overall survival compared with pure SM patients (48 months vs. not-reached, P < 0.001). Karyotypic abnormalities were detected in 9/28 (32%) patients with SM-AHNMD but not in pure SM patients (P < 0.001). Combined imaging/ fluorescence-in-situ hybridization performed in four SM-AHNMD cases revealed shared abnormal signals in mast cells and myeloid cells in two patients with SM-CMML and one patient with SM-MDS, but not in the mast cells of a case SM-associated with chronic lymphocytic leukemia with ATM-deletion. Quantitative mutation analysis showed higher levels of mutant KIT D816V in SM-CMML and SM-MDS than in pure SM (P < 0.001). Our data indicate that the SM-AHNMD category in the WHO classification is heterogeneous, including clonally related and unrelated forms of AHNMD. The presentation, treatment, and outcome of patients with SM-AHNMD is often dictated by the type of AHNMD.

Ince IE, Iyilikci L, Yilmaz S, et al.
Sedation for short hemato-oncologic invasive procedures in children: comparison of propofol-remifentanil and propofol-fentanyl.
J Pediatr Hematol Oncol. 2013; 35(2):112-7 [PubMed]

INTRODUCTION: Short hemato-oncologic procedures are often painful in children, and sedation should be performed outside the operating room.
AIM: : The study aims to compare the effects of remifentanil with those of fentanyl administered during short hemato-oncologic interventions in children.
MATERIALS AND METHODS: A prospective, randomized study was planned for 29 ASA I to III children (aged, 2 to 18 y) to undergo a total of 60 short oncologic interventions. The patients were placed into 2 groups: propofol-remifentanil (group PR) and propofol-fentanyl (group PF). Group PR was first administered propofol (2 mg/kg) and then remifentanil bolus (0.5 μg/kg). Group PF was first administered propofol (2 mg/kg) and then fentanyl bolus (0.5 μg/kg). Systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, respiratory rate, peripheral oxygen saturation, and heart rate were recorded every 3 minutes during the intervention and every 5 minutes after the operation. Postanesthetic recovery scores, eye-opening time to speech, and recovery time were recorded.
RESULTS: Comparison of diastolic arterial pressure in groups at minute 3 of the procedure showed significant difference (P<0.05). Eye-opening to speech (P=0.043) and recovery times (P=0.002) were shorter in group PR.
CONCLUSIONS: During short hemato-oncologic interventions in children, the PR combination is a suitable one for early recovery.

Neumann S, Krause SW, Maschmeyer G, et al.
Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematological malignancies and solid tumors : guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO).
Ann Hematol. 2013; 92(4):433-42 [PubMed] Free Access to Full Article

Bacterial infections are the most common cause for treatment-related mortality in patients with neutropenia after chemotherapy. Here, we discuss the use of antibacterial prophylaxis against bacteria and Pneumocystis pneumonia (PCP) in neutropenic cancer patients and offer guidance towards the choice of drug. A literature search was performed to screen all articles published between September 2000 and January 2012 on antibiotic prophylaxis in neutropenic cancer patients. The authors assembled original reports and meta-analysis from the literature and drew conclusions, which were discussed and approved in a consensus conference of the Infectious Disease Working Party of the German Society of Hematology and Oncology (AGIHO). Antibacterial prophylaxis has led to a reduction of febrile events and infections. A significant reduction of overall mortality could only be shown in a meta-analysis. Fluoroquinolones are preferred for antibacterial and trimethoprim-sulfamethoxazole for PCP prophylaxis. Due to serious concerns about an increase of resistant pathogens, only patients at high risk of severe infections should be considered for antibiotic prophylaxis. Risk factors of individual patients and local resistance patterns must be taken into account. Risk factors, choice of drug for antibacterial and PCP prophylaxis and concerns regarding the use of prophylactic antibiotics are discussed in the review.

Stangel-Wojcikiewicz K, Zdebik A, Jach R, et al.
Hormone replacement therapy regimens in chemotherapy-induced premature ovarian failure and the subsequent correction of hormone levels.
Neuro Endocrinol Lett. 2012; 33(7):697-702 [PubMed]

OBJECTIVES: Premature ovarian failure (POF) is a consequence of gonadotoxic chemoradiotherapy given in antyneoplasia treatment. In young women it will correlate with menopausal symptoms which tend to appear due to depleted ovarian follicle reserve.
DESIGN: It was a case series study that included women 18-50 years old who were treated for malignancy with gonadotoxic chemioradiotherapy. We have measured blood hormonal levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and progesterone within one month of various hormone replacement therapy (HRT).
RESULTS: We have observed different kind of hormonal reaction according to FSH, LH, estradiol and progesterone levels due to various hormonal replacement therapy. The administration of various HRT regimens presented with a decrease in the blood concentration of estradiol E2 and progesterone and a concomitant increase of FSH and LH. These findings demonstrate a shift to physiological ranges and a simultaneous improvement of symptoms associated with CI-POF.
CONCLUSIONS: The most appropriate therapy needs to be selected according to the patient's alleviation of symptoms and correction of blood hormone levels.

Velardi A
Haplo-BMT: which approach?
Blood. 2013; 121(5):719-20 [PubMed]

In patients with hematologic malignancies, Di Bartolomeo et al report encouraging outcomes after transplantation of granulocyte-colony stimulating factor (G-CSF)– primed unmanipulated bone marrow from human leukocyte antigen (HLA)– haplotype mismatched (haploidentical) related donors, suggesting that this procedure makes haploidentical transplantation available in all transplant centers.

Groh T, Hrabeta J, Poljakova J, et al.
Impact of histone deacetylase inhibitor valproic acid on the anticancer effect of etoposide on neuroblastoma cells.
Neuro Endocrinol Lett. 2012; 33 Suppl 3:16-24 [PubMed]

OBJECTIVES: Etoposide (Vepesid, VP-16), an inhibitor of topoisomerase II, is a chemotherapeutic drug commonly used for treatment of different types of malignant diseases. By inhibiting the topoisomerase II enzyme activity in cancer cells, this drug leads to DNA damage and subsequently to cell death. In this study, we investigated the effect of this anticancer drug alone and in combination with a histone deacetylase (HDAC) inhibitor, valproic acid (VPA), on a human UKF-NB-4 neuroblastoma cell line.
METHODS: The effects of etoposide and VPA on UKF-NB-4 cells were tested under the normoxic and also the hypoxic (1% O2) cultivation conditions. The cytotoxicity of etoposide and VPA to a UKF-NB-4 neuroblastoma cell line was evaluated with MTT assay. Apoptosis of the cells was analyzed by flow cytometry using an Annexin V and propidium iodide binding method. The effect of etoposide and VPA on the cell cycle distribution was determined by flow cytometric analysis using propidium iodide staining.
RESULTS: The results of the study demonstrate that UKF-NB-4 neuroblastoma cells are sensitive both to etoposide and to VPA. They also indicate that the impact of VPA on cytotoxicity of etoposide in these tumor cells varies depending on the sequence of cultivation of the cells with the drugs. As a suitable sequence of cultivation, with a high rate of suppression of neuroblastoma cell growth was found the preincubation of the cells with etoposide, which was followed by their cultivation with VPA. In contrast, the reversed combination (preincubation of the cells with VPA before their treating with etoposide) did not give any increase in etoposide cytotoxicity. The effect of such combined treatment can be explained by measuring the cell cycle distribution, which shows that both etoposide and VPA change the cell cycle phase distribution.
CONCLUSION: Etoposide and VPA were found as cycle phase specific drugs that are cytotoxic to human UKF-NB-4 neuroblastoma cells used either as single drugs or both together. However, whereas VPA might sensitize the cells to etoposide, inappropriate sequence of cultivation of the cells with VPA can decrease the etoposide cytotoxic efficacy. The results found here warrant further studies of combined treatment of neuroblastoma cells with etoposide with HDAC inhibitors and may help in the design of new protocols geared to the treatment of high risk neuroblastomas.

Frölich K, Alzoubi A, Müller J, Kleinsasser N
Bone marrow carcinosis in head and neck carcinoma in a young adult.
J Oral Maxillofac Surg. 2013; 71(4):e198-202 [PubMed]

Bone marrow carcinosis has been reported as a consequence of several solid tumors. However, in relation to head and neck squamous cell carcinoma, it is an indication of the rarity of the disease that only 2 reported cases exist in the literature. A 36-year-old male patient was admitted with the diagnosis of squamous cell carcinoma on the floor of the mouth. After the exclusion of distant metastatic disease, tumor surgery was performed. After a regular postoperative course over 3 days, the patient complained of progressive pain in the lower back. Extensive workup included position-emission tomography, which detected an enhancement of the bone marrow. Bone marrow biopsy elucidated advanced bone marrow carcinosis. Palliative chemotherapy was recommended, but the patient deteriorated rapidly and died from septic multiorgan failure within 6 weeks after surgery. Thus, bone marrow carcinosis must be considered in patients with head and neck tumor and osseous pain.

McGrath P
"Receptivity": an important factor affecting supportive care provision.
J Psychosoc Oncol. 2013; 31(1):30-50 [PubMed]

The research on psychosocial need provides the foundation informing the drive for the provision of supportive care services for patients and their families. The work on patient access, barriers to participation, and service evaluation are providing some insights that can help guide practitioners in their efforts to ensure that services designed to meet psychosocial need reach and involve the appropriate individuals. However, this direction is presently in its infancy leaving many questions unanswered. This article makes a contribution to advancing and strengthening this line of research through a fresh perspective on the topic provided by consumer research with individuals diagnosed with a hematological malignancy. The research was initiated and funded by the Leukaemia Foundation of Queensland (LFQ) with the aim of exploring the experience of survivorship for individuals diagnosed with a hematological malignancy to inform supportive care service provision and development. The findings from the research posit the notion of "receptivity" as an important new concept that can contribute to the deepening of our understanding of the myriad of factors associated with effectively engaging with individuals in supportive care service provision.

Petersdorf EW, Malkki M, Horowitz MM, et al.
Mapping MHC haplotype effects in unrelated donor hematopoietic cell transplantation.
Blood. 2013; 121(10):1896-905 [PubMed] Article available free on PMC after 07/03/2014

Life-threatening risks associated with HLA-mismatched unrelated donor hematopoietic cell transplantation limit its general application for the treatment of blood diseases. The increased risks might be explained by undetected genetic variation within the highly polymorphic major histocompatibility complex (MHC) region. We retrospectively assessed each of 1108 MHC region single nucleotide polymorphisms (SNPs) in 2628 patients and their HLA-mismatched unrelated donors to determine whether SNPs are associated with the risk of mortality, disease-free survival, transplant-related mortality, relapse, and acute and chronic graft-versus-host disease (GVHD). Multivariate analysis adjusted for HLA mismatching and nongenetic variables associated with each clinical end point. Twelve SNPs were identified as transplantation determinants. SNP-associated risks were conferred by either patient or donor SNP genotype or by patient-donor SNP mismatching. Risks after transplantation increased with increasing numbers of unfavorable SNPs. SNPs that influenced acute GVHD were independent of those that affected risk of chronic GVHD and relapse. HLA haplotypes differed with respect to haplotype content of (un)favorable SNPs. Outcome after HLA-mismatched unrelated donor transplantation is influenced by MHC region variation that is undetected with conventional HLA typing. Knowledge of the SNP content of HLA haplotypes provides a means to estimate risks prior to transplantation and to lower complications through judicious selection of donors with favorable MHC genetics.

Kuzmina Z, Krenn K, Petkov V, et al.
CD19(+)CD21(low) B cells and patients at risk for NIH-defined chronic graft-versus-host disease with bronchiolitis obliterans syndrome.
Blood. 2013; 121(10):1886-95 [PubMed]

Bronchiolitis obliterans syndrome (BOS), pathognomonic for chronic graft-versus-host disease (cGVHD) of the lung, is a progressive and often fatal complication after allogeneic hematopoietic cell transplantation (HCT). Biomarkers for the prediction and diagnosis of BOS are urgently needed to improve patients' prognosis. We prospectively evaluated B-cell subpopulations and B-cell activating factor (BAFF) in 136 patients (46 BOS, 41 no cGVHD, 49 cutaneous cGVHD) to define novel biomarkers for early diagnosis of National Institutes of Health-defined BOS diagnosed a median of 11 mo after HCT. Patients with newly diagnosed BOS had significantly higher percentages of CD19(+)CD21(low) B cells (25.5 versus 6.6%, P < .0001), BAFF (7.3 versus 3.5 ng/mL, P = .02), and BAFF/CD19(+) ratio (0.18 versus 0.02 ng/10(3) CD19(+) B cells, P 5 .007) compared with patients without cGVHD. The area under the receiver operating curve for CD19(+)CD21(low) B cells was 0.97 (95% confidence interval, 0.94-0.99) and a cutoff point >9% was optimal for diagnosing BOS in patients with first drop of pulmonary function tests with a sensitivity of 96% and a negative predictive value of 94%. Thus, elevated levels of CD19(+)CD21(low) B cells are a potential novel biomarker for HCT patients at risk for developing BOS at an early stage and could allow improvement of patient outcome.

Michieli M, Peccatori FA, Lleshi A, et al.
Antiblastic treatment of haematological malignancies during pregnancy: a crucial decision.
Int J Immunopathol Pharmacol. 2012 Apr-Jun; 25(2 Suppl):21S-32S [PubMed]

Antiblastic treatment of hematological malignancies during pregnancy poses a number of issues related to the curability of the maternal disease, the need of a prompt treatment and the potential toxicity of chemotherapy for the fetus. Here we report the results of a systematic literature search about the management of the most frequent hematological malignancies that may occur during pregnancy, focusing on specific issues related to gestational age at diagnosis, fetal toxicity and efficacy on the maternal side. The standard approach in non-pregnant women is illustrated as reference.

Souers AJ, Leverson JD, Boghaert ER, et al.
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.
Nat Med. 2013; 19(2):202-8 [PubMed]

Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.

Zhang Q, Hossain DM, Nechaev S, et al.
TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo.
Blood. 2013; 121(8):1304-15 [PubMed] Article available free on PMC after 21/02/2014

STAT3 operates in both cancer cells and tumor-associated immune cells to promote cancer progression. As a transcription factor, it is a highly desirable but difficult target for pharmacologic inhibition. We have recently shown that the TLR9 agonists CpG oligonucleotides can be used for targeted siRNA delivery to mouse immune cells. In the present study, we demonstrate that a similar strategy allows for targeted gene silencing in both normal and malignant human TLR9(+) hematopoietic cells in vivo. We have developed new human cell-specific CpG(A)-STAT3 siRNA conjugates capable of inducing TLR9-dependent gene silencing and activation of primary immune cells such as myeloid dendritic cells, plasmacytoid dendritic cells, and B cells in vitro. TLR9 is also expressed by several human hematologic malignancies, including B-cell lymphoma, multiple myeloma, and acute myeloid leukemia. We further demonstrate that oncogenic proteins such as STAT3 or BCL-X(L) are effectively knocked down by specific CpG(A)-siRNAs in TLR9(+) hematologic tumor cells in vivo. Targeting survival signaling using CpG(A)-siRNAs inhibits the growth of several xenotransplanted multiple myeloma and acute myeloid leukemia tumors. CpG(A)-STAT3 siRNA is immunostimulatory and nontoxic for normal human leukocytes in vitro. The results of the present study show the potential of using tumoricidal/immunostimulatory CpG-siRNA oligonucleotides as a novel 2-pronged therapeutic strategy for hematologic malignancies.

Galati D, Di Noto R, Del Vecchio L
Diagnostic strategies to investigate cerebrospinal fluid involvement in haematological malignancies.
Leuk Res. 2013; 37(3):231-7 [PubMed]

Central nervous system (CNS) involvement is a fatal complication of certain haematological malignancies with an incidence as high as 25% in specific leukaemia/lymphoma subtypes. It is often accompanied by 'occult' cerebrospinal fluid (CSF) involvement at diagnosis, which is frequently missed by conventional cytology examination. Unfortunately, a diagnostic gold standard is yet unavailable since CSF morphology may be negative for malignant cells in up to 45% of patients with suspected meningeal involvement. New technologies such as flow cytometry, molecular genetics and newer biomarkers may improve sensitivity and specificity facilitating the diagnosis of CNS involvement as well as effective prophylaxis and successful treatment.

Ullmann AJ, Akova M, Herbrecht R, et al.
ESCMID* guideline for the diagnosis and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT).
Clin Microbiol Infect. 2012; 18 Suppl 7:53-67 [PubMed]

Fungal diseases still play a major role in morbidity and mortality in patients with haematological malignancies, including those undergoing haematopoietic stem cell transplantation. Although Aspergillus and other filamentous fungal diseases remain a major concern, Candida infections are still a major cause of mortality. This part of the ESCMID guidelines focuses on this patient population and reviews pertaining to prophylaxis, empirical/pre-emptive and targeted therapy of Candida diseases. Anti-Candida prophylaxis is only recommended for patients receiving allogeneic stem cell transplantation. The authors recognize that the recommendations would have most likely been different if the purpose would have been prevention of all fungal infections (e.g. aspergillosis). In targeted treatment of candidaemia, recommendations for treatment are available for all echinocandins, that is anidulafungin (AI), caspofungin (AI) and micafungin (AI), although a warning for resistance is expressed. Liposomal amphotericin B received a BI recommendation due to higher number of reported adverse events in the trials. Amphotericin B deoxycholate should not be used (DII); and fluconazole was rated CI because of a change in epidemiology in some areas in Europe. Removal of central venous catheters is recommended during candidaemia but if catheter retention is a clinical necessity, treatment with an echinocandin is an option (CII(t) ). In chronic disseminated candidiasis therapy, recommendations are liposomal amphotericin B for 8 weeks (AIII), fluconazole for >3 months or other azoles (BIII). Granulocyte transfusions are only an option in desperate cases of patients with Candida disease and neutropenia (CIII).

Noun P, Farah R, Bechara E, et al.
Pandemic (H1N1) 2009 influenza in pediatric hematology/oncology units in Lebanon.
J Pediatr Hematol Oncol. 2013; 35(2):144-7 [PubMed]

BACKGROUND: The impact of pandemic (H1N1) 2009 influenza on immunocompromised patients in western countries has been described, but reports from pediatric patients in the Middle East or Arab countries are deficient. In this study, we describe the clinical characteristics of children with hematological malignancies and laboratory-proven H1N1 influenza.
PATIENTS AND METHODS: Patients were recruited from 3 pediatric hematology/oncology units in Lebanon. A confirmed case of pandemic (H1N1) 2009 influenza is a clinically suspected case with positive H1N1 test by either a rapid immunofluorescence test or by real-time polymerase chain reaction. Data were collected retrospectively from the medical charts.
RESULTS: From October 2009 to March 2010, 14 immunocompromised children were infected with H1N1 influenza. Eight were male and 6 were female. The median age of patients was 4.5 years (range, 1 to 14). All children were hospitalized and treated with oseltamivir. Twelve children responded to treatment; the other 2 patients with severe respiratory distress were transferred to intensive care unit and resuscitated but died after 7 and 12 days.
CONCLUSIONS: Immunocompromised children infected with pandemic 2009 influenza may respond very well when the diagnosis and treatment are rapid. However, on the basis of our experience, if the underlying disease is more severe (immunodeficiency with significant immunosuppressive treatment and induction of high-risk leukemia), the odds of mortality are likely greater.

Radulović V, de Haan G, Klauke K
Polycomb-group proteins in hematopoietic stem cell regulation and hematopoietic neoplasms.
Leukemia. 2013; 27(3):523-33 [PubMed]

The equilibrium between self-renewal and differentiation of hematopoietic stem cells is regulated by epigenetic mechanisms. In particular, Polycomb-group (PcG) proteins have been shown to be involved in this process by repressing genes involved in cell-cycle regulation and differentiation. PcGs are histone modifiers that reside in two multi-protein complexes: Polycomb Repressive Complex 1 and 2 (PRC1 and PRC2). The existence of multiple orthologs for each Polycomb gene allows the formation of a multitude of distinct PRC1 and PRC2 sub-complexes. Changes in the expression of individual PcG genes are likely to cause perturbations in the composition of the PRC, which affect PRC enzymatic activity and target selectivity. An interesting recent development is that aberrant expression of, and mutations in, PcG genes have been shown to occur in hematopoietic neoplasms, where they display both tumor-suppressor and oncogenic activities. We therefore comprehensively reviewed the latest research on the role of PcG genes in normal and malignant blood cell development. We conclude that future research to elucidate the compositional changes of the PRCs and methods to intervene in PRC assembly will be of great therapeutic relevance to combat hematological malignancies.

Guido M, Quattrocchi M, Zizza A, et al.
Molecular approaches in the diagnosis of sepsis in neutropenic patients with haematological malignances.
J Prev Med Hyg. 2012; 53(2):104-8 [PubMed]

INTRODUCTION: Sepsis is a major cause of significant morbidity and mortality in neutropenic patients. Blood culture remains the gold standard in the microbiological diagnosis of bacterial or fungal bloodstream infections, but it has clear limits of rapidity and sensitivity. The objective of the study was to compare the real-time polymerase chain reaction (RT-PCR) with automated blood cultures (BC) method in detection in whole blood of pathogens in febrile neutropenic patients with hematological malignancies.
METHODS: A total of 166 consecutive febrile neutropenic patients were enrolled. Blood samples for cultures and SeptiFast testing were obtained at the onset of fever, before the implementation of empirical antibiotic therapy.
RESULTS: Forty (24.1%) samples out of the 166 blood samples tested, were positive by at least one method. Twenty-three (13.9%) samples were positive by blood culture and 38 (22.9%) by multiplex real-time PCR. The analysis of concordance evidenced a low correlation between the two methods (n = 21; 52.5%), mainly due to samples found negative by culture but positive with the Septi-Fast assay. Sensitivity, specificity, and positive and negative predictive values of RT-PCR were 91.3%, 88.1%, 55.3%, and 98.4%, respectively, compared with BC.
DISCUSSION: Multiplex real-time PCR assay improved detection of the most bacteria associated with febrile neutropenia episodes. Further studies are needed to assess the real advantages and clinical benefits that molecular biology tests can add in diagnosis of sepsis.

Shugay M, Ortiz de Mendíbil I, Vizmanos JL, Novo FJ
Genomic hallmarks of genes involved in chromosomal translocations in hematological cancer.
PLoS Comput Biol. 2012; 8(12):e1002797 [PubMed] Article available free on PMC after 21/02/2014

Reciprocal chromosomal translocations (RCTs) leading to the formation of fusion genes are important drivers of hematological cancers. Although the general requirements for breakage and fusion are fairly well understood, quantitative support for a general mechanism of RCT formation is still lacking. The aim of this paper is to analyze available high-throughput datasets with computational and robust statistical methods, in order to identify genomic hallmarks of translocation partner genes (TPGs). Our results show that fusion genes are generally overexpressed due to increased promoter activity of 5' TPGs and to more stable 3'-UTR regions of 3' TPGs. Furthermore, expression profiling of 5' TPGs and of interaction partners of 3' TPGs indicates that these features can help to explain tissue specificity of hematological translocations. Analysis of protein domains retained in fusion proteins shows that the co-occurrence of specific domain combinations is non-random and that distinct functional classes of fusion proteins tend to be associated with different components of the gene fusion network. This indicates that the configuration of fusion proteins plays an important role in determining which 5' and 3' TPGs will combine in specific fusion genes. It is generally accepted that chromosomal proximity in the nucleus can explain the specific pairing of 5' and 3' TPGS and the recurrence of hematological translocations. Using recently available data for chromosomal contact probabilities (Hi-C) we show that TPGs are preferentially located in early replicated regions and occupy distinct clusters in the nucleus. However, our data suggest that, in general, nuclear position of TPGs in hematological cancers explains neither TPG pairing nor clinical frequency. Taken together, our results support a model in which genomic features related to regulation of expression and replication timing determine the set of candidate genes more likely to be translocated in hematological tissues, with functional constraints being responsible for specific gene combinations.

de Lima M, McNiece I, Robinson SN, et al.
Cord-blood engraftment with ex vivo mesenchymal-cell coculture.
N Engl J Med. 2012; 367(24):2305-15 [PubMed]

BACKGROUND: Poor engraftment due to low cell doses restricts the usefulness of umbilical-cord-blood transplantation. We hypothesized that engraftment would be improved by transplanting cord blood that was expanded ex vivo with mesenchymal stromal cells.
METHODS: We studied engraftment results in 31 adults with hematologic cancers who received transplants of 2 cord-blood units, 1 of which contained cord blood that was expanded ex vivo in cocultures with allogeneic mesenchymal stromal cells. The results in these patients were compared with those in 80 historical controls who received 2 units of unmanipulated cord blood.
RESULTS: Coculture with mesenchymal stromal cells led to an expansion of total nucleated cells by a median factor of 12.2 and of CD34+ cells by a median factor of 30.1. With transplantation of 1 unit each of expanded and unmanipulated cord blood, patients received a median of 8.34×10(7) total nucleated cells per kilogram of body weight and 1.81×10(6) CD34+ cells per kilogram--doses higher than in our previous transplantations of 2 units of unmanipulated cord blood. In patients in whom engraftment occurred, the median time to neutrophil engraftment was 15 days in the recipients of expanded cord blood, as compared with 24 days in controls who received unmanipulated cord blood only (P<0.001); the median time to platelet engraftment was 42 days and 49 days, respectively (P=0.03). On day 26, the cumulative incidence of neutrophil engraftment was 88% with expansion versus 53% without expansion (P<0.001); on day 60, the cumulative incidence of platelet engraftment was 71% and 31%, respectively (P<0.001).
CONCLUSIONS: Transplantation of cord-blood cells expanded with mesenchymal stromal cells appeared to be safe and effective. Expanded cord blood in combination with unmanipulated cord blood significantly improved engraftment, as compared with unmanipulated cord blood only. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00498316.).

Shima T, Miyamoto T, Kikushige Y, et al.
Quantitation of hematogones at the time of engraftment is a useful prognostic indicator in allogeneic hematopoietic stem cell transplantation.
Blood. 2013; 121(5):840-8 [PubMed]

UNLABELLED: Transient marrow expansion of normal B-cell precursors, termed hematogones, is occasionally observed after hematopoietic stem cell transplantation (HSCT). To understand the clinical significance of this phenomenon, we enumerated hematogones in 108 consecutive patients who received allogeneic HSCT for the treatment of hematologic malignancies, including acute myelogenous leukemia, advanced myelodysplastic syndromes, acute lymphoblastic leukemia, and non-Hodgkin lymphoma. Hematogone quantitation was performed at the time of complete donor engraftment (median day 25 and 32 in patients who received bone marrow and cord blood cell transplants, respectively). Hematogones were polyclonal B cells, and their frequencies correlated positively with blood B-cell numbers, and inversely with donors’ but not recipients' age, suggesting that hematogones reflect cell-intrinsic B-cell potential of donor cells. Interestingly, patients developing hematogones that comprised > 5% of bone marrow mononuclear cells constituted a group with significantly prolonged overall survival and relapse-free survival, irrespective of their primary disease or donor cell source. In addition, patients with > 5% hematogones developed severe acute graft-versus-host diseases less frequently, which may contribute toward their improved survival. We therefore conclude that the amount of hematogones at the time of engraftment may be a useful tool in predicting the prognosis of patients treated with allogeneic HSCT.
KEY POINTS: Quantitation of hematogones at engraftment is useful to predict prognosis of patients treated with allogeneic stem cell transplantation.

Chen D, Bachanova V, Ketterling RP, et al.
A case of nonleukemic myeloid sarcoma with FIP1L1-PDGFRA rearrangement: an unusual presentation of a rare disease.
Am J Surg Pathol. 2013; 37(1):147-51 [PubMed]

Rearrangement of the PDGFRA gene defines a distinct group of hematopoietic neoplasms that commonly present with persistent eosinophilia and are highly sensitive to low-dose imatinib mesylate treatment. Although rare cases of PDGFRA rearrangement-associated acute myeloid or lymphoblastic leukemia can occur, nonleukemic myeloid sarcoma has not been reported, and its sensitivity to imatinib treatment is unknown. Herein, we report a 31-year-old man with nonleukemic myeloid sarcoma and marked peripheral blood and bone marrow eosinophilia. Fluorescent in situ hybridization studies demonstrated that both bone marrow hematopoietic precursors and blasts of the myeloid sarcoma were positive for FIP1L1-PDGFRA rearrangement. The patient consequently received imatinib treatment at a dosage of 100 mg daily. After 3 weeks of therapy, his eosinophilia and myeloid sarcoma completely resolved, and at evaluation after 3 months he had attained bone marrow cytogenetic remission. To our knowledge, this is the first case of a nonleukemic myeloid sarcoma with the FIP1L1-PDGFRA rearrangement. Despite its aggressive clinical behavior attributed to myeloid sarcoma in general, the presence of PDGFRA rearrangement in this case conferred a high sensitivity to imatinib treatment and a favorable clinical outcome.

Kim KI, Kim JW, Lee HJ, et al.
Recombinant human epidermal growth factor on oral mucositis induced by intensive chemotherapy with stem cell transplantation.
Am J Hematol. 2013; 88(2):107-12 [PubMed]

Oral mucositis (OM) is one of the most common and debilitating complications in patients undergoing intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) oral spray for OM induced by intensive chemotherapy followed by HSCT. Patients were randomly assigned to either the rhEGF group or placebo group. The severity of OM and self-reported quality of life (QOL) were assessed daily. A total of 58 patients were analyzed. Baseline characteristics were similar between the two groups. The incidence of NCI grade ≥ 2 OM was higher in the rhEGF group (78.6% vs. 50%, P = 0.0496). However, the duration of OM in patients with NCI grade ≥ 2 tended to be shorter in the rhEGF group (8.5 days vs. 14.5 days, P = 0.262). The QOL analysis in patients with World Health Organization (WHO) grade ≥ 3 OM showed that rhEGF significantly reduced limitations in swallowing (P = 0.039) and drinking (P = 0.042). The duration of hospitalization (P = 0.047), administration of total parenteral nutrition (P = 0.012), and the usage of opioid analgesics (P = 0.018) were significantly shorter in the rhEGF group with WHO grade ≥ 3 OM. Adverse events were mild and similar between the two groups. In conclusion, this analysis showed that rhEGF did not reduce the incidence of NCI grade ≥ 2 OM. However, the patients with WHO grade ≥ 3 OM in the rhEGF group showed better results compared to the placebo group for several secondary endpoints.

Greaves P, Gribben JG
The role of B7 family molecules in hematologic malignancy.
Blood. 2013; 121(5):734-44 [PubMed] Article available free on PMC after 31/01/2014

The B7 family consists of structurally related, cell-surface proteins that regulate immune responses by delivering costimulatory or coinhibitory signals through their ligands. Eight family members have been identified to date including CD80 (B7-1), CD86 (B7-2), CD274 (programmed cell death-1 ligand [PD-L1]), CD273 (programmed cell death-2 ligand [PD-L2]), CD275 (inducible costimulator ligand [ICOS-L]), CD276 (B7-H3), B7-H4, and B7-H6. B7 ligands are expressed on both lymphoid and nonlymphoid tissues. The importance of the B7 family in regulating immune responses is clear from their demonstrated role in the development of immunodeficiency and autoimmune diseases. Manipulation of the signals delivered by B7 ligands shows great potential in the treatment of cancers including leukemias and lymphomas and in regulating allogeneic T-cell responses after stem cell transplantation.

Karadimitris A, Chaidos A
The role of invariant NKT cells in allogeneic hematopoietic stem cell transplantation.
Crit Rev Immunol. 2012; 32(2):157-71 [PubMed]

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative procedure for a number of hematological malignancies including leukemia and lymphoma. However, the anti-leukemia (graft-versus-leukemia, GVL) effect mediated by T cells transferred to the host with the allograft is often negated by the graft-versus-host (GVH) reaction imparted by the same cells. Acute graft-versus-host disease (aGVHD), an allogeneic reaction triggered in response to minor and major histocompatibility antigen disparities between donor and recipient, remains the main source of morbidity and mortality in T-cell-replete allogeneic HSCT. Here we review the biological properties, the pre-clinical work, and the recent clinical observations suggesting that invariant natural killer (iNK) T cells, a CD1d-restricted subset of immunoregulatory T cells, are important regulators of GVH and GVL reactions. Further, we outline strategies for manipulating iNKT cells to translate their therapeutic promise into clinical benefit in the context of allogeneic HSCT.

Riwes MM, Wingard JR
Diagnostic methods for invasive fungal diseases in patients with hematologic malignancies.
Expert Rev Hematol. 2012; 5(6):661-9 [PubMed] Article available free on PMC after 01/10/2013

Invasive fungal disease is associated with increased morbidity and mortality in hematologic malignancy patients and hematopoietic stem cell transplant recipients. Timely recognition and treatment of invasive fungal diseases in these patients are essential and decrease mortality. However, conventional definitive diagnostic methods are difficult and time consuming. While conventional microbiological and histopathological methods are still needed for a definitive diagnosis of invasive fungal disease, new noninvasive diagnostic methods including serologic and molecular biomarkers are now available. These new diagnostic methods facilitate an early diagnosis of invasive fungal disease and allow for utilization of a pre-emptive treatment approach, which may ultimately lead to improved treatment outcomes and reduced toxicity.