Cancer Stem Cell Treatment

Autologous Dendritic Cell Therapy for Cancer is available at SIRM

Cancer represents one of the major causes of mortality worldwide. More than half of patients suffering from cancer succumb to their condition. The primary approaches to treating cancer are surgical resection followed by radiation therapy and chemotherapy. These treatments have resulted in significant benefits to patients with the majority of tumor types, and the clinical outcomes have become more satisfactory. It is recognized that multidisciplinary treatments should be used in cancer treatments, another option proposed for this is immunotherapy. The combination of the traditional methods of surgery, chemotherapy and radiotherapy with immunotherapy, is a new way for anti-cancer therapies to reduce the mortality of cancer patients. The dysfunction of the antigen-specific T cells required to kill the cancer leads to cancer cells being able to grow in cancer patients. Active and adoptive T cell immunotherapies generate T cells that can target cancer cells.

Dendritic cells (DCs) are immune cells that function as antigen-presenting cells. They are able to activate naive CD4+ T helper cells and unprimed CD8+ cytotoxic T lymphocytes. Active immunotherapy, represented by DC-based regimens, has been used to produce tumor-specific antigen-presenting cells and to generate cytotoxic T lymphocyte responses against cancer cells. DCs can capture antigens, process them, and present them with co-stimulation cytokines/messengers to initiate an immune response, like inducing primary T-cell responses.

Adoptive immunotherapy, as conducted at our Asian Stem Cell Institute, is a personalized therapy that uses a patient’s own anti-tumor immune cells to kill cancer cells and may be used to treat several types of cancer, and represents another therapeutic approach against cancer. To date, the adoptive immunotherapy approach is one of the most effective methods for using the body’s immune system to treat cancer. To be used clinically, protocols for the development of these functional DCs must be established for in-clinic use via defined, xenobiotic-free medium conditions.

The purpose of the present study is to determine the cellular immune response in terms of the delayed-type hyper-sensitivity (DTH) skin test and evaluate the subjective clinical outcome and safety of the regimen in cancer patients receiving a DC vaccine.

Vaccination against a single antigen is available using purified and synthetic products, but these have disadvantages because it is unknown which of the identified antigens have the potential to induce an effective antitumor immune response. This study uses unfractionated, autologous, tumor-derived antigens in the form oftumor cell lysates which circumvents this disadvantage.

Tumor lysates as addressed in this protocol, contain multiple known as well as unknown antigens that can be presented to T cells by both MHC class I- and class II-pathways. Therefore, lysate-loaded DCs are more likely to induce the more preferred polyclonal expansion of T cells, including MHC class II restricted T-helper cells. These have been recognized to play an important role in the activation of Cytotoxic T Lymphocytes (CTLs), probably the most important cells in effecting an antitumor immune response. The generation of CTL clones with multiple specificities may be an advantage in heterogeneous tumors and could also reduce the risk of tumor escape variants. Furthermore, lysate from the autologous tumor can be used independently of the HLA type of the patient. A drawback of unfractionated tumor antigens is the possibility of inducing an autoimmune reactivity to epitopes that are shared by normal tissues. However, in clinical trials using lysate or whole tumor cells as the source of antigen, no clinically relevant autoimmune responses have ever been detected.

Personalized dendritic cell vaccines for cancer, via adoptive immunotherapy, are successfully developed and autologously administered to patients coming to Asia, and more specifically, within the Philippines at the Subic Institute for Regenerative Medicine. The results of this case study of cancer and immunotherapy via pulsed dendritic cells, can serve as another example of safety for future cancer vaccine development.

Dendritic Cell Therapy for Cancer:
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Related Articles Neurocognitive Dysfunction in Hematopoietic Cell Transplant Recipients: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Complications and Quality of Life Working Party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2018 02;24(2):228-241 Authors: Kelly DL, Buchbinder D, Duarte RF, Auletta JJ, Bhatt N, Byrne M, DeFilipp Z, Gabriel M, Mahindra A, Norkin M, Schoemans H, Shah AJ, Ahmed I, Atsuta Y, Basak GW, Beattie S, Bhella S, Bredeson C, Bunin N, Dalal J, Daly A, Gajewski J, Gale RP, Galvin J, Hamadani M, Hayashi RJ, Adekola K, Law J, Lee CJ, Liesveld J, Malone AK, Nagler A, Naik S, Nishihori T, Parsons SK, Scherwath A, Schofield HL, Soiffer R, Szer J, Twist I, Warwick A, Wirk BM, Yi J, Battiwalla M, Flowers ME, Savani B, Shaw BE Abstract Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and nonmalignant diseases. Despite increasing survival rates, long-term morbidity after HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction after HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction after HCT. In this review we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Finally, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae after HCT. PMID: 28939455 [PubMed - indexed for MEDLINE]
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Related Articles Hematopoietic Cell Transplantation for Myelofibrosis: the Dynamic International Prognostic Scoring System Plus Risk Predicts Post-Transplant Outcomes. Biol Blood Marrow Transplant. 2018 02;24(2):386-392 Authors: Samuelson Bannow BT, Salit RB, Storer BE, Stevens EA, Wu D, Yeung C, Fang M, Petersdorf EW, Linenberger ML, Woo J, Sorror ML, Doney K, Sandmaier BM, Deeg HJ, Scott BL Abstract Hematopoietic cell transplantation (HCT) provides potentially curative treatment for patients with myelofibrosis (MF). HCT outcomes are associated with the Dynamic International Prognostic Scoring System (DIPSS) risk scores. In the present study we analyzed results in 233 patients to determine if the DIPSS plus classification, which adds cytogenetics, thrombocytopenia, and RBC transfusion dependence as risk factors, would better predict post-HCT outcomes than the original DIPSS. Multivariate analysis showed that each risk parameter incorporated into the DIPPS plus model contributed to its predictive power of overall mortality, relapse-free survival, and nonrelapse mortality. The 5-year overall survival (OS), relapse, and treatment-related mortality (TRM) rates for patients with low/intermediate-1 risk MF were 78%, 5%, and 20%, respectively. The 5-year OS, relapse, and TRM rates for patients with high-risk MF were 35%, 28%, and 40%, respectively. The HCT-specific comorbidity index of 3 or greater was associated with higher nonrelapse and overall mortality and reduced relapse-free survival. The relapse incidence was significantly increased in older patients (HR, 3.02; P = .0007). With a median follow-up of 8 years 124 patients (53%) were surviving. The components of the DIPSS plus classification still have prognostic relevance after adjustment by the DIPSS classification. This information should enhance our ability to advise patients when making decisions regarding timing of transplant. PMID: 28970176 [PubMed - indexed for MEDLINE]
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Related Articles Prevention of Cytomegalovirus Reactivation in Haploidentical Stem Cell Transplantation. Biol Blood Marrow Transplant. 2018 02;24(2):353-358 Authors: Hammerstrom AE, Lombardi LR, Pingali SR, Rondon G, Chen J, Milton DR, Chemaly RF, Champlin RE, Gulbis A, Ciurea SO Abstract Cytomegalovirus (CMV) infection can increase the morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Because of a higher degree of immunosuppression, haploidentical transplant recipients may be at an increased risk of viral infections, particularly CMV. We retrospectively analyzed 86 haploidentical HCT recipients at our institution to determine whether a more intensified antiviral strategy would reduce the incidence of CMV reactivation compared with a traditional antiviral prophylaxis regimen. According to practice changes over time in antiviral prophylaxis at our institution, patients were divided into the following 3 groups: hybrid (n = 15), traditional (n = 26), and intermediate dose (n = 45). The hybrid group received valganciclovir from admission to day -2 followed by standard-dose valacyclovir. The traditional group received standard-dose valacyclovir starting on day -1. The intermediate-dose group received ganciclovir from admission through day -2, followed by intermediate-dose valacyclovir. The hybrid and intermediate-dose groups were combined into an intensified group for further analysis. We found the cumulative incidence (CI) of CMV reactivation within 100 days post-HCT was higher for patients receiving the traditional strategy compared with the hybrid and intermediate-dose strategy groups (81% versus 53% versus 71%, respectively; P = .08) and was significantly higher when the traditional group was compared against the intensified group (81% versus 67%, respectively; P = .032). Median time to CMV reactivation was also shorter in the traditional group versus the intensified group (31 versus 41 days, respectively). Moreover, the CI of CMV disease by day 100 was significantly worse for patients receiving the traditional prophylaxis strategy among the 3 groups (8% traditional versus 0% hybrid versus 0% intermediate dose; P = .032). Renal toxicity did not differ between the traditional and intensified group. In conclusion, an intensified approach to prevention of CMV reactivation was associated with lower incidence of CMV reactivation and less CMV disease without increased toxicity. Because the most benefit was observed in the intensified group, further studies are needed to assess which antiviral intervention is the most beneficial on lowering the rates of CMV viremia and disease. PMID: 28986189 [PubMed - indexed for MEDLINE]
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Related Articles Incidence and Risk Factors for Nontuberculous Mycobacterial Infection after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2018 02;24(2):366-372 Authors: Beswick J, Shin E, Michelis FV, Thyagu S, Viswabandya A, Lipton JH, Messner H, Marras TK, Kim DDH Abstract Allogenic hematopoietic stem cell transplant (HCT) recipients are at risk of many infections. Nontuberculous mycobacteria (NTM) are increasingly recognized as clinically significant pathogens in this population. We investigated the incidence and risk factors for NTM infection after allogeneic HCT. This retrospective cohort study included all patients with allogeneic HCT at our institution during 2001 to 2013. Patients who developed significant NTM infection (NTM disease) were identified. Multivariable modeling was used to identify risk factors for NTM disease, and a risk score model was constructed to identify high-risk patients. Of 1097 allogeneic HCT patients, 45 (4.1%) had NTM isolated and 30 (2.7%) had NTM disease (28 [93.3%] exclusively pulmonary, 2 [6.7%] pulmonary plus another site). Incidence of NTM infection by competing risk analysis was 2.8% at 5 years (95% CI, 1.9% to 4.0%). The median time to diagnosis was 343 days (range, 19 to 1967). In Fine-Gray proportional hazards modeling, only global severity of chronic graft-versus-host disease (cGVHD) (HR, 1.99; 95% CI, 1.12 to 3.53; P = .019,) and cytomegalovirus (CMV) viremia (HR, 5.77; 95% CI, 1.71 to 19.45; P = .004) were significantly associated with NTM disease. Using these variables a risk score was calculated: 1 point for CMV viremia or moderate cGVHD and 2 points for severe cGVHD. The score divided patients into low risk (0 to 1 points, n = 820 [77.3%], 3-year NTM risk 1.2%), intermediate risk (2 points, n = 161 [15.4%], 3-year NTM risk 7.1%), and high risk (3 points, n = 56 [5.4%], 3-year NTM risk 14.3%). NTM disease after allogeneic HCT is common. Severe cGVHD and CMV viremia are associated with increased risk, permitting risk stratification. PMID: 28986190 [PubMed - indexed for MEDLINE]
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Related Articles Graft-Derived Reconstitution of Mucosal-Associated Invariant T Cells after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2018 02;24(2):242-251 Authors: Bhattacharyya A, Hanafi LA, Sheih A, Golob JL, Srinivasan S, Boeckh MJ, Pergam SA, Mahmood S, Baker KK, Gooley TA, Milano F, Fredricks DN, Riddell SR, Turtle CJ Abstract Mucosal-associated invariant T (MAIT) cells express a semi-invariant Vα7.2+ T cell receptor (TCR) that recognizes ligands from distinct bacterial and fungal species. In neonates, MAIT cells proliferate coincident with gastrointestinal (GI) bacterial colonization. In contrast, under noninflammatory conditions adult MAIT cells remain quiescent because of acquired regulation of TCR signaling. Effects of inflammation and the altered GI microbiota after allogeneic hematopoietic cell transplantation (HCT) on MAIT cell reconstitution have not been described. We conducted an observational study of MAIT cell reconstitution in myeloablative (n = 41) and nonmyeloablative (n = 66) allogeneic HCT recipients and found that despite a rapid and early increase to a plateau at day 30 after HCT, MAIT cell numbers failed to normalize for at least 1 year. Cord blood transplant recipients and those who received post-HCT cyclophosphamide for graft versus host disease (GVHD) prophylaxis had profoundly impaired MAIT cell reconstitution. Sharing of TCRβ gene sequences between MAIT cells isolated from HCT grafts and blood of recipients after HCT showed early MAIT cell reconstitution was due at least in part to proliferation of MAIT cells transferred in the HCT graft. Inflammatory cytokines were required for TCR-dependent MAIT cell proliferation, suggesting that bacterial Vα7.2+ TCR ligands might promote MAIT cell reconstitution after HCT. Robust MAIT cell reconstitution was associated with an increased GI abundance of Blautia spp. MAIT cells suppressed proliferation of conventional T cells consistent with a possible regulatory role. Our data identify modifiable factors impacting MAIT cell reconstitution that could influence the risk of GVHD after HCT. PMID: 29024803 [PubMed - indexed for MEDLINE]
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Related Articles Hypoalbuminemia at Day +90 Is Associated with Inferior Nonrelapse Mortality and Overall Survival in Allogeneic Hematopoietic Cell Transplantation Recipients: A Confirmatory Study. Biol Blood Marrow Transplant. 2018 02;24(2):400-405 Authors: Murthy HS, Sheets K, Kumar A, Nishihori T, Mina A, Chavez JC, Ayala E, Field T, Mathews J, Locke F, Perez L, Betts BC, Khimani F, Miladinovic B, Tsalatsanis A, Ochoa-Bayona JL, Alsina M, Fernandez H, Pidala J, Anasetti C, Kharfan-Dabaja MA Abstract Prognostic biomarkers in allogeneic hematopoietic cell transplantation (allo-HCT) are needed to improve risk assessment and help guide therapeutic and surveillance strategies to mitigate the risk of death from the procedure. We previously identified hypoalbuminemia at day +90 post-transplantation as an independent predictor of increased nonrelapse mortality (NRM) and inferior overall survival (OS) in patients with acute myelogenous leukemia and myelodysplastic syndrome who were treated with an allo-HCT. Here, we aim to confirm the prognostic significance of day +90 hypoalbuminemia in 783 patients, median age 52 years (range, 18 to 76), who received an allo-HCT for various hematologic malignancies and bone marrow failure syndromes. Multivariate analysis for NRM demonstrated a negative effect of low serum albumin levels (<3.0 versus 3.0 to 3.5 versus >3.5 g/dL) at day +90 post-transplantation (hazard ratios, 8.03 [95% CI, 3.59 to 17.97] versus 2.84 [95% CI, 1.59 to 5.08] versus reference; P < .0001). This was also the case for OS (hazard ratios, 6.86 [95% CI, 4.24 to 11.10] versus 1.52 [95% CI, 1.05 to 2.20] versus reference; P < .0001). Patients with hypoalbuminemia at day +90 post-transplantation are more likely to die from causes other than relapse, particularly infections. This large study confirms the ability of day +90 serum hypoalbuminemia to predict worse NRM and inferior OS. Presence of hypoalbuminemia at day +90 should drive a more rigorous real-time surveillance strategy considering the anticipated high-risk of NRM and poor survival in these patients. Future studies should consider incorporating day +90 serum albumin levels in prognostic models of NRM and OS. PMID: 29032266 [PubMed - indexed for MEDLINE]
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Related Articles Long-Term Follow-Up of a Donor versus No-Donor Comparison in Patients with Multiple Myeloma in First Relapse after Failing Autologous Transplantation. Biol Blood Marrow Transplant. 2018 02;24(2):406-409 Authors: Patriarca F, Bruno B, Einsele H, Spina F, Giaccone L, Montefusco V, Isola M, Nozzoli C, Nozza A, Morabito F, Corradini P, Fanin R Abstract We report the long-term clinical outcomes of a retrospective multicenter study that enrolled 169 patients with multiple myeloma (MM) in first relapse after failing autologous stem cell transplantation (SCT). After HLA typing at relapse, 79 patients with a suitable donor, 72 (91%) of whom eventually underwent salvage allogeneic SCT (allo-SCT), were compared with 90 patients without a donor who were treated with multiple lines of salvage treatment with bortezomib and/or immunomodulatory agents. At a median follow-up of 30 months (range, 2-180 months) for all patients and 110 months (range, 38-180 months) for surviving patients, 7-year progression-free survival (PFS) was 18% in the donor group and 0% in the no-donor group (hazard ratio [HR], 2.495; 95% confidence interval [CI], 1.770-3.517; P < .0001). Seven-year overall survival (OS) was 31% in the donor group and 9% in the no-donor group (HR, 1.835; 95% CI, 1.306-2.577; P < .0001). By multivariate analysis, chemosensitivity to salvage treatments and presence of a suitable donor were significantly associated with better PFS and OS. The long-term follow-up of this study confirms the significant PFS benefit and provides new evidence of an OS advantage for patients with MM who have a suitable donor and undergo allo-SCT. Allo-SCT should be considered as a treatment option in young relapsed patients with high-risk disease features after first-line treatment. PMID: 29032267 [PubMed - indexed for MEDLINE]
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Related Articles Total Marrow Lymphoid Irradiation/Fludarabine/ Melphalan Conditioning for Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2018 02;24(2):301-307 Authors: Jensen LG, Stiller T, Wong JYC, Palmer J, Stein A, Rosenthal J Abstract Reduced-intensity conditioning (RIC) regimens for hematopoietic stem cell transplantation (HCT) can reduce morbidity and mortality, but patients with advanced disease may require alternative approaches. In an initial report of RIC with fludarabine (FLU) and melphalan (MEL) with total marrow lymphoid irradiation (TMLI) in HCT for advanced hematologic malignancies in 33 patients, we found that the addition of TMLI to RIC was feasible and safe. Here we report long-term outcomes for these patients. This prospective study included 61 patients treated with TMLI to a dose of 12 Gy (1.5 Gy twice daily for 4 days), FLU (25 mg/m2/day for 5 days), and MEL (140 mg/m2/day for 1 day). Overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) were measured from the date of HCT. Survival outcomes were analyzed using Kaplan-Meier analysis. Patients were categorized as low/intermediate or high/very high risk using the Disease Risk Index. The median follow-up was 7.4 years. The majority of patients had acute leukemia (72%); 49% had high/very high-risk disease. The median patient age was 55 years (range, 9-70 years). Two-year OS, EFS, CIR, and NRM were 54% (95% confidence interval [CI], 41%-66%), 49% (95% CI, 36%-61%), 21% (95% CI, 13%-35%), and 30% (95% CI, 20%-43%), respectively. Five-year OS, EFS, CIR, and NRM were 42% (95% CI, 30%-54%), 41% (95% CI, 28%-53%), 26 (95% CI, 17%-40%), and 33% (95% CI, 23%-47%, respectively). Acute (any grade) and chronic (limited or extensive) graft-versus-host disease occurred in 69% and 74% of patients, respectively. The most common toxicity was mucositis. The addition of TMLI to FLU/MEL conditioning was well tolerated, with favorable outcomes. Dosage escalation of TMLI or other modifications may be needed to improve disease control. PMID: 29032268 [PubMed - indexed for MEDLINE]
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Related Articles Association of Socioeconomic Status with Chronic Graft-versus-Host Disease Outcomes. Biol Blood Marrow Transplant. 2018 02;24(2):393-399 Authors: Hamilton BK, Rybicki L, Arai S, Arora M, Cutler CS, Flowers MED, Jagasia M, Martin PJ, Palmer J, Pidala J, Majhail NS, Lee SJ, Khera N Abstract Chronic graft-versus host disease (GVHD) is a chronic and disabling complication after hematopoietic cell transplantation (HCT). It is important to understand the association of socioeconomic status (SES) with health outcomes in patients with chronic GVHD because of the impaired physical health and dependence on intensive and prolonged health care utilization needs in these patients. We evaluated the association of SES with survival and quality of life (QOL) in a cohort of 421 patients with chronic GVHD enrolled on the Chronic GVHD Consortium Improving Outcomes Assessment study. Income, education, marital status, and work status were analyzed to determine the associations with patient-reported outcomes at the time of enrollment, nonrelapse mortality (NRM), and overall mortality. Higher income (P = .004), ability to work (P < .001), and having a partner (P = .021) were associated with better mean Lee chronic GVHD symptom scores. Higher income (P = .048), educational level (P = .044), and ability to work (P < .001) also were significantly associated with better QOL and improved activity. In multivariable models, higher income and ability to return to work were both significantly associated with better chronic GVHD Lee symptom scores, but income was not associated with activity level, QOL, or physical/mental functioning. The inability to return to work (hazard ratio, 1.82; P = .019) was associated with worse overall mortality, whereas none of the SES indicators were associated with NRM. Income, race, and education did not have statistically significant associations with survival. In summary, we did not observe an association between SES variables and survival or NRM in patients with chronic GVHD, although we found some association with patient-reported outcomes, such as symptom burden. Higher income status was associated with less severe chronic GVHD symptoms. More research is needed to understand the psychosocial, biological, and environmental factors that mediate this association of SES with major HCT outcomes. PMID: 29032275 [PubMed - indexed for MEDLINE]
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Related Articles Reversal of Low Donor Chimerism after Hematopoietic Cell Transplantation Using Pentostatin and Donor Lymphocyte Infusion: A Prospective Phase II Multicenter Trial. Biol Blood Marrow Transplant. 2018 02;24(2):308-313 Authors: Bar M, Flowers MED, Storer BE, Chauncey TR, Pulsipher MA, Thakar MS, Bethge W, Storb R, Maloney DG, Sandmaier BM Abstract In a multicenter, prospective, phase II study we evaluated the safety and efficacy of pentostatin followed by donor lymphocyte infusion (DLI) in patients with low donor Tcell chimerism after allogeneic hematopoietic cell transplantation (HCT). Thirty-six patients with low donor blood CD3 chimerism were enrolled in this study. Thirty-five patients received a total of 41 DLIs after a dose of pentostatin, and 1 patient received pentostatin only. Median donor CD3 chimerism prompting the initiation of pentostatin and DLI was 28% (range, 5% to 47%). Responses (defined by increases in donor CD3 chimerism ≥10% maintained to day 56 post-DLI) were seen in 16 patients (44.4%) with a median rise in CD3 donor chimerism to 64% (range, 48% to 100%). There was a trend for better responses among 21 patients who received first treatment within 100 days after transplant (57% response rate) compared with15 patients who received first treatment more than 100 days after HCT (27% response rate, P = .07). Fourteen patients (39%) developed grades II to IV acute graft-versus-host disease (GVHD) at a median of 10 days (range, 0 to 83) after DLI. Ten patients (28%) developed extensive chronic GVHD. Seventeen patients (47%) developed new grade 4 cytopenias after DLI. There was no difference in relapse between nonresponders and responders. Twenty-eight patients (78%) died, most (n = 21) because of relapse. Five of 16 responders (31%) are alive, all disease-free, at a median of 60 months (range, 21 to 132) after DLI. Six of 20 nonresponders (30%) are alive at a median of 47 months (range, 16 to 100) after DLI, 3 in complete remission. Pentostatin and DLI had acceptable toxicity and appeared to increase low donor CD3 chimerism after HCT but had no impact on mortality. PMID: 29032276 [PubMed - indexed for MEDLINE]
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Related Articles Double-Expressor Lymphoma Is Associated with Poor Outcomes after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2018 02;24(2):294-300 Authors: Kawashima I, Inamoto Y, Maeshima AM, Nomoto J, Tajima K, Honda T, Shichijo T, Kawajiri A, Takemura T, Onishi A, Ito A, Tanaka T, Fuji S, Kurosawa S, Kim SW, Maruyama D, Tobinai K, Kobayashi Y, Fukuda T Abstract Double-expressor lymphoma (DEL) is a diffuse large B cell lymphoma that exhibits co-expression of MYC and BCL2 proteins by immunohistochemistry. Patients with double-expressor lymphoma have a poor prognosis after standard chemoimmunotherapy or after high-dose chemotherapy with autologous transplantation, but the prognostic impact of DEL after allogeneic hematopoietic cell transplantation has not been well characterized. We retrospectively analyzed 60 consecutive patients with de novo diffuse large B cell lymphoma or transformed follicular lymphoma who underwent allogeneic transplantation at our center and had available immunohistochemistry data. Thirty-seven patients (62%) had DEL. The 2-year progression-free and overall survival rates were lower in patients with DEL than in those without DEL (20% versus 78%; overall P <.001 and 46% versus 77%; overall P = .016, respectively). The cumulative incidence of disease progression at 2 years was higher in patients with DEL (60% versus 13%; overall P = .005). The cumulative incidence of nonrelapse mortality did not differ statistically in the 2 groups. Even in patients with DEL and chemosensitive disease at transplantation, the 2-year progression-free survival rate was only 27% due to early disease progression. Multivariate analysis showed associations between DEL and increased risks of progression-free survival events (hazard ratio [HR], 4.58; 95% confidence interval [CI], 2.07-10.2; P <.001), overall mortality (HR, 2.29; 95% CI, 1.03-5.09; P = .042) and disease progression (HR, 3.60; 95% CI, 1.38-9.44; P = .009). Patients with DEL had poor outcomes after allogeneic transplantation. Innovative strategies are needed to improve outcomes in this population. PMID: 29037890 [PubMed - indexed for MEDLINE]
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Related Articles Chemotherapy-Based Stem Cell Mobilization Does Not Result in Significant Paraprotein Reduction in Myeloma Patients in the Era of Novel Induction Regimens. Biol Blood Marrow Transplant. 2018 02;24(2):276-281 Authors: Oyekunle A, Shumilov E, Kostrewa P, Burchert A, Trümper L, Wuchter P, Wulf G, Bacher U, Kröger N Abstract Novel induction agents markedly improved remission rates in multiple myeloma (MM), and the continued use of chemotherapy for CD34+ stem cell mobilization (SCM) has been questioned. We examined the additional effect of chemotherapy in SCM regarding remission status/morbidity. We reviewed 236 consecutive MM patients (aged 36 to 75 years) with first autologous stem cell transplantation from January 2009 to March 2016 after chemotherapy-based SCM. Responses were measured by changes in intact Ig and free light chain levels before and after chemomobilization (International Myeloma Working Group [IMWG] criteria). Most patients (225/236, 95.3%) received novel induction regimens, which were bortezomib-based (n = 223) and/or lenalidomide-based (n = 19). Most patients (170/190, 89.5%) achieved at least partial remission postinduction and pre-SCM. Stem cells were mobilized with granulocyte colony-stimulating factor and cyclophosphamide-based (212/227, 93.4%) or etoposide-based (15/227, 6.6%) regimens. There were insignificant changes in serum Ig and free light chain levels before and after chemomobilization either in the whole cohort or subgroups. Significant improvements of the IMWG remission status were documented in only 7 of 236 patients (3.0%). Sixty-seven patients (28.4%) developed chemotherapy-related complications (neutropenic fever, sepsis, and others), resulting in 9 hospitalizations (3.8%). Our study suggests that although causing significant morbidity, chemotherapy-based mobilization fails to improve remission status. The value of incorporating additional chemotherapy for SCM is thus not evident. PMID: 29037891 [PubMed - indexed for MEDLINE]
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Related Articles Impact of Allogeneic Stem Cell Transplantation in First Complete Remission in Acute Myeloid Leukemia: A National Population-Based Cohort Study. Biol Blood Marrow Transplant. 2018 02;24(2):314-323 Authors: Østgård LSG, Lund JL, Nørgaard JM, Nørgaard M, Medeiros BC, Nielsen B, Nielsen OJ, Overgaard UM, Kallenbach M, Marcher CW, Riis AH, Sengeløv H Abstract To examine the outcomes of allogeneic stem cell transplantation (HSCT) in first complete remission (CR1) compared with chemotherapy alone in a population-based setting, we identified a cohort of patients with acute myeloid leukemia (AML) aged 15 to 70 years diagnosed between 2000 and 2014 in Denmark. Using the Danish National Acute Leukemia Registry, we compared relapse risk, relapse-free survival (RFS), and overall survival (OS) between patients with unfavorable cytogenetic features receiving postremission therapy with conventional chemotherapy only versus those undergoing HSCT in CR1. To minimize immortal time bias, we performed Cox proportional hazards regression, included date of allogeneic HSCT as a time-dependent covariate, and stratified the results by age (<60 or ≥60 years) and cytogenetic risk group. Overall, 1031 patients achieved a CR1. Of these, 196 patients (19%) underwent HSCT. HSCT was associated with a lower relapse rate (24% versus 49%) despite a similar median time to relapse (287 days versus 265 days). In all subgroups, the risk of relapse was lower and both RFS and OS were superior in recipients of HSCT (OS, adjusted mortality ratios: all patients, .54 [95% confidence interval (CI), .42-.71]; patients age <60 years, .58 [95% CI, .42-.81]; patients age ≥60 years, .42 [95% CI, .26-.69]; patients with intermediate-risk cytogenetics, .63 [95% CI, .43-.87]; patients with adverse-risk cytogenetics, .40 [95% CI, .24-.67]). In conclusion, in this population-based nationwide cohort study, HSCT was associated with improved survival in both younger and older patients and in patients with both intermediate and adverse cytogenetic risk. PMID: 29051022 [PubMed - indexed for MEDLINE]
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Related Articles Granulocyte Colony-Stimulating Factor Use after Autologous Peripheral Blood Stem Cell Transplantation: Comparison of Two Practices. Biol Blood Marrow Transplant. 2018 02;24(2):288-293 Authors: Singh AD, Parmar S, Patel K, Shah S, Shore T, Gergis U, Mayer S, Phillips A, Hsu JM, Niesvizky R, Mark TM, Pearse R, Rossi A, van Besien K Abstract Administration of granulocyte colony-stimulating factor (G-CSF) after autologous peripheral blood stem cell transplantation (PBSCT) is generally recommended to reduce the duration of severe neutropenia; however, data regarding the optimal timing of G-CSFs post-transplantation are limited and conflicting. This retrospective study was performed at NewYork-Presbyterian/Weill Cornell Medical Center between November 5, 2013, and August 9, 2016, of adult inpatient autologous PBSCT recipients who received G-CSF empirically starting on day +5 (early) versus on those who received G-CSF on day +12 only if absolute neutrophil count (ANC) was <0.5 × 109/L (ANC-driven). G-CSF was dosed at 300 µg in patients weighing <75 kg and 480 µg in those weighing ≥75 kg. One hundred consecutive patients underwent autologous PBSCT using either the early (n = 50) or ANC-driven (n = 50) G-CSF regimen. Patient and transplantation characteristics were comparable in the 2 groups. In the ANC-driven group, 24% (n = 12) received G-CSF on day +12 and 60% (n = 30) started G-CSF earlier due to febrile neutropenia or at the physician's discretion, 6% (n = 3) started after day +12 at the physician's discretion, and 10% (n = 5) did not receive any G-CSF. The median start day of G-CSF therapy was day +10 in the ANC-driven group versus day +5 in the early group (P < .0001). For the primary outcome, the median time to neutrophil engraftment was 12 days (interquartile range [IQR] 11-13 days) in the early group versus 13 days (IQR, 12-14 days) in the ANC-driven group (P = .07). There were no significant between-group differences in time to platelet engraftment, 1-year relapse rate, or 1-year overall survival. The incidence of febrile neutropenia was 74% in the early group versus 90% in the ANC-driven group (P = .04); however, there was no significant between-group difference in the incidence of positive bacterial cultures or transfer to the intensive care unit. The duration of G-CSF administration until neutrophil engraftment was 6 days in the early group versus 3 days in the ANC-driven group (P < .0001). The median duration of post-transplantation hospitalization was 15 days (IQR, 14-19 days) in the early group versus 16 days (IQR, 15-22 days) in the ANC-driven group (P = .28). Our data show that early initiation of G-CSF (on day +5) and ANC-driven initiation of G-CSF following autologous PBSCT were associated with a similar time to neutrophil engraftment, length of stay post-transplantation, and 1-year overall survival. PMID: 29061534 [PubMed - indexed for MEDLINE]
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Related Articles Total Body Irradiation Is Safe and Similarly Effective as Chemotherapy-Only Conditioning in Autologous Stem Cell Transplantation for Mantle Cell Lymphoma. Biol Blood Marrow Transplant. 2018 02;24(2):282-287 Authors: Tseng YD, Stevenson PA, Cassaday RD, Cowan A, Till BG, Shadman M, Graf SA, Ermoian R, Smith SD, Holmberg LA, Press OW, Gopal AK Abstract Autologous stem cell transplant (ASCT) consolidation has become a standard approach for patients with mantle cell lymphoma (MCL), yet there is little consensus on the role of total body irradiation (TBI) as part of high-dose transplantation conditioning. We analyzed 75 consecutive patients with MCL who underwent ASCT at our institution between 2001 and 2011 with either TBI-based (n = 43) or carmustine, etoposide, cytarabine, melphalan (BEAM; n = 32) high-dose conditioning. Most patients (97%) had chemosensitive disease and underwent transplantation in first remission (89%). On univariate analysis, TBI conditioning was associated with a trend toward improved PFS (hazard ratio [HR], .53; 95% confidence interval [CI], .28-1.00; P = .052) and similar OS (HR, .59; 95% CI, .26-1.35; P = .21), with a median follow-up of 6.3 years in the TBI group and 6.6 years in the BEAM group. The 5-year PFS was 66% in the TBI group versus 52% in the BEAM group; OS was 82% versus 68%, respectively. However, on multivariate analysis, TBI-based conditioning was not significantly associated with PFS (HR, .57; 95% CI .24-1.34; P = .20), after controlling for age, disease status at ASCT, and receipt of post-transplantation rituximab maintenance. Likewise, early toxicity, nonrelapse mortality, and secondary malignancies were similar in the 2 groups. Our data suggest that both TBI and BEAM-based conditioning regimens remain viable conditioning options for patients with MCL undergoing ASCT. PMID: 29061536 [PubMed - indexed for MEDLINE]
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Related Articles Poor Adherence Is Associated with More Infections after Pediatric Hematopoietic Stem Cell Transplant. Biol Blood Marrow Transplant. 2018 02;24(2):381-385 Authors: Pai ALH, Rausch J, Drake S, Morrison CF, Lee JL, Nelson A, Tackett A, Berger S, Szulczewski L, Mara C, Davies S Abstract We prospectively examined rates of outpatient oral medication adherence in children after hematopoietic stem cell transplant (post-HSCT). For 6 months after first discharge post-HSCT, 50 patients (aged 0 to 16 years) and their primary caregivers agreed to store 1 oral medication in an electronic pill bottle that date and time stamps each bottle opening. Demographics, disease, donor type, and prescribed post-HSCT medication regimen were collected via chart review. For each patient percent adherence was calculated by dividing the number of doses taken as indicated by the electronic pill bottle by the number of doses prescribed for the same time period. Average percent adherence ranged from 63% at 1 month after discharge to 57% at 6 months after discharge. For patients who received an allogeneic transplant, lower adherence was associated (P < .005) with higher infection rates, after controlling for age and time since transplant. No such relationship was observed for patients who received an autologous transplant. This study demonstrates that poor oral medication adherence is prevalent, persistent, and, for patients receiving an allogeneic transplant, associated with increased incidence of infections during the outpatient treatment period. This study highlights the need for further research examining factors that hinder medication adherence as well as monitoring, promoting, and intervening to maximize medication adherence throughout the HSCT course. PMID: 29102720 [PubMed - indexed for MEDLINE]
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Related Articles Long-term results in children with head and neck rhabdomyosarcoma: A report from the Italian Soft Tissue Sarcoma Committee. Pediatr Blood Cancer. 2018 03;65(3): Authors: Affinita MC, Ferrari A, Milano GM, Scarzello G, De Leonardis F, Coccoli L, Pericoli R, Basso E, Zanetti I, Scagnellato A, Bisogno G Abstract BACKGROUND: Rhabdomyosarcoma (RMS) occurring at nonparameningeal head and neck (NPM-HN) sites carries a better prognosis than parameningeal RMS and some other sites. We analyzed the treatments administered and results obtained in patients with localized NPM-HN RMS, included in the protocols coordinated by the Italian Soft Tissue Sarcoma Committee (STSC), in an effort to identify prognostic factors that could facilitate the tailoring of treatment. METHODS: Sixty-six patients up to 18 years of age with previously untreated, localized NPM-HN RMS were prospectively registered in three consecutive protocols: RMS79, RMS88, and RMS96. Primary surgery was recommended when complete tumor resection was deemed feasible without mutilations. In other cases, only a biopsy was performed, followed by chemotherapy and delayed surgery and/or radiotherapy (RT). RESULTS: NPM-HN RMS showed favorable characteristics: 72.7% were <5 cm, 72.7% were T1, and 80.3% were N0. With a median follow-up of 16 years (range 7-27), the 10-year progression-free survival and overall survival for the whole group were 65.1% (confidence interval [CI]: 52.3-75.3) and 74.2% (CI: 61.8-83.1). Progressive improvement has been seen in the successive protocols. Age and RT emerged as independent prognostic factors. The group of young children (age <l year) not irradiated was at high risk of failure. CONCLUSION: The experience of the Italian STSC confirms that NPM-HN RMS has a favorable prognosis, which has improved over the years due to a better, multimodal treatment approach. RT has an important role, but different modalities such as proton therapy and brachytherapy should be explored in systematic ways in very young children. PMID: 29115716 [PubMed - indexed for MEDLINE]
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Related Articles Impact of radiation therapy and extent of resection for ependymoma in young children: A population-based study. Pediatr Blood Cancer. 2018 03;65(3): Authors: Snider CA, Yang K, Mack SC, Suh JH, Chao ST, Merchant TE, Murphy ES Abstract BACKGROUND: Young children with posterior fossa ependymoma (PF-EPN) have a worse prognosis than older children, and they have a unique molecular profile (PF-EPN-A subtype). Alternative treatment strategies are often used in these young patients, and their prognostic factors are less clear. METHODS: We characterized the prognostic factors and treatment outcomes of 482 patients between ages 0 and 3 years with the diagnosis of ependymoma identified from the Surveillance, Epidemiology, and End Results registry (1973-2013). RESULTS: Radiation therapy (RT) was delivered to 52.3% of patients, and gross total resection (GTR) was performed in 51.0% of patients. Overall survival (OS) at 10 years was 48.4% with median follow-up of 3.3 years. WHO grade was not predictive of OS. Extent of resection was significant for survival; the 10-year OS with GTR was 61.0%, and with subtotal resection (STR) and biopsy was 38.2% and 35.0%, respectively (P < 0.001). RT significantly benefitted OS for both grades II and III. The 10-year OS for grade II was 50.5% with RT and 43.4% without (P = 0.030); 10-year OS for grade III was 66.0% with RT and 40.0% without (P = 0.002). Multivariate analysis showed significantly improved OS with RT (hazard ratio [HR] 0.601, 95% CI: 0.439-0.820, P = 0.001) and GTR (HR 0.471, 95% CI: 0.328-0.677, P < 0.0001). CONCLUSIONS: Ependymoma outcomes in patients within 0-3 years of age significantly improved with RT and GTR. Histopathologic grading of ependymoma demonstrated no prognostic significance. Given the poor OS for this population and unique genetic profile, future prospective studies with molecular-based stratification should be performed to evaluate additional prognostic factors. PMID: 29115718 [PubMed - indexed for MEDLINE]
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Related Articles Combined Haploidentical and Umbilical Cord Blood Allogeneic Stem Cell Transplantation for High-Risk Lymphoma and Chronic Lymphoblastic Leukemia. Biol Blood Marrow Transplant. 2018 02;24(2):359-365 Authors: Hsu J, Artz A, Mayer SA, Guarner D, Bishop MR, Reich-Slotky R, Smith SM, Greenberg J, Kline J, Ferrante R, Phillips AA, Gergis U, Liu H, Stock W, Cushing M, Shore TB, van Besien K Abstract Limited studies have reported on outcomes for lymphoid malignancy patients receiving alternative donor allogeneic stem cell transplants. We have previously described combining CD34-selected haploidentical grafts with umbilical cord blood (haplo-cord) to accelerate neutrophil and platelet engraftment. Here, we examine the outcome of patients with lymphoid malignancies undergoing haplo-cord transplantation at the University of Chicago and Weill Cornell Medical College. We analyzed 42 lymphoma and chronic lymphoblastic leukemia (CLL) patients who underwent haplo-cord allogeneic stem cell transplantation. Patients underwent transplant for Hodgkin lymphoma (n = 9, 21%), CLL (n = 5, 12%) and non-Hodgkin lymphomas (n = 28, 67%), including 13 T cell lymphomas. Twenty-four patients (52%) had 3 or more lines of therapies. Six (14%) and 1 (2%) patients had prior autologous and allogeneic stem cell transplant, respectively. At the time of transplant 12 patients (29%) were in complete remission, 18 had chemotherapy-sensitive disease, and 12 patients had chemotherapy-resistant disease. Seven (17%), 11 (26%), and 24 (57%) patients had low, intermediate, and high disease risk index before transplant. Comorbidity index was evenly distributed among 3 groups, with 13 (31%), 14 (33%), and 15 (36%) patients scoring 0, 1 to 2, and ≥3. Median age for the cohort was 49 years (range, 23 to 71). All patients received fludarabine/melphalan/antithymocyte globulin conditioning regimen and post-transplant graft-versus-host disease (GVHD) prophylaxis with tacrolimus and mycophenolate mofetil. The median time to neutrophil engraftment was 11 days (range, 9 to 60) and to platelet engraftment 19.5 days (range, 11 to 88). Cumulative incidence of nonrelapse mortality was 11.6% at 100 days and 19 % at one year. Cumulative incidence of relapse was 9.3% at 100 days and 19% at one year. With a median follow-up of survivors of 42 months, the 3-year rates of GVHD relapse free survival, progression-free survival, and overall survival were 53%, 62%, and 65%, respectively, for these patients. Only 8% of the survivors had chronic GVHD. In conclusion, haplo-cord transplantation offers a transplant alternative for patients with recurrent or refractory lymphoid malignancies who lack matching donors. Both neutrophil and platelet count recovery is rapid, nonrelapse mortality is limited, excellent disease control can be achieved, and the incidence of chronic GVHD is limited. Thus, haplo-cord achieves high rates of engraftment and encouraging results. PMID: 29128555 [PubMed - indexed for MEDLINE]
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Related Articles Chemo-Mobilization in Myeloma-Diminishing Returns in the Era of Novel Agent Induction? Biol Blood Marrow Transplant. 2018 02;24(2):203-204 Authors: Hari P PMID: 29272697 [PubMed - indexed for MEDLINE]
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Related Articles Utility of Routine Surveillance Imaging for Hodgkin Disease following Autologous Transplant: Experiences from a Single Institution. Acta Haematol. 2018;139(1):52-57 Authors: Mohyuddin GR, Clark AE, Roller J, Shune L, Lin T, Dunavin N, Dias A, Ganguly S, Abhyankar S, McGuirk J, Singh A Abstract BACKGROUND: Surveillance scans performed after autologous stem cell transplant (auto-HCT) for patients with Hodgkin disease (HD) have no proven survival benefit. METHODS: We studied survival differences among patients with HD after auto-HCT whose recurrences were detected on clinical history and exam, versus those detected on routine surveillance scan. RESULTS: Among the 98 patients with HD that underwent auto-HCT from 2000 to 2014 at our institution, 30 relapsed, of which 21 were detected radiologically and 9 clinically. There were no statistically significant differences in patient characteristics between the 2 groups. The median time to progression was 118 days for the clinical cohort and 284 days for the radiological cohort (p = 0.05). Median overall survival (OS) was 728 days for the clinical cohort, and was not reached for the radiological cohort (p = 0.02). DISCUSSION: In our review, most patients with HD after auto-HCT were diagnosed radiologically. Patients whose relapse was diagnosed clinically were likely to be detected earlier and have a shorter OS. Patients with aggressive disease may be detected when clinically relevant, regardless of scanning. Routine scanning may not be necessary in the majority of patients with HD following auto-HCT. PMID: 29339629 [PubMed - indexed for MEDLINE]
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Related Articles Significance of Salvage Autologous Stem Cell Transplantation for Relapsed Multiple Myeloma: A Nationwide Retrospective Study in Japan. Acta Haematol. 2018;139(1):35-44 Authors: Muta T, Miyamoto T, Kamimura T, Kanda Y, Nohgawa M, Ueda Y, Iwato K, Sasaki O, Mori T, Uchida N, Iida S, Fukuda T, Atsuta Y, Sunami K Abstract Autologous stem cell transplantation (ASCT) has been employed for patients with relapsed multiple myeloma (MM) after up-front ASCT. The present retrospective study aimed to examine the survival benefit from salvage ASCT. Among 446 patients with relapsed MM after up-front single ASCT, 70 patients received salvage ASCT, the employment of which reduced the risk of mortality after relapse (p = 0.041). Using the parameters before initial ASCT, the advantage of salvage ASCT compared to standard therapy was confirmed in the subgroup with an international staging system stage of I or II (p = 0.040), good performance status (PS; p = 0.043), or no/mild renal comorbidity (p = 0.029). The advantage of salvage ASCT was also confirmed in the subgroup excluding those with early relapse within 7 months after initial ASCT (p = 0.026). Among patients who received salvage ASCT, a favorable prognosis is apparent for those with a time to relapse after initial ASCT of longer than 24 months. The overall survival after salvage ASCT was favorable excluding patients with the following factors: early relapse, poor PS, moderate/severe renal comorbidity, and progressive disease (p < 0.001). In conclusion, our results reinforced the evidence for encouraging salvage ASCT for eligible patients. PMID: 29339642 [PubMed - indexed for MEDLINE]
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Related Articles Second Autologous Hematopoietic Stem Cell Transplant as Salvage Therapy for Relapsed Multiple Myeloma: A Global Treatment Option for Eligible Patients. Acta Haematol. 2018;139(1):45-46 Authors: Gonsalves WI, Kansagra A PMID: 29402801 [PubMed - indexed for MEDLINE]
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Related Articles Autologous Hematopoietic Cell Transplantation for Dialysis-Dependent Myeloma: More Efficient, Less Toxic. Acta Haematol. 2018;139(2):104-105 Authors: Amit O, Ram R PMID: 29414800 [PubMed - indexed for MEDLINE]
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Related Articles Incidence, Survival, and Risk Factors for Adults with Acute Myeloid Leukemia Not Otherwise Specified and Acute Myeloid Leukemia with Recurrent Genetic Abnormalities: Analysis of the Surveillance, Epidemiology, and End Results (SEER) Database, 2001-2013. Acta Haematol. 2018;139(2):115-127 Authors: Song X, Peng Y, Wang X, Chen Y, Jin L, Yang T, Qian M, Ni W, Tong X, Lan J Abstract BACKGROUND/AIM: As the knowledgebase of acute myeloid leukemia (AML) has grown, classification systems have moved to incorporate these new findings. METHODS: We assessed 32,941 patients with AML whose records are contained in the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: Half of all patients diagnosed between 2001 and 2013 did not have a World Health Organization (WHO) classification. Acute promyelocytic leukemia and acute panmyelosis with myelofibrosis were associated with the longest leukemia-specific survival (110 and 115 months, respectively), and AML with minimal differentiation and acute megakaryoblastic leukemia with the shortest (30 and 28 months, respectively). For patients in the WHO groups AML not otherwise specified (AML-NOS) and AML with recurrent genetic abnormalities (AML-RGA), the risk of death was greater for older patients and less for married patients. Black patients with any type of AML-NOS also had a higher risk of death. Patients whose case of AML did not receive a WHO classification were older and this group had a higher risk of death when compared to patients with a WHO type of AML-NOS. CONCLUSION: Our findings highlight the divergent outcomes of patients with AML and the importance of using the WHO classification system and demographic factors to gauge their prognosis. PMID: 29455198 [PubMed - indexed for MEDLINE]
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Related Articles Bone marrow-derived mesenchymal stem cells promote invasiveness and transendothelial migration of osteosarcoma cells via a mesenchymal to amoeboid transition. Mol Oncol. 2018 05;12(5):659-676 Authors: Pietrovito L, Leo A, Gori V, Lulli M, Parri M, Becherucci V, Piccini L, Bambi F, Taddei ML, Chiarugi P Abstract There is growing evidence to suggest that bone marrow-derived mesenchymal stem cells (BM-MSCs) are key players in tumour stroma. Here, we investigated the cross-talk between BM-MSCs and osteosarcoma (OS) cells. We revealed a strong tropism of BM-MSCs towards these tumour cells and identified monocyte chemoattractant protein (MCP)-1, growth-regulated oncogene (GRO)-α and transforming growth factor (TGF)-β1 as pivotal factors for BM-MSC chemotaxis. Once in contact with OS cells, BM-MSCs trans-differentiate into cancer-associated fibroblasts, further increasing MCP-1, GRO-α, interleukin (IL)-6 and IL-8 levels in the tumour microenvironment. These cytokines promote mesenchymal to amoeboid transition (MAT), driven by activation of the small GTPase RhoA, in OS cells, as illustrated by the in vitro assay and live imaging. The outcome is a significant increase of aggressiveness in OS cells in terms of motility, invasiveness and transendothelial migration. In keeping with their enhanced transendothelial migration abilities, OS cells stimulated by BM-MSCs also sustain migration, invasion and formation of the in vitro capillary network of endothelial cells. Thus, BM-MSC recruitment to the OS site and the consequent cytokine-induced MAT are crucial events in OS malignancy. PMID: 29517849 [PubMed - indexed for MEDLINE]
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Related Articles Improving surgical outcome for gliomas with intraoperative mapping. Expert Rev Neurother. 2018 04;18(4):333-341 Authors: Ferracci FX, Duffau H Abstract INTRODUCTION: Radical glioma resection improves overall survival, both in low-grade and high-grade glial tumors. However, preservation of the quality of life is also crucial. Areas covered: Due to the diffuse feature of gliomas, which invade the central nervous system, and due to considerable variations of brain organization among patients, an individual cerebral mapping is mandatory to solve the classical dilemma between the oncological and functional issues. Because functional neuroimaging is not reliable enough, intraoperative electrical stimulation, especially in awake patients benefiting from a real-time cognitive monitoring, is the best way to increase the extent of resection while sparing eloquent neural networks. Expert commentary: Here, we propose a paradigmatic shift from image-guided resection to functional mapping-guided resection, based on the study of the dynamic distribution of delocalized cortico-subcortical circuits at the individual level, i.e., the investigation of brain connectomics and neuroplastic potential. This surgical philosophy results in an improvement of both oncological outcomes and quality of life. This highlights the need to reinforce the link between glioma surgery and cognitive neurosciences. PMID: 29521555 [PubMed - indexed for MEDLINE]
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Related Articles Efficacy and Survival Outcome Associated with the Use of Novel Agents and Autologous Stem Cell Transplantation in Cases of Immunoglobulin D Multiple Myeloma in Korea. Acta Haematol. 2018;139(3):185-192 Authors: Kang J, Hong JY, Yoon DH, Kim S, Lee KM, Park JS, Park CJ, Min WK, Seo EJ, Jang S, Suh C Abstract BACKGROUND: Immunoglobulin D multiple myeloma (IgD MM) is characterized by a poor prognosis. Data are lacking on the survival benefits associated with the use of novel agents followed by autologous stem cell transplantation (ASCT) in IgD MM patients. We evaluated the clinical outcomes of induction treatment with novel agents followed by ASCT. METHODS: This was a single-center, retrospective study of 22 IgD MM patients who underwent ASCT between 1995 and 2016. Of these, 10 (45.4%) received novel agents and 12 (54.6%) received nonnovel agents. Clinical features and survival outcomes were examined. RESULTS: Median overall survival (OS) was 37.7 months in the 22 patients. Those in the novel-agents group received bortezomib or thalidomide-based regimens, whereas 91.7% of the nonnovel-agents group received a vincristine-based regimen. The median progression-free survival and OS in the novel-agent/nonnovel-agent groups were 8.3/7.4 and 38.6/12.5 months, respectively. The median OS of patients receiving maintenance therapy was not reached. CONCLUSION: This study showed improved survival outcomes compared to our previous study (37.7 vs. 12 months), suggesting that the use of a novel agent as induction and maintenance therapy may be beneficial in patients with IgD MM who undergo ASCT. PMID: 29635247 [PubMed - indexed for MEDLINE]
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Related Articles Tolerability and efficacy of deferasirox in patients with transfusional iron overload: results from a German 2-year non-interventional study. J Cancer Res Clin Oncol. 2018 Aug;144(8):1531-1538 Authors: Nolte F, Nückel H, Schmidt B, Geer T, Rubanov O, Hebart H, Jarisch A, Albrecht S, Johr C, Schumann C, Hofmann WK Abstract BACKGROUND: Iron overload (IOL) due to repetitive transfusions of packed red blood cells (pRBC) has a major impact on morbidity and mortality in patients with inherited bone marrow failure syndromes and hemoglobinopathies such as thalassemia and sickle cell disease. However, whether IOL influences the outcome of elderly patients with myeloid malignancies is not yet clear. Moreover, clinical trials have reported high drop-out rates during treatment with the oral iron chelator deferasirox (DFX). AIM: Here we report the results of a 2-year prospective observational study that aimed at describing the routine use of DFX in patients with hematological malignancies with regard to safety, efficacy and handling of the drug in a routine setting. RESULTS: A total of 406 patients were included. 58% of the patients were male. Most of the patients had myelodysplastic syndromes (MDS) (68%) and myeloproliferative neoplasms (MPN) (14%). Median time from first transfusion to study enrollment was 1.1 years (0-25.5 years) and most patients were chelation naive (91%) at enrollment. With regard to transfusion burden, most of the patients were moderately or mildly transfusion-dependent with 53% receiving 2-4 and 27% receiving less than 2 units of pRBC per month. Serum ferritin decreased from a mean of 2305 μg/l (± 1449 μg/l) to a mean of 1910 μg/l (± 1529 μg/l) at 24 months. There was no substantial change in transfusion-dependence during the observation period. Dose adjustments were reported in 48% of the patients with dose-escalation strategies being the most frequent reason for dosage increases (49%). The median observation time was 355 days (5-1080 days). Median duration of exposure to DFX was 322 days (2-1078 days). Two-hundred and ninety (72%) patients discontinued the trial prematurely after a median time of 235 days (1-808 days). Death (29%) and adverse events (23%) were the main reasons for discontinuation. Eleven percent of the patients discontinued treatment due to sufficient decrease in serum ferritin. Most frequent adverse events were decrease in creatinine clearance (22%), increase in serum creatinine (18%) and diarrhea (16%). CONCLUSION: This descriptive trial confirms the efficacy of DFX in decreasing the serum ferritin. Moreover, the high drop-out rates seen in prospective trials are recapitulated in this study, which can be attributed to adverse events in a substantial proportion of patients. PMID: 29761371 [PubMed - indexed for MEDLINE]
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Related Articles Blast Percentage of Bone Marrow Aspirate on Day 14 of Induction Chemotherapy Predicts Adult Acute Lymphoblastic Leukemia Treatment Outcomes. Acta Haematol. 2018;139(4):220-227 Authors: Park HS, Kim DY, Choi EJ, Lee JH, Lee JH, Jeon M, Kang YA, Lee YS, Seol M, Cho YU, Jang S, Chi HS, Lee KH, Park CJ Abstract The prognosis of adult acute lymphoblastic leukemia is much worse than that of pediatric acute lymphoblastic leukemia, even when patients achieve complete remission. Early response to treatment can be an important alternative indicator of treatment outcomes. The purpose of our current study was to identify the prognostic value of the blast percentage of the induction interim bone marrow, which might predict relapse-free survival and overall survival in patients with adult acute lymphoblastic leukemia. A retrospective analysis was performed on 80 adult patients diagnosed with Philadelphia chromosome-negative acute lymphoblastic leukemia from 1994 to 2011. Complete remission was observed in 75 (93.8%) patients after induction chemotherapy. On multivariate analysis, a reduction of blasts to a level of 5% or less in the induction interim bone marrow and CD20 positivity were significant prognostic predictors of relapse-free survival (hazard ratio, HR = 2.88, p = 0.006, and HR = 2.67, p = 0.010) and overall survival (HR = 2.10, p = 0.033, and HR = 2.39, p = 0.013). The blast percentage of the induction interim bone marrow may be a useful prognostic factor to predict outcome. PMID: 29860259 [PubMed - indexed for MEDLINE]
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Related Articles NSG-S mice for acute myeloid leukemia, yes. For myelodysplastic syndrome, no. Haematologica. 2018 06;103(6):921-923 Authors: Griessinger E, Andreeff M PMID: 29866886 [PubMed - indexed for MEDLINE]
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Related Articles Lmo2 expression defines tumor cell identity during T-cell leukemogenesis. EMBO J. 2018 07 13;37(14): Authors: García-Ramírez I, Bhatia S, Rodríguez-Hernández G, González-Herrero I, Walter C, González de Tena-Dávila S, Parvin S, Haas O, Woessmann W, Stanulla M, Schrappe M, Dugas M, Natkunam Y, Orfao A, Domínguez V, Pintado B, Blanco O, Alonso-López D, De Las Rivas J, Martín-Lorenzo A, Jiménez R, García Criado FJ, García Cenador MB, Lossos IS, Vicente-Dueñas C, Borkhardt A, Hauer J, Sánchez-García I Abstract The impact of LMO2 expression on cell lineage decisions during T-cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T-cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stem/progenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human-like T-ALL In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stem/progenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction of T-ALL The resulting T-ALLs lacked LMO2 and its target-gene expression, and histologically, transcriptionally, and genetically similar to human LMO2-driven T-ALL We next found that during T-ALL development, secondary genomic alterations take place within the thymus. However, the permissiveness for development of T-ALL seems to be associated with wider windows of differentiation than previously appreciated. Restricted Cre-mediated activation of Lmo2 at different stages of B-cell development induces systematically and unexpectedly T-ALL that closely resembled those of their natural counterparts. Together, these results provide a novel paradigm for the generation of tumor T cells through reprogramming in vivo and could be relevant to improve the response of T-ALL to current therapies. PMID: 29880602 [PubMed - indexed for MEDLINE]
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Related Articles CD56 Expression Is an Important Prognostic Factor in Multiple Myeloma Even with Bortezomib Induction. Acta Haematol. 2018;139(4):228-234 Authors: Skerget M, Skopec B, Zadnik V, Zontar D, Podgornik H, Rebersek K, Furlan T, Cernelc P Abstract OBJECTIVES: In this retrospective study, we evaluated the impact of CD56, CD117, and CD28 expression on clinical characteristics and survival in newly diagnosed myeloma patients treated with bortezomib-based induction therapy. METHODS: We analyzed 110 myeloma patients. Immunophenotype was determined using panels consisting of CD19/CD38/CD45/CD56/CD138 and CD20, CD28, and CD117 were used additionally. All samples were tested for recurrent chromosomal aberrations. RESULTS: CD56, CD117, and CD28 expression rates were 71, 6, and 68%, respectively. The lack of CD56 expression was associated with light chain myeloma. The lack of CD117 expression was associated with elevated creatinine levels (p = 0.037). We discovered the correlation between CD 28 expression and female gender. The median progression-free survival (PFS) for patients with revised International Staging System stage 2 disease with CD56 expression or the lack of CD56 expression was 20.5 vs. 13.8 months (p = 0.03). In patients undergoing autologous hematopoietic stem cell transplantation (aHSCT), we found no difference in PFS and overall survival regarding the CD56 expression. We found no impact of CD117 and CD28 expression on PFS in patients regarding aHSCT. CONCLUSIONS: Induction treatment incorporating bortezomib diminishes the negative impact of the lack of CD117 expression and aberrancy of CD28 but does not overcome the negative impact of the lack of CD56 expression. PMID: 29920491 [PubMed - indexed for MEDLINE]
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Related Articles Early-stage melanoma and hematopoietic stem cell transplantation outcomes. J Am Acad Dermatol. 2019 Mar;80(3):786-788 Authors: Puza CJ, Mosca PJ, Cardones AR PMID: 30025826 [PubMed - indexed for MEDLINE]
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Related Articles Implementing and sustaining an evidence-based nutrition service in a haematology unit for autologous stem cell transplant patients. Support Care Cancer. 2019 Mar;27(3):951-958 Authors: Atkins L, Steer B, Ray H, Kiss N Abstract PURPOSE: Effective, timely and evidence-based nutritional management is important in patients receiving autologous haematopoietic stem cell transplant (HSCT) to prevent the negative consequences of developing malnutrition. This study describes a robust process for development and implementation of an evidence-based nutrition care pathway for HSCT patients in a tertiary cancer centre. METHODS: A comprehensive review of the literature was completed to identify relevant articles and evidence-based guidelines to inform the development of the pathway. Evidence from the literature review was assessed and utilised to underpin the development of pathway. The pathway was implemented in the haematology service in collaboration with the multidisciplinary haematology team. Dietetic resource requirements for implementation of the pathway were determined and clinician compliance with the care pathway was assessed to evaluate the feasibility of the pathway in supporting delivery of evidence-based care. RESULTS: The evidence-based care pathway was implemented in 2011 with the final care pathway based on recommendations from five international evidence-based guidelines. Overall clinician compliance with delivering nutrition management described in the care pathway was high at 84%. The dietetic resource requirement for implementation of the care pathway was 300 to 400 h per 100 patients depending on conditioning chemotherapy regimen. CONCLUSION: A robust process for developing and implementing a nutrition care pathway for HSCT patients was effective in supporting the delivery of evidence-based nutritional management for patients treated with HSCT. PMID: 30073411 [PubMed - indexed for MEDLINE]
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Related Articles Retrospective study of the digestive tract mucositis derived from myeloablative and non-myeloablative/reduced-intensity conditionings with busulfan in hematopoietic cell transplantation patient. Support Care Cancer. 2019 Mar;27(3):839-848 Authors: Eduardo FP, Bezinelli LM, Gobbi M, Rosin FCP, Carvalho DLC, Ferreira MH, da Silva CC, Hamerschlak N, Corrêa L Abstract Busulfan is a major component of chemotherapy conditioning in hematopoietic cell transplantation (HCT). This alkylating agent is highly toxic at myeloablative doses, exposing HCT patients to risks of mortality. Non-myeloablative (NMA) and reduced-intensity conditioning (RIC) using busulfan have shown impaired toxicity. However, the toxicity of NMA/RIC in the digestive tract is poorly described. This study aimed to characterize the mucositis in the oral cavity (OM), oropharynx/esophagus, and gastrointestinal tract derived from conditionings with myeloablative and non-myeloablative doses of busulfan. We retrospectively retrieved clinical data of HCT patients (n = 100) who underwent myeloablative conditioning (MAC) or NMA/RIC with busulfan. Frequency and time duration of mucositis in the oral cavity and oropharynx/esophagus, diarrhea, and prescription of total parenteral nutrition (TPN) and opioids were also collected. OM severity (p = 0.009) and time duration of mucositis in oropharynx/esophagus (p = 0.022) were frequently higher in MAC than NMA/RIC. A myeloablative dose of busulfan was a risk factor for OM grade ≥ 2 (OR = 4.8, p = 0.002) and for mucositis in oropharynx/esophagus ≥ 5 days (OR = 2.64, p = 0.035). A longer duration of mucositis in the oropharynx/esophagus was also associated with an increase in the prescription of opioids (OR = 7.10, p < 0.001).Overall survival (OS) in MAC was significantly higher than that in NMA/RIC (p = 0.017). No variables related to mucositis interfere significantly in OS. In conclusion, myelosuppression in busulfan-based regimens are predisposed to a high risk for severe OM and to prolonged mucositis in the oropharynx/esophagus. PMID: 30109488 [PubMed - indexed for MEDLINE]
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Related Articles Gemcitabine, cisplatin, and dexamethasone (GDP) in combination with methotrexate and pegaspargase is active in newly diagnosed peripheral T cell lymphoma patients: a phase 2, single-center, open-label study in China. Ann Hematol. 2019 Jan;98(1):143-150 Authors: Zhang Y, Zhang W, Li J, Duan M, Han B, Zhu T, Zhuang J, Cai H, Cao X, Chen M, Zhou D Abstract Peripheral T cell lymphomas (PTCL) are less responsive to anthracycline-containing regimen such as CHOP and carry a poor prognosis. In this prospective study, we investigated gemcitabine, cisplatin, and dexamethasone (GDP) combined with methotrexate (MTX) and pegaspargase (PEG-L) as front-line treatment in PTCL. Eligible newly diagnosed PTCL patients received 4 cycles of the GDP-ML chemotherapy every 28 days. After 4 cycles, responding patients continued to receive either autologous stem cell transplantation or the MTX/cytarabine (MA) regimen for consolidation. This trial is registered with www.chictr.org.cn (ChiCTR-ONC-12002055). A total of 65 patients were enrolled with a median follow-up of 38.5 months. The overall response rate (ORR) was 55.4%, and complete remission rate (CR) was 33.8%. The median overall survival (OS) was 16 months, and the 1-year and 2-year OS were 59.1% and 38.2%, respectively. The median PFS was only 8 months. The main adverse event was hematologic toxicity: 50% patients showed grade III/IV neutropenia. GDP-ML for the first-line treatment of PTCL patients is an effective induction regimen compared with standard CHOP, and the toxicity was more significant but acceptable. However, future studies exploring new drug combinations are warranted to overcome relapse after remission. ClinicalTrials.gov Identifier: NCT02987244. PMID: 30209556 [PubMed - indexed for MEDLINE]
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Related Articles Vitamin E-based redox-sensitive salinomycin prodrug-nanosystem with paclitaxel loaded for cancer targeted and combined chemotherapy. Colloids Surf B Biointerfaces. 2018 Dec 01;172:506-516 Authors: Liang DS, Liu J, Peng TX, Peng H, Guo F, Zhong HJ Abstract Cancer stem cells (CSCs) can resist conventional chemotherapy to lead to cancer recurrence. For complete eradication of cancers, an effective CSCs therapeutic strategy should be developed to combine with conventional chemotherapy. In this work, a novel vitamin E-based redox-sensitive salinomycin (SAL, an inhibitor for CSCs) prodrug nanoparticles (TS NPs) and hyaluronic acid (HA)-coated TS NPs (HTS NPs) were fabricated to deliver paclitaxel (PTX) for cancer-targeted and combined chemotherapy. Both TS and HTS prodrug NPs had mean diameter of about 200 nm with uniform size distribution, excellent drug loading capacity for PTX, and glutathione-triggered SAL and PTX release profiles. The HTS prodrug NPs had enhanced cellular uptake efficiency over TS NPs due to CD44 receptor-mediated endocytosis, hence exerting stronger potency of SAL upon CSCs-enriched mammospheres formation and G0/G1 cell phase arresting. Cytotoxicity and 3D tumor spheroids assays demonstrated that both TS and HTS prodrug NPs themself can synergize with loaded PTX to maximize the chemotherapeutic effect. Obviously, the latter demonstrated a more potent anticancer efficacy due to improved intracellular drug delivery efficiency. These results suggested that the designed TS prodrug NPs, especially the coated HTS NPs can serve as an effective anti-CSCs strategy for cancer targeted and combination treatments. PMID: 30212688 [PubMed - indexed for MEDLINE]
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Related Articles VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy. Diabetes. 2019 01;68(1):172-187 Authors: Onions KL, Gamez M, Buckner NR, Baker SL, Betteridge KB, Desideri S, Dallyn BP, Ramnath RD, Neal CR, Farmer LK, Mathieson PW, Gnudi L, Alitalo K, Bates DO, Salmon AHJ, Welsh GI, Satchell SC, Foster RR Abstract Elevated levels of vascular endothelial growth factor (VEGF) A are thought to cause glomerular endothelial cell (GEnC) dysfunction and albuminuria in diabetic nephropathy. We hypothesized that VEGFC could counteract these effects of VEGFA to protect the glomerular filtration barrier and reduce albuminuria. Isolated glomeruli were stimulated ex vivo with VEGFC, which reduced VEGFA- and type 2 diabetes-induced glomerular albumin solute permeability (Ps'alb). VEGFC had no detrimental effect on glomerular function in vivo when overexpression was induced locally in podocytes (podVEGFC) in otherwise healthy mice. Further, these mice had reduced glomerular VEGFA mRNA expression, yet increased glomerular VEGF receptor heterodimerization, indicating differential signaling by VEGFC. In a model of type 1 diabetes, the induction of podVEGFC overexpression reduced the development of hypertrophy, albuminuria, loss of GEnC fenestrations and protected against altered VEGF receptor expression. In addition, VEGFC protected against raised Ps'alb by endothelial glycocalyx disruption in glomeruli. In summary, VEGFC reduced the development of diabetic nephropathy, prevented VEGF receptor alterations in the diabetic glomerulus, and promoted both glomerular protection and endothelial barrier function. These important findings highlight a novel pathway for future investigation in the treatment of diabetic nephropathy. PMID: 30389746 [PubMed - indexed for MEDLINE]
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Related Articles Role of vitamin D and vitamin D receptor (VDR) in oral cancer. Biomed Pharmacother. 2019 Jan;109:391-401 Authors: Fathi N, Ahmadian E, Shahi S, Roshangar L, Khan H, Kouhsoltani M, Maleki Dizaj S, Sharifi S Abstract Oral cancer is known as one of the most common cancers, with a poor prognosis, related to delayed clinical diagnosis, either due to the lack of particular biomarkers related to the disease or costly therapeutic alternatives. Vitamin D executes its functions by interacting with the vitamin D receptor (VDR), both in healthy and diseased individuals, including oral cancer. This review discusses the role of vitamin D and VDR on tumorigenesis, emphasizing on oral cancer. Furthermore, regulation of VDR expression, mechanisms of anticancer effects of calcitriol, oral cancer chemoresistance and its relation with VDR and polymorphisms of VDR gene will be discussed. The manuscript is prepared mainly using the information collected from PubMed and MEDLINE. PMID: 30399574 [PubMed - indexed for MEDLINE]
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Related Articles Vascular density and inflammatory infiltrate in primary oral squamous cell carcinoma and after allogeneic hematopoietic stem cell transplantation. Ann Hematol. 2019 Apr;98(4):979-986 Authors: Tamma R, Limongelli L, Maiorano E, Pastore D, Cascardi E, Tempesta A, Carluccio P, Mastropasqua MG, Capodiferro S, Covelli C, Pentenero M, Annese T, Favia G, Specchia G, Ribatti D Abstract Hematopoietic stem cell transplantation (HSCT) recipients have been reported to have an increased risk of chronic graft versus host disease (cGVHD) and hematological and solid cancers. Oral manifestations are the first signs of cGVHD observed in the majority of patients, and oropharyngeal cancer is the most frequent secondary malignancy occurred after HSCT. In this study, we have evaluated the inflammatory infiltrate cell content and correlated with the vascular density in patients affected by primary oral squamous cell carcinoma (OSCC) from previous healthy controls and OSCC after cGVHD. Results have demonstrated that patients with OSCC after GVHD show a more consistent inflammatory infiltrate as compared with the OSCC ones. In detail, the inflammatory background composed of CD3-positive T cells, tryptase-positive mast cells, CD31-positive endothelial cells, and CD68-positive macrophages may be more pronounced in the setting of GVHD + OSCC than in the control group. By contrast, CD20-positive B cells and CD1a-positive dendritic cells were more abundant in the latter population. Finally, a positive correlation was found as between vascular density and inflammatory cell infiltration in both GVHD + OSCC and OSCC groups. Overall, these results confirm the role played by immune cells in enhancing tumor progression and angiogenesis and suggest a potential therapeutic strategy involving inhibition of recruitment of immune cells to the tumor microenvironment and blockade of pro-tumoral effects and pro-angiogenic functions. PMID: 30519712 [PubMed - indexed for MEDLINE]
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Related Articles (R)-GEMOX chemotherapy for unfit patients with refractory or recurrent primary central nervous system lymphoma: a LOC study. Ann Hematol. 2019 Apr;98(4):915-922 Authors: Collignon A, Houillier C, Ahle G, Chinot O, Choquet S, Schmitt A, Agape P, Soussain C, Hoang-Xuan K, Tabouret E Abstract Recurrent primary central nervous system lymphomas (PCNSL) have a very poor prognosis. For young and fit patients, intensive chemotherapy followed by autologous stem cell transplantation could be proposed at relapse. In the other cases (unfit or elderly patients), therapeutic options are limited with no consensual regimen. The poly-chemotherapy by (R)-GEMOX is associated with anti-tumor activity in systemic lymphomas and a favorable toxicity profile. Our objective was to evaluate the activity and tolerance of (R)-GEMOX in PCNSL patients enrolled in the French nation-wide LOC cohort. We retrospectively analyzed all refractory or recurrent patients included in the LOC network who benefited from (R)-GEMOX (rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatine 100 mg/m2). Administration, tolerance, and efficacy data were analyzed. Thirteen patients, treated in five different institutions, benefited from the (R)-GEMOX regimen from February 2013 to August 2017. At the initiation of (R)-GEMOX, median age was 71.4 years old (range, 49.5-82.5) and median Karnofsky performance status (KPS) was 60 (range, 40-80). Seven patients were in second line of treatment whereas the six others were in third line or over. All patients had received methotrexate-based polychemotherapy as first-line treatment except one. Overall response rate was 38% with two complete responses and three partial responses. Median progression-free survival was 3.2 months (95%CI: 0.2-6.2), and median overall survival was 8.2 months (95%CI: 0.6-15.8). Toxicity was mainly hematological including grade ¾ neutropenia (38%), lymphopenia (23%), and thrombopenia (23%). Older age (p = 0.046) and low KPS (p = 0.054) tended to be associated with a worse prognosis. (R)-GEMOX is associated with substantial response rate and favorable toxicity profile in unfit patients with recurrent PCNSL. (R)-GEMOX could be considered to be an additional option in patients with recurrent/refractory PCNSL. PMID: 30535802 [PubMed - indexed for MEDLINE]
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Related Articles Cyclosporine levels > 195 μg/L on day 10 post-transplant was associated with significantly reduced acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Ann Hematol. 2019 Apr;98(4):971-977 Authors: Bianchi M, Heim D, Lengerke C, Halter J, Gerull S, Kleber M, Tsakiris DA, Passweg J, Tzankov A, Medinger M Abstract Acute graft-versus-host disease (aGvHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Prophylaxis with cyclosporine A (CsA) is the backbone of GvHD prevention. In a retrospective analysis of patients treated with allo-HSCT, we correlated CsA levels on the day of transplantation (day 0) and on day + 10 with the incidence of acute and chronic GvHD. We assessed 660 patients with either AML n = 248, lymphoma/myeloma n = 127, MDS/MPN n = 124, ALL n = 79, CLL n = 36, CML n = 23, or bone marrow failure n = 22. In patients with clinically relevant aGvHD grade ≥ 2, mean CsA levels was lower on day 0 and day + 10 (142 ± 88 μg/L and 183 ± 64 μg/L, respectively) compared to patients without aGvHD (156 ± 81 μg/L and 207 ± 67 μg/L, respectively; day 0: p = 0.003; day + 10: p = 7.57 × 10-9). In patients with CsA level < 200 μg/L, the incidence of aGvHD was significantly more frequent compared to patients with CsA levels > 200 μg/L [(234/356 (66%) versus 91/248 (37%); p = 1.34 × 10-12]. In patients with cGvHD, there was no significant difference between CsA levels < 200 μg/L (128/330) compared to CsA levels > 200 μg/L (96/233; p = 0.312). The optimal CsA cutoff level for the prevention (i.e., roughly 50% incidence reduction) of aGvHD was > 201 μg/L at day 0 and > 195 μg/L at day + 10. In a competing risk analysis, time to aGvHD grade ≥ 2 (using death of other causes as competing risk) was associated with CsA levels > 200 μg/L on day 0 and on day 10, unrelated donors, myeloablative conditioning (MAC), and for the diagnosis lymphoma/myeloma. Our data support close monitoring with active adjustments of CsA dosing to maintain therapeutic CsA levels above 195 μg/L in the first 10 days of allo-HCST to reduce aGvHD. PMID: 30542943 [PubMed - indexed for MEDLINE]
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Related Articles Prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan and stem cell transplantation: review of the evidence and suggestions. Support Care Cancer. 2019 Mar;27(3):793-803 Authors: Tendas A, Marchesi F, Mengarelli A, Annibali O, Tomarchio V, Saltarelli D, Chierichini A, Di Venanzio M, Sollazzo F, Piedimonte M, Cupelli L, Bruno A, De Angelis G, Delbono L, Niscola P, Perrotti AP, de Fabritiis P, Arcese W, Rome Transplant Network Abstract INTRODUCTION: High-dose melphalan (HDMel) is the most common conditioning chemotherapy regimen for autologous stem cell transplantation (SCT) in patients affected by multiple myeloma (MM). No consensus exists for the emetogenicity or prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in this regimen. METHODS: Data on the incidence and efficacy/safety of CINV prophylaxis among patients affected by MM undergoing autologous SCT with the HDMel regimen was extracted from electronic databases and analyzed. RESULTS: Eleven studies involving multiple CINV prophylaxis regimens were identified and included. No consensus on HDMel emetogenicity was reached, but most studies summarized the emetogenicity as moderate-high risk. An aprepitant-based three-drug regimen (aprepitant + serotonin receptor antagonist (5HT3RA) + dexamethasone) showed better efficacy than a two-drug regimen (5HT3RA + dexamethasone) for CINV prevention without increasing the frequency in adverse events. CONCLUSIONS: The aprepitant-based three-drug regimen should be the regimen of choice for CINV prophylaxis for MM patients undergoing autologous SCT with HDMel conditioning. PMID: 30564934 [PubMed - indexed for MEDLINE]
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Related Articles Allogeneic hematopoietic stem cells transplantation improves the survival of intermediate-risk acute myeloid leukemia patients aged less than 60 years. Ann Hematol. 2019 Apr;98(4):997-1007 Authors: Zhang Y, Zhang Y, Chen Q, Tang G, Zhang W, Yang J, Wang J, Hu X Abstract The prognosis of acute myeloid leukemia (AML) with normal karyotype is further determined by specific genetic alterations. The optimal post-remission therapy (PRT) in younger patients within this group after first complete remission (CR1) remains to be determined. We report a retrospective evaluation of PRT approaches in 223 patients under the age of 60 years old with intermediate-risk AML in CR1. Patients receiving allogenic hematopoietic stem cell transplantation (alloHSCT) obtained improved overall survival (OS) than patients who treated with chemotherapy (5-year 61.6 ± 5.2% versus 41.1 ± 5.3%, p = 0.004). AlloHSCT led to fewer cases of relapse (hazard ratio [HR] 0.14, p < 0.001) and increased the relapse-free survival (RFS, HR 0.45, p < 0.001). With alloHSCT, the outcome of patients who reached negative minimal residual disease after 2 cycles of consolidation could be further improved with an increased OS of 66% and RFS of 61%. Nucleophosmin-1 (NPM1) mutation negative, CCAAT/enhancer binding protein alpha (CEBPA) double mutation negative, and FLT-3 internal tandem duplication negative (NPM1mut-negCEBPAdm-negFLT3-ITDneg) patients had a significantly longer RFS with alloHSCT. In conclusion, our results provide additional evidence that alloHSCT is preferential PRT in patients with intermediate-risk AML that are under the age of 60 years old in CR1. PMID: 30607578 [PubMed - indexed for MEDLINE]
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Related Articles Cytomegalovirus infection is associated with AML relapse after allo-HSCT: a meta-analysis of observational studies. Ann Hematol. 2019 Apr;98(4):1009-1020 Authors: Zhang YL, Zhu Y, Xiao Q, Wang L, Liu L, Luo XH Abstract Cytomegalovirus (CMV) infection and primary disease relapse remain challenging problems after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We sought to assess the association between CMV infection and disease relapse after transplantation. PubMed, EMBASE, the Cochrane Library, SCI, and Chinese Biomedicine Databases were searched up to July 1, 2018, for all studies that investigate pre-transplant CMV serostatus, CMV replication, and primary disease relapse in allo-HSCT patients with hematologic malignancies. Meta-analysis of 24 eligible cohort studies showed a significantly lower relapse risk after allo-HSCT in patients with CMV replication in acute myeloid leukemia (AML) (HR = 0.64, 95% CI, 0.50-0.83; P < 0.001) subgroup. However, CMV replication was associated with increased non-relapse mortality (NRM) in AML patients (HR = 1.64, 95% CI, 1.46-1.85; P < 0.001), but not associated with overall survival (OS) or graft-versus-host disease for AML patients (P > 0.05). There was no association between pre-transplant CMV serostatus and disease relapse, although D-/R- was associated with better OS in acute leukemia patients (HR = 0.89, 95% CI, 0.83-0.96; P = 0.003). In AML patients, CMV replication may be a protective predictor against disease relapse, although the potential benefit of CMV replication is offset by increased NRM. PMID: 30666434 [PubMed - indexed for MEDLINE]
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Related Articles High-dose etoposide could discriminate the benefit from autologous peripheral blood stem cell transplantation in the patients with refractory diffuse large B cell lymphoma. Ann Hematol. 2019 Apr;98(4):823-831 Authors: Cai Y, Wan L, Yang J, Zhu J, Jiang J, Li S, Song X, Wang C Abstract To evaluate the strategy of using high-dose etoposide mobilization followed by autologous peripheral blood stem cell transplantation (APBSCT) in patients with diffuse large B cell lymphoma (DLBCL) refractory to rituximab-based chemotherapy. Forty patients with refractory DLBCL were treated with high-dose etoposide for stem cell mobilization. All patients were in progressive disease (PD) prior to mobilization and underwent high-dose chemotherapy followed by APBSCT. Successful PBSC mobilization was achieved in all patients. Twenty-three patients (57.5%) showed a clinical response to high-dose etoposide. After APBSCT, 17 patients (42.5%) achieved CR. The 2-year progression-free (PFS) and overall survival (OS) rate were higher in patients responding to high-dose etoposide (64.1% and 77.7%) compared to those without response (11.8% and 11.8%; P < 0.001 for both). The response to high-dose etoposide mobilization therapy was an independent prognostic factor for CR achievement, PFS and OS after APBSCT. High-dose etoposide mobilization chemotherapy followed by APBSCT could rescue a proportion of patients with refractory DLBCL who responded to etoposide mobilization regimen. PMID: 30715566 [PubMed - indexed for MEDLINE]
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Related Articles Targeting Glioma Stem Cells by Functional Inhibition of Dynamin 2: A Novel Treatment Strategy for Glioblastoma. Cancer Invest. 2019 Mar 25;:1-12 Authors: Luwor R, Morokoff AP, Amiridis S, D'Abaco G, Paradiso L, Stylli SS, Nguyen HPT, Tarleton M, Young KA, O'Brien TJ, Robinson PJ, Chircop M, McCluskey A, Jones NC Abstract Glioma stem cells (GSCs) play major roles in drug resistance, tumour maintenance and recurrence of glioblastoma. We investigated inhibition of the GTPase dynamin 2 as a therapy for glioblastoma. Glioma cell lines and patient-derived GSCs were treated with dynamin inhibitors, Dynole 34-2 and CyDyn 4-36. We studied about cell viability, and GSC neurosphere formation in vitro and orthotopic tumour growth in vivo. Dynamin inhibition reduced glioblastoma cell line viability and suppressed neurosphere formation and migration of GSCs. Tumour growth was reduced by CyDyn 4-36 treatment. Dynamin 2 inhibition therefore represents a novel approach for stem cell-directed Glioblastoma therapy. PMID: 30907150 [PubMed - as supplied by publisher]
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Related Articles Guidelines for Cervical Cancer Screening in Immunosuppressed Women Without HIV Infection. J Low Genit Tract Dis. 2019 Apr;23(2):87-101 Authors: Moscicki AB, Flowers L, Huchko MJ, Long ME, MacLaughlin KL, Murphy J, Spiryda LB, Gold MA Abstract EXECUTIVE SUMMARY: The risk of cervical cancer (CC) among women immunosuppressed for a variety of reasons is well documented in the literature. Although there is improved organ function, quality of life and life expectancy gained through use of immunosuppressant therapy, there may be increased long-term risk of cervical neoplasia and cancer and the need for more intense screening, surveillance, and management. Although guidance for CC screening among HIV-infected women (see Table 1) has been supported by evidence from retrospective and prospective studies, recommendations for CC screening among non-HIV immunosuppressed women remains limited because quality evidence is lacking. Moreover, CC screening guidelines for HIV-infected women have changed because better treatments evolved and resulted in longer life expectancy.The objective of this report was to summarize current knowledge of CC, squamous intraepithelial lesions, and human papillomavirus (HPV) infection in non-HIV immunocompromised women to determine best practices for CC surveillance in this population and provide recommendations for screening. We evaluated those with solid organ transplant, hematopoietic stem cell transplant, and a number of autoimmune diseases.A panel of health care professionals involved in CC research and care was assembled to review and discuss existing literature on the subject and come to conclusions about screening based on available evidence and expert opinion. Literature searches were performed using key words such as CC, cervical dysplasia/squamous intraepithelial lesion, HPV, and type of immunosuppression resulting in an initial group of 346 articles. Additional publications were identified from review of citations in these articles. All generated abstracts were reviewed to identify relevant articles. Articles published within 10 years were considered priority for review. Reviews of the literature were summarized with relevant statistical comparisons. Recommendations for screening generated from each group were largely based on expert opinion. Adherence to screening, health benefits and risks, and available clinical expertise were all considered in formulating the recommendations to the degree that information was available. RESULTS: Solid Organ Transplant: Evidence specific for renal, heart/lung, liver, and pancreas transplants show a consistent increase in risk of cervical neoplasia and invasive CC, demonstrating the importance of long-term surveillance and treatment. Reports demonstrate continued risk long after transplantation, emphasizing the need for screening throughout a woman's lifetime.Hematopoietic Stem Cell Transplant: Although there is some evidence for an increase in CC in large cohort studies of these patients, conflicting results may reflect that many patients did not survive long enough to evaluate the incidence of slow-growing or delayed-onset cancers. Furthermore, history of cervical screening or previous hysterectomy was not included in registry study analysis, possibly leading to underestimation of CC incidence rates.Genital or chronic graft versus host disease is associated with an increase in high-grade cervical neoplasia and posttransplant HPV positivity.Inflammatory Bowel Disease: There is no strong evidence to support that inflammatory bowel disease alone increases cervical neoplasia or cancer risk. In contrast, immunosuppressant therapy does seem to increase the risk, although results of observational studies are conflicting regarding which type of immunosuppressant medication increases risk. Moreover, misclassification of cases may underestimate CC risk in this population. Recently published preventive care guidelines for women with inflammatory bowel disease taking immunosuppressive therapy recommend a need for continued long-term CC screening.Systemic Lupus Erythematosus and Rheumatoid Arthritis: The risk of cervical high-grade neoplasia and cancer was higher among women with systemic lupus erythematosus than those with rheumatoid arthritis (RA), although studies were limited by size, inclusion of women with low-grade neoplasia in main outcomes, and variability of disease severity or exposure to immunosuppressants. In studies designed to look specifically at immunosuppressant use, however, there did seem to be an increase in risk, identified mostly in women with RA. Although the strength of the evidence is limited, the increase in risk is consistent across studies.Type 1 DM: There is a paucity of evidence-based reports associating type 1 DM with an increased risk of cervical neoplasia and cancer. RECOMMENDATIONS: The panel proposed that CC screening guidelines for non-HIV immunocompromised women follow either the (1) guidelines for the general population or (2) current center for disease control guidelines for HIV-infected women. The following are the summaries for each group reviewed, and more details are noted in accompanying table:Solid Organ Transplant: The transplant population reflects a greater risk of CC than the general population and guidelines for HIV-infected women are a reasonable approach for screening and surveillance.Hematopoietic Stem Cell Transplant: These women have a greater risk of CC than the general population and guidelines for HIV-infected women are a reasonable approach for screening. A new diagnosis of genital or chronic graft versus host disease in a woman post-stem cell transplant results in a greater risk of CC than in the general population and should result in more intensive screening and surveillance.Inflammatory Bowel Disease: Women with inflammatory bowel disease being treated with immunosuppressive drugs are at greater risk of cervical neoplasia and cancer than the general population and guidelines for HIV-infected women are a reasonable approach for screening and surveillance. Those women with inflammatory bowel disease not on immunosuppressive therapy are not at an increased risk and should follow screening guidelines for the general population.Systemic Lupus Erythematosus and Rheumatoid Arthritis: All women with systemic lupus erythematosus, whether on immunosuppressant therapy or not and those women with RA on immunosuppressant therapy have a greater risk of cervical neoplasia and cancer than the general population and should follow CC screening guidelines for HIV-infected women. Women with RA not on immunosuppressant therapy should follow CC screening guidelines for the general population.Type 1 Diabetes Mellitus: Because of a lack of evidence of increased risk of cervical neoplasia and cancer among women with type 1 DM, these women should follow the screening guidelines for the general population. PMID: 30907775 [PubMed - in process]
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