bluuebunny/crossref_metadata_2025 huggingface dataset:
Graft Versus Host Disease after Granulocyte Infusion.
Authors: Barrenetxea Cristina , Zuazu Francisco J. , Bueno Javier , Julia Antonio , Diaz Jose L.
Published: October 2019

INTRODUCTION

Graft versus host disease (GVHD) occurs when immunologycally competent cells are introduced into an immunoincompetent host. GVHD refers to both the immunologic insult and the consequences to the organism. The leading cause of GVHD is hematopoietic cell transplantation (HCT), other causes like solid organ transplants, blood transfusions, and maternal-fetal transfusions also reportedly cause GVHD.

CASE

We present a 33 years old man, who was diagnosed in October 1997 of acute myeloid leukemia, treated with idarrubicin, etoposid and citarabine (IDICE), with complete remission; after that he received intensification treatment with mitoxanthrone and citarabine, and consolidation with an allogeneic HSCT from a sibling donor.

The chimerism was 100% of the donor since first month.

There wasn’t any important complications after HSCT; except a GVHD skin, resolved with corticoids.

Seven years after HCST, in November 2004, a routine control detected donor’s chimerism 34% with a medullar relapse. Leukemia characteristics were the same than the initials, and a new treatment with IDICE was administrated, showing no response, therefore, a second cycle was administrated.

One week after the first treatment fever appeared, which persisted besides large spectre antibiotics, so empiric antifungal treatment was added. Two months after the relapse the patient remained febrile, and skin lesions appeared in head, arms, legs, abdomen and oral mucosa. A biopsy was performed and diagnosed with Fusarium sp.

The neutropenia persisted, and the overall status was worsening, so we decided donor granulocyte infusions from two HLA identical sisters; ten days later, neutropenia disappeared, the bone marrow hadn’t blastic cells, and chimerism was 100% donor. A month later, new skin lesions appeared, the biopsy confirmed GVHD and severe liver affectation was also demonstrated by biopsy. It was treated with corticoids and cyclosporine, with rapid resolution.

The patient left hospital, and until now chimerism remains 100% donor with complete remission, without treatment for GVHD.

CONCLUSION: Graft versus Host disease is usually presented after hematopoietic stem cells infusion but other causes are been reported as lymphocytes infusion, where is not a rare event, and in other cases as granulocytes infusion as in our patient.

GVHD after granulocyte infusion is not a common complication even though it has to be taken in mind in patients that show skin or liver affectation after infusion.
Impact of Occult Hepatitis B Virus Infection in Hematopoietic Stem Cell Transplantation.
Authors: Chen Po-Min , Hsiao Liang-Tsai
Published: October 2019

Using sensitive PCR assays, lower titers of hepatitis B virus (HBV) DNA has been detected in surface antigen (HBsAg)-negative patients, i.e., occult HBV infection, especially for those from HBV-endemic area. The pathogenic role of occult HBV infection has been studied in patients with HIV and HCV infection; however, its impact on hematopoietic stem cell transplantation (HSCT) is not understood at present. To examine the prevalence of occult HBV infection and resulting hepatic events through the course of HSCT, allogeneic HSCT recipients (and their donors) who were negative to HCV infection and HBsAg-negative before transplantation and had an at least 12 months of follow-up after transplantation were enrolled for the study, with serial follow up of serum HBV-DNA, HBV serology, and liver function tests through the course of HSCT. Nested PCR with 3 independent sets of primers were used to detect pre-S/S, precore/core and X viral regions of HBV as previously described, and those reactive by at least two of the three PCR assays were considered to have occult HBV infected. The impact of pre-transplant occult HBV infection was evaluated in terms of post-transplant HBV infection after transplantation. Between 1995 and 2004, 60 HBsAg-negative pairs of allogeneic HSCT recipients and donors were enrolled, with the characteristics of recipients: median age of 30 years (9–59), F/M=20/40, diagnosis including 18 AML, 12 ALL, 18 CML, 4 NHL and 8 SAA, graft including 28 BM and 32 PBSC, and preparative regimens including 44 myeloablative (BUCY and CYTBI) and 16 nonmyeloablative (fludarabine, busulfan and ATG). At transplant, total 6 recipients (10%, 6/60) and 2 donors (3%, 2/60) in different transplant pairs were found to occult HBV infection as defined. With a median follow up of 28 months (from 12.5 to 72 months) after transplantation, three of those 6 recipients with pre-transplant occult HBV infection (of whom all their donors had no occult HBV infection) had HBsAg appearance after transplantation. Importantly, for those two HSCT in which only donors were found to have occult HBV infection, occult HBV was only transiently detected in their recipients immediately after transplantation with a paralleled and transient elevation of quantitative serum HBV-DNA, but there was no HBsAg appearance. For the other recipients who did not have pre-transplant occult HBV infection, three also had HBsAg appearance. In conclusion, the impact of occult HBV infection on HSCT is mainly derived from those existed in the recipients rather than those from the donors.
Cryptogenic Organizing Pneumonia Following Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Jinta Minako , Ohashi Kazuteru , Sakurai Chihiro , Nashima Yuho , Tsuji Masanori , Harada Kyoichi , Sakai Miwa , Yamashita Takuya , Akiyama Hideki , Sakamaki Hisashi
Published: October 2019

Although encouraging survival statistics are now reported after hematopoietic stem cell transplantation (HSCT), pulmonary complications occur in up-to half of patients after HSCT and are major causes of morbidity and mortality. In this study, we describe cryptogenic organizing pneumonia (COP) after allogeneic HSCT in our institution between January 1986 and December 2005. Charts and chest radiographs of 601 transplant recipients were retrospectively reviewed for COP. Total 12 cases of COP were observed (2.0%) at a median interval of 148 days after HSCT (range, 53–475 days). They presented low-grade fever, non-productive cough and dyspnea at the onset of COP. The initial antibiotics treatment did not ameliorate these symptoms, but all patients well responded to 0.5–1mg/kg of prednisolone. However, in 9 out of 12 patients, COP eventually flared-up after the tapering-off of steroid, but responded to the retreatment. Although 3 patients died, there was no death due to pulmonary failure and 5-year survival was 74.1%. In remaining 9 patients, there was no relapse of primary disease for which the patient underwent HSCT. The clinical features of 12 patients were similar in that they all received an irradiation containing conditioning and most patients had a history of acute graft-versus-host disease (GVHD). Furthermore, 8 patients had active chronic GVHD (6 extensive and 2 limited) at the onset of COP. These findings suggest that both the irradiation and allogeneic immune reaction may play a crucial role in the development of COP after HSCT. Moreover, the patients with COP might enjoy a relatively good prognosis due to low rate of relapse of primary disease through graft-versus-leukemia reaction, even though facing multiple episodes of disease exacerbation of COP.
Eight Cases of Leukemia Treated with HLA Haploidentical Related Bone Marrow Transplantation and Chinese Herbal Medicine.
Authors: Zhou Yuhong , Yu Rongxi , Ye Baodong , Lin Shengyun , Zheng Zhiyin , Luo Xiusu , Shen Jianping , Hu Zhiping , Cheng Junfa
Published: October 2019

Objective: To explore the feasibility of Chinese herbal medicine in haploidentical related allogeneic bone marrow transplantation (Allo-BMT) without T-cell depletion for the treatment of leukemia.

Methods: From 2003 to 2005, four patients with CML and four patients with AML received allo-BMT with grafts from 1 or 3 HLA antigen mismatched related donors. All patients were preconditioned with high dose Ara-c, cyclophosphamide (CY)and total body irradiation (TBI) or Busulfan (Bu). Donors were given G-CSF 250μg/d for seven days prior to marrow harvest. GVHD prevention regimen consisted of CSA, MTX, ATG, MMF and CD25-mab. Chinese herbal medicine was given orally to all patients after transplantation according to the theory (syndrome differentiation) of Traditional Chinese Medicine (TCM). One or 2 weeks after transplantation, TCM were given with the purpose to increase Qi and cultivate Yin, strengthen the function of Spleen and Stomach. At the time of bone marrow convalescence, about 1 month post transplantation, different TCM was prescribed for increasing Qi, cultivating Blood, strengthening the function of Kidney, and fasting distillation.

Results: All patients were successfully engrafted. The median days of granulocyte >0.5×109/L and platelet >20×109/L were 12 (10–14) and 20(18–25) days, respectively. Seven patients developed grade I-IVGVHD, with two of them advanced to grade IV gut and liver GVHD and died of concurrent infection eventually. Two patients developed hemorrhagic cystitis. Six patients were alive in a disease-free situation after median following-up of 20 (6–36) months.

Conclusion: The major histoincompatibility barriers in the haploidentical related donor/recipient allo-BMT could be successfully carried out with G-CSF stimulated donor bone marrow combined with GVHD preservation and Chinese Herbal Medicine. Our patients were treated with TCM to regulate immunity immediately after clearing out of their bong marrow; With this remedy method, we improved the curative effect of bone marrow transplant and this deserves further study with a well designed clinical trial.
Allogeneic Hematopoietic Stem Cell Transplantation in T-Cell Non-Hodgkin Lymphoma.
Authors: Dulley Frederico L. , Sturaro Daniel , Ruiz Milton A. , Chiattone Carlos , Saboya Rosaura , Barros Jose C. , Sarmento-Neto Jose P. , Amigo-Filho Jose U. , Piron-Ruiz Lilian , Pereira Juliana , Chamone Dalton A.F.
Published: October 2019

T-cell non-Hodgkin Lymphoma (T-NHL) are uncommon malignancies that represent approximately 10% of all NHL. With few exceptions T-NHL have generally been reported to have a worse prognosis compared with B-cell lymphomas. Standard therapy for most T-NHL still need to be defined. To elucidate the feasibility and efficacy, we retrospectively analysed the data of 11 patients who underwent allogeneic hematopoietic stem cell transplantation from July 1991 to july 2006. Five female and five male patients with a matched sibling donor and a female mismatched underwent a transplant. The median age was 22 years (16 – 34). Six patients were diagnosed as lymphoblastic T, two were anaplastic large cell, two were peripheral T-cell unspecified and one was NK/T extranodal nasal-type. One was in first hard remission, three in second remission, one in third complete remission, one in early first relapse, one in second partial remission and four had refractory disease. Six patients were conditioned with TBI + cyclophosphamide (CY-TBI) and five with busulfan 16 mg/kg and melphalan 140 mg/sqm (Bu-Mel). Graft versus host disease (GVHD) prophylaxis was done with cyclosporin and short course methotrexate for most of the cases. 63 % had acute GVHD grade I to III and 45% had chronic GVHD. Overall survival is 36%. Four of the 11 patients are alive, still in complete remission, after one year, 12 years, 14 years, and 15 years from transplantation. Two of these patients were conditioned with CY-TBI and two with Bu-Mel. Allogeneic transplant can be useful to treat advanced T-NHL patients.
A Distinct Pattern of Non-HLA Polymorphisms Predicts an Increased Risk for GvHD without Benefit of GvL in HLA Matched Sibling Transplants for Chronic Myeloid Leukemia (CML).
Authors: Dickinson Anne M. , Pearce Kim F. , Norden Jean , Neylor A. , Holler Ernst , Rocha Vanderson , Gluckman Eliane , Kolb Hans-Jochem , Hromadnikova Ilona , Sedlacek Petr , Niederwieser Dietger W. , Brand Ronald , Ruutu Tapani , Apperley Jane , Goulmy E.A.J.M. , Olavarria Eduardo , de Witte T.M. , Roosnek Eddy , Siegert Wolfgang , Gratwohl Alois
Published: October 2019

Non-HLA polymorphisms (NHP) influence risk of GVHD and outcome of allogeneic hematopoietic stem cell transplants (HSCT) however their influence on GvHD vs GvL remains to be defined. A cohort of 291 CML HLA matched sibling transplants with known clinical risk factors; eg stage of disease, gender mismatch (female donor/male recipient), patient age and time from diagnosis to transplant as defined by the EBMT risk score, were typed via SNPs or microsatellites for cytokines (IL-1Ra, IL-4, IL-6, IL-10, IFNγ, TNFα, TNFR 11), steroid hormone receptors (VDR and ERα) and NOD2/CARD15 mutations. TNFRII-196 allele R; IL-10 ATC/ACC; IL-1 Ra (allele 2) and IL-4T were significantly associated with survival using univariate analysis. Two clinical Cox proportional hazards models were generated for the statistical analysis and used as a basis for further development: (i) using the EBMT risk score as a single variable on an ordinal scale or (ii) using the individual clinical factors of the EBMT risk score as categorical variables. After step-wise variable selection using the significant genetic factors as candidates, the resulting multivariate models indicated that absence of TNFRII-196 R, i.e. down regulation of TNF in the recipient, absence of IL-10 ATC/ACC, i.e. intermediate IL-10 production in the donor and presence of IL-1Ra (allele 2) i.e. down regulation of IL-1 in the donor were associated with poor outcome. The addition of the genetic variables significantly improved the preferred model containing the EBMT risk score as a single variable. The Goodness of Fit of the models was assessed by Kaplan-Meier curves showing clinically relevant differences between good, intermediate and poor prognostic groups. The worst prognostic scores included the absence of ATA/ACC in the donor, evidenced by a steep change in survival probability. Relapse was associated with clinical factors; absence of female to male transplants; absence of bone marrow transplants and presence of T cell depletion but no significant association was found with genetic factors. This study suggests that distinct high risk patterns of NHP of patients and donors can be defined, which influences survival due to factors associated with an increased risk of GvHD without the potential benefit of increased GvL response. Data add to the clinical factors (eg age, sex, multiparity of the donor) where an unrelated donor might be the preferred choice compared to a high risk sibling donor.
The Serum M-Spike and Transplant Outcome in Patients with Multiple Myeloma.
Authors: Dingli David , Pacheco Jorge M. , Dispenzieri Angela , Hayman Suzanne R. , Kumar Shaji , Lacy Martha , Gastineau Dennis A. , Gertz Morie Abraham
Published: October 2019

Background: High dose therapy with autologous stem cell transplantation (HDT-ASCT) has prolonged survival in patients with multiple myeloma. Patients who achieve a complete response (CR) benefit the most from this form of therapy. Thus, achieving a CR is an important goal of therapy and it will be beneficial if the probability of achieving CR can be determined for any patient before transplant.

Patients and Methods: A large cohort of patients with myeloma who received HDT-ASCT at Mayo Clinic Rochester was studied. The impact of various demographic, clinical and laboratory characteristics relating to the patients and their disease acquired were studied for their impact on response to HDT-ASCT, especially CR. Patients with a serum M-protein <0.1g/dL were excluded. Response definitions were as defined by established criteria. Survival analysis was performed according to the Kaplan-Meier method while univariate and multivariate analyses were performed with the proportional hazards method. We utilized knowledge of the rate of M-protein production by myeloma cells together with the clearance of the protein to estimate the pre-transplant disease burden.

Results: We studied 224 patients with a median age of 56.5 years (32.6 – 71). Patients were transplanted a median of 8.7 months after diagnosis. Almost all patients had a response to HDT-ASCT and 78 (35%) achieved a CR. Those patients who achieved a CR had a longer time to progression (TTP) compared to those who did not achieve CR (Figure 1). The cohort was thus divided into two groups: patients who achieved CR and those that did not. The clinical and laboratory characteristics of the two groups were compared. Among the pre-transplant parameters tested, only the size of the serum M-spike was a predictor for CR (p<0.0001). A simple function that describes the probability of achieving CR based on the serum M-spike before HDT-ASCT is described. The estimated rate of tumor re-growth after HDT-ASCT in patients who obtain a CR and in patients who only get a partial response are presented.

Conclusions: The pre-transplant disease burden in myeloma is the main determinant of response to HDT-ASCT. The individual probability of achieving CR can be estimated from simple clinical parameters providing a quantitative risk assessment prior to such a high-risk procedure. There is significant expansion of myeloma cells after HDT-ASCT. The design of clinical trials may benefit from knowledge of the kinetic aspects of the disease.

Figure Figure
Initial Identification of a Mouse Human Factor IX-Specific CD8+ T-Cell Epitope.
Authors: Hoffman Brad E. , Herzog Roland W.
Published: October 2019

A significant complication associated with treatment of inherited protein deficiencies, such as hemophilia B, by gene replacement therapy is the potential for the activation of transgene specific B and T cells to the therapeutic protein, coagulation factor IX (F.IX). In addition to the potential for inhibitor formation as a result of MHC class II antigen presentation (CD4+ T cell-dependent activation of B cells, which may also be observed in conventional protein-based therapy), gene expression may lead to MHC class I presentation of F.IX-derived peptides to CD8+ T cells. Upon in vivo gene transfer, such immune responses to may elicit a cytotoxic T lymphocyte (CTL) response capable of destroying target cells that express the F.IX transgene product. Therefore, to better understand the role of F.IX-specific CD8+ T-cell responses, it is essential that MHC I-restricted CD8 T-cell epitopes be identified. Here, we used a peptide library consisting of 82 individual 15-mer peptides overlapping by ten residues that spans the complete human F.IX (hF.IX) protein to preliminarily identify a specific immunodominate CD8+ T-cell epitope. The peptides were pooled into groups, each containing 8–11 peptides to create a matrix of 18 pools, with each peptide represented in two pools. C3H/HeJ were immunized with 5×1010 vector genomes of E1/E3-deleted adenovirus expressing hF.IX (Ad-hF.IX) via intramuscular injection into the quadriceps. Nine days later, the harvested spleen and popliteal lymph node cells were pooled and evaluated for CD8+ T-cell responses by intracellular cytokine staining for IFN-γ after being stimulated for 5h with peptides or controls. The frequency of IFN-γ producing hF.IX-specific CD8+ T-cells was determined by flow cytometry. While 16 pools from Ad-hF.IX immunized C3H/HeJ mice showed no response above the frequency of mock-stimulated cells, lymphocytes from two overlapping pools demonstrated a ~2.5-fold increase in frequency of CD8+ IFN-γ+ cells. From these results we can conclude that peptide 74 (SGGPHVTEVEGTSFL) contains a CD8+ T cell epitope for C3H/HeJ mice (H-2k haplotype). Furthermore, splenocytes from naive mice failed to respond to any of the peptide pools. The amino acid sequence corresponding to peptide 74 is located within the catalytic domain of hF.IX. This finding is of particular interest, in that, we previously reported a peptide containing the immunodominate CD4+ T-cell epitope in C3H/HeJ is also located within the catalytic domain of hF.IX (Blood 108:408). The definitive identification of hF.IX-specific CD8+ epitopes will facilitate the evaluation of experimental gene therapy strategies in murine models by providing a reagent for in vitro stimulation of F.IX specific CD8+ lymphocytes. For example, we can now determine the efficiency of CD8+ T cell activation as a function of vector, route, and dose following in vivo gene transfer.
Psychosocial Impairment and Lower Quality of Life among Childhood Cancer Survivors in Egypt, Single Institution Experince.
Authors: Elsamahy Mona , Abdelmonem Ashraf , Abdelrahman Shahinda
Published: October 2019

Survival itself has, until recently, been the marker of successful cancer therapy, but now more attention is being focused on the long-term effects of cancer therapy and the quality of life (QOL)of the survivors.

OBJECTIVE: To assess health related quality of life and behavior and emotional problems among childhood cancer survivors at Ain Shams Pediatric Oncology Clinic, Cairo, Egypt.

DESIGN: This study was conducted on 30 childhood cancer survivors attending the cancer survivors’ clinic at Ain Sham Children’s University Hospital in the period of October 2004–April 2005. The PedsQL™ 4.0 Generic Core Scales (physical, emotional, social and, school functioning) translated into Arabic language has been utilized. Parallel child self-report and parent proxy-report questionnaire formats have been used. Items were reverse-scored and linearly transformed to a 0–100 scale, so that higher scores indicate better QOL. Assessment of behavioral and emotional disturbance was performed using The Child Behavior Checklist (CBCL)

Results: Age range 6–16 years with a mean age of 10.7±2.9 years, 18 (60%) were males and 12(40%) were females. Seventeen patients (56.6%) were acute leukemia survivors and 10(43.4%) lymphomas and solid tumors. There was statistically significant (p<0.001) decrease in the overall generic PedsQL in cancer survivors (mean 67±11.6) compared to normal children (mean 83.9±12.5) with school functioning area being the most affected (score 47.5±13). ALL survivors had significantly lower mean QOL (62.5±11.8) compared to other cancer survivors (72.8±8.8) (p<0.05). Gender (females) and CNS-directed therapy were risk factors for poorer QOL. Strong agreement between parents and their children QOL rating was seen in most of the QOL domains {overall QOL (p=0.001) physical well being (p=0.04), emotional feelings (p=0.0004), and social interaction (p=0.003) with the strongest correlation in the school domain (p=0.000004)}. Fifty three percent of the survivors showed clinical range of social incompetence with survivors who were diagnosed before the age of 3 were less socially competent than those who were diagnosed after this age (p<0.05), 63% expressed Internalizing behavioral problems and while 23% had Externalizing problems.

CONCLUSION: This results demonstrate Chidhood cancer survivors are at significant risk of poor psychosocial functioning and QOL.
Internet Use by Patients with Lymphoma and Caregivers.
Authors: Garcia-Nieto Antonia A. , Duran Soledad S. , Fernandez-Valle Maria Carmen M.C. , Rios Eduardo E. , Rodriguez Juan Nicolas J.N. , Martin-Reina Maria Vicencia M.V. , Duran Jose J. , Bailen Alicia A. , Lopez Pilar P. , Almagro Manuel M. , Capote Francisco Javier F.J.
Published: October 2019

The Internet is changing the way that people learn about health and illness. At present do not exist data of the use of Internet by patients of lymphoma and her caregivers in Spain.

OBJECTIVE: To investigate the distribution and patterns of Internet use by patients with lymphoma and her caregivers.

PATIENTS AND METHODS: 585 subjects (258 patients, 264 relatives and 63 health professionals), 228 male and 357 female, they have responded a questionnaire on diverse aspects of the use of Internet.

RESULTS: Two hundred fifty (42,7%) subjects use Internet, although only 27% make to obtain data on lymphoma. With respect to the group of patients 31% recognize to use Internet, but only the 23,3% do it by questions related to their disease. The main reasons for Internet use are to obtain information about treatments (74.7%) or second opinion medical (9.3%). The 77,6% have been using Internet for more than 3 years; the 47,2% have university studies and the 58,4% have between 33–50 years. Mainly the information search is made in Spanish language and through the Google finder. They consider that Information on lymphoma is acceptable (44.9%) or of enough quality (43.7%), trustworthy (50.6%) or of enough reliability (33.5%) and useful (45.6%) or quite useful (37.3%).

COMMENTARIES: This study contributes data on the use of Internet by patients with lymphoma and her caregivers in Spain. Oncologists should be familiar with this important resource to help patients access appropriate material.
Therapeutic Dilemma of Chemotherapy Dosing in Morbidly Obese Patient with AML: A Case Report and a Review of the Literature.
Authors: Hussain Sakeer , Glass Jonathan , Ballester Oscar
Published: October 2019

Obesity is a common and increasing problem affecting the developed world. There is no consensus on a standard approach to chemotherapy dosing has been adopted in obese patients. We present a 25 year old white male with worsening fatigue, dyspnea and recurrent cellulites. Physical examination was significant for morbid obesity of 616 lb (BMI 86.4 and BSA 3.43m2). Initial laboratory values were WBC 0.870/ml (3400–9200/ml), Hb 6.5g/dL (11.5–15.4g/dl), platelet count of 35,000/mm3 (130000–400000/mm3), MCV 91 mm3 (80–100mm3). Basic metabolic and coagulation panel was normal except elevated D-dimer and LDH. Peripheral smear consistent with hypochromic normocytic RBC, occasional schistocytes, premature myeloid cells, myeloid blasts 26% with granularity of cytoplasm and a few Auer rods were evident. Bone marrow biopsy was consistent with acute myeloid leukemia. Flowcytometry was positive for CD33, CD 38 and myeloperoxidase. Lymphoid antigens were negative. Cytogenetic analysis revealed normal karyotype and negative for t (15; 17). Patient was treated with standard induction regimen with cytarabine 243mg (100mg/m2) and daunorubicin 109mg (45mg/m2). Chemotherapy dosing was done according to the adjusted body weight (BSA 2.43 m2). Day 14 bone marrow was consistent with significant disease. Reinduction with high dose cytarabine 14000mg (3000mg/m2) had no response. Patient was then received gemtuzumab ozagomycin 22mg (9mg/m2) on day 1 and 14. Bone marrow analysis 30 days after the treatment was consistent with remission. Interestingly patient developed little adverse effect from the initial induction chemotherapy. Hospital course was complicated with Clostridium difficile colitis and neutropenic fever which was treated with antibiotics and voricanazole. Voricanazole dosing was done according to the actual body weight (1000mg IV twice daily). The peak and trough levels were within normal range. Failed response to initial induction treatment could be due to refractory disease or inadequate dosing of chemotherapy in this patient. BSA has been used to calculate the dose in anticancer therapy since 1950s. Experimental studies have demonstrated BSA based dosing failed to standardize the variation in pharmacokinetics of cytotoxic drugs. In obese cancer patients, the pharmacokinetics of the drug demonstrated a prolonged elimination time for several agents. Risk of both under dosing and overdosing can have detrimental affect outcome in obese patients. Prospective studies of chemotherapy pharmacokinetics are needed to address the issue of optimal chemotherapy dosing in obese population.
Can Exposure to Jet Fumes Lead to Acute Leukemia?.
Authors: Khalil Maged F. , Sangal Ashish , Arora Alka , Niak Seema , He Zili , Steier William , Kalavar Madhumati
Published: October 2019

Introduction:

AML/MDS is usually diagnosed in older adults with median age of 64 in patients at time of diagnosis, after occupational exposure to organic solvents, such as benzene, or previous therapeutic exposure to alkylating agents, topoisomerase inhibitors, or ionizing radiation.

We are presenting a case of AML/MDS in a young female without previous history of exposure to alkylating agents or ionizing radiation, but with history of exposure to jet fumes.

Case Report:

This is a 30-year old Carribean woman, chronic smoker, ethanol user, employed for eight years at the airport, working on the ground with heavy direct exposure to jet fumes, who presented with 2 weeks of progressive dyspnea, fatigue and bone pains. She was found to have pancytopenia, hemoglobin 2.8 gm/dL, platelets 37,000/mL, and neutrophils 1100/mL. Peripheral smear showed many nucleated red blood cells and blasts. Bone marrow aspiration was “dry” and bone biopsy revealed hypercellularity with dysplastic changes in erythrocyte, granulocyte and megakaryocytic lineages with 46% blasts. Flow cytometry of peripheral blood showed positivity for CD13, CD33, CD34, and CD117 and HLA-DR with complex cytogenetics showing deletions involving chromosomes 5q, 7q, 12p, 20q and loss of chromosome 17. Fluorescent in situ hybridization (FISH) studies were negative for t(15,17), MLL, t(8,21), inv(16) seen in classical de novo AML. FISH also did not show abnormalities in the probe regions 5q31, 7q31, 8cen and 20q12 of chromosomes 5, 7, 8 and 20 classically seen in de novo MDS. The blast cell morphology suggested acute myelocytic leukemia on a background of myelodysplasia. Precise FAB subtype was not possible in the absence of special stains like myeloperoxidase, and specific and non-specific esterase stains. The patient was treated with two induction courses of cytosine arabinoside and idarubicin. With persistence of 4.5% blasts on the peripheral blood and severe bone marrow aplasia, she was referred for allogeneic stem cell transplantation, in view of failed induction remission and complex cytogenetics at presentation.

Conclusion:

Case-control studies of leukemia demonstrated only slight increase in risk of disease after many years of occupational or chemical exposures. More studies to investigate leukemia incidence in airport employees, or even communities near airports are needed.
Effect of Mild Hemophilia A on Quality of Life Using the SF-36.
Authors: Walsh Meghan C. , Macgregor David , Barrett Brendan , Stuckless Susan , Kawaja Marc , Scully Mary-Frances
Published: October 2019

Using a cross-sectional study design we determined the impact of mild hemophilia A on quality of life. Adult males (n=47) with the same mutation (Val2016ala) were compared to unaffected adult males (n=32). The Short Form-36 (SF-36) and the Health Assessment Questionnaire (HAQ) were used to measure quality of life and physical function. Measures included bleeding history, Body Mass Index (BMI), age, and viral status. Using the SF-36, mild hemophilia was found to be statistically and negatively associated with quality of life in both the general health scale (p<0.039) and role emotional (p<0.005) dimensions. Age (>40) was associated with lower quality of life in four of eight dimensions namely, physical functioning (p<0.023), bodily pain (p<0.049), general health scale (p<0.034) and role emotional (p<0.025). A positive viral status of hepatitis (HCV) was found to be negatively associated with bodily pain (p<0.044) in affected males. Finally, those who experienced bleeding episodes (>2 in previous 5 years) were also associated with lower quality of life in social functioning (p<0.02) and the health transition scale (p<0.043). Additionally, a greater than 5-point difference was found in affected males in five out of eight dimensions when compared to the Canadian male population. No significant differences were found between groups from the HAQ scores. Mild hemophilia A, age, bleeding frequency and a positive hepatitis status were found to negatively affect quality of life in our study.
Twenty Years of Follow-Up among Survivors of Childhood and Young Adult Acute Myeloid Leukemia (AML): A Report from the Childhood Cancer Survivor Study (CCSS).
Authors: Mulrooney Daniel A. , Dover Douglas C. , Yasui Yutaka , Ness Kirsten K. , Mertens Ann C. , Neglia Joseph P. , Sklar Charles A. , Robison Leslie L. , Davies Stella M.
Published: October 2019

Survival rates for childhood AML continue to improve. Limited data exist on the comprehensive assessment of late medical and social effects experienced by these aggressively treated individuals. This analysis includes 272 5-yr survivors of AML participating in the CCSS diagnosed ≤ age 21, between 1970–1986. AML survivors who received a blood or marrow transplant are excluded from the current analysis. Comparisons among treatment groups and to a sibling control group are age and gender adjusted. Survivors (55% female) were on average 7 yrs old at dx and 28 yrs at follow-up, 56% received chemotherapy only, 34% chemotherapy/RT. Average follow-up was 22.6 yrs (16.1–33.5). Among these 5-yr survivors, overall survival was 97% (95% CI, 94–98%) at 10 yrs and 94% (95% CI, 92–97%) at 20 yrs. Six individuals reported 8 recurrences a mean of 11.1 yrs (5.6–16.6) from diagnosis, 2 died from relapse, 1 from congestive heart failure (CHF), and 1 from a myocardial infarction (MI). All cause standardized mortality ratio was 4.7 (95% CI 2.8–7.5). Cumulative incidence of recurrent AML at 10 and 20 years was 1.8% (95% CI 0.2–3.4%) and 3.7% (95% CI 1.4–5.9%), respectively. Eight survivors reported 10 subsequent malignant neoplasms (SMN) (5 breast cancers, 3 CNS tumors, 1 ovarian tumor, 1 salivary gland tumor) a mean of 18.7 yrs (9.2–26.4) from diagnosis, 3 with a history of RT exposure. SMN cumulative incidence at 20 yrs was 1.6% (95% CI 0.02–3.3%) with a standardized incidence ratio of 3.2 (95% CI 1.4–6.0). Six cardiac events (5 CHF and 1 MI) occurred a mean of 16.4 yrs (12.8–18.4) from diagnosis, 20-yr cumulative incidence 2.4% (95% CI 0.5–4.4%). Among those aged 25 yrs or more, marriage rates were similar among AML survivors and the general U.S. population (59%), but lower compared to siblings (69%) (p<0.01). College graduation rates were lower among survivors compared to siblings, but higher than in the general population (42% vs. 52% vs. 34%, respectively, p<0.01). No significant difference in graduation rates was found among those treated with or without CNS directed RT (p=0.9). All survivors and siblings were employed (100%) and most had health insurance (93% vs. 90%). Long-term survival from childhood AML greater than 5 yrs from diagnosis is favorable. Late occurring medical events remain concerning. Marriage and education rates may be lower than expected within individual family units; yet not significantly different from the U.S. population.
In Chronic Lymphocytic Leukemia, Zap70 Identifies a Survival Pathway Signal Cascade Involving p85 PI-3-Kinase, CrkL, and Cbl with Syk En Route to JNK1 and bcl-2.
Authors: Hartman Amy D. , Wilson-Weekes Annique , Cripe Larry D. , Bennett Brydon , Friedman Glenn , Worland Peter , Druker Brian , Ren Shuyue , Skorski Tomasz , Boswell H. Scott
Published: October 2019

Bcl-2 expression is high in CLL and this appears to participate in disease progression. Zap70 expression is a poor prognostic marker for the disease whose function may be to contribute in a pathway promoting heightened bcl-2 levels. We recently identified a pathway to heightened bcl-2 transcriptional expression involving the bcl-2 promoter CRE (TGACGTCA) element and c-jun/ATF-2 downstream of JNK1. Indeed, JNK activation is a known survival pathway in B cell lymphoma (Gururajan, et al. Blood106: 1382, 2005). We confirmed a strict correspondence of Zap70 expression with JNK activity in CLL cell lysates by immunoblot identification of Zap70 and of phospho-S73-c-jun; and we found bcl-2 levels to be high in cells with Zap70 and JNK activity. We uncovered an adaptor/scaffolding pathway physically linking these mediators. By immunoprecipitation from lysates in a series of Zap70+ CLL’s we found JNK1 to coimmunoprecipitate with CrkL, a JNK1 scaffolding that binds by its SH3 domain to polyproline sequences of JNK1, and with p85 and Cbl and Zap70 as well as Syk. By contrast, using GST-p85 as bait in pull-down experiments, a selective interaction was found for Zap70 with p85, particularly of the p85 C-terminal SH2 domain, in lysates with heavy Y319 phosphorylation of Zap70. In parallel pull-downs with such lysates, exclusion of Cbl N-terminal TKB domain binding from Zap70 but not Syk was observed. Zap70+ CLL cell growth stimulated by the cytokine April was inhibited by the novel JNK inhibitor, CC-401, 5 uM, without significant effect on inhibition of NFkB or AKT activations. Such inhibition of JNK1 also led to upregulation of bim mRNA and downregulation of bcl-2 mRNA, and modest-to-moderate bcl-2 protein downregulation, in cells whose nuclear proteins contained abundant phospho-ATF2/c-jun binding activity for the bcl-2 promoter CRE site indicative of a transcriptional connection. Thus, Zap70 represents a point of origin in CLL cells for parallel pathways of Zap70 and Syk signaling to JNK1, involving specific complexes of Zap70 and Syk with p85/CrkL/JNK1(Cbl), respectively. These dual routes to JNK activation promote cell survival, in part, through the ability of JNK to contribute in a bcl-2 regulatory mechanism.
The IL-2 Induced De-Ubiquitinating Enzyme, DUB-2, Is a Nuclear-Cytoplasmic Shuttle Which Requires Catalytic Activity for Nuclear Localization.
Authors: Galardy Paul J. , D’Andrea Alan D. , Ploegh Hidde L.
Published: October 2019

DUB-2 is a T-cell specific de-ubiquitinating enzyme whose expression is induced by IL-2. Expression of DUB-2 results in prolonged STAT5 phosphorylation, enhanced IL-2 induced gene expression, and resistance to apoptosis resulting from cytokine withdrawal. The molecular basis of DUB-2s effects, however, is not understood. In order to better understand the role of DUB-2 in the IL-2 response, we performed a systematic analysis of DUB-2 catalytic activity, subcellular localization, and domain organization. Subcellular localization of DUB-2 was examined using a C-terminal DUB-2-Cherry (enhanced red fluorescence) fusion and live-cell imaging. When expressed in HeLa cells, wild-type DUB-2-Cherry is predominantly localized to the cytoplasm, although 8–10% of cells have a strong nuclear accumulation. Strikingly, the nuclear localization is entirely eliminated by a mutation in the catalytic cysteine (c60s). This effect on DUB-2s localization is not due to changes in cell cycle progression, as we observe identical cell cycle profiles (DNA content) in wt or c60s expressing cells. Conversely, enhanced DUB-2 nuclear localization is seen following nocodazole-induced cell cycle synchronization and with mutant DUB-2-Cherry fusions lacking a duplicated 8-residue sequence within the C-terminal domain.

We next analyzed the catalytic activity of DUB-2 toward ubiquitin and other ubiquitin-like (UbL) molecules using a series of semi-synthetic activity-based probes. These probes consist of full-length Ub or UbL molecules equipped with a C-terminal electrophilic group. These probes act as suicide substrates, forming a covalent bond with the active site cysteine of catalytically active (but not inactive) Ub(L) isopeptidases. Unexpectedly, DUB-2 forms adducts not only with the Ub-based probe, but also the probe derivative of the UbL molecule ISG15, which suggests that it has dual-specificity. The activity towards Ub and ISG15 is abrogated by a mutation in the catalytic cysteine (c60s) of DUB-2, but is not affected by deletions of the poly-lysine or hypervariable domains.

Taken together, these results suggest that DUB-2 is a bi-specific (Ub and ISG15) isopeptidase which shuttles between the cytoplasm and the nucleus in a manner dependent on its catalytic activity. This work, and the ultimate elucidation of the molecular target of DUB-2, will further increase our understanding of DUB-2’s role in IL-2-dependent T-cell proliferation and immunologic tolerance.
Effects of Renal Impairment on the Pharmacology of Rivaroxaban (BAY 59-7939) - An Oral, Direct, Factor Xa Inhibitor.
Authors: Halabi Atef , Maatouk Haidar , Klause Norbert , Lufft Volkmar , Kubitza Dagmar , Zuehlsdorf Michael , Becka Michael , Mueck Wolfgang , Schäfers Rafael , Wand Dominic , Philipp Thomas , Bruck Heike
Published: October 2019

Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. It has predictable pharmacokinetics and pharmacodynamics in healthy subjects. Approximately 30% of rivaroxaban is excreted unchanged in the urine; therefore, renal excretion is an important route of elimination. This multicenter study was performed to evaluate the effect of renal impairment on the tolerability, pharmacokinetics, and pharmacodynamics of a single oral 10 mg dose of rivaroxaban. Subjects (N=32) were allocated to one of four groups (matched by age and gender), based on calculated creatinine clearance (CrCL): ≥80 mL/min (control); 50–79 mL/min (mild impairment); 30–49 mL/min (moderate impairment); and <30 mL/min (severe impairment). Rivaroxaban was well tolerated; treatment-emergent adverse events occurred in 62.5% of control subjects, and 12.5%, 12.5%, and 37.5% of those with mild, moderate, and severe renal impairment, respectively. All adverse events were mild to moderate in severity, and resolved by the end of the study. Decreased CrCL led to increased rivaroxaban plasma concentrations: AUC was 44%, 52%, and 64% higher in subjects with mild, moderate, and severe renal impairment, respectively, compared with control subjects (p<0.05); Cmax was relatively unaffected, and tmax was delayed in subjects with CrCL <50 mL/min (3 hours vs 2 hours for control). Renal clearance of rivaroxaban decreased with decreasing renal function; 29% of rivaroxaban was excreted via the urine in control subjects, compared with 20%, 13%, and 10% in those with mild, moderate, and severe renal impairment, respectively. The pharmacodynamic effects of rivaroxaban (inhibition of FXa activity and prolongation of prothrombin time [PT]) were increased with decreasing renal function. The AUC for inhibition of FXa activity increased by 50% (mild impairment), 86% (moderate impairment), and 100% (severe impairment) (p<0.01; Pearson’s correlation coefficient −0.49), and the AUC for prolongation of PT increased by 33%, 116%, and 144%, respectively (p<0.001; correlation −0.56), compared with control. The maximum effects (Emax) of rivaroxaban on inhibition of FXa activity or prolongation of PT did not differ to a relevant extent among the different groups. In conclusion, rivaroxaban plasma concentrations and, as a result, inhibition of FXa activity and prolongation of PT, are inversely correlated with CrCL. In phase II clinical studies of rivaroxaban, patients with mild or moderate renal impairment were included without dose adjustment. However, whether dose adjustment is necessary in patients with renal impairment will require investigation in future clinical trials.
FCyIIIa Gene Polymorphisms as Response Predictor in Patients with Non-Hodgkin Lymphoma after Treatment with Anti-CD 20 Monoclonal Antibody (Rituximab).
Authors: Molnar Soledad , Nuñez Mariana , Rizzi Maria L. , Lavarda Marcelo , Balseiro Maria I. , Ryser Ricardo , Jarchum Gustavo
Published: October 2019

Background: The main mechanism of action of rituximab is through antibody-dependent cellular cytotoxicity via Fc receptors for immunoglobulin G. Recently a polymorphism of Fc was reported, which consists in the substitution of phenylalanine for valine in position 158. Patients with homozygous 158 valine/valine (V/V) alleles of Fc showed a higher response rate to rituximab treatment in contrast to patients with phenylalanine/valine (F/V) or homozygous phenilalanine (F/F). It would have clinical value to know which patients could have a greater benefit from the treatment with rituximab.

Aims: 1-to determine the Fc genotype in patients with Non-Hodgkin lymphoma (NHL) in our population. 2- to analyze the response rate to rituximab of these patients according to the Fc polymorphism.

Methods: DNA was isolated from peripheral blood. Genotyping of FCyIIIa polymorphism was performed using a polymerase chain reaction and were confirmed by direct sequencing of the region of interest. To analyse the results the patients were divided into two groups: with valine expression: V/V or V/F, and without valine expression F/F. The response was evaluated after 3 months of treatment and at the end of it. Chi-square and Fisher’s exact tests were used for statistical analysis.

Results: 34 patients with NHL: 19 follicular lymphoma, 12 diffuse large B-cell lymphoma, 3 mantle lymphoma. The FcyIIIa polymorphism expression was 11.8% V/V, 52.9% V/F and 35.3% F/F. The complete response (CR) after 3 months of treatment was 50% and 41.7% for V/V-V/F and F/F respectively (not statistically significant (ns)). After end of treatment CR was 86.7% in V/V-V/F and 72.7% in F/F(ns). In patients with follicular lymphoma the CR after end of treatment was 87.5% in V/V-V/F and 79% in F/F (ns). In patients with diffuse large B-cell lymphoma the CR was reached in all patients regardless of polymorphism.

Conclusions: FcyIIIa gene polymorphism did not help in predicting response after treatment with rituximab in our group of patients with NHL. A large number of patients would be necessary to draw conclusions, especially in the group with follicular lymphoma.
PTEN Regulates VEGF, VEGFR1 Expression and Its Clinical Significance in Myeloid Leukemia.
Authors: Cheng Zhiyong , Pan Lin , Guo Xiaoling , Zhang Xuejun , Wang Fuxu
Published: October 2019

Abstract 1001

Poster Board I-23

Phosphatase and tensin homology deleted on chromosome ten (PTEN) as a novel tumor suppressor gene, plays an important role in regulating proliferation, apoptosis, invasion and migration of many cancer cells. PTEN also modulates angiogenesis mediated by vascular endothelial growth factor (VEGF) via down-regulating the activity of PI3K/Akt pathway in many solid tumors. However, in myeloid leukemia, the effects of PTEN on VEGF and VEGFR1 (FLT1) mediated angiogenesis, migration, invasion of leukemia cells and its clinical significance are still unknown. Therefore, in the present study, we investigated the effect of PTEN on the activity of PI3K/Akt and VEGF/FLT1 pathways. Wild type PTEN gene was transfected into K562 cells, a cell line establish from a chronic myelogenous leukemia in blast crisis, to induce high expression of wild-type PTEN gene and protein by the cells. The correlation between the expression levels of PTEN and VEGF/FLT1 and its clinical significance in myeloid leukemia patients were also observed. We found that the expression reconstitution of wild-type PTEN had significance effect on inhibiting proliferation, migration and invasion ability of K562 cells via down-regulation of Akt phosphorylation and inhibition of VEGF/FLT1 expression. In myeloid leukemia patients, a negative correlation was found between the expression level of PTEN mRNA and that of VEGF and FLT1 mRNA. Low expression of PTEN mRNA and high expression of VEGF and FLT1 mRNA indicated a higher tendency of extramedullary disease in acute myeloid leukemia patients. Taken together, our findings indicated that PTEN could modulate the function of VEGF/VEGFR signaling pathway via down regulating Akt phosphorylation and that PTEN would be a candidate target for the treatment of myeloid leukemia.

Disclosures:

Pan: Nature science foundation of Hebei Province: Research Funding; Research Fund for the Doctoral Program of Higher Education of China: Research Funding; Emphases follow up pregram of Health Bureau of Hebei Province: Research Funding.