bluuebunny/crossref_metadata_2025_split huggingface dataset:
Minimal Residual Disease(MRD) in Childhood Acute Lymphoblastic Leukemia(ALL) in Relapse. A Children’s Oncology Group (COG) Study.
Authors: Borowitz Michael J. , Devidas Meenakshi , Hunger Stephen P. , Carroll William L. , Raetz Elizabeth 
Published: October 2019

Abstract
In spite of the excellent outcome of children with ALL, those who relapse fare poorly. To date, time to relapse is the most powerful predictor of outcome. Most studies indicate that children with early marrow relapse (ER), occurring within 36 months of diagnosis, have a long-term event-free survival (EFS) of 10–20%, while those with a late marrow relapse (LR) have an EFS of 40–45%. MRD, detected either by flow cytometry or polymerase chain reaction is an important prognostic factor in patients with newly diagnosed ALL, and recent studies indicate that it is prognostic of outcome following relapse. However studies in relapse are more limited and generally only one time point at end induction has been tested. COG AALL01P2 is a pilot study designed to administer three sequential blocks of intensive therapy to children and adolescents with first marrow relapse of ALL with the goal of improving remission rates and achieving a lower level of disease burden prior to post induction therapy such as bone marrow transplantation. We measured MRD in 52 patients on COG AALL01P2 by flow cytometry using the 4-color combinations CD20-FITC/CD10-PE-CD45-PerCP/CD19-APC; CD34/9/45/19; and CD38/58/45/19. We detected MRD in 35 patients (67%) after the first block, a much higher figure than the 28% seen at end induction in more than 2000 patients with newly diagnosed ALL, consistent with the poor prognosis of relapse patients. Of 32 ER patients, 26(81%) were MRD+ compared to only 45% (9/20) of LR patients (p<.01). Serial MRD samples measured after each block of therapy were collected in 32 patients, and several patterns of kinetic changes in MRD levels were noted. Twenty-two patients were classified as responders: 7 patients had no detectable disease at any time point(R1); 9 patients were initially MRD positive, but became negative(R2); and 6 additional patients showed at least a 1 log decrement in MRD(R3). No patient negative at any time point became positive at a later time point. Six patients had >1% MRD at all time points tested, while 4 patients with a level <1% on at least one timepoint had an increase of at least 1 log in MRD burden between 2 timepoints. All 10 of these latter patients were ER while all 7 R1 patients were LR. While it is too early to correlate MRD with EFS, our results show that the incidence of MRD is different in ER and LR patients in a pattern that correlates well with expected outcome. Serial measurements of MRD can be used to identify different patterns of treatment response and may be useful to dissect out effective components of therapy. Moreover, it may be possible to assess efficacy of novel agents added to this backbone of therapy by measuring changes in MRD response.
Unmutated Immunoglobulin Heavy Chain Variable Region Genes and Disease Progression Post Splenectomy Are Poor Prognostic Factors in Splenic Marginal Zone Lymphoma.
Authors: Oscier David Graham , Mould Sarah J. , Gardiner Anne C. , Glide Sharron , Parker Anton E. , Davis Zadie A. , Orchard Jenny A. 
Published: October 2019

Abstract
Splenic marginal zone lymphoma (SMZL) is generally an indolent disorder which has a median survival of 10 – 13 years, but a minority of patients pursue a more aggressive clinical course. A number of adverse prognostic factors including the level of haemoglobin, lymphocyte count and platelet count, B2 microglobulin, presence of a paraprotein, IgVH gene mutational status and p53 loss or mutation have been identified, but these have not been consistent among recent series. We have studied 89 patients with SMZL, diagnosed on the basis of lymphocyte morphology, immunophenotype and marrow and splenic histology, when available, and have evaluated the impact of presenting Hb, lymphocyte count, spleen size, presence of a paraprotein, cytogenetic abnormalities and IgVH gene mutational status on both the need for treatment and on overall survival. In 43 patients the diagnosis was made following a routine blood count performed for an incidental reason. The M:F ratio was 1:1.78, median age at presentation was 67.5 years (range; 49 – 91) and mean follow-up was 78.1 months. 63/89 (71%)patients presented with palpable splenomegaly, and a further 5 developed splenomegaly during the course of their disease. 42/89 (47%) patients required treatment of whom 29 (32%) underwent splenectomy. 36 patients have not required treatment, 25 have received an alkylating agent, 12 have received fludarabine and 4 were treated with rituximab.15/29 (17%) received chemotherapy for progressive disease post splenectomy. In six patients there was transformation to a high grade lymphoma. 14 patients (16%) died, 11 of whom had a disease-related death. 24/83 patients (29%) had a paraprotein, 67/87 (77%) had an abnormal karyotype of whom 39 (45%) had an abnormality of 7q. Using interphase FISH, 7/78((9%) showed trisomy 3 and 7/74(9%) had p53 loss. Of the patients with high grade transformation, 3/6 had p53 loss. 47/67 patients (70%) had mutated IgVH genes, and 15 cases utilised the VH1-02 gene segment. Only spleen size >10cm (p=0.0002) and Hb <100 gm/l (p=0.008) correlated with the need for treatment. Only unmutated IgVH genes (p=0.032) and the need for further therapy following initial treatment with splenectomy (p=0.034) correlated with overall survival.The median survival of unmutated cases was 113 months and was not reached for mutated cases.The median survival of patients for whom splenectomy has been their only treatment has not been reached, but was 110 months for patients requiring additional treatment post splenectomy. There is a need for larger, multi-centre studies to identify poor risk patients with SMZL.
Pre-Transplantation FDG-PET Is the Best Predictor for Outcome in Relapsed Lymphoma Patients Treated with Autologous Stem Cell Transplantation.
Authors: Schot Bart , Sluiter Wim , van Imhoff Gustaaf , Pruim Jan , de Brouwer Miryam , Verhoogt Carolien , Vaalburg Wim , Vellenga Edo 
Published: October 2019

Abstract
Intensive chemotherapy followed by autologous stem cell transplantation (ASCT) is the prefered treatment for young patients with chemosensitive relapsed aggressive lymphoma (NHL) and Hodgkin’s disease (HD). FDG-PET appears to be an excellent tool to evaluate chemosensitivity in lymphoma. In the present study we analyzed the predictive value for outcome of pre-transplantation PET as compared to initial prognostic factors at relapse.
Methods: Clinical and PET data from all consecutive patients with relapsed lymphoma (aggressive NHL and HD) were assessed. All patients were treated with DHAP-VIM-DHAP, followed by ASCT if responsive (at least PR based on CT after DHAP-VIM). Whole-body FDG-PET was performed after DHAP-VIM. Visual analysis was obtained in each scan and standardized uptake value (SUV) of the 3 most intense lesions in attenuation-corrected scans. Minimal follow-up after ASCT was 6 months. Predictive factors used were secondary age-adjusted IPI (sAAIPI) for NHL and secondary IPS (sIPS) for HD, duration of first remission and LDH at relapse. Univariate and multivariate Cox regression models and ROC analysis were used to assess predictive factors for relapse/progressive disease (PD) and Fisher’s exact test to assess relative risk.
Results: Between 1999 and 2003, 93 relapsed lymphoma patients were treated. 68/93 (73%) patients had responsive disease and ultimately 63/93 (68%) were transplanted. Post transplantation 36 (25 NHL and 11 HD) were in continued complete remission after a median follow up of 20 months.
PET was performed in 84 (63 NHL and 21 HD). All scans were used for visual assessment. SUV could be assessed in 70% of the scans. PET was positive in 76% and negative in 24% of the patients. Relapse/PD was observed in 44/64 (69%) PET-positive and only in 6/20 (30%) PET-negative patients (RR 5.1 (1.7–15.3), p=0.002).
SUV (p=0.001), sAAIPI/sIPS (p=0.023) and LDH (p=0.028) were predictive for outcome. In a multivariate Cox regression model adding separate parameters to SUV, no additional significant predictor was found. There was no difference between NHL and HD. ROC analysis showed a maximal predictive value at a SUV of 1.8 with a sensitivity and specificity of 0.66. A SUV ≥ 6.0 after DHAP-VIM was highly predictive for relapse/PD (spec. 0.95, sens. 0.27).
Conclusion: Pre-transplantation PET is the best predictor for outcome in patients with relapsed aggressive lymphoma as compared to other prognostic factors. Persisting lymphoma lesions on PET with a SUV ≥ 6.0 after reinduction chemotherapy predict progressive disease. Pre-transplantation PET may be helpful in the selection of patients for ASCT.
Fas or Fas Ligand Expression Can Determine the Clinical Outcome of Germinal Center Type in Diffuse Large B Cell Lymphoma.
Authors: Kojima Yasushi , Tsurumi Hisashi , Goto Naoe , Sawada Michio , Yamada Toshiki , Hara Takeshi , Takahashi Takeshi , Yamada Tetsuya , Saio Masanao , Tomita Eiichi , Takami Tsuyoshi , Moriwaki Hisataka 
Published: October 2019

Abstract
In recent years, diffuse large B cell lymphoma (DLBCL) has been classified by a cDNA microarray, an oligonucreotide microarray, or a tissue microarray. From the prognostic point of view, DLBCL consists of germinal center B-cell-like (GC) type, activated B-cell-like (ABC) type and type 3. ABC type and type 3 can be collectively categorized as non-GC (NGC) type. GC type has favorable prognosis compared with NGC type. Escape from apoptosis is considered to be an important mechanism for the progression of lymphoma. Fas is the major protein which leads to apoptosis by binding with Fas-ligand (FasL). We evaluated the prognostic significance of such markers as CD10, Bcl-6, MUM1, Fas and FasL, as well as GC or NGC type with paraffin embedded sections from 69 DLBCL patients immunohistochemicaly. The patients were 40 men and 29 women with median age of 67 years old (range, 20–82 years old). The median follow-up of surviving patients was 43 months. The 3-year OS for the entire group was 56%. There was no significant difference in sex, age, clinical stage, lactate dehydrogenase, or International Prognostic Index between GC and NGC type. Expression of CD10 was seen in 29% (20 of 69 of the patients), Bcl-6 in 27% (19 of 69), MUM1 in 27% (19 of 69), Fas in 51% (36 of 69), and FasL in 50% (35 of 69). We divided 69 DLBCLs to 26 GC type (CD10 positive or Bcl-6 positive and MUM1 negative) and 43 NGC type (the other). Positive CD10 was the best marker to indicate favorable overall survival (p=0.0156). GC type had tendency to have better overall survival than NGC type, though it was not significant (p=0.0723). Although Fas or FasL expression was not significant for overall survival in all DLBCL, it predicted significantly a longer over all survival (Fas; p=0.0021, FasL; p=0.0165) in GC type. These results may suggest that the presence of a subtype of DLBCL in which Fas/FasL system works effectively. This group is approximately 20% of DLBCL and mainly belongs to the GC type. Fas expression in GC type of DLBCL may predict the prognosis and be useful to choose the appropriate therapy. Furthermore, CD10 was more significant than GC type and, thus, we may need to build the strict consensus for GC type.
Low-Dose Recombinante Urate Oxidase (Rasburicase) Is Effective in Hyperuricemia.
Authors: Trifilio S. , Tallman M. , Singhal S. , Gordon L. , Evens A. , Mehta J. 
Published: October 2019

Abstract
Hyperuricemia is a feature of tumor lysis syndrome (TLS), and is treated with hydration, urine alkalinization, and allopurinol. Allopurinol inhibits the conversion of hypoxanthine to xanthine, and xanthine to uric acid (UA) by inhibiting xanthine oxidase. It has no direct effect on existing UA. Rasburicase lowers UA rapidly to very low levels at the labeled dose of 0.15–0.2 mg/kg daily for 5 days by converting UA to allantoin which is rapidly excreted. Despite this dramatic effect on UA, rasburicase has not been shown to have any beneficial impact on survival. We administered 0.2 mg/kg ideal body weight rasburicase to an obese hyperuricemic patient (actual 120 kg, ideal 60 kg). Serum UA declined from 11 mg/dL to 1.4 mg/dL in 3 h and 0.4 mg/dL in 11 h. The serum UA level remained low for several days and a second dose was not needed. After seeing this dramatic and sustained response, low rasburicase doses were used in patients with malignant diseases with close monitoring of biochemical parameters. No dose level was systematically explored and the doses used ranged from 1.5 mg to 12 mg. This analysis is a retrospective review of all patients who received low-dose rasburicase. 23 adults (39–78 y) with cancer and hyperuricemia received a single low dose of rasburicase at 12 mg (n=1; index case), 6 mg (n=2), 4.5 mg (n=1), 3 mg (n=18), and 1.5 mg (n=1). 6 patients received 1 and 1 patient received 2 more doses of 3 mg each. Allopurinol and other supportive therapy including hydration were administered. UA levels (baseline 7.4–19 mg/dL, median 11.6) declined by 4–96% (median 40%) within 24 h of rasburicase administration (Fig 1; the dashed lines show patients receiving more than 1 rasburicase dose).
Figure Figure
The decline was 31–68% (median 46%) amongst the 12 patients receiving a single 3 mg dose (Fig 2).
Figure Figure
The baseline serum creatinine was 0.9–8.4 mg/dL (median 2.4), and the minimum and maximum values in the week following rasburicase were 0.7–5.8 (median 1.8) and 1.0–8.8 (median 2.6) respectively. No clinically significant renal dysfunction developed in any patient. The total rasburicase dose administered, 3–12 mg (median 3 mg), was 3–12% (median 5%) of the recommended dose. Based on the Red Book rasburicase cost of $387 for a 1.5 mg vial, the amount of money saved ranged from $11,000 to $29,000 per patient; for a total saving of between $373,000 and $507,000. While this was not a systematic dose-reduction study and patients were treated by multiple physicians and pharmacists on clinical grounds, the data suggest that rasburicase is effective at a fraction of the recommended dose. While a formal investigation of low doses is warranted, we recommend using rasburicase at a standard dose of 3 mg in hyperuricemic patients, checking UA levels frequently, and repeating rasburicase administration if needed. This approach has the potential for substantial cost saving while providing appropriate therapy to lower UA.
Respect of Average Relative Dose Intensity Correlates with Survival in Diffuse Large B Cell Lymphoma Patients Treated by CHOP: A National Retrospective Study (1995–2000).
Authors: Bosly Andre , Dominique Bron , Achiel Van Hoof , Robbrecht De Bock , Zwi Berneman , Augustin Ferrant , Gregor Verhoef 
Published: October 2019

Abstract
Aims: To describe the different regimens of chemotherapy (CT), the average relative dose (ARD) and dose-intensity (ARDI) for first line treatment of patients (pts) with diffuse large B-cell lymphoma (DLBCL).
Methods: 373 adult patients files from 29 centers receiving at least 3 cycles of treatment for DLBCL, included or not in a protocol between 1995 and 2000, were retrospectively reviewed. ARD and ARDI analysis (delivered vs planned) was only performed for cyclophosphamide (C) and anthracyclines (A) as they are considered to be the most important agents.
Results: 348 pts treated with CHOP-like, ACVBP-like or CHVmP-BV were evaluable for the analysis. CHOP-like was the most commonly used regimen (273 pts, 79 %) of which CHOP-21 (210 pts) was the most frequent; followed by ACVBP (57 pts, 16 %) (with ACVBP-14 (46 pts) as the most important type) and CHVmP-BV (18 pts, 5 %). For all regimens the relative total dose (RTD) effectively received was 96 % for C and 94 % for A, respectively, and the relative total dose intensity (RTDI) scored 92 % for C and 90 % for A. This results in an ARD of 94 % (SD 14 %) for CHOP, 99 % (SD 4 %) for ACVBP and 95 % (SD 16 %) for CHVmP-BV and an ARDI of 92 % (SD 13 %) for CHOP, 88 % (SD 13 %) for ACVBP and 91 % (SD 16 %) for CHVmP-BV, respectively. 10 % of the pts dit not receive an ARD > 80 % (CHOP: 12 %, ACVBP: 2 % and CHVmP-BV: 6 %) and 16.5 % of pts had an ARDI below 80 % (CHOP: 15 %, ACVBP: 26 % and CHVmP-BV: 11 %). Overall, 45 % of the pts had dose modifications (dose delays (DD), dose reductions (DR) or both). Hematological toxicity was the major reason for CT-adjustment. In total, 56 % of pts received granulocyte colony-stimulating factor (G-CSF) treatment (CHOP: 47 %, ACVBP: 100 %, CHVmP-BV: 61 %). The different regimens used having a very different dose-intensity, analysis of effect of ARDI on survival was restricted to the 210 patients treated with CHOP-21. Mean overall survival of these patients according to ARDI category (> 90 %, £ 90 %) was respectively (mean ± SD) 5.38 y ± 0.58 and 2.24 y ± 0.30. Cox regression for effect of ARDI on overall survival was significant (p = 0.002).
Conclusions: (1) With respect to dose-intensity, lymphoma pts treated in hematological departments in Belgium benefit from optimal treatment. (2) CHOP-21 is the most frequently used CT regimen, followed by ACVBP and CHVmP-BV. (3) In pts treated with CHOP-21, overall survival was significantly improved when ARDI was superior to 90 %.
Peripheral Blood Stem Cells vs Bone Marrow for Matched Sibling Transplant in AML and ALL in First Remission.
Authors: Kirschbaum Mark , O’Donnell M. , Spielberger R. , Bhatia R. , Pullarkat V. , Stein A. S. , Kogut N. , Bolotin E. , Chang K. , Land J. , Sarkodee-Adoo C. , Snyder D. , Forman S. J. 
Published: October 2019

Abstract
We report a retrospective comparison of peripheral blood (PBSC) versus bone marrow derived stem cells for allogeneic transplant in a cohort of similarly treated patients based on eight year data from a single institution. Over the period 1995 to 2003, a total of 151 patients with AML or ALL in first CR underwent allogeneic matched sibling donor transplant, 98 AML patients and 53 with ALL. The source of stem cells was bone marrow in 69, G-CSF mobilized peripheral blood stem cells (PBSC) in 82. Of the AML patients, 40 (58%) received marrow, 58 (71%) received PBSC. Of the ALL patients, 29 (42%) received marrow, 24 (29%) got PBSC. The age of patients receiving marrow was 32.7 ± 13.6, and for those getting PBSC was 36.1 ± 16.1. The conditioning regimen was fully ablative (TBI/VP-16) in all but five patients (Fludarabine/Melphalan in 1 marrow and 4 PBSC pts). GVHD prophylaxis was with cyclosporine/methotrexate in patients receiving ablative conditioning, and CSP/MMF in the flu/mel patients.
The time to achieving an ANC >1000 was significantly shorter (P value=.0001) in the PBSC group, 18.2 ±6.6 days vs. 27.2 ±48.7 in the marrow group. Time to achieving a platelet count greater than 25K was significantly shorter (P value=2x10−11) for the PBSC group, 20.9 ± 8.5 vs. 31.8 ± 11.2 for marrow. This was true as well for time to reach platelet counts greater than 100K (P value=10−8), 29.7 ± 28 days for PBSC, 55.8 ±55.6 for marrow. In fact there was a significant increase (P=.0001) in the number of patients, 29 (42%) of marrow recipients vs 11 (13%) of PBSC, who did not at any time achieve a platelet count of >100K. There was no significant difference in survival at 2 years or 4 years between marrow or PBSC-Kaplan-Meier survival probability at 2 and 4 years respectively for AML was.66 and.54 for marrow, and.67 and.54 for PBSC. In ALL, the 2 and 4 year K-M survival probability was.72 and.65 for marrow;.69 and.69 for PBSC recipients. There was no significant difference in acute GVHD, with grade I-II described in 19 (28%) of the marrow pts, 29 (35%) in the PBSC pts, and grade II-IV in 8 (12%) marrow pts and 11 (13%) receiving PBSC (p value =.57), or chronic GVHD (P value=.62). Interestingly, in a subset analysis of patients who were diagnosed with acute GVHD, there was a significant difference in disease free survival at 5 years (see graph), suggesting that there is a qualitative difference between acute GVHD observed as a result of bone marrow versus PBSC as a source of stem cells.
Figure Figure
Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) - EBMT Risk Score Evaluation for Chronic Myeloid Leukemia in Brazil.
Authors: De Souza Carmino , Vigorito Afonso C. , Ruiz Milton A. , Nucci Márcio , Dulley Frederico L. , Fincke Vaneusa M. , Tabak Daniel , Azevedo Alexandre M. , Byington Rita , Macedo Maria C.M. , Saboya Rosaura , Aranha Francisco J.P. , Oliveira Gislaine B. , Zulli Roberto , Miranda Eliana C.M. , Azevedo Wellington M. , Lodi Fernanda M. , Voltarelli José C. , Simões Belinda P. , Colturato Vergílio , De Souza Mair P. , Silla Lúcia , Bittencourt Henrique , Ruiz Lilian P. , Maiolino Angelo , Gratwohl Alois , Pasquini Ricardo 
Published: October 2019

Abstract
This is a retrospective analysis of 1084 patients who received an allogeneic HSCT in 10 Brazilian Centers, from February 1983 to March 2003, aiming to validate the EBMT risk score. Data from transplanted patients and donors regarding patients age, disease stage at transplantation, HLA full-match sibling donor or full-match unrelated donors, donor-recipient gender match and the interval from diagnosis to transplantation, were used as variables to calculate the EBMT risk score. This score was analyzed using Cox Proportional Hazards Model. The OS, DFS, TRM and relapse were analyzed using Kaplan-Meier and cumulative incidence, whenever appropriate. In all there were 647 (60%) males and 437 (40%) females, the median age was 32 years old (range 1 – 59); 898 (83%) were in chronic phase, 146 (13%) were in accelerated phase and 40 (4%) were in blast crisis; 151 (14%) were younger than 20 years old, 620 (57%) were between 20 and 40 and 313 (29%) were older than 40; 1025 (95%) received HLA full-match sibling transplant and only 59 (5%) received an unrelated transplant. Female donor to male recipient occurred in 283 (26%) transplants. The interval from diagnosis to transplantation was less than 12 months in 223 (21%) cases and greater in 861 (79%). The OS, DFS, TRM and, relapse were 49%, 50%, 45%, 25%, respectively. The risk score 0–1 occurred in 179 (17%), score 2 in 397 (37%), score 3 in 345 (32%), score 4 in 135 (12%), and score 5–6 in 28 (2%). The risk scores 0–1 and 2 did not show any difference in terms of OS (58% and 55%, respectively) but they were significantly better than scores 3 or more (score 3 – 44%, 4 – 36 % and, 5-6 - 27%, respectively) (P<0.001). DFS and TRM beyond score 3 were 46%, 49%, respectively and the relapse rate beyond score 5–6 was 77%. Disease status had a negative impact on all outcomes (OS, DFS, TRM, and relapse). OS for female donor - male recipient was 40% compared to 52% for the other patients (P=0.004). DFS and TRM were significant for disease phase and female donor-male recipient (P<0.001 and P<0.003, respectively). In our experience, age and interval from diagnosis and transplant did not show any difference in terms of OS, DFS, TRM, and relapse rate. Our results confirm the usefulness of the EBMT risk score for point-decision in the Imatinib era.