bluuebunny/crossref_metadata_2025_split huggingface dataset:
Management of Febrile Neutropenia: Single Agent or Combination Therapy?.
Authors: Caldas Joana , Fernandes Teresa , Monteiro Alexandra , Carande Luisa , Silva Madalena , Cruz Ernesto , Sousa Aida B. 
Published: October 2019

Abstract
The best strategy for the empirical treatment of fever in profoundly neutropenic patients (pts) remains unclear. We retrospectively compared the efficacy and safety of 2 antibacterial regimens consecutively used in our center for febrile neutropenia (FN) in pts undergoing intensive chemotherapy for acute leukemia or autologous stem cell transplantation. From 1/99 to 6/01, 374 episodes of FN in 179 pts were treated with piperacillin-tazobactam plus amikacin (PTA, 4.5 g q6h and 20 mg/kg q24h respectively), then from 7/01 to 12/03, 428 episodes in 223 pts were treated with cefepime (CEF, 2g q8h). Any modification of the initial regimen was evaluated as a failure. Pts were nursed in HEPA-filtered rooms and received prophylactic aciclovir (and ciprofloxacin until 12/99) with no antifungal primary prophylaxis. There were no significant differences between the PTA and CEF episodes regarding median age of the pts, median days with neutrophils <500/μl or presence of an intravenous central catheter. The proportion of documented bacteremias was similar (33/30%) with a Gram negative predominance in both periods (60/66%), mainly due to E. coli (61/64%) and P. aeruginosa (14/14%). As for Gram positive bacteremias, there was an increase in S. aureus (18% in PTA vs 27% in CEF) and a marked decrease in S. viridans (24/4%). Resistance of Gram negative bacteria to the protocol drugs remained low (7% to PT and 4% to A in the first period, 5% to CEF in the second); resistance of coagulase negative staphylococci to ciprofloxacin dropped from 33 to 15%. Success rates were 35% for PTA and 32% for CEF. The reasons for modification of the initial empirical regimen were similar in the 2 periods, the most frequent being persistent fever (56/59%) followed by progression of infection (20/18%), relapsing fever (19/14%), withdrawal due to toxicity (3/6%) and resistant pathogen (1/3%). The addition of an antifungal was the most usual modification, occuring in 44% of PTA and 39% of CEF episodes. Vancomycin (for which a restriction policy had been introduced in 1995 after an outbreak of vancomycin-resistant enterococci) was added in 17 and 15% of the episodes. Amikacin was added in 38% of the CEF episodes. The occurence of further infections did not differ between the 2 periods (26 and 29%) nor did the mortality due to infection (7.7 and 6%). The proportion of severe adverse events (CTC-NCI grades 3/4) was low in both periods (4 and 1%). Cutaneous allergic reactions were less frequent with PTA than with CEF (5 vs 9%). We conclude that monotherapy with CEF was as effective as the combination of PTA for empirical treatment of FN. Both regimens resulted in a low infectious mortality and a very low emergence of resistance, and both were well tolerated.
MRI-Detectable Focal Lesions (FL) in Multiple Myeloma (MM) at Relapse Frequently Involve Novel Sites Not Involved at Diagnosis.
Authors: Walker Ronald , Jones-Jackson L. , Rasmussen Eric , Miceli M. , Anaissie Elias , Epstein Joshua , Tricot Guido , Shaughnessy John , Barlogie Bart 
Published: October 2019

Abstract
Macrofocal lesions (FL) in the medullary space are a hallmark of mm readily detected by MRI scans, both at diagnosis and at relapse. In this study we evaluated, among 25 patients enrolled in TT II, with FL at relapse and a preceding clinical CR (by M protein and marrow examinations) the relationship to presence and location of FL at diagnosis. On relapse, 17/25 (68%) had fewer FL, 5/25 (20%) had the same number of FL, 3/25 (12%) had more FL than on baseline examination. There was a general trend for the larger FL at baseline to still be present on relapse (Table 1). Despite the trend to fewer focal lesions on relapse compared to baseline, 11/25 (44%) of patients presented with FL in new sites that were not present on baseline. Finally, in relapsing patients, 4/25 (16%) presented with new sites of extramedullary tumor (EMD). These data establish that although there are usually fewer MRI-defined FL on relapse than on baseline examination, the vast majority of FL on relapse represent new areas of macrofocal disease that were not present at diagnosis.
MRI FL Persisting from Baseline to Relapse (n=25)
Size (cm) Baseline FL Present upon Relapse % < 0.5 1/2 50 0.5–1cm 8/10 80 1–2 cm 13/18 72 > 2 cm 10/16 63 All Sizes 26/36 72
A Matched Pair Retrospective Comparison of Adult Unrelated and Sibling Donor Allogeneic Transplantation for AML.
Authors: Moore John J. , Bradstock Ken B. , Dodds Anthony , Szer Jeff , Smith Ian Nivison , Goh Kim , Ma David 
Published: October 2019

Abstract
Aim: Recent studies have shown equivalent survival outcomes for unrelated donor transplants for CML compared to siblings. This study compares outcomes for a set of unrelated donor transplants for AML and a strictly selected matching set of sibling donor transplants.
Method: A set of 100 adult first 6/6 compatible unrelated donor transplant recipients with AML were selected from the ABMTRR database. A set of 100 adult first 6/6 compatible sibling donor controls were selected, matched with the subjects on disease stage, sex and age. Additional data was collected from participating centres on conditioning, prophylaxes, GVHD and other outcome factors.
Results: A total of 162 forms were returned: 22 for good risk (CR1 - 15 siblings, 7 unrelated) and 140 for poor risk (past CR1 - 77 siblings, 63 unrelated). A Kaplan-Meier comparison of post transplant disease free survival between good risk sibling and unrelated donor recipients was not statistically significant (p=0.2). However the 5-year DFS of poor risk unrelated recipients was significantly worse than sibling recipients (sibling 29.5%, unrelated 14.1%, p=0.01). In a multivariate Cox regression model, the independent risk factors for DFS among all patients were unrelated donor (p=0.003), disease stage beyond CR1 (p=0.04), recipient male (p=0.04), aged 40 and over (p=0.04) and CMV positive (p=0.03).
Conclusion: Adult unrelated donor allograft recipients in poor risk AML have poorer DFS probability than sibling recipients. However in good risk AML allograft recipients, donor type is not a significant DFS risk factor. The ABMTRR is an important national data resource providing a large and readily accessible sample frame for retrospective studies on specific transplant indications.
Peg-Filgrastim after Autologous Peripheral Blood Stem Cell Transplantation in Hematological Malignancies.
Authors: Musto Pellegrino , Rosario Scalzulli Potito , Melillo Lorella , Nobile Michele , Dell’Olio Matteo , La Sala Antonio , Mantuano Saverio , Bodenizza Carlo , Falcone Antonietta , Sanpaolo Grazia , Michele Carella Angelo , Greco Michele Mario , Beltrami Germana , Cascavilla Nicola 
Published: October 2019

Abstract
ASCO guidelines recommend the use of granulocyte-colony stimulating factors (G-CSF) as adjuvant agents after autologous peripheral blood stem cell transplantation (PBSCT), for shortening the period of severe neutropenia and reducing the related risk of life-threatening infections. The recently available pegylated formulation of G-CSF (peg-filgrastim) could have some potential advantages in phase of recovery after PBSCT, such as self-regulation mechanisms, particularly useful when neutropenia duration is unforeseeable, possible reduction/standardization of growth factor costs and possibility of more manageable outpatient treatments. We investigated the effects of a single s.c. injection of peg-filgrastim (6 mg) on day 3 in 11 patients (8 with multiple myeloma, MM; 2 with non-Hodgkin’s lymphomas, NHL; 1 with acute myeloid leukemia, AML) planned to receive autologous PBSCT. Mean age was 55 years (range 24–65). In 7 patients PBSCT was performed as consolidation in first complete or partial remission, while 4 patients received the procedure as salvage treatment for chemo-sensitive disease. Conditioning regimens were intermediate/high dose melphalan in MM, BEAM protocol in NHL and TBI plus cyclophosphamide in AML. For comparison, we selected a group of 11 historical controls matched for age, type and status of disease, conditioning regimen, and number of CD34+ stem cells infused, who had received standard daily s.c. administration of G-CSF (300 mcg/d) from day 5 to neutrophil recovery after autologous PBSCT. No adverse events occurred in patients treated with peg-filgrastim. Bone pain was the only side effect referred by one patient. There was no difference between the two groups in terms of median time to hemoglobin recovery, days of febrile neutropenia and number of red cell or platelet transfusions received. However, the median times to neutrophil > 0.5 x 109/L (10 days, range 9–13 vs 12 days , range 11–14, p < 0.000) and platelet > 20 x 109/L (10 days, range 8–15 vs 13 days, range 12–20, p < 0.003) were significantly shorter in peg-filgrastim group. The median number of G-CSF injections in controls was 12 (range 9–20), so that the mean cost of this drug for single patient was 1,764 euros, as compared to 910 euros for patients receiving peg-filgrastim. We conclude that peg-filgrastim and G-CSF have comparable safety and efficacy profiles in patients affected by hematological malignancies who undergo autologous PBSCT. In this specific setting of patients, peg-filgrastim could be cost-effective. Whether peg-filgrastim may be also superior in reducing the periods of neutropenia and thrombocytopenia, requires to be confirmed and further investigated in larger studies.
Follow-Up of Chronic Lymphocytic Leukemia (CLL) Patients Who Relapse after Autologous Stem Cell Transplantation (ASCT).
Authors: Trisolini Silvia M. , Mauro Francesca R. , Capria Saveria , Cimino Giuseppe , De Propris Maria S. , Proia Anna , Foà Robin , Meloni Giovanna 
Published: October 2019

Abstract
It is now clear that ASCT despite being a feasible and potentially beneficial therapeutic strategy in the treatment of CLL patients (pts), does not lead to cure. Whether, how and when to utilize this procedure in the course of the disease is still matter of debate. In order to evaluate whether or not pts relapsed after an ASCT could be retreated, also with intensive approaches, we evaluated the outcome of our CLL pts with recurrence of disease after an ASCT. Between 1995 and 2002, 30 CLL pts, median age 50 years (range 24–61), with advanced disease (Binet stage B or C), in clinical complete remission (CR) after fludarabine (FLU), were autografted at our institution using bone marrow (4 pts) or peripheral blood stem cells (26 pts); the BEAM (BCNU, etoposide, ara-c, melphalan) conditioning regimen was utilized in most pts (24). At the time of transplant, 17 pts had received one line of therapy, 8 two lines and 5 three or more lines, and the median interval from diagnosis to transplant was 41 months (range 8–131). Eighteen of the 30 pts (60%) showed a clinical relapse after a median time of 31.5 months (range 2–79) from transplant. All relapsed pts required treatment which was administered after a median interval from relapse of 4 months (range 1–38). Seventeen pts were evaluable for response, 1 pt being too early. Two of the 17 pts proved refractory to two lines of therapy (chlorambucil (CB), FLU plus cyclophosphamide (CY): 1 pt; CB, vincristine: 1 pt) and died 28 and 32 months from relapse, respectively. Fifteen of the 17 pts (88%) achieved a response. A partial response was obtained in 12 pts after first line therapy (CB: 6 pts; mabthera alone: 3 pts; FLU-CY and mabthera: 2 pts; PVABEC regimen: 1 pt). A CR was achieved after one line of therapy (FLU-CY and mabthera) in 1 pt and after a second line of therapy in 2 pts (mabthera, FAND plus allo: 1 pt; CB, FLU plus campath-1H: 1 pt). The median response duration was 16 months. At the present time, 11/18 relapsed patients are alive with a median follow-up of 37 months from relapse (range 18–63) with a projected probability of overall survival of 40% at 5 years from relapse. Seven patients have died because of disease progression after a median interval of 36 months from relapse (range 28–50). Based on our results, ASCT does not jeopardize the possibility of submitting CLL patients who relapse after such a procedure to further treatment, also intensive, which can induce good and lasting responses with a possibility of survival of 40% at 5 years from relapse.
Evaluation of Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) in Patients with Non-Hodgkin’s Lymphoma (NHL) Having Previously Received Autologous Stem Cell Transplant (ASCT).
Authors: Jacobs Samuel A. , McCook Barry , Torok Frank , Avril Norbert , Vidnovic Nick , Joyce Judy , Molina Arturo 
Published: October 2019

Abstract
Background: As the first radioimmunotherapeutic (RIT) agent approved for the treatment of relapsed or refractory B-cell NHL, yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) has been shown to achieve durable responses in heavily pretreated NHL patients. In phase 1–2, the eligibility criteria for 90Y ibritumomab tiuxetan therapy excluded patients with hypocellular bone marrow (<15%), lymphomatous involvement >25%, or prior ASCT due to concern of depleting the bone marrow reserve. However, Kaminski et al previously demonstrated that a parallel RIT agent, 131I tositumomab, was safe and efficacious when administered after ASCT (Blood2000; 96:1259–66). We report our experience of using ibritumomab tiuxetan in NHL patients with a prior history of ASCT.
Methods: Patients with histologically confirmed relapsed or refractory B-cell NHL, ≥18 years, platelet counts >100,000/mm3, bone marrow cellularity >15%, and lymphomatous involvement <25% were eligible for treatment. In a series of 40 patients treated with ibritumomab tiuxetan at the UPMC Cancer Center, 6 patients with prior ASCT were treated. A standard course of ibritumomab tiuxetan was given, with the therapeutic dose of 90Y ibritumomab tiuxetan administered at 0.3 mCi/kg (the initial patient, and another with platelet count ≥150,000/mm3) or the standard dose of 0.4 mCi/kg 90Y in the 4 remaining cases (baseline platelet count >150,000/mm3). Pretreatment diagnostic PET/CT scans were taken for all patients and evaluated for areas of lymphomatous involvement. Follow-up scans were performed approximately 12 weeks after treatment to assess patient response. Maximum toxicities were monitored weekly over a 12-week period after therapy and classified according to CTCAE v. 3.0 toxicity criteria.
Results: Patients with a prior history of ASCT had received a minimum of 4 previous regimens (range, 4–7). Subjects presented with follicular NHL (n = 3), transformed NHL (n = 1), large cell lymphoma (n = 1), and mantle cell lymphoma (n = 1). Six patients were evaluable for toxicity and 5 patients were evaluable for response. Observed toxicities were consistent with those expected in this patient population, with 33% (2/6) and 17% (1/6) of patients experiencing grade 4 thrombocytopenia and grade 3 neutropenia, respectively. Episodes of bleeding or neutropenic fever were not observed. Of the 5 patients evaluable for response, 1 patient with follicular lymphoma had a complete response to ibritumomab tiuxetan as determined by FDG-PET imaging.
Conclusions: Ibritumomab tiuxetan therapy is feasible and safe in NHL patients who have previously received ASCT. Heavily pretreated patients can benefit from the administration of ibritumomab tiuxetan although additional data are needed to further characterize the degree of clinical response after ASCT.
Autologous Peripheral Blood Stem Cell Transplant for Relapsed or Refractory T-Cell Non-Hodgkin’s Lymphoma Results in Inferior Long Term Survival when Compared to Relapsed or Refractory B-Cell Non-Hodgkin’s Lymphomas.
Authors: Hsu Jack W. , Singh Priya , Goldberg Stuart L. , Pecora Andrew L. , Siegel David S. , Rowley Scott D. 
Published: October 2019

Abstract
Autologous transplant has emerged as the standard of care for the treatment of relapsed B-cell non-Hodgkin’s lymphomas (NHL). However, for the treatment of T-cell NHL, the role is not as clear. We report our experience with 24 patients with T-cell NHL who underwent autologous transplantation at time of first relapse. Lymphoma types were varied (peripheral T-cell = 8, lymphoblastic = 6, anaplastic large cell = 5, not otherwise specified = 5). All patients received CHOP as primary therapy, except one patient who received ProMACE/CytaBOM, one who received Stanford V, and two who received HyperCVAD. Patients had either relapsed disease (14 patients) or primary refractory disease (9 patients). One patient underwent autologous transplant as consolidation therapy. Mobilization regimens varied, consisting of dexamethasone, ifosphamide, etoposide, and cisplatin (DICE, 12 patients), dose intensive cyclophosphamide, etoposide, cisplatin (DICEP, 5 patients), cyclophosphamide/etoposide (3 patients), cyclophosphamide (2 patients), or other regimens (2 patients). Adequate collection of stem cells was seen in all but one case, which required bone marrow collection. The conditioning regimen used was BVAC (BCNU 600 mg/m2, etoposide 1600 mg/m2, cytarabine 24 g/m2, and cyclophosphamide 90 mg/kg) in 23 patients. One patient received melphalan conditioning. For the entire group, the overall survival at 3 years was 50%. This compares favorably with 336 relapsed B-cell NHL patients who underwent autologous transplant with the identical conditioning regimen (BVAC) in the same period of time (OS = 52%). At 5 years, the overall survival of the B-cell lymphoma group was stable at 49%. However, the overall survival for the T-cell NHL group declined to 30%. The primary cause of death post transplant was disease relapse. When divided among specific lymphoma subtypes, 3 of 8 patients with peripheral T-cell lymphoma, 4 of 5 patients with anaplastic large cell lymphoma, 3 of 6 patients with lymphoblastic lymphoma and 3 of 5 patients with other T-cell lymphoma subtypes remain alive. Although there are too few patients to draw any definite conclusions, it appears that autologous stem cell transplant for relapsed or refractory T-cell NHL results in similar 3-year overall survivals when compared to B-cell NHL using the same conditioning regimen. However, T-cell NHL appear to be associated with a higher late relapse rate which is reflected in the lower overall survivals at 5 years. Although there may be a benefit to autologous transplant in relapsed anaplastic large cell lymphomas, relapsed/refractory T-cell NHL had inferior long term overall survival compared to their B-cell counterpart transplanted with the same regimen. Novel approaches should be considered in the treatment of relapsed or refractory T-cell NHL.
Co-Epression of Two Transgenes in Lentiviral Vector Using Independent Transcriptional Units.
Authors: Schuening Friedrich G. , Zaboikin Michail M. , Srinivasakumar Narasimhachar , Zaboikina Tatiana N. 
Published: October 2019

Abstract
There are several gene therapy approaches, which require transfer and co-expression of two transgenes within one target cell. To this end, we have created and tested two-gene expression HIV-1 based vectors, which encode enhanced green fluorescent protein (EGFP) and P144K mutant of canine O6-methylguanine-DNA-methyltransferase (MGMT) transgenes under either the phosphoglycerate kinase gene promoter (PGKp), or the elongation factor 1 alpha promoter (EF1a_p). Eight different configurations of the two transgene expression cassettes were created and tested within the same lentiviral backbone (see Figure). Individual VSV-G pseudotyped vectors stocks were produced and used for infection of canine thyroid adenocarcinoma (CTAC) cells at low multiplicity of infection (MOI = 0.1) to ensure 1 copy of proviral vector per transduced cell. The cells were harvested one week later and an aliquot was assayed for EGFP expression by flow cytometry. Another portion was subjected to selection with O6-benzylguanine (BG, 40 m M for 18 hrs) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, 100 m M for 2 hrs) and kept in culture for additional two weeks to eliminate cells expressing insufficient MGMT. The percentage of GFP positive cells, prior to selection with BG and BCNU, ranged between 0.1 % to 6.6% for the dual-transgene expression cassette encoding HIV-1 vectors. Following selection with BG and BCNU, the percentage of GFP positive cells increased for all vectors with the exception of vector #2 PGEM. Two of the vectors (#1 PMEG and #8 EGMP) demonstrated over 80% GFP positivity after selection. The results of flow cytometry after selection were corroborated by fluorescence microscopy of individual BCNU-resistant colonies. GFP expression was readily detected in drug-resistant colonies transduced with vectors #1 PMEG or #8 EGMP. Weaker GFP expression was detected in drug resistant cells transduced with vectors #3 PMGE, #5 EMPG or #6 EGPM. No significant GFP expression was observed in drug-resistant colonies transduced with vectors #2 PGEM, #4 PGME or #7 EMGP. Drug resistance to BCNU (IC50 values) provided by each of the vectors, was also determined. The data showed that the IC50 values for #1 PMEG and #8 EGMP vectors were 2.4-fold and 4.4-fold, respectively, higher than for mock transduced control cells. The above results indicate that coordinated co-expression of two transgenes using independent expression cassettes is promoter, position and orientation dependent. The data also indicate that two potentially useful vectors (#1 PMEG and #8 EGMP) have been identified for evaluation, ex vivo and in vivo, in the canine model for co-expression of two transgenes.