bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimising Haemoglobin Response to Exogenous Erythropoietin in Anaemic Patients Treated in Routine Haemato-Oncology Practice.
Authors: Agrawal Samir G. , Greaves Paul , Lim Christina , Poole Chris D. , Walker Mel D. 
Published: October 2019

Abstract
Patients’ response to treatment with human recombinant erythropoietin (Epo) for chemotherapy-associated anaemia varies between 50% and 70%. The cost-effectiveness of Epo may be maximized by targeting treatment at patients most likely to respond. In this study, modified ASH/ASCO guidelines were combined with a systematic approach to iron supplementation in order to maximize haemoglobin (Hb) response in iron deficient patients. Patients with haematological malignancy and chemotherapy-associated anaemia received Epo alone (n = 25) or Epo plus intravenous iron sucrose (iv iron) if functional iron deficiency was present (n=24). The cohort had a male/female ratio of 48:52% and a mean age 62.8 years (SD 12.8; range 24 to 81). Baseline measurements were repeated at 4-weekly intervals for a period of 32 weeks. Overall, 80% of cases experienced a Hb response greater than 1g/dl, with 65% of patients achieving a major Hb response (≥ 2g/dl increase above baseline). There was no difference in Hb response between the Epo alone vs. Epo plus iv iron groups (∅ 2.72 vs. 2.84 g/dl; p=0.831), indicating equivalent outcomes for functionally iron deficient patients treated with effective iv iron supplementation and iron replete patients. General Linear Modelling was used to explore the independent contributions of demographics, baseline iron parameters, and disease progression in predicting Hb response to Epo. In the final model three independent variables emerged as significant, which together accounted for 40% of variance in Hb response. Progression of the underlying malignancy was associated with a mean reduction in Hb response of 1.9g/dl (p<0.001). Lower baseline Hb was associated with an increased response - each 1g/dl decrement was associated with a mean increased response of 0.87g/dl (p=0.012). Early change in reticulocyte count (between baseline and early follow up (< 4 weeks) was found to be positively associated with Hb response - each additional 1% change was associated with a 0.016g/dl increase in Hb response (p=0.006). These findings are in contrast to previous reports that the response to Epo was
independent of the outcome of the underlying malignancy and diminished at lower Hb levels.
Disease progression, baseline Hb and early increases in reticulocytes were all highly significantly correlated with the Hb response to Epo. In fact, in this cohort, all cases of non-response to Epo or loss of a response were associated with disease progression. To maximise response rates to Epo requires detection of functional iron deficiency and supplementation with iv iron. Furthermore, early reticulocyte response and disease progression should be closely followed and can help guide when to stop Epo therapy. This would allow rational use of resources and improve the health economics of Epo therapy by focusing on those most likely to benefit.
Elevated HIF-1α Levels in CLL B Cells May Explain Their Autocrine VEGF Secretion.
Authors: Lee Yean K. , Shanafelt Tait , Chan Denise , Giaccia Amato , Mukhopadhyay Debabrata , Taccioli Cristian , Calin George , Croce Carlo , Kay Neil E. 
Published: October 2019

Abstract
We and others previously reported that leukemic CLL cells spontaneously secrete VEGF and that VEGF can enhance the leukemic B cell apoptosis resistance via unknown mechanisms. Here, we report elevated VEGF secretion is associated with CLL B cell over-expression of hypoxia inducible factor-1 alpha (HIF-1α), a transcription factor that is a key regulator of VEGF synthesis. Immunostaining analysis confirmed CLL B cells in blood and bone marrow over-expressed both HIF-1α and VEGF. The high HIF-1α levels were not linked to proline residue (402/564) mutations in oxygen dependent degradation domains; absence of proline hydroxylation dependent enzymes (PHD1, 2, 3, and FIH); or to pVHL mutation (exon 1, 2 and 3); or aberrant transcription of HIF-1α. However, pVHL, a regulator of HIF-1α degradation, was found to be lower in CLL B cells and unable to physically interact with HIF-1α in CLL B cells. Nuclear extraction assay revealed that HIF-1α interacted with its co-factor, p300/CRP in B cells, indicating that HIF-1α was transcriptionally active. We hypothesized that reduction of pVHL expression in CLL B cells could be related to repression by micro RNA function which is known to be aberrantly expressed in CLL. We focused on miR-92-1 known to be over-expressed in CLL B cells and it has pVHL as a putative target. In a luciferase assay of transfected human megakaryocytic cell line, MEG-01, we found a direct effect for miR-92-1 on pVHL, with significant repression of luciferase activity of VHL expression by miR-92-1 compared to both control vectors and a mutated target mRNA sequences. This result indicated that wild-type miR-92-1 was able to interact directly with the 3′ UTR sequence of pVHL and subsequently repress pVHL expression. To further confirm this finding, we did transient transfections of either the CLL cell line Mec-1, primary CLL B cells or normal B cells with a sense oligo miR-92-1 (both Mec-1 and CLL B cells) or wild-type miR-92-1 plasmid (normal B cells). We found the level of flow detectable pVHL lower when compared to non-transfected cells. Because we were interested in the relationship of HIF-1α to CLL B cell survival we studied if chemotherapeutic drugs can downregulate HIF-1α in CLL B cells. To do this we studied flavopiridol a drug that has very promising activity in CLL. Our results indicated that flavopiridol does down-regulate HIF-1α levels in CLL B cells. This latter change was associated with induction of apoptosis in CLL B cells. Overall, our data show that elevated VEGF secretion is related to constitutively elevated HIF-1α levels and is an explanation for the VEGF-based autocrine pathway found in CLL B cells. We also show that elevated HIF-1α levels could be partially related to depressed pVHL with a unique mechanism for its repression: the over-expressed microRNA, miR-92-1 in CLL-B cells.
Bi-Directional Notch Signaling Via Signal-Sending and Signal-Receiving Microdomains of the Partnered Immunological Synapses during Th:DC Interaction.
Authors: Vyas Yatin M. , Parness Jerome , Rodeberg David , Huang Winifred 
Published: October 2019

Abstract
The Notch pathway regulates adaptive immune responses, yet the temporal development of a specific molecular anatomy underlying the directionality of Notch signaling, central to cell-fate decisions, remains unknown. Using the development of the functional immune synapse (IS) of the human physiological T-helper lymphocyte (Th): Dendritic cell (DC) interaction as our model, we followed the temporal accumulation of Notch signaling components, unprocessed and processed, in the developing ThIS and the apposed DCIS of these cells by 2D and 3D immunofluorescense microscopy. Downstream Notch targets in both cell types were followed, as well. We demonstrate that Th-Notch1 receptor and DC-Notch ligands (Delta-like1, Jagged-1) cluster in their apposed central-supramolecular-activation-clusters (cSMAC), whereas DC-Notch1 receptor and Th-Notch ligands cluster in their apposed peripheral-SMAC in an anti-parallel arrangement to that seen in the cSMAC. The resultant accumulation in both cell types of processed nuclear Notch receptor, its ligands, as well as HES-1 and phosphorylated-STAT3, supports antiparallel, reciprocal Notch signal propagation in the DC-to-Th direction via the cSMAC and Th-to-DC direction via the pSMAC. The imposed asymmetric recruitment of the components of Notch pathway, therefore, provides a novel bi-directional route by which the partnered ThIS and DCIS regulate Notch-mediated immune responses. Our data indicate that terminally differentiated immune cells communicate bidirectionally using unidirectional Notch signaling platforms that are spatially segregated into reciprocally signaling microdomains. Significantly, our observations of bidirectional Notch signaling indicate that the heterologous Th:DC interaction is cooperative, requiring reciprocal information transfer across both cell types to mount an appropriate immune response.
The Bcl-2 Family Inhibitor ABT-263 Shows Significant Anti-Tumor Efficacy in Models of B Cell Non-Hodgkin’s Lymphoma.
Authors: Shoemaker Alex R. , Mitten Michael J. , Oleksijew Anatol , O’Connor Jacqeuline M. , Wang Baole , Ackler Scott , Joseph Mary , Zhang Haichao , Nimmer Paul , Xiao Yu , Tse Christin , Frost David J. , Fesik Stephen W. , Rosenberg Saul H. , Elmore Steven W. 
Published: October 2019

Abstract
ABT-263 is an orally bioavailable small molecule inhibitor of Bcl-2 family proteins with a Ki of ≤ 1 nM against Bcl-2, Bcl-XL, and Bcl-w. Non-Hodgkin’s B-cell lymphomas represent clinically relevant disease targets for this molecule due, in part, to strong expression of Bcl-2 often associated with various types of NHL (frequently involving a t(14;18) translocation including the Bcl-2 locus). ABT-263 exhibits sub-micromolar in vitro activity against a variety of NHL cell lines. DoHH-2 and WSU-DLCL2 are two B-cell NHL lines harboring the t(14;18) translocation that exhibit differential in vitro sensitivity to ABT-263. Granta-519 is a mantle cell lymphoma line with the characteristic t(11;14)(q13:q32) translocation resulting in overexpression of cyclin D1. ABT-263 has an EC50 of approximately 150 nM in the Granta-519 cell line. Here we present efficacy data evaluating the activity of ABT-263 in several NHL xenograft models. ABT-263 has significant in vivo anti-tumor efficacy in established flank tumor models both as monotherapy and in combination with cytotoxic agents. The efficacy of ABT-263 at 100 mg/kg/day, p.o., q.d. ×21 was evaluated as monotherapy and in combination with etoposide, vincristine, modified CHOP, R-CHOP, bortezomib, rapamycin, and rituximab. Results show that ABT-263 significantly inhibits tumor growth as a monotherapy (~50–60% tumor growth inhibition) and enhances the efficacy of these cytotoxic agents in combination therapy. Statistically significant enhancement of tumor growth inhibition was observed for each combination relative to monotherapy treatment. Efficacy was maintained even when therapy was initiated on larger (~500 mm3) tumors. Combinations of ABT-263 + rapamycin and ABT-263 + rituximab result in complete regression of a significant percentage of established B cell lymphoma tumors for a sustained period of time in vivo. The combination of ABT-263 + R-CHOP resulted in complete regression of 100% of the tumors in the mantle cell lymphoma model. The strong in vitro potency and tumor regressions seen in vivo suggest that ABT-263 has great potential for the oral treatment of NHL B-cell lymphomas.
Low Dose Prothrombin Complex Concentrates Reverse Oral Anticoagulation with Minimal Complications.
Authors: Bagot Catherine N. , Kothari Jaimal , Patel Raj K. , Arya Roopen 
Published: October 2019

Abstract
Prothrombin complex concentrate (PCC) is widely used for the reversal of warfarin in the context of life threatening haemorrhage or emergency surgery. For these indications, it is considered superior to fresh frozen plasma (FFP), in terms of viral safety, efficacy and speed of administration. Dosage of PCCs for coumarin reversal (30–50IU/kg) is based on that required for patients with haemophilia B. This dose is frequently associated with thrombosis, particularly in the presence of liver disease. Factors underlying the prothrombotic potential of PCCs include the activation of clotting factors during the manufacturing process, coexisting co morbidities in the patient and repeated administration leading to clotting factor accumulation in vivo. The risk of thrombosis has led to a reluctance to administer PCCs, despite proven efficacy, in patients with arterial or venous thromboembolism, sepsis and liver disease. Recent work suggests that PCCs can effectively reverse anticoagulation when administered in much lower doses. We collected data on 38 patients (mean age 70 years) who received Beriplex (Aventis Behring) to reverse anticoagulation either for life threatening haemorrhage or emergency surgery. Patients were receiving warfarin for atrial fibrillation (50%), recurrent thromboembolic disease (18.5%) and mechanical heart valves (13%). 52.5% received Beriplex following haemorrhage, 26.5% to correct the INR prior to emergency surgery and 2.5% for an excessively elevated INR. 87.6% received 500IU Beriplex with the remainder receiving 1000IU. Of 38 patients, 18 out of 29 received Vitamin K. Mean INR fell significantly (p<0.01) following Beriplex administration (mean INR pre-Beriplex 4.8, post-Beriplex 1.8). 81% had an INR <2 following Beriplex. Of patients with an INR <8 receiving one vial, 64% corrected their INR to <1.4 (96% patients had an INR <2). 59% of patients had additional risk factors including ischaemic heart disease, recurrent thromboembolism, sepsis or abnormal liver function. No patients had thrombotic complications. Three had evidence of DIC following administration of Beriplex, all in association with sepsis and no patient experienced bleeding complications at the time of surgery. Bleeding was well controlled in those experiencing life threatening haemorrhage except in two patients, who presented with massive intracranial bleeds. This data indicates that PCCs should be considered in all patients on warfarin who require urgent anticoagulation reversal, at a dose of 500IU only. PCCs at a fixed low dose appear to correct anticoagulation effectively based on both clinical and laboratory parameters, without the need for repeated administration. Importantly, PCCs at this lower dose were not associated with thromboembolic events. Low dose PCCs therefore provide patients with a safe and effective antidote to warfarin.
A Multicenter Study of a Gemcitabine-Based Regimen in Relapsed or Refractory Hodgkin’s Lymphoma Patients.
Authors: Validire Patricia , Fermé Christophe , Brice Pauline , Diviné Marine , Gabarre Jean , Bouabdallah Krimo , Fitoussi Olivier , Chaoui Driss , Pacquement Hélène , Soussain Carole , Carde Patrice , Sahli Rafika , Decaudin Didier 
Published: October 2019

Abstract
The aim of this study was to assess the efficacy of a gemcitabine-based regimen in pretreated Hodgkin’s lymphoma (HL) patients. Relapsed or refractory HL patients treated with gemcitabine, used alone or in combination with other cytotoxic agents, were retrospectively reviewed. Fifty-five patients were included in the study. Initial characteristics before gemcitabine administration were: Ann Arbor stage III–IV: 84%; International Prognostic Score less than 3 in 20/43 cases (47%); thirty-one primary refractory patients at the end of first-line therapy (56%); median number of previous chemotherapy regimens of 3. Twenty-nine patients received gemcitabine alone with a median starting dose of 750 mg/m2 per injection (range: 180–1250 mg/m2); Gemcitabine was administered at a starting dose of 1000 mg/m2 per injection (range: 500–1250) in combination with vinorelbine in 10 patients, oxaliplatin in 13 patients, and other drugs in 3 patients, with a median of 6 injections (range: 1–18). Overall response rate was 20% with 11% of complete remission. On univariate analysis, two adverse factors at progression were significant for response to gemcitabine-based regimen: stage III–IV disease and hemoglobin level less than 10.5 g/dl. In conclusion, the two identified prognostic factors for response to gemcitabine are part of the International Prognostic Score of HL, suggesting that response to gemcitabine is mainly influenced by the specific prognostic factors of HL. Moreover, with an ORR of 29%, our results of the gemcitabine administered alone regimen are not different from those reported in the literature. In contrast, the results of the various series of HL patients treated by gemcitabine-combined regimens, mainly with cisplatin or derivatives, vinorelbine, ifosfamide, doxorubicin, and prednisone, are very different due to different patient characteristics. In heavily pretreated cases, as in our study, the ORR was 26%; inversely, in patients who had received only one or two lines of chemotherapy, the ORR varied between 64% and 82% with 9% to 54% of complete remissions. This discordance can probably be explained by the prognostic impact of previous treatment lines in the response to gemcitabine. This observation emphasizes the possible interest of using gemcitabine earlier in the treatment of Hodgkin’s lymphoma, namely at the time of first relapse or after first-line treatment in primary refractory HL patients.
Treatment of Extranodal Marginal Zone Lymphoma and Primary Cutaneous B Cell Lymphoma with Rituximab: A Single Institution Experience.
Authors: Chen Robert , Peterson Glen , Vucurevich Diana , Lee Choon-kee , Robinson William , Myint Han 
Published: October 2019

Abstract
Extranodal marginal zone lymphoma is a low grade B cell lymphoma. It comprises about 5% of all non-hodgkin’s lymphoma. They typically present in the lung, thyroid, breast, lacrimal and salivary gland, orbit, and skin. Primary cutaneous B cell lymphoma is an extremely rare form of lymphoma with 3 histological variants: marginal zone, follicular, and diffuse large B cell. In general, they have a high remission rate with overall survival up to 80% at 10 years. At the University of Colorado Health Sciences Center, we have seen ten such cases from July 2005 to July 2007. There is no standard treatement for either extranodal marginal zone lymphoma or primary cutaneous B cell lymphoma, but prior reports have shown long term survival with surgery, radiation, and chemotherapy. Most institutions use radiation therapy as the main modality after excisional biopsy. There is one report by Gitelson et al (leuk lymphoma 2006) using single agent rituximab as the only modality. Out of the ten cases at our institution, six cases were primary cutaneous B cell lymphoma (4 marginal zone, 1 follicular, one diffuse large B cell), and four cases were extranodal marginal zone lymphoma. Four out of six cases of primary cutaneous B cell lymphoma and three out of four of extranodal marginal zone lymphoma was treated with single agent rituximab. Two out of the six cases of primary cutaneous B cell lymphoma and one out of four of extranodal marginal zone lymphoma was treated with radiation. Patients were given induction therapy rituximab at the dose of 375mg/m2 IV weekly x 4 weeks and maintenance therapy at 375 mg/m2 IV every two to three month interval for 8 cycles. 7 patients were given rituximab single agent. All achieved CR (100%) immediately after induction therapy at 1 month. They were also given maintenance treatment. No relapses has occured at the medium follow up of 7 month (3–24 month). Our preliminary result supports the recent report of single agent rituximab. Even though extranodal marginal zone lymphoma is a rare disorder and primary cutaneous B cell lymphoma even more rarer, we feel that a well designed prospective randomized trial would determine the role of rituximab for this disease.
Phase II Study of 2-Weekly CHOP+Rituximab Followed by Yttrium 90 Ibritumomab Tiuxetan (Zevalin) in Patients with Previously Untreated Diffuse Large B Cell Lymphoma (DLBCL).
Authors: Venugopal Parameswaran , Gregory Stephanie A. , Obrien Teresa , Drasga Ray , Bayer Robert 
Published: October 2019

Abstract
Interval reduction from 3 to 2 weeks (CHOP-14; Pfreundschuh et al, Blood, 2004), addition of Rituximab to CHOP-21 (R-CHOP-21, Coiffier et al NEJM 2002) and consolidation with radioimmunotherapy following CHOP chemotherapy have all been shown to improve the outcome of DLBCL. We report the results of a Phase II clinical trial designed to evaluate the safety and efficacy of combination of the above, using 2-weekly CHOP+Rituximab followed by consolidation with Zevalin in patients with untreated DLBCL.
Patients and Methods: Patients with previously untreated DLBCL with measurable disease, age>18 years and performance status 0-2 were eligible. Patients were required to have adequate marrow, liver and kidney functions. Patients with transformed lymphoma were excluded. Patients received standard CHOP along with Rituximab 375mg/m2 IV on day 1. Treatment was repeated every two weeks for a total of 6 cycles. Zevalin was administered within 6–8 weeks after the last dose of CHOPR therapy.
Results: 14 patients were enrolled. The median age was 59.5 years (range 48–82), and 6 patients were men. All patients had an ECOG performance status of 0 or 1. 3 (21%) had stage II, 5 (36%) stage III and 6 (43%) had stage IV disease. IPI was 2 in 13 (93%) and 3 in 1 (7%). Bone marrow showed lymphoma in two patients only. LDH was elevated in 9 patients. All patients except 2 completed all 6 cycles of CHOP+R. One patient withdrew consent after 5 cycles and one patient with multiple lung masses could not be continued on therapy after two cycles because of prolonged rehab. Following CHOP+R alone in patients who received a minimum of 4 cycles of CHOP+R (13), 8 patients achieved CR and 5 achieved PR. Following consolidation with Zevalin, three patients in PR were converted to CR. After a median follow-up of 17.5 months, OSS is 14/14 (100%). 11 patients (79%) remain in CR. One patient progressed and proceeded to stem cell transplant; one came off study after 2 cycles of CHOP+R and remains with evidence of disease; and the third patient, who achieved PR with CHOP+R is waiting restaging after Zevalin. Most common adverse events were hematologic. Grade 3 Neutropenia was observed in 10 patients and grade 4 in 7. Grade 3 thrombocytopenia was observed in 3 and grade 4 in 1. Non-hematologic toxicities included: grade 3 pneumonia in 3, DVT in 1, grade 4 pneumonia in 1, grade 3 fever in 2 and grade 4 fever in 1.
Conclusion: Consolidation with Zevalin radioimmunotherapy following dose dense CHOP+R therapy is well tolerated, effective and able to convert PRs to CRs.