bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence and Clinical Course of Peripheral Neuropathy in Patients Receiving Thalidomide for the Treatment of Multiple Myeloma.
Authors: Naina Harris V.K. , Lacy Martha Q. , Dispenzieri Angela , Kumar Shaji , Greipp Philip R. , Witzig Thomas E. , Gertz Morie A. , Rajkumar S. Vincent 
Published: April 2020

Abstract
Background: Although thalidomide induced neuropathy has been described for decades, many features such as incidence, risk factors, severity and character of the neuropathy are not well defined. We retrospectively reviewed the incidence and clinical course of peripheral neuropathy in patients treated with thalidomide or thalidomide/dexamethasone (Thal/Dex) on a Phase II Mayo Clinic trial.
Methods: Patients who participated in a Mayo Clinic Phase II trial of thalidomide in myeloma were studied. In this trial, patients with SMM and RMM received thalidomide 200 mg per day escalated as tolerated to a maximum of 800 mg/day. Patients with NMM received thalidomide 200 mg/day plus dexamethasone 40 mg/day orally on days 1–4, 9–12, 17–20 (odd cycles) and 40 mg/day days 1–4 (even cycles) repeated monthly. The incidence and clinical course of neuropathy was assessed by chart review. The study was approved by the Mayo Clinic Institutional Review Board.
Results: All 113 patients (70 male, 43 female) treated on trial were studied; 31 patients with smoldering/indolent myeloma (SMM), 32 patients with relapsed/refractory myeloma (RMM) and 50 patients with newly diagnosed myeloma (NMM). Patients were accrued to the parent protocol from April 1999 through March 2002. The median age was 62 years (range, 36–78). The median duration of thalidomide therapy on protocol was 15 months in SMM, 6 months in RMM and 4 months in NMM. Overall, 63 patients (56 %) developed symptoms of peripheral neuropathy. The incidence of neuropathy was 77%, 50%, and 46% in patients with SMM, RMM, and NMM, respectively. Neuropathy worsened during the treatment phase with/without dose reduction or after cessation in 15%, remained stable in 52%, and improved in 27%. Overall grade of neuropathy was grade 1 in most pts; 11% of all patients had grade 2 neuropathy and 2% had grade 3 neuropathy. Predominant symptoms of neuropathy were tingling and numbness involving both upper limb and lower limbs. Small subsets of patients complained of hearing loss 6 patients), and erectile dysfunction (4 patients). Electromyographic studies and nerve conduction studies were performed in 11 patients; the most common finding was a length dependent axonal neuropathy.
Conclusion: Peripheral neuropathy is an important and common adverse event with thalidomide therapy that often limits the dose and duration of treatment. Its incidence and severity are likely related to dose and duration of therapy.
Multimodular Analysis of Angiogenic Biomarkers in the Primary Treatment of Multiple Myeloma: Correlative Studies of the BiRD Trial.
Authors: Jin David K. , Young Lauren M. , Vincent Loic , Gelbshtein Udi , Pekle Karen , Lam George , Shido Koji , Cho Hearn J. , Pearse Roger , Leonard John P. , Chen-Kiang Selina , Coleman Morton , Rafii Shahin , Niesvizky Ruben 
Published: April 2020

Abstract
Biomarkers that predict the angiogenic propensity of multiple myeloma and the impact of therapy on angiogenesis remain unknown. Nevertheless, many putative anti-angiogenic agents are currently being evaluated in clinical trials. We describe the results of a multimodular analysis of angiogenic biomarkers including a novel in vitro functional assay, the human umbilical vein endothelial cell (HUVEC)-based angiogenic scale (HBAS), to assess the overall angiogenic activity in the plasma of patients with multiple myeloma. Plasma fractionated from the peripheral blood of myeloma patients was added to primary HUVEC and cultured under serum-free conditions for 24 hours. Angiogenic morphology was then examined and scored using a six-point angiogenic scale. Analysis of a cohort of ten consecutive patients with multiple myeloma undergoing the BiRD protocol (Biaxin, Revlimid and dexamethasone) showed that the majority had higher HBAS scores at baseline than age-matched normal subjects. Plasma samples from stage IIIA disease consistently scored higher than those from stage II disease on the functional angiogenic scale (mean score of 2.8 versus 1.0, p&lt;0.005), suggesting a more pro-angiogenic state for further advanced disease. The HBAS also correlated with increased levels of plasma and platelet vascular endothelial growth factor-A (VEGF-A) as quantified by ELISA. Interestingly, VEGF-A levels in platelet lysate were significantly higher than those in plasma and more closely paralleled the functional HBAS scores. In addition, two-color flow cytometric analysis of cellular biomarkers demonstrated an angiogenic switch defined by increased mobilization of circulating CD133+VEGFR2+ endothelial progenitor cells in patients with active disease as compared to normal subjects (2.2-fold increase; p&lt;0.005). Treatment with BiRD effectively attenuated all tested angiogenic parameters and correlated with a positive clinical response. Collective assessment of angiogenic biomarkers may be a promising resource for predicting clinical outcomes and for validating the potential impact of anti-angiogenic therapy in multiple myeloma.
SNP Genotypes Show Association with Common Toxicities during both VAD Induction and High Dose Melphalan with Autologous Transplant Support in Intergroup Trial S9321 for Myeloma: From the Bank on a Cure.
Authors: Van Ness Brian G. , Crowley John C. , Ramos Christine , Grindle Suzanne , Rasmussen Erik , Hoering Antje , Greipp Philip , Barlogie Bart , Durie Brian 
Published: April 2020

Abstract
Patients with multiple myeloma show significant heterogeneity with respect to progression, therapeutic response and toxicities. Part of the Bank On A Cure project is to examine potential genetic polymorphisms that may be associated with common toxicities monitored in clinical trials. The SWOG/ECOG intergroup trial S9321 therapy includes VAD induction followed by randomization to high dose melphalan with autologous transplant support. Paticularly important toxicities with VAD include infection, thrombosis and hyperglycemia; and with melphalan toxicities in GI function are noted. Toxicities and genotypes were assessable during VAD induction on 569 patients; and during high dose melphalan on 161 patients. Toxicities examined included an array of symptoms: cardiovascular, flu-like, GI, neurologic, infection, lung, metabolic, and pain. Grade 3 toxicities found in at least 20 patients were compared to SNP genotypes. For VAD induced toxicities,TNF-alpha SNP genotypes showed association with fatigue, dyspnea and thrombosis; CYP3A4 SNP genotypes showed association with fatigue; DNA repair SNP genotypes in XRCC1 showed associations with infection, hyperglycemia and dyspnea; LT-alpha SNP genotypes showed association with dyspnea; and IL-6 and IL-10 SNP genotypes were marginally associated with neuropathy. After high dose melphalan, diarrhea was associated with SNP genotypes in TGF-beta, CYP3A4 and ERCC2. Interestingly, IL-6 polymorphisms were significantly associated with infection. The p values on the above associations ranged from .05 to .004. In addition, we noted ethnic distributions of some SNP genotypes were significantly different; and significant ethnic disparities in therapy induced hyperglycemia, fatigue, dyspnea and thrombosis were noted (p values range from .04 to .009). Of particular note is that the high producer IL-6 genotype is present in over 90% African Americans, compared to 35% Caucasians. Details of each association will be presented. Not all associations can easily be explained by known biologic function of the genotype, and it is important to qualify these results, as the likelihood of seeing some genotype associations by chance is quite high given the number of comparisons made. Further, we are continuing to examine additional prognostic factors that may, together with genotypes, provide collective predictors of toxicities. We consider these associations as targets for further study through the increasing sample acquisition in the Bank On A Cure project.
Maintenance Rituximab after CVP Results in Superior Clinical Outcome in Advanced Follicular Lymphoma (FL): Results of the E1496 Phase III Trial from the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B.
Authors: Hochster Howard S. , Weller Edie , Gascoyne Randy D. , Ryan Teresa S. , Habermann Thomas M. , Gordon Leo I. , Frankel Stanley R. , Horning Sandra J. 
Published: April 2020

Abstract
E1496 is a phase III trial designed to evaluate the ability of 2 years (yr) of maintenance rituximab (MR) to prolong progression-free survival (PFS) after CVP (cyclophosphamide 1 G/m2 day [d] 1, vincristine 1.4 mg/m2 [max = 2 mg] d 1, prednisone 100 mg/m2 d 1–5) chemotherapy in stage III–IV follicular grade 1 and 2 and small lymphocytic lymphoma. After CVP treatment to maximum response, (6–8 cycles), stable and responding patients (pt) were randomized to MR (375 mg/m2 weekly x 4) every 6 months x 4 or observation (OBS). Stratification factors included histology, response and residual disease after CVP. With 3-yr median follow-up, survivals (from time of randomization, one-sided logrank p values) for all pt (n=304) favored MR for PFS (p = 3 x 10–8; hazard rate {HR} = 0.38 [0.28;0.54, 95% confidence intervals]) and OS (p = 0.09; HR = 0.66 [0.36–1.22]). Because the large majority of pt have FL and because rituximab efficacy is notably greater in FL, we focused in this report on the 237 FL pt. Median age was 58 yr, 65% were stage IV, 64% had marrow disease, 64% had high tumor burden and 37% had high-risk disease by the follicular lymphoma prognostic index. PFS after randomization was significantly longer for MR vs OBS (p = 3 x 10-7; HR = 0.39 [0.27;0.57]). The estimated PFS at 4 yr (~4.5 yr after start of treatment) was 56% for MR vs 33% for OBS. Differences in PFS were significant within the predefined strata and the differences were most significant in favor of MR for pt with high initial tumor burden and minimal residual disease after CVP. Overall survival was superior for MR (p = 0.03; HR = 0.51 [0.25;1.04]. Estimated OS at 4 yr (~4.5 years after start of treatment) was 88% for MR vs 72% for OBS. Of 33 deaths, 21 occurred on the OBS arm. These data demonstrate that maintenance rituximab not only significantly delays disease progression in FL compared with OBS but that a substantial proportion of patients treated with MR remain disease-free at 4 years after the completion of CVP. These are the first data to strongly suggest a survival benefit with a therapy that includes rituximab and CVP and the first to strongly suggest a survival benefit with maintenance rituximab in FL.
Structural and Signaling Requirements for Transformation Mediated by Shp2 Mutants.
Authors: Mohi M. Golam , Neel Benjamin G. 
Published: April 2020

Abstract
The SH2-containing tyrosine phosphatase Shp2 (PTPN11) is required for normal growth factor and cytokine signaling. Germline Shp2 mutations cause ~50% of Noonan Syndrome (NS), which is associated with an increased risk of juvenile myelomonocytic leukemia (JMML). Somatic Shp2 mutations are found in ~35% of sporadic JMML, and at lower incidence in various chronic and acute leukemias. JMML patients without Shp2 mutations have either activating Ras mutations or homozygotic inactivation of Nf1. Nearly all disease-associated Shp2 mutations affect residues known to control catalytic activity. NS and leukemia mutations can involve the same residues, but when they do, the latter are less conservative, suggesting that they may be more activating. We previously showed that leukemia-associated mutants E76K or D61Y, but not wild type (WT) Shp2 could transform bone marrow (BM) or fetal liver cells and give rise to cytokine-independent myeloid colony formation. Leukemia-associated mutants yielded much higher number and larger size of colonies than NS-associated mutants (e.g., N308D, N308S, E76D) whereas, mutants associated with both NS and leukemia (T73I, E139D, Q506P) evoked intermediate numbers. Transplantation of E76K− or D61Y− (but not parental virus or WT Shp2) transduced BM into lethally irradiated recipients evoked a fatal JMML-like disorder. To understand the structural requirements of Shp2 for transformation, we made a series of second site mutations in Shp2 E76K and expressed these mutants in murine BM. Mutation of the canonical arginine residue to methionine in the FLVRES motif in either N-SH2 or C-SH2 domain of Shp2 E76K ablated myeloid transforming ability. Mutation of the conserved arginine residue within the Shp2 E76K phosphatase domain signature motif to methionine, which diminishes phosphatase activity, also eliminated myeloid transformation. Tyrosine residues 542 and 580 in the C-terminus of Shp2 are known to undergo phosphorylation in response to many growth factors and required for Grb2 binding. Mutation of tyrosine 542 to phenylalanine markedly reduced transformation, whereas tyrosine 580 mutation alone had little effect. However, mutation of both tyrosines eliminated Shp2 E76K-evoked transformation, suggesting that Grb2-binding to Shp2 could be important for transformation. We observed that Gab2, a major Shp2 SH2 domain binding protein, was absolutely required for transformation by Shp2 E76K but not activating RasV12. Gab3, another member of Gab family protein mainly expressed in hematopoietic cells, was not critical for Shp2 E76K-evoked transformation. We also found that Stat5 was important for Shp2 E76K-mediated transformation. Mast cells derived from E76K− and D61Y− transplanted mice BM exhibited increased proliferation and enhanced activation of Erk, p38MAPK, Akt and Stat5 in response to IL-3. These results provide some mechanistic insights into how Shp2 mutants could transform primary myeloid cells and result in JMML-like MPD.
Does Combined Immunochemotherapy with the Monoclonal Antibody Rituximab Improve Overall Survival in the Treatment of Patients with Indolent Non-Hodgkin Lymphoma? Preliminary Results of a Comprehensive Meta-Analysis.
Authors: Schulz Holger , Skoetz Nicole , Bohlius Julia , Trelle Sven , Kober Thilo , Greb Alexander , Engert Andreas 
Published: April 2020

Abstract
Background: The monoclonal anti-CD20 antibody Rituximab (R) has been shown to induce high response rates and to improve progression free survival when added to combined chemotherapy in newly diagnosed and relapsed indolent lymphoma. It remains unclear if R combined with chemotherapy may also have an impact on overall survival (OS).
Objectives: To determine the effectivness of a combination chemotherapy plus R versus chemotherapy alone with respect to overall survival.
Methods: Randomized controlled trials (RCT) comparing chemotherapy plus R vs chemotherapy alone in patients with newly diagnosed or relapsed indolent lymphoma and mantle cell lymphoma. Medical databases (Cochrane Library, MEDLINE, EMBASE) and conference proceedings were searched (1990–2005). We included full-text and abstract publications. Data extraction and quality assessment were done in duplicate. Data were pooled under a fixed-effects model. Number needed to treat were calculated to facilitate interpretation.
Main results: We identified six eligible RCTs involving patients with follicular and mantle cell lymphoma. Treatment regimen combined with R were CHOP (2x), CNOP, CVP, FCM and MCP. A total of 5 trials with 994 randomized untreated pts were included in the survival analysis. The included studies were described by the authors as randomized. In all studies, the method for allocation concealment could not be determined. Three studies were published as full text, and two were abstract publications. Overall survival was statistically significantly improved in the R-chemotherapy group compared to chemotherapy alone (HR 0.61; 95%-CI: 0.47–0.80). There was no statistical heterogeneity between the trials compared. Assuming a survival chance of 85% after 18 months for patients with low grade NHL we estimated that it would be necessary to treat 17 (95%-CI: 13–33) patients with R in addition to chemotherapy to prevent one death. For patients with mantle cell lymphoma and a survival chance of 60% after 18 months the corresponding estimate is 6 (95%-CI: 5–13).
Conclusion: This preliminary meta-analysis demonstrated evidence for improved overall survival among patients with indolent lymphoma and mantle cell lymphoma treated with a combination of rituximab plus chemotherapy compared to chemotherapy alone.
Clonal Expansion in Paroxysmal Nocturnal Hemoglobinuria (PNH): Expression of Mutant HMGA2 Suggests That PNH Is a Benign Tumor of the Bone Marrow.
Authors: Inoue Norimitsu , Izui Tomohisa , Murakmai Yoshiko , Endo Yuichi , Nishimura Jun-ichi , Kanakura Yuzuru , Meyers Gabrielle , Wittwer Carl , Chen Zhong , Babcock William , Frei-Lahr Debra , Parker Charles , Kinoshita Taroh 
Published: April 2020

Abstract
In PNH, a somatic mutation of PIGA in hematopoietic stem cells causes the deficiency of glycosylphosphatidylinositol-anchored proteins (GPI-AP), but the basis of clonal expansion of the PIGA-mutant cells is speculative. Because some patients with aplastic anemia develop PNH, GPI-AP deficient stem cells may have a survival advantage in the setting of immune-mediated bone marrow injury. However, in many patients with aplastic anemia, the GPI-AP deficient cell populations remain small or disappear. Therefore, we hypothesized that additional abnormalities in the PIGA-mutant stem cells account for clonal expansion. We previously reported a patient with PNH/aplastic anemia (J20) whose PIGA-mutant hematopoietic cells had a coexistent cytogenetic abnormality [46,XX,ins(12;12)(q14;q12q14)]. In this patient, the insertion disrupted the 3′ untranslated region of HMGA2, an architectural transcription factor whose aberrant expression causes benign mesenchymal tumors. Truncated HMGA2 transcripts lacking the acidic tail (the pathophysiologically relevant form) were identified in the double mutant cells. In the present study, we characterized a similar genetic abnormality in a patient with classical PNH. In this case, PIGA-mutant cells again had a concurrent der(12) [46,XX,ins(12)(p13q14q13)]. A 20 Mbp fragment from 12q13 to q14 and a 300bp fragment from 12q14 together containing exons 1–4 and part of exon 5 of HMGA2 were inserted inversely and directly, respectively, into intron 1 of TEL at 12p13. One of the breakpoints in the HMGA2 locus was at almost the same position as the HMGA2 breakpoint in patient J20. Truncated HMGA2 transcripts (lacking the acidic tail) were highly expressed in bone marrow cells. Full-length transcripts of TEL without any fusion partners were normally expressed and no other transcription units were disrupted by the breakpoints. That similar cytogenetic abnormalities were observed in these two patients suggests that aberrant expression of HMGA2, in concert with mutant PIGA, accounted for the clonal expansion and explains the benign tumor characteristics of PNH.
Hepcidin Inhibits Erythroid Colony Formation In Vitro at Decreased Erythropoietin Concentrations.
Authors: Means Robert T. , Dallalio Gail , Law Erin 
Published: April 2020

Abstract
The anemia of chronic disease (ACD) results from three major processes: slightly shortened red cell survival, impaired reticuloendothelial system iron mobilization, and impaired erythropoiesis. Hepcidin is an acute phase protein with specific iron regulatory properties, which, along with the anemia seen with increased hepcidin expression, have led many to consider it the major mediator of ACD. However, if hepcidin is the major factor responsible for ACD, then it should also contribute to the impaired erythropoiesis observed in this syndrome. In this study, the effects of hepcidin on erythroid colony formation in vitro are examined. At the standard recombinant human erythropoietin (rhEPO) concentration used for erythroid colony-forming unit (CFU-E) assays in vitro (1 U/mL), hepcidin had no significant effects on colony formation. However, ACD is a syndrome associated with relative reductions in EPO concentration. The effects of hepcidin 100 ng/mL on CFU-E colony formation were evaluated at lower rhEPO concentrations (0.1 _ 0.5 U/mL). Colony formation was significantly decreased in the presence of hepcidin. The regulatory pathways controlling apoptosis and proliferation of HCD57 erythroleukemia cells replicate those observed in primary human erythroid progenitors. This cell line was studied in order to more fully define the effects of hepcidin on erythropoiesis. HCD57 cells were incubated in Iscove’s modified Dulbecco’s medium with 10% fetal calf serum with 0.3 U/mL rhEPO at 37°C for 24 hrs, with or without hepcidin 100 ng/mL. No difference in cell proliferation was seen. Apoptosis in HCD57 cells is regulated by the Bad/Bcl-xL pathway. Total Bad and Bcl-xL protein expression were unchanged by exposure to hepcidin; however, the proportion of the anti-apoptotic protein pBad was decreased approximately 50%. A recent report has demonstrated that hepcidin reduces macrophage iron efflux by binding to the iron transporter ferroportin, causing its internalization and subsequent degradation. It is unlikely that the inhibition of CFU-E colony formation reported here results from this effect: although macrophages are present in the marrow cell population, and iron is required for erythropoiesis in vitro, the amount of iron-saturated transferrin contributed to the culture medium by FCS is comparable to the amount required for maximal CFU-E colony formation in serum-free medium. CONCLUSION: At reduced rhEPO concentrations, CFU-E colony formation is inhibited by hepcidin. Short-term exposure to hepcidin induces a pro-apoptotic pattern in HCD57 erythroleukemia cells. The studies reported here do not disprove the possibility that hepcidin-induced impairment of iron flow to erythroid cells contributes to ACD: rather, they suggest an additional mechanism by which hepcidin can inhibit erythropoiesis.