bluuebunny/crossref_metadata_2025_split huggingface dataset:
PAD Combination Therapy (PS-341/Bortezomib, Adriamycin and Dexamethasone) for Previously Untreated Patients with Multiple Myeloma.
Authors: Cavenagh James D. , Popat Rakesh , Curry Nikki , Stec Jim , Morris Treen C. , Drake Mary , Agrawal Samir , Smith Patricia , Schenkein David P. , Esseltine Dixie-Lee , Oakervee Heather 
Published: October 2019

Abstract
Background: The most favourable outcomes for patients with MM are seen in those achieving a complete or near complete response following initial therapy. Therefore, it is logical to explore strategies aimed at improving initial response rates. Bortezomib has shown significant activity in patients with advanced MM and has been shown to be superior to pulsed dexamethasone in this setting. Additional efficacy is seen when dexamethasone is combined with bortezomib and in vitro synergy is observed with cytotoxic agents such as adriamycin. On this basis, the PAD regimen was investigated as front line therapy for patients with MM.
Aims: The primary objective of this Phase I/II study was to assess the feasibility of harvesting PBSCs after PAD, with secondary objectives being assessments of safety, toxicity, response rate (RR), PFS and OS.
Methods: Patients with previously untreated MM were eligible. Patients were treated with 4x21 day cycles of PAD comprising bortezomib 1.3 mg/m2 on days 1,4,8 & 11 along with 40 mg dexamethasone on days 1–4, 8–11 & 15–18 during cycle 1 and days 1–4 during cycles 2–4. During days 1–4 of each cycle, patients also received 0 mg/m2, 4.5 mg/m2 or 9 mg/m2 of adriamycin at levels 1,2 & 3 respectively. Following harvesting, patients received high dose melphalan (MEL200) with stem cell (PBSC) rescue. Gene expression profiling was performed on purified plasma cells from diagnostic samples for pharmacogenomic analysis.
Results: Thus far, 21 patients have been enrolled (19 male 2 female, median age 55 years [range 36–66]). All 21 have completed PAD with a 95% PR/CR rate. 20/21 patients mobilised PBSC successfully (median collection 3.8 x 106 CD34+ cells/kg, range 1.6–10.4). 16 patients have received MEL200 with median neutrophil (>0.5 x109/L) and platelet engraftment (>20 x109/L) of 15 (1–24) and 13 (10–33) days respectively. Of patients who are assessable at 3 months post MEL200, 11/12 have achieved at least a PR (CR 4, nCR 1, VGPR 4 & PR 2). Toxicities have generally been acceptable with 15 grade 3 events: 6 infections, 4 episodes of shingles, 2 nausea and vomiting, 2 neuropathy and 1 postural hypotension. Overall, 48% of patients have experienced sensory or painful neuropathy which is of Grade 1 severity in 43% of cases. Of note, neuropathic symptoms are improving in all patients after completion of therapy.
Summary: These preliminary data show that PAD is well tolerated in the majority of patients, is highly effective and does not prejudice subsequent PBSC collection. A further cohort of patients will receive PAD with bortezomib at 1.0 mg/m2 in order to determine whether the frequency of neuropathy can be reduced whilst preserving efficacy. PAD should be further evaluated as first line therapy in prospective randomised trials.
Thalidomide and Rituximab in Waldenström’s Macroglobulinemia.
Authors: Branagan Andrew , Hunter Zachary , Santos Daniel Ditzel , Treon Steven P. 
Published: October 2019

Abstract
Rituximab and thalidomide are active agents in Waldenstrom’s macroglobulinemia (WM) producing major response rates of 25–50%. Moreover, as previously shown by us, thalidomide enhances rituximab mediated ADCC killing of lymphoplasmacytic cells (Blood 100:314b). As such, we conducted this phase II study using combination rituximab and thalidomide in WM patients who previously had not received rituximab or thalidomide. Intended therapy was as follows:
Weeks 1–52 Thalidomide (200 mg po qhs for 2 weeks, then 400 mg po qhs)
Weeks 2–5 Rituximab (375 mg/m2/week)
Weeks 13–16 Rituximab (375 mg/m2/week)
Patients were evaluated at week 12, and if they had at least stable disease (SD) were eligible for further therapy and for response evaluation. Dose modifications, delay, and/or discontinuation of thalidomide were permitted for toxicities. Twenty-five patients have been enrolled, 20 of whom were previously untreated. Six patients are off study, 4 because of no response and 2 because of deaths unrelated to protocol therapy. Grade 3/4 toxicities to thalidomide included neuropathy (n=15); somnolence or confusion (n=12); rash (n=7); tremors (n=2); bradycardia (n=2); other (n=3); and led to its eventual discontinuation in 11/19 patients. All evaluable patients received the intended rituximab therapy. Paradoxical IgM spikes following rituximab occurred during both courses of therapy and were observed in 12/25 (48%) patients similar to those spikes which we reported with rituximab monotherapy (ASH2003; 102:690a). Responses to date among the 23 evaluable patients are as follows: CR (n=1); PR (n=12); MR (n=2); SD (n=4). Four patients had no response to therapy. No patients with stable disease or better have progressed with a median follow-up of 10 months (range 6–13 months). Response to therapy is associated with cumulative dose of thalidomide. Patients who responded to therapy received a median thalidomide cumulative dose of 37,600 (range 5700–74,500) mg as compared to 5,650 (range 2100–21,000) mg among non-responding or stable disease patients. These studies demonstrate that thalidomide in combination with rituximab is active in WM, and associated with the cumulative dose of thalidomide. In view of the encouraging response rates obtained with this combination and the potential for improved toxicity profile, a phase II study examining the thalidomide analogue CC-5013 (Revlimid) plus rituximab is planned.
Prognostic Significance of Magnetic Resonance Imaging (MRI) of Bone Marrow in Previously Untreated Patients with Multiple Myeloma.
Authors: Moulopoulos Lia Angela , Gika Dimitra , Dellasale Kay , Weber Donna , Anagnostopoulos Athanasios , Alexanian Raymond , Dimopoulos Meletios A. 
Published: October 2019

Abstract
Purpose: To determine the prognostic value of spinal bone MRI in symptomatic patients with multiple myeloma requiring treatment.
Materials and methods: Between January 1990 and Decmber 2001, 142 patients with symptomatic multiple myeloma (MM) underwent MRI of the spine before initiation of treatment. All patients received primary treatment based on high dose pulse dexamethasone (D) such as VAD or Melphalan + D. High-dose therapy with autologous stem cell transplantation was administered to 61 patients. MRI patterns of involvement were correlated with known prognostic variables of myeloma (including the International Staging System (ISS)), with response to treatment and with survival.
Results: Focal marrow lesions with intervening normal marrow were identified in 50% of patients, diffuse marrow replacement in 28%, a variegated pattern consisting of innumerable small foci of marrow replacement on a background of normal marrow in 14% and normal MRI pattern in 8% of patients. When patients with diffuse pattern were compared to patients with other MRI patterns, they had features of more advanced disease such as higher ISS, anemia, hypercalcemia, extensive bone marrow plasmacytosis, elevated serum LDH and impaired renal function. Patients and disease features were similar among patients with normal, focal or variegated MRI patterns. The frequency of response to primary treatment was similar among patients with different MRI patterns. Median survival was 24 months for patients with a diffuse pattern, 51 months for those with a focal pattern, 52 months for variegated and 56 months for patients with normal pattern (p=0.001). The presence or absence of diffuse MRI pattern separated the patients with ISS 1 and 2 into two subgroups with significantly different survival times of 28 months and 61 months respectively (p=0.01). Among patients with ISS 3, those with a diffuse pattern had a median survival of 18 months, whereas the remaining patients survived for a median of 30 months (p=0.5). Furthermore, a diffuse pattern predicted an inferior outcome both in patients who did or did not receive high dose therapy with autologous stem cell transplantation.
Conclusion: MRI of the spine before treatment provides prognostic information for symptomatic patients with myeloma, especially for those with ISS 1 or 2. Diffuse marrow replacement on MRI of the spine identifies patients with advanced MM who have a poor prognosis. Such patients are candidates for innovative treatments.
Long-Term Id Vaccination Combined with IL-12 or IL-12 and GM-CSF in Early Stage Multiple Myeloma Patients.
Authors: Hansson Lotta , Abdalla Amir O. , Rabbani Hodjattallah , Osterborg Anders , Mellstedt Hakan 
Published: October 2019

Abstract
The idiotypic structures expressed on the myeloma Ig protein may serve as tumor specific antigens and can be used as target structures for Id (Id) vaccination. In this study, 28 patients with IgG myeloma stage I-II were repeatedly immunized intracutaneously during a 110 week period with the autologous M-protein, either in combination with interleukin-12 (IL-12) (n=15), or with IL-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (n=13). An Id-specific T cell response, as assessed by [3H]-thymidine incorporation, ELISPOT assay and delayed type hypersensitivity (DTH) reaction and strictly defined by 3 specified criteria, developed in 4/15 patients (27%) in the IL-12 group and 11/13 patients (85%) in the GM-CSF/IL-12 group (p=0.003). Three of 15 patients (20%) showed a gradually increasing Id-specific T cell response during the study whereas 10/15 patients (67%) showed an initial response which then disappeared rapidly; the latter pattern was frequently associated with subsequent progressive disease. In two patients (both in the IL-12 group) a reduction of the M-protein concentration by > 50% and >25%, respectively, was observed 18 and 21 months after the last immunization. These results indicate that Id immunization of myeloma patients using IL-12 and GM-CSF may more frequently induce a specific T cell response than with IL-12 alone, but also that repeated immunizations may result in a non-reversible state of tolerogenic T cells.
Pediatric Essential Thrombocythemia (ET): Evaluation of Clonality Status.
Authors: Pacquola Enrica , Scapin Margherita , Putti Maria C. , Tucci Fabio , Randi Maria L. , Fabris Fabrizio 
Published: October 2019

Abstract
ET is a very rare disease in pediatric age and some evidence suggest that ET in childhood may be a possible variant of the ET as described in adults. Clonal assays using X chromosome inactivation patterns (XCIPs) have been used to demonstrate the clonal origin of ET. However, about half women with ET seem to have a polyclonal XCIPs and the occurrence of thrombosis seems to be higher in patients with monoclonal XCIPs. We report 7 females in pediatric age affected with ET (mean age at diagnosis 9 years). The diagnosis of ET was made in agreement with the Polycythemia Vera Study Group Criteria. The main clinical data of our children are summarized in the table. None of the children had heavy haemorrhages nor splenomegaly. HUMARA trinucleotide repeated polymorphism in granulocytes DNA amplified using two primers flanking the STR, was used to assess myeloid clonality of our patients. The PCR products will be quantified after electrophoresis with density analysis. T lymphocytes DNA of the patients were also tested for the HUMARA polymorphism as control. Monoclonal granulocytes XCIPs was demonstrated in only 1 asymptomatic child who had polyclonal T-lymphocytes, while 5 other children had polyclonal XCIPs of both granulocytes and T-lymphocytes. Omozygous XCIP of 1 chlid did not permit clonality evaluation.
In conclusion, as observed in adults, also children with ET seem to be heterogeneous concerning clonality status. The percentage of polyclonal cases seem to be higher in pediatric age if compared with adults (data of the literature). The sole patient with a major thrombotic complication is polyclonal. Again pediatric ET seems to be different than adults ET: more studies are needed to clarify the biological characteristics of pediatric ET
age plts x 10to9/L clinical symptoms TPO pg/ml clonality granulocytes/T lymphocytes CV 9 m 945 Budd Chiari syndrome 30 polyclonal/polyclonal GM 12 y 1611 headache 30 omozygous TF 10 y 1038 headache 9 polyclonal/polyclonal FE 6 y 3266 headache + purpura 15 polyclonal/polyclonal BC 14 y 1308 asymptomatic 25 monoclonal/polyclonal GI 9 y 2718 asymptomatic 22 polyclonal/polyclonal 8 y 1550 asymptomatic 64 polyclonal/polyclonal
Cooperation between MYC and BCL2 to Induce Lymphoma Is Uncovered in an Adult Context.
Authors: Fan Alice C. , Giuriato Sylvie , Feng Charles , Padua Rose Ann , Felsher Dean 
Published: October 2019

Abstract
MYC overexpression is thought to induce tumorigenesis through a variety of different mechanisms including the induction of proliferation, inhibition of differentiation and disruption of genomic stability. Conventional transgenic systems that have been used to study the role of oncogenes in tumorigenesis continuously overexpress transgenes and hence preclude the investigation of the initial and age specific consequences of oncogene activation. To investigate the developmental specific consequences of MYC overexpression in the pathogenesis of lymphoma in vivo, we used transgenic mice in which the MYC proto-oncogene is conditionally regulated via the Tetracycline Regulatory System (Tet system). The ability of MYC to induce lymphomagenesis was found to be inversely correlated with the age of the host at the time of MYC activation. When MYC was activated constitutively, the mean time until tumor development was 13 weeks. When MYC was activated at increasing developmental ages of 3 and 5 weeks, identical tumors arose, but with an increased mean tumor latency. When MYC was activated at 7 weeks, an age equivalent to an adult mouse, no tumors developed even after 40 weeks of observation. However, we found that in adult mice, if both MYC and BCL2 are overexpressed at 7 weeks of age, mice succumbed to lymphoma with a mean latency of 27 weeks. Surprisingly, we could not find evidence that MYC overexpression induces apoptosis or that BCL2 overexpression reduced apoptosis. We conclude that the ability of MYC to induce lymphomagenesis is highly dependent on the developmental context. MYC and BCL2 cooperate to permit tumorigenesis in adult mice. Since lymphoma occurs generally as a disease in adults, this suggests that previous reports may have greatly overestimated the ability of MYC activation to induce tumorigenesis and underestimated the potential cooperation between MYC and BCL2 oncogenes. Our results also suggest that BCL2 may cooperate with MYC to induce lymphomagenesis through additional mechanisms other than preventing MYC from inducing apoptosis.
Disruption of the Hexb/Enc-1 Antisense Gene and Identification of Elevated Enc-1 Expression in Patients with Hairy Cell Leukemia.
Authors: Lerner Mikael , Hammarsund Marianne , Sangfelt Olle , Zhu Chaoyong , Merup Mats , Jansson Monika , Gahrton Goesta , Kluin-Nelemans Hanneke , Einhorn Stefan , Grander Dan , Corcoran Martin 
Published: October 2019

Abstract
Chromosomal aberrations on chromosome 5 and in particular band 5q13 is frequently seen in Hairy Cell Leukemia (HCL). Detailed characterization of a constitutional inv (5)(p13.1q13.3) breakpoint in one HCL patient yielded a number of candidate genes that might be important for the development of this malignancy. One of these was beta-hexosaminodase, HEXB, commonly mutated in the lysosomal storage disorder Sandhoff disease. The 5q13.3 breakpoint disrupts a novel evolutionarily conserved alternative isoform of HEXB. This isoform directly overlaps, in a cis-antisense fashion, the first exon of the gene for ectodermal neuronal cortex 1, ENC-1, and was thus named ENC-1AS. The ENC-1 gene has previously been shown to be overexpressed in a variety of malignancies and has been described as a potential oncogene. Analysis of ENC-1 in purified primary HCL tumor cells showed marked upregulation of ENC-1 expression in all patients examined, compared to normal peripheral blood lymphocytes from healthy donors. Although initially found as a p53-induced gene, the upregulation of ENC-1 in HCL follows a p53-independent pathway since activation of the p53 pathway did not lead to further increase in ENC-1 expression in HCL cells. Examining the ENC-1/ENC-1AS locus in more detail, we identified a complex regulatory mechanism involving an inverse expression of the ENC-1 sense and the ENC-1AS transcripts in several tissues. Thus, it appears as if upregulation of ENC-1 is a common phenomenon in HCL and that the regulation of this gene may be dependent on its novel antisense partner ENC-1AS.
Human Platelet Glycoprotein VI: Identification of Residues Involved in the Binding to Collagen.
Authors: Jandrot-Perrus Martine , Lecut Christelle , Arocas Veronique , Ulrichts Hans , Villeval Jean-Luc , Lacapere Jean-Jacques , Deckmyn Hans 
Published: October 2019

Abstract
Glycoprotein VI (GPVI), an essential platelet collagen receptor, belongs to the immunoglobulin (Ig) superfamily and presents two Ig-like loops in its extracellular domain (EC1, EC2). Little is known about the structures involved in GPVI binding to collagen and to its specific ligands, convulxin and collagen related peptides (CRP). Our aim was to characterize these sites using different approaches: competition assays, monoclonal antibodies (MoAb) directed against the GPVI extracellular par, phage display, molecular modelling and site-directed mutagenesis. In binding assays using soluble or cell-expressed human GPVI, we observed that: (i) collagen, CRP and convulxin, competed with one another for the binding to GPVI; (ii) GPVI interaction with either ligand is inhibited by at least two MoAb directed to different independent epitopes, and (iii) MoAb displayed selective inhibitory properties on GPVI interaction with each ligand. These observations indicate that the binding sites on GPVI for the diverse ligands seem to be distinct, exhibiting specific features but at the same time sharing common elements. MoAb 9O12 is a potent inhibitor of GPVI binding to collagen. Its epitope was mapped by screening a 15 mer linear peptide library. This allowed the identification of a motif of 7 residues of which 5 are conserved and that presented a relative homology with the GPVI 30–40 sequence. In a computer model, these residues appeared in close vicinity on a surface loop exposed at the surface of the molecule and accessible to ligands. Site-directed mutagenesis revealed that Val34 and Leu36 are critical for GPVI interaction with collagen and CRP. This study allowed the identification of residues within a loop on GPVI EC1 that might be part of a collagen/CRP-binding site.
The Cytoplasmic Tail of GPIbß Modulates Signalling Induced by GPIb/VWF Interactions under High Shear Conditions.
Authors: Martin Kenneth , Feng Shuju , Kroll Michael H. , Kenny Dermot 
Published: October 2019

Abstract
The platelet glycoprotein (GP) Ib/IX/V receptor complex controls crucial steps in haemostasis and thrombosis by mediating adhesion to von Willebrand factor (VWF). Nevertheless, the downstream consequences of VWF binding to GPIb remain unclear. The GPIb/IX/V complex consists of four polypeptides GPIbα, GPIbβ, GPIX and GPV. We have shown that a palmitylated (Pal-) peptide based on the sequence of the GPIbβ cytoplasmic domain between R151 and A161 (Pal-RRLRARARARA abbreviated to RARA) increases the velocity of platelets rolling on VWF, and inhibits VWF-dependent adhesion and aggregation.
The peptide RARA is delivered into platelets and does not cause any reduction in the surface expression of GPIb-IX-V. We examined the effect of RARA and control peptides (Pal-RAAAARARARA and Pal-RRLRADADADA) on GPIb/IX/V-mediated tyrosine kinase signalling induced by VWF/GPIb interactions under shear conditions using a cone and plate viscometer. Whole platelet lysate phosphotyrosine immunoblots were characterised in the presence and absence of RARA and the control peptides before and after shearing at 120 dynes/cm2 for 5 mins. We then further investigated the effect of RARA on PI-3 kinase signalling, the tyrosine kinase Src and calcium influx under the conditions described above.
The platelet permeable peptide RARA alone specifically caused protein tyrosine phosphorylation under resting conditions and caused platelet microaggregate formation with a 35% reduction in single platelets as assessed by flow cytometry. In addition RARA significantly inhibited shear-induced aggregation. When tyrosine phosphorylation was examined in platelets sheared for 5 minutes at 120 dynes/cm2, we observed RARA failed to inhibit tyrosine phosphorylation despite inhibiting shear-induced aggregation.
RARA caused Src kinase activation as determined by site-specific phosphorylation of Y416 on Src. Furthermore the Src inhibitor PP1 inhibited RARA induced tyrosine phosphorylation. RARA caused a Src-dependent increase in intracellular [Ca2+] and inhibited any further increase in intracellular calcium induced by thrombin. Pretreatment of platelets with the PI-3 kinase inhibitor wortmannin demonstrated that tyrosine phosphorylation induced by RARA was not PI-3 kinase dependent.
These results indicate that a platelet permeable peptide corresponding to specific residues of the cytoplasmic tail of GPIbβ directly stimulates Src, and suggest that the mechanism of its inhibitory effect on VWF-mediated platelet adhesion and aggregation involves the tyrosine kinase-mediated desensitisation of a GPIb/IX/V-triggered signalling pathway. This study demonstrates a novel role for the GPIbβ cytoplasmic tail in mediating Src-dependent shear induced signalling through GPIb/VWF.