bluuebunny/crossref_metadata_2025 huggingface dataset:
Bilateral total shoulder arthroplasty: A systematic review of clinical outcomes
Authors: Smith John-Rudolph H , Houck Darby A , Hart Jessica A , Bravman Jonathan T , Frank Rachel M , Vidal Armando F , McCarty Eric C
Published: April 2020

Background

The purpose of this study was to describe the clinical outcomes following bilateral total shoulder arthroplasty (TSA).

Methods

A systematic search of the PubMed, Embase, and Cochrane Library databases following PRISMA guidelines was performed. English-language literature published from 2010 to 2018 analyzing bilateral TSA (anatomic and/or reverse) with a minimum one-year follow-up was reviewed by two independent reviewers. Study quality was evaluated with the Modified Coleman Methodology Score and the methodological index for non-randomized studies score.

Results

Eleven studies (1 Level II, 3 Level III, 7 Level IV) with 292 patients were included. Two studies reported on bilateral anatomic TSA ( n = 54), six reported on bilateral reverse TSA (RTSA; n = 168), two reported on anatomic TSA with contralateral RTSA (TSA/RTSA; n = 31), and one compared bilateral anatomic TSA ( n = 26) and bilateral RTSA ( n = 13). Among studies, mean revision rate ranged from 0% to 10.53% and mean complication rate ranged from 4.9% to 31.3%. At final follow-up, patients experienced significant overall improvements in range of motion and patient-reported outcome score measurements. However, bilateral anatomic TSA resulted in greater improvements in external rotation compared to bilateral RTSA. Overall patient satisfaction was 91.0%.

Conclusion

The available data indicate that bilateral TSA allows for functional and pain improvements and result in high patient satisfaction.

Level of evidence

IV.
Glenoid bone grafting in primary anatomic total shoulder arthroplasty: a systematic review
Authors: Zhang Betty , Niroopan Gavinn , Gohal Chetan , Alolabi Bashar , Leroux Timothy , Khan Moin
Published: April 2020

Background

Primary anatomic total shoulder arthroplasty can be challenging in patients with complex glenoid wear patterns and bone loss. Severe retroversion (>15°) or significant bone loss may require bone grafting. This review summarizes the rate of revision and long-term outcomes of anatomic total shoulder arthroplasty with bone graft.

Methods

A systematic search of MEDLINE, Embase, PubMed, and CENTRAL databases was conducted from the date of inception to 23 October 2018. Two reviewers independently screened articles for eligibility and extracted data for analysis. The primary outcome was rate of revision. The secondary outcomes were rate of component loosening, functional outcome, and range of motion.

Results

Of the 1056 articles identified in the search, 26 underwent full-text screening and 7 articles were included in the analysis. All procedures were one-stage anatomic total shoulder arthroplasties. The rate of revision was 5.4% with component loosening and infection listed as indications over a weighted mean follow-up period of 6.3 years. Complications occurred in 12.6% of patients.

Conclusion

Glenoid bone grafting in anatomic total shoulder arthroplasty results in comparable revision rates and improvement in pain compared to augmented glenoid components and reverse shoulder arthroplasty. Due to the low quality of evidence, further prospective studies should be conducted.

Level of evidence

IV
Subclinical progression of systemic sclerosis-related cardiomyopathy
Authors: Stronati Giulia , Manfredi Lucia , Ferrarini Alessia , Zuliani Lucia , Fogante Marco , Schicchi Nicolò , Capucci Alessandro , Giovagnoni Andrea , Russo Antonio Dello , Gabrielli Armando , Guerra Federico
Published: April 2020

Aims

Cardiac involvement in patients with systemic sclerosis (SSc) is frequent and represents a negative prognostic factor. Recent studies have described subclinical heart involvement of both the right ventricle (RV) and left ventricle (LV) via speckle-tracking-derived global longitudinal strain (GLS). It is currently unknown if SSc-related cardiomyopathy progresses through time. Our aim was to assess the progression of subclinical cardiac involvement in patients with SSc via speckle-tracking-derived GLS.

Methods

This was a prospective longitudinal study enrolling 72 consecutive patients with a diagnosis of SSc and no structural heart disease nor pulmonary hypertension. A standard echocardiographic exam and GLS calculations were performed at baseline and at follow-up.

Results

Traditional echocardiographic parameters did not differ from baseline to 20-month follow-up. LV GLS, despite being already impaired at baseline, worsened significantly during follow-up (from –19.8 ± 3.5% to –18.7 ± 3.5%, p = .034). RV GLS impairment progressed through the follow-up period (from –20.9 ± 6.1% to –18.7 ± 5.4%, p = .013). The impairment was more pronounced for the endocardial layers of both LV (from –22.5 ± 3.9% to –21.4 ± 3.9%, p = .041) and RV (–24.2 ± 6.2% to –20.6 ± 5.9%, p = .001). A 1% worsening in RV GLS was associated with an 18% increased risk of all-cause death or major cardiovascular event (p = .03) and with a 55% increased risk of pulmonary hypertension (p = .043).

Conclusion

SSC-related cardiomyopathy progresses over time and can be detected by speckle-tracking GLS. The highest progression towards reduced deformation was registered for the endocardial layers, which supports the hypothesis that microvascular dysfunction is the main determinant of heart involvement in SSc patients and starts well before overt pulmonary hypertension.
Major Cytogenetic Responses to BMS-354825 in Patients with Chronic Myeloid Leukemia Are Associated with a One to Two Log Reduction in BCR-ABL Transcript.
Authors: Shah Neil P. , Branford Susan , Hughes Timothy P. , Nicoll John M. , Decillis Arthur P. , Sawyers Charles L.
Published: April 2020

The success of imatinib for the treatment of chronic myeloid leukemia (CML) has created a need for a sensitive and accurate method of monitoring disease response and burden. Quantitative PCR (Q-PCR) has been previously shown to correlate well with cytogenetic response in patients treated with imatinib, whereby a one-log reduction in BCR-ABL transcript level corresponded well with attainment of a major cytogenetic response (MCyR) and a two-log reduction correlated with a complete cytogenetic response (CCyR) (Branford et al, Leukemia17:2401, 2003). BMS-354825 is a novel orally bioavailable SRC/ABL kinase inhibitor with impressive activity against imatinib-resistant BCR-ABL mutant isoforms in vitro (Shah et al, Science305:399, 2004). The compound is presently undergoing evaluation in phase I clinical trials (see Sawyers et al, Talpaz et al, abstracts submitted for this meeting). We sought to address whether cytogenetic responses in patients treated with BMS-354825 correlated with reduction in BCR-ABL transcript levels as determined by Q-PCR. Of 13 evaluable imatinib-resistant/intolerant patients with chronic phase CML treated at UCLA, four have attained a MCyR. Achievement of MCyR corresponded with a one to two-log reduction in BCR-ABL transcript as assessed by Q-PCR. In the majority of cases, a substantial reduction in BCR-ABL transcript was detected four weeks after initiation of BMS-354825. Overall, the median reduction in BCR-ABL transcript level after four weeks of therapy was 32%. Three of these patients had developed resistance to imatinib, and two harbored the common imatinib-resistant M351T mutation. Of the nine patients who have failed to achieve a MCyR, none have achieved a one log reduction in BCR-ABL transcript level. We conclude that similar to imatinib, BMS-354825-associated MCyR in chronic phase CML is highly associated with a one to two-log reduction in BCR-ABL transcript level. Furthermore, Q-PCR offers a rapid and reliable method to assess for disease response in this setting, which promises to be of significant clinical value. Although the maximal tolerated dose of BMS-354825 has yet to be determined, the compound is clearly capable of substantially reducing disease burden in patients with imatinib-resistant CML. Updated Q-PCR data from all chronic, accelerated, and blast crisis-phase patients on study at UCLA will be presented.
Single Daily Dose of I.V. Busulfan (BU) in Pediatric Patients. Feasibility, Pharmacokinetics (PK) and Toxicity.
Authors: Kletzel Morris , Jacobsohn David , Tse William , Duerst Reggie
Published: April 2020

Administration of oral BU is a challenge in pediatric patients. The I.V preparation can improve compliance and eliminate variability in absorption. The metabolism and clearance of BU is age dependant. A prospective trial using a single daily dose of I.V. BU as part of a reduced Intensity Regimen was undertaken. Patients were enrolled after proper informed consent was signed... The regimen consisted of a test dose of BU (0.8mg/kg as a 2 hr infusion) on day -10, Fludarabine 25mg/m2/day from day-10 to -5, BU 3.2 mg/Kg/Day on days -5 ,-4.and rabbit ATG 2mg/kg daily on days -4 to-1. Cells were infused on day 0. The stem cell source were UCB (n=4), MUD (n=7) and MSD (n=1). PK samples (2, 4, 6,8,12 hrs) were obtained and submitted to the Seattle Cancer Care Alliance for determination of the Area Under the Curve (AUC) and clearance for BU. Twelve patients were enrolled (8F, 4M), median age 8 (0.5–16), median weight 22.6 kg (4.3–58.8) with the following diagnoses: Neuroblastoma (n=3), ALL (n=3), CML (n=2), Aplastic Anemia and X linked Lymphoprolipherative Disease, Ommen’s syndrome, Severe Combined Immune Deficiency. An AUC of 800–1200 and 3200–4800 uMol*min were targeted for the test dose and the single daily dose respectively. The median AUC for the test dose was 1003 uMol*min (804–1315), and the median clearance was 3.1 (ml/min)/Kg (2.4–7.3). The median AUC for the single daily dose was 3512 uMol*min (1511–4097) and the clearance 3.4 (ml/min)/kg (2.8–6.8). After the test dose 4 patients had their dose adjusted (2 patients lower and 2 patients higher). In the very young patients (< 1 year of age) the AUC of the single daily dose could not be predicted due to abnormal clearance. No instances of VOD or seizures were observed. Full donor chimerism was achieved in 8 patients in a median of 23 days (14–53), 2 patients developed graft failure, 1 patient was not evaluable for engraftment due to early TRM from pre-existing CMV pneumonia and 1 patient is too early. In conclusion, a single daily dose of I.V. BU is feasible, a test dose can be a predictor of the single daily dose AUC except in the very young, No regimen related toxicity was observed and engraftment was prompt and complete in 8 evaluable patients.
A Genomic and Proteomic Research for the Regulatory Networks of ATRA-Induced Differentiation of Acute Promyelocytic Leukemia Cells.
Authors: Huang Qiu-Hua , Zhang Qun-Ye , Shen Shu-Hong , Zheng Pei-Zheng , Lu Jing , Jing Yi , Zhang Ji , Wang Kan-Kan , Chen Sai-Juan , Chen Zhu
Published: April 2020

The treatment of acute promyelocytic leukemia (APL) with all trans retinoic acid (ATRA) has set a model for the differentiation induction-based new therapy. Although a substantial body of data related to ATRA-induced differentiation mechanisms has been obtained, the molecular events down stream of RA receptor complexes remain obscure. With the goal to get further insights into regulatory networks underlying ATRA-induced differentiation in APL, we applied 2DG, MS and cDNA microarray combined with bioinformatics analysis such as self-organizing map(SOM) to profile NB4 cells treated with ATRA over 3 time points (0h, 12h, 48h). Our results showed that cell cycle was arrested and proliferation was suppressed. For instance, ;the Origin recognition complex subunit 3 involved in initiating DNA replication that make the cell switch to S phase was downregulated significantly at protein (67.55 times) and mRNA levels; Breast cancer type 2 susceptibility protein (BRCA2) that can interact with BRAF335 as the checkpoint of G2 / M phase was upregulated while mRNA expression unchanged. Our results showed that the expression of many proteins associated with Ca2+ signal pathway such as IP3 receptor isoform 1 and phospholipase C-β changed upon induction with ATRA, implying that Ca2+ signal pathways may play an important role during ATRA-induced APL cell differentiation. Our results also indicated that the cell apoptosis was inhibited in the process of ATRA-induced differentiation. For example, BFL1, one of the BCL-2 family and the main apoptosis repressor in neutrophils, was upregulated at protein and mRNA levels. BCL2-like13 is one of the BCL-2 families and its overexpression initiated the cell apoptosis pathway by activating caspase-3. It was downregulated at protein level. Our results revealed that the phosphopentose pathway and ribonucleotide synthesis were repressed obviously. The protein expressions of the key enzyme of phosphopentose pathway - Glucose-6-phosphate dehydrogenase and rate-limiting enzyme of purine nucleotide de novo synthesis - AICAR methylferase and adenylosuccinate synthetase were all downregulated remarkably. Moreover, the protein expression of nitricoxide synthase 2A was upregulated 236 times after 12 hours of treatment with ATRA. The dramatic changes imply that the effect of NO on the differentiation induced by ATRA deserves more investigation. In brief, the data presented above indicated the expression of a large number of genes and proteins is modulated upon effect of ATRA during ATRA-induced APL cell differentiation, resulting in a complex and well-organized network to ensured cell reprogramming.
The Follicular Lymphoma International Prognostic Index (FLIPI) as Part of a Proposed Prognostic Model for Follicular Lymphoma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation (ASCT).
Authors: Keeney Grant E. , Gooley Theodore A. , Press Oliver W. , Pagel John M. , Petersdorf Stephen H. , Maloney David G. , Gopal Ajay K.
Published: April 2020

The FLIPI has recently been demonstrated to correlate with survival in patients (pts) with newly diagnosed follicular lymphoma (FL). No such index has been developed or evaluated to predict outcome for FL pts in the setting of myeloablative therapy and ASCT, despite data suggesting that ASCT may improve overall and progression-free survival (PFS). We examined the factors that contribute to the FLIPI as well as other factors assessed at time of transplant for their association with overall survival (OS) in 189 pts undergoing ASCT for FL. Baseline characteristics included: median age = 47 years (range, 24 – 64), stage III–IV = 94%, >4 nodal areas = 7.7%, elevated LDH = 30%, >5 cm maximal bulk of disease = 18%, chemoresistant disease = 13%, median number of prior chemotherapy regimens = 2. The FL histologies included: Grade 1 (49%), Grade 2 (31%), Grade 3 (13%), and transformation to diffuse large B-cell lymphoma (6%). Patients were conditioned with chemotherapy-only (21%), chemo+TBI (45%), or radioimmunotherapy +/− chemo (34%). Among all pts, the five-year estimated OS and PFS are 58% and 39%, respectively, with a median follow-up among surviving pts of 8 years (range, 1 – 18). The five factors that were found to be most significantly associated with OS include two FLIPI factors [age, hazard ratio for death (HR) = 1.37 per ten-year increase in age; elevated LDH, HR = 1.57] and three other clinical factors [>1 maximal extranodal site of disease, HR = 1.67; ≥2 prior chemotherapy regimens, HR = 1.99; chemoresistant disease, HR = 2.8]. Patients with 0 – 1 adverse factors (with age dichotomized as < 45 vs. ≥ 45) had an estimated 5-year OS of 79%, those with 2 factors 50%, 3 factors 41%, 4 or 5 factors 13% (Figure). Although prospective validation of this proposed model is required, this approach may be used to counsel FL pts regarding expected outcome following ASCT, to compare data between trials, and to design future studies.

Figure Figure
Ferritin Heavy Chain, a Repressor of the Human β-Globin Gene That Binds a Conserved Cagtgc Motif, Is Bound to the Repressed β-Globin Promoter In Vivo in K562 Cells and Specifically Binds an Analogous Site in the Mouse βMajor-Globin Promoter.
Authors: Broyles Robert H. , Belegu Visar , Stewart Charles A. , Pye Quentin N. , Roth Austin C. , Harris Katharine M. , Floyd Robert A. , Jani Klodianna , Trudel Marie
Published: April 2020

Ferritin heavy chain (FH), an embryonically-expressed protein in the erythroid lineage, localizes to the nucleus and represses the human adult β-globin promoter in transient expression assays (Broyles et al., PNAS98: 9145, 2001). Recently, we have performed chromatin immunoprecipitation (ChIP) assays with cross-linked chromatin of K562 cells in which the β-globin gene is repressed, using anti-FH polyclonal antisera. These results strongly indicate that FH occupies the repression site (a CAGTGC motif) in vivo. Binding to this -150 site has been previously demonstrated to be required for β-promoter repression in co-transfections. EMSA assays (competitive gel shifts) have revealed that the mouse βMajor-globin promoter has an analogous CAGTGN motif at -160 bp from the cap site that competes specifically with the human CAGTGC site for FH binding. The mouse βMinor-globin promoter lacks the -150/-160 CAGTGN motif and, therefore, the FH binding site. Thus, a human FH transgenic mouse, in which the FH gene is driven by a truncated β-promoter lacking the CAGTGN motif, should express human FH in definitive erythroid cells where the FH would be predicted to repress βMajor-globin but not βMinor-globin. Such a mouse would be predicted to survive but be born with a mild β-thalassemia due to the decreased βMajor/βMinor ratio in its definitive erythroid cells. Preliminary results from the litters of F1 generation FH-tg mice indicate that such is indeed the case, i.e., that human FH functions as a βMajor-globin repressor in vivo.
A Multi-Institutional Study of Extracorporeal Photoimmune Therapy with UVADEX® for the Prevention of Acute GVHD in Patients Undergoing Standard Myeloablative Conditioning and Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Shaughnessy Paul J. , Bolwell Brian J. , Abhyankar Sunil , van Besien Koen , Mistrik Martin , Grigg Andrew , Dodds Anthony , Prince H. Miles , Machado Alexandra , Thienel Ulrich , Wang Jim , Foss Francine , Apperley Jane
Published: April 2020

Acute graft-versus-host disease (aGVHD) is partly mediated by host antigen presenting cells (APCs) that activate donor T-cells. Extracorporeal photoimmune therapy with UVADEX® (ECP) has shown benefit in some patients (pts) with GVHD, which was associated with decreased host APCs. We report preliminary results of the first multi-institutional phase II study examining ECP with a standard myeloablative preparative regimen prior to allogeneic hematopoietic stem cell transplantation (ASCT). ECP was given on two consecutive days between D-10 and D-6, followed by cyclophosphamide 60 mg/kg/day for 2 days and TBI 1200 cGy over 3 days. GVHD prophylaxis was Cyclosporine 3–5 mg/kg IV daily beginning D-1, and latter switched to PO, adjusted to keep levels 200–600 ng/ml, and methotrexate 10 mg/m2 on D1, 3, 6, and 11 for pts who had matched unrelated donors (MUD) or HLA class 1 one-antigen mismatched related donors (MMRD), or 10 mg/m2 on D1 and 5 mg/m2 on D3, 6, and 11 for pts who had matched related donors (MRD). Enrollment has been completed and data are available on 61 of 65 pts. The median age was 39 (20–60) years and 40 (66%) pts were male. Diagnoses included AML/MDS (n=20), ALL (n=14), CML (n=16), lymphoma (n=5), CLL (n=3), and other (n=3). Pts who received bone marrow (n=28) engrafted at a median of 20 (9–30) days, and pts who received peripheral blood (n=33) engrafted at a median of 15 (10–32) days. Grade II–IV and III/IV aGVHD occurred in 11 (38%) and 2 (7%) pts, respectively, who received MRD transplants (n=29), and in 16 (52%) and 10 (32%) pts, respectively, who received MUD transplants (n=31). No aGVHD occurred in 1 pt who received a MMRD transplant. Mild reversible hypotension related to ECP occurred in 1 pt who was able to continue on study. Chronic GVHD occured in 23 (42%) of 54 evaluable pts; limited in 15, extensive in 6, and unknown in 2 pts. There are 49 (80%) pts alive at a median follow up of 272 (23–560) days. Actuarial estimates of survival at one year are 93% for pts who received MRD transplants and 69% for pts who received MUD or MMRD transplants. Causes of death include relapse (n=4), aGVHD (n=3), multi-organ-system-failure (n=2), and 1 each of infection, interstitial pneumonitis, and neurologic toxicity. Preliminary results of this study reveal no adverse affects of ECP in combination with conventional preparative regimens or on engraftment after a standard myeloablative ASCT. Data correlating measurement of APCs with the incidence and severity of acute and chronic GVHD is pending. The overall survival of pts in this trial is encouraging and warrants further study.
ABO Incompatibility Is a Risk Factor for Intestinal Thrombotic Microangiopathy (TMA) after Allogeneic Stem Cell Transplantation.
Authors: Matsumoto Kimikazu , Hirabayashi Norio , Kato Koji , Matsuyama Takaharu
Published: April 2020

Intestinal thrombotic microangiopathy (TMA) after allogeneic stem cell transplantation is emerging as a major clinical issue, which is different from aGVHD in pathogenesis and clinical management. We performed a retrospective analysis of 140 pediatric patients with acute leukemia (82 ALL and 58 AML) who underwent allogeneic stem cell transplantation in Japanese Red Cross Nagoya First Hospital from 1991 to 2003 (69 from HLA matched sibling, 13 from HLA mismatched family donors and 58 from unrelated volunteer donors). Blood type was matched in 78 patients and mismatched in 62 patients (25 in minor , 26 in major and 11 in bidirectional). Seventeen patients developed intestinal TMA with a cumulative incidence of 13%. The median time to onset was 28 days (range, 10–104 days). Intestinal TMA was defined histopathologically by colonoscopic biopsies in 7 patients and bloody diarrhea and laboratory findings. Intestinal TMA occured in 28% of ABO minor mismatched transplantation, 32.5% of bidirectional, 14.4% of major mismatched and 5.8% in matched transplantation (p<0.01)(Fig1)p. In multivariate analysis, ABO minor mismatched transplants (HR=5.3, 95%CI 1.4–19.7, p=0.01), HLA mismatched related donors (HR=16.6, 95%CI 1.6–173.3, p=0.02 ) and unrelated donors (HR=16.4, 95%CI 2.0–130.6, p<0.01 ) were significantly associsted with the risk of intestinal TMA. The estimated 5-year overall survival (OS) was 47.1% in intestinal TMA patients compared with 56.7% in patients with no intestinal TMA (p=0.18). Intensified immunosuppressants for the treatment of intestinal TMA (n=5) lead to poor OS (20%). Seven out of 12patients (58%) who had reduced immunosuppressant were still alive with a median follow-up of 24 months (p=0.29). Our findings suggest that ABO mismatched transplantation, especially ABO minor mismatch, is a risk factor for developing intestinal TMA. Successful treatment for intestinal TMA by diminishing immunosuppressive drugs is warranted.

Figure Figure Figure Figure
Classification of Familial Hemophagocytic Lymphohistiocytosis Based on Genetic and Immunologic Analyses.
Authors: Ishii Eiichi , Ueda Ikuyo , Yamamoto Ken , Ohga Shouichi , Furuno Kenji , Morimoto Akira , Imayoshi Miyoko , Sako Masahiro , Takada Hidetoshi , Hara Toshiro , Imashuku Shinsaku , Sasazuki Takehiko , Yasukawa Masaki
Published: April 2020

Background: Familial hemophagocytic lymphohistiocytosis (FHL) is a disorder with an autosomal recessive mode of inheritance in infancy. Recently, mutations of the perforin (PRF1) and MUNC13–4 genes have been identified in FHL patients. Since natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) involve mechanisms to kill virus-infected and malignant cells via perforin/granzyme-mediated granule exocytosis pathway, cytotoxic functions of NK cells and CTLs are impaired in FHL. In the present study, we analyzed the correlation between clinical features, genetic abnormalites and cytotoxic functions of CTLs in patients with different FHL subtypes.

FHL families: In Japan HLH Study Group, total 57 Japanese patients fulfilled the diagnostic criteria of FHL and their family members were registered and the clinical data were collected from each family. Since the majority of FHL patients in Japan were registered in our study, it is thought that our data reflect the epidemiology of FHL in Japanese.

Results: Among 57 patients registered in this study, PRF1 mutations were detected in 11 patients (FHL2), whereas 8 showed mutations of MUNC13–4 gene (FHL3). When the clinical findings were compared, the FHL2 patients with PRF1nonsense mutation showed early onset, while the onset of those with both PRF1 missense mutation and MUNC13–4 mutation was late. Alloantigen-specific CD8+ CTL lines were established from the FHL patients and their healthy parents. The degrees of cytotoxicity mediated by CTL lines generated from the patients with various FHL subtypes were compared. CTLs generated from the FHL2 patients with PRF1 nonsense mutation exerted no antigen-specific cytotoxicity. The cytotoxicity of CTLs from the patients with MUNC13–4 mutation was low but still remained, whereas cytotoxicity of CTLs from those with PRF1 missence mutation appeared to be moderate. By Western blot analysis, the missense mutant PRF1 gene also produced full length protein, but the active mature form was markedly reduced, indicating that the proteolytic cleavage of perforin is inhibited in these patients.

Conclusion: The present study demonstrates that the subtypes of FHL can be classified by the patterns of genetic mutation and dysfunction of CTLs responsible for the pathogenesis of FHL. Although it has been established that allogeneic hematopoietic stem cell transplantation (HSCT) is a sole curative therapy for FHL, early identification of genetic defects and cytotoxic activity of CTLs may confirm whether HSCT should be really needed in each patient.
Mutator Genes UDG and AID Appear To Be Normal in Class-Switch Deficient and Clonally Homogeneous Waldenstrom’s Macroglobulinemias Having Either Germline or Hypermutated Clonotypic IgH VDJ.
Authors: Kriangkum Jitra , Taylor Brian J. , Strachan Erin R. , Treon Steven P. , Mant Michael J. , Reiman Tony , Belch Andrew R. , Pilarski Linda M.
Published: April 2020

Clonotypic B cells of Waldenstrom’s macroglobulinemia (WM) are characterized as CD20+IgM+IgD+ cells that are usually somatically mutated in IgH VDJ but for some patients, the clonotypic IgH VDJ is germline (unmutated).For both mutated and unmutated clones, WM lack ongoing somatic hypermutation (SHM) and class switch recombination (CSR). This may be due to abnormalities in switching and/or mutator genes. To understand the nature of unswitched tumor B cells, uracil DNA glycosylase (UDG) and activation-induced cytidine deaminase (AID), the two essential elements for CSR, were analysed in WM. Analysis of 12 WM clones characterized by somatic hypermutation showed that the mutation profile of VH genes had normal transition/transversion ratios at C or G, and thus did not suggest UDG abnormalities. Expression of AID was determined by single stage RT-PCR. Out of 14 patients studied (2 unmutated and 12 mutated VH clones), two of them (WM1-01 and WM1-08,with mutation rates of 0% and 6.2% respectively) gave positive bands. In WM1-01, despite having a germline IgH VDJ, AID is consistently expressed in two bone marrow samples collected three years apart and from which the identical unmutated clonotypic VDJ sequence was isolated. Full-length (FL) AID transcripts of WM have a conserved sequence, thus ruling out the possibility of functional defects due to point mutation. In addition, detection of AID in an unmutated VH clone suggested that lack of SHM does not result from an inability to produce AID. In addition to FL transcripts, three other splice variants were identified in both patients. Single cell analysis indicated that only a small compartment (10% or less), not all, of clonotypic B cells expressed AID, and multiple isoforms may be detectable in individual cells. Whether these splice variants that contain truncated C-terminal ends play a role in the regulation of CSR in WM remains to be investigated. Splice variants, nevertheless, may not characterize tumor B cells since up to 10% of AID-expressing normal activated B cells (n=3) also carried them. In vitro activation of clonotypic WM B cells by CD40L and IL4, using conditions that induced CSR in normal B cells, did not yield detectable class switching in WM B cells. In cultures of B cells from WM, the number of non-clonal B cells increased but the clonotypic B cells did not appear to expand, as indicated by the reduction of clonotypic IgM transcript at 5-days of culture. Thus, as well as failing to undergo somatic mutation or class switching, WM tumor B cells appear unresponsive to CD40L+IL4. They may be fundamentally unresponsive to signals for class switching and their clonal expansion may depend upon alternate signaling pathways.
Primary Central Nervous System Lymphoma of T Cell Origin: A Descriptive Analysis of 45 Cases from the International PCNSL Collaborative Group.
Authors: Shenkier Tamara , Blay Jean-Yves , O’Neill Brian P. , Poortmans Philip , Janke Kristoph , Abrey Lauren E. , Neuwelt Edward , Tsang Richard , Batchelor Tracy , Harris Nancy , Ferreri Andres J. , Ponzoni Maurilio , O’Brien Peter , Rubenstein James , Connors Joseph M.
Published: April 2020

To describe the demographic and tumor related characteristics and outcomes for patients with primary T-cell central nervous system lymphoma (TPCNSL). A retrospective series of patients with TPCNSL was compiled from twelve cancer centers and seven countries. This study involved 35 male and 10 female patients with a median age of 60 years (range 3–84). Twenty (44%) had Eastern Cooperative Oncology Group performance status (PS) of 0 or 1. Twenty six (58%) had involvement of a cerebral hemisphere and sixteen (36%) had lesions of deeper sites in the brain. Two patients had primary spinal cord lesions and one had meningeal disease only. Serum lactate dehydrogenase (LDH) was elevated in 7 of the 22 cases (32%) and cerebrospinal fluid (CSF) protein was elevated above normal in 19 of the 24 cases (79%) with available data. The median disease specific survival (DSS) for all patients was 25 months (95% confidence interval (CI) 11–38 months). The two and five-year DSS were 51 % (CI 35–66 %) and 17 % (CI 6–34 %) respectively. Univariate and multivariate analyses were conducted for the following factors: age (≤ 60 vs. > 60 years), PS (0 or 1 vs. 2, 3 or 4), involvement of deep structures of the central nervous system (no vs. yes), and methotrexate (MTX) use in the primary treatment (yes vs. no). Only PS and MTX use were significantly associated with better outcome with hazard ratios (HR) of 0.2 (CI 0.1–0.4) and 0.4 (CI 0.2–0.8) respectively. This is the largest series ever assembled of TPCNSL. The presentation and outcome appear similar to that of PCNSL of B cell origin. PS 0 or 1 and administration of MTX are associated with better survival. TPCNSL does not appear to require a different therapeutic management approach than B-cell PCNSL.
A Selective Inhibitor of c-Met Blocks an Autocrine HGF Growth Loop in ANBL-6 Cells and Prevents Migration and Adhesion of Myeloma Cells.
Authors: Borset Magne , Hov Hakon , Holt Randi U. , Ro Torstein B. , Fagerli Unn-Merete , Hjorth-Hansen Henrik , Baykov Vadim , Christensen James G. , Waage Anders , Sundan Anders
Published: April 2020

We examined the role of the hepatocyte growth factor (HGF) receptor c-Met in multiple myeloma by applying a novel selective small-molecule tyrosine kinase inhibitor, PHA-665752, directed against the receptor.

Four biological sequels of HGF related to multiple myeloma were studied: (1) proliferation of myeloma cells; (2) secretion of interleukin-11 from osteogenic cells; (3) migration of myeloma cells; and (4) adhesion of myeloma cells to fibronectin. We also examined effects of the c-Met inhibitor on intracellular signaling pathways in myeloma cells.

PHA-665752 effectively blocked the biological responses to HGF in all assays, with 50 % inhibition at 5-15 nM concentration and complete inhibition at around 100 nM. PHA-665752 inhibited phosphorylation of several tyrosine residues in c-Met (Y1003, Y1230/1234/1235, and Y1349), blocked HGF-mediated activation of Akt and p44/42 Mitogen-activated protein kinase (MAPK), and prevented the adaptor molecule Gab1 from complexing with c-Met. In the HGF-producing myeloma cell line ANBL-6, PHA-665752 revealed an autocrine HGF/c-Met-mediated growth loop. The inhibitor also blocked proliferation of purified primary myeloma cells, suggesting that autocrine HGF/c-Met-driven growth loops are important for progression of multiple myeloma. Conclusions: Collectively, these findings support the role of c-Met and HGF in the proliferation, migration, and adhesion of myeloma cells and identify c-Met kinase as a therapeutic target for treatment of patients with multiple myeloma.
Pretreatment Cytogenetic Abnormalities in Polycythemia Vera (PV) Determines the Effectivnes of Imatinib : Studies from a Multi-Institutional Trial.
Authors: Najfeld Vesna , Silver Richard T. , Hoffman Ronald , Salvado August , Weinberg Rona , Fruchtman Steven
Published: April 2020

In patients (pts) with hypereosinophilic syndrome imatinib selectively inhibits a receptor for the platelet-derived growth factors, PDGFRA and PDGFRB, and the receptor for stem cell factor (c-kit), the expression of which is increased in PV. Preliminary data suggests imatinib reduces phlebotomy requirements and may suppress endogenous erythroid colonies in PV. One goal of the multi-institutional trial of imatinib in PV (400 mg po/day at initiation) was to determine the possibility of eliminating abnormal cytogenetic clones. Of 27 PV pts enrolled, 20 had cytogenetic studies. Fifteen pts showed a normal initial karyotype and 5 pts (25%) were cytogenetically abnormal at imatinib initiation. These included: trisomy 9 (2 pts), isochromosome for 9p and 9q (1pt), monosomy 21 (1 pt) and del(5)(q15q32) (1pt). Fifteen sequential cytogenetic studies of 180 metaphase cells from 3 pts showing chromosome 9 abnormalities did not show a reduction in the percentage of abnormal cells. In contrast, monosomy 21, present in 5 of 25 metaphases was gradually eliminated with imatinib within 7 months. In the subsequent 8 months two follow up studies demonstrated only normal cells in 40 metaphase and 600 interphase cells. Deletion (5)(q15q32), detected in 55% metaphase and 77% interphase cells (using EGR1 probe), prior to imatinib, was reduced to 23% in interphase cells within 5 months. However, conventional cytogenetics showed 15 of 16 metaphase cells (94%) with del(5q), consistent with a proliferative advantage of the del(5q) clone. In addition, there was marked diminution in splenomegaly. Due to imatinib intolerance and persistent thrombocytosis of over 1 X 106, the drug was discontinued. To further elucidate the mechanism of imatinib in PV, progenitor cells were grown before and during imatinib treatment. Before imatinib, from the marrow sample showing 77% del(5q) cells, both epo- dependent and independent colonies, as well as CFU colonies were examined and all 800 evaluated interphase cells were normal. With a diminution of the del(5q) clone to 23%, 600 cellsi from epo independent colonies did not show del (5q). The inability to detect del (5q) in progenitor marrow cells is consistent with the notion that PV, like CML, has a multistep pathogenesis in which chromosome abnormalities are a later event in clonal progression. These observations further suggest that imatinib did not eradicate rearrangements of chromosome 9. However, 2 of 5 pts with abnormalities, -21 and del(5q), had either complete eradication or diminution of the abnormal cytogenetic clone. These findings suggest that different cytogenetic abnormalities, representing different molecular events, determine the diverse responses to imatinib observed in PV. Thus, cytogenetic abnormalities may be useful in predicting the biologic effect of imatinib in patients with PV.
Phase 2 Multicenter Trial of Gallium Nitrate in Patients with Advanced Non-Hodgkin’s Lymphoma (NHL).
Authors: Pro Barbara , Bociek R. G. , Chitambar Christopher R. , Gregory Stephanie A. , Leonard John P. , Smith Sandra , Novick Steven
Published: April 2020

While approved for treatment of cancer-related hypercalcemia, gallium nitrate (Ganite®; GN) has displayed broad antitumor activity as a single agent in Phase 2 trials, particularly in patients (pts) with bladder disease, Hodgkin’s disease, and NHL who received GN by bolus or continuous IV infusion (CIVI). To establish the safety profile and clincial activity in a large cohort of patients with a wide variety of histologies, we conducted a Phase 2 study in pts with both T- and B-cell lymphoma who had relapsed from standard anti-lymphoma therapy.

Eligibility criteria included: relapsed NHL; ECOG PS ≤ 2; measurable disease; adequate renal and hepatic function. GN was administered by CIVI daily via ambulatory infusion pump x 7 days every 3 wks at 1 of 2 daily dose levels, 200 or 300 mg/m2/d. Evaluation for efficacy required treatment with ≥ 2 cycles; all treated pts were considered evaluable for safety. A total of 88 pts were accrued to the trial, 44 pts at each dose level. Pt characteristics included: median age, 61 yrs (range 19–83); median prior regimens, 5 (range 1–13); median prior drugs, 9 (range, 1–15); median prior rituximab regimens, 2 (range, 1–6); no. of pts with prior stem cell transplant, 25 (28%); no. of pts with prior radiation therapy, 29 (33%).

At the 300 mg/m2 dose level, 30 pts are evaluable for response. The ORR in this dose level was 30% (7% CR or uCR), including 3/12 pts with diffuse LCL (DLCL) (2 post-BMT), 3/11 with follicular lymphomas (1 post-BMT), 2/3 pts with mantle cell NHL (1 CR), 0/2 pts with SLL, and 1/2 pts with peripheral T-cell NHL (1 uCR). The results in the 200 mg/m2 dose level are preliminary and currently under evaluation.

Most frequent (> 10%) grade 3/4 adverse reactions (through July 2004) included: anemia (32%); hypocalcemia (19%) (occasionally requiring parenteral replacement with Ca++ and Mg++); dyspnea (15%); and hypotension (11%). Optic neuritis or visual disturbance occurred in 4 pts: 3 pts at the 300 mg/m2 dose level (after 2, 3 and 6 cycles, respectively) and 1 pt at the 200 mg/m2 dose level (after 7 cycles). All patients discontinued therapy as a consequence of this adverse event; two pts were treated with high-dose corticosteroids. All patients improved after discontinuation.

These results demonstrate that gallium nitrate is an active and well tolerated agent in a heavily pretreated population of patients with NHL and suggest that it may be particularly useful in patients who cannot tolerate myelosuppressive regimens.
Preliminary Phase II Study Results of BBR2778 in Combination with Cyclophosphamide, Vincristine, and Prednisone in Patients with Relapsed Aggressive Non-Hodgkin’s Lymphoma.
Authors: Herbrecht Raoul , Borchmann Peter , Wilhelm Martin , Morschhauser Franck , Hess Georg , Kutz Klaus , Comis Silvia , Laffranchi Bernard L. , Engert Andreas
Published: April 2020

Background: Pixantrone (BBR 2778) is a novel aza-anthracenedione with superior activity compared to doxorubicin and mitoxantrone in various tumor models including hematological malignancies. Pixantrone single agent therapy led to major responses in patients (pts) with aggressive lymphoma including diffuse large B-cell lymphoma (DLCL). The safety of a CHOP-like regimen with pixantrone replacing doxorubicin (CPOP) was assessed in a dose-ranging study indicating a recommended dose of 150 mg/m² for pixantrone.

Method: In this phase II study the primary objective was to assess the efficacy of the CPOP regimen (cyclophosphamide 750 mg/m² d1, pixantrone 150mg/m² d1, vincristine 1.4mg/m² d1, limited to 2mg, and prednisone 100mg d1 to 5) in pts with relapsed DLCL, transformed follicular lymphoma (tFL) and mantle cell lymphoma (MCL) for a total of 6 cycles given every 3 weeks. Hematopoietic growth factors were not permitted for the first cycle and used thereafter according to the ASCO guidelines. Inclusion/exclusion criteria included at least one but not more than two previous chemotherapy lines containing an anthracycline/anthracenedione with a cumulative dose of less than 450mg/m² doxorubicin equivalent, a left ventricular ejection fraction (LVEF) >50%, no meningeal involvement, and HIV negative serology.

Results: 21 pts have currently been included. Data is available for the first 15 pts. Main baseline characteristics are: median age 65 y [35 – 76]; DLCL 10 cases, tFL 2 cases, MCL 3 cases; stage I/II 4 cases, stage III/IV 11 cases; median number of previous therapy lines 2 [1–5], median prior cumulative dose of anthracyclines 320 mg/m² [104 – 452 mg/m²]. 48 cycles of CPOP have been administered to date, with a median number of 4 per pt. Most common grade 3 or 4 adverse events were neutropenia [39 episodes in 10 (67%) pts], leucopenia [37 episodes in 10 (67%) pts], thrombocytopenia [3 episodes in 3 (20%) pts] and febrile neutropenia [8 episodes in 4 (27%) pts]. There was no treatment related death and no grade 3 or 4 organ toxicity. Treatment was delayed in 6 pts and the doses of pixantrone and cyclophosphamide were reduced in 5 pts for a grade 4 hematological toxicity or infection. Only one patient had a decrease of ≥10% of LVEF from 72% at screening to 56% after 6 cycles without clinical symptoms. Out of 12 pts currently evaluable for response, 6 (50%) responded to CPOP therapy: 5 CR and 1 PR (responses maintained for ≥8 weeks).

Conclusion : These early results of the CPOP regimen with 150 mg/m² of pixantrone indicates a high response rate in pts with relapsed aggressive B cell lymphoma with an acceptable and manageable safety profile.
Superagonistic Anti-CD28 Antibody TGN1412 as a Potential Immunotherapeutic for the Treatment of B Cell Chronic Lymphocytic Leukemia.
Authors: Lin Chia-Huey , Kerkau Thomas , Guntermann Christine , Trischler Martin , Beyersdorf Niklas , Scheuring Yvonne , Tony Hans-Peter , Kneitz Christian , Wilhelm Martin , Mueller Peter , Huenig Thomas , Hanke Thomas
Published: April 2020

B cell chronic lymphocytic leukemia (B-CLL) is characterised by an accumulation of malignant B cells, and impaired humoral and cellular immune responses. Evasion strategies of leukemic cells appear to involve down-regulation of co-stimulatory molecules as well as increased resistance to apoptosis. Here we provide data supporting a novel concept to treat B-CLL with a humanized, superagonistic monoclonal antibody specific for CD28 (TGN1412). Superagonistic anti-CD28 antibodies have been shown to activate human T cells in vitro without requirement for engagement of the T cell antigen receptor (Luhder et al., J. Exp. Med. 2003. 197(8):955–66). Indicative of their activation, TGN1412-triggered T cells from healthy donors upregulate, among other activation markers, CD40L, that has been reported to promote anti-leukemic effects when ectopically expressed on B-CLL cells (Wierda et al., Blood. 2000. 96 (9): 2917–2924). In this report, the responses of PBMCs from B-CLL patients to soluble TGN1412 were examined. We show that in a dose-dependent fashion, polyclonal T cell activation was induced by TGN1412 including proliferation, cytokine production and induction of activation markers such as CD25, CD71, CD134 (Ox40), CTLA-4 (CD152) and CD154 (CD40L). Significantly, modulation of malignant B-CLL cells was also observed. MHC class II molecules (HLA-DR), CD95 and the co-stimulatory molecules CD80 and CD86, but not the proliferation marker Ki-67, were strongly up-regulated upon TGN1412 stimulation. These data suggested that improved antigen-presenting functions of B-CLL cells were induced by TGN1412. Accordingly, preliminary data indicate that B-CLL cells isolated from TGN1412 stimulated cultures induced enhanced proliferation of both allogeneic and autologous T cells, and importantly, TGN1412 activated T cells exhibited enhanced CTL-activity against B-CLL cells. In conclusion, our data suggest that TGN1412 induces polyclonal T cell expansion and activation as well as increased APC function of B-CLL cells. They imply that TGN1412 may have future therapeutic benefit for B-CLL patients.
Characterization of T Cell Epitopes of the Receptor for Hyaluronic Acid Mediated Motility (RHAMM/CD168) in Acute Myeloid Leukemia.
Authors: Schmitt Michael , Li Li , Ringhoffer Mark , Barth Thomas , Wiesneth Markus , Dohner Hartmut , Greiner Jochen
Published: April 2020

To improve the clinical outcome of patients with acute myeloid leukemia (AML), immune therapies targeting leukemia associated antigens (LAAs) might be an approach complementary to chemotherapy and transplantation of hematopoetic stem cells. The receptor for hyaluronic acid mediated motility (RHAMM/CD168) has been defined as a LAA with specific expression. To define T cell epitopes of RHAMM/CD168 towards specific T cell immunotherapies, ten peptides were synthesized considering different computer algorithms and subjected to ELISPOT assays for interferon gamma and granzyme B, and to Cr-51 release assays. CD8+ T cells taken from the peripheral blood (PB) of 13 AML patients and presensitized with the RHAMM/CD168-derived peptides R3 (ILSLELMKL) or R5 (SLEENIVIL) did specifically recognize T2 cells pulsed with R3/R5. In contrast, CD8+ T cells isolated from the PB of 21 healthy volunteers were not able to lyse R3 or R5 pulsed T2 cells, even after presensitization. COS7 cells co-transfected with HLA-A*0201 and RHAMM/CD168 were lysed by R3 or R5 presensitized CD8+ T cells. Single HLA-A*0201 or RHAMM/CD168 transfected COS7 were not recognized. Cross-reactivity of the T cells was excluded by the use of unrelated peptides. K562 cells positive for RHAMM/CD168, but lacking HLA-class I molecules were not recognized indicating T cells and not NK cells as effector cells. The HLA class-I restricted lysis of COS-7 HLA-A*0201 and RHAMM/CD168 double- transfectants was confirmed by HLA class-I blocking antibody experiments. In an AML patient having received AML blast-derived dendritic cells, a higher frequency of RHAMM/CD168-peptide specific T cells was observed after four vaccinations when compared to his T cell status before vaccination. RHAMM/CD168 is also expressed in patients with other hematological malignancies which suggests a broad clinical applicability of its newly characterized T cell epitope peptides as a potential cancer vaccine.