bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amplification at 7q22 Targets CDK6 in T-Cell Lymphoma.
Authors: Nagel Stefan , Leich Ellen , Quentmeier Hilmar , Meyer Corinna , Zettl Andreas , Drexler Hans G. , Rosenwald Andreas , MacLeod Roderick A.F. 
Published: April 2020

Abstract
Genomic amplification is microscopically visible extrachromosomally as double-minute chromosomes (DMIN) or intrachromosomally as homogeneously stained regions (HSR). Both DMIN and HSR comprise iterated copies of discrete genomic regions (amplicons) effecting copy number increases associated with upregulation of target genes. In cancer cells, these usually comprise oncogenes such as MYC. Cytogenetic analysis of the anaplastic large cell lymphoma (ALCL) cell line SU-DHL-1 revealed an HSR on the long arm region of chromosome 7 (7q). Detailled analysis of this region by fluorescence in situ hybridization (FISH) using tilepath BAC clones identified an amplicon corresponding to 86–95 Mb (NCBI Build 36.1) at 7q22. Expression analysis using reverse transcription (RT)-PCR of candidate oncogenes mapped within the amplicon, comprising DBF4, SRI, AKAP9, GATAD1, CDK6 and PPP1R9A, highlighted cyclin-dependent kinase 6 (CDK6) as a plausible amplification target. With reference to other ALCL cell lines, including SR-786, lacking this amplicon, SU-DHL-1 displays upregulation of CDK6 at both the RNA and protein levels as indicated by semiquantitative RT-PCR, real-time quantitative (RQ)-PCR and immuno-cytochemistry. Another ALCL cell line, L-82, containing a larger amplicon (7q21-31), also showed enhanced CDK6 expression as analyzed by RQ-PCR. For a functional test both SU-DHL-1 and SR-786 cells were treated with rapamycin, an inhibitor of the AKT-pathway which is involved in degradation of CDK-inhibitor p27. In contrast to SR-786, SU-DHL-1 cells are resistant to the effects of rapamycin on both proliferation and G1 cell cycle arrest, implying that CDK6 overexpression may confer proliferative advantage. Copy number analysis of several tumor-relevant genes using a commercial PCR-based approach (MLPA) determined a nearly 5-fold amplification of the CDK6 gene in SU-DHL-1. Interphase FISH confirmed copy number increase in SU-DHL-1 and identified CDK6 amplification in 1/77 ALCL and 4/38 peripheral T-cell lymphoma patient samples, indicating that this genetic event is relatively rare among T-cell lymphomas. Taken together, we have identified an amplicon at 7q22 in T-cell lymphoma cells targeting CDK6 which is an important cell cycle regulator and probably connected to the increased proliferative capacity of these malignant cells. Although CDK6 amplification seems to be infrequent overall, it strengthens the importance of this gene in regulating proliferation among T-cell lymphomas and may, therefore, represent a potential molecular target for therapeutic intervention in these disease entities.
A Long-Term Study on Indolent Adult T-Cell Leukemia/Lymphoma (ATLL).
Authors: Takasaki Yumi , Tsukasaki Kunihiro , Iwanaga Masako , Imaizumi Yoshitaka , Tawara Masayuki , Joh Tatsuro , Kohno Tomoko , Yamada Yasuaki , Kamihira Shimeru , Ikeda Schuichi , Tomonaga Masao 
Published: April 2020

Abstract
Background: Previous report on the subclassification and the clinical course of ATLL with maximum follow-up duration of 7 years revealed that the prognosis of indolent (smouldering or chronic) type was much better than that of aggressive (lymphoma or acute) types. (Shimoyama M, et al. Brit J Haematol, 1991). The median survival time (MST) was 6.2, 10.2 and 24.3 months for acute, lymphoma and chronic types, respectively. A MST has not been established for the smouldering type. However, long-term prognosis of the indolent types has not been elucidated.
Method: The diagnosis of ATLL was made based on seropositivity for HTLV-1 and histologically- and/or cytogically-proven peripheral T-cell malignancy. Subclassification of ATLL was based on the Shimoyama’s criteria. A total of 90 patients with indolent ATLL (65 chronic type and 25 smouldering type) with a median age of 61 years, newly diagnosed from 1974 to 2003 at Nagasaki University, were analyzed for the clinical course and prognostic factors.
Results: MST for the patients was 4.5 years with 12 patients alive for more than 10 years. Projected 5-, 10- and 15-yr survival rates were 47%, 23% and 13%, respectively, with first steep slope and sequential slow slope without plateau phase of the survival curve. Sixty-three of the patients died; 46 died of ATLL, 11 of other disease, 2 of transplantation related death and 4 of unknown. Unfavorable prognostic factor for survival included advanced performance status (PS) (p=0.005), high LDH value (p=0.004), more than 4 total involved lesions (p=0.03), more than 3 extranodal lesions (p=0.004), the presence of neutrophilia (p=0.02) by univariate analyses. In multivariate analysis, advanced PS was significant. There was no significant survival-difference in relation to age, subtypes of ATLL or lymphocyte count. Thirty-five patients with complications at diagnosis tended to be poor prognostic, especially those with active multiple cancers (n=7) or opportunistic infections (n=9). Most patients were treated as a subtype of chronic lymphoid leukemia (CLL) with watchful waiting until disease progression to acute ATLL. Twelve patients, who were treated with chemotherapy immediately after diagnosis of indolent ATLL, showed poorer prognosis as compared to the others. Five patients with at least one of the following 4 factors: alteration in tumor suppressor genes, p14ARF, p16 INK4a or p53, or aneuploidy &gt;1 chromosomal locus by Comparative Genomic Hybridization analysis in ATLL cells, showed extremely poor prognosis.
Conclusions: The long-term prognosis of indolent ATLL was not good without plateau phase in the survival curve, similar to the findings in B-CLL. Advanced PS and genetic alterations in ATLL cells were poor prognostic factors.
Folicular and Diffuse Large B Cell Lymphoma Can Be Distinguished by 1H -Magnetic Resonance Spectroscopy.
Authors: Sanz Carolina , Barba Ignasi , Tapia Gustavo , Mate Jose-Luis , Barbera Angels , Ribera Josep-Maria , Ariza Aurelio , Garcia-Dorado David , Oriol Albert 
Published: April 2020

Abstract
Proton nuclear magnetic resonance spectroscopy (1H MRS) has proven useful in the metabolic characterization of neoplastic tissues both in vitro and in vivo. In vivo 1H MRS can be easily performed in conjunction with conventional MR imaging. Although 1H MRS studies of lymphoma have been performed both in cell lines and animal models, its usefulness as a differential diagnostic tool in lymphoma remains to be explored. T2-filtered high resolution proton magic-angle spinning (HRMAS) MRS of small tissue samples provides sufficient spectral resolution for the identification of chemical cell changes associated with malignancy. HRMAS data from 16 fresh frozen lymph nodes were studied. Histologically, 7 lymph nodes revealed grade I or II follicular lymphoma (FL) and 9 showed diffuse large B cell lymphoma (DLBCL). Each spectrum consisted of the accumulation of 64 scans with a CPMG sequence with an effective T2 delay of 32 ms and an overall experimental time of 6 minutes. Pattern recognition analysis was feasible in all cases except in one FL sample consisting almost exclusively of adipose tissue. Compared with DLBCL, FL cases showed increases in the signal intensity of resonances associted to taurine (3.43 ppm) and decreases in the signal intensity of resonances associated to alanine (1.47 ppm). The mean taurine/alanine ratio was 4.63 (95%SD 1.67) for FL and 1.41 (95%SD 0.69) for DLBCL (P = 0.004). The taurine/alanine ratio proved to be a powerful discriminator between FL and DLBCL at a 2.5 cutpoint, yelding a 90% specificity and an 83% sensitivity to identify DLBCL. Overlapping cases included a case of FL with a diffuse pattern and two cases of DLBCL evolving from indolent lymphomas. The 1H MRS assay proved that FL and DLBCL can be differentiated from a metabolomic standpoint and offers a unique way to explore the underlying biochemistry of malignant transformations. Unlike other techniques, MRS is potentially applicable in vivo and non-invasively in the diagnostic setting. The rapid assessment of nodes or masses before tissue sampling would allow preoperative decisions to be made more efficiently.
Follicular Lymphomas with and without Translocation t(14;18) Differ in Gene Expression Profiles and Genetic Alterations.
Authors: Leich Ellen , Salaverria Itziar , Bea Silvia , Zettl Andreas , Gascoyne Randy D. , Chan Wing-Chung , Braziel Rita M. , Rimsza Lisa M. , Weisenburger Dennis D. , Delabie Jan , Jaffe Elaine S. , Lister Thomas A. , Norton Andrew J. , Staudt Louis M. , Hartmann Elena M. , Mueller-Hermelink Hans-Konrad , Campo Elias , Ott German , Rosenwald Andreas 
Published: April 2020

Abstract
Follicular lymphoma (FL) is a B-cell non-Hodgkin lymphoma that is characterized in approximately 85% of cases by the chromosomal translocation t(14;18) involving BCL2. While FL3b generally lack the t(14;18), this translocation is also absent in 15% of FL grades 1, 2 and 3a. The current study was designed to identify the frequency of t(14;18)-negative FL in a series of 166 cases of FL1, 2 and 3a in which global gene expression profiles had been established previously (Dave et al., NEJM351:2159–69, 2004). Furthermore, we sought to compare genetic alterations and gene expression profiles between FL with and without the t(14;18). Combined polymerase chain reaction (PCR) and tissue microarray-based fluorescence in situ hybridization (FISH) identified 17 t(14;18)-negative FL cases in this series (9%). Virtually all FL cases carrying the t(14;18) showed BCL2 expression by immunohistochemistry (Dako, clone 124), whereas 11 of the FL cases without a t(14;18) were BCL2-negative at the protein level. Clinically, there was no difference between the t(14;18)-negative and -positive FL subgroups regarding age and gender distribution as well as in median survival times. Comparative genomic hybridization (CGH) in the 166 FL cases revealed a characteristic pattern of chromosomal gains and losses, as previously described. However, significant differences were observed between the t(14;18)-negative and -positive FL subgroups. Specifically, the t(14;18)-positive FL subgroup showed gains of chromosomes 18q (18%), 8q (12%) and X (13%), as well as losses of 13q (16%) and 10q (16%), whereas none of these aberrations were observed in the t(14;18)-negative FL cases. To compare gene expression between the two groups, we used gene set enrichment analysis (GSEA), BRB array tools and a two-sided t-test. Cell cycle-associated genes were found to be enriched in the t(14;18)-negative FL subset. These differences were even more pronounced in FL cases that lacked both the t(14;18) and BCL2 expression at the protein level. Importantly, genes expressed in non-malignant bystander cells appeared also differentially enriched and a cytotoxic gene expression signature was found to be more prominent in t(14;18)-negative FL. These findings point to a different composition of the non-neoplastic cells in t(14;18)-positive and -negative FL and could indicate subtle differences in the immunological microenvironment of t(14;18)-negative FL.
Bortezomib, Thalidomide, and Dexamethasone as Induction Therapy for Patients with Symptomatic Multiple Myeloma.
Authors: Kaufman Jonathan L. , Gleason Charise , Heffner Leonard , Lonial Sagar 
Published: April 2020

Abstract
The optimal induction regimen for patients with symptomatic myeloma who are eligible for transplantation is currently unknown. While thalidomide and dexamethasone is an effective regimen, it only has a 60 to 65% response rate and few complete responses (CR). Bortezomib based inductions have demonstrated a high response rate and an improved CR as well. Recently the IFM reported the initial results of the randomized bortezomib plus dexamethasone versus VAD induction followed by transplant, which demonstrated that fewer patients treated with bortezomib required tandem transplants. Wang et al reported a high induction response rate with the combination of BTD for only 2 cycles given over a 28 day cycle. Here we report our experience with the combination of BTD as induction therapy. 38 patients with symptomatic myeloma were treated with BTD as induction therapy. Patients received standard dose and schedule bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 with thalidomide at 100 mg/day, and 8 days of 40 mg dexamethasone every 21 days. The median age was 58 years (38–70) with 19 males. This was first line therapy for 29 patients, second line for 7 patients and 3rd line for 2. 12 patients had ISS stage 2 and 8 had ISS stage 3. The median β2M was 3.4 (1.66–41.89). Median creatinine was 1.1 (0.6–21.0). Nineteen patients had an IgG paraprotein, 6 an IgA, and 16 patients had light chain disease. The median number of cycles administered was 4 (2–8). Fifteen patients developed neuropathy of any grade. One patient developed grade 3 neuropathy. The overall response rate (CR, VGPR, plus PR) was 92%, with 58% of patients achieving a VGPR or better, and 21% of patients achieving an immunofixation negative CR. 1 patient had a minimal response and 2 patients had progressive disease (both patients presented with plasma cell leukemia). These two patients were treated with the combination of BTD with PACE chemotherapy. One of the two died from progressive disease and the other patient remains in complete remission after high dose therapy and autologous transplantation. 29 patients had consolidation therapy with high dose melphalan and autologous peripheral blood stem cell transplantation. Eight patients have collected stem cells without proceeding with immediate consolidation therapy. After a median follow up of 373 days, median progression free survival and overall survival have not been reached. One year overall survival is 97%. One year progression free survival is 87%. In conclusion, we report a very high response rate with a short course of bortezomib, thalidomide and dexamethasone with an acceptable toxicity profile. Follow up of patients in CR treated without high dose therapy and autologous transplant is in progress. Further studies of this active regimen are warranted.
Decreased Incidence of Osteonecrosis of the Jaw (ONJ) in Patients with Multiple Myeloma (MM) Treated with Zoledronic Acid (ZA) after Application of Preventive Measures.
Authors: Dimopoulos Meletios Athanasios , Kastritis Efstathios , Bamia Christina , Melakopoulos Ioannis , Gika Dimitra , Roussou Maria , Migkou Magdalini , Eleutherakis-Papaiakovou Evangelos , Bamias Aristotle 
Published: April 2020

Abstract
Background. Bisphosphonates are widely used in the treatment of MM. ONJ can occur during treatment with bisphosphonates. We have shown that use of ZA and longer exposure are associated with higher frequency of ONJ in a series of patients with both MM and solid tumors. Dental problems or interventions are precipitating factors of ONJ. For this reason, since 2003, we have implemented assessment (and management if necessary) of all patients who are candidates for ZA or who are on treatment with ZA and have dental problems by specialists with particular experience on ONJ. In addition, we recommend improved oral hygiene and we avoid dental procedures during treatment with ZA. We have investigated whether the occurrence of ONJ decreased after the implementation of these measures.
Patients and Methods. According to the policy of our center, all patients with MM who demonstrate lytic lesions or osteopenia receive ZA 4 mg i.v. every 4 weeks indefinitely. In our current analysis we included patients who received only ZA wheras patients who initially received pamidronate and were later switched to ZA were excluded. Patients were stratified into two groups depending on the date of initiation of treatment in relation to the start of implementation of the preventive measures (Group A: 26/8/1998–31/12/2002, Group B: 1/1/2003–1/12/2006). Occurrence of ONJ was studied as row percentages as well as incidence rate rates (IR: number of cases of osteonecrosis /person-months). The proportions of patients with ONJ between the two groups were compared with the Fisher’s exact test whereas the respective incidence rates were compared with the score test. The 95% confidence interval of the incidence rate ratio was also estimated.
Results. One hundred twenty-eight patients with MM were included in the analysis (Group A: 35, Group B: 93; M/F: 66/62). Overall there were 10 cases of ONJ (8%): 8 cases in Group A (23%) and 2 cases in Group B (2%) (p&lt;0.001). The IR was 0.560/100 person-month for Group A and 0.118/100 person-month for Group B. The IRR was Group A/Group B: 4.76 (p=0.029, 95% CI: 1.01–22.40). Median time of exposure among patients with ONJ was 31 months for Group A and 8 months for Group B (p=0.044).
Conclusions. The implementation of detailed assessment by experienced specialists of patients with MM and dental problems and the avoidance of dental procedures during treatment with ZA results in a significant 5-fold reduction of ONJ. Our data provide a basis for a safer use of ZA in MM.
Bortezomib in Combination with Pegylated Liposomal Doxorubicin and Thalidomide (VDT) for the Treatment of Previously Untreated Multiple Myeloma.
Authors: Chanan-Khan Asher A. , Miller Kena C. , DePaolo Dawn , Padmanabhan Swaminathan , Whitworth Amy , Ailawadhi Sikander , Lee Kelvin , Czuczman Myron S. 
Published: April 2020

Abstract
Introduction: Orlowski et al were the first to report that addition of PLD resulted in enhanced efficacy of bortezomib. To further optimize the clinical efficacy of these agents we included thalidomide to the regimen. In a previous report we described the clinical efficacy of this novel, non-steroidal regimen that incorporated bortezomib (V), pegylated liposomal doxorubicin (D) and thalidomide (T) in patients with relapsed or refractory multiple myeloma (MM). High clinical responses in heavily pretreated patients, even in the absence of steroids encouraged us to investigate this regimen in previously untreated MM patients. Here we report for the first time the efficacy and toxicity profile of the VDT regimen in treatment naïve MM patients enrolled on a phase II clinical study at our center.
METHOD: All previously untreated MM patients were eligible for this study. Bortezomib (1.3mg/m2) was given on days 1, 4, 15, and 18, pegylated liposomal doxorubicin was given (20mg/m2) on days 1 and 15 and thalidomide (200mg) was given everyday continuously throughout the treatment. Patients received treatment on a 4-week cycle. Acyclovir 400mg PO BID and low-dose warfarin was given for prophylaxis of herpes zoster and venous thromboembolism respectively.
RESULTS: A total of 26 patients (median age-- 60 range 40–82 years), 16 M and 10 F have so far been enrolled. Advance stage III disease was noted in ---of the patients. The median beta 2 microglobulin was 4 (range1.6–9.7), albumin of 4 (range 3.1–4.8) and LDH was 333 (range 152–1057). Patients received a median of 5 treatment cycles (range 1–8). Toxicity: The most common grade 3 or 4 hematologic toxicities included lymphopenia (27%) and neutropenia (15%), while the non-hematologic toxicity included infections 15% (n=4 patients). The incidence of grade 3 or 4 plantar palmar erythrodysthesia was 4% (n=1). Venous thromboembolism was not observed in any patient to date. Response: To date 17 patients are available for response assessment (EBMT criteria?), 7 patients are too early for response assessment. The ORR of this regimen is 65% with IFE negative CR observed in 3 patients (17.6%). Another 5 patients achieved a stable disease with only 1 progressive disease observed on the regimen so far.
Conclusion: VDT is a novel non-steroidal regimen with clinical efficacy in previously untreated myeloma patients. Overall toxicity is manageable. Several patients remain on treatment and currently not evaluable for response. Detailed and updated results of this study will be presented at the meeting.
FcγRIIa Is Required for Outside-In β3 Integrin Signaling in Human Platelets.
Authors: Boylan Brian , Gao Cunji , Rathore Vipul , Crockett Jimmy , Newman Debra K. , Newman Peter J. 
Published: April 2020

Abstract
ITAMs (Immunoreceptor Tyrosine-based Activation Motifs) are signaling motifs that are found within the cytoplasmic domains of T and B cell antigen receptors, and in the Fc receptor γ (FcRγ) chain that is associated with Fc receptors for IgG and IgE and with the GPVI collagen receptor on platelets. ITAMs are also an intrinsic component of the cytoplasmic domain of the platelet and leukocyte low affinity receptor for IgG, FcγRIIa. When ITAM-bearing receptors are engaged or cross-linked, ITAM tyrosines undergo Src-dependent phosphorylation, providing a docking site for the protein-tyrosine kinase, Syk. Activation of Syk results in assembly of a multi-protein signaling complex containing the adaptor molecule SLP-76, ultimately resulting in the activation of phospholipase Cγ2 (PLCγ2), which via its lipase activity initiates a multitude of cellular activation responses. Recent studies in platelets and neutrophils have found that ITAM-mediated signaling cascades also play a novel and unexpected role in outside-in integrin signaling, as cells containing mutant forms of Syk, SLP-76, or PLCγ2 fail to become activated normally following integrin engagement. Furthermore, the FcRγ chain and DAP12 have been identified as ITAM-bearing subunits required for integrin signaling in neutrophils and macrophages, and we and others have reported that the GPVI/FcRγ chain complex can function as a weak integrin amplifier in human platelets. Nevertheless, the complement of ITAM-bearing receptors in platelets that are involved in integrin signaling in platelets is not known. To identify candidate receptors that might couple integrins to ITAM signaling, we initiated fibrinogen (Fg) binding to the integrin αIIbβ3 by
activating the thrombin receptor, PAR1, on platelets in suspension, or by allowing platelets to spread directly on immobilized Fg.
Interestingly, both forms of platelet activation initiated strong, ligand binding-dependent tyrosine phosphorylation of FcγRIIa, as well as downstream phosphorylation of Syk and PLCγ2. Importantly, prior addition of Fab fragments of the FcγRIIa blocking monoclonal antibody, IV.3, inhibited platelet spreading on immobilized Fg, as well as downstream tyrosine phosphorylation of FcγRIIa, Syk, and PLCγ2. Finally, platelets from a patient with a mild bleeding disorder whose platelets express only 30% of the normal level of FcγRIIa exhibit markedly reduced spreading on immobilized Fg. Taken together, these studies identify FcγRIIa as the major ITAM-bearing receptor in human platelets that supports outside-in integrin signaling.