bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Small Subset of CD5-Negative Diffuse Large B-Cell Lymphomas Express Nuclear Cyclin D1 with Evidence of Amplified Cyclin D1 Signals or the t(11;14) Translocation.
Authors: Ehinger Mats , Linderoth Johan , Christensson Birger , Sander Birgitta , Ståhl Eva 
Published: October 2019

Abstract
The expression of cyclin D1 in malignant lymphomas is largely restricted to mantle cell lymphoma, plasma cell myeloma and hairy cell leukemia. In virtually all cases of mantle cell lymphoma and some cases of plasma cell myeloma, the t(11;14) translocation between the immunoglobulin heavy chain and the CYCLIN D1 genes can be demonstrated using fluoroscence in situ hybridization. There are also anecdotal reports of the expression of cyclin D1 in other lymphoma subtypes including small lymphocytic lymphoma, Hodgkin lymphoma and anaplastic large cell lymphoma. In our routine practice, we have encountered a few cases of diffuse large B-cell lymphomas with immunohistochemical evidence of cyclin D1-expression. Therefore, an unselected large number of diffuse large B-cell lymphomas (n=231) from archived material collected at three university hospitals in Sweden were stained for cyclin D1 and microscopically evaluated with regard to cyclin D1-expression. The lymphomas studied included 11 of anaplastic subtype, 4 of immunoblastic subtype, 6 of T-cell/histiocyte rich subtype and the remainder of centroblastic subtype. 10 (4%) of the 231 cases showed nuclear positivity for cyclin D1. 9 of these were of centroblastic subtype and 1 of anaplastic subtype. All of the cyclin D1 positive cases were negative for CD5. The cyclin D1-positive cases were further subjected to fluoroscence in situ hybridization to determine the presence of the t(11;14) translocation. One of these cases (of centroblastic subtype) showed a hybridization pattern consistent with the t(11;14) rearrangement. Two other cases (one of centroblastic subtype and one of anaplastic subtype) displayed a fluoroscence pattern with amplified cyclin D1 signals in the absence of evidence of the t(11;14) translocation, possibly related to CYCLIN D1 gene amplification. Thus, contrary to the current view, there appears to exist a certain number of cyclin D1-positive and CD5-negative diffuse large B-cell lymphomas some of which display amplified cyclin D1 signals or the t(11;14) translocation. The results emphasize the importance of CD5 and cyclin D1 immunostaining in routine diagnostics of diffuse large B-cell lymphomas. Whether CD5-negative cyclin D1-positive lymphomas with the t(11;14) translocation and classic centroblastic morphology should be classified as mantle cell lymphomas or diffuse large B-cell lymphomas remains debatable.
International T-Cell Lymphoma Classification Project: Angioimmunoblastic T-Cell Lymphoma.
Authors: Ruediger Thomas , Coiffier Bertrand , Weisenburger Dennis D. , Federico Massimo 
Published: October 2019

Abstract
Peripheral T-cell lymphomas are rare diseases: therefore, the International T-cell Lymphoma Project was undertaken to compare lymphomas at different sites throughout North America, Asia and Europe. Within this project, 243 angioimmunoblastic T-cell lymphomas (AILTs) were diagnosed which made up 21% of all peripheral T-cell lymphoma (PTCL). At presentation, generalized lymphadenopathy was noted in 76% of the patients. Interestingly, three patients presented with extranodal disease only. Among the skin symptoms, erythroderma was the most frequent (21% of patients). Hemolytic anemia was seen in 13% and dysproteinemia occurred in 50%, and among these monoclonal serum immunoglobulin was seen in 8% of the patients. Anemia, hypergammaglobulinemia and elevated LDH were significantly more frequent in AILT than in PTCL-unspecified. Similarly, patients with AILT had a significantly higher frequency of high stage disease (89% of the patients were stage 3 or 4), as well as worse prognostic indices. Despite this, their 5-year overall (33%) and failure-free survivals (18%) were similar to patients with PTCL-unspecified. Treatment was usually administered in combination with anthracycline. A few factors at presentation were prognostic for outcome, including the PIT (prognostic index for T-cell lymphoma; Gallamini et al.: Blood. 2004 Apr 1;103(7):2474–9), age, B-symptoms and performance status. The IPI, however, was not prognostic. Controlling for the PIT, a platelet count <150.000 μl was prognostic for overall survival whereas B-symptoms were prognostic for failure-free survival. In conclusion, AILT is an aggressive disease for which the optimum treatment has not yet been developed.
Adult T-Cell Leukemia/Lymphoma: A Clinicopathologic Study of 126 Cases from the International T-Cell Lymphoma Project.
Authors: Suzumiya Junji , Ohshima Koichi , Tamura Kazuo , Karube Kennnosuke , Uike Naokuni , Armitage James Olen O. 
Published: October 2019

Abstract
To assess the clinicopathological applicability and reproducibility of the new WHO classification against peripheral T/NK-cell lymphomas, International T-cell Lymphoma Study Group was organized. Our task is to show the clinicopathologic and therapeutic results of ATLL from International T-cell Lymphoma Project. In the study, 1159 cases of T/NK-cell lymphomas, excluding mycosis fungoides and Sezary syndrome, were collected from the 21 centers in 13 countries of North America, Europe and Asia. All cases were reviewed by expert hematopathologists.
ATLL was diagnosed in 126 (10.9%) patients. It was rare in North America (2.0%), and Europe (1.5%), but frequent in Asia (24.8%). There were clinical subtypes of ATLL from smoldering, chronic, lymphoma to acute type, and 87% of the patients fell into lymphoma type. The median age was 60 (range; 15–92) and male to female ratio was 1. B symptoms, PS 2–4(ECOG) and two or more extranodal sites were found in 39 (31%), 29 (23%) and 43 (34%) patients, respectively. Bone marrow involvement was present in 28% of the patients. Stage I/II was seen in 10% of the patients, stage III in 18% and stage IV in 73%. There were 23 (19%) patients in score 0/1, 41 (33%) in score 2, 40(32%) in score 3 and 20(16%) in score 4/5 of International Prognostic Index (IPI). There were 20 (17%) patients with less than 150x103/ml of platelet counts, 107 (85%) with over 20% transformed T cells in absolute lymphocyte counts, and 113 (94%) with over 20% Ki-67 positive cells. The 5- year-overall survival (OS) and failure free survival (FFS) were 14.4% and 12.1%, respectively. The significant prognostic factors for OS were B symptoms (p=0.018), PS (p=0.0022), stage (p=0.019), extranodal sites (p=0.045) and IPI (p=0.019). By using the multivariate analysis, the important prognostic factors were found to be B symptoms, platelet counts (<150x103/ml), transformed T-cell counts (>20%), and Ki67+ cells (>20%). However, the Cox model analysis showed that no significant prognostic factors were found after adjusting by IPI. For treatment, the combination chemotherapy using anthracycline as an initial therapy was given in 109 of 120 (91%) treated patients. The overall and complete response rates were 69% and 33%, respectively. It is unfortunate that 71 (63%) patients had relapsed. Many drugs were used including prednisone 105 (88%), vincristine 102 (85%), cyclophosphamide 92 (77%), doxorubicin 77 (64%), etoposide 53 (44%), mitoxantrone 14 (12%), cisplatin 11 (9%), methotrexate 8 (7%) , bleomycin 6 (5%) and cytarabine 5 (4%). There was no difference in OS and FFS according to the treatment arms includ.
DA-EPOCH-R Is Highly Effective in Both BCL-6+ and BCL-6− Untreated De Novo Diffuse Large B-Cell Lymphoma (DLBCL): Study Update and Analysis of Survival Outcomes for Multiple Biomarkers.
Authors: Wilson Wyndham H. , Dunleavy Kieron , Pittaluga Stefania , Grant Nicole , Shovlin Margaret , Steinberg Seth , Raffeld Mark , Staudt Louis , Jaffe Elaine S. , Janik John 
Published: October 2019

Abstract
Gene expression profiling has yielded a new molecular taxonomy of DLBCL in which 3 subtypes are distinguished; germinal center B-cell (GCB) subtype, derived from a germinal center B-cell; activated B-cell (ABC) subtype, derived from a post-germinal center B-cell; and primary mediastinal B-cell (PMBL) subtype, likely derived from a “thymic” B-cell. To define the effect of pathobiology on treatment outcome, immunophenotype has been used as an “approximate surrogate” biomarker for molecular taxonomy. Recent studies suggest that rituximab (R) benefit is primarily in BCL-6− (Winter et al Blood107:4207, 2006) and BCL-2+ (Mounier et al Blood101:4279, 2003) DLBCL, both more frequent in post-germinal center subtypes. Conversely, R-CHOP appears equivalent to CHOP in BCL-6+ DLBCL, which comprise up to 75% of all cases. We analyzed the outcome of DA-EPOCH-R using the immunophenotypic biomarkers BCL-6, BCL-2, MIB-1, CD10, MUM-1, and GCB vs ABC subtypes by the method of (Hans et al Blood 103:275, 2003). Patients had untreated de novo DLBCL excluding PMBL, stage II-IV, HIV-, and adequate organ function. No patients received radiation. Characteristics of 72 patients include median (range) age 50 (19–85); stage III/IV 69%; and High Intermediate/High International Prognostic Index (3–5) (IPI) 40%. Of 71 evaluable patients, response is CR/CRu 94%. At the median potential follow-up of 43 months, PFS is 82% and OS is 79% (Fig 1). PFS by Low/Low Intermediate (0–2) and High Intermediate/High (3–5) IPI is 93% and 64%, respectively, at 43 months. PFS by BCL-6 (Fig 1), and BCL-2 and GCB vs. ABC (Fig 2) is shown. PFS of DLBCL with MIB-1 < and > 80% was 92% and 81%, respectively. There was no significant difference in survival outcome by CD10 or MUM-1 expression (data not shown). Distribution by immunophenotype is shown below for patients with available tissue.
Biomarker Distribution Biomarker Number Percent BCL-6 Neg 14 24 BCL-6 Pos 44 76 BCL-2 Neg 24 41 BCL-2 Pos 35 59 GCB 34 67 ABC 17 33 MIB-1 < 80% 13 33 MIB-1 > 80% 39 67 CD10 Neg 36 63 CD10 Pos 21 37 Mum-1 Neg 30 64 Mum-1 Pos 17 36
In conclusion, DA-EPOCH-R appears equally effective among all biomarker subgroups. Of note, DA-EPOCH-R is highly effective in BCL-6+ DLBCL, in which R does not appear to be very useful, suggesting the DA-EPOCH regimen itself may be highly effective in this group. The CALGB has initiated a Phase III randomized study of R-CHOP vr. DA-EPOCH-R to determine if DA-EPOCH-R represents a treatment advance. Gene expression profiling will be performed to assess the effect of the new molecular taxonomy and tumor biology on outcome.
Figure Figure
Predictive Value of Clonal Peripheral Blood γTCR Rearrangement in Patients with Peripheral T-Cell Lymphoma.
Authors: Schuetzinger Christian , Esterbauer Harald , Skrabs Cathrin , Uffmann Martin , Raderer Markus , Hauswirth Alexander , Gaiger Alexander , Mannhalter Christine , Dieckmann Karin , Wagner Oswald , Jaeger Ulrich 
Published: October 2019

Abstract
Peripheral T-cell lymphoma is a rare heterogeneous disease with generally poor outcome. Known risk factors include the International Prognostic Index (IPI) and b2 microglobulin. However, there is little information on molecular risk factors. In this single center analysis we have prospectively studied the prognostic value of a clonal T-cell receptor rearrangement (TCR) determined by conventional PCR for the γTCR (sensitivity 1 in 102) from DNA from peripheral blood MNC. Thirty nine consecutive patients diagnosed between 1987 and 2006 were assessed for clonality at diagnosis.
Patient characteristics: Median age 53 years (range 28–89). M:F = 29 vs. 10. Histological diagnosis included: PTCL-NOS 7 (18%); Large cell 1 (2.5%); Large + medium-sized 5 (13%); Pleomorphic 7 (18%); Small cell 3 (8%); Small+medium mixed cell 1 (2.5%); Lennert’s type 4 (10%); Hepatosplenic 3 (8%); Intestinal 4 (10%); Kimura’s disease: 1 (2.5%);
AILD: 3 (8%). Assessment of γTCR showed monoclonality in 24 (62%) and polyclonality in 15 (38%) patients. Patients with a monoclonal TCR had higher clinical stages, higher LDH levels, higher IPI scores, and higher ß2 microglobulin levels.
Clinical stage: CS I–III (clonal 42%; polyclonal 58%) vs. CS IV (clonal 93%; polyclonal 7%). LDH above 240 U/L (clonal 78%; polyclonal 22%). IPI 0,1 (clonal 44%; polyclonal 56%), IPI 2 (clonal 75%; polyclonal 25%), IPI 3 (clonal 87%; polyclonal 13%), IPI 4,5 (clonal 60%; 40%). ß2 microglobulin above 2 mg/L (clonal 68%; polyclonal 32%). Patients with a clonal TCR tended to be older (57 vs. 49 yrs.). No major differences were found for age and sex. Induction treatment consisted of polychemotherapy (CHOP-like=34), prednisone (1), radiation (1). 3 patients received no therapy. Nine patients received subsequent involved field radiation and 6 pts. had an autologous stem cell transplant. Significant differences were observed in terms of disease outcome: The presence of a clonal γTCR (n=24) was associated with low clinical remission rates: CR 38%, PR 21%, SD 8%, PD 33%, relapse rate 38%. Remission rates in patients with polyclonal rearrangements (n=15) were: CR 66%, PR 20%, SD 7%, PD 1%, relapse rate 47%. The estimated 3-year overall survival for the monoclonal group was 26% vs. 69% for the polyclonal group (P=0.01). Importantly, patients with CS I–III and a monoclonal γTCR rearrangement (n=10) had a similarly poor survival when compared to the monoclonal group with CS IV (n=14) (18 months vs. 12 months; P=0.23). This indicates that γTCR positivity is of particular predictive value in patients with CS I–III. The data from this unique cohort suggest that γTCR-PCR is a useful prognostic tool in patients with peripheral T-cell lymphoma.
Figure Figure
Loss of Heterozygosity in Acute Myeloid Leukemia with Normal Karyotype.
Authors: Traikov Sofia , Steudel Christine , Oelschlaegel Uta , Schaich Markus , Ehninger Gerhard , Thiede Christian 
Published: October 2019

Abstract
Loss of heterozygosity (LOH) is detectable in many forms of cancer, including leukaemia. LOH contributes to tumorigenesis through the loss of one of the two alleles of one tumor suppressor gene at a given locus, caused by deletion or uniparental disomy (UPD). In this study, we analysed 146 patients with primary AML, using high-density single nucleotide polymorphisms (SNPs) arrays. Leukemic cells and healthy T-cells from each patient were obtained using FACS-Vantage cell sorting. The genome wide SNP analysis was carried out using Human Mapping 10K Arrays (Affymetrix). So far LOH was identified in 27 cases with normal karyotype (18.5%). Potential LOH regions were confirmed by analysis of short tandem repeat (STR) markers using DNA samples from T-cells and blasts. In 21 of these cases, STR-analysis of T-cells representing the corresponding tumor-free material confirmed the regions of UPD. This aberration affected different chromosomes, but most frequently chromosome 2, 6, 11, 13, 21, and covered between 11.5 and 88 Mb. In the remaining 6 LOH cases, long stretches of homozygosity occurring at identical positions in the T-cells and in the leukemic blasts were found. These cases were detected and separated from those with UPD.
So far, correlation of clinical variables and LOH results in this cohort did not indicate significant differences based on age, WBC-counts, sex and FAB-subtype. Additionally, we did not detect any proven correlation between FLT3-ITD, MLL-PTD, NPM1 mutations and UPD. Interestingly, 80% of the patients with UPD that had achieved CR after chemotherapy relapsed within 6 months. In contrast, the rate of relapse in patients without UPD was only 54% . Furthermore, we were able to confirm the relationship between UPD and gene aberrations. We demonstrated that the UPD cases found in chromosomes 21, 19, and 11 were correlated with point mutations in the RUNX1, CEBPA and WT1 genes, respectively. Furthermore, AML cases with and without UPD showed different gene expression profiles, revealing different expression levels for some genes involved in double strand brake repair.
In conclusion, the use of the SNP array technology allowed the identification and mapping of LOH in 18.5% of AML patients with normal karyotype. Our data also underline the necessity of analysing tumour-free material in order to confirm the somatic origin of the alteration. Furthermore, our results indicate a higher relapse rate in patients with UPD.
Combined aCGH and Mutational Analysis of CLL Patients with 17p Deletion.
Authors: Rudenko Hannah C. , Brito-Babapulle Vasantha , Gonzalez David , Martinez Pilar , Leone Paola E. , Jones Chris , Dexter Tim , Fenwick Kerry , Mackay Alan , Ashworth Alan , Matutes Estella , Catovsky Daniel , Dearden Claire , Morgan Gareth J. 
Published: October 2019

Abstract
We have utilised aCGH (Breakthrough Breast Cancer Research Centre 5.8K array) and mutational analysis of the TP53 gene (exons 4–10) on 74 cases of CLL to define the extent of deletion at 17p, TP53 mutational status, additional genomic changes, and how this affects clinical outcome. 17p- cases were selected by FISH (n=37, Vysis LSI P53 probe) and 37 cases were selected as being representative of the survival curve of CLL patients without 17p-. FISH identified 22 cases with TP53- in ≥ 50% of cells, 4 cases with TP53- 20–50% and 11 cases with TP53- ≤ 20%. aCGH can detect abnormalities present in >50% of cells and all of the TP53- cases greater than 50% by FISH were detected with deletion ranging between 6-20Mb in length, the majority encompassing the entire p-arm. In addition aCGH detected deletion of 17p in 5/15 cases with TP53- <50%, and 2/37 with no detectable TP53- by FISH, these deletions clustered at 17p13.3 and 17p11.2, and did not involve the TP53 gene. Cases with 17p- >20% have a poor clinical outcome (median survival 11 months, median progression free survival 3 months), the majority of these (85%) also have a mutation of TP53 whereas in cases with ≤ 20% 17p- only 10% were mutated.
The 17p- group was characterised by additional recurrent deletions involving 18p, 20p and 22q, which tended to occur as single additional events. Understanding the order in which these events occur is important, 18p- was found in 6 cases, 2 of which had <50% 17p- by FISH, suggesting that 18p- is present in a higher percentage of cells and by implication occurs prior to the 17p deletion, a similar finding was also present for the 20p- cases. 18p deletion varied in length between 5.9Mb and 12Mb, with the minimally deleted region (MDR) involving a 2.5Mb region spanning 18p11.23-p11.22. 20p- was found in 8 cases of which 3 covered almost the entire p-arm, and 5 formed 2 clusters at each end of the p-arm. 22q- was found in 8 cases, with only 1 outside of the 17p- group. Out of these 8 cases with deletion, 6 covered almost the complete q-arm but a MDR was difficult to define, however if the non-17p- case is excluded the MDR covers 1.4Mb at 22q12.3.
Recurrent abnormalities were also found on other chromosomes, but did not differ between the two groups. These included regions with previously identified abnormalities; trisomy 12 (n=11), loss of 6q14.1–24.3 (n=11), loss of 11q12.1–25 (n=17) and loss of 13q12.1–21.1 (n=6) as well as detection of novel abnormalities; gain of 4p16.3–16.1 (n=23), gain of 11p15.5–15.3 (n=22), gain of 22q11.21–13.33 (n=22) and deletions on chromosome 9 (n=9).
These results show that deletion of TP53 and mutation of the other allele are critical adverse prognostic factors. We have also defined a genetic background (18p-, 20p- and 22q-) on which these changes arise.
High Density Oligonucleotide Array CGH Analysis of CLL Reveals Areas of Recurrent Genomic Gain or Loss.
Authors: Schop Roelandt F.J. , Mancini Catherine , Chng Wee-Joo , Tschumper Renee C. , Jelinek Diane F. , Kay Neil E. , Bergsagel Peter Leif , Carpten John D. , Fonseca Rafael 
Published: October 2019

Abstract
The study of genomic aberrations in chronic lymphocytic leukemia (CLL) has yielded critical information, now routinely used for the prognostication of patients. An unbiased search for genome wide areas of copy number change is needed to identify possible primary genetic events in CLL and to elucidate their relationship to other known cytogenetic factors, such as deletions of 13q14, 11q23 and 17p13 and trisomy 12. Here we report on a study where we used a 60-mer oligo array-based Comparative Genomic Hybridization (aCGH, 44B platform from Agilent Technologies, Palo Alto, CA). We observed the most common genetic aberrations in CLL and in similar frequencies as would be predicted for CLL (e.g. 44% showing deletions of chromosome 13q14). Among those patients, 45% had no apparent other aberration. Of great interest, small bi-allelic deletions of chromosome 13, which predominantly involved the DLEU1 and DLEU2 locus, were detected in 4 patients (16%). Deletions of 11q23 were observed in 6 cases (24%), and while some involved the ATM locus one did not, casting doubt on the precise gene deregulated by these deletions. Large deletions of the whole 17p-arm were detected in three cases (12%). Trisomy 12 was present in only two cases (8%). No other trisomies were detected and also small regions of copy gain were uncommon. Monosomy of chromosomes 19, X and Y were present in three separate cases. Large deletions of chromosome 2p were seen in two cases, but an additional case had a small deletion involving the ALK gene. This case also had a breakpoint at chromosome 5 involving the NMP1 locus, suggestive of a t(2;5). A recent study (Mayr et al., Blood 2006) indicates that chromosomal translocations in CLL are present in 33% and were associated with a dismal prognosis. In our analysis we detected several breakpoints indicative of translocations. Detailed study is necessary to elucidate possible molecular events associated with these translocations. Other small regions of DNA copy loss were found at several locations throughout the genome. Regions of interest are shown in the table. In summary we show that multiple areas of recurrent genomic gain and loss can be identified in clonal cells of CLL and should lead to further insights into the understanding of disease pathogenesis.
Chromosome Location Gene(s) of interest Loss 6q24.3 LATS Loss 10q23.3 LG11 Loss 10q24.2 PAX2, WNT8B, TLX1, POLL, NFKB2 Loss 11p15.4 PPFIBP2 Loss 12p13 TNFRSF1A and 7 Loss 15q22.1 TCF12 Loss 19p13.3 BAX, RUVBL2 Loss 20q11.2 TP53INP2 Loss 20q13.1 WFDC13