A revision of the nearly 8-year-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among ...hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations, and therapeutic strategies for the lymphoid neoplasms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The World Health Organization classification of lymphoid neoplasms updated in 2008 represents a worldwide consensus on the diagnosis of these tumors and is based on the recognition of distinct ...diseases, using a multidisciplinary approach. The updated classification refined the definitions of well-recognized diseases, identified new entities and variants, and incorporated emerging concepts in the understanding of lymphoid neoplasms. However, some questions were unresolved, such as the extent to which specific genetic or molecular alterations define certain tumors, and the status of provisional entities, categories for which the World Health Organization working groups felt there was insufficient evidence to recognize as distinct diseases at this time. In addition, since its publication, new findings and ideas have been generated. This review summarizes the scientific rationale for the classification, emphasizing changes that have had an effect on practice guidelines. The authors address the criteria and significance of early or precursor lesions and the identification of certain lymphoid neoplasms largely associated with particular age groups, such as children and the elderly. The issue of borderline categories having overlapping features with large B-cell lymphomas, as well as several provisional entities, is reviewed. These new observations chart a course for future research in the field.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUND:Both intramedullary nails and sliding hip screws are used with good results in the treatment of intertrochanteric and subtrochanteric fractures. The aim of our study was to assess whether ...use of the TRIGEN INTERTAN nail, as compared with a sliding hip screw, resulted in less postoperative pain, improved functional mobility, and reduced surgical complication rates for patients with an intertrochanteric or subtrochanteric fracture.
METHODS:In a prospective, randomized multicenter study, 684 elderly patients were treated with the INTERTAN nail or with a sliding hip screw with or without a trochanteric stabilizing plate. The patients were assessed during their hospital stay and at three and twelve months postoperatively. A visual analogue scale (VAS) pain score was recorded at all time points, and functional mobility was assessed with use of the timed Up & Go test. The Harris hip score (HHS) was used to assess hip function more specifically. Quality of life was measured with the EuroQol-5D (EQ-5D). Radiographic findings as well as intraoperative and postoperative complications were recorded and analyzed.
RESULTS:Patients treated with an INTERTAN nail had slightly less pain at the time of early postoperative mobilization (VAS score, 48 versus 52; p = 0.042), although this did not influence the length of the hospital stay and there was no difference at three or twelve months. Regardless of the fracture and implant type, functional mobility, hip function, patient satisfaction, and quality-of-life assessments were comparable between the groups at three and twelve months. The numbers of patients with surgical complications were similar for the two groups (twenty-nine in the sliding-hip-screw group and thirty-two in the INTERTAN group, p = 0.67).
CONCLUSIONS:INTERTAN nails and sliding hip screws are similar in terms of pain, function, and reoperation rates twelve months after treatment of intertrochanteric and subtrochanteric fractures.
LEVEL OF EVIDENCE:Therapeutic Level I. See Instruction for Authors for a complete description of levels of evidence.
Summary Background Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve ...risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. Methods We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5–9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7–7·6). Findings We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes ( EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP , and CARD11 ), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31–57·95) versus 77·21% (95% CI 69·21–86·14) for the low-risk group (hazard ratio HR 4·14, 95% CI 2·47–6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10–6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%, respectively, with a C -index of 0·80 (95% CI 0·71–0·89). In the validation cohort, m7-FLIPI again defined a high-risk group (22%, 24/107) with 5-year failure-free survival of 25·00% (95% CI 12·50–49·99) versus 68·24% (58·84–79·15) in the low-risk group (HR 3·58, 95% CI 2·00–6·42; p<0.0001). The positive predictive value for 5-year failure-free survival was 72% and 68% for negative predictive value, with a C -index of 0·79 (95% CI 0·69–0·89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2·18, 95% CI 1·21–3·92), and FLIPI combined with ECOG performance status (HR 2·03, 95% CI 1·12–3·67). Interpretation Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. Funding Deutsche Krebshilfe, Terry Fox Research Institute.
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Purpose To explore the prognostic impact and interdependence of the cell-of-origin (COO) classification, dual expression (DE) of MYC and BCL2 proteins, and MYC, BCL2, and BCL6 translocations in two ...prospectively randomized clinical trials of patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Overall, 452 formalin-fixed paraffin-embedded samples from two prospective, randomized DLBCL trials (RICOVER-60, prospective, randomized study for patients > 60 years, all IPI groups; and R-MegaCHOEP, prospective, randomized study for patients ≤ 60 years with age-adjusted IPI 2,3) of the German High-Grade Non-Hodgkin Lymphoma Study Group were analyzed with the Lymph2Cx assay for COO classification, with immunohistochemistry for MYC and BCL2, and with fluorescent in situ hybridization for MYC, BCL2, and BCL6 rearrangements. Results COO classification was successful in 414 of 452 samples. No significant differences with respect to COO (activated B-cell ABC-like DLBCL v germinal center B-cell GCB-like DLBCL) were observed in event-free survival, progression-free survival, and overall survival in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the RICOVER-60 trial. Also, no differences with respect to COO were observed in multivariable analyses adjusted for International Prognostic Index factors in event-free survival (hazard ratio HR of ABC-like disease v GCB-like disease, 1.0; 95% CI, 0.6 to 1.6; P = .93), progression-free survival (HR, 1.1; 95% CI, 0.6 to 1.8; P = .82), and overall survival (HR, 1.0; 95% CI, 0.6 to 1.8; P = .96). Similar results were observed in the R-MegaCHOEP trial. In patients treated with R-CHOP, DE status was associated with significantly inferior survival compared with nonDE within the GCB, but not within the ABC subgroup. DE status was associated with significantly inferior outcome compared with patients with ABC-like DLBCL without DE (5-year PFS rate, 39% 95% CI,19% to 59% v 68% 95% CI, 52% to 85%; P = .03) and compared with patients with GCB-like DLBCL without DE. When data from patients with nonDE were analyzed separately, the outcome of patients in the ABC subgroup was inferior to that of patients in the GCB subgroup (5-year PFS rate, 68% 95% CI, 52% to 85% v 85% 95% CI, 74% to 96%; P = .04). Conclusion COO profiling in two prospective randomized DLBCL trials failed to identify prognostic subgroups, whereas dual expression of MYC and BCL2 was predictive of poor survival. Evaluation of prognostic or predictive biomarkers in the management of DLBCL, such as the COO, within prospective clinical trials will be important in the future.
Analysis of gene-expression patterns led to the development of a molecular definition of Burkitt's lymphoma that distinguishes it from other types of mature aggressive B-cell lymphoma. Almost all ...cases defined by the gene-expression signature as Burkitt's lymphoma had the typical Burkitt's
IG-myc
translocation. Patients whose tumors did not have the Burkitt's signature had a poor outcome if the tumor cells had complex chromosomal changes.
Analysis of gene-expression patterns led to the development of a molecular definition of Burkitt's lymphoma that distinguishes it from other types of mature aggressive B-cell lymphoma. Patients whose tumors did not have the Burkitt's signature had a poor outcome if the tumor cells had complex chromosomal changes.
Burkitt's lymphoma and diffuse large-B-cell lymphoma are mature aggressive B-cell lymphomas. If left untreated, they follow a rapid clinical course and are fatal within months. Burkitt's lymphoma is a distinct entity that includes endemic and sporadic types and cases associated with immunodeficiency or immunosuppression.
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With the use of chemotherapy regimens that involve methotrexate and cytarabine, cure rates for sporadic Burkitt's lymphoma approach 90 percent in children and 70 percent in adults.
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Diffuse large-B-cell lymphoma, by contrast, is biologically and clinically heterogeneous and comprises five morphologic variants and three subtypes.
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Treatment with a combination of chemotherapy based on cyclophosphamide, doxorubicin, vincristine, . . .
Pemetrexed, a multi-folate inhibitor combined with a platinum compound is the first-line treatment of malignant mesothelioma, but median survival is still one year. Intrinsic and acquired resistance ...to pemetrexed is common, but its biological basis is obscure. Here we report for the first time a genome-wide profile of acquired resistance in the tumour from an exceptional case with advanced pleural mesothelioma and almost six years survival after 39 cycles of second-line pemetrexed/carboplatin treatment.
Genome-wide analysis with Illumina BeadChip Kit of 25,000 genes was performed on mRNA from pre-treatment and post-resistance biopsies from this individual as well on case and control samples from our previously published study (in total 17 samples). Cell specific expression of proteins encoded by selected genes were analysed by immunohistochemistry. Serial serum levels of CA125, CYFRA21-1 and SMRP levels were examined. TS protein, the main target of pemetrexed was overexpressed. Proteins and genes related to DNA damage response, elongation and telomere extension and repair related directly and indirectly to platinum resistance were overexpressed, as the CHK1 protein and the genes CHEK2, LIG3, POLD1, POLA2, FANCD2, PRPF19, RECQ5 respectively, the last two not previously described in mesothelioma. We observed a down-regulation of leukocyte transendothelial migration and cell adhesion molecules pathways. Silencing of NT5C in two mesothelioma cell lines did not sensitize the cells to Pemetrexed. Proposed resistance markers are TS, KRT7/ CK7, TYMP/ thymidine phosphorylase and down-regulated SPARCL1 and CDKN1B. Moreover, comparison of the primary expression of the sensitive versus a primary resistant case showed multi-fold overexpressed DNA repair, cell cycle, cytokinesis, and spindle formation in the latter. Serum CA125 and SMRP reflected the clinical and radiological course and tumour burden.
Genome-wide microarray of mesothelioma pre- and post-resistance biopsies indicated a novel resistance signature to pemetrexed/carboplatin that deserve validation in a larger cohort.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Creatine kinase (CK) has been associated with reduced inflammation in obesity while inflammation is associated with obesity-related cardiovascular diseases. We investigated the relationship between ...CK and high sensitive C-reactive protein (hs-CRP) in a general population.
CK and hs-CRP were measured in the population-based Tromsø study that included entire birth cohorts and random samples of citizens between 30-87 years of age. The analyses were performed sex-stratified in 5969 men and 6827 women.
CK correlated negatively with hs-CRP in men (r = -0.08, P <0.001) and women (r = -0.06, P <0.001). In univariable regression analyses, CK associated negatively with hs-CRP in men (ß = -0.14, 95% CI -0.19 to -0.10, P <0.001) and women (ß = -0.13, 95% CI -0.18 to -0.08, P <0.001). Mean CK declined from the 2. to the 4. quartiles of hs-CRP in both genders (P <0.001 for trends). There were positive correlations between CK and body mass index (BMI) in men (r = 0.10, P <0.001) and women (r = 0.07, P <0.001). Multiple regression analyses showed a 0.13 unit decrease in hs-CRP (mg/dl) per unit CK increase in men (95% CI -0.35 to -0.20) and 0.29 mg/dl in women (95% CI -0.36 to -0.21) when adjusted for age, BMI, lipids, s-glucose, s-creatinine, transaminases and coronary heart disease.
CK were inversely and independently associated with hs-CRP in a general population. These data provide evidence that CK might have anti-inflammatory properties, but the mechanism and clinical implications are unclarified.
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On examination, she had generalised, mild abdominal tenderness especially in the left lower quadrant where there was guarding and rebound tenderness; her vital signs were normal—blood pressure 127/66 ...mm Hg, temperature 37·3 oC, heart rate of 59 beats per min, and respiratory rate was 12 breaths per min. Blood tests showed elevated white blood cell count of 12·4 × 109 per mL and serum C-reactive protein (CRP) concentration of 22 mg/L. (C) Abdominal CT coronal view of the left colon shows focal wall thickening, pericolic fat stranding, and extraluminal air (arrow). *Indicates the cecum.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical ...trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy. Methods In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkin's lymphoma aged 18–60 years were randomly assigned to receive either eight cycles of BEACOPPescalated (8×Besc group), six cycles of BEACOPPescalated (6×Besc group), or eight cycles of BEACOPP14 (8×B14 group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041. Findings Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×Besc group, 711 in the 6×Besc group, and 710 in the 8×B14 group. Freedom from treatment failure was sequentially non-inferior for the 6×Besc and 8×B14 groups as compared with 8×Besc . 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0–87·7) for the 8×Besc group, 89·3% (86·5–92·1) for 6×Besc group, and 85·4% (82·1–88·7) for the 8×B14 group (97·5% CI for difference between 6×Besc and 8×Besc was 0·5–9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×Besc than with 8×Besc (97·5% CI 0·2–6·5). The 8×Besc group showed a higher mortality (7·5%) than the 6×Besc (4·6%) and 8×B14 (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1–96·1); and 225 (11%) of 2126 patients received additional radiotherapy. Interpretation Treatment with six cycles of BEACOPPescalated followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPPescalated should be the treatment of choice for advanced stage Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting. Funding Deutsche Krebshilfe and the Swiss Federal Government.
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