Key Points• Population-based data show a favorable outcome with upfront autologous stem cell transplantation in PTCL.• The addition of etoposide to CHOP was associated with favorable PFS in patients #60 years with PTCL.Peripheral T-cell lymphomas (PTCLs) are rare lymphomas with mostly poor outcome with current treatment. The addition of etoposide to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and upfront consolidation with autologous stem cell transplantation (auto-SCT) have shown promising results but have never been tested in randomized trials. As a complement to retrospective analyses of clinical trials, we aimed at analyzing prognostic factors and outcome in an unselected, population-based cohort. Through the Swedish Lymphoma Registry, we identified 755 PTCL patients diagnosed during a 10-year period. In addition to International Prognostic Index factors, male gender was associated with an adverse overall survival (OS) (hazard ratio [HR], 1.28; P 5 .011) and progression-free survival (PFS) (HR, 1.26; P 5 .014). In an intention-to-treat analysis in 252 nodal PTCL and enteropathy-associated T-cell lymphoma patients (excluding anaplastic lymphoma kinase-positive anaplastic large cell lymphoma), upfront auto-SCT was associated with a superior OS (HR, 0.58; P 5 .004) and PFS (HR, 0.56; P 5 .002) compared with patients treated without auto-SCT. The addition of etoposide to CHOP resulted in superior PFS in patients £60 years (HR, 0.49; P 5 .008). This study is the largest population-based PTCL cohort reported so far and provides important information on outcome in PTCL outside the setting of clinical trials. (Blood. 2014;124(10):1570-1577

Heparan sulfate is a sulfated polysaccharide present on most cell surfaces and in the extracellular matrix. In vivo functions of heparan sulfate can be studied in mouse strains lacking enzymes involved in the biosynthesis of heparan sulfate. Glucosaminyl N-deacetylase/ N-sulfotransferase (NDST) catalyzes the first modifying step in the biosynthesis of the polysaccharide. This bifunctional enzyme occurs in several isoforms. We here report that targeted gene disruption of NDST-1 in the mouse results in a structural alteration of heparan sulfate in most basement membranes as revealed by immunohistochemical staining of fetal tissue sections using antibodies raised against heparan sulfate. Biochemical analysis of heparan sulfate purified from fibroblast cultures, lung, and liver of NDST-1-deficient embryos demonstrated a dramatic reduction in N-sulfate content. Most NDST-1-deficient embryos survive until birth; however, they turn out to be cyanotic and die neonatally in a condition resembling respiratory distress syndrome. In addition, a minor proportion of NDST-1-deficient embryos die during the embryonic period. The cause of the embryonic lethality is still obscure, but incompletely penetrant defects of the skull and the eyes have been observed.

Key Points• CNS involvement at relapse/ progression in PTCL occurred at a frequency similar to what is seen in aggressive B-cell lymphomas.• Outcome after relapse is generally very poor in patients with PTCL and is not significantly altered by presence of CNS involvement at relapse.Central nervous system (CNS) relapse in non-Hodgkin lymphoma (NHL) carries a very poor prognosis. Risk factors and outcome have been studied in aggressive B-cell lymphomas, but very little is known about the risk in peripheral T-cell lymphoma (PTCL). We aimed at analyzing risk factors for CNS involvement at first relapse or progression, as well as the outcome of these patients, in a large population-based cohort of patients with PTCL. Twenty-eight out of 625 patients (4.5%) developed CNS disease over time. In multivariable analysis, disease characteristics at diagnosis independently associated with an increased risk for later CNS involvement were involvement of more than 1 extranodal site (hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.07-6.29; P 5 .035) and skin (HR, 3.51; 95% CI, 1.26-9.74; P 5 .016) and gastrointestinal involvement (HR, 3.06; 95% CI, 1.30-7.18; P 5 .010). The outcome of relapsed/refractory patients was very poor, and CNS involvement was not associated with a significantly worse outcome compared with relapsed/refractory patients without CNS involvement in multivariable analysis (HR, 1.6; 95% CI, 0.96-2.6; P 5 .074). The results from the present study indicate that CNS relapse in PTCL occurs at a frequency similar to what is seen in aggressive B-cell lymphomas, but the poor outcomes in relapse are largely driven by systemic rather than CNS disease. (Blood. 2015;126(1):36-41)

During early mouse embryogenesis, each laminin (Lm) chain of the first described Lm, a heterotrimer of ␣1, ␤1, and ␥1 chains (Lm-1), is essential for basement membrane (BM) assembly, which is required for pregastrulation development. Individual domains may have other functions, not necessarily structural. The cell binding C terminus of Lm ␣1 chain contains five Lm globular (LG) domains. In vitro, ␣1LG1-3 domains bind integrins, and ␣1LG4 binds dystroglycan, heparin, and sulfatides. A prevailing hypothesis is that ␣1LG4 is crucial as a structural domain for BM assembly, whereas integrin-binding sites conduct signaling. The in vivo role of ␣1LG4 -5 (also called E3) has not been studied. Mice lacking ␣1LG4 -5 were therefore made. Null embryos implanted, but presumptive epiblast cells failed to polarize and did not survive past day 6.5. BM components including truncated Lm ␣1 were detected in Reichert's membrane. Surprisingly, embryonic BM assembly between visceral endoderm and stem cells was normal in null embryos and in embryoid bodies of ␣1LG4 -5-null embryonic stem cells. Yet, stem cells could not develop into polarized epiblast cells. Thus, ␣1LG4 -5 provides vital signals for the conversion of stem cells to polarized epithelium.epiblast ͉ epithelial polarity ͉ stem cells ͉ mouse development

Purpose Peripheral T-cell lymphomas (PTCLs) have aggressive clinical behavior. We have previously shown that event-free survival (EFS) at 24 months (EFS24) is a clinically useful end point in diffuse large B-cell lymphoma. Here, we assess EFS24 and subsequent overall survival (OS) in large, multinational PTCL cohorts. Patients and Methods Patients with systemic PTCL newly diagnosed from 2000 to 2012 and treated with curative intent were included from the United States and Sweden (initial cohorts) and from Canada (replication cohort). EFS was defined as time from date of diagnosis to progression after primary treatment, retreatment, or death. Subsequent OS was measured after achieving EFS24 or from the time of progression if it occurred within 24 months. OS rates were compared with the age-, sex-, and country-matched general population. Results Seven hundred seventy-five patients were included in the study (the median age at diagnosis was 64 years; 63% were men). Results were similar in the initial and replication cohorts, and a combined analysis was undertaken. Sixty-four percent of patients progressed within the first 24 months and had a median OS of only 4.9 months (5-year OS, 11%). In contrast, median OS after achieving EFS24 was not reached (5-year OS, 78%), although relapses within 5 years of achieving EFS24 occurred in 23% of patients. Superior outcomes after achieving EFS24 were observed in younger patients (≤ 60 years of age: 5-year OS, 91%). Conclusion EFS24 stratifies subsequent outcome in PTCL. Patients with PTCL with primary refractory disease or early relapse have extremely poor survival. However, more than one third of patients with PTCL remain in remission 2 years after diagnosis with encouraging subsequent OS, especially in younger patients. These marked differences in outcome suggest that EFS24 has utility for patient counseling, study design, and risk stratification in PTCL.

Anaplastic large cell lymphomas (ALCLs) are rare CD30+ peripheral T-cell lymphomas (PTCLs) classified according to the expression of the anaplastic lymphoma kinase (ALK+) protein or not (ALK-). We have analysed the outcome and risk factors for survival in a population-based bi-national cohort of patients with systemic ALK+ ALCL. A total of 122 adult (≥18 years) patients diagnosed with ALK+ ALCL between 2000 and 2010 were identified from the Danish and Swedish lymphoma registries, representing 0·4% of all lymphomas. The median age of the cohort was 40 years (range 18-85). The 5-year overall survival and progression-free survival (PFS) was 78% and 64%, respectively. Age was strongly associated with outcome, and only bone marrow (BM) involvement was independently associated with poorer PFS in multivariate analysis (Hazard Ratio [HR] = 8·57, P < 0·001). Age stratification of the patients demonstrated an association between treatment with CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisolone) and improved overall survival for patients aged 41-65 years, even when adjusted for risk factors (HR = 0·38, P = 0·047). Our results suggest that the addition of etoposide to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) in the treatment for ALK+ ALCL seems reasonable in this age group.

Background . T-cell lymphoblastic lymphoma (T-LBL) is a rare neoplasm of precursor lymphoblast origin, for which there is no standard treatment for adults. Results of current treatment strategies in selected populations do exist but are largely unreported for unselected series. Here, we aimed to investigate treatment outcome in a population-based cohort. Material and methods. Patients were identifi ed through the Swedish Lymphoma Registry and data was retrospectively collected for all adult ( Ն 18 years) Swedish T-LBL patients diagnosed during 2000 -2009. Results . A total of 39 patients with median age 40 years (range 18 -78) were identifi ed with females being significantly older than males (median age 66 vs. 37, p ϭ 0.027). The fi ve-year overall survival for all patients was 42%. Female gender was associated with shorter survival also when adjusted for treatment strategy and age [hazard ratio (HR) 4.29; p ϭ 0.002]. Thirty patients received intensive chemotherapy, otherwise used for treatment of acute lymphoblastic leukemia (ALL), which resulted in an overall response rate of 97% and a fi ve-year progression-free survival (PFS) of 49%. In this group only CNS involvement at diagnosis predicted shorter PFS (HR 13.3; p ϭ 0.03). Among patients treated with hyper-CVAD the addition of mediastinal irradiation resulted in prolonged time to progression compared to patients receiving only chemotherapy (p ϭ 0.047). The major reason for treatment failure was relapse and in this series 18-fl uoro-deoxyglucose positron emission tomography (PET) did not predict this risk.Conclusion . This population-based study indicates that all fi t T-LBL patients should be considered for intensive treatment. Our results also suggest a benefi cial effect of mediastinal irradiation in combination with hyper-CVAD treatment. Relapsing patients have a dismal outcome irrespective of salvage treatment.

Non-endemic Burkitt lymphoma (BL) is a rare germinal centre B-cellderived malignancy with the genetic hallmark of MYC gene translocation and with rapid tumour growth as a distinct clinical feature. To investigate treatment outcomes, loss of lifetime and relapse risk in adult BL patients treated with intensive immunochemotherapy, retrospective clinic-based and population-based lymphoma registries from six countries were used to identify 264 real-world patients. The median age was 47 years and the majority had advanced-stage disease and elevated LDH. Treatment protocols were R-CODOX-M/IVAC (47%), R-hyper-CVAD (16%), DA-EPOCH-R (11%), R-BFM/GMALL (25%) and other (2%) leading to an overall response rate of 89%. The two-year overall survival and event-free survival were 84% and 80% respectively. For patients in complete remission/unconfirmed, the two-year relapse risk was 6% but diminished to 0Á6% for patients reaching 12 months of post-remission event-free survival (pEFS12). The loss of lifetime for pEFS12 patients was 0Á4 (95% CI: À0Á7 to 2) months. In conclusion, real-world outcomes of adult BL are excellent following intensive immunochemotherapy. For pEFS12 patients, the relapse risk was low and life expectancy similar to that of a general population, which is important information for developing meaningful follow-up strategies with increased focus on survivorship and less focus on routine disease surveillance.