Harald Holte

Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project

Few large, international series of enteropathy-associated T-cell lymphoma (EATL) have been reported. We studied a cohort of 62 patients with EATL among 1153 patients with peripheral T-cell or natural killer (NK)-cell lymphoma from 22 centers worldwide. The diagnosis was made by a consensus panel of 4 expert hematopathologists using World Health Organization (WHO) criteria. Clinical correlations and survival analyses were performed. EATL comprised 5.4% of all lymphomas in the study and was most common in Europe (9.1%), followed by North America (5.8%) and Asia (1.9%). EATL type 1 was more common (66%) than type 2 (34%), and was especially frequent in Europe (79%). A clinical diagnosis of celiac sprue was made in 32.2% of the patients and was associated with both EATL type 1 and type 2. The median overall survival was only 10 months, and the median failure-free survival was only 6 months. The International Prognostic Index (IPI) was not as good a predictor of survival as the Prognostic Index for Peripheral T-Cell Lymphoma (PIT). Clinical sprue predicted for adverse survival independently of the PIT. Neither EATL subtype nor other biologic parameters accurately predicted survival. Our study confirms the poor prognosis of patients with EATL and the need for improved treatment options.

Prognostic Value of Lymphoma-specific S-Phase Fraction Compared with that of Other Cell Proliferation Markers

The proliferation-associated antigens Ki67 (immunohistochemistry) and proliferative cell nuclear antigen (PCNA) (immunohistochemistry and immunoblotting) were analysed together with DNA synthesis (3H-thymidine incorporation) and cell-cycle distribution (tumour-specific S-phase fraction determined by flow cytometry) in lymph node suspensions from 63 patients with newly diagnosed B-Cell non-Hodgkins lymphomas. Details of clinical parameters, treatment and patient outcome were available for all patients, and retrospectively analysed. Of the proliferation-associated parameters, only high S-phase fraction (p < 0.00001) and high PCNA expression by immunoblotting (p = 0.012) were predictive of a poor prognosis. Of the conventional parameters, high-grade malignancy, high International Prognostic Index (IPI) score, bulky disease and presence of B symptoms predicted a patient for poor survival. High S-phase fraction was predictive of a short survival for the low-grade lymphomas analysed separately (p < 0.00001), as well as for patients treated with an Adriamycin- and a non-Adriamycin-containing regimen (p < 0.005 for both groups). In a multivariate analysis, S-phase fraction (p = 0.00006), IPI score (p = 0.015) and B symptoms (p = 0.017) had independent prognostic values, but not histological grade.

The prognostic significance of lymphopenia in peripheral T-cell and natural killer/T-cell lymphomas: A study of 826 cases from the International Peripheral T-cell Lymphoma Project

Lymphopenia is a marker of inferior survival in patients with various malignancies. However, the prognostic significance of lymphopenia in peripheral T‐cell lymphoma (PTCL) is unclear. We analyzed the prognostic significance of lymphopenia in 826 patients with different types of PTCL and natural killer/T‐cell lymphoma (NKTCL) from the International Peripheral T‐cell Lymphoma Project. Lymphopenia was defined as an absolute lymphocyte count of less than 1,000 cells per microliter. The overall frequency of lymphopenia was 35.3%, ranging from 21.1% in ALK+ anaplastic large cell lymphoma (ALCL) to 47.5% in angioimmunoblastic T‐cell lymphoma (AITL). Lymphopenia was independently associated with an inferior overall survival (OS) in patients with the lymphoma type of adult T‐cell leukemia/lymphoma (ATLL), with a 2‐year OS of 15% versus 40% for those without lymphopenia (P < 0.001). Lymphopenia was also an adverse predictor of survival in PTCL, not otherwise specified, but was associated with other unfavorable prognostic factors. A trend toward inferior survival for lymphopenic patients was also observed in AITL, ALK− ALCL and extranasal NKTCL lymphoma, whereas no difference in survival was found in nasal NKTCL, ALK+ ALCL, or enteropathy‐associated T‐cell lymphoma. In this study, lymphopenia was identified as a new adverse prognostic factor in the lymphoma type of ATLL. Am. J. Hematol. 2012.

Laparoscopic versus open surgery in stage I-III adrenocortical carcinoma-a retrospective comparison of 32 patients

Abstract Laparoscopic surgery (LS) for resectable adrenocortical carcinoma (ACC) has been questioned due to uncertainty with regard to long-term oncological outcome. We analyzed the experience with LS compared to open surgery (OS) at Oslo University Hospital (OUH). Material and methods. Between 1998 and 2011 32 patients were identified with ACC stage I–III operated either by LS (17 patients) or OS (15 patients). Patients’ records were reviewed retrospectively with regard to pre- and intraoperative findings, short-term surgical outcome, relapse and survival. The patients in the LS group had significantly smaller tumors and higher body mass index, otherwise the groups did not differ significantly. Thirty-one patients had been operated at surgical departments of the OUH, and all had been followed at OUH. Results. Short-term outcome favored LS by significantly shorter operation time, lower blood loss and need for transfusions, fewer postoperative complications and shorter hospitalization. The completeness of resection was similar in both groups with R0 resection accomplished in 12 patients in the LS group and 12 in the OS group. Twelve and 15 patients have relapsed in the LS and OS groups, respectively, with a similar pattern of relapse (local, peritoneal or distant). Median progression-free survival (15.2 months for LS vs. 8.1 months for OS) and median overall survival (103.6 months for LS vs. 36.5 months for OS) were not significantly different. Discussion. LS seems to offer short-term advantages and similar long-term outcome compared to OS in patients with resectable ACC stage I–III.

New molecular assay for the proliferation signature in mantle cell lymphoma applicable to formalin-fixed paraffin-embedded biopsies

Purpose Mantle cell lymphoma is an aggressive B-cell neoplasm that displays heterogeneous outcomes after treatment. In 2003, the Lymphoma/Leukemia Molecular Profiling Project described a powerful biomarker-the proliferation signature-using gene expression in fresh frozen material. Herein, we describe the training and validation of a new assay that measures the proliferation signature in RNA derived from routinely available formalin-fixed paraffin-embedded (FFPE) biopsies. Methods Forty-seven FFPE biopsies were used to train an assay on the NanoString platform, using microarray gene expression data of matched fresh frozen biopsies as a gold standard. The locked assay was applied to pretreatment FFPE lymph node biopsies from an independent cohort of 110 patients uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Seventeen biopsies were tested across three laboratories to assess assay reproducibility. Results The MCL35 assay, which contained a 17-gene proliferation signature, yielded gene expression of sufficient quality to assign an assay score and risk group in 108 (98%) of 110 archival FFPE biopsies. The MCL35 assay assigned patients to high-risk (26%), standard-risk (29%), and low-risk (45%) groups, with different lengths of overall survival (OS): a median of 1.1, 2.6, and 8.6 years, respectively (log-rank for trend, P < .001). In multivariable analysis, these risk groups and the Mantle Cell Lymphoma International Prognostic Index were independently associated with OS ( P < .001 for both variables). Concordance of risk assignment across the three independent laboratories was 100%. Conclusion The newly developed and validated MCL35 assay for FFPE biopsies uses the proliferation signature to define groups of patients with significantly different OS independent of the Mantle Cell Lymphoma International Prognostic Index. Importantly, the analytic and clinical validity of this assay defines it as a reliable biomarker to support risk-adapted clinical trials.

ChlVPP is as effective AS alternating ChlVPP/ABOD in advanced stage Hodgkin's disease

The purpose of the study was to evaluate and compare the efficacy and tolerability of two cytostatic regimens-chlorambucil, vinblastine, procarbazine and prednisone (ChlVPP) vs. ChlVPP alternating with doxorubicin, bleomycin, vincristine and dacarbazine (ABOD). One hundred eligible patients with stage IIIA-IVB Hodgkins disease were randomized to either ChlVPP or ChlVPP alternating with ABOD. The complete response rate (CR) was 80% in both treatment groups. After a median follow-up time of 59 months, 42 (84%) of the patients in the ChlVPP-treated group were in CR compared with 39 (78%) treated with ChlVPP/ABOD. The estimated five-year overall and relapse-free survival rates were 87% and 74%, respectively, for the ChlVPP-treated patients and 76% and 73% for the ChlVPP/ABOD-treated patients. The ChlVPP regimen showed a slightly better subjective tolerance than the ChlVPP/ABOD regimen. The given dose intensity was very close to optimal, and equal for the two regimens.

Physical activity in Hodgkin's lymphoma survivors with and without chronic fatigue compared with the general population – a cross-sectional study

BackgroundHodgkins lymphoma survivors (HLSs) commonly report chronic fatigue, defined as high levels of fatigue for 6 months or more. Underlying mechanisms are poorly understood. Based upon knowledge from other populations, lifestyle parameters may be related to this increased and persistent fatigue. The primary objective of the present study was to assess self-reported levels of physical activity, smoking habits and sleep patterns in HLSs with and without chronic fatigue. The secondary objective was to compare these results with data from age and gender adjusted data from the general population (Gen-Pop).MethodsThe Fatigue Questionnaire (FQ) and questions about daily smoking, sleep patterns and level of physical activity were completed by 476 HLSs treated at Rikshospitalet-Radiumhospitalet Trust (RR). The Gen-Pop data was derived from 56.999 inhabitants in a Norwegian county responding to a mail survey. Fischers exact test, chi square test and t-tests were used to compare groups. P-values < .05 were considered statistically significant. A logistic regression analysis was performed in comparing the Gen-Pop with the HLSs.ResultsLevel of physical activity, smoking habits and sleep patterns did not differ significantly between HLSs with and without chronic fatigue. The multivariate logistic regression analysis adjusting for different covariates, showed significantly more physically active men among HLSs compared with the Gen-Pop (OR = 1.50, CI 1.04 – 2.17), p = .031. No significant difference was found among females (OR = 1.20, CI = 0.83 – 1.74), p = .33.ConclusionLifestyle parameters did not seem to be related to increased and persistent fatigue among HLSs. The results may indicate that the experience of Hodgkins lymphoma increases the level of physical activity among male HLSs.

Identification of Highly Methylated Genes across Various Types of B-Cell Non-Hodgkin Lymphoma

Epigenetic alterations of gene expression are important in the development of cancer. In this study, we identified genes which are epigenetically altered in major lymphoma types. We used DNA microarray technology to assess changes in gene expression after treatment of 11 lymphoma cell lines with epigenetic drugs. We identified 233 genes with upregulated expression in treated cell lines and with downregulated expression in B-cell lymphoma patient samples (nu200a=u200a480) when compared to normal B cells (nu200a=u200a5). The top 30 genes were further analyzed by methylation specific PCR (MSP) in 18 lymphoma cell lines. Seven of the genes were methylated in more than 70% of the cell lines and were further subjected to quantitative MSP in 37 B-cell lymphoma patient samples (diffuse large B-cell lymphoma (activated B-cell like and germinal center B-cell like subtypes), follicular lymphoma and Burkitt`s lymphoma) and normal B lymphocytes from 10 healthy donors. The promoters of DSP, FZD8, KCNH2, and PPP1R14A were methylated in 28%, 67%, 22%, and 78% of the 36 tumor samples, respectively, but not in control samples. Validation using a second series of healthy donor controls (nu200a=u200a42; normal B cells, peripheral blood mononuclear cells, bone marrow, tonsils and follicular hyperplasia) and fresh-frozen lymphoma biopsies (nu200a=u200a25), confirmed the results. The DNA methylation biomarker panel consisting of DSP, FZD8, KCNH2, and PPP1R14A was positive in 89% (54/61) of all lymphomas. Receiver operating characteristic analysis to determine the discriminative power between lymphoma and healthy control samples showed a c-statistic of 0.96, indicating a possible role for the biomarker panel in monitoring of lymphoma patients.

Progressive loss of vision in patients with high-grade non-Hodgkin's lymphoma

Three cases of double‐sided neuritis of the optic nerve in patients with lymphomas are described. Two patients with lymphoblastic lymphoma had no other signs of central nervous system (CNS) relapse. All three cases responded to high doses of corticosteroids and/or radiotherapy, suggesting a lymphomatous cause of the papillitis. Optic nerve involvement is reported to be rare in lymphomas, but may become more prominent with aggressive systemic therapy controlling manifestations outside the CNS. Possible causes of optic neuritis in patients with lymphoma are discussed and therapeutic measures are suggested.

Sample-Index Misassignment Impacts Tumour Exome Sequencing

Sample pooling enabled by dedicated indexes is a common strategy for cost-effective and robust high-throughput sequencing. Index misassignment leading to mutual contamination between pooled samples has however been described as a general problem of the latest Illumina sequencing instruments utilizing exclusion amplification. Using real-life data from multiple tumour sequencing projects, we demonstrate that index misassignment can induce artefactual variant calls closely resembling true, high-quality somatic variants. These artefactual calls potentially impact cancer applications utilizing low allelic frequencies, such as in clonal analysis of tumours. We discuss the available countermeasures with an emphasis on improved library indexing methods, and provide software that can assist in the identification of variants that may be consequences of index misassignment.