Low 5-year cumulative incidence of post-transplant lymphoproliferative disorders after solid organ transplantation in Switzerland.

Post-transplant lymphoproliferative disorder (PTLD) is a potentially life-threatening complication of transplantation occurring in the setting of immunosuppression and oncogenic viral infections. However, little is known about the cumulative incidence, histological subtypes, risk determinants and outcome of PTLD in solid organ transplant (SOT) recipients in Switzerland. This retrospective observational study investigated adult SOT recipients from two sequential cohorts, the pre-SCTS (Swiss Transplant Cohort Study) series, with data collected from January 1986 to April 2008, and the STCS series, with data collected from May 2008 to December 2014 in Switzerland. SOT recipients were cross-referenced with the data of all the patients with a lymphoma diagnosis in each transplant centre and with the data of the Swiss Transplant Cohort Study (STCS) to determine the cumulative incidence of PTLD, pre-therapeutic clinical features, clinical course and outcome. Kaplan-Meier analysis was performed for overall survival after PTLD. We identified 79 cases of PTLD during the study period in the two cohorts: pre-STCS from 1986 to 2008 (n = 62) and STCS from 2008 to 2014 (n = 17). Histological subgroups included: early lesions (pre-STCS n = 2, STCS n = 0); polymorphic PTLD (pre-STCS n = 8, STCS n = 7); monomorphic PTLD (pre-STCS n = 47, STCS n = 10), and Hodgkin's lymphoma (pre-STCS n = 5, STCS n = 0). Median time to PTLD diagnosis was 90 months (range 3-281 months) and 14 months (range 2-59 months) in the pre-STCS and STCS cohorts, respectively. Median follow-up after transplantation was 141 months for the pre-STCS patients and 33 months for the STCS patients. Cumulative incidences of PTLD during the STCS period at 0.5, 1 and 5 years were 0.17% (95% confidence interval 0.07-0.46%), 0.22% (0.09-0.53%) and 0.96% (0.52-1.80%), respectively. For the pre-STCS case series, it was not possible to estimate the incidence rate of PTLD. Survival after PTLD diagnosis was 80% (68-87%) at 1 year and 56% (42-68%) at 5 years for the pre-STCS and STCS cohorts combined. At 5 years, the cumulative incidence of PTLD, regardless of the organ transplanted, was only 0.96% in the STCS cohort, which is lower than that reported in the literature

Mycobacterium tuberculosis Rv3802c Encodes a Phospholipase/Thioesterase and Is Inhibited by the Antimycobacterial Agent Tetrahydrolipstatin

The cell wall of M. tuberculosis is central to its success as a pathogen. Mycolic acids are key components of this cell wall. The genes involved in joining the α and mero mycolates are located in a cluster, beginning with Rv3799c and extending at least until Rv3804c. The role of each enzyme encoded by these five genes is fairly well understood, except for Rv3802c. Rv3802 is one of seven putative cutinases encoded by the genome of M. tuberculosis. In phytopathogens, cutinases hydrolyze the waxy layer of plants, cutin. In a strictly mammalian pathogen, such as M. tuberculosis, it is likely that these proteins perform a different function. Of the seven, we chose to focus on Rv3802c because of its location in a mycolic acid synthesis gene cluster, its putative essentiality, its ubiquitous presence in actinomycetes, and its conservation in the minimal genome of Mycobacterium leprae. We expressed Rv3802 in Escherichia coli and purified the enzymatically active form. We probed its activities and inhibitors characterizing those relevant to its possible role in mycolic acid biosynthesis. In addition to its reported phospholipase A activity, Rv3802 has significant thioesterase activity, and it is inhibited by tetrahydrolipstatin (THL). THL is a described anti-tuberculous compound with an unknown mechanism, but it reportedly targets cell wall synthesis. Taken together, these data circumstantially support a role for Rv3802 in mycolic acid synthesis and, as the cell wall is integral to M. tuberculosis pathogenesis, identification of a novel cell wall enzyme and its inhibition has therapeutic and diagnostic implications

The genetic basis of transformation and progression in follicular lymphoma

The clonal evolution theory of cancer has been recognized for decades and follows principles of Darwinian selection, in which there is selection of the fittest clones in an ecosystem that is fundamentally heterogeneous and undergoes selective pressure. Follicular lymphoma (FL) emerges as a prototypical disease in which to study clonal evolution. It is the most common indolent lymphoma and, although the median overall survival largely surpasses 10 years, patients almost invariably experience progressive disease. Furthermore, a subset of FL patients is at risk of early lymphoma-related death due to rapid progression or transformation to aggressive lymphoma. Yet, the clonal dynamics and the landscape of genomic alterations underlying progression and transformation remain to be uncovered. Herein, we applied whole genome sequencing to a discovery set of transformed, progressed and non-progressed FL cases, re-constructed clonal phylogenies, and interrogated a larger set of transformed FLs and clinical extremes by capture-based targeted sequencing. Moreover, we applied the Lymph2Cx cell-of-origin assay to determine whether molecular subtypes can be defined in transformed follicular lymphoma (TFL) by gene-expression profiling. We discovered that transformation is typically the result of drastic clonal shifts during which TFL-specific clones rapidly outcompete indolent clones. In a subset of cases, these aggressive clones can be found at low levels (< 1% of tumour cells) at diagnosis. In contrast, primary progression generally results from the outgrowth of subclones that are readily detectable at diagnosis, suggesting that the genomic features conferring treatment resistance can be detected prior to initial treatment using low-pass sequencing technology. In addition, we identified discrete gene mutations that are associated with early progression and transformation, and uncovered that a subset of TFLs (16%) have an activated B-cell phenotype and are enriched for mutations in CD79B and BCL10. In summary, we found striking contrast in clonal trajectories between distinct clinical scenarios and described novel associations of gene mutations with transformation and progression. Our findings have translational relevance as they suggest that early progression, and to a lesser extent transformation, can potentially be predicted at diagnosis and thus provide a rationale for novel therapeutic approaches in TFL.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat

Prevention of CNS relapse in diffuse large B-cell lymphoma

CNS relapse occurs in about 5% of patients during the course of diffuse large B-cell lymphoma and entails a dismal prognosis. This consideration has led to the adoption of CNS prophylaxis, although known risk factors do not allow for an accurate prediction of CNS recurrences because they have insufficient sensitivity and specificity. Here, we review the reports of CNS events in major studies of diffuse large B-cell lymphoma before and after the introduction of rituximab, and probe the evidence that underlies prophylactic strategies such as intrathecal or high-dose intravenous chemotherapy. Now that rituximab is available, CNS prophylaxis relies on little-if any-evidence and should not be routinely administered. Nonetheless, several patient subgroups probably have a high risk of systemic and CNS relapses, and how to manage their treatment is a challenge. These subgroups include patients with testicular lymphoma or those who have more than one extranodal site involved plus at least one additional risk factor. For such patients, we recommend against prophylactic intrathecal chemotherapy because of the rare occurrence of isolated leptomeningeal relapses, the absence of evidence-based efficacy, and the potential harmful side-effects that are associated with this procedure. Because many CNS events are a result of primary resistance to treatment or accompany systemic relapses, high-dose intravenous methotrexate has been suggested as an alternative approach that needs to be validated in prospective controlled trials

Bullough, Robert V., Jr., and Craig Kridel, Adolescent Needs, Curriculum, and the Eight-Year Study, Journal of Curriculum Studies, 35(March, 2003), 151-169.

Describes the historical debate over adolescent needs among members of the Progressive Education Association during the period of the Eight-Year Study; traces views of Alberty, Zachry, Thayer, and Bode; discusses the role of social philosophy in current curriculum development

Kridel, Craig, and Robert V. Bullough, Jr., Stories of the Eight-Year Study: Reexamining Secondary Education in America. Albany, NY: State University Press of New York,2007.

Details many aspects of the history of the Eight-Year Study (1930-1942) and includes vignettes of several of its leading contributors (Aikin, Thayer, Eugene Smith, Tyler, Keliher, Zachry, Alberty, Bode, Willis). A review appears in Curriculum Inquiry, 40(March, 2010), 2905-316

Kridel, Craig, and Robert V. Bullough, Jr., Conceptions and Misperceptions of the Eight-Year Study, Journal of Curriculum and Supervision, 18(Fall, 2002), 63-82.

Re-examines the facts and interpretations of the Eight-Year Study; argues for numerous corrections and reinterpretations based on historical research

Bullough, Robert V., Jr., and Craig Kridel, Workshops, In-Service Teacher Education, and the Eight-Year Study, Teaching and Teacher Education, 19 (October, 2003), 665-679.

Explores the workshop form of in-service teacher education as it was developed and used during the Eight-Year Study

Kridel, Craig, Robert V. Bullough, Jr., and Paul Shaker, eds., Teachers and Mentors: Profiles of Distinguished Twentieth-Century Professors of Education. New York: Garland Publishing, Inc, 1996.

Contains 22 biographical sketches (8 are leading curriculum theorists from Caswell to Tyler to Macdonald, etc.) written by professors who saw them as professorial mentors