Cancer mortality in Europe, 2005-2009, and an overview of trends since 1980.

BACKGROUND: After a peak in the late 1980s, cancer mortality in Europe has declined by ∼10% in both sexes up to the early 2000s. We provide an up-to-date picture of patterns and trends in mortality from major cancers in Europe. METHODS: We analyzed cancer mortality data from the World Health Organization for 25 cancer sites and 34 European countries (plus the European Union, EU) in 2005-2009. We computed age-standardized rates (per 100 000 person-years) using the world standard population and provided an overview of trends since 1980 for major European countries, using joinpoint regression. RESULTS: Cancer mortality in the EU steadily declined since the late 1980s, with reductions by 1.6% per year in 2002-2009 in men and 1% per year in 1993-2009 in women. In western Europe, rates steadily declined over the last two decades for stomach and colorectal cancer, Hodgkin lymphoma, and leukemias in both sexes, breast and (cervix) uterine cancer in women, and testicular cancer in men. In central/eastern Europe, mortality from major cancer sites has been increasing up to the late 1990s/early 2000s. In most Europe, rates have been increasing for lung cancer in women and for pancreatic cancer and soft tissue sarcomas in both sexes, while they have started to decline over recent years for multiple myeloma. In 2005-2009, there was still an over twofold difference between the highest male cancer mortality in Hungary (235.2/100 000) and the lowest one in Sweden (112.9/100 000), and a 1.7-fold one in women (from 124.4 in Denmark to 71.0/100 000 in Spain). CONCLUSIONS: With the major exceptions of female lung cancer and pancreatic cancer in both sexes, in the last quinquennium, cancer mortality has moderately but steadily declined across Europe. However, substantial differences across countries persist, requiring targeted interventions on risk factor control, early diagnosis, and improved management and pharmacological treatment for selected cancer sites.

Molecular underpinning of extranodal NK/T-cell lymphoma.

Peripheral NK/T-cell lymphoma (PTCL) is a heterogeneous group of uncommon hematologic malignancies with aggressive clinical course and unfavorable prognosis. Extranodal NK/T-cell lymphoma, nasal type (NKTCL) is the most common extranodal entity worldwide, with heterogeneous geographic distribution, and it is characterized by its association with EBV, a nasal or less often extranasal presentation and aggressive behavior. Recent works using array-based technologies have provided novel insights into the pathogenesis and discovered new biomarkers with diagnostic and therapeutic implications in NKTCL. Gene expression profiling identified that most of the NKTCL are derived from activated natural killer cells with distinctively high expression of granzyme H compared to other PTCLs, which might serve as a new diagnostic biomarker. Frequent deletions and promoter methylations in PRDM1, ATG5, AIM1, FOXO3, HACE1 mapping to 6q21-q25, suggest their roles as potential tumor suppressors. The deregulation of oncogenic pathways (PDGF, JAK-STAT, AKT) provides a rationale for developing targeted therapies in the future.

TNF deficiency fails to protect BAFF transgenic mice against autoimmunity and reveals a predisposition to B cell lymphoma.

TNF is well characterized as a mediator of inflammatory responses. TNF also facilitates organization of secondary lymphoid organs, particularly B cell follicles and germinal centers, a hallmark of T-dependent Ab responses. TNF also mediates defense against tumors. We examined the role of TNF in the development of inflammatory autoimmune disorders resembling systemic lupus erythematosus and Sjögren's syndrome induced by excess B cell-activating factor belonging to the TNF family (BAFF), by generating BAFF-transgenic (Tg) mice lacking TNF. TNF(-/-) BAFF-Tg mice resembled TNF(-/-) mice, in that they lacked B cell follicles, follicular dendritic cells, and germinal centers, and have impaired responses to T-dependent Ags. Nevertheless, TNF(-/-) BAFF-Tg mice developed autoimmune disorders similar to that of BAFF-Tg mice. Disease in TNF(-/-) BAFF-Tg mice correlates with the expansion of transitional type 2 and marginal zone B cell populations and enhanced T-independent immune responses. TNF deficiency in BAFF-Tg mice also led to a surprisingly high incidence of B cell lymphomas (>35%), which most likely resulted from the combined effects of BAFF promotion of neoplastic B cell survival, coupled with lack of protective antitumor defense by TNF. Thus, TNF appears to be dispensable for BAFF-mediated autoimmune disorders and may, in fact, counter any proneoplastic effects of high levels of BAFF in diseases such as Sjögren's syndrome, systemic lupus erythematosus, and rheumatoid arthritis.

Purpura of the face and neck: an atypical clinical presentation revealing a hepatosplenic T cell lymphoma

BACKGROUND: Hepatosplenic T cell lymphoma (HSTL) is a rare but very aggressive peripheral T cell lymphoma whose initial silent clinical presentation unfortunately delays the diagnosis and worsens the prognosis of patient survival. Efforts should be aimed at early recognition and treatment. METHODS: We describe a case of a 62-year-old woman who presented at our clinic with a non-palpable purpuric eruption of the face. Investigations revealed thrombocytopenia with hepatosplenomegaly, which showed rapid progression together with accentuation of the purpura. Two months later, a bone marrow biopsy revealed the diagnosis of a HSTL. RESULTS: The patient received six cycles of CHOP chemotherapy (vincristine, cyclophosphamide, doxorubicin, methylprednisolone) followed by a well-tolerated autologous bone marrow graft. Normalization of the platelet count resulted in regression of the purpuric rash. CONCLUSION: To our knowledge, this is the first report of a facial thrombocytopenic purpura as the inaugural symptom of HSTL. It emphasizes the privileged position of the dermatologist for early recognition of potentially lethal HSTL.

Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma.

A key element for the development of suitable anti-cancer drugs is the identification of cancer-specific enzymatic activities that can be therapeutically targeted. Mucosa-associated lymphoid tissue transformation protein 1 (MALT1) is a proto-oncogene that contributes to tumorigenesis in diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, the least curable subtype of DLBCL. Recent data suggest that MALT1 has proteolytic activity, but it is unknown whether this activity is relevant for tumor growth. Here we report that MALT1 is constitutively active in DLBCL lines of the ABC but not the GCB subtype. Inhibition of the MALT1 proteolytic activity led to reduced expression of growth factors and apoptosis inhibitors, and specifically affected the growth and survival of ABC DLBCL lines. These results demonstrate a key role for the proteolytic activity of MALT1 in DLBCL of the ABC subtype, and provide a rationale for the development of pharmacological inhibitors of MALT1 in DLBCL therapy.

Diagnosis and treatment of follicular lymphoma.

Follicular lymphoma is a slow-growing disease exhibiting a heterogeneous clinical course, with a subset of patients experiencing a rapid disease course in the first two years and some developing disease transformation to a more aggressive phenotype. The advent of highly effective therapies has resulted in an increasing number of patients who achieve long-term progression-free survival alongside a good quality of life. Monoclonal antibodies, such as rituximab, either alone or in combination with chemotherapy regimens or radioimmunotherapy have been used with significant improvements in outcome. New treatment strategies such as new antibodies, biologic agents or vaccination therapy are also under investigation for the treatment of relapsed or refractory disease, further expanding the available options for patients and physicians alike. This article presents an overview of the current therapeutic strategies for the management of follicular lymphoma, focusing on the issues encountered in clinical practice.

High-dose therapy and autologous hematopoietic stem cell transplantation in T-cell lymphoma : a single centre experience

Le diagnostic de lymphome représente 4% de tous les cancers et a une incidence particulièrement élevée dans les pays industrialisés. La proportion de lymphomes T, évaluée en Europe et aux Etats Unis, représente environ 5 à 10% des lymphomes. Alors que des progrès très sensibles ont été apportés dans la prise en charge et le pronostic des lymphomes B agressifs durant ces dernières décennies et en particulier depuis le début des années 2000 avec l'utilisation des anticorps anti-CD20 associés à la chimiothérapie, le pronostic des lymphomes T reste très décevant. La survie globale des lymphomes T à 5 ans est estimée entre 28% et 38%. Le bénéfice réel d'une chimiothérapie intensive suivie d'une autogreffe de cellules souches hématopoïétiques périphériques au terme d'un traitement de chimiothérapie d'induction dans le lymphome T périphérique reste débattu. Les résultats des rares études prospectives et des études rétrospectives à disposition sont discordants. Nous avons donc analysé rétrospectivement 43 patients successifs de mars 2000 à mars 2011, atteints de lymphome T, issus de notre base de données du programme autogreffe lausannois. Nos analyses statistiques permettent, sur la base d'un suivi médian de 63 mois, une estimation à 12 ans, de la survie globale de nos patients à 40%, de la survie sans progression à 34% et de la survie sans événement à 30%. Ces chiffres s'inscrivent parfaitement dans les résultats des études prospectives qui montrent un bénéfice de l'autogreffe dans le lymphome T. Parmi les différents paramètres pronostiques habituellement évalués, l'âge et l'absence de symptômes B au diagnostic sont les seuls paramètres statistiquement significatifs en analyse univariée dans notre cohorte. En effet, Les patients de moins de 50 ans et ceux qui ne présentent pas de symptômes B au diagnostic ont un meilleur pronostic. Nous concluons de cette analyse que les patients traités par chimiothérapie intensive et autogreffe de cellules souches hématopoïétiques périphériques ont une survie moyenne supérieure aux résultats rapportés dans la littérature avec des traitements de chimiothérapie conventionnelle de type CHOP. En effet, on estime à environ 50% les patients répondant à une chimiothérapie conventionnelle de type CHOP.

A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma.

BACKGROUND: Mantle cell lymphoma accounts for 6% of all B-cell lymphomas and is generally incurable. It is characterized by the translocation t(11;14) leading to cyclin D1 over-expression. Cyclin D1 is downstream of the mammalian target of rapamycin threonine kinase and can be effectively blocked by mammalian target of rapamycin inhibitors. We set out to examine the single agent activity of the orally available mammalian target of rapamycin inhibitor everolimus in a prospective, multicenter trial in patients with relapsed or refractory mantle cell lymphoma (NCT00516412). DESIGN AND METHODS: Eligible patients who had received a maximum of three prior lines of chemotherapy were given everolimus 10 mg for 28 days (one cycle) for a total of six cycles or until disease progression. The primary endpoint was the best objective response. Adverse reactions, progression-free survival and molecular response were secondary endpoints. RESULTS: Thirty-six patients (35 evaluable) were enrolled and treatment was generally well tolerated with Common Terminology Criteria grade ≥ 3 adverse events (>5%) including anemia (11%), thrombocytopenia (11%) and neutropenia (8%). The overall response rate was 20% (95% CI: 8-37%) with two complete remissions and five partial responses; 49% of the patients had stable disease. At a median follow-up of 6 months, the median progression-free survival was 5.5 months (95% CI: 2.8-8.2) overall and 17.0 (6.4-23.3) months for 18 patients who received six or more cycles of treatment. Three patients achieved a lasting complete molecular response, as assessed by polymerase chain reaction analysis of peripheral blood. CONCLUSIONS: Everolimus as a single agent is well tolerated and has anti-lymphoma activity in relapsed or refractory mantle cell lymphoma. Further studies of everolimus in combination with chemotherapy or as a single agent for maintenance treatment are warranted.

PTLD Burkitt Lymphoma in a Patient with Remote Lymphomatoid Granulomatosis.

Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of solid organ transplantation. The majority of PTLD is of B-cell origin, and 90% are associated with the Epstein-Barr virus (EBV). Lymphomatoid granulomatosis (LG) is a rare, EBV-associated systemic angiodestructive lymphoproliferative disorder, which has rarely been described in patients with renal transplantation. We report the case of a patient with renal transplantation for SLE, who presented, 9 months after renal transplantation, an EBV-associated LG limited to the intracranial structures that recovered completely after adjustment of her immunosuppressive treatment. Nine years later, she developed a second PTLD disorder with central nervous system initial manifestation. Workup revealed an EBV-positive PTLD Burkitt lymphoma, widely disseminated in most organs. In summary, the reported patient presented two lymphoproliferative disorders (LG and Burkitt's lymphoma), both with initial neurological manifestation, at 9 years interval. With careful reduction of the immunosuppression after the first manifestation and with the use of chemotherapy combined with radiotherapy after the second manifestation, our patient showed complete disappearance of neurologic symptoms and she is clinically well with good kidney function. No recurrence has been observed by radiological imaging until now.

Lymphome surrénalien primaire bilatéral [Primary bilateral adrenal lymphoma]

When abdominal imaging reveals the existence of unsuspected adrenal masses, a diagnostic strategy is necessary. We report the case of a woman presenting with pulmonary embolism, in whom abdominal ultrasound revealed voluminous masses in both adrenals without clinical or biological signs of hormone hypersecretion, but with mild primary adrenal failure. From a CT scan-directed needle biopsy of the right adrenal mass and subsequent staging we were able to diagnose a primary bilateral adrenal lymphoma, diffuse large B-cell type (REAL/WHO). On CHOP chemotherapy both adrenal masses decreased dramatically and the patient is in remission 18 months later. Primary adrenal lymphoma is a rare condition, since 65 cases have been reported to date. Histological diagnosis is nevertheless important, in view of the excellent response to specific therapy observed in some cases.

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This chapter presents a series of case studies with multiple choice questions and answers that focus on the pitfalls in the diagnosis of non-Hodgkin's lymphomas. It commences with a discourse on the diagnosis B-cell lymphomas. A subset of aggressive and high grade B-cell lymphomas that feature characteristics intermediate between those of diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) are grouped together under the designation BCLU-DLBCL/BL. The chapter discusses the diagnosis of nodular lymphocytic predominant Hodgkin lymphoma (NLPHL). It also focuses on the diagnosis of primary mediastinal (thymic) large B-cell lymphoma T-lymphoblastic leukemia/lymphoma, pediatric follicular lymphoma, and cyclin D1-negative mantle cell lymphoma (MCL).

Dosimetry of 90Y-ibritumomab tiuxetan as consolidation of first remission in advanced-stage follicular lymphoma: results from the international phase 3 first-line indolent trial.

The objective of this analysis was to assess the radiation exposure associated with (90)Y-ibritumomab tiuxetan when used as consolidation therapy in adults with low or minimal tumor burden after first-line therapy of advanced follicular lymphoma (FL). METHODS: The patients who were enrolled in the phase 3 first-line indolent trial were 18 y or older, with CD20(+) grade 1 or 2 stage III or IV FL, and a partial response, complete response, or unconfirmed complete response to first-line chemotherapy. The patients were allocated randomly to receive a single infusion of unlabeled rituximab 250 mg/m(2) on day -7 and consolidation on day 0 with a single dose of (90)Y-ibritumomab tiuxetan, 14.8 MBq/kg, immediately after unlabeled rituximab, 250 mg/m(2), or no further treatment. On day -7, a subset of patients received an injection of 185 MBq of (111)In-ibritumomab tiuxetan immediately after unlabeled rituximab, 250 mg/m(2), for central dosimetry analysis. Correlations were assessed between organ radiation absorbed dose and toxicity, body weight, body mass index, and progression-free survival. RESULTS: Central dosimetry evaluations were available from 57 of 70 patients. Median radiation absorbed doses were 100 cGy (range, 28-327 cGy) for the red marrow and 72 cGy (range, 46-106 cGy) for the whole body. Radiation absorbed doses did not differ significantly between patients who had a partial response or complete response to initial therapy. Progression-free survival correlated significantly with the whole-body (r = 0.4401; P = 0.0006) and bone marrow (r = 0.2976; P = 0.0246) radiation dose. Body weight was significantly negatively correlated with whole-body radiation dose (r = -0.4971; P < 0.0001). Neither the whole-body radiation dose nor the bone marrow radiation dose correlated with hematologic toxicity. CONCLUSION: In patients with low or minimal residual tumor burden after first-line chemotherapy of advanced FL, whole-body and bone marrow exposure after (90)Y-ibritumomab tiuxetan consolidation showed a significant positive correlation with progression-free survival, whereas dosimetric data could not predict hematologic toxicity.

Improving the chance of cure of follicular lymphoma by combining immunotherapy and radioimmunotherapy based on anti-CD20 antibodies?

Right ventricular and left ventricular systolic time intervals (RVSTIs and LVSTIs) were measured in normal term and preterm infants from 1 hour to 90 days of life. LVSTIs in both term and preterm infants were similar in the first five days of life. The ratio of left pre-ejection period (LPEP) to left ventricular ejection time (LVET) was lower in preterm infants older than age 5 days. Estimated gestational age had no influence on LVSTI. The ratio of right pre-ejection period (RPEP) to right ventricular ejection time (RVET) was lower in preterm infants (0.32) than in term newborns (0.37). The preterm RPEP/RVET ratio decreased with age, but at a slower rate than in term babies. This was consistent with the lower pulmonary vascular resistance present in preterm infants.

Childhood cancer mortality in America, Asia, and Oceania, 1970 through 2007.

BACKGROUND: Over the last 4 decades, childhood cancer mortality declined in most developed areas of the world. However, scant information is available from middle-income and developing countries. The authors analyzed and compared patterns in childhood cancer mortality in 24 developed and middle-income countries in America, Asia, and Oceania between 1970 and 2007. METHODS: Childhood age-standardized annual mortality rates were derived from the World Health Organization (WHO) database for all neoplasms, bone and kidney cancer, non-Hodgkin lymphoma (NHL), and leukemias. RESULTS: Since 1970, rates for all childhood cancers dropped from approximately 8 per 100,000 boys to 3 per 100,000 boys and from 6 per 100,000 girls to 2 per 100,000 girls in North America and Japan. Latin American countries registered rates of approximately 5 per 100,000 boys and 4 per 100,000 girls for 2005 through 2007, similar to the rates registered in more developed areas in the early 1980s. Similar patterns were observed for leukemias, for which the mortality rates were 0.81 per 100,000 boys and 0.55 per 100,000 girls in North America, 0.86 per 100,000 boys and 0.68 per 100,000 girls in Japan, and 1.98 per 100,000 boys and 1.65 per 100,000 girls in Latin America for 2005 through 2007. Bone cancer rates for 2005 through 2007 were approximately 2-fold higher in Argentina than in the United States. During the same period, Mexico registered the highest rate for kidney cancer and Colombia registered the highest rate for NHL, whereas the lowest rates were registered by Japan for kidney and by Japan and the United States for NHL. CONCLUSIONS: Improvements in the adoption of current integrated treatment protocols in Latin American and other lower- and middle-income countries worldwide would avoid a substantial proportion of childhood cancer deaths.

Radioimmunotherapy combined with maintenance anti-CD20 antibody may trigger long-term protective T cell immunity in follicular lymphoma patients.

Growing evidence suggests that the patient's immune response may play a major role in the long-term efficacy of antibody therapies of follicular lymphoma (FL). Particular long-lasting recurrence free survivals have been observed after first line, single agent rituximab or after radioimmunotherapy (RIT). Rituximab maintenance, furthermore, has a major efficacy in prolonging recurrence free survival after chemotherapy. On the other hand, RIT as a single step treatment showed a remarkable capacity to induce complete and partial remissions when applied in recurrence and as initial treatment of FL or given for consolidation. These clinical results strongly suggest that RIT combined with rituximab maintenance could stabilize the high percentages of patients with CR and PR induced by RIT. While the precise mechanisms of the long-term efficacy of these 2 treatments are not elucidated, different observations suggest that the patient's T cell immune response could be decisive. With this review, we discuss the potential role of the patient's immune system under rituximab and RIT and argue that the T cell immunity might be particularly promoted when combining the 2 antibody treatments in the early therapy of FL.