Absence of residual Hodgkin's disease demonstrated by PET/CT in a deceased organ donor.

With the current limited availability of organs for transplantation, it is important to consider marginal donor candidates, including survivors of potentially curable malignancies such as lymphoma. The absence of refractory/recurrent residual disease at the time of brain death can be difficult to establish. Therefore, it is critical to have objective data to decide whether to proceed or not with organ procurement and transplantation. We report a unique situation in which (18)F-fluorodeoxyglucose positron emission tomography (PET) was used to rule out Hodgkin's lymphoma recurrence in a 33-year-old, heart-beating, brain-dead, potential donor with a past history of Hodgkin's disease and a persistent mediastinal mass. PET showed no significant uptake in the mass, allowing organ donation and transplantation to occur. We present a new means of evaluating potential brain-dead donors with a past history of some lymphoma, whereby PET may help transplant physicians by optimizing donation safety while rationalizing the inclusion of marginal donors.

Early stage primary bone lymphoma - a retrospective, multicenter rare cancer network (rcn) study

Purpose: Primary bone lymphoma (PBL) accounts for less than 1% of all malignant lymphomas, and 4-5% of all extra-nodal lymphomas. In this study, the disease profile, outcome, and prognostic factors were assessed in patients with stage I and II PBL.Patients and Methods: Thirteen Rare Cancer Network (RCN) institutions enrolled 116 consecutive patients with PBL treated between 1987 and 2008 in this study. Inclusion criteria were age > 16 years, stage I and II, minimum 6 months follow-up and a biopsy-proven confirmation of non-Hodgkin's lymphoma (NHL). Eighty-seven patients underwent chemoradiotherapy (CXRT), 15 radiotherapy (RT) without (13) or with (2) surgery, 14 chemotherapy (CXT) without (9) or with (5) surgery. Median RT dose was 40 Gy (range: 4-60). The median number of CXT cycles was 6 (range: 2-8). Median follow-up was 41 months (range: 6-242).Results: The overall response rate at the end of treatment was 91% (CR 74%, PR 17%). Local recurrence or progression was observed in 12 (10%) patients, and systemic recurrence in 17 (15%). Causes of death included disease progression in 21, unrelated in 5, CXT-related toxicity in 1, and second primary cancer in 2 patients. The 5-yr overall survival (OS), lymphoma-specific survival (LSS), and local control (LC) were 76%, 78% and 92%, respectively. In univariate analyses (log-rank test), favorable prognostic factors for OS were age <50 years (P=0.008), international prognostic index (IPI) score ≤1 (P=0.009), high grade histology (P=0.04), CXRT (P=0.05), CXT (P=0,0004), complete response (CR) (P<0.0001), number of CXT cycles ( ≥6 ) (P=0.01), and RT dose > 40 Gy (P=0.005). All above-mentioned parameters were also significant for LSS except for age and number of chemotherapy cycles. For LC, only CR and stage I were favorable factors. In multivariate analysis, IPI score, RT dose, complete response, and chemotherapy were independently influencing the outcome (OS and LSS). Complete response at the end of treatment was the only predicting factor for LC. Six patients developed grade 3 or more toxicities, according to Common Terminology Criteria for Adverse Events (CTCAE) V3.0.Conclusion: This large multicenter study confirms the relatively good prognosis of early stage PBL treated with combined CXRT. Local control was excellent, while systemic failures were rare. An adequate dose of RT (40 Gy or more) and complete CXT regime (≥ 6 cycles) were associated with better outcome.

Early Stage Primary Bone Lymphoma: A Retrospective, Multicenter Rare Cancer Network Study

PURPOSE/OBJECTIVE(S): Primary bone lymphoma (PBL) represents less than 1% of all malignant lymphomas, and 4-5% of all extranodal lymphomas. In this study, we assessed the disease profile, outcome, and prognostic factors in patients with stage I and II PBL. MATERIALS/METHODS: Between 1987 and 2008, 116 consecutive patients with PBL treated in 13 RCNinstitutions were included in this study. Inclusion criteriawere: age.17 yrs, PBLin stage I and II, andminimum6months follow-up. The median agewas 51 yrs (range: 17-93).Diagnosticwork-up included plain boneXray (74%of patients), scintigraphy (62%), CT-scan (65%),MRI (58%), PET (18%), and bone-marrow biopsy (84%).All patients had biopsy-proven confirmation of non-Hodgkin's lymphoma (NHL). The histopathological type was predominantly diffuse large B-cell lymphoma (78%) and follicular lymphoma (6%), according to theWHOclassification. One hundred patients had a high-grade, 7 intermediate and 9 low-gradeNHL. Ninety-three patients had anAnn-Arbor stage I, and 23 had a stage II. Seventy-seven patients underwent chemoradiotherapy (CXRT), 12 radiotherapy (RT) alone, 10 chemotherapy alone (CXT), 9 surgery followed by CXRT, 5 surgery followed by CXT, and 2 surgery followed by RT. One patient died before treatment.Median RT dosewas 40Gy (range: 4-60).Themedian number ofCXTcycleswas 6 (range, : 2-8).Median follow-upwas 41months (range: 6-242). RESULTS: Following treatment, the overall response rate was 91% (CR 74%, PR 17%). Local recurrence was observed in 12 (10%) patients, and systemic recurrence in 17 (15%) patients. Causes of death included disease progression in 16, unrelated disease in 6, CXT-related toxicity in 1, and secondary cancer in 2 patients. The 5-yr overall survival (OS), disease-free survival (DFS), lymphoma- specific survival (LSS), and local control (LC) were 76%, 69%, 78%, and 92%, respectively. In univariate analyses (log-rank test), favorable prognostic factors for survival were: age\50 years (p = 0.008), IPI score #1 (p = 0.009), complete response (p\0.001), CXT (p = 0.008), number of CXT cycles $6 (p = 0.007), and RT dose . 40 Gy (p = 0.005). In multivariate analysis age, RT dose, complete response, and absence of B symptoms were independent factors influencing the outcome. There were 3 patients developing grade 3 or more (CTCAE.V3.0) toxicities. CONCLUSIONS: This large multicenter study, confirms the relatively good prognosis of early stage PBL, treated with combined CXRT. Local control was excellent, and systemic failure occurred infrequently. A sufficient dose of RT (. 40 Gy) and complete CXT regime (. 6 cycles) were associated with a better outcome. Combined modality appears to be the treatment of choice.

Genetic aberrations in pediatric follicular lymphoma

Background: Pediatric follicular lymphoma (FL) is a rare disease that differs from its adult counterpart both genetically and clinically. Excluding pediatric FL with IRF4-translocation, the genetic events associated with pediatric FL have not yet been defined. Objectives: The aim of this study was to perform a complete genetic characterization of IRF4-translocation negative pediatric follicular lymphomas to elucidate the genetic profile of these rare pediatric cases and determine common genetic alterations that could be associated to this phenotype. Design/Methods: We applied array-comparative genomic hybridization and molecular inversion probe assay adapted to formalin-fixed paraffin-embedded tissues from 18 patients aged £18 years diagnosed with FL. With the exception of one case with only focal involvement by lymphoma, the tumor cell content exceeded 50% in the evaluable samples. Eleven of 18 patients were treated according to NHL-BFM group multicenter trials whereas the remaining according to different protocols. All lacked t(14;18) translocation. Mutational analysis of TNFRSF14 gene was performed in 17 cases. Results: Only six pediatric cases displayed chromosomal imbalances, with gain/amplification of 6pter-p24.3 (including IRF4) and deletion/ copy number neutral-loss of heterozygosity in 1p36 (including TNFRSF14) being the most frequent alterations. Sequencing of the candidate gene TNFRSF14 at 1p36.32 showed nine mutations in seven cases. Conclusion: Combination of molecular and genetic features differentiated a recurrent pattern of genomic imbalances as well as of TNFRSF14 mutations in pediatric FL which together with other genetic alterations distinguishes two subsets of pediatric follicular lymphomas. The first group shows genomic aberrations and is associated with more aggressive histopathologic and clinical features. The second group lacks genetic alterations detectable with the present approaches and is associated with a more limited disease. Despite the absence of genomic aberrations, these cases resembled FL by their histopathological features.

Amifostine (WR-2721), a cytoprotective agent during high-dose cyclophosphamide treatment of non-Hodgkin's lymphomas: a phase II study

Clinical trials indicate that amifostine may confer protection on various normal tissues without attenuating anti-tumor response. When administered prior to chemotherapy or radiotherapy, it may provide a broad spectrum of cytoprotection including against alkylating drugs. The mechanism of protection resides in the metabolism at normal tissue site by membrane-bound alkaline phosphatase. Toxicity of this drug is moderate with hypotension, nausea and vomiting, and hypocalcemia being observed. We report a phase II study using amifostine as a protective drug against high-dose cyclophosphamide (HDCY) (7 g/m2), used to mobilize peripheral blood progenitor cells (PBPC) and to reduce tumor burden. We enrolled 29 patients, 22 (75.9%) affected by aggressive and 7 (24.1%) by indolent non-Hodgkin's lymphoma (NHL), who were submitted to 58 infusions of amifostine and compared them with a historical group (33 patients) affected by aggressive NHL and treated with VACOP-B followed by HDCY. The most important results in favor of amifostine were the reduction of intensity of cardiac, pulmonary and hepatic toxicity, and a significant reduction of frequency and severity of mucositis (P = 0.04). None of the 29 patients died in the protected group, while in the historical group 2/33 patients died because of cardiac or pulmonary toxicity and 2 patients stopped therapy due to toxicity. Amifostine did not prevent the aplastic phase following HDCY. PBPC collection and hematological recovery were adequate in both groups. The number of CFU-GM (colony-forming units-granulocyte/macrophage) colonies and mononuclear cells in the apheresis products was significantly higher in the amifostine group (P = 0.02 and 0.01, respectively). Side effects were mild and easily controlled. We conclude that amifostine protection should be useful in HDCY to protect normal tissues, with acceptable side effects.

High-dose cyclophosphamide followed by autologous peripheral blood progenitor cell transplantation improves the salvage treatment for persistent or sensitive relapsed malignant lymphoma

Trials have demonstrated that high-dose escalation followed by autologous transplantation can promote better long-term survival as salvage treatment in malignant lymphomas. The aim of the present nonrandomized clinical trial was to demonstrate the role of high-dose cyclophosphamide (HDCY) in reducing tumor burden and also to determine the effectiveness of HDCY followed by etoposide (VP-16) and methotrexate (MTX) in Hodgkin's disease plus high-dose therapy with peripheral blood progenitor cell (PBPC) transplantation as salvage treatment. From 1998 to 2000, 33 patients with a median age of 33 years (13-65) affected by aggressive non-Hodgkin's lymphoma (NHL) (60.6%) or persistent or relapsed Hodgkin's disease (39.4%) were enrolled and treated using high dose escalation (HDCY + HDVP-16 plus HDMTX in Hodgkin's disease) followed by autologous PBPC transplantation. On an "intention to treat" basis, 33 patients with malignant lymphomas were evaluated. The overall median follow-up was 400 days (40-1233). Thirty-one patients underwent autografting and received a median of 6.19 x 10(6)/kg (1.07-29.3) CD34+ cells. Patients who were chemosensitive to HDCY (N = 22) and patients who were chemoresistant (N = 11) presented an overall survival of 96 and 15%, respectively (P<0.0001). Overall survival was 92% for chemosensitive patients and 0% for patients who were still chemoresistant before transplantation (P<0.0001). Toxicity-related mortality was 12% (four patients), related to HDCY in two cases and to transplant in the other two. HDCY + HDVP-16 plus HDMTX in only Hodgkin's disease followed by autologous PBPC proved to be effective and safe as salvage treatment for chemosensitive patients affected by aggressive NHL and Hodgkin's disease, with acceptable mortality rates related to sequential treatment.

Adhesion molecule profiles of B-cell non-Hodgkin's lymphomas in the leukemic phase

We evaluated the expression of 10 adhesion molecules on peripheral blood tumor cells of 17 patients with chronic lymphocytic leukemia, 17 with mantle-cell lymphoma, and 13 with nodal or splenic marginal B-cell lymphoma, all in the leukemic phase and before the beginning of any therapy. The diagnosis of B-cell non-Hodgkin's lymphomas was based on cytological, histological, immunophenotypic, and molecular biology methods. The mean fluorescence intensity of the adhesion molecules in tumor cells was measured by flow cytometry of CD19-positive cells and differed amongst the types of lymphomas. Comparison of chronic lymphocytic leukemia and mantle-cell lymphoma showed that the former presented a higher expression of CD11c and CD49c, and a lower expression of CD11b and CD49d adhesion molecules. Comparison of chronic lymphocytic leukemia and marginal B-cell lymphoma showed that the former presented a higher expression of CD49c and a lower expression of CD11a, CD11b, CD18, CD49d, CD29, and CD54. Finally, comparison of mantle-cell lymphoma and marginal B-cell lymphoma showed that marginal B-cell lymphoma had a higher expression of CD11a, CD11c, CD18, CD29, and CD54. Thus, the CD49c/CD49d pair consistently demonstrated a distinct pattern of expression in chronic lymphocytic leukemia compared with mantle-cell lymphoma and marginal B-cell lymphoma, which could be helpful for the differential diagnosis. Moreover, the distinct profiles of adhesion molecules in these diseases may be responsible for their different capacities to invade the blood stream.

Geographic variation in Epstein-Barr virus-associated Burkitt's lymphoma in children from Brazil

In developing countries, BL has a strong association with EBV infection during childhood. In South America, the data have shown an EBV association intermediate between that reported in the United States (30%) and that in equatorial Africa (95%). Early age at EBV infection and lower socioeconomic status have been related to increased EBV-associated BL in developing countries. In Brazil, there are not enough data on childhood BL related to EBV infection. Our aim was to evaluate the clinicopathologic features and EBV association of 44 children with NHL from the state of Rio de Janeiro, situated in the southeast of Brazil. EBV was detected using RNA in situ hybridization in 36 biopsy specimens. DNA from fresh tumor samples and from paraffin-embedded tissues of patients were analyzed by PCR, in which the first reaction included primers for an EBNA-2 common region while the nested reaction amplified the region discriminating between EBV types I and 2 in separate reactions. EBV was detected in 21 of 29 BLs (72%), and type I virus infected the majority of EBV-positive BLs (18/21). There was a trend for younger age in children with EBV-positive BL compared to EBV-negative BL (median age 4 compared to 6 years, respectively; p = 0.056). Our study confirmed that in the southeast of Brazil BL had an intermediate association with EBV. A higher rate of EBV-associated BL was described in the northeast of Brazil. These differences are probably related to regional socioeconomic status. In conclusion, our study suggests that early infection with EBV in the background of a low socioeconomic condition associated with other environmental factors could contribute to BL in Brazil. (C) 2003 Wiley-Liss, Inc.

AIDS-related lymphoma in Brazil - Histopathology, immunophenotype, and association with Epstein-Barr virus

The occurrence of malignant lymphoma is an increasingly important cause of morbidity and mortality in AIDS patients. The incidence of AIDS-related lymphoma in some developing countries such as Brazil is increasing as the survival of HIV infection has improved. Although there is a clear association between several types of immunodeficiency related lymphomas and Epstein-Barr virus (EBV), the association of EBV infection in AIDS-related lymphoma in Brazil, where the incidence of AIDS is high, is unknown. Formalin-fixed, paraffin-embedded tissue from 24 cases of AIDS-related lymphoma in Brazil were analyzed for morphologic classification, immunophenotype, and EBV association using in situ hybridization studies with an EBV-EBER1 biotinylated probe. Twenty cases of AIDS-related lymphoma were classified as non-Hodgkin's lymphoma and four cases were Hodgkin's disease. Eleven non-Hodgkin's lymphomas were classified as diffuse large cell type, five cases were small non-cleaved cell, Burkitt-type, and four cases were large cell immunoblastic non-Hodgkin's lymphoma. Eighteen cases were of B-cell phenotype; one was a T-cell lymphoma, and one was classified as null. Epstein-Barr virus (EBV) was demonstrated in the majority of tumor cells of 11 of 20 (55%) of the cases non-Hodgkin's lymphomas and in 3 of 4 (75%) cases of Hodgkin's disease. AIDS-related lymphomas in Brazil are usually of large cell/immunoblastic type, but Hodgkin's disease is also seen. Both non-Hodgkin's lymphoma and Hodgkin's disease are often associated with EBV infection. The non-Hodgkin's lymphoma is predominantly of B-cell phenotype.

Síndrome de Garcin relacionada a linfoma não-Hodgkin

The complete unilateral cranial nerve paralysis syndrome, or Garcin 's Syndrome, is a rare clinical condition. The purpose of this paper is to describe a case associated with non-Hodgkin s lymphoma. A 41-year-old male patient developed a progressive cranial nerve disorder. On the right hand side, there was impairment of all cranial nerves. We report the clinical and laboratorial findings. Lymph node exeresis revealed a Diffuse Non-Hodgkin s Lymphoma, with diffuse hone marrow infiltration. Cerebrospinal fluid showed pleocytosis, with 100% of immunoblasts. The CT scan showed no tumoral masses on the brain stem. This is the first clinical description of a complete Garcin 's Syndrome caused by diffuse lymphomatous infiltration of the cranial nerves.

The multicenter trial SAKK 37/95 of cladribine, cyclophosphamide and prednisone in the treatment of chronic lymphocytic leukemias and low-grade non-Hodgkin's lymphomas

A multicenter trial was performed to confirm the therapeutic efficacy and the toxicity profile of the combination of cladribine, cyclophosphamide and prednisone in low-grade non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Twenty-three adults with previously treated (61%) or untreated (39%) NHL International Working Formulation A or Binet B and C CLL were administered cladribine 0.1 mg/kg/day as a subcutaneous bolus for 5 days, intravenous cyclophosphamide 500 mg/m2 on day 1, and oral prednisone 40 mg/m2 on days 1-5, every 4 weeks. Unexpected early hematological toxicities led to dose modifications for pretreated patients who received cladribine for 3 days only up to a maximum of five courses. Responses were observed in 75%, with 7 patients obtaining a complete clinical and hematological response. Median duration of complete response was 9 months. Median time to progression or relapse was 31 months. Myelosuppression and infections were dose limiting whereas posttreatment complications, including fatalities, resulted from infections. Median overall survival time from trial entry was 60 months. Activity of the combination of cladribine, cyclophosphamide and prednisone was confirmed. However, in the specific setting of a multicenter trial, unexpected fatal infectious episodes occurred in pretreated patients. Great caution is thus required in these susceptible patients and the routine use of corticosteroids should probably be abandoned.

Treatment and prognosis of AIDS-related lymphoma in the era of highly active antiretroviral therapy: findings from the Swiss HIV Cohort Study

OBJECTIVE: To assess the characteristics of combination antiretroviral therapy (cART) administered concomitantly with chemotherapy and to establish prognostic determinants of patients with AIDS-related non-Hodgkin's lymphoma. METHODS: The study included 91 patients with AIDS-related non-Hodgkin's lymphoma from the Swiss HIV Cohort Study enrolled between January 1997 and October 2003, excluding lymphomas of the brain. We extracted AIDS-related non-Hodgkin's lymphoma- and HIV-specific variables at the time of lymphoma diagnosis as well as treatment changes over time from charts and from the Swiss HIV Cohort Study database. Cox regression analyses were performed to study predictors of overall and progression-free survival. RESULTS: During a median follow up of 1.6 years, 57 patients died or progressed. Thirty-five patients stopped chemotherapy prematurely (before the sixth cycle) usually due to disease progression; these patients had a shorter median survival than those who completed six or more cycles (14 versus 28 months). Interruptions of cART decreased from 35% before chemotherapy to 5% during chemotherapy. Factors associated with overall survival were CD4+ T-cell count (<100 cells/microl) (hazard ratio [HR] 2.95 [95% confidence interval (CI) 1.53-5.67], hepatitis C seropositivity (HR 2.39 [95% CI 1.01-5.67]), the international prognostic index score (HR 1.98-3.62 across categories) and Burkitt histological subtypes (HR 2.56 [95% CI 1.13-5.78]). CONCLUSIONS: Interruptions of cART were usually not induced by chemotherapy. The effect of cART interruptions on AIDS-related non-Hodgkin's lymphoma prognosis remains unclear, however, hepatitis C seropositivity emerged-as a predictor of death beyond the well-known international prognostic index score and CD4+ T-cell count.

Abnormalities on 1q and 7q are associated with poor outcome in sporadic Burkitt's lymphoma. A cytogenetic and comparative genomic hybridization study.

Comparative genomic hybridization (CGH) studies have demonstrated a high incidence of chromosomal imbalances in non-Hodgkin's lymphoma. However, the information on the genomic imbalances in Burkitt's Lymphoma (BL) is scanty. Conventional cytogenetics was performed in 34 cases, and long-distance PCR for t(8;14) was performed in 18 cases. A total of 170 changes were present with a median of four changes per case (range 1-22). Gains of chromosomal material (143) were more frequent than amplifications (5) or losses (22). The most frequent aberrations were gains on chromosomes 12q (26%), Xq (22%), 22q (20%), 20q (17%) and 9q (15%). Losses predominantly involved chromosomes 13q (17%) and 4q (9%). High-level amplifications were present in the regions 1q23-31 (three cases), 6p12-p25 and 8p22-p23. Upon comparing BL vs Burkitt's cell leukemia (BCL), the latter had more changes (mean 4.3 +/- 2.2) than BL (mean 2.7 +/- 3.2). In addition, BCL cases showed more frequently gains on 8q, 9q, 14q, 20q, and 20q, 9q, 8q and 14q, as well as losses on 13q and 4q. Concerning outcome, the presence of abnormalities on 1q (ascertained either by cytogenetics or by CGH), and imbalances on 7q (P=0.01) were associated with a short survival.

The occurrence of cancer in a cohort of New South Wales coal miners

To describe the incidence of cancer in coal miners in New South Wales (NSW) between 1973 and 1992, an inception cohort of all male coal industry employees who entered the industry between 1 January 1973 and 31 December 1992 was constructed from the medical examination records of the Joint Coal Board. This cohort was matched with the NSW State Cancer Registry to determine the occurrence and type of cancer. In the cohort of 23 630 men, 297 developed 301 primary cancers in the 20-year period of observation. The standardised incidence ratio (SLR) for all cancers was 0.82. Stomach cancer has been reported to be common in coal miners but the SIR for stomach cancer was not higher than average in this cohort. A cluster of non-Hodgkin's lymphoma has been reported in a NSW coal mine but an increased risk of this cancer was not evident in the industry as a whole. Similarly a cluster of cases of brain tumour has been reported. In this cohort, the SIR for brain tumour was 1.05 (95 per cent confidence interval (CI) 0.57 to 1.76) and a risk for brain tumour remains unconfirmed. The SIR for malignant melanoma was 1.13 (CI 0.90 to 1.39) altogether and 2.02 (CI 1.31 to 2.98) for those workers who started in an open-cut mine. Overall, there does not appear to be a general risk of cancer in the NSW coal industry. Open-cut miners have an increased risk of malignant melanoma, which may be related to their exposure to the sun at work.

Functional association of human Ki-1/57 with pre-mRNA splicing events

The cytoplasmic and nuclear protein Ki- 1 / 57 was first identified in malignant cells from Hodgkin`s lymphoma. Despite studies showing its phosphorylation, arginine methylation, and interaction with several regulatory proteins, the functional role of Ki- 1 / 57 in human cells remains to be determined. Here, we investigated the relationship of Ki- 1 / 57 with RNA functions. Through immunoprecipitation assays, we verified the association of Ki- 1 / 57 with the endogenous splicing proteins hnRNPQ and SFRS9 in HeLa cell extracts. We also found that recombinant Ki- 1 / 57 was able to bind to a poly- U RNA probe in electrophoretic mobility shift assays. In a classic splicing test, we showed that Ki- 1 / 57 can modify the splicing site selection of the adenoviral E1A minigene in a dose- dependent manner. Further confocal and. uorescence microscopy analysis revealed the localization of enhanced green. uorescent protein - Ki- 1 / 57 to nuclear bodies involved in RNA processing and or small nuclear ribonucleoprotein assembly, depending on the cellular methylation status and its N- terminal region. In summary, our findings suggest that Ki- 1 / 57 is probably involved in cellular events related to RNA functions, such as pre- mRNA splicing.