Children and the coronavirus disease 2019 pandemic: a Caribbean perspective / La población infantil y la pandemia de COVID-19: una perspectiva del Caribe / As crianças e a pandemia da doença do coronavírus de 2019: uma perspectiva do Caribe

ABSTRACT This study aims to assess coronavirus disease 2019 (COVID-19) surveillance methods, health resources, vaccination coverage and income stratification and quantify burdens of disease and death in children and adolescents in the Caribbean. The investigation was a descriptive, cross-sectional study that included 15 Caribbean countries/territories and utilized surveys and secondary data sources. Quarantine and isolation measures were robust and surveillance strategies were similar. Pediatric specialists were available across the region, but few had designated pediatric hospitals or high-dependency units. There were more cases in children on islands with larger populations. Compared to high-income countries/territories, upper and lower middle-income countries/territories had higher disease burdens, fewer doctors and nurses per 1 000 population, lower bed capacities, and lower vaccination coverage. Child and adolescent cases ranged from 0.60% to 16.9%, compared with a global case rate of 20.2% in 2021. By August 2021 there were 33 deaths among children from Haiti, Jamaica, Trinidad and Tobago, and Barbados. The respective case fatality rates for 0-9-year-olds and 10-19-year-olds were 2.80 and 0.70 in Haiti, 0.10 and 0.20 in Jamaica, and 0.00 and 0.14 in Trinidad, compared with 0.17 and 0.1 globally. Overall COVID-19 incidence and mortality in children were consistent with global estimates. Limited resources have been offset by availability of pediatricians across the region, and minimally direct effects on children. Prioritization of admission of specific at-risk groups, training of first responders and vaccination campaigns targeting pregnant women and vulnerable children and adolescents could benefit countries with low vaccine coverage rates and limited resources.

RESUMEN El presente estudio tiene como objetivo evaluar los métodos de vigilancia, los recursos de salud, y la cobertura de vacunación y la estratificación de los ingresos, así como cuantificar las cargas de enfermedad y muerte de la enfermedad por coronavirus del 2019 (COVID-19) en niños, niñas y adolescentes en el Caribe. La investigación consistió en un estudio descriptivo y transversal que incluyó a 15 países o territorios del Caribe y empleó encuestas y fuentes de datos secundarios. Las medidas de cuarentena y aislamiento fueron sólidas, igual que las estrategias de vigilancia. Había especialistas pediátricos disponibles en toda la región, pero pocos designados en hospitales pediátricos o unidades de alta dependencia. Hubo más casos en pacientes pediátricos en las islas más pobladas. En comparación con los países y territorios de ingresos altos, los de ingresos medianos altos y medianos bajos presentaron una mayor carga de morbilidad, menos personal médico y de enfermería por 1 000 habitantes, menor capacidad de camas y menor cobertura de vacunación. Los casos de niños, niñas y adolescentes oscilaron entre 0,60% y 16,9%, en comparación con una tasa general de casos de 20,2% en el 2021. En agosto del 2021, hubo 33 muertes de pacientes pediátricos de Haití, Jamaica, Trinidad y Tabago y Barbados. Las tasas de mortalidad de los grupos etarios de 0 a 9 años y de 10 a 19 años fueron respectivamente de 2,80 y 0,70 en Haití; 0,10 y 0,20 en Jamaica; y 0,00 y 0,14 en Trinidad; en comparación con 0,17 y 0,1 a nivel mundial. La incidencia general de COVID-19 y la mortalidad en la población infantil fueron coherentes con las estimaciones mundiales. Se compensaron los recursos limitados con la disponibilidad de pediatras en toda la región y efectos directos mínimos en los niños. Priorizar la admisión de grupos específicos de riesgo, la capacitación de los equipos de respuesta inicial y las campañas de vacunación dirigidas a mujeres embarazadas y niños, niñas y adolescentes vulnerables podría beneficiar a los países con recursos limitados y bajas tasas de cobertura de vacunación.

RESUMO Este estudo visa a avaliar os métodos de vigilância, recursos de saúde, cobertura vacinal e estratificação de renda relacionados à doença do coronavírus de 2019 (COVID-19) e quantificar a carga de morbimortalidade a ela atribuível em crianças e adolescentes no Caribe. Foi realizado um estudo descritivo e transversal que incluiu 15 países e territórios caribenhos e utilizaram-se levantamentos e fontes de dados secundárias. As medidas de quarentena e isolamento foram robustas, e as estratégias de vigilância foram semelhantes. Houve disponibilidade de especialistas pediátricos em toda a região, mas poucos países/territórios tinham hospitais pediátricos ou unidades semi-intensivas especificamente designados. Ocorreram mais casos em crianças nas ilhas com populações maiores. Em comparação com os países/territórios de alta renda, aqueles de renda média-alta e média-baixa apresentaram uma maior carga de morbidade, menos médicos e enfermeiros por 1 000 habitantes, menor capacidade de leitos e menor cobertura vacinal. De 0,60% a 16,9% dos casos ocorreram em crianças e adolescentes, contra uma média mundial de 20,2% em 2021. Até agosto de 2021, haviam ocorrido 33 óbitos de crianças em Barbados, Haiti, Jamaica e Trinidad e Tobago. Os respectivos índices de letalidade nas faixas etárias de 0-9 anos e de 10-19 anos foram 2,80 e 0,70 no Haiti, 0,10 e 0,20 na Jamaica e 0,00 e 0,14 em Trinidad, em comparação com 0,17 e 0,1 no âmbito mundial. Em geral, a incidência e a mortalidade por COVID-19 em crianças foram condizentes com as estimativas mundiais. Os recursos limitados foram compensados pela disponibilidade de pediatras em toda a região e pelos pouquíssimos efeitos diretos sobre as crianças. Priorização de grupos de risco específicos para internação, treinamento de socorristas e campanhas de vacinação dirigidas a gestantes e a crianças e adolescentes vulneráveis poderiam beneficiar países com baixos índices de cobertura vacinal e recursos limitados.

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.

Characterization of tissue findings in bone marrow biopsy specimens with small monoclonal B-cell populations.

OBJECTIVES: Bone marrows (BMs) with incidentally identified, small monotypic B-cell populations (MBPs) were evaluated. METHODS: BM aspirates with MBPs representing 5% or less of total events by flow cytometry, less than 5.0 × 10(9)/L B cells in blood, and no history of lymphoma or MBP with a different phenotype from prior lymphoma were selected. Clinical, immunophenotypic, and histologic findings were evaluated. RESULTS: Forty-one of 3,052 BMs had MBPs at 5% or less of total events (median, 1%); 17 were females and 24 were males aged 30 to 87 years (median, 73 years). The MBPs were CD5- in 24, CD5+ resembling chronic lymphocytic leukemia (CLL) in 13, and CD5+ unlike CLL in four. Eighteen of 40 had lymphoid aggregates (LAs) with mostly T cells or a mixture of B and T cells, but three cases had B-cell-rich LAs. CONCLUSIONS: Unlike monoclonal B lymphocytosis in blood, MBPs in BMs were more commonly CD5-. Forty-five percent of BMs had LAs; none were interpreted as lymphoma, although three were suspicious for B-cell lymphoma.

Bone marrow involvement by subcutaneous panniculitis-like T-cell lymphoma: a report of three cases.

Subcutaneous panniculitis-like T-cell lymphoma is a rare subtype of cutaneous T-cell lymphoma. Virtually all cases are confined to the subcutaneous adipose tissue. In this report, we describe the first small series of subcutaneous panniculitis-like T-cell lymphoma (three patients) with bone marrow involvement. All patients presented with skin or soft tissue nodules, fever, and constitutional symptoms, and were diagnosed with subcutaneous panniculitis-like T-cell lymphoma based on the characteristic morphologic and immunophenotypic features of the subcutaneous lesions. Bone marrow core biopsies in these cases showed focal involvement by lymphoma with pathologic features similar to those seen in the diagnostic biopsies. Our observations suggest bone marrow involvement by subcutaneous panniculitis-like T-cell lymphoma does occur, and can be identified histologically and confirmed using standard immunohistochemistry. Our findings raise awareness of bone marrow involvement in this rare entity. However, the incidence and significance of bone marrow involvement in subcutaneous panniculitis-like T-cell lymphoma requires further evaluation.

Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies.

Post-transplant lymphoproliferative diseases (PTLD) are heterogeneous lymphoid disorders ranging from indolent polyclonal proliferations to aggressive lymphomas that complicate solid organ or hematopoietic transplantation. Risk factors for PTLD include viral infections, degree of immunosuppression, recipient age and race, allograft type, and host genetic variations. Clinically, extra-nodal disease is common including 10-15 % presenting with central nervous system (CNS) disease. Most PTLD cases are B cell (5-10 % T/NK cell or Hodgkin lymphoma), while over one-third are EBV-negative. World Health Organization (WHO) diagnostic categories are: early lesions, polymorphic, and monomorphic PTLD; although in practice, a clear separation is not always possible. Therapeutically, reduction in immunosuppression remains a mainstay, and recent data has documented the importance of rituximab +/- combination chemotherapy. Therapy for primary CNS PTLD should be managed according to immunocompetent CNS paradigms. Finally, novel treatment strategies for PTLD have emerged, including adoptive immunotherapy and rational targeted therapeutics (e.g., anti-CD30 based therapy and downstream signaling pathways of latent membrane protein-2A).

Early posttransplant lymphoproliferative disease: clinicopathologic features and correlation with mTOR signaling pathway activation.

Early posttransplant lymphoproliferative disorders (EPTLDs) represent the first changes in posttransplant lymphoproliferative disorders (PTLDs) morphologic spectrum. EPTLD data are available mostly from case reports and series that include other types of PTLD. Fifteen EPTLDs were reviewed retrospectively. Clinical data, histopathology, clonality, and Epstein- Barr virus (EBV) status were correlated with staining intensity to an antibody for phosphorylated S6 (pS6) ribosomal protein, a downstream effector of mammalian target of rapamycin (mTOR). Median time from transplantation to EPTLD was 50 months (range, 7-135 mo). EPTLDs involved tonsil and/or adenoids (n = 11) and lymph nodes (n = 4), all of which were nonclonal and EBV-encoded RNA-positive. Most (n = 11) were plasmacytic hyperplasia and florid follicular hyperplasia (n = 4). All regressed with reduced immunosuppression, and had increased pS6 staining compared with normal tonsil (P = .002, F test). EPTLDs developed later than previously reported, involved mostly tonsils/adenoids, were EBV-encoded RNA (EBER) positive, showed increased pS6, and had excellent clinical outcome with reduction of immunosuppression.

Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas.

Lymphoid-enhancer-binding factor 1 (LEF1), coupling with ß-catenin, functions as a key nuclear mediator of WNT/ß-catenin signaling, which regulates cell proliferation and survival. LEF1 has an important role in lymphopoiesis, and is normally expressed in T and pro-B cells but not mature B cells. However, gene expression profiling demonstrates overexpression of LEF1 in chronic lymphocytic leukemia, and knockdown of LEF1 decreases the survival of the leukemic cells. So far, the data on LEF1 expression in B-cell lymphomas are limited. This study represents the first attempt to assess LEF1 by immunohistochemistry in a large series (290 cases) of B-cell lymphomas. Strong nuclear staining of LEF1 was observed in virtually all neoplastic cells in 92 of 92 (100%) chronic lymphocytic leukemia/small lymphocytic lymphomas including two CD5- cases, with strongest staining in cells with Richter's transformation. LEF1 also highlighted the morphologically inconspicuous small lymphocytic lymphoma component in three composite lymphomas. All 53 mantle cell lymphomas, 31 low-grade follicular lymphomas and 31 marginal zone lymphomas, including 3 CD5+ cases, were negative. In 12 grade 3 follicular lymphomas, LEF1 was positive in a small subset (5-15%) of cells. Diffuse large B-cell lymphoma, however, demonstrated significant variability in LEF1 expression with overall positivity in 27 of 71 (38%) cases. Our results demonstrate that nuclear overexpression of LEF1 is highly associated with chronic lymphocytic leukemia/small lymphocytic lymphoma, and may serve as a convenient marker for differential diagnosis of small B-cell lymphomas. The expression of ß-catenin, the coactivator of LEF1 in WNT signaling, was examined in 50 chronic lymphocytic leukemia/small lymphocytic lymphomas, of which 44 (88%) showed negative nuclear staining. The findings of universal nuclear overexpression of LEF1 but lack of nuclear ß-catenin in the majority of chronic lymphocytic leukemia/small lymphocytic lymphoma suggest that the pro-survival function of LEF1 in this disease may be independent of WNT/ß-catenin signaling.

Healthcare team members' perception of staffing adequacy in a comprehensive cancer center.

PURPOSE/OBJECTIVES: to describe the perceptions of staffing adequacy of healthcare team members working together on units in a comprehensive cancer center. RESEARCH APPROACH: a descriptive, phenomenologic design was used. Semistructured interviews were conducted with participants. SETTING: an urban, Magnet-designated comprehensive cancer center in the southwestern United States. PARTICIPANTS: a purposive sample of 10 RNs, 5 nursing assistants, and 5 associate directors. METHODOLOGIC APPROACH: data analysis was guided by Streubert's procedural interpretation of the phenomenologic method. FINDINGS: themes emerged, including alterations to care; challenges to an already challenging shift; the right mix; effects on patients, safety, and quality; mitigating factors; and the aftermath. CONCLUSIONS: perceived inadequate staffing affects healthcare staff both personally and professionally, triggering responses that influence approaches to patient care, unit operations, and relationships. INTERPRETATION: the unique and sometimes varied perspectives and experiences of frontline staff are critical to understanding factors that influence and affect willingness to work and remain in hospital settings, and may serve as a basis for shaping interventions and strategies to ensure adequate numbers of caregivers at the bedside.

Primary cutaneous and systemic anaplastic large cell lymphoma: clinicopathologic aspects and therapeutic options.

Anaplastic large cell lymphoma (ALCL) is a biologic and clinically heterogenous subtype of T-cell lymphoma. Clinically, ALCL may present as localized (primary) cutaneous disease or widespread systemic disease. These two forms of ALCL are distinct entities with different clinical and biologic features. Both types share similar histology, however, with cohesive sheets of large lymphoid cells expressing the Ki-1 (CD30) molecule. Primary cutaneous ALCL (C-ALCL) is part of the spectrum of CD30+ lymphoproliferative diseases of the skin including lymphomatoid papulosis. Using conservative measures, 5-year disease-free survival rates are > 90%. The systemic ALCL type is an aggressive lymphoma that may secondarily involve the skin, in addition to other extranodal sites. Further, systemic ALCL may be divided based on the expression of anaplastic lymphoma kinase (ALK) protein, which is activated most frequently through the nonrandom t(2;5) chromosome translocation, causing the fusion of the nucleophosmin (NPM) gene located at 5q35 to 2p23 encoding the receptor tyrosine kinase ALK. Systemic ALK+ ALCLs have improved prognosis compared with ALK-negative ALCL, although both subtypes warrant treatment with polychemotherapy. Allogeneic and, to a lesser extent, autologous stem cell transplantation play a role in relapsed disease, while the benefit of upfront transplant is not clearly defined. Treatment options for relapsed patients include agents such as pralatrexate (Folotyn) and vinblastine. In addition, a multitude of novel therapeutics are being studied, including anti-CD30 antibodies, histone deacetylase inhibitors, immunomodulatory drugs, proteasome inhibitors, and inhibitors of ALK and its downstream signaling pathways. Continued clinical trial involvement by oncologists and patients is imperative to improve the outcomes for this malignancy.

Expression of p21 protein predicts clinical outcome in DLBCL patients older than 60 years treated with R-CHOP but not CHOP: a prospective ECOG and Southwest Oncology Group correlative study on E4494.

PURPOSE: To prospectively investigate the prognostic significance of p21 and p53 expression in diffuse large B-cell lymphoma in the context of the U.S. Intergroup trial comparing conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy to rituximab-CHOP (R-CHOP) induction, with or without maintenance rituximab. EXPERIMENTAL DESIGN: Immunohistochemical staining of 197 paraffin-embedded biopsy specimens was scored by an independent panel of experts. RESULTS: The cyclin-dependent kinase inhibitor, p21, was expressed in 55% of cases examined. In a multivariable analysis adjusting for International Prognostic Index score and BCL2 status, p21 expression was a significant, independent, favorable predictive factor for failure-free survival (relative risk, 0.3; P = 0.001) and overall survival (relative risk, 0.3; P = 0.003) for patients treated with R-CHOP. Expression of p21 was not predictive of outcome for CHOP-treated patients. Only p21-positive cases benefited from the addition of rituximab to CHOP. Among p21-positive patients, treatment with R-CHOP was associated with a higher failure-free survival rate at 5 years compared with CHOP (61% versus 24%; P = 0.01). In contrast, no significant differences were detected in failure-free survival according to treatment arm for p21-negative patients. Expression of p53, alone or in combination with p21, did not predict for outcome in univariable or multivariable analyses. CONCLUSIONS: In this study, p21 protein expression emerged as an important independent predictor of a favorable clinical outcome when rituximab was added to CHOP therapy. These data suggest that rituximab-related effects on lymphoma survival pathways may be functionally linked to p21 activity.

Hypoxia-inducible factor-1 {alpha} expression predicts superior survival in patients with diffuse large B-cell lymphoma treated with R-CHOP.

PURPOSE Hypoxia-inducible factor (HIF) controls the expression of genes in response to hypoxia, as well as a wide range of other cellular processes. We previously showed constitutive stabilization of HIF-1alpha in the majority of patients with diffuse large B-cell lymphoma (DLBCL). To our knowledge, the prognostic significance of HIF in lymphoma has never been investigated. PATIENTS AND METHODS We studied the immunohistochemical protein expression of HIF-1alpha on tissue microarrays from 153 patients with DLBCL treated in sequential cohorts with cyclophosphamide, doxorubicin, oncovin, and prednisone (CHOP) or rituximab-CHOP (R-CHOP) from 1999 to 2002. Results were correlated with patient outcome. Results Median follow-up for all patients was 80 months. Among all patients, HIF-1alpha was expressed in 62% of germinal center and 59% of non-germinal center patients. With HIF-1alpha analyzed as a dependent variable, there were no survival differences in CHOP-treated patients. In the R-CHOP group, however, HIF-1alpha protein expression correlated with significantly improved progression-free survival (PFS) and overall survival (OS). Five-year PFS for HIF-1alpha-positive patients was 71% v 43% for HIF-1alpha-negative patients (P = .0187), whereas 5-year OS was 75% and 54%, respectively (P = .025). In multivariate analysis with International Prognostic Index criteria, HIF-1alpha remained a significant predictor for PFS (P = .026) and OS (P = .043). Compared with other biomarkers, HIF-1alpha correlated only with BCL6 (P = .004). In terms of gene expression, we found several common gene associations of HIF-1alpha and the stromal-1 signature with genes predominantly involved in regulation of the extracellular matrix (eg, BGN, COL1A2, COL5A1, and PLOD2). CONCLUSION The expression of HIF-1alpha protein is an important independent favorable prognostic factor for survival in patients with DLBCL treated with R-CHOP.

Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era.

PURPOSE Adult post-transplantation lymphoproliferative disease (PTLD) has a reported 3-year overall survival (OS) of 35% to 40%. The impact of rituximab on the outcome of PTLD is not well defined. METHODS We examined the clinical features and outcomes among a large cohort of solid organ transplantation (SOT) -related patients with PTLD who were recently treated at four Chicago institutions (from January 1998 to January 2008). Results Eighty patients with PTLD were identified who had a median SOT-to-PTLD time of 48 months (range, 1 to 216 months). All patients had reduction of immunosuppression as part of initial therapy, whereas 59 (74%) of 80 patients received concurrent first-line rituximab with or without chemotherapy. During 40-month median follow-up, 3-year progression-free survival (PFS) for all patients was 57%, and the 3-year overall survival (OS) rate was 62%. Patients who received rituximab-based therapy as part of initial treatment had 3-year PFS of 70% and OS 73% compared with 21% (P < .0001) and 33% (P = .0001), respectively, without rituximab. Notably, of all relapses, only 9% (4 of 34 patients) occurred beyond 12 months from PTLD diagnosis. On multivariate regression analysis, three factors were associated with progression and survival: CNS involvement (PFS, 4.70; P = .01; OS, 3.61; P = .04), bone marrow involvement (PFS, 2.95; P = .03; OS, 3.14; P = .03), and hypoalbuminemia (PFS, 2.96; P = .05; OS, 3.64; P = .04). Furthermore, a survival model by multivariate CART analysis that was based on number of adverse factors present (ie, 0, 1, > or = 2) was formed: 3-year PFS rates were 84%, 66%, 7%, respectively, and 3-year OS rates were 93%, 68%, 11%, respectively (P < .0001). CONCLUSION This large, multicenter, retrospective analysis suggests significantly improved PFS and OS associated with early rituximab-based treatment in PTLD. In addition, clinical factors at diagnosis identified patients with markedly divergent outcomes.

Therapy-related myelodysplastic syndrome presenting as fulminant heart failure secondary to myeloid sarcoma.

Rapidly progressive heart failure is commonly caused by an extensive myocardial infarction, a mechanical complication of infarction, myocarditis, or acute valvular insufficiency. We present an unusual case that was caused by a diffuse infiltration of the myocardium with leukemic cells (myeloid sarcoma). The patient presented with episodic shortness of breath, he was anemic and thrombocytopenic, and his bone marrow biopsy revealed myelodysplastic syndrome from treatment for oligodendroglioma. His clinical course was characterized by a chronic leak of cardiac enzymes, a new right bundle branch block, and a large pericardial effusion causing tamponade and death from fulminant heart failure and ventricular arrhythmias within 2 weeks. At autopsy, the heart was massively infiltrated with myeloblasts and other immature myeloid cells. There was no evidence of acute leukemia in the bone marrow or peripheral blood. Cardiac infiltration in a patient with myelodysplastic syndrome is extremely rare, especially in the absence of bone marrow involvement by blasts. The recognition of this entity is becoming increasingly important as the incidence of cardiac myeloid sarcoma may be on the rise as the number of patients receiving chemotherapy increases.

Immunophenotypic variations in mantle cell lymphoma.

Mantle cell lymphoma (MCL) expresses pan-B-cell antigens and is usually CD5+/CD10-/CD23-/FMC7+. In this study, we evaluated 52 patients with confirmed diagnoses of MCL and identified variant immunophenotypes in 21 patients (19/48 classical and 2/4 variant MCLs), including CD5- in 6 (12%) of 52, CD10+ in 4 (8%) of 50, CD23+ in 10 (21%) of 48, and FMC7- in 4 (11%) of 37 cases. Three cases showed variations in 2 antigens, including CD5-/CD23+, CD10+/FMC7-, and CD23+/FMC7-; they were all classical MCLs. One blastoid variant MCL was CD23+, and one was FMC7-. Evaluation for proliferation index by immunohistochemical analysis for Ki-67 demonstrated no significant difference between MCLs with variant immunophenotypes and MCLs with typical immunophenotypes. The high proliferation index (>60%) was exclusively seen in the blastoid and pleomorphic variants. Our results indicate that immunophenotypic variations are common in MCL, and recognizing the variability is important for accurate subclassification of B-cell lymphoma.

CD23+ mantle cell lymphoma: a clinical pathologic entity associated with superior outcome compared with CD23- disease.

Mantle cell lymphoma (MCL) commonly lacks expression of CD23. However, a significant minority of MCLs express CD23, as assessed by flow cytometric immunophenotyping (FCIP). The aims of our study were to investigate the expression of CD23 by FCIP in patients with MCL and to correlate CD23 expression with pathologic and clinical parameters, including outcome. We studied 53 patients with untreated MCL who had CD23 expression determined by FCIP. At diagnosis, 14 MCLs (26%) were CD23+ at all tissue sites, whereas 33 (62%) were CD23-, and 6 (11%) had discordant CD23 expression among different tissue sites. Patients with CD23- MCL had extranodal disease more commonly compared with patients with CD23+ MCL. Moreover, with 57-month median follow-up, the 4-year event-free and overall survival rates for CD23+ MCL were 45% and 75%, respectively, compared with 19% and 51% for CD23- MCL. In multivariate Cox regression analysis, CD23 status and leukemic-phase MCL were the most important factors predicting outcome.

Instability of immunophenotype in plasma cell myeloma.

Little information has been reported describing antigen stability in plasma cell myeloma. In this study, the expression frequency and stability of 2 potential therapeutic targets, CD20 and CD52, along with the frequently aberrantly expressed CD56 antigen, were evaluated by flow cytometric analyses in 56 patients with plasma cell myeloma. Of the 56 patients, 23 (41%) showed immunophenotype change, including CD56 in 6 cases, CD20 in 7 cases, and CD52 in 17 cases. Combined CD56/CD52 change was seen in 3 cases and combined CD20/CD52 in 4 cases. No correlation was found between immunophenotype change and age, sex, stage, plasma cell morphologic features, extent of marrow involvement, time between analyses, type of therapy, or response to therapy. Immunophenotype shift was more common in patients with IgA than in patients with IgG paraprotein. Recognition of lack of stability in immunophenotype may be important, especially in antigen-directed treatment decisions and when specific phenotypes are used to detect residual disease.

Hypoxia inducible factor-alpha activation in lymphoma and relationship to the thioredoxin family.

Hypoxia inducible factors (HIFs) activate oncogenic pathways, while thioredoxins (Trx), including Trx1 and Trx reductases-1 and -2 (TrxR1 and TrxR2), promote HIF-alpha stabilization. In immunoblotting studies in lymphoma cell lines we found that Raji and SUDHL4 cells exhibited normoxic HIF-2alpha protein stabilization. Five cell lines showed increased TrxR1 expression, while only Namalwa, HF1 and SUDHL4 had Trx1 and TrxR2 activation. Tissue microarrays in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) identified different HIF expression among histological subgroups (e.g. 44% DLBCL vs. 11% of FL cases with moderate-to-high expression of HIF-1alpha and HIF-2alpha, P = 0.0017). These data demonstrate that HIF and the thioredoxin family are abnormally activated in lymphoma.

A phase II clinical trial of intensive chemotherapy followed by consolidative stem cell transplant: long-term follow-up in newly diagnosed mantle cell lymphoma.

Mantle cell lymphoma (MCL) is associated with high relapse rates and poor survival when treated with conventional chemotherapy, with or without rituximab. We report the long-term follow-up of a phase II clinical trial using a new intensive multiagent chemotherapeutic regimen [cyclophosphamide, teniposide, doxorubicin and prednisone (CTAP) alternating with vincristine and high-dose methotrexate and cytarabine (VMAC)] in newly diagnosed MCL. Following 4-6 cycles of CTAP/VMAC induction, patients aged < or =65 years proceeded to consolidative autologous haematopoietic stem cell transplantation (auto-HSCT), while patients < or =55 years who had a HLA-identical sibling received allogeneic-HSCT (busulfan/cyclophosphamide conditioning for both). Twenty-five untreated MCL patients enrolled on the protocol between 1997 and 2002. Among evaluable patients, overall response rate (ORR) was 74% following induction chemotherapy. Seventeen patients received HSCT (autologous-13/allogeneic-4). On intent-to-treat analysis, ORR for patients who received consolidative HSCT was 100% (complete remission 76%). Therapy was well-tolerated with 4% treatment-related mortality (including HSCT). The 5-year event-free-survival (EFS) and overall survival (OS) for all patients was 35% and 50% respectively. Furthermore, at 66-months median follow-up, the 5-year EFS and OS for patients who received consolidative auto-HSCT was 54% and 75% respectively. Patients who received auto-HSCT had improved outcomes compared to no auto-HSCT (EFS P = 0.001; OS P = 0.0002). CTAP/VMAC induction followed by consolidative auto-HSCT for newly diagnosed MCL is associated with high ORR and durable survival.

Chronic lymphocytic leukemia FISH panel: impact on diagnosis.

Interphase fluorescence in situ hybridization (FISH) is an alternative to conventional chromosome analysis of chronic lymphocytic leukemia (CLL) cells. We analyzed 172 samples from 136 possible CLL cases using a FISH panel. Reflex testing with probes to CCND1, BCL2, BCL3, BCL11A, c-MYC, MALT1, and a break-apart immunoglobulin heavy chain (IGH) probe was done if more than 2 signals for 14q32 occurred. For 111 cases, there were sufficient data for analysis. Of 111 cases, 81 (72.9%) had 1 or more genetic abnormalities. The most frequent abnormality was 13q-, followed by trisomy 12, 11q-, and 17p-. In 13 cases, there were IGH abnormalities. Two cases with CCND1/IGH fusion were reclassified as mantle cell lymphoma. Four CLL cases had IGH fusion with BCL2, BCL3 (2 cases), and BCL11A; no fusion partner was detected in 7 cases. Morphologic features were atypical for CLL in 2 cases with IGH fusion (BCL11A and BCL3). The FISH CLL panel is useful to identify prognostic aberrations and to clarify diagnosis in cases with unusual morphologic features.

Surface immunoglobulin positive lymphoblastic leukemia in adults; a genetic spectrum.

Precursor B-lymphoblastic leukemia is typically surface immunoglobulin (sIg) negative. Although rare cases of sIg+ precursor lymphoblastic leukemia are recognized, sIg+ leukemia often represent leukemic phase of Burkitt lymphoma or other non-Hodgkin lymphoma such as blastic mantle cell lymphoma. This study reports four adults, two women (56 and 58 years old) and two men (35 and 41 years old) with lymphoblastic leukemia that displayed lambda, surface immunoglobulin restriction (sIg+). The leukemic cells were all dim CD45 positive with side scatter light characteristic of blasts. Two cases were positive with the blasts associated with antigens TdT and CD34. Genetic abnormalities were detected in all cases and in three cases included abnormalities commonly present in precursor lymphoblastic leukemia. Translocation (1;19) (q23;p13) was present in the first case. Deletion of the 3' region of the mixed lineage leukemia (MLL) gene at chromosome 11q23 as well as t(14;18) were detected in the second case. In the 3rd case, a BCR-ABL fusion gene was detected as part of a complex abnormal karyotype. Translocation (1;19)(q23;p13) was present in one case. Deletion of the 3' region of the mixed lineage leukemia (MLL) gene at chromosome 11q23 as well as t(14;18) were detected in one case. BCR-ABL fusion gene was detected as part of a complex abnormal karyotype in one case. These cases illustrate that lymphoblastic leukemias occurring in adults exhibit a morphologic, immunophenotypic as well as a genetic spectrum and represent either non-Hodgkin lymphoma or precursor lymphoblastic leukemia. A multi-parameter approach including flow cytometric and genetic studies is crucial in separating these cases.