Adoptive Immunotherapy for Hodgkin’s Lymphoma

Adoptive transfer of tumor-specific T-cells is an attractive strategy for the treatment of patients with refractory or relapsed Hodgkin's lymphoma. However, Hodgkin's lymphomas possess a range of tumor-evasion mechanisms, which must be overcome before the full potential of immunotherapies can be achieved. In this article, we discuss the promise of Epstein-Barr virus-specific cytotoxic T-lymphocytes, the roles of cytokines, and other strategies for overcoming the immune-evasion mechanisms in Hodgkin's lymphoma.     

Genomic Alterations in Hodgkin’s Lymphoma

Cytogenetic analysis of Hodgkin’s lymphoma (HL) is hampered by the scarcity of neoplastic cells within a sea of reactive cells. There is accumulating evidence that HL represents 2 disease entities, classic HL (cHL) with its morphologic variants and nodular lymphocyte predominant HL (NLPHL). This subdivision, initially worked out in morphologic and immunohisto-chemical studies, has been further substantiated by molecular cytogenetic investigations. Two recurrent chromosomal aberrations, namely gains of 2p13–p16 and 9p24, have been found by comparative genomic hybridization analysis in microdissected cells from cHL patients as well as in cHL cell lines, but not in NLPHL cells. The available cHL cell lines are remarkably heterogeneous in their karyotypes, suggesting profound genomic instability leading to numeric chromosomal aberration and multiple chromosomal breaks and translocations. In this article, we review genomic aberrations that may contribute to the development and maintenance of the morphologic and clinical presentation of these B-cell lymphoma entities. Furthermore, we delineate current data on the genomic changes observed in the neoplastic cells of HL that are created by epigenetic mechanisms, which are alternative mechanisms that regulate the expression of relevant genes.     

Hodgkin’s Lymphoma and CD30 Signal Transduction

Advances in molecular biology have shed light on the biological basis of Hodgkin's lymphoma (HL). Knowledge of the biological basis has enabled us to understand that most Hodgkin and Reed-Sternberg (H-RS) cells are derived from germinal center B-cells and constitutive nuclear factor kappaB (NF-kappaB) activation is a common molecular feature. Molecular mechanisms responsible for constitutive NF-kappaB activation, Epstein Barr virus latent membrane protein 1, and defective IkappaBalpha and IkappaB kinase activation have been clarified in the past several years. A recent study revealed the biological link between 2 characteristic features of H-RS cells: CD30 overexpression and constitutive NF-kappaB activation. Ligand-independent signaling by overexpressed CD3O was shown to be a common mechanism that induced constitutive NF-kappaB activation in these cells. These results suggest the self-growth-promoting potential of H-RS cells and redefine the biology of HL composed of H-RS cells and lymphocytes.     

The Molecular Basis of α-Thalassemia in the Qatari Pediatric Population

Abstract

α-Thalassemia (α-thal) is widely reported in the Arabian Peninsula as one of the main causes of asymptomatic microcytic hypochromic red blood cells with or without anemia in the pediatric population. This is the first study that provides information about the molecular basis of α-thal in the Qatari population. Qatari school children between the ages of 5 and 15, exhibiting laboratory findings suggestive of microcytic anemia were pooled, and those with a mean corpuscular volume (MCV) of <80.0?fL and a hemoglobin (Hb) electropherogram that ruled out β-thalassemia (β-thal), were narrowed down to a group of 127. This group was screened for the ?α^3.7 (rightward) deletion, and the α^?5?nt, α^polyA1 (α^T-Saudi), α^polyA2 mutations. A second group of randomly selected Qatari individuals was also screened in order to determine the population’s allele frequency for the ?α^3.7 deletion. Thirty-nine point four percent of the individuals with microcytic hypochromic anemia were positive for the ?α^3.7 deletion (heterozygotes 30.0%, homozygotes 9.4%), 2.6% were positive for the α^polyA1 deletion and 0.8% positive for the α^?5?nt mutation. None of the children exhibited changes in α^polyA2. Analysis of the random samples determined that 26.4% were heterozygous and 4.5% homozygous for the ?α^3.7 deletion with a 17.7% allele frequency. Our results suggest that a significant number of the Qatari pediatric population with microcytic hypochromic anemia are carriers of α-thal mutations. However, 45.6% of the children failed to exhibit any of the above four mutations tested. This suggests the possibility of other mutations in the Qatari pediatric population that are yet to be elicited.     

Clinical features and outcomes of Hodgkin’s lymphoma in Korea: Consortium for Improving Survival of Lymphoma (CISL)

Ethnic and regional differences in the epidemiology and pathological aspects of Hodgkin's lymphoma (HL) between Western and Asian patients may be associated with differences in clinical features and prognosis. We retrospectively analyzed the clinical and histopathological characteristics, therapeutic outcomes, and prognostic factors of 539 HL patients treated at 16 centers in Korea. We found that the incidence of histological subtypes of HL in Korea was similar to that in Western and other Asian countries. However, the incidence peaked between 16 and 30?years of age, unlike the bimodal age distribution seen in Western countries. In patients with stage I-IIA non-bulky disease, the complete response (CR) rate was similar between combined modality therapy and chemotherapy alone (93% vs. 84%, P?=?0.44), and there was no difference in relapse-free survival (RFS) and overall survival (OS). Patients with stage I-II disease plus unfavorable factors and those with advanced-stage disease treated with combination chemotherapy regimens had an overall CR rate of 77%, with no difference between doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and non-ABVD regimens (77.2% vs. 76.8%, P?=?0.95). Among those patients who achieved final CR, there was no significant difference in RFS or OS between those who achieved interim CR and PR. Only the presence of B symptoms was independently predictive of a shorter RFS. Age?>?45?years, Eastern Cooperative Oncology Group 2-4, and B symptoms were independent risk factors for death. Although the incidence of HL was lower in Korea than in Western countries, the distribution of morphological subtypes, treatment outcomes, and patient prognosis were similar.     

Classical Hodgkin’s lymphoma: the Lymphoma Study Association guidelines for relapsed and refractory adult patients eligible for transplant

The Hodgkin’s Lymphoma Committee of the Lymphoma Study Association (LYSA) gathered in 2012 to prepare guidelines on the management of transplant-eligible patients with relapsing or refractory Hodgkin’s lymphoma. The working group is made up of a multidisciplinary panel of experts with a significant background in Hodgkin’s lymphoma. Each member of the panel of experts provided an interpretation of the evidence and a systematic approach to obtain consensus was used. Grades of recommendation were not required since levels of evidence are mainly based on phase II trials or standard practice. Data arising from randomized trials are emphasized. The final version was endorsed by the scientific council of the LYSA. The expert panel recommends a risk-adapted strategy (conventional treatment, or single/double transplantation and/or radiotherapy) based on three risk factors at progression (primary refractory disease, remission duration < 1 year, stage III/IV), and an early evaluation of salvage chemosensitivity, including ¹⁸fluorodeoxy glucose-positron emission tomography interpreted according to the Deauville scoring system. Most relapsed or refractory Hodgkin’s lymphoma patients chemosensitive to salvage should receive high-dose therapy and autologous stem-cell transplantation as standard. Efforts should be made to increase the proportion of chemosensitive patients by alternating non-cross-resistant chemotherapy lines or exploring the role of novel drugs.     

Increased Risk of Second Lung Cancer in Hodgkin’s Lymphoma Survivors: A Meta-analysis

Background

Patients treated for Hodgkin’s lymphoma (HL) have a higher risk of developing second lung cancer (SLC) compared with the general population. The aim of this meta-analysis was to quantify such risk and to analyze contributing risk factors in HL survivors.

Methods

According to predefined selection criteria, a literature search identified 21 studies that were included in the analysis.

Results

After eliminating overlapping or duplicate data, 793 (76 % males) incidences of SLC were encountered in 74,831 patients (58 % males) with HL over a median follow-up of 11.5 years. The median age at HL diagnosis and the median age at SLC diagnosis were 33.0 and 45.9, respectively. The mean latency between treatment of HL and development of SLC was 11.5 years. The pooled relative risk (RR) of SLC was 4.62 (95 % confidence interval [CI], 3.18–6.70], I ² = 98 %), with a median absolute excess rate of 10.4 per 10,000 person-years. RR was positively related to study size, male-to-female ratio, institutional versus population-based data sets, and the use of any radiotherapy (RT) or combined modality therapy (CMT), while age at diagnosis of HL was not significant. The highest risk was shown among patients aged 15–24 years (RR = 8.76 [95 % CI, 4.55–16.89]), while the lowest risk occurred in patients ≥55 years at primary treatment (RR = 2.88 [95 % CI, 2.33–3.56]). RR increased by increasing duration of follow-up, reaching the highest value at 10–14 years (RR = 4.17 [95 % CI, 3.62–8.81]), but did not increase after ≥15 years (RR = 4.01 [95 % CI, 2.68–5.98]). RT only, CMT, or chemotherapy only was associated with RR (95 % CI) of 4.88 (3.14–7.60), 5.15 (4.08–6.50), and 2.39 (1.60–3.55), respectively. Patients with SLC demonstrated poor prognosis.

Conclusions

The current meta-analysis provided a detailed estimate of the risk of SLC among HL survivors. The obtained results may provide guidelines concerning lung cancer screening for this population.     

Molecular Basis of α-Thalassemia in Algeria

An epidemiological molecular study was carried out to evaluate the spectrum and allelic frequency of α-thalassemia (α-thal) defects in Algeria. A series of 153 randomly selected blood donors was screened for 10 α-thal alleles described in the Mediterranean area. In addition, six unrelated cases with hematological and biochemical data suggestive of Hb H disease were investigated. Our data revealed an allele frequency of 4.6%. The presence of α⁰-thal determinants (?α^20.5 and – –^{MED I}) was observed both in Hb H patients and in the randomly collected samples. Overall, the ?α^3.7 deletion was the most prevalent allele (2.9%), followed by the α^{Nco I}α (HBA2:c.1A>G) allele (0.6%) and by the α^{Hph I}α (HBA2:c.95 + 2_95 + 6delTGAGG), ?α^20.5, – –^{MED I} alleles (0.3% each). The ?α^4.2 deletion was observed in only one Hb H patient. These results outline the heterogeneity of the α-thal alleles in Algeria which reflects the anthropological history of the country. Because of their frequency, α-thal alleles are probably frequent modulators of prevalent β-globin gene-related hemoglobinopathies in Algeria.     

A Hodgkin’s Disease Cell Line, KM-H2, Shows Biphenotypic Features of Dendritic Cells and B Cells

The origin of Reed-Sternberg (RS) cells, the neoplastic cells of Hodgkin's disease, has long remained controversial. Dendritic cells (DCs) are highly specialized antigen-presenting cells that have the unique capacity to prime naive T cells, and they may be progenitors of RS cells in a population of Hodgkin's disease cells. In this study, the KM-H2 cell line, previously established from a patient with Hodgkin's disease of mixed cellularity, was reevaluated for its cellular derivation, particularly in terms of DCs. KM-H2 cells were demonstrated to carry the newly proposed DC-associated molecules fascin, CD83, and DEC-205, as well as costimulatory molecules such as CD40, CD80, and CD86. In addition, KM-H2 cells were shown to be able to potently stimulate peripheral blood T cells and to have the strong endocytotic activity of fluorescein isothiocyanate-dextran. On the other hand, KM-H2 cells were shown to have variable-diversity-joining recombination of the immunoglobulin H gene, although they did not express any subclasses of immunoglobulin and they were negative for CD79a and CD79b. In addition, KM-H2 cells produced the messenger RNA of the Pax-5 gene. These findings lead to a hypothesis that KM-H2 cells originated from the cells that had differentiated through the possible common DC-B-cell progenitors along the newly proposed pathway.     

The endoscopist’s role in the diagnosis and management of pancreatic cancer

Pancreatic cancer remains one of the most lethal malignancies with little improvement in survival over the past several decades in spite of advances in imaging, risk factor identification, surgical technique and chemotherapy. This disappointing outcome is mainly due to failures to make an early diagnosis. In fact, the majority of the patients present with inoperable advanced stages of the disease. Though some of the new tumor markers are promising, we are still in search of the one that has a high sensitivity and accuracy, yet is inexpensive and easy to obtain. The paradigm of management has shifted from up-front surgery followed by adjuvant chemotherapy to neoadjuvant chemoradiation followed by surgery, especially for borderline resectable cancers and even for some resectable cancers. In this article, we will critically assess the limitations of tumor markers and review the advancements in endoscopic techniques in the management of pancreatic cancer.     

The role of endoscopy in the allergist’s office

The introduction of nasal endoscopy has revolutionized the diagnosis and management of patients with sinonasal disorders. The brilliant illumination and magnification afforded by the nasal endoscopes has markedly enhanced the current knowledge of sinonasal anatomy and understanding of patterns of mucociliary clearance. Nasal endoscopy facilitates accurate diagnosis of sinonasal pathology and assessment of response to medical and surgical therapy by serial examination. Rigid telescopes also facilitate officebased procedures, including cultures of purulent secretions and biopsy of sinonasal masses. Indeed, nasal endoscopy forms the foundation of the surgical paradigm of functional endoscopic sinus surgery. In this review, the rationale, technique and current state of endoscopic applications of nasal endoscopy are described, with special focus on the role of endoscopy in the allergist’s office.     

A Case of Primary Bone Marrow B-Cell Non Hodgkin’s Lymphoma with Severe Thrombocytopenia: Case Report and A Review of the Literature

A 78-year-old man presented with persistent gingival bleeding. He had low platelet count of 1.0 × 10⁹/L without any lymphadenopathy. Bone marrow specimen showed diffusely distributed small-sized lymphocytes. Combined with immunophenotypic analysis, a diagnosis of primary bone marrow B-cell non-Hodgkin’s lymphoma was made. Thrombocytopenia was considered to be caused by autoimmune destruction of platelets.     

The role of a defunctioning stoma for colonic and perianal Crohn’s disease in the biological era

Objective: A defunctioning stoma is a therapeutic option for colonic or perianal Crohn’s disease. In the pre-biologic era the response rate to defunctioning in our unit was high (86%), but intestinal continuity was only restored in 11–20%. Few data exist on the outcome of defunctioning since the widespread introduction of biologicals.

Material and methods: All patients undergoing a defunctioning stoma for colonic/perianal Crohn’s disease since 2003–2011 were identified from a prospective database. Indications for surgery, medical therapy, response to defunctioning and long-term clinical outcome were recorded. Successful restoration of continuity was defined as no stoma at last follow up.

Results: Seventy-six patients were defunctioned (57 with biologicals) and at last follow up, 20 (27%) had continuity restored. Early clinical response rate (<3 months) was 15/76 (20%) and overall response 31/76 (41%). Complex anal fistulae/stenosis were associated with a very low chance of restoring continuity (10% and 0%, respectively), while colitis was associated with a higher chance of restoring continuity (48%). Endoscopic or histological improvement in colitis after defunctioning was associated with a higher rate of restoring continuity (10/16, 63%) compared to no such improvement (4/15, 27%, p?=?0.05). Those failing biologics had similar chance of restoration as those not receiving biologics, 15/57 (26%) and 5/19 (26%), respectively.

Conclusion: Overall response to colonic defunctioning was 41%. Successful restoration of continuity occurred in 27%, but 48% in the absence of perianal disease. Response is appreciably less in the pre-biologic era, so patient and physician expectations need to be managed appropriately.