Nonlymphoid Malignancies Research Articles

Impact of therapeutic inhibition of oncogenic cell signaling tyrosine kinase on cell metabolism: in vivo-detectable metabolic biomarkers of inhibition

BackgroundInhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition.MethodsWe employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton’s tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS.ResultsEffective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth.ConclusionsOur results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.

Novel anti-CD30/CD3 bispecific antibodies activate human T cells and mediate potent anti-tumor activity.

CD30 is expressed on Hodgkin lymphomas (HL), many non-Hodgkin lymphomas (NHLs), and non-lymphoid malignancies in children and adults. Tumor expression, combined with restricted expression in healthy tissues, identifies CD30 as a promising immunotherapy target. An anti-CD30 antibody-drug conjugate (ADC) has been approved by the FDA for HL. While anti-CD30 ADCs and chimeric antigen receptors (CARs) have shown promise, their shortcomings and toxicities suggest that alternative treatments are needed. We developed novel anti-CD30 x anti-CD3 bispecific antibodies (biAbs) to coat activated patient T cells (ATCs) ex vivo prior to autologous re-infusions. Our goal is to harness the dual specificity of the biAb, the power of cellular therapy, and the safety of non-genetically modified autologous T cell infusions. We present a comprehensive characterization of the CD30 binding and tumor cell killing properties of these biAbs. Five unique murine monoclonal antibodies (mAbs) were generated against the extracellular domain of human CD30. Resultant anti-CD30 mAbs were purified and screened for binding specificity, affinity, and epitope recognition. Two lead mAb candidates with unique sequences and CD30 binding clusters that differ from the ADC in clinical use were identified. These mAbs were chemically conjugated with OKT3 (an anti-CD3 mAb). ATCs were armed and evaluated in vitro for binding, cytokine production, and cytotoxicity against tumor lines and then in vivo for tumor cell killing. Our lead mAb was subcloned to make a Master Cell Bank (MCB) and screened for binding against a library of human cell surface proteins. Only huCD30 was bound. These studies support a clinical trial in development employing ex vivo-loading of autologous T cells with this novel biAb.

Chronic lymphocytic leukemia and second primary nonlymphoid malignancies: cytopathologic study of 17 cases

Second primary nonlymphoid malignancies (SPNLM) have long been recognized as a complication of chronic lymphocytic leukemia (CLL). A search was made of our cytopathology database for cases of CLL that also contained a SPNLM. Seventeen cases from 13 known CLL patients [M:F = 2.3:1; age range: 47-77 years, x = 67 years] met criteria for this study. SPNLMs consisted of different forms of metastatic carcinoma (10 patients) and malignant melanoma (3). Of 16 FNA biopsies and 1 pleural fluid, 82% had ancillary testing; 35% had the specimen subdivided for both flow cytometry (FCM) and immunohistochemistry (IHC). Lymph node was the most common site for FNA biopsy (12), followed by face (2), and soft tissue (2). Squamous cell carcinoma was the most common SPNLM (6), followed by melanoma (3), and there were single cases of adenocarcinoma, large cell neuroendocrine carcinoma, Merkel cell carcinoma, and papillary thyroid carcinoma. A correct specific cytologic diagnosis was made in 15 (88%) cases. Cytopathology is highly proficient in recognizing SPNLM in CLL patients. Utilization of cytologic material for FCM and IHC is feasible, and extremely helpful in achieving diagnostic accuracy.

Post-treatment benign changes versus recurrence in non-lymphoid head and neck malignancies: can diffusion-weighted magnetic resonance imaging end up the diagnostic challenge?

BackgroundThe aim of this prospective cohort study is to substantiate the added value of diffusion-weighted magnetic resonance imaging (DW-MRI) over conventional MRI assessment in the differentiation between locoregional recurrence/residual tumour and post-treatment benign changes in patients with non-lymphoid head and neck malignancies.Thirty adult patients, each with a suspicious lesion on post-treatment imaging scans at the primary site of a previously treated non-lymphoid head and neck malignancy, were evaluated by MRI and diffusion-weighted imaging (DWI). The apparent diffusion coefficient (ADC) values of the lesions were calculated.ResultsDiffusion-weighted MRI yielded an accuracy of 90%, a sensitivity of 88.9%, a specificity of 91.7%, a positive predictive value of 94.1% and a negative predictive value of 84.6%. The mean ADC value of the lesions was lower in the “locoregional recurrence/residual tumour” group (1.08 × 10−3 mm2/s) compared to the “post-treatment benign changes” group (1.95 × 10−3 mm2/s); P < 0.001. An ADC cutoff value of 1.43 × 10−3 mm2/s achieved the same accuracy as the visual assessment by DW-MRI.ConclusionIncorporating the DWI sequence into the post-treatment imaging assessment protocol brings a substantial added value to conventional MRI assessment in patients with non-lymphoid head and neck malignancies. This valuable merit of DW-MRI can help avoid or, at least, largely minimize unnecessary or unfeasible tissue sampling. An ADC cutoff value of 1.43 × 10−3 mm2/s can also be utilized to aid in the assessment process.

Cancer risk following lymphoid malignancies among HIV-infected people.

HIV-infected people have increased cancer risk. Lymphoma survivors have an increased risk of certain second primary cancers in the general population, but second cancer risk among HIV-infected people is poorly understood. Herein, we characterized the risk of cancers following lymphoid malignancies among HIV-infected people. Population-based linkage of HIV and cancer registries. We used data from the US HIV/AIDS Cancer Match Study (1996-2015) and evaluated the risk of first nonlymphoid malignancy in Cox regression models, with first lymphoid malignancy diagnosis as a time-dependent variable. Among 531 460 HIV-infected people included in our study, 6513 first lymphoid and 18 944 first nonlymphoid malignancies were diagnosed. Risk of nonlymphoid cancer following a lymphoid malignancy was increased overall [adjusted hazard ratio (aHR) = 2.7; 95% confidence interval (CI) = 2.3--3.2], and specifically for cancers of the oral cavity (aHR = 2.6; 95% CI = 1.2-5.5), colon (2.4; 1.1-5.0), rectum (3.6; 1.9-6.7), anus (3.6; 2.5-5.1), liver (2.0; 1.2-3.5), lung (1.6; 1.1-2.4), vagina/vulva (6.1; 2.3-16.3), and central nervous system (5.0; 1.6-15.6), Kaposi sarcoma (4.6; 3.4-6.2), and myeloid malignancies (9.7; 6.1-15.4). After additional adjustment for prior AIDS diagnosis and time since HIV diagnosis, aHRs were attenuated overall (aHR = 1.7; 95% CI = 1.5-2.0) and remained significant for cancers of the rectum, anus, and vagina/vulva, Kaposi sarcoma, and myeloid malignancies. HIV-infected people with lymphoid malignancies have an increased risk of subsequent non-lymphoid cancers. As risks remained significant after adjustment for time since HIV diagnosis and prior AIDS diagnosis, it suggests that immunosuppression may explain some, but not all, of these risks.

Is There an Increased Risk of ALL in Patients with First Cancers Treated with Radiotherapy and/or Chemotherapy?

Is There an Increased Risk of ALL in Patients with First Cancers Treated with Radiotherapy and/or Chemotherapy?

Abstract 3173: Lymphocyte-specific chromatin accessibility predetermines glucocorticoid resistance in acute lymphoblastic leukemia

Abstract Glucocorticoids are well known for their immunosuppressive activity, and play a critical role in the treatment of lymphoid malignancies. However, the development of resistance remains a significant barrier to cure and the mechanisms are poorly defined. Moreover, glucocorticoids are rarely efficacious in treating myeloid and other non-lymphoid malignancies, and the mechanisms of lymphocyte-specific efficacy are unclear. To address these issues, we first carried out a global analysis of DNase I hypersensitive sites in 18 lymphoid and 64 non-lymphoid cell types to map lymphocyte-specific open chromatin domains (LSOs). We then integrated these domains with genome-wide glucocorticoid-induced gene transcription and epigenetic modulation in an in vivo patient-derived xenograft (PDX) model of acute lymphoblastic leukemia (ALL). Performing chromatin immunoprecipitation and assays for transposase-accessible chromatin (ATAC), we determined a strong correlation between glucocorticoid receptor (GR) binding and chromatin accessibility, acetylated histone marks and binding of a DNA structural protein (CTCF), and identified 1,536 GR bound LSOs. We next analyzed RNA-seq data in glucocorticoid sensitive and resistant ALL PDXs for expression changes in genes located within 100 kb of the LSOs after glucocorticoid treatment in vivo, and identified four groups comprising 389 genes that were significantly differentially expressed. Of the 198 up-regulated genes, 143 showed increased H3K27Ac enrichments at 177 LSOs. Forty-two LSOs showed the increase only in glucocorticoid sensitive but not resistant ALLs. Applying this to an extended panel of ALL PDXs, basal DNA methylation at the 42 LSOs was significantly higher in resistant ALLs despite no difference within the gene bodies, whereas the basal chromatin accessibility indicated by ATAC abundance was diminished. Pathway analysis indicated that the LSO regulated genes were involved in repressing B- and T- cell receptor signaling pathways and activating the apoptotic pathway. One such LSO was at the pro-apoptotic BIM gene locus, where CTCF binding was found only in lymphocytes but not in other cell types. The GR cooperated with CTCF to mediate interactions between the promoter and the BIM LSO to direct DNA looping, thus triggering BIM transcription. Importantly, this LSO was heavily methylated in resistant ALLs as well as non-lymphoid cells. Azacitidine, a DNA demethylating drug that is routinely used in the clinic, could partially reverse these changes and restore glucocorticoid sensitivity. Taken together, this study demonstrated for the first time that lymphocyte-specific epigenetic modifications pre-determine glucocorticoid resistance in ALL and may account for the lack of glucocorticoid sensitivity in other cell type. Reversal of these epigenetic changes may lead to improvements in the use of glucocorticoids in the clinic. Citation Format: Duohui Jing, Yizhou Huang, Xiaoyun Liu, Keith Sia, Rebecca C. Poulos, Miriam Span, Chao Zhang, Jianqing Mi, Jason WH Wong, Dominik Beck, John E. Pimanda, Richard B. Lock. Lymphocyte-specific chromatin accessibility predetermines glucocorticoid resistance in acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3173.

CD30 Expression in Pediatric Neoplasms, Study of 585 Cases.

CD30 is a member of the tumor necrosis factor receptor superfamily, member 8 (TNFRSF8), and its normal expression is restricted to activated T and B cells. In tumor cells, CD30 expression is most commonly associated with lymphoid malignancies (Hodgkin and non-Hodgkin lymphomas) and is a therapeutic target using anti-CD30 antibody. CD30 expression has been reported also in mostly adult non-lymphoid malignancies, raising the possibility of CD30-targeted therapy for additional tumors. In this study, we examined the incidence of CD30 expression in 251 hematopoietic and 334 non-hematopoietic cases of pediatric tumors. As expected, strong and membranous CD30 staining was seen in anaplastic large cell lymphoma, classical Hodgkin lymphoma, and embryonal carcinoma while variable staining was seen in diffuse large B cell lymphoma. In addition, positive CD30 staining was also seen in cases of neuroblastoma (33 of 56), neoplasm with chondroid differentiation (8 of 25), myeloid neoplasms (11 of 120), hemangioma (2 of 12), and mature teratoma (1 of 11). In neuroblastoma, the CD30 expression was generally restricted to cells with ganglion differentiation; staining of ganglion cells was also seen in the one positive case of mature teratoma. In neoplasm with chondroid differentiation, the positive cases were chondrosarcoma (3 of 5), chondroblastic osteosarcoma (2 of 10), and chondroblastoma (3 of 7). In acute myeloid leukemia, the CD30 positive cases were more common in AML with monocytic differentiation but did not correlate with any specific molecular change. We conclude that CD30 expression in pediatric tumors is more general than anticipated and future studies are warranted to understand the biologic and therapeutic significances.

Genetic and epigenetic aberrations of p16 in feline primary neoplastic diseases and tumor cell lines of lymphoid and non-lymphoid origins

The p16 gene acts as a tumor suppressor by regulating the cell cycle and is frequently inactivated in human and canine cancers. The aim of this study was to characterize genetic and epigenetic alterations of the p16 in feline lymphoid and non-lymphoid malignancies, using 74 primary tumors and 11 tumor cell lines. Cloning of feline p16 and subsequent sequence analysis revealed 11 germline sequence polymorphisms in control cats. Bisulfite sequencing analysis of the p16 promoter region in a feline lymphoma cell line revealed that promoter methylation was associated with decreased mRNA expression. Treatment with a demethylating agent restored mRNA expression of the silenced p16. PCR amplification and sequencing analysis detected homozygous loss (five tumors, 6.7%) and a missense mutation (one tumor, 1.4%) in the 74 primary tumors analyzed. Methylation-specific PCR analysis revealed promoter methylation in 10 primary tumors (14%). Promoter methylation was frequent in B cell lymphoid tumors (7/21 tumors, 33%). These genetic and epigenetic alterations were also observed in lymphoma and mammary gland carcinoma cell lines, but not detected in non-neoplastic control specimens. These data indicate that molecular alterations of the p16 locus may be involved in the development of specific types of feline cancer, and warrant further studies to evaluate the clinical value of this evolutionarily-conserved molecular alteration in feline cancers.

EBV-Related Malignancies, Outcomes and Novel Prevention Strategies.

Epstein Barr Virus (EBV) is a common gamma herpes virus with a high prevalence in adults worldwide. Infection is mostly latent in affected individuals. EBV has been linked mostly with lymphoid malignancies but its association with epithelial and other non-lymphoid malignancies has also been described. Using MEDLINE, the terms "Epstein Barr Virus AND Malignancy"; "EBV mechanisms"; EBV treatment AND outcomes"; and "EBV prevention" were combined to find articles pertinent to this review. The search was limited to more recent publications between January 1, 2000 and August 1, 2015. In this review, we describe current knowledge about the pathogenesis of EBV-related malignancies and evaluate their therapeutic options and outcomes. Current and prospective novel preventive options are also critically reviewed. EBV infection is a very common viral infection worldwide and has been implicated in various malignancies including lymphomas, gastric cancer, and nasopharangeal cancer. Patients with EBV positive PTLD and NK/T-cell lymphoma tend to have a better prognosis than EBV negative patients. On the other hand, patients with EBV positive HL or DLBCL tend to have a poorer prognosis especially in elderly patients. Further research is needed to better understand if EBV status is a true prognostic indicator in most malignancies. Treatment approaches remain similar for EBV positive and EBV negative malignancies while the use of novel agents remain under investigation. EBV vaccination trials are underway and these remain a potentially effective strategy to prevent EBV-related malignancies and the associated sequela.

Follicular lymphoma in situ in intra-abdominal lymphadenectomies- a study of 5 cases: revisiting the entity

&lt;p&gt;&lt;strong&gt;Background&lt;/strong&gt;: Follicular lymphoma &lt;em&gt;in situ&lt;/em&gt; (FLIS) is characterized by the presence of germinal centers that strongly express BCL-2 protein and germinal center markers CD10 and BCL-6, although most of the remaining lymph node shows a pattern of follicular hyperplasia, in the absence of interfollicular infiltration. Here, we present five cases of FLIS and discuss their presentation and pathological identification in a wide variety of clinical settings. &lt;strong&gt;Materials and Methods&lt;/strong&gt;:&lt;strong&gt; &lt;/strong&gt;The present study includes five cases of FLIS diagnosed in the department of surgical pathology over a period of three years (2010 to 2013). The clinical data and the follow-up information were obtained from the medical records. &lt;strong&gt;Results&lt;/strong&gt;: The present study included three male and two female patients with an age range of 46–72 years. One case of FLIS was associated with diffuse large B-cell lymphoma (DLBCL), while in two cases this was an incidental finding associated with other non-lymphoid malignancies. &lt;strong&gt;Conclusion&lt;/strong&gt;: FLIS has a very low rate of progression to clinically significant follicular lymphoma (FL), and the management strategy recommended is to watch and wait. However, some cases may develop into full blown FL and also many non-FL lymphoid malignancies have been seen associated with it. Hence, a staging workup is strongly advocated by many authors for FLIS.&lt;/p&gt;

Anaplastic Large Cell Lymphoma: A Cytological Masquerade

Anaplastic large cell lymphoma accounts for less than 10% cases of all lymphomas. It is a distinct category of large cell lymphomas that shows strong expression of CD30. The reproducibility of ALCL on the morphological ground is poor and at times it may mimic other non-lymphoid malignancies. The cytomorphology of anaplastic large cell lymphoma (ALCL) is distinctive yet variable. Till date only few cases have described the cytologic findings of ALCL. We here present a case of ALCL who presented to us with cervical lymphadenopathy and high grade fever.

Hodgkin lymphoma: Diagnostic criteria and pitfalls

The histopathological and fine-needle aspiration (FNA) cytologic diagnosis of Hodgkin lymphoma (HL) is based on demonstration of pathognomonic mononucleated Hodgkin and bi- to multinucleated Reed-Sternberg (HRS) cells among reactive cellular components composed of lymphocytes, benign histiocytes, neutrophils and eosinophils. In the WHO classification, Hodgkins lymphoma is classified as nodular lymphocytic predominant HL (NLPHL) and classical HL which is in turn sub-classified into lymphocyte-rich (LR), mixed cellular (MC), lymphocytic depleted (MC) and nodular sclerosis (NS) types. The sub-classification of classical HL into LR, MC, and LD depends on relative proportions of neoplastic HRS cells and reactive cellular components. Whereas in HL-NS shows a special type of R-S cells called lacunar cells, NLPHL is characterized by popcorn cells. CHL-MC to some extent and other HL subtypes to a large extent may pose diagnostic challenges in the cytologic material. Reed-Sternberg-like cells have been reported in benign lympho-proliferative conditions like reactive hyperplasia and infectious mononucleosis, and certain of non-Hodgkin lymphoma subtypes as well as non-lymphoid malignancies like metastatic carcinoma, melanoma, sarcomas and germ cell tumors. Non-Hodgkin lymphoma subtypes, e.g., anaplastic large cell lymphoma, T-cell-histiocytic-rich B-cell lymphoma, and pleomorphic peripheral T-cell lymphoma, which can be misdiagnosed as Hodgkin lymphoma, need immunohistochemical studies to be differentiated.

Free Circulating Epstein Barr Virus DNA Load In Indian Children With Hodgkin Lymphoma As a Biomarker Of EBV-Associated Disease

IntroductionEpstein-Barr virus (EBV) association has been described in a large majority of children with Hodgkin lymphoma (HL) in India. The significance of circulating plasma EBV load and its kinetics during HL therapy is largely unknown. This study aimed at assessing the value of circulating EBV-DNA as a biomarker of EBV-associated pediatric HL and of tumour burden, and the value of serial monitoring during therapy. MethodAll pediatric cases presenting with lymphadenopathy were prospectively recruited between 2007 and 2012. Lymph node biopsy was performed. Children with HL and controls with reactive nodal hyperplasia were enrolled in the study after prior informed consent. Untreated non-lymphoid malignancies and healthy controls were also included in the control group. Plasma EBV real-time quantitative-PCR (RQ-PCR) was assessed with LightCycler2.0, Roche. EBV-associated HL was defined by positive EBV latent membrane protein-1 immunohistochemistry on lymph-node biopsies. Risk-adapted ABVD chemotherapy was given to HL cases, and early treatment response was assessed. RQ-PCR was repeated after the first cycle, at the end of treatment and on follow-up. Kaplan-Meier survival analysis was done, including loss to follow-up as an event. ResultsThirty cases of HL (newly diagnosed–28, relapses–2) and 70 age/ sex-matched controls (benign lymphadenopathy–19, non-lymphoid malignancy–29, Burkitt lymphoma–5, healthy children–17) were included. HL stage distribution was stage I–4, II–9, III–4 and IV–13. EBV immunohistochemistry was positive in 16 (59.3%) out of 27 HL cases analyzed (14/19 MC, 1/6 NS, 0/2 LP, 1 unclassified). RQ-PCR was detectable in 19 (63.3%) out of 30 HL, with 87.5% accuracy (Kappa coefficient=0.69 [0.42-0.97]). All 70 controls were RQ-PCR negative (p<0.0001). RQ-PCR sensitivity and specificity in EBV-associated HL detection were 87.5% and 81.8% respectively. Three out of 4 cases with more than 10,000 EBV copies/mL had advanced stage disease (III-IV) and B symptoms. The highest viral load (430,000 copies/mL) was seen in a boy with stage IV-B disease and end-stage liver involvement. However, viral load was not significantly associated with tumor burden or with survival. All treated Q-PCR positive cases showed EBV clearance after the first cycle. One case, RQ-PCR negative 10 years after primary treatment of stage-I HL, relapsed locally and became RQ-PCR positive. Five-year overall survival (OS) and event-free survival (EFS) were 82.6±8.5% and 77.2±8.3% respectively. OS and EFS were not significantly different in EBV-positive and EBV-negative HL. ConclusionRQ-PCR detection of circulating EBV-DNA is a biomarker of EBV-associated HL, in contrast with pediatric non-lymphoid malignancies, sporadic Burkitt lymphoma and benign lymphadenopathies. EBV-DNA may be used as an early marker of response to therapy in EBV-associated HL and may increase in case of relapse. Disclosures:No relevant conflicts of interest to declare.

Gammaherpesviruses and Lymphoproliferative Disorders

Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV), formally designated human herpesvirus 4 (HHV-4) and 8 (HHV-8), respectively, are viruses that can cause a variety of cancers in humans. EBV is found in non-Hodgkin and Hodgkin lymphomas, as well as in lymphoproliferative disorders, which occur more commonly but not exclusively in individuals with immunodeficiency. EBV also causes nonlymphoid malignancies such as nasopharyngeal carcinoma. KSHV causes primary effusion lymphomas, multicentric Castleman's disease, and Kaposi's sarcoma. The frequency of lymphoid malignancies related to infection by one of these two herpesviruses is greatly increased in individuals with immunodeficiency, whether primary or acquired, for example, as a consequence of HIV infection and AIDS or in the case of therapeutic immunosuppression for organ transplantation. Our current understanding indicates that EBV and KSHV contribute to lymphomagenesis by affecting genomic stability and by subverting the cellular molecular signaling machinery and metabolism to avoid immune surveillance and enhance tumor cell growth and survival. Understanding the viral associations in specific lymphoproliferative disorders and the molecular mechanisms of viral oncogenesis will lead to better prevention, diagnosis, and treatment strategies for these diseases.

Twenty Years Survivors after Heart Transplantation: La Pitié Experience

Purpose To evaluate patients surviving >20 years after orthotopic heart transplantation (OHT). Methods and Materials Medical records of all OHT recipients surviving >20 years were reviewed retrospectively. Patients undergoing heterotopic, multiorgan or re-transplantation were excluded. Results From 1981 to 1992, 758 OHTs were performed at our institution. Among these, 115 (15%) patients survived >20 years with a single graft. Eighty-three (72%) were males and mean age at transplant was 41±13 years. Causes for heart failure were dilated cardiomyopathy in 63 (55%) and ischemic heart disease in 32 (28%), patients. Thirty-six (31%) patients died during follow-up. Actuarial survival was 72±5%, 62±6% and 50±7% at 23, 25 and 27 years, respectively. Allograft rejection grade ≥2R was noted in 42 (36%) patients. Rejection-free survival was 63±5% at 20 and 25 years. Cardiac allograft vasculopathy (CAV) grade 2-3 was diagnosed in 29 (35%) patients. CAV-free survival was 79±4% and 74±5% at 20 and 25 years, respectively. Malignancies were diagnosed in 61 (53%) and were multiple in 25 (22%) patients. Most common type was skin malignancy (57%), followed by non-lymphoid (44%) and lymphoid (26%) malignancies. Malignancy-free survival was 55±5% and 43±5% at 20 and 25 years, respectively. At latest follow-up, 106 (92%) survivors had hypertension and 23 (20%) diabetes. Forty (35%) patients had renal dysfunction, 18 (16%) received hemodialysis and 8(7%) had undergone renal transplantation. Echocardiography performed 23±3 years after OHT showed LV ejection fraction of 62±12%, LV end-systolic and end-diastolic diameters of 30±5mm and 50±6mm, respectively. Tricuspid regurgitation (grade ≥2) was found in 7 (9%) survivors. Quality of life (SF-36 health survey) showed mean physical and mental scores of 56±26 and 56±22, respectively. Conclusions Fifteen percent of early OHT recipients survived more than 20 years and showed excellent LV performance and good quality of life. CAV and malignancies account for significant late morbidity and mortality.

Herpes zoster is associated with an increased risk of subsequent lymphoid malignancies - A nationwide population-based matched-control study in Taiwan

BackgroundInfectious agents have been shown to contribute to the development of lymphoid malignancies. The different distribution of lymphoid malignancies in Asian and Western populations suggests possibly different etiologies in Asian populations. Herpes zoster infection, commonly seen in immunocompromised persons, has been reported to be associated with lymphoid malignancies in retrospective case–control studies from Western populations, but the results are controversial and large-scale prospective studies from Asian populations are lacking.MethodsA nationwide population-based matched-controlled prospective study on Taiwanese patients was performed using the National Health Insurance Research Database from 1996 to 2007. Herpes zoster and malignancies were defined by compatible ICD-9-CM (International Classification of Disease, 9th Revision, Clinical Modification) codes. Patients who had been diagnosed with any malignancies before herpes zoster, with known viral infections including human immunodeficiency virus, and duration from herpes zoster to diagnosis of malignancies less than 6 months were excluded.ResultsOf 42,498 patients with herpes zoster prior to the diagnosis of any malignancies, the cumulative incidence for lymphoid malignancies was 0.11% (n = 48), compared with 0.06% (n = 106) in 169,983 age- and gender-matched controls (univariate hazard ratio (HR): 1.82, 95%CI: 1.29-2.55). The most common lymphoid malignancy was non-Hodgkin’s lymphoma (60.4%, n = 29), followed by multiple myeloma (27.1%, n = 13). Risk for developing lymphoid malignancies is significantly higher in herpes zoster patients (log rank P = 0.005). After adjusting for presence of any comorbidities in Charlson comorbidity index, time-dependent covariate for herpes group, and income category using Cox proportional hazard regressions, herpes zoster patients had an increased risk of developing lymphoid malignancies (adjusted HR: 1.68, 95%CI: 1.35-2.42, P = 0.0026), but did not have an increased risk of developing non-lymphoid malignancies (adjusted HR: 1.00, 95%CI: 0.91-1.05, P = 0.872).ConclusionPreceding herpes zoster infection is an independent risk marker for subsequent lymphoid malignancies in Taiwanese subjects. Further studies are warranted for pathogenesis exploration and preventive strategies in Asian populations.

Abstract 766: Galiximab disrupts the dysregulated NF-κB/YY1/Snail/BclXL circuit that regulates the resistance of B-NHL cell lines: Sensitization to chemo-immunotherapeutic drugs

Abstract The combination of Rituximab and chemotherapy is currently the standard treatment for several B-NHL malignancies. However, there is a subset of patients that does not initially respond and a subset that fails to respond to further treatment. Therefore, there is an urgent need to develop new therapeutic modalities for those patients. Galiximab (anti-CD80 mAb) has been developed with the objective of overcoming the resistance to rituximab and/or used in combination with rituximab to improve response rates. A Phase II double blind placebo controlled trial of rituximab+galiximab vs. rituximab+placebo in 337 subjects with relapsed or refractory, grade I-IIIa, follicular NHL in relapse were followed up of 13.8 month. The addition of Galiximab to rituximab reduced the hazard for disease progression or death by 26% compared to the rituximab+placebo group. However, the mechanisms by which Galiximab mediates its effects have not been examined. Preliminary findings demonstrated that treatment of B-NHL cell lines with Galiximab resulted in the inhibition of cell growth and sensitization of drug-resistant tumor cells to both CDDP and TRAIL-mediated apoptosis. Sensitization was a result of Galiximab-induced inhibition of the constitutively activated NF-κB pathway and downstream the resistant factors Yin Yang 1 (YY1), Snail, and BclXL. The role of each of these factors in the regulation of resistance and whether they also regulate each other were assessed by transfection with siRNAs. Treatment of Raji (CD80+) Burkitt's Lymphoma cell line with YY1 siRNA resulted in the inhibition of YY1, Snail, phospho-p65, and BclXL as assessed by western. Likewise, transfection with Snail siRNA resulted in the inhibition of Snail, YY1, phospho-p65, and BclXL. In both cases, the transfected cells resulted in the reversal of resistance and sensitization to apoptosis by both CDDP and TRAIL. These findings revealed that NF-κB regulates YY1, Snail, and BclXL and that both YY1 and Snail, in turn, regulate NF-κB and BclXL. It has been reported that YY1 regulates NF-κB via miR29 and, in turn, NF-κB regulates YY1 transcription. Also, YY1 regulates Snail transcription. However, it is not known how does Snail regulate NF-κB and YY1. We speculate that Snail regulates phospho-p65 via transcription or indirectly through the regulation of NF-κB by YY1. The present findings reveal a new dysregulated NF-κB/YY1/Snail/BclXL circuit in the regulation of resistance of B-NHL to cytotoxic drugs. Galiximab interferes with this circuit and results in the reverse of resistance. In addition, the findings revealed new targets that may be of prognostic significance as well as targets for therapy. The present findings in B-NHL cell lines may be also generalized to non-lymphoid malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 766. doi:1538-7445.AM2012-766

In situ follicular lymphoma associated with nonlymphoid malignancies

In situ follicular lymphoma (FL) is usually an incidental finding in otherwise reactive lymph node. This report describes two cases of lymph nodal in situ FL complicated by the association with nonlymphoid neoplasms. In case 1, in situ FL was discovered incidentally on a biopsy performed for an unexplained cervical lymphadenopathy 6 months after the resection of a carotid body paraganglioma. In case 2, in situ FL was detected incidentally during surgery for radical resection of prostatic carcinoma. In the lymph nodes, the in situ FL foci were characterized immunohistologically by strong coexpression of BCL2 and CD10 in the involved GCs. FISH study demonstrated BCL2 rearrangement in one of the two tested cases. These data extend the spectrum of the clinical situations that may be associated with in situ FL, but the biological and clinical significance of the association of in situ FL with nonlymphoid neoplasms deserves further investigation. Important fields of investigation should include: (1) how to approach these patients who have a risk of progression to overt lymphoma; (2) is the association of in situ FL with concurrent nonlymphoid neoplasia incidental, related to immunosuppression or to previous treatment?

Rapid detection of neoplastic cells in serous cavity effusions in children with flow cytometry immunophenotyping

The aim of the study was to evaluate the role of flow cytometric immunophenotyping (FCI) as a rapid diagnostic tool for pediatric malignancy in serous cavity effusions (SCEs). FCI results for 103 SCEs in a pediatric population were compared with retrospective clinical outcomes (RCOs). Among 41 patients assessed as having malignancies by RCO, 36 patients were diagnosed with lymphoma (n =25), acute myeloid leukemia (n =2), neuroblastoma (n =8) and retinoblastoma (n =1) by FCI, respectively. The sensitivity and specificity of FCI for detecting neoplastic cells were 87.8% and 98.4%, respectively. The concordance of FCI data with final diagnoses of the patients was 94.2%. FCI data for lymphoma was concordant with the final diagnosis in 89.3% of cases. When Hodgkin lymphoma was excluded, the overall correlation increased to 96.1%. FCI is a useful tool for rapid and reliable diagnosis of pediatric non-Hodgkin lymphoma in SCE samples and also to suggest the presence of non-lymphoid malignancies, especially neuroblastoma.