Lymphatic Malignancies Research Articles

High Parathyroid Hormone Rather than Low Vitamin D Is Associated with Reduced Event-Free Survival in Childhood Cancer.

Vitamin D deficiency is linked to poor cancer outcomes but the impact of its consequence, elevated parathyroid hormone (PTH), remains understudied. PTH receptor activation influences cancer progression in vitro, yet the effect of elevated PTH on pediatric cancer survival is unexamined. This retrospective study examines associations between PTH, 25-OH vitamin D (25OHD), and event-free survival (EFS) and overall survival (OS) in patients with pediatric cancer. Laboratory data from 4,349 patients (0-18 years) at a tertiary pediatric cancer unit were analyzed for the highest PTH and lowest 25OHD levels at diagnosis and the following 5 years. Data on relapse, secondary malignancies, and mortality were stratified by PTH levels above/below the cohort median (47 pg/mL) and 25OHD levels ≤30 nmol/L. EFS and OS were analyzed and hazard ratios (HR) were calculated for the entire cohort and six cancer subgroups. PTH and 25OHD values were available for 1,286 patients (731 male). Higher PTH associated with inferior EFS in primary malignant brain tumors [HR, 1.80 (1.19-2.72)], embryonal malignancies [HR, 2.20 (1.1-4.43)], and lymphatic malignancies [HR 1.98 (1.05-3.72)]. Vitamin D deficiency associated with inferior EFS in embryonal malignancies [HR 2.41 (1.24-4.68)]. In a multivariate Cox model, only higher PTH remained significant for inferior EFS. Elevated PTH may indicate adverse outcomes in certain pediatric cancers. This study identifies elevated parathyroid hormone as a potential marker for poor outcomes in patients with pediatric cancer, emphasizing the need for adequate vitamin D and calcium management.

Impact of prior cancer history on survival in brain malignancy: A propensity score-adjusted, population-based study.

Individuals with a Prior Cancer History (PCH) are often excluded from clinical trials. However, a growing body of evidence suggests that prior cancer history does not present adverse outcomes on cancer patients. The evidence on the survival of brain cancer patients in this regard remains widely unknown. We conducted a retrospective cohort study to estimate the prevalence and impact of prior cancer on survival of patients diagnosed with brain cancer. Data of patients who were diagnosed with brain cancer as their first or second primary malignancy between 2000 and 2019 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity Score Matching (PSM) was used to ensure comparable baseline characteristics among the patients. Survival analysis was conducted using the Kaplan-Meier method, as well as multivariate Cox proportional hazard and multivariate competing risk models. Out of 42 726 patients, 1189 (2.78%) had PCH. Genitourinary (40.4%), Breast (13.6%), Hematologic and Lymphatic (11.4%), and Gastrointestinal malignancies (11.3%) were the most common types of prior cancer. PCH served as a significant risk factor for Overall Survival (OS) (Adjusted Hazard Ratio [AHR] 1.26; 95% CI [1.15-1.39]; p < .001) but did not have a statistically significant impact on Brain Cancer-Specific Survival (BCSS) (AHR 0.97; 95% CI [0.88-1.07]; p = .54). Glioblastoma exhibited the most substantial and statistically significant impact on survival as compared to other histological types. Of all the organs systems, only prior Gastrointestinal and Hematologic and Lymphatic malignancies had a statistically significant impact on OS of patients. Our findings indicate that PCH does not exert a substantial impact on the survival of brain cancer patients, except in cases involving gastrointestinal or hematologic and lymphatic PCH, or when the brain cancer is glioblastoma.

Molecular genetic markers of chemotherapy-induced cardiotoxicity in patients with oncohematological diseases (review)

Cardiotoxicity of anticancer therapy is a severe adverse cardiovascular event affecting the survival of cancer patients. Modern methods for diagnosing cardiotoxicity allow to identify already occurred myocardial transformations, accompanied by symptoms of heart failure and are not predict and detect early changes in the heart tissue during treatment. Recently, increasing attention is paid to the search for molecular genetic markers, a single identification of which before starting treatment will make possible to determining the risks of cardiotoxicity and change treatment taking into account individual genetic characteristics. At the same time, most research on the effect of allelic variants of genes on cardio-vascular complications relate to chemotherapy of solid tumors. The review considered possible prognostic genetic variants of cardiotoxicity induced by chemotherapy in patients with the hematopoietic and lymphatic malignancies.

Acquired Angioedema Due to C1-Inhibitor Deficiency (AAE-C1-INH)—A Bicenter Retrospective Study on Diagnosis, Course, and Therapy

Acquired angioedema with C1-inhibitor deficiency (AAE-C1-INH) is a rare condition resembling hereditary angioedema (HAE), but with late onset and low C1-inhibitor (C1-INH) due to consumption potentially caused by autoimmune diseases and mainly lymphatic malignancies. Being about 10-fold rarer than HAE, there is limited knowledge and no licensed therapy. To report clinical and biological data from a newly described population of 20 patients with AAE-C1-INH assessing diagnostic delay, AAE-C1-INH:HAE-ratio, underlying conditions, and therapeutic management in Germany. Retrospective data analysis of 20 patients from 2 angioedema centers in southern Germany. Median age at symptoms' onset was 64 years (60% females), with predominant swellings of the face (85%) and low levels for C1-INH in almost all patients. The ratio AAE-C1-INH:HAE was 1:9.7. From symptoms' onset to diagnosis of AAE-C1-INH, the median delay was 7.5 months, and between AAE-C1-INH symptoms' onset and diagnosis of the underlying hematological condition (n= 9) it was 4 months (median). Four patients had a history of solid neoplasm, 1 had a papillary thyroid carcinoma as the only potential cause for AAE-C1-INH, with treatment of the malignancy resulting in resolution of AAE-C1-INH. All the symptomatic patients were treated with off-label on-demand icatibant subcutaneously or C1-INH concentrate intravenously, and 6 severely affected patients needed off-label long-term prophylaxis with good symptom control. AAE-C1-INH is characterized by late-onset swellings mainly involving the face and low C1-INH levels. Diagnostic delay for AAE-C1-INH is further decreasing despite being about 10-fold rarer than HAE. Patients severely affected without underlying condition or no indication for treatment could benefit from off-label therapy.

Dietary Heat-Treatment Contaminants Exposure and Cancer: A Case Study from Turkey.

In this study, the 10-year dietary habits of patients diagnosed with cancer (n = 1155) were retrospectively analyzed, and the relationships between dietary (red meat, white meat, fish meat, French fries, bread, instant coffee, ready-to-drink coffee, Turkish coffee, and black tea) heterocyclic amines, polycyclic aromatic hydrocarbons, acrylamide, and N-nitrosamine-based risk scores and cancer types were statistically evaluated. The foods with the highest and lowest mean dietary heat-treatment contaminant risk scores were red meat and ready-to-drink coffee, respectively. There were statistically significant differences in the dietary heat-treatment contamination risk scores based on the cancer patients' demographic characteristics (sex, age, smoking, and body mass index) (p < 0.05). According to the cancer types, the systems with the highest and lowest dietary heat-treatment contaminant risk scores were determined as other (brain, thyroid, lymphatic malignancies, skin, oro- and hypopharynx, and hematology) and the reproductive (breast, uterus, and ovary) system, respectively. The relationship between instant coffee consumption and respiratory system cancer types, the frequency of consumption of French fries and urinary system cancer types and the consumption of meat products and gastrointestinal system cancer types were determined. It is thought that this study contains important findings regarding the relationship between dietary habits and cancer and will be a good source for other studies to be conducted in this context.

SAM-Competitive EZH2-Inhibitors Induce Platinum Resistance by EZH2-Independent Induction of ABC-Transporters.

T-cell lymphomas are heterogeneous and rare lymphatic malignancies with unfavorable prognosis. Consequently, new therapeutic strategies are needed. The enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 and responsible for lysine 27 trimethylation of histone 3. EZH2 is overexpressed in several tumor entities including T-cell neoplasms leading to epigenetic and consecutive oncogenic dysregulation. Thus, pharmacological EZH2 inhibition is a promising target and its clinical evaluation in T-cell lymphomas shows favorable results. We have investigated EZH2 expression in two cohorts of T-cell lymphomas by mRNA-profiling and immunohistochemistry, both revealing overexpression to have a negative impact on patients' prognosis. Furthermore, we have evaluated EZH2 inhibition in a panel of leukemia and lymphoma cell lines with a focus on T-cell lymphomas characterized for canonical EZH2 signaling components. The cell lines were treated with the inhibitors GSK126 or EPZ6438 that inhibit EZH2 specifically by competitive binding at the S-adenosylmethionine (SAM) binding site in combination with the common second-line chemotherapeutic oxaliplatin. The change in cytotoxic effects under pharmacological EZH2 inhibition was evaluated revealing a drastic increase in oxaliplatin resistance after 72 h and longer periods of combinational incubation. This outcome was independent of cell type but associated to reduced intracellular platinum. Pharmacological EZH2 inhibition revealed increased expression in SRE binding proteins, SREBP1/2 and ATP binding cassette subfamily G transporters ABCG1/2. The latter are associated with chemotherapy resistance due to increased platinum efflux. Knockdown experiments revealed that this was independent of the EZH2 functional state. The EZH2 inhibition effect on oxaliplatin resistance and efflux was reduced by additional inhibition of the regulated target proteins. In conclusion, pharmacological EZH2 inhibition is not suitable in combination with the common chemotherapeutic oxaliplatin in T-cell lymphomas revealing an EZH2-independent off-target effect.

Sinonasal Cancer: A National Population-based Study in Iran

Background: Cancer is a leading cause of death in the 21st century. Sinonasal malignancies comprise less than 0.5% of all cancers. There are limited epidemiologic studies on them. Objectives: The current study aimed to estimate the patient demographics, as well as the incidence rates of nasal cavity and paranasal sinuses (NC-PNS) cancers, using a population based registry. Methods: The current study was a descriptive cohort using the Iranian national population based cancer registry (INPCR) data in 2016. The incidence rate of NC-PNS cancer and its distribution considering age, gender, geographical location and histopathology were determined. Results: A total of 258 cases (62.4 % males) were included in the study. Age standardized incidence rate (ASIR) of NC-PNS cancer was 0.36 per 100,000 population. ASIR had the highest value in the 7th, 8th, and 6th decades of life, in descending order. Squamous cell carcinoma (SCC) was the most common histopathologic subtype (23.64%). The most frequent non-epithelial cancer were hematopoietic and lymphatic malignancies (12.40%). The most prevalent site of involvement was the nasal cavity (43.02%), followed by the maxillary sinus (24.81%). The geographical distribution of NC-PNS cancer did not follow any particular pattern. The highest crude incidences were detected in Chahar-Mahal-Bakhtiari, Kerman, and West Azarbaijan in decreasing order. Conclusion: As evidenced by the obtained results, NC-PNS cancers are rare malignancies. Men in their fifties and older are at a higher risk of involvement. Epithelial cancers are more prevalent, among which SCC is the most common histopathologic subtype.

Abstract 4095: Preclinical characterization of switchable allogeneic chimeric antigen receptor T cells to support first in human clinical study in CD123-positive hematologic and lymphatic malignancies

Abstract Approximately 80% of AML patients express CD123 on their leukemic blasts and CD123 is frequently expressed on other hematologic and lymphatic malignancies. Chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant efficacy in B cell malignancies. Breakthrough of conventional CAR-T technology in AML has been hampered by expression of suitable target antigens on normal hematopoietic progenitor cells posing a risk for continued aplasia. Thus, innovative approaches putting the power of CAR-T technology under the control of reliable and fast-acting on/off switches to avoid and/or abrogate acute and long-term side effects are required. We have recently reported clinical proof-of-concept for autologous switchable CAR-T cell therapy in AML (Wermke et al. Blood 2021). However, manufacturing of autologous products is very costly and rrAML patients are often in urgent need for a product and multiple prior lines of treatment may be detrimental for product quality. While current clinical allogeneic approaches successfully prevent graft-versus-host disease, observed persistence has been limited due to rejection of the grafted T cells by host immune cells. Here, we report preclinical development of a donor-derived allogeneic switchable CAR-T therapy for CD123-positive hematologic and lymphatic malignancies (AVC-201). The reverse universal chimeric antigen receptor platform (RevCAR) is a 2-component CAR-T platform. The first component is a universal CAR-T cell. Its binding domain is a short, non-immunogenic peptide that by itself does not recognize any human cell surface antigen but is specifically bound by an scFv included in the second component, a soluble adaptor called targeting module (TM). To target CD123, a TM with a short half-life was selected (R-TM123), enabling a rapid switch-off of the RevCAR system by TM withdrawal to avoid acute and long-term toxicity usually associated with continuous activation of CAR-T cells. The allogeneic cells are generated by three edits with CRISPR-Cas9, which is meant to fully overcome graft-versus-host disease as well as graft rejection by host T and NK cells. Therefore, we expect a persistent T cell product that can be re-expanded with additional TM cycles. A summary of preclinical characterization of AVC-201 will be presented at the meeting including in vitro and in vivo pharmacology and toxicology experiments. Activation of Allo-RevCAR-T cells is strictly dependent on the presence of CD123-positive target cells and R-TM123. Allo-RevCAR-T cells redirected by R-TM123 efficiently lyse CD123-positive AML cells in vitro and in vivo, and in vitro EC50 values are in the low picomolar range of R-TM123 concentrations. In conclusion, preclinical data support the clinical exploration of AVC-201 in a first in human study. Citation Format: Armin Ehninger, Johannes Spehr, Simon Loff, Anika Langer, Julia Riewaldt, Julia Reinhardt, Jan-Erik Meyer, Josephine Dietrich, Gabriel Jurado, Reynald Lescarbeau, Marc Cartellieri. Preclinical characterization of switchable allogeneic chimeric antigen receptor T cells to support first in human clinical study in CD123-positive hematologic and lymphatic malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4095.

New insights into hepatitis B virus lymphotropism: Implications for HBV-related lymphomagenesis.

HBV is one of the most widespread hepatitis viruses worldwide, and a correlation between chronic infection and liver cancer has been clearly reported. The carcinogenic capacity of HBV has been reported for other solid tumors, but the largest number of studies focus on its possible lymphomagenic role. To update the correlation between HBV infection and the occurrence of lymphatic or hematologic malignancies, the most recent evidence from epidemiological and in vitro studies has been reported. In the context of hematological malignancies, the strongest epidemiological correlations are with the emergence of lymphomas, in particular non-Hodgkin's lymphoma (NHL) (HR 2.10 [95% CI 1.34-3.31], p=0.001) and, more specifically, all NHL B subtypes (HR 2.14 [95% CI 1.61-2.07], p<0.001). Questionable and unconfirmed associations are reported between HBV and NHL T subtypes (HR 1.11 [95% CI 0.88-1.40], p=0.40) and leukemia. The presence of HBV DNA in peripheral blood mononuclear cells has been reported by numerous studies, and its integration in the exonic regions of some genes is considered a possible source of carcinogenesis. Some in vitro studies have shown the ability of HBV to infect, albeit not productively, both lymphomonocytes and bone marrow stem cells, whose differentiation is halted by the virus. As demonstrated in animal models, HBV infection of blood cells and the persistence of HBV DNA in peripheral lymphomonocytes and bone marrow stem cells suggests that these cellular compartments may act as HBV reservoirs, allowing replication to resume later in the immunocompromised patients (such as liver transplant recipients) or in subjects discontinuing effective antiviral therapy. The pathogenetic mechanisms at the basis of HBV carcinogenic potential are not known, and more in-depth studies are needed, considering that a clear correlation between chronic HBV infection and hematological malignancies could benefit both antiviral drugs and vaccines.

Prospective Cohort Study of Ginseng Consumption in Association with Cancer Risk: Shanghai Women’s Health Study

BackgroundGinseng has been commonly used in Asian countries to promote longevity and health for >2000 years. Recent in vitro and in vivo studies, coupled with limited epidemiologic studies, have suggested that regular ginseng consumption may be related to lower cancer risk. ObjectivesWe evaluated the association of ginseng consumption with risk of total and 15 site-specific cancers in a large cohort study conducted among Chinese women. Given the previous literature on ginseng consumption and cancer risk, we hypothesized that ginseng consumption might be associated with varying risks of cancer. MethodsThis study included 65,732 female participants (mean age: 52.2 years) of the Shanghai Women’s Health Study, an ongoing prospective cohort study. Baseline enrollment occurred between 1997 and 2000, and follow-up concluded on 31 December 2016. Ginseng use and covariates were assessed via an in-person interview conducted at the baseline recruitment. The cohort was followed for cancer incidence. Cox proportional hazard models were used to estimate HRs and 95% CIs for ginseng-cancer associations after adjusting for confounders. ResultsDuring a mean 14.7 years of follow-up, 5067 incident cancer cases were identified. Overall, regular ginseng use was mostly not associated with risk of any site-specific cancer, or all cancers combined. Short-term (<3 years) ginseng use was found to be significantly associated with increased risk of liver cancer (HR = 1.71; 95% CI: 1.04, 2.79; P = 0.035), whereas long-term (≥3 years) ginseng use was found to be associated with increased risk of thyroid cancer (HR = 1.40; 95% CI: 1.02, 1.91; P = 0.036). Long-term ginseng use was found to be significantly associated with decreased risk of lymphatic and hematopoietic tissue malignancy (HR = 0.67; 95% CI: 0.46, 0.98; P = 0.039) and non-Hodgkin’s lymphoma (HR = 0.57; 95% CI: 0.34, 0.97; P = 0.039). ConclusionsThis study provides suggestive evidence that ginseng consumption may be associated with risk of certain cancers.

Paternity through use of assisted reproduction technology in male adult and childhood cancer survivors: a nationwide register study.

How does a history of cancer affect the likelihood of using assisted reproduction in order to achieve paternity? As compared to men with no history of cancer, use of assisted reproduction to achieve paternity was more frequent in fathers with a history of cancer, mainly those with testicular, prostate, and hematological and lymphatic malignancies. Although it is well known that different types of cancer and their treatment may have a negative impact on fertility, there is a lack of data regarding the use of IVF and ICSI among male cancer survivors. In this population-based nation-wide study using the Swedish Medical Birth Register, we identified all men who fathered their first-born child in Sweden between 1994 and 2014. Using personal identification numbers, anonymized data from the Swedish National Quality of Assisted Reproduction Register, Swedish Cancer Register, Swedish Multi-generation Register, and Swedish Education Register were linked with the Swedish Medical Birth Register. During the study period, a total of 1 181 488 men fathering their first-born child were identified. Of these, 26 901 fathers had a cancer diagnosis. Fathers diagnosed with cancer with <12 months from offspring conception, or with a cancer diagnosis after offspring conception, were excluded (n = 21 529). The remaining fathers who had a history of cancer (n = 5372) were divided into three groups based on age at cancer diagnosis (<15, ≥15 and <24, or ≥24 years). For subgroup analyses, they were also grouped according to the cancer location using ICD-7 codes. The fathers with no cancer diagnosis (n = 1 154 587), were included as controls. In total, 1 159 959 men were included. Associations between IVF/ICSI use and history of cancer were evaluated using logistic regression models, unadjusted and adjusted for paternal education, fathers age at childbirth, and year of conception, yielding crude and adjusted odds ratio (aOR), respectively, with a 95% CI. As compared to controls, childhood cancer survivors were only more likely to achieve paternity through ICSI (aOR 3.52, 95% CI 2.52-4.93; P < 0.001) but not through IVF treatment (aOR 1.02, 95% CI 0.61-1.70; P = 0.955). Similarly, teenage and young adult cancer survivors were more likely to father through ICSI treatment (aOR 6.84, 95% CI 5.64-8.30; P < 0.001) but not using IVF (aOR 1.27, 95% CI 0.90-1.80; P = 0.17). However, adult cancer survivors were more likely to conceive through either ICSI (aOR 5.52, 95% CI 4.86-6.27; P < 0.001) or IVF treatment (aOR 1.32, 95% CI 1.09-1.60; P = 0.004). In subgroup analyses, childhood survivors of testicular cancer (aOR 5.15, 95% CI 1.20-22.0; P = 0.027), soft tissue and bone cancers (aOR 4.70, 2.13-10.4; P < 0.001), hematological and lymphatic cancers (aOR 4.49, 95% CI 2.72-7.40; P < 0.001), or central nervous system (CNS) and eye cancers (aOR 2.64, 95% CI 1.23-5.67; P = 0.012), were at an increased likelihood of fathering through ICSI. Teenage and young adult survivors of testicular cancer (aOR 15.4, 95% CI 11.5-20.7; P < 0.001), hematological and lymphatic cancers (aOR 9.84, 95% CI 6.93-14.0; P < 0.001), or soft tissue and bone cancers (aOR 6.83, 95% CI 3.53-13.2; P < 0.001) were more likely to father through ICSI treatment. Adult survivors of prostate cancer (aOR 15.7, 95% CI 6.70-36.9; P < 0.001), testicular cancer (aOR 9.54, 95% CI 7.81-11.7; P < 0.001), hematological and lymphatic cancers (aOR 11.3, 95% CI 8.63-14.9; P < 0.001), digestive, respiratory, and urogenital tract cancers (aOR 2.62, 95% CI 1.75-3.92; P < 0.001), CNS and eye cancers (aOR 2.74, 95% CI 1.48-5.08; P = 0.001), or skin cancer (aOR 1.68, 95% CI 1.08-2.62; P = 0.022) were more likely to father through ICSI treatment. Only teenage and young adult survivors of hematological and lymphatic cancers (aOR 1.98, 95% CI 1.10-3.56; P = 0.022) and adult survivors of testicular cancer (aOR 1.88, 95% CI 1.37-2.58; P < 0.001) were significantly more likely to achieve fatherhood using IVF treatment. Information on men failing to father children was not available, and thus our results cannot estimate the risk of infertility in men with a history of cancer. Use of ART, in particular ICSI, was significantly more frequent in fathers with malignancies of the male reproductive tract or hematological and lymphatic systems. Our findings highlight which groups of male cancer survivors would benefit from access to fertility care, thereby improving future fertility treatment policies. The study received funding from the Swedish Cancer Society, Swedish Childhood Cancer Society, and the Swedish Government Fund for Clinical Research. There are no competing interest. N/A.

Proteomic Portrait of Human Lymphoma Reveals Protein Molecular Fingerprint of Disease Specific Subtypes and Progression.

The online version contains supplementary material available at 10.1007/s43657-022-00075-w.

Incidence, mortality, risk factors, and trends for Hodgkin lymphoma: a global data analysis

BackgroundHodgkin lymphoma is a lymphatic malignancy commonly found in cervical lymph nodes. This study evaluated the worldwide incidence, mortality, associated risk factors, and temporal trends of Hodgkin lymphoma by sex, age, and country.MethodsThe age-standardised Hodgkin lymphoma incidence and mortality were retrieved from the GLOBOCAN, CI5 volumes I-XI, WHO mortality database, the NORDCAN and SEER Program. The age-standardised prevalence of smoking, alcohol drinking, obesity, and hypertension was also extracted for each country. Trends were tested using Average Annual Percentage Change (AAPC) from Joinpoint regression analysis.ResultsThe Hodgkin lymphoma incidence and mortality were 0.98 and 0.26 per 100,000 in 2020. A higher incidence was observed in high-income countries, while higher mortality was found in low-income countries. Incidence and mortality were associated with GDP per capita, prevalence of smoking, obesity, and hypertension at the population level. Despite the decreasing mortality trend, there was an increasing incidence, especially among females, younger population, and subjects from Asian countries.ConclusionsThere was an increasing trend in Hodgkin lymphoma incidence, especially among subjects who were female, younger population, and from Asian countries. Further studies are needed to investigate the reasons for these epidemiologic trends.

Annals for Educators - March 2022.

Annals for Educators - March 2022.

Comprehensive Analysis of TP53 Mutation Characteristics and Identification of Patients with Inferior Prognosis and Enhanced Immune Escape in Diffuse Large B Cell Lymphoma

Background: Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous lymphatic malignancy from both the clinical and molecular standpoints. TP53 mutations have been observed in DLBCL with high frequency mutations, which play a crucial role in lymphomagenesis. Considering the complex pathophysiological mechanisms involved in DLBCL, we herein assume that the interaction of TP53 with other genetic variants together promote the development of DLBCL. We also explore that these genetic interactions shape the discrepant immune landscape in DLBCL.Methods: We performed a comprehensive analysis of TP53 mutations in the DNA-binding domain (DBD) region. Genome alterations that were mutually exclusive or co-occurring with TP53 mutations were identified, and their potential value in prognosis and possible relationships with tumor microenvironment (TME) were further examined using targeted next-generation sequencing (n=176), transcriptome sequencing (n=152) and circulating tumor DNA sequencing (n=38).Results: TP53 was frequently mutated in DLBCL with a rate of 30% (53 of 176). The occurrence of TP53 mutations was skewed toward the early stages of DLBCL pathogenesis. Among these variants of TP53, 74% were missense mutations, and the remaining were inactivating frameshift indels, nonsense mutations, coding sequencing indels and splicing mutations. Importantly, most mutations (87.5%) occurred in exons 5-8, which encoded the DNA-binding domain (DBD) region of TP53. Codons 175, 273, and 248 of the p53 protein had the highest mutation frequency, which are also the hot spots of TP53 mutation found in most human cancers. However, TP53 alone is insufficient to effectively differentiate the risk of DLBCL, even when only considering mutations in the DBD region. CD58 mutations, which are mutually exclusive from TP53 mutations, in combination with TP53 mutations, could significantly differentiate the prognosis of DLBCL. The survival of patients with either one of the mutually exclusive mutation patterns, namely, TP53MUT&CD58WT or TP53WT&CD58MUT, was inferior to those harboring both wild-type TP53 and CD58. Notably, patients with TP53WT&CD58MUT mutation pattern had the worst outcome and were characterized by a higher overall tumor mutation burden (TMB) and immune score. An enhanced immune escape feature, including the abundant infiltration of inflammatory cells and upregulation of inhibitory immunomodulatory molecules such as PD-1, TIM3, LAG3, KLRC1, KLRC3, KLRD1, IDO1, IDO2 and TDO2, was observed in these patients with TP53WT&CD58MUT mutation pattern. A larger number of terms related to cytokine and chemokine and inflammatory pathways were enriched in the TP53WT&CD58MUT group, including cytokine and chemokine production, binding and activity, and interferon-γ pathway. Additionally, GSEA demonstrated that interferon-α and -γ responses and IL-6/JAK/STAT3 signaling enriched in the TP53WT&CD58MUT group. These patients with TP53WT&CD58MUT mutation pattern represent the candidate populations for immune therapy.Conclusions: Our findings indicated that the mutation patterns of TP53 and CD58 accurately stratified patients with DLBCL to permit the optional immunotherapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical Utility of Flow Cytometry Immunophenotyping and Hematological Profile in Chronic Lymphoproliferative Disorders

Background: Chronic lymphoproliferative disorders (CLPD) are a group of lymphatic malignancies characterized by proliferation of neoplastic mature lymphocytes, and may be sourced B, T and natural killer cells (NK). Flow cytometric (FC) immunophenotyping is a routine practice in the differential diagnosis of these tumors, contributing to greater accuracy and new therapeutic perspectives. Methods: Patients (n = 500) with CLPD were assessed by FC. In addition, we gathered patient information such as age, sex and hematologic data. Results: The results showed that 86.6% of cases were B-cell and 13.4% T/NK CLPD. B-cell CLPD distribution was as follows: 265 B-cell chronic lymphocytic leukemia, 17 B-cell prolymphocytic leukemia, 11 hairy cell leukemia, 3 follicular lymphoma in leukemic phase, 3 splenic lymphoma with villous lymphocytes, 12 mantle cell lymphoma, one Waldenstrong macroglobulinemia, 47 multiple myeloma, 12 plasma cell leukemia, 9 Burkitt lymphoma and 37 B-cell CLPD with non-specific immunoclassification. The T/NK CLPD classifications were as follows: 11 large granular lymphocyte leukemia, 14 T-cell prolymphocytic leukemia, 10 adult T-cell leukemia lymphoma, 8 Sézary syndrome and 24 T-cell peripheral lymphoma. Conclusion: The data suggest that immunophenotyping is an important method in diagnosis, monitoring and prognosis when determining the pathological mechanisms of CLPD evolution. DisclosuresNo relevant conflicts of interest to declare.

Chyloperitoneum as the Initial Manifestation of Gastrointestinal Neoplasia

Chyloperitoneum is defined as the presence of lymph within the peritoneal cavity, resulting from obstruction or injury of lymph ducts, mostly at the level of the gastrointestinal tract. This can occur in the context of congenital diseases, traumas, infections, neoplasms, hepatic disease, heart disease, and postoperative complications. The most common symptoms described are abdominal distention and mild pain in a course of weeks to months, with dyspnea, peritonitis, and in a few cases weight gain is observed due to the high intra-abdominal pressure. We present a case of a 56-year-old male with no significant personal history, who has a clinical picture of approximately three months of evolution, consisting in sensation of an abdominal mass predominantly in the left hemiabdomen, associated with progressive abdominal distension, changes in intestinal habit, lower limb edema, dyspepsia, occasional postprandial emesis, and unintentional weight loss of 20 kg. In non-traumatic conditions, the most frequent cause of chylous ascites is a malignancy disease followed by cirrhosis and mycobacterial infections. Taking into consideration that adenocarcinoma is the most frequently reported histologic subtype of jejunum neoplasm, and that not all cases of lymphoma debut with chylous ascites, it can be concluded that the proportion of patients that present with this condition is exceptionally low. Chyloperitoneum is an infrequent finding, having the higher detection rate in lymphatic alterations and malignancies of gastrointestinal location, in which some of the most commonly neoplasms associated with this complication are lymphoma, neuroendocrine tumors, sarcomas, and leukemia.

Targeting the PI3K/AKT/mTOR Signaling Pathway in Primary Central Nervous System Lymphoma: Current Status and Future Prospects.

Primary Central Nervous System Lymphoma (PCNSL) is a rare invasive extranodal non- Hodgkin lymphoma, a vast majority of which is Diffuse Large B-Cell Lymphoma (DLBCL). Although high-dose methotrexate-based immunochemotherapy achieves a high remission rate, the risk of relapse and related death remains a crucial obstruction to long-term survival. Novel agents for the treatment of lymphatic malignancies have significantly broadened the horizons of therapeutic options for PCNSL. The PI3K/AKT/mTOR signaling pathway is one of the most important pathways for Bcell malignancy growth and survival. Novel therapies that target key components of this pathway have shown antitumor effects in many B-cell malignancies, including DLBCL. This review will discuss the aberrant status of the PI3K/AKT/mTOR signaling pathways in PCNSL and the application prospects of inhibitors in hopes of providing alternative clinical therapeutic strategies and improving prognosis.

Current concepts and future directions for hemato-oncologic diagnostics.

At present, hemato-oncologic diagnostics is facing dynamic changes. This applies to the exploration and introduction of novel technologies such as next-generation sequencing or digital droplet PCR for myeloid and lymphatic malignancies in laboratory routine, or liquid biopsy for patients with lymphoid malignancies. Targeted therapies such as FLT3 or IDH1/IDH2 inhibitors for acute myeloid leukemia are entering clinical practice. Thus, the demand for hematologic precision diagnostics both at initial diagnosis and during the course of the disease are equally increasing, and a short turn-around time becomes crucial. NGS expands the armamentarium for minimal residual disease diagnostics, but novel questions arise relating to sensitivity, the appropriate time points of this analysis, or the thresholds triggering therapeutic interventions. In this review article, we summarize some of the most relevant current changes and subsequent challenges for diagnostics in various myeloid and lymphatic malignancies. Future directions of hemato-oncologic diagnostics in the next 5-10 years are highlighted.

Trial With UniCAR02-T Cells and Cluster of Differentiation (CD)123 Target Module (TM123) in Patients With Hematologic and Lymphatic Malignancies

Trial With UniCAR02-T Cells and Cluster of Differentiation (CD)123 Target Module (TM123) in Patients With Hematologic and Lymphatic Malignancies