Hematologic Malignant Neoplasms Research Articles

MethylationToActivity: a deep-learning framework that reveals promoter activity landscapes from DNA methylomes in individual tumors

Although genome-wide DNA methylomes have demonstrated their clinical value as reliable biomarkers for tumor detection, subtyping, and classification, their direct biological impacts at the individual gene level remain elusive. Here we present MethylationToActivity (M2A), a machine learning framework that uses convolutional neural networks to infer promoter activities based on H3K4me3 and H3K27ac enrichment, from DNA methylation patterns for individual genes. Using publicly available datasets in real-world test scenarios, we demonstrate that M2A is highly accurate and robust in revealing promoter activity landscapes in various pediatric and adult cancers, including both solid and hematologic malignant neoplasms.

Indoleamine 2,3-Dioxygenase Activity Is Increased in Myelodysplastic Syndrome Patients

Tryptophan (TRP) metabolism via the indoleamine 2,3-dioxygenase (IDO) subset of the kynurenine (KYN) pathway is one of the most important mechanisms of immune escape in cancer. TRP is converted into several biologically active KYN metabolites. However, the role of KYN metabolic products and related enzymes has not been clarified in patients with hematological malignant tumors. Here, we examined the serum concentrations of TRP, KYN, and the KYN metabolites kynurenic acid, anthranilic acid, and 3-hydroxyanthranilic acid in 157 patients stratified into five different hematological malignant tumors. KYN was the most abundant product of the TRP metabolic pathway among all five diagnostic categories. Serum KYN was increased in myelodysplastic syndrome (MDS) patients. The KYN/TRP ratio was significantly higher in MDS patients than in acute myeloid leukemia patients. In conclusion, IDO activity is increased in MDS patients, and IDO inhibitors might represent a new therapeutic approach for MDS treatment.

The effects of cytarabine combined with ginsenoside compound K synergistically induce DNA damage in acute myeloid leukemia cells

AML is a kind of hematological malignant tumor that urgently requires different treatment options in order to increase the cure rate and survival rate. Cytarabine (ara-C) is currently the main drug used to treat AML patients and is usually combined with different chemotherapeutic agents. However, due to resistance to ara-C, a new combination is needed to reduce ara-C resistance and improve treatment outcome. As is known to all, ginseng is a traditional Chinese herb; compound K is the principal metabolic product of ginsenoside which also has anti-cancer activity in some cancer cells, while the mechanism is unclear. In our previous study, we found that compound K inhibited AML cell viability and induced apoptosis, and compound K combined with ara-C synergistically induced AML cell proliferation arrest. Thus, we sought to investigate the reason for this by focusing on the mitochondrial dysfunction and DNA damage. In this paper, our results provide a foundation for the clinical evaluation of concomitant administration of compound K and ara-C in order to reduce the resistance to ara-C and improve AML treatment.

Abstract 586: Anti-leukemia activities of selenium nanoparticles embedded in nanotube consisted of triple-helix β-D-glucan

Abstract Background: Acute myeloid leukemia (AML) is a hematological malignant tumor. The common chemotherapy results in various side-effect and drug-resistance for AML, so it is urgent to find a non-toxic natural drug for AML therapy. Herein, for the first time, the Se nanoparticles embedded in nanotube consisted of triple helix β-D-glucan (BFP) exhibit the high anti-leukemia effects. Methods: A triple helix β-(1, 3)-D-glucan (BFP) extracted from the black fungus was self-assembled into nanotube in water, and Se nanoparticles (SeNPs) were wrapped to form stable inclusion complex BFP-Se. The CCK8 assays, lactose dehydrogenase release assays, optofluidics chips and flow cytometry were used to test the anti-leukemia effects of BFP-Se in vitro and in vivo. Results: The SeNPs embedded in the BFP nanotubes exhibited high stability in water, avoiding aggregation and dispersion to out. In vitro, the BFP-Se significantly inhibited the proliferation of AML cell lines and patient cells and markedly increased the cytotoxicity on AML cells. BFP-Se slowed the Molm-13 GFP+ cells growth. On single-cell levels, the U937 cells were gradually swelled and lysed with BFP-Se treatment. In addition, BFP-Se had little toxic to hematopoietic stem cells (HSC) and T cells compared to Ara-c. Flow cytometry indicated that BFP-Se promoted the cell apoptosis and blocked cell cycle of AML cells. Further, after injection of BFP-Se, the survival was longer on AML PDX model constructed with B-NSG mice. The blood and bone marrow analysis indicated the anti-leukemia effects of BFP-Se in vivo. Moreover, BFP-Se extremely increased the total antioxidant capacity (T-AOC) of AML cells, and decreased the expression of c-Jun activation domain-binding protein-1 (Jab1) and thioredoxin 1 (Trx1). Conclusion: This biocompatible polysaccharide nanotube containing Se nanoparticles - against AML would provide a novel strategy for AML therapy. Citation Format: Yanxia Jin, Liqin Cai, Qian Yang, Ziyi Luo, Lina Zhang, Fuling Zhou. Anti-leukemia activities of selenium nanoparticles embedded in nanotube consisted of triple-helix β-D-glucan [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 586.

Clinical Predictors of Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory hematologic malignant neoplasm causes severe neurologic adverse events ranging from encephalopathy and aphasia to cerebral edema and death. The cause of neurotoxicity is incompletely understood, and its unpredictability is a reason for prolonged hospitalization after CAR T-cell infusion. To identify clinical and laboratory parameters predictive of neurotoxicity and to develop a prognostic score associated with its risk. This single-center diagnostic/prognostic accuracy study was conducted at Brigham and Women's Hospital/Dana Farber Cancer Institute from April 2015 to February 2020. A consecutive sample of all patients undergoing CAR T-cell therapy with axicabtagene ciloleucel for relapsed or refractory lymphoma were assessed for inclusion (n = 213). Patients who had previously received CAR T cells or who were treated for mantle cell lymphoma were excluded (n = 9). Patients were followed up for a minimum of 30 days from the date of CAR T-cell infusion. The primary outcomes were measures of performance (accuracy, sensitivity, specificity, area under the curve) of a diagnostic tool to predict the occurrence of CAR-associated neurotoxicity, as graded by the Common Terminology Criteria for Adverse Events criteria. Two hundred four patients (127 men [62.2%]; mean [SD] age, 60.0 [12.1] years) were included in the analysis, of which 126 (61.8%) comprised a derivation cohort and 78 (38.2%), an internal validation cohort. Seventy-three patients (57.9%) in the derivation cohort and 45 patients (57.7%) in the validation cohort experienced neurotoxicity. Clinical and laboratory values obtained early in admission were used to develop a multivariable score that can predict the subsequent development of neurotoxicity; when tested on an internal validation cohort, this score had an area under the curve of 74%, an accuracy of 77%, a sensitivity of 82%, and a specificity of 70% (positive:negative likelihood ratio, 2.71:0.26). The score developed in this study may help predict which patients are likely to experience CAR T-cell-associated neurotoxicity. The score can be used for triaging and resource allocation and may allow a large proportion of patients to be discharged from the hospital early.

Killing Effect of A CD7 Chimeric Antigen Receptor-Modified NK-92MI Cell Line on CD7-Positive Hematological Malignant Cells

To investigate the killing effect of NK-92MI cells modified by chimeric antigen receptor (CD7-CAR) and specifically targeting CD7 to CD7+ hematological malignant cells. Three types of hematological malignant tumor cells, including 5 cases of CD7+ acute T-lymphoblastic leukemia (T-ALL), 10 cases of acute myeloid leukemia (AML) and 6 cases of T-cell lymphoma were collected, centrifuged, cultured and used to detect the expression levels of tumor cell surface targets; 7-AAD, CD56-APC, CD3-FITC, IgG Fc-PE flow cytometry were used to detected the transfection efficiency of NK-92MI and CD7-CAR-NK-92MI cells, killing efficiencies of CD7-CAR-NK-92MI cells to CD7+ hematological tumor cells in vitro were determined by flow cytometry using PE Annexin V Apoptosis Detection Kit. Secretion differences of NK-92MI and CD7-CAR-NK-92MI cytokines interleukin (IL)-2, interferon (IFN)-γ, and granzyme B detection were estimated by using CBA kit. The killing efficiencies of CD7-CAR-modified NK-92MI cells to CD7+ T-ALL, AML, T-cell lymphoma tumor cells were significantly higher than those of NK-92MI cells without genetical modification. The difference showed statistically significant (P＜0.05). The level of IFN-γ and granzyme B were significantly increased among cytokines secreted by CD7-CAR-modified NK-92MI cells as compared with those of NK-92MI cells without genetical modification (P＜0.05) . CD7-CAR-modified NK-92MI cells have significantly improved killing efficiency against CD7+ T-ALL, AML and T lymphoma cells, and shows specific targeting effects, which provides a clinical basis for the treatment of CD7+ hematological malignancies.

Autophagy in Hematological Malignancies: Molecular Aspects in Leukemia and Lymphoma.

The organization of the hematopoietic system is dependent on hematopoietic stem cells (HSCs) that are capable of self-renewal and multilineage differentiation to produce different blood cell lines. Autophagy has a central role in energy production and metabolism of the cells during starvation, cellular stress adaption, and removing mechanisms for aged or damaged organelles. The role and importance of autophagy pathways are becoming increasingly recognized in the literature because these pathways can be useful in organizing intracellular circulation, molecular complexes, and organelles to meet the needs of various hematopoietic cells. There is supporting evidence in the literature that autophagy plays an emerging role in the regulation of normal cells and that it also has important features in malignant hematopoiesis. Understanding the molecular details of the autophagy pathway can provide novel methods for more effective treatment of patients with leukemia. Overall, our review will emphasize the role of autophagy and its different aspects in hematological malignant neoplasms.

The dynamics of morbidity and mortality of malignant neoplasms of blood system а population of St. Petersburg

The morbidity of hematologic malignant neoplasms increases all over the world, while mortality rate decreases slowly that causes significant economic losses in society due to blood system tumors. It also proves relevance of research of morbidity and mortality of these diseases both in the Russian Federation and certain regions. The goal of the research was to analyze dynamics of indicators of primary morbidity and mortality of hematologic malignant neoplasms among residents of St. Petersburg in 1990-2017. the study was based on Federal statistical accounting forms and official state statistics. It was established that in 2017 St. Petersburg took the 2nd place among all territories of the Russian Federation in terms of primary morbidity and mortality of hematologic malignant neoplasms. Morbidity and mortality rates of males was higher than in females. The highest morbidity rates were established in the age group of 70-79 years. The same group also had the highest mortality rates. Over the research period, the incidence rate increased by 78.2%. The maximum increase in the incidence rate was registered for the group of active able-bodied age. The mortality rates decreased by 43.4%. The results of the research demonstrated that the need for oncologic hematological medical care will increase in case that actual tendencies of mobility and mortality continue. It proves that this type of medical care is be made more available to population through its active development. Also, comprehensive disease prevention program must be developed.

Immunotherapy in Pediatric Hematologic Malignant Neoplasms

Immunotherapy in Pediatric Hematologic Malignant Neoplasms

Association of a Lay Health Worker Intervention With Symptom Burden, Survival, Health Care Use, and Total Costs Among Medicare Enrollees With Cancer

Undertreated patient symptoms require approaches that improve symptom burden. To determine the association of a lay health worker-led symptom screening and referral intervention with symptom burden, survival, health care use, and total costs among Medicare Advantage enrollees with a new diagnosis of solid or hematologic malignant neoplasms. This quality improvement study conducted at 9 community oncology practices from November 1, 2016, to October 31, 2018, compared newly diagnosed Medicare Advantage enrollees with solid or hematologic malignant neoplasms with patients diagnosed and treated 1 year prior. Analysis was conducted from August 1, 2019, to January 11, 2020. Usual care augmented by a lay health worker trained to screen symptoms and refer patients to palliative care and behavioral medicine. The primary outcome was change in symptoms using the Edmonton Symptom Assessment Scale and the 9-item Patient Health Questionnaire at baseline and 6 and 12 months after enrollment. Secondary outcomes were between-group comparison of survival, 12-month health care use, and costs. Among 425 patients in the intervention group and 407 patients in the control group, the mean (SD) age was 78.8 (8.3) years, 345 (41.5%) were female, and 407 (48.9%) were non-Hispanic white. Patients in the intervention group experienced a lower symptom burden as measured by the Edmonton Symptom Assessment Scale score over time compared with patients in the control group (mean [SD] difference, -1.9 [14.2]; 95% CI, -3.77 to -0.19; P = .01 for the intervention group and 2.32 [17.7]; 95% CI, 0.47 to 4.19; P = .02 for the control group). Similar findings were noted in 9-item Patient Health Questionnaire depression scores (mean [SD] difference, -0.63 [3.99]; 95% CI, -1.23 to -0.028; P = .04 for the intervention group and 1.67 [5.49]; 95% CI, 0.95 to 2.37; P = .01 for the control group). Patients in the intervention group compared with patients in the control group had fewer mean (SD) inpatient visits (0.54 [0.77]; 95% CI, 0.47-0.61 vs 0.72 [1.12]; 95% CI, 0.61-0.83; P = .04) and emergency department visits (0.43 [0.76]; 95% CI, 0.36-0.50 vs 0.57 [1.00]; 95% CI, 0.48-0.67; P = .002) per 1000 patients per year and lower total costs (median, $17 869 [interquartile range, $6865-$32 540] vs median, $18 473 [interquartile range, $6415-$37 910]; P = .02). A total of 180 patients in the intervention group and 189 patients in the control group died within 12 months. Among those who died, patients in the intervention group had greater hospice use (125 of 180 [69.4%] vs 79 of 189 [41.8%]; odds ratio, 3.16; 95% CI, 2.13-4.69; P < .001), fewer mean (SD) emergency department and hospital visits (emergency department: 0.10 [0.30]; 95% CI, 0.06-0.14 vs 0.30 [0.46]; 95% CI, 0.24-0.38; P = .001; hospital: 0.27 [0.44]; 95% CI, 0.21-0.34 vs 0.43 [0.82]; 95% CI, 0.32-0.55; P = .02), and lower costs (median, $3602 [interquartile range, $1076-$9436] vs median, $12 726 [interquartile range, $5259-$22 170]; P = .002), but there was no significant difference in inpatient deaths (18 of 180 [10.0%] vs 30 of 189 [15.9%]; P = .14). This study suggests that a lay health worker-led intervention may be one way to improve burdensome and costly care.

The Incidence Trends of Leukemia from 1990 to 2017: Results from the Global Burden of Disease Study

Background: Leukemia is a critical hematological malignant tumor. This article aimed to demonstrate the incidence trends of leukemia and its main subtypes from 1990 to 2017, which would be an important reference to the public health strategy. Methods: The data was obtained from the Global Burden of Disease (GBD) study. The estimated annual percentage changes (EAPCs) was calculated with age-standardized incidence rate (ASIR) to estimate the incidence trends of leukemia from 1990 to 2017 by sexes, age, subtypes, socio-demographic index (SDI) areas and geographic regions. Findings: The global incident cases of leukemia increased 46·27% in absolute number from 1990 by 518·49×10 3 (95% uncertainty interval (UI): 472·24×103 -548·02×103 ) in 2017. The ASIR of leukemia had a decreasing trend (EAPCs = -0·43, 95% confidence interval (CI): -0·64--0·21). The most pronounced decreasing trend of ASIR occurred in chronic myeloid leukemia (CML) (EPACs = -2·40, 95%CI: -2·86--1·93), while the increasing ones occurred in acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). The decreasing incidence trends of leukemia was observed in most of SDI areas and geographic regions had, while East Asia had a pronounced increasing trend, especially in the CLL incidence (EPACs = 5·94, 95%CI: 4·94-6·95). Among 195 countries/territories, CLL had the most significant increase trends of ASIR in Jamaica and China, and their EAPCs were 7·31(95%CI: 4·05-10·07) and 6·54(95%CI: 5·53-7·55), respectively. CML had the largest decrease trends of ASIR in United Kingdom and Hungary, EAPCs were -4·96(95%CI: -6·39--3·50) and -4·48(95%CI: -5·74--3·21), respectively. Interpretation: An optimistic finding was that the leukemia incidence had a decreasing trend in global and most of regions during the period 1990-2017. However, the leukemia burden remained a substantial challenge globally. Funding Statement: The authors stated: None. Declaration of Interests: The authors declared no competing interests. Ethics Approval Statement: Not required.

Extrahepatic malignant neoplasms after liver transplantation: the experience of a single transplant center

Objective: to evaluate the incidence of de novo malignant neoplasms (MN) after liver transplantation (LT) and compare with indicators among the general Russian population. Materials and methods. The study included 182 patients who had at least a 6-month follow-up period after LT and had no extrahepatic malignancies before LT. All data were analyzed retrospectively. Statistical processing of the results was carried out using the Statistica program for Windows v.10. Results. MN incidence was 5.5% (10 of 182 patients). The average period from transplantation to diagnosis of de novo neoplasm was 47.8 months (8 to 144 months). The patients were 3 men and 7 women. Types of de novo tumors included digestive system tumor (2 out of 10), hematologic malignant tumor (3 out of 10), skin cancer – melanoma (1 out of 10), urologic cancer (1 out of 10), gynecological (2 out of 10) and base of tongue cancer (1 out of 10). Five patients (50.0%) died, mortality was higher than in other LT patients (Z = –2.6; p = 0.009). The average follow-up period after detection of neoplasms was 18.8 months. Incidence of malignant neoplasms following LT was 10 times higher than among the general Russian population. No significant differences were found in the incidence of late acute rejection between 10 patients with MN and other 172 patients (Z = 0.18, p = 0.8). Among surviving patients, 2 patients with lymphomas received tacrolimus immunosuppression monotherapy, while 3 had everolimus-based immunosuppression. Conclusion. Incidence of de novo extrahepatic malignancies after LT is significantly higher than in the general population. To reduce the incidence of neoplasms in the future, patients should undergo regular screening, proliferative signal blockers should be prescribed, although their effectiveness requires further research.

Advances in therapeutic application of CRISPR-Cas9.

Clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) is one of the most versatile and efficient gene editing technologies, which is derived from adaptive immune strategies for bacteria and archaea. With the remarkable development of programmable nuclease-based genome engineering these years, CRISPR-Cas9 system has developed quickly in recent 5years and has been widely applied in countless areas, including genome editing, gene function investigation and gene therapy both in vitro and in vivo. In this paper, we briefly introduce the mechanisms of CRISPR-Cas9 tool in genome editing. More importantly, we review the recent therapeutic application of CRISPR-Cas9 in various diseases, including hematologic diseases, infectious diseases and malignant tumor. Finally, we discuss the current challenges and consider thoughtfully what advances are required in order to further develop the therapeutic application of CRISPR-Cas9 in the future.

A 12-steps desensitization protocol for pediatric patients with hypersensitivity to pegylated asparaginase

Asparaginase is a chemotherapeutic used to treat hematologic malignant tumors. Hypersensitivity reactions to native asparaginase (l-asparaginase) are described in up to 60% of patients 1 Rau R.E. Dreyer Z. Choi M.R. et al. Outcome of pediatric patients with acute lymphoblastic leukemia/lymphoblastic lymphoma with hypersensitivity to pegasparaginase treated with PEGylated Erwinia asparaginase, pegcrisantaspase: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2018; 65e26873 Crossref Scopus (42) Google Scholar in whom case switching to alternative forms of asparaginase is recommended: pegylated asparaginase (PEG-asparaginase), a readily available formulation, or Erwinia-asparaginase, 2 van der Sluis I.M. Vrooman L.M. Pieters R. et al. Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica. 2016; 101: 279 Crossref PubMed Scopus (134) Google Scholar which is currently scarce. Although PEG-asparaginase is considered hypoallergenic, up to 25% of patients receiving it have allergic reactions. 3 Burke Michael J. Devidas Meenakshi Maloney Kelly et al. Severe peg-asparaginase hypersensitivity reaction rates (grade ≥3) with intravenous infusion vs. intramuscular injection: analysis of 54,280 doses administered to 16,534 patients on children’s oncology group (COG) clinical trials. Leuk Lymphoma. 2018; 59: 1624-1633 Crossref PubMed Scopus (28) Google Scholar If no additional asparaginase formulations are available, hypersensitivity to PEG-asparaginase is an important cause of drug use discontinuation, which may compromise disease-free survival. 4 Kyonen M. Folatre I. Zolezzi P. et al. Adverse reactions to l-asparaginase in children with acute lymphatic leukemia. Rev Méd Chile. 2006; 134: 1530-1534 PubMed Google Scholar Because of the importance of asparaginase to treat hematologic malignant tumors, desensitization to PEG-asparaginase has been previously attempted, with mixed results. 5 Sahiner U.M. Yavuz S.T. Gökce M. Anaphylactic reaction to polyethylene-glycol conjugated-asparaginase: premedication and desensitization may not be sufficient. Pediatr Int. 2013; 55: 531-533 Crossref PubMed Scopus (21) Google Scholar ,6 Verma A. Chen K. Bender C. Gorney N. Leonard W. Barnette P. PEGylated E. coli asparaginase desensitization: an effective and feasible option for pediatric patients with acute lymphoblastic leukemia who have developed hypersensitivity to pegaspargase in the absence of asparaginase Erwinia chrysanthemi availability. Pediatr Hematol Oncol. 2019; 36: 277-286 Crossref PubMed Scopus (20) Google Scholar

Risk of Hematologic Malignant Neoplasms after Postoperative Treatment of Breast Cancer.

An indirect consequence of the improved long-term survival seen in patients with breast cancer (BC) is the increased risk of hematologic malignant neoplasms (HM). This study aimed to analyze the role of postoperative treatment for BC in the development of subsequent HM. Using the French National Health Data System, we examined the HM risks in patients diagnosed with an incident primary breast cancer between 2007 and 2015, who underwent surgery as first-line treatment for BC. Main outcomes were acute myeloid leukemia (AML), Myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), multiple myeloma (MM), Hodgkin’s lymphoma or non-Hodgkin’s lymphoma (HL/NHL), and acute lymphoblastic leukemia or lymphocytic lymphoma (ALL/LL). Analyses were censored at HM occurrence, death, loss to follow up, or December 2017. The risk of each type of HM was compared according to the initial postoperative treatment of breast cancer. Of a total of 324,056 BC survivors, 15.5% underwent surgery only, 46.7% received radiotherapy after surgery, 4.3% received chemotherapy after surgery, and 33.5% received all three modalities. Overall, 2236 cases of hematologic malignancies occurred. Compared to the surgery alone group, AML was significantly increased after surgery plus radiation (aHR, 1.5; 95% CI, 1.0–2.1), surgery plus chemotherapy (aHR, 2.1; 95% CI, 1.2–3.6) and all modalities (aHR, 3.3; 95% CI, 2.3–4.7). MDS was significantly increased after surgery plus chemotherapy (aHR, 1.7; 95% CI, 1.1–2.5) or after all modalities (aHR, 1.4; 95% CI, 1.1–1.8). HL/NHL were significantly increased only in the radiotherapy and surgery group (aHR, 1.3; 95% CI, 1.0–1.6). A nonsignificant increase of ALL/LL (aHR, 1.8; 95% CI, 0.6–3.5) was noted after chemotherapy and with all three modalities (aHR, 1.4; 95% CI, 0.7–2.8). Our population based study revealed increased risks of various HM associated with postoperative BC treatment. The added benefit of chemotherapy and radiation therapy should take into consideration these long-term complications.

A study of hundred adults cases presenting with normoblastemia

Introduction: Normoblastemia is the presence of nucleated RBCs (nRBCs) in the peripheral blood. It signifies bone marrow damage or stress and potentially serious underlying disease. Various infiltrating & non-infiltrating conditions present with normoblastemia ranging from infections, sepsis, haemorrhage, haemolysis, anemias to leukemias, lymphomas & metastases. Aims and Objectives: 1. To study the distribution of various conditions presenting with normoblastemia in different age groups and sex. 2. To categorize the spectrum of conditions presenting with normoblastemia into non-infiltrating and infiltrating conditions based on the mechanisms involved.Materials and Methods: A total of 100 adult patients presenting with normoblastemia were studied from June 2018 to December 2018. The patient’s medical history, clinical and hematological findings along with the peripheral smear examination to look for the presence of normoblastemia were evaluated. Bone marrow study was done wherever required. Results: A total of 100 adult patients were included. 26% cases were between the age group of 21-30 years, thus constituting the largest group. 52% were males and 48% were females. The spectrum of conditions presenting with normoblastemia were categorized into non-infiltrating and infiltrating cases. Majority of the cases were non-infiltrating (72%) as compared to that of infiltrating cases (28%). The various mechanisms involved in the non-infiltrating conditions were hyposplenism, anemia and compensatory erythropoiesis, hypoxia and other miscellaneous causes. Iron deficiency anemias (23/72) were the highest followed by megaloblastic anemias (22/72) and sepsis (6/72). Among the infiltrating conditions, highest cases were chronic myeloid leukemias (9/28) followed by acute myeloid leukemias (6/28). Conclusion: Normoblastemia offers an invaluable insight into disease processes. Its presence may indicate that a bone marrow examination is necessary to rule out hematologic malignant neoplasms or unsuspected blood disorders. This study emphasizes on the importance of finding even single nRBC that may lead to more timely medical intervention, thus increasing the chance of a positive outcome.

Second solid (SMN) and hematologic malignant neoplasms (HMN) among 24,900 United States testicular cancer survivors (TCS) after chemotherapy (CHEM), radiotherapy (RT), or surgery only (SURG).

11573 Background: No large, population-based U.S. study has comprehensively examined SMN and HMN risks after TC, taking into account initial therapy and focusing on recent decades. Methods: Standardized incidence ratios (SIR) for SMN and HMN stratified by site and time since TC diagnosis were calculated for 24,900 TCS (median age, TC diagnosis: 33 y) reported to population-based cancer registries in the NCI SEER program (1973-2014). TCS were initially given CHEM (n=6,340), RT (n=9,058), or SURG (n=8,995), with each group accruing 80,700, 156,735, and 128,039 person-years (PY) of follow-up, respectively. Results: During 372,709 PY of follow-up, 1,625 TCS developed SMN and 228 developed HMN, including 107 lymphomas, 92 leukemias, and 29 plasma cell dyscrasias. Among all TCS, overall risk of SMN was increased by 1.06-fold (95% CI 1.01-1.1). Risks of SMN were increased after RT (SIR 1.1, 95% CI 1.06-1.2) and CHEM (SIR 1.3, 95% CI 1.1-1.4); but not after SURG (SIR 0.8). After CHEM, significant excesses of SMN of the pancreas (SIR 2.2), soft tissue (SIR 4.0), kidney (SIR 1.7), thyroid (SIR 3.3) occurred; after RT, significantly elevated risks for SMN of the stomach (SIR 1.7), rectum/sigmoid (SIR 1.4), pancreas (SIR 2.7), soft tissue (SIR 2.2), bladder (SIR 1.5), and thyroid (SIR 2.0) were observed. The 30 year cumulative incidence of SMN after SURG, CHEM, and RT was 8.9% (95% CI 7.8-9.9), 10.1% (95% CI 8.8-11.5) and 17.0% (95% CI 15.8-18.2), respectively. Significantly increased risks of leukemia followed CHEM (SIR 2.7) and SURG (SIR 1.8) and were driven by increased risks for acute myeloid leukemia, with significant excesses restricted to 1-10 y and 1-5 y after TC diagnosis, respectively; nonsignificant 2-fold excesses occurred 1-10 y after RT. Risks for lymphoma and plasma cell dyscrasias were not elevated (1.02 and 1.27, respectively). Conclusions: In the largest population-based study of U.S. TCS to date, we report significant 6% excesses of SMN and 2-fold increased risks of leukemias. Efforts to minimize CHEM exposure and decrease doses/field size of RT in TC should continue. TCS should be educated about cancer prevention and screening.

Risk of Head and Neck Cancer in Patients With Prior Hematologic Malignant Tumors

More than 1.3 million people in the United States have a hematologic malignant tumor currently or in remission. Previous studies have demonstrated an increased risk of secondary neoplasms in patients with hematologic malignant tumors, but research specifically on the risk of head and neck solid tumors in patients with prior hematologic malignant tumors is limited. To examine a possible association between prior hematologic malignant tumors and risk of head and neck cancer and to assess the overall survival (OS) among these patients. This retrospective analysis used the Veterans Affairs (VA) Corporate Data Warehouse (CDW) to identify patients with diagnoses of hematologic malignant tumors and head and neck cancers. All patients in the VA CDW with a birthdate between January 1, 1910, and December 31, 1969, were included, for a cohort of 30 939 656 veterans. Data analysis was performed from August 15, 2018, to January 31, 2019. Outpatient problem lists were queried for diagnoses of hematologic malignant tumor and associated malignant tumors using International Classification of Diseases, Ninth Revision (ICD-9) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes to categorize patients by history of hematologic malignant tumors. Presence of head and neck cancer was determined from ICD-9 and ICD-10 codes of outpatient problem lists, and cancers were grouped by subsite. The OS was determined from date of death or last outpatient visit date. Of 30 939 656 patients (27 636 683 [89.3%] male; 13 971 259 [45.2%] white), 207 322 patients had a hematologic malignant tumor, of whom 1353 were later diagnosed with head and neck cancer. A history of hematologic malignant tumors was significantly associated with overall aerodigestive tract cancer, with a relative risk (RR) of 1.6 (95% CI, 1.5-1.7), as well as oral cavity (RR, 1.7; 95% CI, 1.5-1.9), oropharynx (RR, 1.7; 95% CI, 1.5-1.9), larynx (RR, 1.3; 95% CI, 1.2-1.5), nasopharynx (RR, 2.8; 95% CI, 2.1-3.9), sinonasal (RR, 3.0; 95% CI, 2.2-4.1), salivary gland (RR, 2.8; 95% CI, 2.4-3.3), and thyroid (RR, 2.1; 95% CI, 1.9-2.4) tumors on subsite analysis. A prior hematologic malignant tumor was also negatively associated with 2-year and 5-year OS for multiple subsites. A prior diagnosis of hematologic or associated malignant tumors was associated with an increased risk of solid head and neck cancers in a range of subsites. In addition, for several head and neck cancer subsites, patients with prior hematologic malignant tumors had worse 2-year and 5-year OS. These results indicate that a prior hematologic malignant tumor may be an adverse risk factor in the development and progression of head and neck cancer.

CD40L inhibits cell growth of THP-1 cells by suppressing the PI3K/Akt pathway.

IntroductionAcute myeloid leukemia (AML), the hematological malignant tumor with high mortality, is still difficult to treat. CD40L is a type II transmembrane protein, which has been reported to have the potential to inhibit growth of some cancer cells.Materials and methodsIn order to determine the role of CD40L on AML-M5 cell line THP-1, we overexpressed CD40L in the cells using a lentiviral vector system (pHBLV-CMVIE-Zs Green-T2A-puro vector); overexpression was confirmed by the detection of green fluorescent protein and CD40L protein expression.ResultsCellular apoptosis, proliferation, and cycle assays showed that CD40L could promote the apoptosis of, suppress the proliferation of, and stimulate the arrest of the G1/S phase of THP-1 cells. Finally, the protein expression of P53, Bax/Bcl-2, cyclinD1, PCNA, PTEN, and p-Akt illustrated that CD40L may partly influence cell growth of THP-1 cells through those genes, which was confirmed by immunohistochemistry and a PI3K/Akt activator.ConclusionTaken together, CD40L could inhibit cell growth of THP-1 cells through the PI3K/Akt pathway, indicating that the overexpression of CD40L may be a potential target to treat the AML-M5 disease.

Association of Disease Recurrence With Survival Outcomes in Patients With Cutaneous Squamous Cell Carcinoma of the Head and Neck Treated With Multimodality Therapy

ImportanceIt has previously been demonstrated that immunosuppressed patients with cutaneous squamous cell cancer of the head and neck (cSCC-HN) treated with surgery and postoperative radiotherapy have significantly inferior disease-related outcomes compared with immunocompetent patients, but data on outcomes after disease recurrence are limited.ObjectivesTo report survival outcomes in patients with cSCC-HN after disease recurrence after surgery and postoperative radiotherapy and to investigate the association of immune status with disease-related outcomes.Design, Setting, and ParticipantsA multi-institutional study of 205 patients treated at the Cleveland Clinic, Washington University in St Louis, and the University of California, San Francisco, in which patients who underwent surgical resection and postoperative radiotherapy for primary or recurrent stage I to IV (nonmetastatic) cSCC-HN between January 1, 1995, and December 31, 2014, were identified. Patients with any disease recurrence, defined as local, regional, and/or distant failure, were included. Patients were categorized as immunosuppressed if they received a diagnosis of chronic hematologic malignant neoplasm or HIV or AIDS, or were treated with immunosuppressive therapy for organ transplantation 6 months or more before diagnosis. Statistical analysis was conducted from January 1, 1995, to December 31, 2015.Main Outcomes and MeasuresOverall survival calculated using the Kaplan-Meier method and compared using the log-rank test.ResultsOf the 205 patients in the original cohort, 72 patients (63 men and 9 women; median age, 71 years [range, 43-91 years]) developed disease recurrence after surgery and postoperative radiotherapy. Forty patients (55.6%) were immunosuppressed, and 32 patients (44.4%) were immunocompetent. Locoregional recurrence was the most common first pattern of failure for both groups (31 immunosuppressed patients [77.5%]; 21 immunocompetent patients [65.6%]). After any recurrence, 1-year overall survival was 43.2% (95% CI, 30.9%-55.4%), and median survival was 8.4 months. For patients for whom information on salvage treatment was available (n = 45), those not amenable to surgical salvage had significantly poorer median cumulative incidence of survival compared with those who were amenable to surgical salvage (4.7 months; 95% CI, 3.7-7.0 months vs 26.1 months; 95% CI, 6.6 months to not reached; P = .01), regardless of their immune status.Conclusions and RelevanceResults of this study suggest that patients with cSCC-HN who experience disease recurrence after definitive treatment with surgery and postoperative radiotherapy have poor survival, irrespective of immune status. Survival rates are low for patients with recurrent disease that is not amenable to surgical salvage. The low rate of successful salvage underscores the importance of intensifying upfront treatment to prevent recurrence.