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DNA repair plays an essential role in protecting cells that are repeatedly exposed to endogenous or exogenous insults that can induce varying degrees of DNA damage. Any defect in DNA repair mechanisms results in multiple genomic changes that ultimately may result in mutation, tumor growth, and/or cell apoptosis. Furthermore, impaired repair mechanisms can also lead to genomic instability, which can initiate tumorigenesis and development of hematological malignancy. This review discusses recent findings and highlights the importance of DNA repair components and the impact of their aberrations on hematological malignancies.

The inhibition of the DNA damage response (DDR) pathway in the treatment of cancer has recently gained interest, and different DDR inhibitors have been developed. Among them, the most promising ones target the WEE1 kinase family, which has a crucial role in cell cycle regulation and DNA damage identification and repair in both nonmalignant and cancer cells. This review recapitulates and discusses the most recent findings on the biological function of WEE1/PKMYT1 during the cell cycle and in the DNA damage repair, with a focus on their dual role as tumor suppressors in nonmalignant cells and pseudo-oncogenes in cancer cells. We here report the available data on the molecular and functional alterations of WEE1/PKMYT1 kinases in both hematological and solid tumors. Moreover, we summarize the preclinical information on 36 chemo/radiotherapy agents, and in particular their effect on cell cycle checkpoints and on the cellular WEE1/PKMYT1-dependent response. Finally, this review outlines the most important pre-clinical and clinical data available on the efficacy of WEE1/PKMYT1 inhibitors in monotherapy and in combination with chemo/radiotherapy agents or with other selective inhibitors currently used or under evaluation for the treatment of cancer patients.

Neurotoxic treatments (including proteasome inhibitors, immunomodulatory drugs and vinca-alkaloids) are often used in the treatment of hematologic malignancy. Peripheral neuropathy can be part of a paraneoplastic syndrome accompanying the disease but more commonly is a consequence of treatment with neurotoxic therapies, and produces sensory, motor, autonomic nerve dysfunction or a combination, leading to pain, loss of sensation and functional disability. This review provides an update on peripheral neuropathy in hematologic malignancy, including risk factors, mechanisms and treatment options. We examine the clinical features and risk factors for peripheral neuropathy following bortezomib, thalidomide, brentuximab vedotin and vinca alkaloid treatment, as well as related compounds. We review the current data on pharmacogenetic risk factors for the development of toxicity and highlight areas of future research., Competing Interests: Declaration of competing interest Professor Lazarus is a consultant and promotional speaker for Seattle Genetics and Bristol-Myers Squibb and a consultant for Celgene Corporation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction : Cognitive impairment caused by chemotherapies, a condition known as chemobrain, is a possible side effect that affects alertness, learning, memory, and concentration. Areas covered : Chemobrain has been principally investigated as a possible side-effect among cancer patients. However, numerous drugs used to treat hematological malignancies can determine the appearance of chemobrain. In this review, we have examined some commonly used drugs for the treatment of hematological malignancies which are known to have a deleterious action on cognitive functions.Numerous mechanisms have been suggested, comprising the direct neurotoxicity of chemotherapeutic drugs, oxidative stress, genetic predisposition, cytokine-provoked damage, histone modifications, immune alteration, and the action of chemotherapeutic on trophic factors and structural proteins of brain cells. Expert commentary : Cognitive dysfunction provoked by the treatment of hematological diseases is an actual challenge in clinical practice. Actually, there are no totally efficient and innocuous treatments for this syndrome. It is important that further investigations specify the existence of predictors and gravity factors to pre- and post-therapy cognitive change and identify the influence of tumor treatments on the cognitive alterations in long-term, cancer survivors. Moreover, future studies are needed to analyze the interactions between genetic risk, amyloid accumulation, intrinsic brain networks, and chemotherapy.

In many types of solid tumours, the aberrant expression of the cell adhesion molecule N-cadherin is a hallmark of epithelial-to-mesenchymal transition, resulting in the acquisition of an aggressive tumour phenotype. This transition endows tumour cells with the capacity to escape from the confines of the primary tumour and metastasise to secondary sites. In this review, we will discuss how N-cadherin actively promotes the metastatic behaviour of tumour cells, including its involvement in critical signalling pathways which mediate these events. In addition, we will explore the emerging role of N-cadherin in haematological malignancies, including bone marrow homing and microenvironmental protection to anti-cancer agents. Finally, we will discuss the evidence that N-cadherin may be a viable therapeutic target to inhibit cancer metastasis and increase tumour cell sensitivity to existing anti-cancer therapies.

The aim of the study was to examine endothelial function in patients with hematological malignancies treated with high-dose chemotherapy followed by hematopoietic stem cell transplantation. The studies were conducted on 43 consecutive patients qualified for HSCT following high-dose chemotherapy based on the current standards. Then, due to exclusion criteria, a group of 38 patients were chosen for further investigations. Evaluation of endothelial function by means of flow-mediated dilatation (FMD) was conducted in patients with hematological malignancies before HSCT (test A) and after HSCT (test B). Brachial artery diameter (BAD) after occlusion, change in BAD and FMD were significantly lower after HSCT as compared to the results obtained before the transplantation (p < 0.05). The regression analysis indicated that administration of fludarabine and cytarabine, and also higher blood concentrations of creatinine represented risk factors for the impairment of endothelial function expressed as decreased FMD value. In patients with hematopoietic malignancies treated with HSCT, endothelial function assessed by the flow-mediated dilatation was impaired after chemotherapy and stem cell administration.

Translational research is scientific research that helps to make findings from basic science useful for practical applications in the clinic. The successful use of a drug that interferes with the specific molecular pathophysiology of cancer remains the ultimate vision in cancer medicine. Translational research is a multistep process including the discovery of a cytogenetic/molecular aberration as well as the demonstration of its pathophysiological relevance and its druggability by in vitro experiments and in vivo animal models. Information obtained from preclinical research paves the way for clinical trials in which a drug of interest is developed until its clinical application. Modern pathophysiology-oriented anticancer drugs that have been developed by translational research are available for clinical applications since the beginning of this millennium. By using these drugs higher efficacy and lower toxicity could be achieved as compared with previous treatments. In this article, we will present some of the most prominent examples of this translational approach.

Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression implicated in cancer pathogenesis. Inhibitors of HDACs (HDI) are under investigation as novel anti-cancer drugs, which induce histone hyperacetylation. These agents modulate chromatin structure leading to transcriptional changes of a very large number of genes, which affect signaling pathways, inhibit cell cycle progression and angiogenesis, and induce apoptosis in cancer cells. Currently, several HDI are in clinical trials used in monotherapy or in combination with other cytostatics, showing promising anticancer effects. To date, more than 15 HDIs have been found as potential drugs. This paper reviews the molecular mechanisms of HDI action on cancer cells and summarizes clinical trials of the most promising HDIs in the treatment of patients with hematologic malignancies and solid tumors.

Purpose: Brentuximab vedotin (ADCETRIS®), an antibody-drug conjugate, comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). In vitro studies showed that MMAE does not interfere with hERG K+ channels at clinically relevant concentrations. In pivotal phase 2 clinical trials in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, brentuximab vedotin has shown substantial efficacy and an acceptable safety profile. This phase 1 open-label study was designed to evaluate the effect of brentuximab vedotin on the duration of cardiac ventricular repolarization., Methods: Patients with CD30-positive hematologic malignancies were treated with 1.8 mg/kg brentuximab vedotin by intravenous infusion every 3 weeks for up to 16 cycles. The primary endpoint was the change from baseline to Cycle 1 Days 2, 3, and 4 in the duration of ventricular repolarization using Fridericia's corrected QT interval (QTcF)., Results: There was no clinically meaningful change from baseline in the duration of ventricular repolarization as measured by QTcF in the 46 evaluable patients out of 52 total patients treated with brentuximab vedotin. There was no evidence of treatment-emergent cardiac safety abnormalities. Brentuximab vedotin was generally well tolerated with a response rate and an adverse event profile consistent with prior studies., Conclusion: There is no significant prolongation of the QT/QTc interval with brentuximab vedotin in patients with CD30-positive hematologic malignancies.

Guidelines on how to treat cancer patients receiving cytotoxic chemotherapy in the intensive care unit (ICU) are very limited. Recognizing the severity of the patient, their disease may require the need for chemotherapy whether for localized, metastatic, or hematological malignancies. It may be given alone or in combination with other cancer treatments such as radiation, or hormonal therapies. Nevertheless, the toxicities associated with chemotherapy serve as the driving force for managing complications and safe handling in the ICU. Tumor lysis syndrome, nausea and vomiting, pain management, and adverse medication effects requiring antidotes are complications for patients receiving chemotherapy in the ICU. The administration and safe handling of chemotherapy by nursing is emphasized to provide additional safety precautions. A basic understanding of cytotoxic chemotherapy is reviewed for patients requiring therapy in an ICU.

The interaction between anti-apoptotic and pro-apoptotic members of the Bcl-2 family proteins determines life or death for cancer cells. In this context, BH3-only proteins (such as Bim), members of the pro-apoptotic Bcl-2 family proteins, act as key initiators of apoptosis by activating Bax and Bak through liberating them from anti-apoptotic Bcl-2 members. This then leads to the disruption of mitochondrial outer membrane, and eventually promotes proteolytic cascades for cellular dismantling. We here review the growing evidence of how BH3-only proteins are involved in tumorigenesis and in apoptosis induced by anti-cancer agents in hematologic malignancies. A deeper understanding of the roles of BH3-only proteins in cell death regulation may yield crucial insights for the further development of more effective and rational cell killing strategies. Recent developments in the direct therapeutic manipulation of Bcl-2 proteins using BH3-mimicking agents, such as ABT-737 or GX15-070, for hematologic malignancies are also summarized.

Alkylating drugs represent one of the oldest classes of anticancer medicine used in a broad variety of clinical indications. Bendamustine hydrochloride (Ribomustine, Treanda) is a newer alkylating agent which has already been under intensive clinical investigation and has gained emerging interest due to its unique pharmacological properties, particularly in resistant or refractory diseases. This article provides basic information on the molecular mechanisms of action of bendamustine and its pharmacological characteristics and an overview on published clinical trials where bendamustine is analyzed as a single agent as well as in combination therapies for the treatment of solid tumors and hematologic malignancies., (Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.)

A study of antitumor properties of HLDF-6 was carried out in DBA/2 mice with transplantable ascites lympholeukemia P-388 as well as in tumor cell culture. Immunomodulating characteristics were evaluated. Five-fold administration of HLDF-6 peptide to tumor-bearing mice inhibited tumor growth thus extending survival. As a result metabolic activity decreased which was followed by longer survival of lympholeukemia P-388 cells and enhanced cytological effect of peritoneal macrophages on tumor cells of the same strain.

In the last decade rituximab, alemtuzumab, and gemtuzumab ozogamicin (GO) have been used to treat patients with hematologic malignancies. Their efficacy and safety are now well established. Since their preclinical development, many studies have been performed to optimize dose and schedule. Rituximab is usually given at 375 mg/m(2), a dose that shows activity and little toxicity. It is normally administered as single agent or in combination with chemotherapy to induce remission in B-cell neoplasias. Moreover, given its low toxicity and long half-life, rituximab also can be used as maintenance therapy. Alemtuzumab is administered with a schedule of 30 mg, three times per week, after an initial dose escalation in the first week, showing activity against chronic lymphocytic leukemia (B-CLL) and some T-cell neoplasias. GO is administered at a dose of 9 mg/m(2) at 2-week intervals for two doses; it is the first monoclonal antibody approved for the treatment of relapsed or refractory CD33(+) acute myeloid leukemia (AML).

Increased understanding of the cellular mechanisms associated with various malignancies has allowed researchers to develop agents that selectively target the cellular proteins and pathways implicated in the pathogenesis of malignancy. Tipifarnib is a specific and potent farnesyltransferase inhibitor that demonstrates in vivo and in vitro activity against a variety of human cancers. Although tipifarnib was initially thought to target the Ras protein, recent evidence suggests that the presence of ras mutations is not necessary for the antitumor effects of tipifarnib, and that tipifarnib may exert its effects downstream of Ras. The oral administration and favorable toxicity profile of tipifarnib, combined with its activity in a variety of intracellular pathways that have been implicated in the pathogenesis of hematologic malignancies, make it an especially attractive agent for use in patients with acute myeloid leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia (CML), and multiple myeloma. Because hematologic malignancies are likely driven by multiple genetic aberrations, the most effective treatment strategy will likely combine multiple agents with complementary mechanisms of action. Thus, additional studies of combination regimens that incorporate tipifarnib with other antineoplastic agents are crucial. Early results from studies combining tipifarnib with imatinib or etoposide in CML and AML have been promising and warrant further evaluation in larger clinical trials.

Interleukins are mediators of inflammation, immunity and cancer. IL-15 is a cytokine produced by several leukocytes including phagocytes in response to infections and other signals that trigger innate immunity. IL-15 has many homologies to interleukin-2 (IL-2) and like IL-2, stimulates NK cells. This cytokine acts also on memory CD8+ T-cell. IL-15, therefore acts, probably through selective inhibition of tumor promoting molecules, as a new compound for the adjuvant treatment of solid tumors. In this review we propose a newly revised mechanism of interleukin 15 in inflammation and cancer.

The tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion, and metastasis by providing survival signals and a sanctuary site for tumor cells, by secretion of growth factors, pro-angiogenesis factors and direct adhesion molecule interactions. Our knowledge of microenvironment is only now beginning to unfold. In this review, the morphological and molecular characteristics of microenvironment in various hematological malignancies including acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, lymphoma, chronic lymphocytic leukemia, and multiple myeloma are summarized and the molecular mechanisms of microenvironment contributing to leukemogenesis are elucidated. We also aim to discuss the encouraging preclinical and clinical trials for treatment of hematological malignancies by targeting the tumor microenvironment. Further understanding of the signal transduction pathways between tumor cells and microenvironment will lead to the development of novel targeted therapeutic agents and more effective combination of current drugs for fighting hematological malignancies.

Improvements in cancer survival raise infertility issues in young patients suffering from malignancies. The aim of the study is to review current knowledge on the effect of chemotherapy (CT) and radiotherapy (RT) for testis and hematological neoplasms on testicular function. Cisplatin-based regimens for testis neoplasm induce temporary azoospermia; permanent damage can occur with high doses (400-600 mg/m(2)). Alkylating agents are very effective for hematological neoplasm therapy but extremely dangerous to germinal epithelium. Damage can be irreversible. Spermatozoa cannot tolerate irradiation doses higher than 6 Gy. Leydig cells are damaged by doses higher than 15 Gy. A-Spermatogonia have been shown to survive after CT and RT and their recovery for post-treatment graft has been recently developed in animal models. Infertility counselling before treatment in young oncological patients is mandatory. Cryopreservation is the best option for fertility protection.

Background: Overt testosterone deficiency is associated with a reduction in BMD and alteration in body composition. However, there are few data concerning the impact of mild hypogonadism on these parameters., Patients and Method: We have identified a cohort of 36 men aged < 55 years with mild Leydig cell impairment, defined by a raised LH level (LH >/= 8 IU/l) in the presence of a testosterone level in the lower half of the normal range or frankly subnormal (< 20 nmol/l), following treatment with procarbazine-containing chemotherapy regimens or high-dose chemotherapy for haematological malignancy. These men underwent measurements of BMD (measured by dual-energy X-ray absorptiometry (DXA), single energy X-ray absorptiometry (SXA) and quantitative CT (QCT)), body composition (DXA), markers of bone turnover, serum lipids and serum IGF-1. To allow for changes that may be directly attributable to the underlying disease or its treatment, results were compared with those obtained in 14 men who had received the same chemotherapy for the same diseases but had normal LH and testosterone levels (controls)., Results: When data from all 50 men were considered together there were significant reductions in BMD of the lumbar spine both by DXA (Z = - 0.34, P = 0.01) and QCT (Z = - 1.5, P < 0. 0001), at the femoral neck (Z = - 0.52, P < 0.0001) and distal forearm (Z = - 0.21, P = 0.05). Mean femoral neck BMD was significantly lower in patients compared with controls (Z = - 0.68 vs. Z = - 0.11, P = 0.05) and there was a nonsignificant trend towards lower lumbar spine BMD measured by QCT (Z = - 1.64 vs. Z = - 1.10; P = 0.09). In addition, serum testosterone level and testosterone:LH ratio significantly correlated with femoral neck BMD (r = 0.28, P = 0.05 and r = 0.37, P = 0.008, respectively). There were no significant differences in lean body mass, fat mass and percentage fat between the patients and controls. There was, however, a difference in the distribution of body fat with a propensity for the patients to accrue truncal fat, and the serum testosterone level significantly inversely correlated with percentage of truncal fat (r = - 0.29, P = 0.04). There were no significant differences in lipid levels, IGF-1 levels or markers of bone turnover between the patients and controls., Conclusions: These data suggest that mild Leydig cell impairment may have significant effects on bone mineral density and may result in subtle body composition changes, although in men who have received cytotoxic chemotherapy, other factors also contribute to the observed osteopenia. Testosterone replacement may be beneficial in some of these men and this requires further evaluation.

The flt3 ligand (FL) is a growth factor for primitive hematopoietic cells. Serum levels of FL are inversely related to the number and proliferative capacity of early hematopoietic progenitors. We sought to elucidate the molecular mechanism underlying this regulation. Expression of FL was examined in peripheral blood (PB) and bone marrow (BM) cells under normal steady-state hematopoiesis and during transient BM failure induced by chemoradiotherapy in 16 patients with hematological malignancies. Using anti-FL antibodies in Western analysis, flow cytometry, and confocal microscopy, we detected high levels of preformed FL inside but not on the surface of T lymphocytes in steady-state hematopoiesis. Intracellular FL colocalized with giantin and ERGIC-53, indicating that it is stored within and close to the Golgi apparatus. After chemotherapy-induced hematopoietic failure, FL rapidly translocated to the surface of T lymphocytes and the levels of FL released to serum increased approximately 100-fold. Expression of FL mRNA was enhanced only about sevenfold; a similar, twofold to sixfold increase in mRNA was observed in the thymus and BM of mice with irradiation-induced aplasia. Upregulation of FL mRNA was delayed when compared with the appearance of cell surface-associated and soluble protein isoforms. The described changes in FL expression in response to chemotherapy-induced aplasia were observed in all patients, irrespective of the diagnosis and treatment regimen. Our data demonstrate that mobilization of preformed FL from intracellular stores rather than de novo synthesis is responsible for increased FL levels in BM failure.

We studied 45 patients aged 14-66 years who had undergone stem cell transplantation for a variety of malignant conditions at least 12 months previously. Compared to normal controls, they had significantly reduced absolute numbers of CD4+, CD4+ CD45RA+ and CD4+ CD45RO+ T cells and a reduced CD4+ CD45RA+:CD4+ CD45RO+ ratio. In all subsets T-cell numbers were significantly greater 24 months, compared to 12-24 months, after transplantation and there was a nonsignificant trend towards lower T-cell numbers with increasing age. We conclude that the thymus, or putative thymic-equivalent tissue, remains functional in older adults.