Spontaneous tumor lysis syndrome in a patient with cholangiocarcinoma

Tumor lysis syndrome (TLS) is a potentially deadly complication of tumors or their treatment. This syndrome consists of a constellation of laboratory parameters such as hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia and clinical complications such as seizures, acute renal insult, cardiac dysrhythmias and death. TLS is especially common in patients with hematological malignancies with rapid cellular turnover rates such as acute lymphocytic leukemia and Burkitt lymphoma, but is very rare in patients with solid tumors. However, it is essential to keep in mind that solid tumors can also lead to TLS. We present a case of a 66-year-old African American male with metastatic cholangiocarcinoma complicated by the development of spontaneous TLS. TLS has never been reported in a patient with cholangiocarcinoma.     

Chimeric Antigen Receptor-Natural Killer Cells: A New Breakthrough in the Treatment of Solid Tumours

Natural killer (NK) cells can quickly and directly eradicate tumour cells without recognising tumour-specific antigens. NK cells also participate in immune surveillance, which arouses great interest in the development of novel cancer therapies. The chimeric antigen receptor (CAR) family is composed of receptor proteins that give immune cells extra capabilities to target specific antigen proteins or enhance their killing effects. CAR-T cell therapy has achieved initial success in haematological tumours, but is prone to adverse reactions, especially with cytokine release syndrome in clinical applications. Currently, CAR-NK cell therapy has been shown to successfully kill haematological tumour cells with allogeneic NK cells in clinical trials without adverse reactions, proving its potential to become an off-the-shelf product with broad clinical application prospects. Meanwhile, clinical trials of CAR-NK cells for solid tumours are currently underway. Here we will focus on the latest advances in CAR-NK cells, including preclinical and clinical trials in solid tumours, the advantages and challenges of CAR-NK cell therapy and new strategies to improve the safety and efficacy of CAR-NK cell therapy.     

The role of JAK/STAT signalling in the pathogenesis,prognosis and treatment of solid tumours

Aberrant activation of intracellular signalling pathways confers malignant properties on cancer cells. Targeting intracellular signalling pathways has been a productive strategy for drug development, with several drugs acting on signalling pathways already in use and more continually being developed. The JAK/STAT signalling pathway provides an example of this paradigm in haematological malignancies, with the identification of JAK2 mutations in myeloproliferative neoplasms leading to the development of specific clinically effective JAK2 inhibitors, such as ruxolitinib. It is now clear that many solid tumours also show activation of JAK/STAT signalling. In this review, we focus on the role of JAK/STAT signalling in solid tumours, examining the molecular mechanisms that cause inappropriate pathway activation and their cellular consequences. We also discuss the degree to which activated JAK/STAT signalling contributes to oncogenesis. Studies showing the effect of activation of JAK/STAT signalling upon prognosis in several tumour types are summarised. Finally, we discuss the prospects for treating solid tumours using strategies targeting JAK/STAT signalling, including what can be learned from haematological malignancies and the extent to which results in solid tumours might be expected to differ.     

Tumour Lysis Syndrome: Implications for Cancer Therapy

The tumour lysis syndrome (TLS) is a group of metabolic abnormalities caused by rapid and unexpected releaseof cellular components into the circulation as a result of massive destruction of rapidly proliferating malignantcells. It usually develops in patients with hematologic malignancies like acute lymphoid leukemia, non-Hodgkinand Burkitt’s lymphoma after initiation of chemotherapy or may, rarely, occur spontaneously. Though TLS isseldom observed in relation to solid tumours, there have been reports of connections with examples such aslung, liver, breast, gastric carcinomas. The clinical manifestations of TLS include hyperuricemia, hyperkalemia,hyperphosphatemia and hypocalcemia. These indications if untreated lead to life-threatening complications suchas acute renal failure, cardiac arrhythmias, seizures, and eventually death due to multiorgan failure. Thereforeearly detection of TLS is of vital importance. This can be accomplished by identification of high risk patients,implementation of suitable prophylactic measures andmonitoring of the electrolyte levels in patients undergoingchemotherapy.     

Maxillary Sinus Squamous Cell Carcinoma Presenting with Fatal Tumor Lysis Syndrome: A Case Report and Review of the Literature

Acute tumor lysis syndrome (TLS) is a condition resulting from rapid destruction of tumor cells and subsequent massive release of cellular breakdown products. It has been described following the treatment of many hematologic and solid malignancies. However, spontaneous TLS has rarely been described. Here we report a case of spontaneous TLS that occurred in a patient with a treated maxillary squamous cell carcinoma (SCC) presenting with diffuse liver metastases, which is an infrequent site of distant metastases.Key Words: Squamous cell carcinoma, Tumor lysis syndrome, Liver metastases, Maxillary sinus     

Clinical and biological effects of demethylating agents on solid tumours – A systematic review

BackgroundIt is assumed that DNA methylation plays a key role in both tumour development and therapy resistance. Demethylating agents have been shown to be effective in the treatment of haematological malignancies. Based on encouraging preclinical results, demethylating agents may also be effective in solid tumours. This systematic review summarizes the evidence of the effect of demethylating agents on clinical response, methylation and the immune system in solid tumours.MethodsWe conducted a systematic literature search from 1949 to December 2016, according to the PRISMA guidelines. Studies which evaluated treatment with azacitidine, decitabine, guadecitabine, hydralazine, procaine, MG98 and/or zebularine in patients with solid tumours were included. Data on clinical response, effects on methylation and immune response were extracted.ResultsFifty-eight studies were included: in 13 studies complete responses (CR) were observed, 35 studies showed partial responses (PR), 47 studies stable disease (SD) and all studies except two showed progressive disease (PD). Effects on global methylation were observed in 11/15 studies and demethylation/re-expression of tumour specific genes was seen in 15/17 studies. No clear correlation between (de)methylation and clinical response was observed. In 14 studies immune-related responses were reported, such as re-expression of cancer-testis antigens and upregulation of interferon genes.ConclusionDemethylating agents are able to improve clinical outcome and alter methylation status in patients with solid tumours. Although beneficial effect has been shown in individual patients, overall response is limited. Further research on biomarker predicting therapy efficacy is indicated, particularly in earlier stage and highly methylated tumours.     

Tumor lysis syndrome following hemi-body irradiation for metastatic breast cancer

Tumor lysis syndrome (TLS) is a rare serious acute complication of cancertherapy, reported mainly following chemotherapy in patients with large tumorload and chemosensitive disease. These are mainly patients with non-Hodgkin'slymphoma, leukemia and rarely in solid tumors. It is less frequently describedafter radiotherapy for lymphoid and hematological malignancies. TLS followingradiotherapy for solid tumors is a very rare complication. In thisreport/review we describe a seventy-three-year-old male patient withprogressive metastatic carcinoma of the breast to the lungs, liver and bone.He was referred for radiotherapy because of generalized bony pains. Thepatient was planned for sequential hemi-body irradiation starting with themore symptomatic upper half body. After premedication, he was given 8.5 Gy tothe mid point at the maximum chest separation with anterior lung attenuatorlimiting uncorrected lung dose to 6.15 Gy. A further 3.5 Gy electron boost tothe fungating breast tumor was given to the 100%.Forty-eight hours after irradiation he developed hyperkalemia,hyperphosphatemia, hyperuricemia, hypocalcemia and renal failure. Theseclinical and biochemical changes are typical of tumor lysis syndrome (TLS).Despite hydration, and treating the hyperuricemia, the patient developed comaand died eight days after irradiation.The prophylaxis and management of TLS and in high-risk patients aredescribed to avoid this frequently fatal complication.     

Tumor lysis syndrome and metastatic melanoma

Tumor lysis syndrome (TLS) is a potential emergent complication of oncologic treatment. TLS is commonly reported in hematological malignancies with rapid cell turnover rates, but is relatively rare in solid tumors. TLS is most frequently a result of cancer treatment in combination with a large tumor burden, but has occasionally been reported to occur spontaneously, especially in cases of advanced or metastatic disease. In this article, we describe the case of a patient with newly diagnosed metastatic melanoma that developed TLS two days after initiation of corticosteroids. In addition, we present a brief literature review of melanoma-associated TLS and review the etiology, diagnosis, and management of TLS.     

The promises and pitfalls of epigenetic therapies in solid tumours

Epigenetic inactivation of tumour suppressor genes, in contrast to gene mutations, can be modulated or reversed by small molecules. This has lead to several recent studies of drugs targeting epigenetic mechanisms as novel cancer therapies. So far, epigenetic therapies, including HDAC inhibitors and demethylating agents, show considerable activity in haematological malignancies, but their value in the treatment of solid tumours remains much more uncertain. This review will discuss some of the challenges that are expected in the treatment of solid tumours with epigenetic therapies and discuss approaches to overcome these obstacles. There is an increasing need for trials driven by pharmacodynamic biomarkers for these agents, which are aimed at finding the optimum biological dose rather than the maximal-tolerated dose, and also investigating their use in combination with cytotoxics – for example as chemosensitisers. Such trials already suggest that improved tumour delivery and specificity, with decreased normal tissue toxicity, will be required to take full advantage of this class of agents in solid tumours.     

Antisense therapy in cancer

This review discusses laboratory and clinical studies of antisense oligodeoxynucleotides as potential treatments for haematological malignancies and solid tumours. Mechanisms of action, pharmacokinetics, toxicities and potential clinical applications of these agents are described.     

实体瘤溶解综合征

肿瘤溶解综合征是血液系统肿瘤治疗中常见的并发症,但在实体瘤中较少见,其发病隐匿,极易误诊、漏诊,预后差.实体瘤溶解综合征典型的临床特征为高尿酸血症、高钾血症、高磷血症和低钙血症,并发症主要为急性肾功能衰竭和心律失常.对高危患者进行预防性干预、早期诊断和积极治疗是改善预后的关键.本文回顾既往文献报道的87例实体瘤溶解综合征,对其发病情况、预防和治疗进行综述.     

Cancer and pregnancy: what should we know about the management with systemic treatment of pregnant women with cancer?

The incidence of cancer during pregnancy is a rare phenomenon and is estimated to occur in 1:1000 pregnancies. This co-existence is likely to rise since the delay of childbearing to the later reproductive age is nowadays more common in families. The most frequent malignancies diagnosed during pregnancy are breast cancer, cervical cancer, haematological malignancies (lymphomas and acute leukaemias) and melanoma. Less common tumours are gastrointestinal, urological and lung cancers [1].     

Ewing tumours and synovial sarcomas have critical features of karyotype evolution in common with epithelial tumours

We have analysed the accumulated cytogenetic data on karyotypic evolution in Ewing tumours (ET) and synovial sarcomas (SS). Both tumour types frequently show balanced translocations, t(11;22) and t(X;18), respectively, that result in specific fusion genes. The analyses revealed +8, +12, +1q, and 16q- as important secondary changes to t(11;22) in ET and the imbalances showed a distinct temporal order. By principal component analysis, one major karyotypic pathway dominated by gains and one minor dominated by losses were identified. The kartyotypic evolution pattern in SS was less distinct. Both ET and SS showed a power law distribution of the number of acquired aberrations, which in both tumour types conformed to a distribution with an exponent equal to 1. Similar distributions are frequently found in epithelial tumours. ET and SS differ in this respect from other malignancies with balanced translocations resulting in fusion genes, which typically show a power law distribution of the number of acquired aberrations with exponents close to 2. This suggests that chromosome changes in ET and SS may develop through mechanisms more similar to those in epithelial tumours lacking recurrent balanced rearrangements than in haematological malignancies characterised by balanced translocations leading to fusion genes.     

Antiviral prophylaxis in patients with haematological malignancies and solid tumours: Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Oncology (DGHO).

Morbidity and mortality in patients with malignancies are increased by viral infections. These mostly are reactivations of asymptomatic latent infections. They primarily concern clinical entities associated with the reactivation of herpes viruses, such as varicella zoster virus (VZV) and cytomegalovirus (CMV). Respiratory tract infections caused by influenza, parainfluenza or respiratory syncytial virus (RSV) are less common. Since reactivation of latent infections has major clinical impact, antiviral prophylaxis is an attractive approach for patients expecting immunosuppression. The main risk factor for clinically relevant reactivation is profound disruption of cellular immune response. Duration and severity of chemotherapy induced neutropenia are of lesser importance. The risk of viral complications rises significantly in the presence of sustained suppression of T-cell function, e.g. in recipients of allogeneic stem cell transplants or of alemtuzumab (Campath-1H) antibody therapy. The objective of this guideline is to review the basis of prophylactic strategies and to provide recommendations for clinicians treating patients with haematological malignancies and solid tumors.     

Cancers associated with Kaposi's sarcoma (KS) in AIDS: a link between KS herpesvirus and immunoblastic lymphoma.

Kaposi's sarcoma (KS), common among persons with acquired immunodeficiency syndrome (AIDS), is caused by KS herpesvirus (KSHV) but whether KSHV causes other malignancies is uncertain. Using linked United States AIDS and cancer registries, we measured the incidence of specific malignancies in persons with AIDS (4-27 months after AIDS onset). We identified associations with KSHV by calculating a relative risk: cancer incidence in persons with KS (all were KSHV-infected) divided by incidence in persons without KS. Using Poisson regression, relative risks were adjusted for human immunodeficiency virus risk group, gender, age, race, and calendar year. We included 189 159 subjects (26 972 with KS). Immunoblastic lymphoma was significantly associated with KS (506 cases; relative risks: unadjusted 2.44, 95%CI 2.00-2.96, adjusted 1.58, 95%CI 1.29-1.93). Only one immunoblastic lymphoma had pleura as primary site. None of 37 other specified malignancies (other non-Hodgkin lymphomas, haematological malignancies, solid tumours) was significantly associated with KS. In summary, the association of immunoblastic lymphoma with KS was specific among examined malignancies and remained significant after statistical adjustment. Our findings, and the previously demonstrated presence of KSHV in the histologically related primary effusion lymphoma, suggest that KSHV is involved in the pathogenesis of some immunoblastic lymphomas.     

The use of bisphosphonates in the management of bone involvement from solid tumours and haematological malignancies – a European survey

Bone metastases in patients with solid tumours (ST) and bone lesions in patients with haematological malignancies (HM) are common. Associated skeletal‐related events (SREs) cause severe pain, reduced quality of life and place a burden on health care resources. Bone‐targeted agents can reduce the risk of SREs. We evaluated the management of bone metastasis/lesions in five European countries (France, Germany, Italy, Spain and the UK) by an observational chart audit. In total, 881 physicians completed brief questionnaires on 17 193 patients during the observation period, and detailed questionnaires for a further 9303 individuals. Patient cases were weighted according to the probability of inclusion. Although a large proportion of patients with bone metastases/lesions were receiving bisphosphonates, many had their treatment stopped (ST, 19%; HM, 36%) or will never be treated (ST, 18%; HM, 13%). The results were generally similar across the countries, although German patients were more likely to have asymptomatic bone lesions detected during routine imaging. In conclusion, many patients who could benefit from bone‐targeted agents do not receive bisphosphonates and many have their treatment stopped when they could benefit from continued treatment. Developing treatment guidelines, educating physicians and increasing the availability of new agents could benefit patients and reduce costs.     

CAR T‐cell immunotherapy: The path from the by‐road to?the freeway?

Chimeric antigen receptors are genetically encoded artificial fusion molecules that can re‐program the specificity of peripheral blood polyclonal T‐cells against a selected cell surface target. Unparallelled clinical efficacy has recently been demonstrated using this approach to treat patients with refractory B‐cell malignancy. However, the approach is technically challenging and can elicit severe toxicity in patients. Moreover, solid tumours have largely proven refractory to this approach. In this review, we describe the important structural features of CARs and how this may influence function. Emerging clinical experience is summarized in both solid tumours and haematological malignancies. Finally, we consider the particular challenges imposed by solid tumours to the successful development of CAR T‐cell immunotherapy, together with a number of innovative strategies that have been developed in an effort to reverse the balance in favour of therapeutic benefit.     

Molecular study of CEPBA in familial hematological malignancies

Familial aggregation in patients with several haematological malignancies has been described, but the genetic basis for this familial clustering is not known. Few genes predisposing to familial haematological malignancies have been identified, among which RUNX1 and CEBPA have been described as predisposing genes to acute myeloid leukemia (AML). Recent studies on RUNX1 suggest that germline mutations in this gene predispose to a larger panel of familial haematological malignancies than AML. In order to strengthen this hypothesis, we have screened CEBPA for germline mutations in several families presenting aggregation of hematological malignancies (including chronic or acute, lymphoid or myeloid leukemias, Hodgkin’s or non Hodgkin’s lymphomas, and myeloproliferative or myelodysplastic syndromes) with or without solid tumours. Although no deleterious mutations were found, we report two novel and rare variants of uncertain significance. In addition, we confirm that the in frame insertion c.1175_1180dup (p.P194_H195dup) is a germline polymorphism.