Non-haematological Malignancies Research Articles

CD6 and Its Interacting Partners: Newcomers to the Block of Cancer Immunotherapies.

Cancer management still requires more potent and safer treatments, of which immunomodulatory receptors on the lymphocyte surface have started to show promise in new cancer immunotherapies (e.g., CTLA-4 and PD-1). CD6 is a signal-transducing transmembrane receptor, mainly expressed by all T cells and some B and NK cell subsets, whose endogenous ligands (CD166/ALCAM, CD318/CDCP-1, Galectins 1 and 3) are overexpressed by malignant cells of different lineages. This places CD6 as a potential target for novel therapies against haematological and non-haematological malignancies. Recent experimental evidence for the role of CD6 in cancer immunotherapies is summarised in this review, dealing with diverse and innovative strategies from the classical use of monoclonal antibodies to soluble recombinant decoys or the adoptive transfer of immune cells engineered with chimeric antigen receptors.

MST1 downregulates TAZ tumor suppressor protein in multiple myeloma and is a potential therapeutic target

We have previously reported that TAZ functions as a tumor suppressor in multiple myeloma. MST1 is a serine-threonine kinase upstream of the Hippo-signaling pathway that functions as a tumor suppressor in many non-haematological malignancies. However, its role in hematological malignancies, including MM is still poorly understood. In this paper, we provide evidence that MST1 expression is higher in MM, and negatively correlates with TAZ expression in both cell lines and patient samples. High MST1 expression was associated with poor clinical outcomes. Genetic or pharmacological inhibition of MST1 leads to increased TAZ expression and cell death. Importantly, MST1 inhibitors sensitizes myeloma cells to frontline antimyeloma agent-lenalidomide and dexamethasone. Taken together, our data reveals a key role for MST1 in MM pathogenesis and provide evidence to explore the therapeutic potential of using MST inhibitors to upregulate TAZ expression in MM to promote response to anticancer agents.

Solid tumours: Building bridges to CAR‐T success

AbstractImmunotherapy using chimeric antigen receptor (CAR)‐engineered T‐cells has achieved remarkable impact in the treatment of selected blood cancers. However, meaningful clinical efficacy against nonhaematological malignancies has largely proven elusive. In this minireview, the main challenges to successful CAR‐based intervention against solid tumours are considered. Obstacles are considered in four categories, namely target selection, trafficking of CAR‐engineered cells to tumour deposits, the need to overcome the physical, chemical and biological hurdles to immune effector function that operate within the tumour microenvironment and selection of the best host cells for CAR engineering. A range of pre‐clinical technologies that have been developed in an effort to overcome these issues are also surveyed. Although clinical progress comes dropping slow, rapid and continued advances in cellular engineering and manufacture, coupled with the emergence of several complementary interventions bodes well for the future success of CAR T‐cell immunotherapy of solid tumours.

Laboratory Evaluation and Pathological Features of Bone Marrow Metastasis in Non-haematological Malignancies.

This study aimed to analyse the diagnostic accuracy of different laboratory parameters that can predict bone marrow metastasis. A cross-sectional analytical study was conducted at the Armed Forces Institute of Pathology (AFIP), Rawalpindi from March 2021 to August 2021. Bone marrow aspirates and biopsy procedures were done on 60 newly diagnosed cases of non-haematological malignancies as part of staging. Laboratory parameters noted for the study included peripheral blood smear findings, serum lactate dehydrogenase (LDH), radiological findings, and bone marrow aspirate/trephine biopsy results. Bone marrow metastasis was seen in 21/60 patients. The most common malignancies with bone marrow involvement were retinoblastoma and neuroblastoma. Laboratory findings showed no significant statistical difference in mean haemoglobin and total leukocyte count between cases and controls. Positive cases had a mean platelet count of 261.7 x 109/L and mean LDH of 750.1 U/L (p <0.05) for both parameters. ROC analysis showed the area under the curve (AUC) for LDH to be 0.969 (highly significant) showing a strong predictive value of LDH. Positive radiological findings were detected in only one case with bone marrow metastasis. The elevated level of serum LDH is not only cost-effective but also has high diagnostic accuracy to predict bone marrow metastasis. Key Words: Bone marrow, Biochemical, Lactate dehydrogenase, Metastasis, Non-haematological malignancies.

Role of bone marrow aspiration and biopsy in evaluation of leucoerythroblastic blood picture

Leucoerythroblastosis was considered as a circulating expression of haematological and non-haematological malignancies. However many benign conditions are also associated with leucoerythroblastosis such as hemolytic anaemia, marked infections and congestive cardiac failure, etc. So the study was performed to determine the various causes of leucoerythroblastic blood picture on bone marrow examination. The current retrospective diagnostic analytical study was performed in the hematology section of post graduate department of pathology over a period of one year. 80 patients with leucoerythroblastic picture on peripheral blood film (PBF), who were subjected to bone marrow aspiration and/or biopsy were included in the study. The findings were documented on a predefined performa and results tabulated.Majority of cases were seen in 21-30 years age group (25%) with male to female ratio of 1.1:1. Non-neoplastic disorders accounted for majority of cases (65%) while neoplastic lesions were seen in 35% cases. Megaloblastic anaemia was the commonest neo-neoplastic etiology while acute leukemia was the commonest neoplastic disorder in the present study.Leucoerythroblastosis represents disordered marrow function and is reflected in PBF. Bone marrow aspiration and biopsy help in establishing early diagnosis and management of the underlying condition.

Can nivolumab alone cure patients with relapse or refractory Hodgkin lymphoma? A 5‐year analysis of the French early access program (EPA)

Can nivolumab alone cure patients with relapse or refractory Hodgkin lymphoma? A 5‐year analysis of the French early access program (EPA)

Avatrombopag for chemotherapy-induced thrombocytopenia in patients with non-haematological malignancies: an international, randomised, double-blind, placebo-controlled, phase 3 trial

Chemotherapy-induced thrombocytopenia is common and causes chemotherapy dose reductions or treatment delays, bleeding, and suboptimal oncological outcomes. We aimed to evaluate avatrombopag, a thrombopoietin receptor agonist that increases platelet counts, in patients with non-haematological cancer and platelet counts lower than 50 ×109 cells per L. In this randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18 years or older at 71 hospitals or cancer treatment centres in China, Hungary, Poland, Russia, Serbia, Ukraine, and the USA and with ovarian, bladder, or lung cancer receiving chemotherapy who had severe thrombocytopenia were randomly assigned (2:1) to oral avatrombopag 60 mg or oral placebo once daily given 5 days before and after chemotherapy, with randomisation stratified by number of chemotherapy drugs used. Patients, investigators, and data collectors were masked to group allocation. Eligibility required two previous lines of chemotherapy or fewer, an ECOG performance status of 2 or less, and no previous history of chemotherapy-induced thrombocytopenia. The composite primary endpoint was the proportion of responders not requiring platelet transfusion or either a 15% or more chemotherapy dose reduction or a 4-day or more chemotherapy delay due to thrombocytopenia following study treatment until the start of the subsequent cycle. Analyses were done on the intention-to-treat and per protocol populations. Safety was analysed in all patients who received at least one dose of avatrombopag. The trial is registered with ClinicalTrials.gov, NCT03471078, and has been completed. Between Oct 12, 2018, and June 28, 2020, 122 patients were enrolled and randomly assigned to receive avatrombopag (n=82) or placebo (n=40). Median follow-up was 31 days (IQR 22-61). Similar proportions of patients reached the primary endpoint in the avatrombopag and placebo groups (intention-to-treat: 57 [70%, 95% CI 58-79] of 82 vs 29 [73%, 95% CI 56-85] of 40; difference -3·0% (95% CI -21·6 to 15·6); p=0·72; per protocol: 51 [85%, 95% CI 73-93] of 60 vs 27 [84%, 95% CI 67-95] of 32; 0·6% (95% CI -20·8 to 22·1); p=0·96). 15 (18%) of 82 patients had serious adverse events in the avatrombopag group and eight (20%) of 40 in the placebo group, of which thrombocytopenia was most common (4 [5%] of 82 and 4 [10%] of 40 patients). Common grade 3-4 treatment-emergent adverse events were neutropenia (22 [27%] of 82 and 16 [40%] of 40 patients), leukopenia (19 [23%] of 82 and 5 [13%] of 40), anaemia (16 [20%] of 82 and 9 [23%] of 40), and thrombocytopenia (16 [20%] of 82 and 14 [35%] of 40). Most adverse events were considered unrelated to study drug. No treatment-related deaths were reported. In this population of patients with non-haematological malignancies who are relatively chemotherapy naive, chemotherapy-induced thrombocytopenia treatment outcomes were similar between the avatrombopag and placebo groups. Given its safety and ability to augment platelet counts in patients with chemotherapy-induced thrombocytopenia, evaluation of avatrombopag in populations with more persistent chemotherapy-induced thrombocytopenia is warranted. Dova Pharmaceuticals, a Sobi company.

Payload Delivery: Engineering Immune Cells to Disrupt the Tumour Microenvironment.

Simple SummaryCell-based therapies composed of genetically engineered immune cells have huge potential for treating cancer. T cells modified to express tumour-targeting receptors have been proven to be highly effective against blood cancers but not solid malignancies. Using innovative genetic modifications, we have the potential to enhance solid tumour targeting by cell-based therapies and fulfil this unmet clinical need. Different genetic engineering approaches have been proposed, each designed to overcome specific hurdles associated with solid tumours. In this review, we discuss the novel ways of engineering immune cells to enhance efficacy against solid tumours, and how this has led to a new era of cell-based therapies, capable of delivering immunotherapeutic payloads that disrupt the immunosuppressive tumour microenvironment and generate concerted anti-tumour immune responses.Although chimeric antigen receptor (CAR) T cells have shown impressive clinical success against haematological malignancies such as B cell lymphoma and acute lymphoblastic leukaemia, their efficacy against non-haematological solid malignancies has been largely disappointing. Solid tumours pose many additional challenges for CAR T cells that have severely blunted their potency, including homing to the sites of disease, survival and persistence within the adverse conditions of the tumour microenvironment, and above all, the highly immunosuppressive nature of the tumour milieu. Gene engineering approaches for generating immune cells capable of overcoming these hurdles remain an unmet therapeutic need and ongoing area of research. Recent advances have involved gene constructs for membrane-bound and/or secretable proteins that provide added effector cell function over and above the benefits of classical CAR-mediated cytotoxicity, rendering immune cells not only as direct cytotoxic effectors against tumours, but also as vessels for payload delivery capable of both modulating the tumour microenvironment and orchestrating innate and adaptive anti-tumour immunity. We discuss here the novel concept of engineered immune cells as vessels for payload delivery into the tumour microenvironment, how these cells are better adapted to overcome the challenges faced in a solid tumour, and importantly, the novel gene engineering approaches required to deliver these more complex polycistronic gene constructs.

Coagulation Profile in Non-Haematological Malignancies

A variety of Coagulation abnormalities have been reported in patients with malignant lesions especially in the form of Thromboembolic phenomena. These can be detected with simple and inexpensive tests and can help prevent complications. The aim of the present study is to evaluate the coagulation profile in patients with non-Haematological malignancies with respect to the changes in Prothrombin Time (PT), activated Partial. Thromboplastin Time (aPTT) and fibrinogen levels to elucidate any prognostic significance of haemostatic abnormalities in non-haematological malignancies. A total of 70 cases of non-haematological malignancies were evaluated for changes in PT, aPTT and fibrinogen levels and compared to the normal control values. Significant higher levels of Fibrinogen levels were observed in patient group values when compared to normal control values.

Indications and diagnostic value of bone marrow examination in HIV-positive individuals: A 3-year review at Tygerberg Hospital.

BackgroundBone marrow examination is a useful diagnostic tool in human immunodeficiency virus (HIV)-positive patients presenting with cytopenias and fever. However, its role in the afebrile and asymptomatic patient presenting with an isolated cytopenia is not well established. This study was conducted to determine the indications for bone marrow examination and its diagnostic yield, in HIV-positive patients at Tygerberg Hospital.MethodsA retrospective, cross-sectional descriptive study was performed over a 3-year period from 01 September 2015 to 31 August 2018. The bone marrow examination reports for the HIV-positive patients who had a bone marrow examination during the study period were retrieved. Clinical and laboratory information was captured.ResultsAltogether 374 bone marrow reports for HIV-positive patients were found. The indication of the bone marrow examination included investigation of unexplained cytopenias, suspected haematological malignancies, follow-up examination for patients with known haematological diseases, staging of haematological or non-haematological malignancies and investigation of suspected disseminated infection. The patients’ median age was 43 years and the interquartile range was 27–60 years. There was a slight female predominance with females 51% and males 49%. The diagnostic yield was 33.7%. Acute leukaemia and lymphoma were the most common diagnoses. Haematinic deficiency and pure red cell aplasia were found in the majority of cases with isolated anaemia. All cases with isolated thrombocytopenia were due to immune thrombocytopenia.ConclusionBone marrow examination is a useful investigation for HIV-positive patients with cytopenias, suspected haematological malignancy and lymphoma staging. However, its early use in patients with isolated anaemia and isolated thrombocytopenia is questionable.

Prevalence of and factors influencing vitamin D deficiency in paediatric patients diagnosed with cancer at northern latitudes.

To investigate the prevalence of vitamin D deficiency among children with non-haematological malignancies and to explore possible causes of low vitamin D levels among these patients. We performed a cross-sectional study of 458 children diagnosed with solid tumours, brain tumours, non-Hodgkin lymphoma or Hodgkin disease at the University Children's Hospital, Uppsala, Sweden. Serum 25-hydroxyvitamin D and parathyroid hormone levels were measured in samples taken at the time of cancer diagnosis and related to clinical data. Vitamin D deficiency was defined as a 25-hydroxyvitamin D level below 50nmol/L. The prevalence rate of vitamin D deficiency among children with non-haematological malignancies was 41%. There was no association between sex or diagnosis and vitamin D status. Vitamin D deficiency was more common among school children than preschool children (51% vs. 24%). Older age, season outside summer, and a more recent calendar year were significant predictors of lower 25-hydroxyvitamin D. There was a significant, albeit weak, negative correlation between 25-hydroxyvitamin D and parathyroid hormone. Vitamin D deficiency is common among children diagnosed with cancer, particularly among school-aged children diagnosed outside summer. The prevalence appears to be increasing, underlining the need for adequate replacement of vitamin D in these patients.

COVID-19 risk for patients undergoing anticancer treatment at the outpatient clinic of the National Cancer Institute of Milan: the COVINT study

BackgroundIn the midst of the COVID-19 pandemic, patients with cancer are regarded as a highly vulnerable population. Overall, those requiring hospital admission for treatment administration are potentially exposed to a...

Immunoistochemical Expression of PD-1 and PD-L1 in Bone Marrow Biopsies of Patients with Acute Myeloid Leukemia

Haematological and non-haematological malignancies are able to escape the host immune by the capacity to hijack the immune check-points [...]

A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965

A 47-year-old man with metastatic melanoma presented with refractory hyperlactaemic acidosis following the first dose of the mono-carboxylase transporter 1 inhibitor AZD3965 within a “first time in man” clinical trial. The mechanism of the agent and the temporal relationship suggested that this event was potentially drug related and recruitment was suspended. However, urinary metabolomics showed extensive abnormalities even prior to drug administration, leading to investigations for an underlying metabolic disorder. The lack of clinical symptoms from the elevated lactate and low blood glucose suggested a diagnosis of “hyper-Warburgism”, where the high tumour burden was associated with extensive glucose uptake and lactate efflux from malignant cells, and the subsequent impact on blood biochemistry. This was supported by an FDG-PET scan showing extensive glucose uptake in numerous metastases and lack of uptake in the brain. A review of the literature showed 16 case reports of “hyper-Warburgism” in non-haematological malignancies, none of them with melanoma, with most associated with a poor outcome. The patient was treated symptomatically, but died 2 months later. The development of AZD3965 continues with the exclusion of patients with elevated plasma lactate at screening added to the protocol as a safety measure.Trial identification number ClinicalTrials.Gov. NCT01791595.

Bone marrow dyspoiesis associated with severe refractory anaemia in liver cirrhosis

Background and aimPeripheral cytopaenias and dyspoiesis are common in cirrhosis; however, the prevalence of dyspoiesis and its contribution in cirrhosis-related cytopaenias has not been studied. We aimed to study the...

Intramarrow injection needle: a new technique to treat patients with haematological and non-haematological malignancies by directly injecting therapeutic agents into the bone marrow cavity

AimsThe purpose of this report is to describe a new instrument designed for the injection of therapeutic agents directly into the bone marrow cavity as well as to aspirate bone...

Comparison of Three Assays for Identification of IDH Mutations in AML

Introduction Isocitrate dehydrogenase (IDH) mutations are present in up to 20% of acute myeloid leukemia (AML) patients and lead to production of 2-hydroxyglutarate which promotes impaired differentiation and leukemic cell proliferation. Currently, there are two FDA-approved IDH inhibitors for the treatment of AML: enasidenib and ivosidenib. It is now imperative to establish timely testing so that patients can take advantage of these new therapies. Here we compared three different genotyping strategies to identify the most reliable and cost-effective way of picking up IDH1 and IDH2 mutations in AML. Methodology We have tested 60 AML patient samples across three different methods for detection of IDH1/2 mutations: (i) Capillary Electrophoresis-Single Strand Conformational Analysis (CE-SSCA) with Sanger sequencing, (ii) Next generation sequencing (NGS) myeloid capture panel (SureSeq myPanel, Oxford Gene Technology, OGT; UK) and (iii) multi-cancer NGS amplicon panel (QIAseq Targeted DNA Panel, Qiagen, Germany). The NGS capture assay is a 26 gene panel designed for myeloid-related genes while the NGS amplicon panel includes 33 genes associated with haematological and non-haematological malignancies (Figure 1). We have compared the techniques and assessed the quality of the results by measuring gene coverage, read depth across the panels, sensitivity and specificity per test, and performed a final valuation including some practical considerations: cost analysis, staff timings, ease of assay operation, turnaround times (TATs), ease of analysis and reporting as well as batch size limits. We initially tested 424 AML cases with CE-SSCA and have successfully transferred to amplicon panel testing (to date 200 cases). Results The results from the initial 60 cases were concordant between both NGS technologies and Sanger sequencing. In total across all 3 assays, we have detected IDH mutations in 19% of the 624 samples tested (Figure 2). Two samples showed false positive results by CE-SSCA, but these were identified by Sanger sequencing; therefore CE-SSCA alone is an inadequate test and all positive samples by CE-SSCA have to be confirmed by Sanger sequencing. Two samples showed IDH1 R132H mutation with variant allele frequency less than 10%, which was detected by all methods, however the Sanger sequencing trace was very small and could potentially have been missed. The gene minimum read depth for capture NGS was 682 and 677 for amplicon, and the gene mean depth was 1571 and 934 reads, respectively. We did not identify any new genetic variants in IDH1/2. The cost of reagents was higher for the NGS capture panel at $235 per patient compared to amplicon based at $86 per patient, with CE-SSCA/Sanger sequencing combined costing $50. The amplicon NGS allows processing of up to 96 samples per batch, allowing for high throughput testing, while capture NGS only allows for 16 samples to be processed. The library preparation time (Figure 1) is shorter for NGS amplicon (2 days; 12 hours staff time) compared to capture (3 days; 17 hours staff time), with both techniques taking longer to set-up when compared to CE-SSCA (2 hours) and Sanger sequencing (1 day; 6 hours staff time). Looking at assay operation, CE-SSCA and Sanger are the less complex assays allowing for laboratory accessibility, whereas although NGS amplicon was relatively straight forward, NGS capture was slightly more complex, lending itself to specialist laboratory setup. When looking at analysis, CE-SSCA was straightforward; however certain patterns that are very similar to positive controls can lead to false positives. Both NGS analysis were very straightforward, taking &lt;5min per sample, while CE-SSCA/Sanger can take up to 10min per sample in more difficult cases. Importantly, NGS-based approaches incorporate other clinically-relevant genes whereas CE-SSCA is limited to IDH1/2 evaluation with additional testing being required for other targets. Conclusion: We have established a multi-cancer NGS amplicon assay for the detection of IDH mutations in AML patients. It reduces test costs for patients, improving testing efficiencies, allowing additional clinically-relevant genes to be analysed in parallel It has also helped streamline testing for different cancer types which can now all follow the same workflow and be automated thus improving TAT's contributing to better patient management. Acknowledgements: Celgene provided funding for this study. Disclosures Taussig: Celgene: Research Funding.

CAR exosomes derived from effector CAR-T cells have potent antitumour effects and low toxicity

Genetically engineered T cells expressing a chimeric antigen receptor (CAR) are rapidly emerging a promising new treatment for haematological and non-haematological malignancies. CAR-T therapy can induce rapid and durable clinical responses but is associated with unique acute toxicities. Moreover, CAR-T cells are vulnerable to immunosuppressive mechanisms. Here, we report that CAR-T cells release extracellular vesicles, mostly in the form of exosomes that carry CAR on their surface. The CAR-containing exosomes express a high level of cytotoxic molecules and inhibit tumour growth. Compared with CAR-T cells, CAR exosomes do not express Programmed cell Death protein 1 (PD1), and their antitumour effect cannot be weakened by recombinant PD-L1 treatment. In a preclinical in vivo model of cytokine release syndrome, the administration of CAR exosomes is relatively safe compared with CAR-T therapy. This study supports the use of exosomes as biomimetic nanovesicles that may be useful in future therapeutic approaches against tumours.

The importance of neprilysin (CD10) in hematooncology

CD10 is an extracellular protein with enzymatic activity. Its substrates are various substances with the properties of signal particles. CD10 also has in itself the propriety of transmitting signals via the membrane, and affecting various intracellular signal transduction pathways, through interaction with numerous protein complexes. CD10 expression is observed in many normal tissues as well as in selected tumors. It is therefore particularly important in histopathological differential diagnosis. The following article presents the structure, location and functions of the CD10. The effect of CD10 expression on the clinical course and prognosis in hematological and non-haematological malignancies is also described.

The role of exosomes in diagnosis of non-haematological malignancies

The role of exosomes in diagnosis of non-haematological malignancies