Is Circulating DNA and Tumor Cells in Myeloma the Way Forward?

Multiple myeloma (MM) is the second deadliest hematological cancer. Despite the enormous innovation on MM treatment in the last decades, still 48% of patients die within 5 years after diagnosis. MM diagnosis and therapeutic strategy mainly rely on direct bone marrow (BM) assessment. Given the MM heterogeneity, BM biopsies do not accurately reflect the whole disease status, hampering accurate disease prognosis. Moreover, biopsies are painful and invasive procedures, highlighting the need for non-invasive and more accurate source of biomarkers. Liquid biopsies are promising sources of biomarkers that may overcome these limitations. Peripheral blood carries circulating myeloma components that are being extensively explored since the last few years as an alternative to BM aspirates. These include circulating tumor cells (CTC), cell-free DNA (cfDNA), and extracellular vesicles containing miRNA and proteins. The current review summarizes scientific evidence establishing BM as a gold standard for the diagnosis, prognosis, and evaluation of minimal residual disease. We discuss the last advances regarding cfDNA and CTC biomarkers from peripheral blood in patients with MM as well as the statistical validations. This paper addresses the technological hurdles associated with liquid biopsies and examines the missing steps for their inclusion into the clinical practice.

A strategic reflection for the management and implementation of CAR-T therapy in Spain: an expert consensus paper

CAR-T cell therapy represents a therapeutic revolution in the prognosis and treatment of patients with certain types of hematological cancer. However, they also pose new challenges in the healthcare, regulatory and financial fields. The aim of the RET-A project was to undertake a strategic reflection on the management of CAR-T therapies within the Spanish National Health System, to agree on recommendations that will help to better deal with the new context introduced by these cell therapies in the present and in the future. This think tank involved 40 key agents and opinion leaders. The experts identified three great challenges for implementing advanced therapies in Spain: therapeutic individualisation, with a multidisciplinary approach; acceleration of access times, by minimizing bureaucracy; and increase in the number of centers qualified to manage the CAR-T therapies in the NHS. The experts agreed on the ideal criteria for designating those qualified centers. They also agreed on a comprehensive CAR-T care pathway with the timings and roles which would ideally be involved in each part of the process.

Quantitative Analysis of SARS-CoV-2 Antibody Status between Patients with Cancer and Healthy Individuals with Extended Vaccination Dosing Intervals in Canada

(1) Background: To date, data addressing the antibody response of cancer patients to SARS-CoV-2 vaccines are limited. To our knowledge, this is the first report to evaluate humoral immunity. responses in Canadian cancer patients. (2) Methods: 116 cancer patients and 35 healthy participants were enrolled in this cross-sectional study. The interval between the first and second doses were closely matched during analysis. IgG antibodies against the SARS-CoV-2 spike receptor–binding domain were determined using an enzyme-linked immunosorbent assay (ELISA). (3) Results: Following two doses of SARS-CoV-2 vaccine (including BNT162b2, AZD1222, and mRNA-1273), the mean serum anti-spike protein antibody level was 382.4 BAU/mL (binding antibody unit, SD ± 9.4) in the control group, 265.8 BAU/mL (±145.7) in solid cancer patients, and 168.2 BAU/mL (±172.9) in hematological cancer patients. Observed differences were significantly lower in both solid and hematological groups when comparing to the control group (p ≤ 0.0001). In solid cancer group, patients with cytotoxic chemotherapy demonstrated significantly lower antibody levels (p < 0.01), whereas the rest of the patients showed similar antibody levels as the healthy control. Antibody levels were lower in those on treatment than those off treatment in patients with hematological malignancies (p < 0.0001) but not for those with solid cancers (p = 0.4553). (4) Conclusions: After two doses of the SARS-CoV-2 vaccination, patients with solid and hematological malignancies demonstrated impaired serological responses. This was particularly prominent if there was cytotoxic chemotherapy or systemic therapy in solid and hematological cancer, respectively.

Evaluation of oral mucositis in pediatric cancer patients in Hiwa Hospital in Sulaymaniyah city, Kurdistan Region, Iraq

Background and objective: Oral mucositis is caused by the destruction of the oral mucosal epithelium and suppression of its growth secondary to antineoplastic treatment in the form of chemotherapeutic drugs, substances, or radiotherapy. This study aimed to evaluate oral mucositis in pediatric cancer patients because it is one of the common side effects of cancer therapy that influences the outcome. Methods: This is a cross-sectional study that enrolled 100 pediatric patients with both hematological and non-hematological cancer. The age of the patients ranged from 1-18 years, involving both genders. Cases admitted to Hiwa hospital were clinically evaluated for oral mucositis, and ethical permission was taken from parents. Risk factors were assessed, including age, sex, cancer type, type of chemotherapy, radiotherapy, number of cycles, complete blood count, interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and tumor necrosis factor-beta. Results: Baseline serum cytokines levels showed significant correlation between Interleukin-6 and intensity of the oral mucositis (P = 0.003, rho = 0.314) and no correlation between severity of oral mucositis with tumor necrosis factor-alpha, tumor necrosis factor-beta nor interleukin-1 beta (P = 0.140 and rho = 0.258, P = 0.463 and rho = -0.079, and P = 0.706 and rho = -0.041, respectively). There was significant relationship between Hemoglobin level, neutropenia and type of non-hematological cancer with the intensity of oral mucositis respectively (P ≤0.001 and rho = -0.352, P = 0.027 and rho = -0.221, and P = 0.035 and rho = 0.095, respectively). Correlation between age, gender, white blood cell count, platelet count, type of hematological malignancy and past history with the intensity of the oral mucositis did not show significant result. Conclusion: Intensity of oral mucositis increased with anemia, neutropenia, high interleukin-6 level, and the type of non-hematological cancer. It is recommended to treat anemic, neutropenic patients as soon as possible before exacerbating the mucositis. Methotrexate is the most aggressive drug alone and in combined chemotherapy agents, which may cause mucositis and needs prophylaxis like topical nystatin suspension or other methods. Keywords: Oral mucositis; Pediatric cancer; Non-hematological; Hematological; Sulaymaniyah.

Genomic Instability and Replicative Stress in Multiple Myeloma: The Final Curtain?

Multiple Myeloma (MM) is a genetically complex and heterogeneous hematological cancer that remains incurable despite the introduction of novel therapies in the clinic. Sadly, despite efforts spanning several decades, genomic analysis has failed to identify shared genetic aberrations that could be targeted in this disease. Seeking alternative strategies, various efforts have attempted to target and exploit non-oncogene addictions of MM cells, including, for example, proteasome inhibitors. The surprising finding that MM cells present rampant genomic instability has ignited concerted efforts to understand its origin and exploit it for therapeutic purposes. A credible hypothesis, supported by several lines of evidence, suggests that at the root of this phenotype there is intense replicative stress. Here, we review the current understanding of the role of replicative stress in eliciting genomic instability in MM and how MM cells rely on a single protein, Ataxia Telangiectasia-mutated and Rad3-related protein, ATR, to control and survive the ensuing, potentially fatal DNA damage. From this perspective, replicative stress per se represents not only an opportunity for MM cells to increase their evolutionary pool by increasing their genomic heterogeneity, but also a vulnerability that could be leveraged for therapeutic purposes to selectively target MM tumor cells.

Respiratory viral infections including caused by coronaviruses in oncological and oncohematological patients

BACKGROUND: Patients with cancer are prone to developing infectious complications. They significantly aggravate the course of the underlying disease and worsen the quality of life of patients. The emergence of infections is largely promoted by immunosuppression associated with the use of cytostatic drugs, high-dose chemotherapy and hematopoietic stem cell transplantation in hematological cancer patients. Among infectious agents, respiratory viruses, especially influenza viruses, play an important role. The urgency of this problem has increased many times in connection with the development of the COVID-19 pandemic. AIM: To study the features of the course of respiratory infections, including coronavirus (seasonal and COVID-19), infections in cancer and oncohematological patients during hospitalization and in outpatient settings. MATERIALS AND METHODS: The study of the frequency and course of infectious complications in cohorts of patients with oncological diseases, who were under dispensary supervision in the polyclinic in Kirovsk, Leningrad region. Retrospective analysis of the frequency and characteristics of the course of coronavirus infection caused by HCoVs (OC43, 229E, NL63, HKU1) in patients treated at the clinics of the Russian research institute of Hematology and Transfusionology. Prospective study of the coronavirus COVID-19 of patients hospitalized at the Russian research institute of Hematology and Transfusionology and at the Kirov interdistrict hospital in Leningrad Region during the period of its conversion to specialized infection diseases hospital. RESULTS: Coronavirus infection caused by HCoVs (OC43, 229E, NL63, HKU1), occurs in hematological cancer patients more often in association with other respiratory viruses. In the cases of detection of the SARS-CoV-2 in hospitalized patients, they need to be transferred to specialized infectious hospitals. CONCLUSIONS: Respiratory viral infections are risk factors in cancer and oncohematological patients. Outpatient oncological and oncohematological patients require constant dispensary observation and special attention during the COVID-19 pandemic, outbreaks of influenza and other viral infections.

Tonsil-Derived Mesenchymal Stem Cells Inhibit the Proliferation of Hematological Cancer Cells through Downregulation of IL-6 Gene Expression under Hyperthermia

Stem cells are extensively being studied as promising biological therapeutic candidates in cancer treatment. In various cancer types, some studies show proliferative effects while others show inhibitory effects of MSCs on tumors. Some studies have reported that MSCs isolated from different sources display different anti-cancer properties. Tonsils are one of the secondary lymphoid organs that form an important part of the immune system and located at the mucosal interface. The relation between secondary lymphoid organs and cancer progression lead us to investigate the effect of tonsil-derived MSCs (T-MSC) on cancer treatment. Therefore, we aimed to determine the anti-tumoral effects of tonsil-derived MSCs cultured at febrile temperature on hematological cancer cell lines. We found that co-culture of K562 cells and MOLT-4 with T-MSCs significantly decreased the viable cell number post 7 days of the culture under the febrile and normal culture conditions. Besides, the T-MSC co-culture not only induced the apoptosis on K562 and MOLT-4 cells but also, induced the cell cycle arrest at G2-M phase on MOLT-4 cells. The apoptotic effect of T-MSC co-culture under febrile stimulation was confirmed by upregulation of Bax, c-myc genes for K562 cells and upregulation of Bax, p53 and c-myc genes for MOLT-4 cells in transcriptional level. Our study has contributed to highlight the effect of the cellular interaction between the T-MSCs and human hematological cancer cells during in vitro co-culture under hyperthermia for tumor progression. In the light of these results, we indicated that tonsil-derived MSCs have promising therapeutic potential for cancer therapy.

Mouthwashes with Plain Water Prevent Oral Mucositis Secondary to Hematopoietic Stem Cell Transplantation in Hematological Cancer Patients: A Retrospective Study

Background Oral mucositis (OM) is a common adverse effect in hematological cancer patients who have received hematopoietic stem cell transplantation (HSCT). In this study, we compared mouthwash with nystatin, aloe vera or plain water in OM prevention.Design A retrospective chart review was conducted in participants. The incidence, severity and duration of OM, duration of oral pain, and the use of antalgesics were recorded.Setting/participants Hematological cancer patients who had received HSCT from January 2014 to December 2020 in West China Hospital were included in this study.Results A total of 150 patients were included in our retrospective analysis. The nystatin group had the highest incidence (100.0%) of OM, followed by the aloe vera group (44.8%), the plain water group had the lowest incidence of OM (20.0%), and the nystatin group had the highest severity and the longest duration of oral mucositis. The incidence, severity and duration of pain in the nystatin group were significantly higher than the aloe vera group and plain water group, and the use of analgesic drugs in the nystatin group was also significantly higher than the other two groups (P<0.05).Conclusions In our hospital setting, plain water mouthwash achieves great effect in OM prevention in hematological cancer patients who have received HSCT.

Efficacy and Safety of Tinzaparin in CAT Patients with Hematological Malignancy

Introduction In patients with hematological cancers, the high risk of bleeding raises serious concerns when anticoagulant therapy is initiated for treatment of acute venous thromboembolism (VTE). In the CATCH trial, we showed that tinzaparin is associated with a significantly lower risk of clinically relevant bleeding (CRB) and clinically relevant non-major bleeding (CRNMB) compared with warfarin therapy in patients with a solid tumor or hematological cancer. Hence, we performed a post-hoc analysis to assess the risk of recurrent VTE (rVTE) and bleeding in the hematological cancer patient subgroup. Risk factors associated with rVTE and bleeding were also explored. Methods CATCH (ClinicalTrials.govNCT01130025; Lee A et al. JAMA 2015) was a Phase III, multinational, randomized, active-controlled, open-label trial. Patients with solid tumors or hematological malignancies were randomized to receive therapeutic dosing of tinzaparin (175 IU/kg OD) vs warfarin (INR target 2.0 - 3.0) for treatment of acute VTE. Treatment was given for up to 6 months but was withheld during periods of severe thrombocytopenia (platelet count &lt; 50 x 10 9/L). The primary efficacy outcome was the composite of symptomatic deep vein thrombosis (DVT), symptomatic nonfatal pulmonary embolism (PE), fatal PE, incidental proximal DVT and incidental proximal PE. All thrombosis and bleeding outcomes, including rPE, rDVT, major bleeding (MB), CRB, and CRNMB were objectively documented and centrally adjudicated in a treatment-blinded fashion. Patients with myeloma, lymphoma or leukemia were included in this sub-group analysis. Treatment effect was assessed by means of a cox-regression with time to first event as outcome and deaths not due to fatal PE as a competing risk factor. The cumulative incidence functions and the corresponding 95% CIs were estimated. Results 94 of 900 subjects (10.4%) in CATCH had a hematological cancer. Of these patients, 44 and 50 received tinzaparin and warfarin, respectively. The most common hematological cancer was lymphoma (59.6%), followed by myeloma (30.9%), chronic leukemia (5.3%) and acute leukemia (4.3%). rVTE occurred in fewer patients assigned to tinzaparin versus warfarin (2.4% vs 6.4%) but this difference was not statistically significant (HR 0.36; 95%CI 0.04-3.14). All recurrent thrombotic events were PE; no rDVT occurred. Also, trends for less bleeding with tinzaparin were noted for MB (tinzaparin 0.0% versus warfarin 5.0%), CRB (tinzaparin 10.4% vs warfarin 23.5%; HR 0.53; 95%CI 0.15-1.83) and CRNMB (tinzaparin 10.4% vs warfarin 19.5%; HR 0.69; 95%CI 0.19-2.51). 3 patients in each treatment arm had a fatal bleeding event and there was no difference in overall mortality (tinzaparin 22.7% vs warfarin 22.0%). There were no risk factors associated with rVTE identified. Factors associated with CRB in patients with hematological cancer included the use of antiplatelet agents (HR 7.63; 95%CI 1.17-49.6; p=0.033) and renal insufficiency (HR 12.4; 95%CI 2.15-72.0; p=0.005). Conclusion In this post-hoc subgroup analysis of patients with hematological cancers who received anticoagulation for acute VTE, tinzaparin may be a more effective and safer alternative to warfarin. Randomized controlled trials are warranted to test this hypothesis in this challenging population with a high risk of bleeding. Figure 1 Figure 1. Disclosures Lee: Leo Pharma: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Bauersachs: Bayer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; LEO Pharma: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Janus: LEO Pharma: Current Employment. Leeder: LEO Pharma: Current Employment. Thoning: LEO Pharma: Current Employment. Khorana: Anthos: Consultancy, Honoraria; Halozyme: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.