Early studies have shown how aberrantly expressed microRNAs are a hallmark of several diseases like cancer. MicroRNA expression profiling was shown to be associated with tumour development, progression and response to therapy, suggesting their possible use as diagnostic, prognostic and predictive biomarkers. Moreover, based on the increasing number of studies demonstrating that microRNAs can function as potential oncogenes or oncosuppressor genes, with the goal to improve disease response and increase cure rates, miRNA-based anticancer therapies have recently been exploited, either alone or in combination with current targeted therapies. The advantage of using microRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. Here, we review our current knowledge about the involvement of microRNAs in cancer, and their potential as diagnostic, prognostic and therapeutic tools.

https://www.embopress.org/doi/pdf/10.1002/emmm.201100209

MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review

Although most lung cancers are a result of smoking, approximately 25% of lung cancer cases worldwide are not attributable to tobacco use, accounting for over 300,000 deaths each year. Striking differences in the epidemiological, clinical and molecular characteristics of lung cancers arising in never smokers versus smokers have been identified, suggesting that they are separate entities. This Review summarizes our current knowledge of this unique and poorly understood disease.

Lung Cancer in Never Smokers - Different Disease

Epidemiology of Lung Cancer : Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Lung cancer is the leading cause of cancer-related death in the world. It is broadly divided into small cell (SCLC, approx. 15% cases) and non-small cell lung cancer (NSCLC, approx. 85% cases). The main histological subtypes of NSCLC are adenocarcinoma and squamous cell carcinoma, with the presence of specific DNA mutations allowing further molecular stratification. If identified at an early stage, surgical resection of NSCLC offers a favourable prognosis, with published case series reporting 5-year survival rates of up to 70% for small, localized tumours (stage I). However, most patients (approx. 75%) have advanced disease at the time of diagnosis (stage III/IV) and despite significant developments in the oncological management of late stage lung cancer over recent years, survival remains poor. In 2014, the UK Office for National Statistics reported that patients diagnosed with distant metastatic disease (stage IV) had a 1-year survival rate of just 15–19% compared with 81–85% for stage I.

https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.170070

Progress and prospects of early detection in lung cancer

The small regulatory RNA microRNA-21 (miR-21) plays a crucial role in a plethora of biological functions and diseases including development, cancer, cardiovascular diseases and inflammation. The gene coding for pri-miR-21 (primary transcript containing miR-21) is located within the intronic region of the TMEM49 gene. Despite pri-miR-21 and TMEM49 are overlapping genes in the same direction of transcription, pri-miR-21 is independently transcribed by its own promoter regions and terminated with its own poly(A) tail. After transcription, primiR- 21 is finally processed into mature miR-21. Expression of miR-21 has been found to be deregulated in almost all types of cancers and therefore was classified as an oncomiR. During recent years, additional roles of miR-21 in cardiovascular and pulmonary diseases, including cardiac and pulmonary fibrosis as well as myocardial infarction have been described. MiR-21 additionally regulates various immunological and developmental processes. Due to the critical functions of its target proteins in various signaling pathways, miR-21 has become an attractive target for genetic and pharmacological modulation in various disease conditions.

Regulation and function of miRNA-21 in health and disease

Adenocarcinoma is the most common type of lung cancer, the leading cause of cancer deaths in the world. Early detection is the key to improve the survival of lung adenocarcinoma patients. We have previously shown that microRNAs (miRNAs) were stably present in sputum and could be applied to diagnosis of lung cancer. The aim of our study was to develop a panel of miRNAs that can be used as highly sensitive and specific sputum markers for early detection of lung adenocarcinoma. Our study contained 3 phases: (i) marker discovery using miRNA profiling on paired normal and tumor lung tissues from 20 patients with lung adenocarcinoma; (ii) marker optimization by real-time reverse transcription-quantitative polymerase chain reaction on sputum of a case-control cohort consisting of 36 cancer patients and 36 health individuals and (iii) validation on an independent set of 64 lung cancer patients and 58 cancer-free subjects. From the surgical tissues, 7 miRNAs with significantly altered expression were identified, of which "4" were overexpressed and "3" were underexpressed in all 20 tumors. On the sputum samples of the case-control cohort, 4 (miR-21, miR-486, miR-375 and miR-200b) of the 7 miRNAs were selected, which in combination produced the best prediction in distinguishing lung adenocarcinoma patients from normal subjects with 80.6% sensitivity and 91.7% specificity. Validation of the marker panel in the independent populations confirmed the sensitivity and specificity that provided a significant improvement over any single one alone. The sputum markers demonstrated the potential of translation to laboratory settings for improving the early detection of lung adenocarcinoma.

/pdf/early-detection-of-lung-adenocarcinoma-in-sputum-by-a-panel-16ue2a6fxd.pdf

Early detection of lung adenocarcinoma in sputum by a panel of microRNA markers

Patients with central nervous system (CNS) lymphomas have a poor prognosis. Chimeric antigen receptor-modified (CAR) T-cells have shown remarkable efficacy for B-cell non-Hodgkin's lymphoma. However, few studies have reported the effects of CAR T-cells in the treatment of CNS lymphoma, and the duration of remission is short. In this study, seven CNS lymphoma patients (six patients with secondary CNS lymphomas and one patient with primary CNS lymphoma) were treated with CD19 or CD20 CAR T-cell therapy, and the clinical efficacy and toxicity profiles were evaluated. All patients responded to CAR T-cell therapy. Four patients achieved complete remission (CR), while three demonstrated partial remission. We also found that either CD19 or CD20 CAR T-cells could be detected in the cerebrospinal fluid of four patients. The median progression-free survival and median overall survival were not assessed. The median duration of CR was 22.4 months. Five patients (5/7) in this cohort received combination therapy (bridging with autologous hematopoietic stem cell transplantation and programmed death-1 inhibitor for maintenance treatment) and three (3/7) received CAR T-cell therapy as soon as possible after the relapse of CNS lymphoma. This could help explain why these patients achieved long-term remission. After a median follow-up of 10.4 months, three patients demonstrated disease progression, and the antigen loss of CD20 was confirmed as the reason for relapse in one patient. The results of this study suggest that CD19 or CD20 CAR T-cells are effective against CNS lymphoma.

CD19 or CD20 CAR T-cell Therapy Demonstrates Durable Antitumor Efficacy in Patients with CNS Lymphoma.

Variant acute promyelocytic leukemia (APL) showed quite different aspects, and the current treatments remained challenged at present. Venetoclax, a selective inhibitor of B-cell lymphoma 2 (BCL-2), is a small molecule that has been studied in several hematologic malignancies as both monotherapy and in combination with other agents. However, there is little of its use in the treatment of APL or variant APL. In this report, we identified THRAP3 as novel RARA fusion in resembling APL, which was resistant to all-trans retinoic acid (ATRA) combined arsenic trioxide (ATO) chemotherapy. Then, the patient was salvaged by low-dose venetoclax and decitabine. The treatment in this case demonstrates the potential ability of venetoclax in variant APL, thus providing a new treatment option for all kinds of APL.

https://www.frontiersin.org/articles/10.3389/fonc.2022.828852/pdf

Clinical Response to Venetoclax and Decitabine in Acute Promyelocytic Leukemia With a Novel RARA-THRAP3 Fusion: A Case Report

Dear Editor, Acute myeloid leukemia (AML) is one of the most common types of leukemia in adult with a rapidly progressive hematological malignancy. The prognosis is poor and treatment options are limited. Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment, but disease recurrence is still the main cause of death after transplantation. Most cases represent recurrence of primary disease due to the growth of residual cells that have not been eradicated through conditioning or graftversus disease effect. Occasionally, relapsing diseases may exhibit phenotypic or cytogenetic characteristics different from those of the primary disease due to lineage switch, in which occurring a loss of lineage defining markers of one lineage and a gain of another defining lineage markers. The most frequent lineages involved include B and myeloid lineages and express markers such as CD19 and CD22 for B lineage and CD13, CD33, CD64, and CD14 for myeloid lineage [1]. In this case, we reported a case of linage switch, which should be an unusual case of a lineage switch from AML to ALL to our knowledge. A 39-year-old man presented to our hospital with fatigue in August 2016. Peripheral blood examination results revealed a white blood cell count (WBC) of 1.7 10/L, hemoglobin level (HB) of 67 g/L, and platelet count (PLT) of 174 10/L. Bone marrow aspiration revealed a hypercellular bone marrow with 76% blasts. The bone marrow (BM) blast population (94.7%) was positive for MPO, CD34, CD19, CD13, CD64 and CD33, but negative for CD10, CD79a, CD22, CD3 by flow cytometry. No fusion gene was detected (Table 1). Cytogenetics studies were normal. CREBBP, ETV6 gene mutations were detected by next-generation DNA sequencing. The patient was diagnosed with acute myeloid leukemia. Initially, he underwent induction chemotherapy with idarubicin, cytarabine, and cladribine (IAC), and achieved complete remission (CR). Then he accepted consolidate chemotherapy with fludarabine and cytarabine (FA). A sibling total hematopoietic stem cell transplantation was then performed (female to male), and bone marrow biopsy done on day 60 showed CR with 99% donor chimerism. Four years later, the patient felt fatigue again. A subsequent bone marrow aspiration performed in February 2021 showed recurrent acute B-Lymphoblastic leukemia compromising 12.5% of total cells. Bone marrow fluid flow cytometry showed that B lymphocytes accounted for 21.9%, CD79a, CD34, CD19, cCD22 and CD10 were positive, MPO, CD3, CD64 and CD14 were negative. Cytogenetic analysis also showed that all cells of 20 analyzed were female karyotype (46, XX[20]). Chimerism studies descend to 63.9% donor cells. CREBBP, IKZF1 gene mutations were detected by next-generation DNA sequencing (Figure 1). A re-induction chemotherapy was administered (idarubicin, vincristine, prednisone), and morphological remission was achieved, while flow cytometry revealed minimal residual disease (MRD) was 1.6%. When considering the recurrence of phenotype, CD81, CD123, CD13, CD33, CD22, CD20, CD10, CD38, CD34, CD19 and CD45 antigen combination for MRD detection. The patient was enrolled in an anti-CD19 CAR-T treatment. The highest level of the allogeneic CAR gene in the peripheral blood was reached on day 7 after the infusion of CAR-T cells with a copy number of 7.95 10 per ug of DNA (Figure 2). Response to treatment Leukemic cells in the bone marrow were undetectable 7 days after the CAR-T cell infusion, and minimal residual disease was also negative by flow cytometry in the bone marrow. Before CAR-T cell infusion, the patient received lymphodepleting chemotherapy for 3 days with Fludarabine 30mg/m/day and Cyclophosphamide 250mg/m/day. Considering the patient for disease recurrence, he

Lineage switch from acute myeloid leukemia to acute lymphoblastic leukemia

Background: Patients with hematologic malignancies have poor immunity, and they are more vulnerable to fungal invasion because of disease characteristics and clinical treatment such as chemotherapy. Mucor infections in hematologic malignancies are rare, but once occurred usually lead to high mortality. In this study, we report two cases of hematologic malignancies complicated with breakthrough mucormycosis (BT-MCR), which were treated with amphotericin B colloidal dispersion (ABCD) combined with or without other antifungal agents. Case Presentation: Case 1 shows a patient with natural killer cell leukemia, type 2 diabetes, and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This patient was admitted to the First Affiliated Hospital of Soochow University because of fever with cough and expectoration for a week. Next-generation sequencing (NGS) of alveolar lavage fluid revealed that the patient was infected with Rhizomucor pusillus and Enterococcus faecalis. This patient was infected with fungi although he had taken voriconazole for prevention. Considering the renal toxicity of amphotericin B deoxycholate, the patient received ABCD via intravenous drip combined with posaconazole via oral administration for Rhizomucor pusillus infection and meropenem via intravenous drip for Enterococcus faecalis infection during 45 days of treatment. The patient was free of complaints in the next 2-month follow-up. Case 2 represents a patient with acute myeloid leukemia. During induction chemotherapy, the patient presented with weakness of the left limbs, and head MRI showed multiple cerebral infarctions (MCI). In addition, he had high fever with right-face swelling and pain, and the NGS of blood revealed that he had Mucor circinelloides and Stenotrophomonas maltophilia infection. ABCD and ceftazidime/avibactam were administered to the patients via intravenous drip. The patient also achieved complete remission after later consolidation chemotherapy and successfully underwent allo-HSCT. Conclusion: ABCD shows great efficiency with or without other antifungal agents in treating hematological malignancies complicated with BT-MCR. Despite its infusion-related adverse effects and nephrotoxicity, ABCD shows great application potential for patients with hematologic malignancies, who are often more susceptible to fatal BT-MCR. Furthermore, more valid data should be collected on the combination therapy (ABCD and posaconazole).

/pdf/breakthrough-mucormycosis-in-two-cases-of-hematological-16lrm8nv.pdf

Jian Zhang

Papers

Early detection of lung adenocarcinoma in sputum by a panel of microRNA markers

CD19 or CD20 CAR T-cell Therapy Demonstrates Durable Antitumor Efficacy in Patients with CNS Lymphoma.

Clinical Response to Venetoclax and Decitabine in Acute Promyelocytic Leukemia With a Novel RARA-THRAP3 Fusion: A Case Report

Lineage switch from acute myeloid leukemia to acute lymphoblastic leukemia

Breakthrough Mucormycosis In Two Cases Of Hematological Malignancies Successfully Treated With Amphotericin B Colloidal Dispersion