Gynecomastia in a Chronic Myeloid Leukemia Patient After Switching from Imatinib to Flumatinib.

Gynecomastia refers to the abnormal enlargement of the male breast caused by the proliferation of the glandular component of the breast, typically due to sexual hormone disturbance. Multiple medications have been linked to the development of gynecomastia with varying incidences. This adverse event has also been associated with TKIs such as imatinib, dasatinib, and rarely nilotinib. However, it is poorly described and regarded as a rare event. Herein, we present the first case of a CML patient who developed gynecomastia after switching from imatinib to flumatinib. The patient is an 82-year-old male. He was diagnosed with CML and initially treated with imatinib. However, the treatment response milestone after three months of imatinib was not achieved. Hence, flumatinib was used to replace imatinib. Unexpectedly, two weeks later, he developed gynecomastia. Gynecomastia usually causes distress to patients, and there are currently no clear mechanisms or management strategies for this condition. Inspired by this case and through a review of the literature, we propose possible mechanisms and management strategies for this rare adverse event associated with TKIs, along with future perspectives. This may assist others in dealing with this issue and stimulate research on it.

Bone marrow necrosis: Facts, controversies, and perspective.

Bone marrow necrosis (BMN) is a clinically and pathologically poorly-defined and readily-overlooked entity. The current facts and guidelines pertaining to this entity are scarce, and there exist controversies. Upon reviewing the literature, we present the facts, analyze these controversies, and discourse on future prospects.

Dexamethasone enhances venetoclax-induced apoptosis in acute myeloid leukemia cells.

Acute myeloid leukemia (AML) therapies have been significantly improved by the development of medicines that can target BCL-2. On the other hand, non-recurrent alterations in oncogenic pathways and gene expression patterns have already been linked to therapeutic resistance to venetoclax therapy. Bone marrow mesenchymal stromal cells (BM-MSCs) support leukemic cells in preventing chemotherapy-induced apoptosis by mitochondrial transfer in leukemic microenvironment. In this study, we investigated the enhancement of the antitumor effect of BCL-2 inhibitor venetoclax by dexamethasone. In particular, dexamethasone had no significant effect on the viability of AML cells, but dexamethasone combined with venetoclax could significantly increase the apoptosis of AML cells induced by venetoclax. When AML cells were co-cultured with BM-MSCs, dexamethasone combined with venetoclax showed additional anti-tumor effect compared to venetoclax alone. Venetoclax increased reactive oxygen species level in co-cultured AML cells, contributed to transfer more mitochondria from BM-MSCs to AML cells and protect AML cells from apoptosis. Dexamethasone combined with venetoclax induced more apoptosis, but dexamethasone reduced the venetoclax-induced reactive oxygen species level in AML cells and reduced the transfer of mitochondria from BM-MSCs to AML cells. This may lead to a diminished protective effect of BM-MSCs on AML cells. Together, our findings indicated that venetoclax in combination with dexamethasone could be a promising therapy in AML.

IgD/FcδR is involved in T-cell acute lymphoblastic leukemia and regulated by IgD-Fc-Ig fusion protein.

T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis as a result of severe immunosuppression and rapid tumor progression with resistance to conventional chemotherapy. Excessive IgD may play a role in T cell activation via IgD Fc receptor (FcδR). Here we aimed to investigate the effects of IgD in T-ALL and demonstrated the potential benefit by targeting IgD/FcδR in T-ALL patients with IgD-Fc-Ig fusion protein. In T-ALL patients' blood samples and cell lines, the level of IgD, the percentage of FcδR expressing cells and the binding affinity were determined by flow cytometry. T cell viability, proliferation and apoptosis were analyzed. A mouse xenograft model was used to evaluate the in vivo effect of IgD-Fc-Ig, an IgD-FcδR blocker. The levels of serum IgD and FcδR were abnormally increased in part of T-ALL patients and IgD could induce over-proliferation and inhibit apoptosis of T-ALL cells in vitro. FcδR was constitutively expressed on T-ALL cells. IgD-Fc-Ig showed similar binding affinity to FcδR and selectively blocked the stimulation effect of IgD on T-ALL cells in vitro. In vivo study exhibited that IgD-Fc-Ig may also have therapeutic benefit. IgD-Fc-Ig administration inhibited human T-ALL growth and extended survival in xenograft T-ALL mice. In conclusion, this work supports the idea of targeting IgD/FcδR in T-ALL patients with excessive IgD. IgD-Fc-Ig fusion protein might be a potential biological drug with high selectivity for T-ALL treatment.

Delayed Diagnosis and Multi-TKI Intolerance: A Case Report of CML Concurrent With COVID-19.

Introduction: The hematological manifestations of corona virus disease 2019 (COVID-19) can confound the diagnosis and therapy of other diseases. In this paper, we firstly reported a case of chronic myeloid leukemia (CML) of delayed diagnosis and intolerance to tyrosine kinase inhibitors (TKIs) concurrent with COVID-19. Case Presentation: A 56-year-old female was diagnosed as COVID-19 with no obvious leukocytosis [white blood cell (WBC), ≤17 × 109/L] or splenomegaly until ablation of the virus. Bone marrow aspiration was conducted to establish the diagnosis of CML. She accepted an adjusted dosage of imatinib initially and had to suspend it after myelosuppression (day 41). After hematopoietic therapy, imatinib was given again (day 62), but she was still non-tolerant, and nilotinib at 150 mg twice a day was prescribed from day 214. At just about 4 weeks later, nilotinib was discontinued due to myelosuppression. Then, it was reduced to 150 mg per day and was re-initiated (day 349), but she was still non-tolerant to it. Similarly, from day 398, flumatinib at 200 mg per day was tried, but she was non-tolerant. Her white blood cell or platelet count fluctuated markedly with poor therapeutic response. Considering that she was relatively tolerant and responsive to imatinib, the medication was re-initiated at 200 mg and reduced to 100 mg per day. Her follow-up revealed stable WBC and PLT counts. The latest BCR-ABL-210/ABL was decreased to 0.68% at about 6 months after imatinib was re-initiated, which means an improved response. Conclusion: The offset effect between CML and SARS-CoV-2 infection was supposed to be the underlying mechanism for the absence of leukocytosis or splenomegaly. The impact of immune network by SARS-CoV-2 preserved and disrupted the patient's response to TKIs despite the virus' ablation. We suggest that a continued elevation of basophils may be a useful indicator for CML concurrent with COVID-19, and individualized treatment with adjusted dosage and suitable type of TKIs should be considered to improve the patient's health outcome.

Case Report: Local Cytokine Release Syndrome in an Acute Lymphoblastic Leukemia Patient After Treatment With Chimeric Antigen Receptor T-Cell Therapy: A Possible Model, Literature Review and Perspective.

Chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable clinical efficacy in treatment of many malignancies especially for B-cell hematologic malignancies. However, the application of CAR-T cells is hampered by potentially adverse events, of which cytokine release syndrome (CRS) is one of the severest and the most studied. Local cytokine-release syndrome (L-CRS) at particular parts of the body has been reported once in a while in B-cell lymphoma or other compartmental tumors. The underlying mechanism of L-CRS is not well understood and the existing reports attempting to illustrate it only involve compartmental tumors, some of which even indicated L-CRS only happens in compartmental tumors. Acute lymphoblastic leukemia (ALL) is systemic and our center treated a B-cell ALL patient who exhibited life threatening dyspnea, L-CRS was under suspicion and the patient was successfully rescued with treatment algorithm of CRS. The case is the firstly reported L-CRS related to systemic malignancies and we tentatively propose a model to illustrate the occurrence and development of L-CRS of systemic malignancies inspired by the case and literature, with emphasis on the new recognition of L-CRS.

Distance-based quantification of miRNA-21 by the coffee-ring effect using paper devices.

Enabled by the coffee-ring effect, a paper-based signal transduce method is employed for catalytic hairpin assembly (CHA) amplification and hybridization chain reaction (HCR) to achieve miRNA quantification. Once the target miRNAs appeared, it was circularly used by CHA to initiate HCR amplification to produce a large number of G-quadruplex, which is combined with hemin to form a hemin/G-quadruplex DNAzyme. The DNAzyme catalyzes a colorimetric reaction to produce colored nanoparticles, which were converted to the end edge of the paper by evaporation-driven flow, forming a visible colored band. Higher concentration of miRNA led to more colored nanoparticles and thus a longer colored band that can simply be measured by a ruler. The results of determination of miRNA in samples demonstrate that the relative standard deviation of the proposed approach is 5.2%, highly sensitive and repeatable, with a working range 1.0 to 1000 pM and a LOD of 0.2 pM. The paper-based analytical device as a novel platform offers a new signal transduce pathway toward the detection of low-abundance biomarkers for diagnosis.Graphical abstract Schematic representation of the principle for quantification of miRNA on paper based on the coffee-ring effect.

Vertical flow assays based on core-shell SERS nanotags for multiplex prostate cancer biomarker detection.

Rapid, simultaneous, and sensitive quantification of multiplex prostate biomarkers plays an important role in early diagnosis, especially for obese men and patients. Herein, a surface-enhanced Raman scattering (SERS)-based vertical flow assay (VFA) is presented for simultaneous detection of multiplex prostate cancer biomarkers, such as prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), and alpha-fetoprotein (AFP) on a single test spot. In practice, Raman dyes (RDs) encoded core-shell SERS nanotags instead of conventional gold colloids used in the colorimetric assay are employed in the sensing membrane of SERS based VFAs for multiplex protein detection. Because of the enhanced Raman signal of the core-shell nanostructure and the high surface area to volume ratio (SVR) of the porous sensing membrane, this proposed biosensor shows a wide linear dynamic range (LDR) with detection limits of 0.37, 0.43, and 0.26 pg mL-1 for PSA, CEA, and AFP, respectively, suggesting that this approach can be a good candidate in point of care testing (POCT) for rapid and sensitive biomarker detection and has a huge potential in multiplex analysis and cancer diagnosis.

Folic Acid-Functionalized Hybrid Photonic Barcodes for Capture and Release of Circulating Tumor Cells.

Recovery of circulating tumor cells (CTCs) from cancer patients by an efficient CTCs capture and release method can greatly increase their application in diagnostics and treatment of cancers. In this paper, we presented a folic acid (FA)-functionalized hybrid photonic barcode for capture and release of CTCs. The hybrid photonic barcodes were formed by two nano-ordered parts, poly(ethylene glycol) diacrylate (PEGDA) inverse opal structure for sustaining integrity and methacrylated gelatin (GelMA) gel filler for conjugating FA molecules to mediate cell capture. The nano-ordered structures of the hybrid photonic barcodes not only increased contact area, but also decreased steric hindrance among FA molecules. Thus, the topographic interaction between the barcodes and CTCs was greatly enhanced. In addition, GelMA gel was soft and extracellular matrix (ECM) alike, which was beneficial to decrease impairment to CTCs during the CTCs-barcode interaction as well as preserving their viability. Demonstrated by four CTCs types, Hela (epithelial tissue, folate receptor positive, FR+), A02 (bone marrow, FR+), Raji (lymphoid tissue, FR+), and A549 (epithelial tissue, folate receptor negative, FR-), FR+ CTCs could be captured efficiently with reliability and specificity. The captured cells could be controllably released with high viability just by quick trypsinization. The whole processes were simple and efficient. These features indicated that the FA-functionalized hybrid photonic barcodes were promising for full recovery of CTCs from cancer patients, which was important for diagnosis and treatment of cancer.

Aptamer-based hydrogel barcodes for the capture and detection of multiple types of pathogenic bacteria.

Rapid and sensitive diagnosing hematological infections based on the separation and detection of pathogenic bacteria in the patient's blood is a significant challenge. To address this, we herein present a new barcodes technology that can simultaneously capture and detect multiple types of pathogenic bacteria from a complex sample. The barcodes are poly (ethylene glycol) (PEG) hydrogel inverse opal particles with characteristic reflection peak codes that remain stable during bacteria capture on their surfaces. As the spherical surface of the particles has ordered porous nanostructure, the barcodes can provide not only more surface area for probe immobilization and reaction, but also a nanopatterned platform for highly efficient bioreactions. In addition, the PEG hydrogel scaffold could decrease the non-specificity adsorption by its anti-adhesive effect, and the decorated aptamer probes in the scaffolds could increase the sensitivity, reliability, and specificity of the bacteria capture and detection. Moreover, the tagged magnetic nanoparticles in the PEG scaffold could impart the barcodes with controllable movement under magnetic fields, which can be used to significantly increase the reaction speed and simplify the processing of the bioassays. Based on the describe barcodes, it was demonstrated that the bacteria could be captured and identified even at low bacterial concentrations (100 CFU mL-1) within 2.5h, which is effectively shortened in comparison with the "gold standard" in clinic. These features make the barcodes ideal for capturing and detecting multiple bacteria from clinical samples for hematological infection diagnostics.