Serum CXCL13 level is related to treatment response and predicts disease prognosis in Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a type of B-cell lymphoma that produces IgM. Our study aimed to investigate the role of CXCL13, a chemokine essential for B lymphocytes, in the evaluation of treatment response and prognosis in WM. We collected serum samples and clinical data from 72 WM patients, with 69 patients receiving systemic therapy and 3 patients opting not to receive treatment. Serum CXCL13 levels at baseline and after six months of treatments were measured by enzyme-linked immunosorbent assay. The median serum level of CXCL13 was 1 539.2 pg/ml (range 10.0-21 389.9) at baseline and significantly decreased to 123.1 pg/ml (range 0.0-6 741.5) after 6 months of treatments. At baseline, higher CXCL13 levels were associated with lower hemoglobin levels (p = 0.001), higher ß2-microglobulin levels (p = 0.001), lower albumin levels (p = 0.046), and higher IPSS-WM scores (p = 0.013). After 6 months of treatment, patients who achieved PR/VGPR had significantly lower CXCL13 levels compared to those with SD (70.2 pg/ml vs 798.6 pg/ml, p = 0.002). The median follow-up period was 40 months (range 4.2-188). Eight patients died during the follow-up period. Overall survival differed based on CXCL13 levels. When grouped by baseline CXCL13 levels, the median OS was 60.0 months in patients with serum CXCL13 > 2 000 pg/ml, while it was not reached in patients with low CXCL13 levels (p < 0.001). Based on CXCL13 levels after the treatments, the median OS was 74.0 months in patients with serum CXCL13 > 200 pg/ml, while it was not reached in patients with CXCL13 ≤ 200 pg/ml. In a subgroup of 28 patients with a series of serum samples, the increase of serum CXCL13 level was associated with disease progression or the start of next-line therapy (p < 0.001). Our study concludes that serum CXCL13 levels decrease in WM patients treated with various regimens and correlate with treatment response. Detecting serum CXCL13 at baseline or after treatment help in predicting prognosis.

Detection of the MYD88L265P and CXCR4S338X mutations by cell-free DNA in Waldenström macroglobulinemia.

We aimed to detect the MYD88L265P and CXCR4S338X mutations in cell-free DNA (cfDNA) in patients with Waldenström macroglobulinemia (WM). We collected peripheral blood and paired bone marrow aspirates from 27 WM patients (including 16 patients with newly diagnosed WM, 3 patients with WM in relapse and 8 patients with WM during treatment). cfDNA was extracted from peripheral blood using a QIAamp Circulating Nucleic Acid Kit. The MYD88L265P and CXCR4S338X mutations were detected by real-time allele-specific PCR (AS-PCR) in cfDNA and genomic DNA (gDNA) extracted from bone marrow aspirates. The sensitivity of real-time AS-PCR for detecting MYD88L265P in cfDNA was determined using a serial dilution of 10%, 2%, 0.4% and 0.08% MYD88L265P cfDNA in wild-type cfDNA. Among the 27 patients, MYD88L265P was detected in 88.9% of them in gDNA and in 85.2% of them in cfDNA, with a concordance rate of 96.3%. The concordance rates were 93.8%, 100% and 100% in patients with newly diagnosed WM, patients with WM in relapse and patients with WM during treatment, respectively. The sensitivity of real-time AS-PCR for detecting MYD88L265P in cfDNA was 0.4%. CXCR4S338X was detected in 6.3% of the 16 newly diagnosed WM patients in both gDNA and cfDNA, with a concordance rate of 100.0%. It is feasible to apply cfDNA to detect MYD88L265P and CXCR4S338X in WM patients with a high concordance rate.

Identification of a new GLDC gene alternative splicing variant and its protumorigenic roles in lung cancer.

Aim: To clarify the regulatory roles of GLDCV1, the first identified truncated glycine decarboxylase (GLDC), on cancer stem cells and tumorigenesis. Materials & methods: RT-PCR or RT-qPCR, immunoblotting and immunohistochemical staining were applied to assess gene expression. MTT, BrdU incorporation and colony formation assays were used to examine cell proliferation capacity. Soft agar colony formation and in vivo transplantation were applied to evaluate cellular transformation and tumorigenesis. Results & conclusion: Expression of GLDCV1 or GLDC was enhanced in non-small-cell lung cancer cell line and clinical samples. GLDCV1 overexpression induced MRC5 cell proliferation, transformation and tumorigenesis. Additionally, GLDCV1 increased lactate production and cancer stem cell marker expression and activated ERK and P38 pathways. Our study gained deeper insight into GLDC oncogene.

Single-cell transcriptome analysis reveals stem cell-like subsets in the progression of Waldenström's macroglobulinemia.

Waldenström's macroglobulinemia (WM) is an uncommon lymphoproliferative disorder, and the precise cellular landscape and the mechanisms of progression from IgM monoclonal gammopathy of undetermined significance (MGUS) to WM remain unclear. We performed single-cell RNA sequencing of CD19 + and CD19-CD38 + cells from healthy donors, IgM MGUS and WM patients. We found that samples from IgM MGUS and WM patients were composed of fewer early B-cell subsets and more T cells and NK cells than those from healthy controls. Compared with those of IgM MGUS patients, mature B cells of WM patients showed upregulation of HES1, GADD45B, NEAT1, DUSP22, RGS1, RGS16, and PIM1. We also identified a subpopulation of CD3 + CD19 + cells in IgM MGUS and WM patients, and trajectory analysis suggested that this subpopulation might be a stem cell-like subset. Further targeted gene sequencing of CD3 + CD19 + and CD3-CD19 + cells proved that MYD88 might be the early events in tumorigenesis according to variant allele fraction analysis. Additional subclonal hits such as CXCR4 and MAP2K1 mutations could be acquired during tumor progression. CXCL signaling, CCL signaling, IL2 signaling and TGFß signaling pathways were involved in communication between CD3 + CD19 + cells and other immune cells. Our findings reveal the composition of CD38 + immune microenvironment together with B cells and plasma cells in IgM MGUS and WM patients, and provide comprehensive insights into mechanisms of progression from IgM MGUS to WM. The rare CD3 + CD19 + cells might be cells with "stemness" feature.

Distinct Mutation Landscapes Between Acute Myeloid Leukemia With Myelodysplasia-Related Changes and De Novo Acute Myeloid Leukemia.

OBJECTIVES: To explore the distinct mutation profiles between acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) and de novo AML and their relationships with prognosis. METHODS: Next-generation sequencing of 42 myeloid neoplasm-related genes in 293 newly diagnosed patients with AML. RESULTS: Eighty-four patients had AML-MRC, and 161 patients had de novo AML. The mutation rates of ASXL1 (25% vs 8.7%, P = .001), NRAS (17.9% vs 8.1%, P = .022), PTPN11 (11.9% vs 5%, P = .048), SETBP1 (6% vs 0.6%, P = .033), SRSF2 (11.9% vs 5.6%, P = .08), TP53 (16.7% vs 1.2%, P < .001), and U2AF1 (17.9% vs 7.5%, P = .014) in AML-MRC were higher than those in de novo AML, while the rates of FLT3-ITD (3.6% vs 15.5%, P = .005), KIT (0% vs 6.2%, P = .046), WT1 (3.6% vs 9.9%, P = .077), NPM1 (1.2% vs 21.7%, P < .001), and CEBPA (4.8% vs 24.2%, P < .001) mutation were lower. The appearance of ASXL1, TP53, U2AF1, SRSF2, and SETBP1 mutation could predict AML-MRC-like features in de novo AML, which was related to older age (60 vs 51 years, P = .001), low WBC counts (4.7 × 109/L vs 11.6 × 109/L, P = .001), and inferior outcomes (median overall survival, 15 months vs not reached, P = .003). CONCLUSIONS: The presence of AML-MRC-related mutations can reveal a subset of patients with de novo AML similar to patients with AML-MRC.

UCD with MCD-like inflammatory state: surgical excision is highly effective.

Unicentric Castleman disease (UCD) is a rare lymphoproliferative disorder presenting as a single nodal mass with characteristic histopathology. Patients with UCD are typically asymptomatic with normal laboratory markers, whereas patients with multicentric Castleman disease (MCD) demonstrate multicentric lymphadenopathy and cytokine storm-induced systemic inflammatory symptoms. This retrospective analysis of 116 UCD cases identified 19 (16.4%) cases with an MCD-like inflammatory state (UCD-MIS). We compared treatments and outcomes between cases of UCD-MIS and UCD-non-MIS to evaluate the role of surgery and illuminate biological behavior of UCD-MIS. There were differences in the distribution of histopathological subtypes (plasmacytic histopathology was more frequently seen, 52.6% vs 13.4%; P < .001) between the 2 groups. However, both groups demonstrated good responses to surgical treatment, suggesting that UCD-MIS in some patients still shared common biological behavior with UCD in other patients. Sixteen (94.2%) patients with UCD-MIS underwent complete surgical excision alone, and the systemic inflammation resolved completely in all of them. This high response rate suggests surgical treatment as a potential cure for this unique subset of patients. After a median follow-up duration of 64 months (range, 2-239 months), neither lymphadenopathy nor the inflammatory state recurred. However, inflammation may progress in patients with irresectable disease, and treatment options other than surgery should be considered in these patients.

Lung function and blood gas abnormalities in patients with acromegaly.

OBJECTIVE: Respiratory disorders are common complications of acromegaly patients. We conducted a large-scale survey in the patients with acromegaly and demonstrated the characteristics of their lung function and blood gas. METHODS: A prospective cohort study was conducted with 115 patients with active acromegaly and 56 patients with nonfunctioning pituitary adenomas. All patients underwent clinical, biological, radiological, lung functional and blood gas assessments. RESULTS: Acromegaly patients had a higher lung volume than those with nonfunctioning adenomas (forced vital capacity value (FVC) and FVC% predicted: p < 0.001). The small airway was less obstructive in acromegaly patients (higher FEV1% predicted, PEF% predicted, MEF75% predicted, MEF50% predicted, MEF25% predicted: p ≤ 0.001 for all analyses, FEV1/FVC: p = 0.151). The average partial pressure of carbon dioxide in acromegaly patients was higher (p < 0.001), but there was no significant difference in the average partial pressure of oxygen or oxygen saturation between the two groups (p > 0.05). In acromegaly patients, the average age of patients with small airway obstruction was higher than that of patients with normal lung function (p < 0.05), but no significant difference in GH or IGF-1 levels between the two groups were found (p > 0.05). CONCLUSION: The acromegaly patients in this cohort had increased lung volume. However, there was no evidence demonstrating hypoxemia in acromegaly patients. The small airway was less obstructive in acromegaly patents. Small airway obstruction was observed in elderly patients with acromegaly.

Rituximab-containing therapy for cold agglutinin disease: a retrospective study of 16 patients.

Cold agglutinin disease (CAD) is a rare form of autoimmune haemolytic anaemia, and because of its rareness, there is no standard treatment for CAD patients. We retrospectively analysed the response to rituximab-containing therapy in CAD patients at our hospital. All patients received rituximab-containing therapy for at least 1 month. A total of 16 patients (11 males and 5 females) were included. The median age at the onset of the disease was 63.5 years (range 41-79). Most patients had manifestations including anaemia (81.3%) or cold-induced circulatory symptoms (75.0%). The median haemoglobin level was 72 g/L (range 29-101), and the median cold agglutinin titre was 1,024 (range 64-2,048). Thirteen of 16 patients (81%) responded to the therapy. Responders achieved a median increase in haemoglobin levels of 45 g/L. Grade 3-4 neutropenia occurred in 3 patients (19%), but only 1 (6%) of them experienced infection. Anaphylaxis related to rituximab occurred in 1 patient. During follow-up, five patients experienced relapse, and two patients died. The estimated median progression-free survival was 36 months, and median overall survival was not yet reached. In conclusion, A rituximab-based therapy in accordance with individual patient characteristics may be a reasonable choice for CAD patients.