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Summary Chronic lymphocytic leukaemia (CLL) is associated with immunocompromise and high risk of severe COVID‐19 disease and mortality. Monoclonal B‐cell lymphocytosis (MBL) patients also have immune impairment. We evaluated humoural and cellular immune responses in 181 patients with CLL (160) and MBL (21) to correlate failed seroconversion [<50 AU/ml SARS‐CoV‐2 II IgG assay, antibody to spike protein; Abbott Diagnostics)] following each of two vaccine doses with clinical and laboratory parameters. Following first and second doses, 79.2% then 45% of CLL, and 50% then 9.5% of MBL patients respectively remained seronegative. There was significant association between post dose two antibody level with pre‐vaccination reduced IgM (p < 0.0001), IgG2 (p < 0.035), and IgG3 (p < 0.046), and CLL therapy within 12 months (p < 0.001) in univariate analysis. By multivariate analysis, reduced IgM (p < 0.0002) and active therapy (p < 0.0002) retained significance. Anti‐spike protein levels varied widely and were lower in CLL than MBL patients, and both lower than in normal donors. Neutralisation activity showed anti‐spike levels <1000 AU/ml were usually negative for both an early viral clade and the contemporary Delta variant and 72.9% of CLL and 53.3% of MBL failed to reach levels ≥1000 AU/ml. In a representative sample, ~80% had normal T‐cell responses. Failed seroconversion occurred in 36.6% of treatment‐naïve patients, in 78.1% on therapy, and in 85.7% on ibrutinib.

Chronic lymphocytic Leukemia (CLL) and Monoclonal B-Lymphocytosis (MBL) patients have impaired response to COVID-19 vaccination. A total 258 patients (215 CLL and 43 MBL) had anti-spike levels evaluable for statistical analysis. The overall seroconversion rate for CLL was 94.2% (anti-spike ³50AU/mL Abbott Diagnostics) and for MBL 100%. After 3 doses (post-D3) in 167 CLL patients, 73.7% were seropositive, 17.4% had anti-spike levels 50-999AU/mL, and 56.3% ≥1000AU/mL with a median rise from 144.6AU/mL to 1800.7AU/mL. Of patients seronegative post-D2, 39.7% seroconverted post-D3. For those who then remained seronegative after their prior dose, seroconversion occurred in 40.6% post-D4, 46.2% post-D5, 16.7% post-D6, and 0% after D7 or D8. Following seroconversion, most had a progressive increment in anti-spike antibody level: in CLL after the latest dose, 70.2% achieved anti-spike level ≥1,000AU/mL, 48.1% ≥5,000AU/mL, and 30.3% ≥10,000AU/mL. Neutralization was associated with higher anti-spike levels, more vaccines and earlier COVID variants; 65.3% detected neutralizing antibody against early clade D614G, 52.0% against Delta, and 36.5% against Omicron. COVID-specific T-cell production of IFN-γ occurred in 73.9% and IL-2 in 60.9% of 23 tested, and more consistently with higher anti-spike levels. After multiple vaccine doses, by multivariate analysis, IgM ≥0.53g/L (OR=2.90, p=0.0314), IgG3 ≥0.22g/L (OR=3.26, p=0.0057), and lack of current CLL therapy (OR=2.48, p=0.0574) were independent predictors of positive serological responses. Strong neutralization and T-cell responses had high concordance with high anti-spike levels. Multiple sequential COVID-19 vaccination significantly increased seroconversion and anti-spike antibody levels in CLL and MBL.

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Everolimus, an mTOR inhibitor, showed great clinical efficacy in combination with tamoxifen, letrozole, or exemestane for the treatment of estrogen receptor-positive (ER+) breast cancer. However, its antitumor activity was shown to be compromised by a compensatory process involving AKT activation. Here, it was determined whether combining an additional PI3K inhibitor can reverse this phenomenon and improve treatment efficacy. In breast cancer cells

Purpose To analyze the current randomized controlled trials (RCTs) of dynamic fixations (DFs) and static fixations (SFs) in treating distal tibiofibular syndesmosis injuries (DTSIs). Methods The Cochrane Central Register of Controlled Trials, PubMed, and EMBASE were systematically searched according to the PRISMA guidelines to identify RCTs comparing the DFs and SFs for DTSIs. Included studies were assessed using the Cochrane Risk of Bias Tool. Postoperative functional scores, range of motion (ROM), complication rate, and incidence of reoperation were statistically analyzed using review manager software, and a p value of < 0.05 was considered statistically significant. Results Five RCTs with a total of 282 patients were included. Analysis revealed statistically significant differences in favor of DFs with regard to American Orthopaedic Foot and Ankle Society (AOFAS) Ankle–Hindfoot score at a follow‐up less than 6 months (MD 5.29; 95% CI 0.99–9.59; p = 0.02; I2 = 0%) and at a follow‐up more than 2 years (MD 7.53; 95% CI 3.30–11.76; p = 0.0005; I2 = 0%), Olerud–Molander ankle (OMA) score at 1 year follow‐up (MD 4.62; 95% CI 0.91–8.32; p = 0.01; I2 = 14%), and overall postoperative complication rate (RR 0.22; 95% CI 0.07–0.77; p = 0.02; I2 = 73%). There was no significant difference between the DFs and SFs regarding ROM and incidence of reoperation. Conclusions The DF procedure leads to significantly improved functional scores as well as lower rate of overall postoperative complications when compared with SF procedure. On the basis of results of this meta‐analysis, the DF should be recommended for managing the DTSI. Level of evidence I.

Microenvironments within the lymph node and bone marrow promote proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Successful treatment of CLL must therefore target the leukemic cells within these compartments. A better understanding of the interaction between CLL cells and the tumor microenvironment has led to the development of in vitro models that mimic the mechanisms that support leukemic cell survival and proliferation in vivo. Employing these models as part of the pre-clinical evaluation of novel therapeutic agents enables a better approximation of their potential clinical efficacy. In this review we summarize the current literature describing how different aspects of the tumor microenvironment have been modeled in vitro and detail how these models have been employed to study the biology of the disease and potential efficacy of novel therapeutic agents.

Chronic lymphocytic leukaemia (CLL) is invariably accompanied by some degree of immune failure, and CLL patients have a high rate of second primary malignancy (SPM) compared to the general population. We comprehensively documented the incidence of all forms of SPM including skin cancer (SC), solid organ malignancy (SOM), second haematological malignancy (SHM) and separately Richter's syndrome (RS) across all therapy eras. Among the 517 CLL/small lymphocytic lymphoma (SLL) patients, the overall incidence of SPMs with competing risks was SC 31.07%, SOM 25.99%, SHM 5.19% and RS 7.55%. Of the 216 treated patients, 106 (49.1%) had at least one form of SPM, and 63 of 106 (29.2% of treated patients) developed an SPM 1.5 years (median) after treatment for their CLL. Melanoma accounted for 30.3% of SC. Squamous cell carcinoma (SCC), including eight metastatic SCCs, was 1.8 times more than basal cell carcinoma (BCC), a reversal of the typical BCC:SCC ratio. The most common SOMs were prostate (6.4%) and breast (4.5%). SHM included seven acute myeloid leukaemia (AML) and five myelodysplasia (MDS) of which eight (four AML, four MDS) were therapy‐related. Any SPM occurred in 32.1% of 53 Monoclonal B‐lymphocytosis (MBL) patients. Age‐adjusted standardised rates of SPM (per 100,000) for CLL, MBL and the general Australian population were 2648, 1855 and 486.9, respectively. SPMs are a major health burden with 44.9% of CLL patients with having at least one SPM, and apart from SC, associated with significantly reduced overall survival. Dramatic improvements in CLL treatment and survival have occurred with immunochemotherapy and targeted therapies, but mitigating SPM burden will be important to sustain further progress.