Men are consistently overrepresented in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and coronavirus disease 2019 (COVID-19) severe outcomes, including higher fatality rates. These differences are likely due to gender-specific behaviors, genetic and hormonal factors, and sex differences in biological pathways related to SARS-CoV-2 infection. Several social, behavioral, and comorbid factors are implicated in the generally worse outcomes in men compared with women. Underlying biological sex differences and their effects on COVID-19 outcomes, however, have received less attention. The present review summarizes the available literature regarding proposed molecular and cellular markers of COVID-19 infection, their associations with health outcomes, and any reported modification by sex. Biological sex differences characterized by such biomarkers exist within healthy populations and also differ with age-and sex-specific conditions, such as pregnancy and menopause. In the context of COVID-19, descriptive biomarker levels are often reported by sex, but data pertaining to the effect of patient sex on the relationship between biomarkers and COVID-19 disease severity/outcomes are scarce. Such biomarkers may offer plausible explanations for the worse COVID-19 outcomes seen in men. There is the need for larger studies with sex-specific reporting and robust analyses to elucidate how sex modifies cellular and molecular pathways associated with SARS-CoV-2. This will improve interpretation of biomarkers and clinical management of COVID-19 patients by facilitating a personalized medical approach to risk stratification, prevention, and treatment.
BACKGROUND Waldenström macroglobulinemia (WM) is preceded by asymptomatic WM (AWM), for which the risk of progression to overt disease is not well defined. METHODS We studied 439 patients with AWM, who were diagnosed and observed at Dana-Farber Cancer Institute between 1992 and 2014. RESULTS During the 23-year study period, with a median follow-up of 7.8 years, 317 patients progressed to symptomatic WM (72%). Immunoglobulin M 4,500 mg/dL or greater, bone marrow lymphoplasmacytic infiltration 70% or greater, β2-microglobulin 4.0 mg/dL or greater, and albumin 3.5 g/dL or less were all identified as independent predictors of disease progression. To assess progression risk in patients with AWM, we trained and cross-validated a proportional hazards model using bone marrow infiltration, immunoglobulin M, albumin, and beta-2 microglobulin values as continuous measures. The model divided the cohort into three distinct risk groups: a high-risk group with a median time to progression (TTP) of 1.8 years, an intermediate-risk group with a median TTP of 4.8 years, and a low-risk group with a median TTP of 9.3 years. We validated this model in two external cohorts, demonstrating robustness and generalizability. For clinical applicability, we made the model available as a Web page application ( www.awmrisk.com ). By combining two cohorts, we were powered to identify wild type MYD88 as an independent predictor of progression (hazard ratio, 2.7). CONCLUSION This classification system is positioned to inform patient monitoring and care and, for the first time to our knowledge, to identify patients with high-risk AWM who may need closer follow-up or benefit from early intervention.
The treatment approaches for Waldenstrom macroglobulinemia (WM) are largely based upon information from single-arm phase II trials, without comparative data. We compared the efficacy of two commonly used regimens in routine practice (bendamustine-rituximab (BR) and dexamethasone, rituximab plus cyclophosphamide (DRC)) and evaluated their activity with respect to the patients' MYD88 mutation status. Of 160 consecutive patients, 60 received BR (43 with relapsed/refractory WM) and 100 received DRC (50 had relapsed/refractory WM). In the treatment-naïve setting, overall response rate (ORR) was 93% with BR versus 96% with DRC (p = 0.55). Two-year progression-free survival (PFS) with BR and DRC was 88 and 61%, respectively (p = 0.07). In salvage setting, ORR was 95% with BR versus 87% with DRC, p = 0.45; median PFS with BR was 58 versus 32 months with DRC (2-year PFS was 66 versus 53%; p = 0.08). Median disease-specific survival was not reached with BR versus 166 months with DRC (p = 0.51). The time-to-event endpoints and depth of response were independent of the MYD88 mutation status. Grade ≥ 3 adverse events of both regimens were comparable. A trend for longer PFS was observed with BR although the regimens have comparable toxicities. The activity of BR and DRC appears to be unaffected by patients' MYD88 mutation status.
Waldenström macroglobulinemia (WM) is an immunoglobulin M-associated lymphoma, with majority of cases demonstrating MYD88 locus alteration, most commonly, MYD88 . Owing to low prevalence of the wild-type (WT) MYD88 genotype in WM, clinically relevant data in this patient population are sparse, with one study showing nearly a 10-fold increased risk of mortality in this subgroup compared to patients with MYD88 mutation. We studied a large cohort of patients with MYD88 and MYD88 WM, evaluated at Mayo Clinic, Rochester, between 1995 and 2016, to specifically assess the impact of these genotypes on clinical course. Of 557 patients, MYD88 mutation status, as determined by allele-specific polymerase chain reaction, was known in 219, and 174 (79%) of those exhibited MYD88 , 157 of 174 patients had active disease. Of 45 (21%) patients with MYD88 genotype, 44 had active disease. The estimated median follow-up was 7.0 years; median overall survival was 10.2 years (95% CI: 8.4-16.5) for MYD88 versus 13.9 years (95% CI: 6.4-29.3) for the MYD88 (P = 0.86). The time-to-next therapy from frontline treatment and the presenting features were similar in the two patient populations. For patients with smoldering WM at diagnosis, the median time-to-progression to active disease was 2.8 years (95% CI: 2.2-3.8) in the MYD88 cohort and 1.9 years (95% CI: 0.7-3.1) in the MYD88 cohort (P = 0.21). The frequency of transformation to high-grade lymphoma, or the development of therapy-elated myelodysplastic syndrome was higher in the MYD88 cohort (16% versus 4% in the MYD88 , P = 0.009). In conclusion, MYD88 mutation does not appear to be a determinant of outcome, and its presence may not be a disease-defining feature in WM. Our findings warrant external validation, preferably through prospective studies.
Orange peels were evaluated as a fermentation feedstock, and process conditions for enhanced ethanol production were determined. Primary hydrolysis of orange peel powder (OPP) was carried out at acid concentrations from 0 to 1.0% (w/v) at 121 degrees C and 15 psi for 15 min. High-performance liquid chromatography analysis of sugars and inhibitory compounds showed a higher production of hydroxymethyfurfural and acetic acid and a decrease in sugar concentration when the acid level was beyond 0.5% (w/v). Secondary hydrolysis of pretreated biomass obtained from primary hydrolysis was carried out at 0.5% (w/v) acid. Response surface methodology using three factors and a two-level central composite design was employed to optimize the effect of pH, temperature, and fermentation time on ethanol production from OPP hydrolysate at the shake flask level. On the basis of results obtained from the optimization experiment and numerical optimization software, a validation study was carried out in a 2 L batch fermenter at pH 5.4 and a temperature of 34 degrees C for 15 h. The hydrolysate obtained from primary and secondary hydrolysis processes was fermented separately employing parameters optimized through RSM. Ethanol yields of 0.25 g/g on a biomass basis (YP/X) and 0.46 g/g on a substrate-consumed basis (YP/S) and a promising volumetric ethanol productivity of 3.37 g/L/h were attained using this process at the fermenter level, which shows promise for further scale-up studies.
Ibrutinib-related data in Waldenstr€ om macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment-na€ ıve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off-study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major-response rate (MRR) was 78%. The median time to first response and best response was 2Á9 [95% confidence interval (CI): 2-4] and 5Á7 (95% CI: 4-12) months, respectively. The median follow-up was 19 (95% CI: 14-21) months; 18-month progression-free survival (PFS) was 82%. The median time on therapy was 12Á5 (95% CI: 9Á3-16Á7) months, and the median duration-of-response was 32 (range: 23-32) months. Twenty-five patients (31%) had discontinued therapy at last follow-up (68% due to treatmentrelated toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial-fibrillation (11%) were common non-haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression.
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