Analysis of Time Between Skin Lesion and Lymph Node Biopsies and Lymph Node Metastasis in Patients With Melanoma
1. In this retrospective cohort study, cutaneous melanomas with a classification of T1b-T4 but without clinical evidence of metastatic disease (N0M0) at time of diagnosis, delay of surgical intervention up to 90 days after diagnosis did not increase risk of upstaging disease.
Evidence Rating Level: 2 (Good)
The current standard of care treatment for cutaneous melanomas stage T1b to T4 without evidence of widespread metastatic disease is wide local excision (WLE) and sentinel lymph node biopsy (SLNB). While surgery for melanoma should always be offered in a timely manner, it is unclear what time frame between diagnosis and surgical intervention is safest. This retrospective cohort study conducted by researchers at the University of Colorado School of Medicine sought to quantify sentinel lymph node status as a function of time from diagnosis to surgery. Data on a total of 642 patients being treated surgically for melanoma either at a Colorado community hospital (n = 389) or academic hospital (n = 253) were included. Patients were classified based on whether they underwent surgery within 30 days (39.4%), 31 to 60 days (50.3%), or 61 to 90 days (10.3%) from diagnosis. Multivariable logistic regressions found that patients undergoing surgery within 30 days of diagnosis did not significantly differ from patients in the 31 to 60-day group (OR, 0.79; 95% CI, 0.50-1.23) or 61-to-90-day group and (OR, 0.77; 95% CI, 0.37-1.63) in final N stage greater than 0 when adjusting for treatment location, age, sex, race, T stage, ulceration, and mitoses. When time to surgery was analyzed as a continuous variable, there was no significant association with final N stage greater than 0 patients with stage T3 and T4 disease. The results of this study may indicate that although surgical intervention for cutaneous melanoma should be offered in a timely manner, the risk of upstaging the disease may not change significantly within 90 days of diagnosis. This may have implications for alleviating patient anxieties and clinician stress when a delay is unavoidable or may be desired from the patient.
Association Between Chronic Pain and Risk of Incident Dementia: Findings From a Prospective Cohort
1. Participants reporting a greater number of chronic pain sites had a higher proportion of developing incident all-cause dementia, AD, and vascular dementia than those without chronic pain in this prospective cohort study.
Evidence Rating Level: 2 (Good)
Dementia is a major public health concern, and there is no current cure or effective disease-modifying agent. Therefore, identifying and targeting modifiable risk factors continues to be a mainstay in preventive care. Existing literature supports a link between chronic musculoskeletal pain and accelerated cognitive and memory decline, though current evidence is still lacking. This prospective cohort study sought to explore whether the number of chronic pain sites could be associated with increased risk of dementia. Data on 356,383 individuals aged 40 to 69 years who did not have dementia at baseline were obtained from the UK Biobank, a large population-based cohort study. Patients were classified into six groups: no chronic pain lasting over three months, 1, 2, 3, and 4 sites of chronic pain (choosing from hip, knee, back, or neck/shoulder), or chronic pain ‘all over the body’. All-cause dementia and its subtypes were ascertained using hospital inpatient and death registry records. After follow-up (median of 13.3 years), there were 4959 new dementia events recorded. There was a significant association between the number of chronic pain sites and an increased risk of incident all-cause dementia (hazard ratio [HR]=1.08 per 1 site increase, 95% confidence interval [CI] 1.05–1.11), even when adjusted for covariates including SES, BMI, lifestyle, comorbidities, pain medications, psychological problems, and sleep. This was observed as a dose-response relationship, with each increase in sites affected by chronic pain reflecting incremental increases in risk for all-cause dementias and Alzheimer’s disease, but not vascular or frontotemporal subtypes of dementia (possibly due to small sample sizes and lower statistical power in these subgroups). There was a cumulative incidence of dementia >40% higher in those with pain in four sites or ‘all over the body’ compared to those without chronic musculoskeletal pain. Limitations to this study include a lack of generalizability to other ethnicities given the high proportion of Caucasian individuals registered in the UK Biobank, as well as a lack of access to detailed neuropsychological assessments in confirming the recorded diagnoses of dementia in these patients. Baseline cognitive status was also not fully accounted for. Overall, study findings suggest that musculoskeletal pain may be an underrecognized risk factor for dementia.
Venetoclax Consolidation in High-Risk Cll Treated With Ibrutinib for ≥1 Year Achieves A High Rate of Undetectable MRD
1. High genetic risk participants with chronic lymphocytic leukemia (CLL) taking venetoclax in addition to ibrutinib achieved high rates of achievement of undetectable measurable disease, very low risk of on-treatment disease progression, and durable off-treatment remissions.
Evidence Rating Level: 2 (Good)
Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK), and one of its indicated uses is in chronic lymphocytic leukemia (CLL). However, the standard of care for those receiving Ibrutinib for CLL is continuous and indefinite maintenance therapy since patients rarely achieve complete remission (CR) with undetectable measurable disease at sensitivity 10-4 (U-MRD4). Adverse events (e.g., atrial fibrillation, major hemorrhage, hypertension, ventricular arrhythmia, sudden cardiac death), cost-related barriers, and rates of disease progression result in increased cumulative risk of treatment discontinuation of ibrutinib. The current study, a phase II, investigator-initiated, response-adapted clinical trial added venetoclax, a B-cell lymphoma-2 inhibitor with a mechanism distinct from ibrutinib, as an adjunct for patients already receiving ibutrinib to test whether this combination could achieve durable treatment-free remission those with CLL and at least one high-risk genetic feature (del[17p] or TP53 mutation, complex karyotype, del[11q]; or β2-microglobulin above the upper limit of normal). Venetoclax added to ibrutinib in patients with high-risk CLL was well-tolerated and achieved a cumulative bone marrow (BM) U-MRD4 rate of 73%. Additionally, 55% of patients improved response to complete remission, and there was a median 70% reduction in sum product diameters of target lymph node groups, indicating that benefits of venetoclax extended beyond the bone marrow compartment. The rate of BM U-MRD4 achievement was not affected by presence of TP53 abnormalities (p = 0.32), complex karyotype (p = 0.61), or treatment naïve versus relapsed/refractory CLL (p = 0.12). U-MRD4 did not change significantly between patients requiring venetoclax dose reduction versus not requiring it (p = 0.25), or those requiring ibrutinib dose reduction versus not requiring it (p = 0.64). The majority of patients who achieved BM U-MRD4 did so within 12 months of therapy, and at completion of venetoclax treatment (6, 12, 18, or 24 cycles), 22 of the 32 patients with BM U-MRD4 stopped ibrutinib with a three-year estimated progression free survival of 95%. At a median follow-up of 41 months, only 5 patients had progressed. Results of this study provide promising results that may allow patients to avoid cumulative risks of indefinite ibrutinib use and achieve BM U-MRD4 or complete remission for CLL.
Vitamin K2 Supplementation Improves Impaired Glycemic Homeostasis and Insulin Sensitivity for Type 2 Diabetes Through Gut Microbiome and Fecal Metabolites
1. This double-blind 1:1 randomized control trial of vitamin K2 administration for type 2 diabetes mellitus revealed the potential role of vitamin K2 as a regulator of glycemic homeostasis, with potential for use as a TD2M intervention.
Evidence Rating Level: 2 (Good)
Type 2 diabetes mellitus (T2DM) remains a major public health issue, and in recent years, evidence has emerged associating gut microbiota dysbiosis to the disease. The literature has also demonstrated potential benefits of vitamin K2 on insulin sensitivity and glucose metabolism, as well as changes to microbiota composition when diets are insufficient in Vitamin K. This study sought to investigate vitamin K2 probiotic administration as a potential metabolic intervention that regulates blood glucose by acting on the gut microbiota. First, a double-blind 1:1 randomized controlled intervention of MK-7 (natural form of vitamin K2) for 6 months was conducted, with n = 30 in both experimental and control groups. After a 6-month intervention, circulating levels of vitamin K2 in the body were significantly increased in the experimental group (P < 0.001). Reductions of 13.4% in fasting serum glucose (Vkchange= −1.08±0.49 mmol/L, P = 0.048), 28.3% in insulin (Vkchange= −3.15±0.39 μU/mL, P = 0.005), and 7.4% in Hb1Ac levels (Vkchange= −0.57±0.23%, P = 0.019) were observed in the experimental group, with modest improvements in HOMA index and lipid parameters. Additionally, 16S rRNA sequencing and metabolomics analysis revealed increased beta diversity of microbial community composition in the experimental group compared to control group (P < 0.05). The ratio of Firmicutes and Bacteroidetes (F/B), an indicator of gut microbiota balance that is usually higher in those with T2DM, was significantly higher in the control group than the MK-7 groups (NC0=4.95±0.96, NC6=11.22±2.18, P = 0.012). Ruminococcaceae, Lachnospiraceae, and Bacteroidaceae were relatively dominant families in the MK-7 treatment group compared to controls, whereas Enterobacteriaceae was a dominant family in the control group. A significant decrease in the total of branched-chain amino acids and histidine concentrations was observed (P <0.05), as well as an increase in secondary bile acids (SBAs) and short-chain fatty acids (SCFAs) associated with reductions in serum Hb1Ac, glucose, insulin and insulin resistance found in fecal samples for the MK-7 treated group. Finally, within 4 weeks of fecal microbiota transplantation (FMT) in mice, they displayed significantly improved glucose tolerance and insulin sensitivity, activated colon bile acid receptors, improved host immune-inflammatory responses, and increased GLP-1 concentrations. The above results evidence the potential role of vitamin K2 as an intervention for diabetes management.
Defining the Optimal Duration of Therapy for Hospitalized Patients With Complicated Urinary Tract Infections and Associated Bacteremia
1. In bacteremic patients with complicated UTI, a 10-day course of typical antibiotics or a 7-day course of IV beta-lactams or highly available antibiotics were statistically similar to 14-day courses when comparing 30-day reinfection and antibiotic-resistant infection rates.
Evidence Rating Level: 2 (Good)
Urinary tract infections (UTIs) are the most common bacterial infections worldwide. Complicated UTIs (cUTIs) occur in the setting of pre-existing structural or functional abnormalities of the urinary tract (or any male patient with UTI), and generally have poorer outcomes. Currently, there is ongoing uncertainty regarding the optimal duration of antibiotic therapy. In this retrospective cohort study, researchers analyzed patient cases with both a cUTI and current gram-negative bloodstream infection who either received 7 days (n = 265), 10 days (n = 382), or 14 days (n = 452) of antibiotic therapy. E. Coli, K. pneumoniae, P. mirabilis, and P. aeruginosa were the most common pathogens isolated in this cohort, respectively. Inverse probability of treatment weighting (IPTW) incorporated propensity scores to attempt to account for several factors/baseline differences between patients. Those who received 7 days of therapy had an approximately 2.5-fold increase in odds of recurrent infection within 30 days of treatment completion compared to those in the 14-day arm (adjusted OR [aOR]: 2.54; 95% CI: 1.40–4.60; P = .002). However, there was no increase in the odds of recurrent infection for those in the 10-day arm compared to the 14-day arm ([aOR]: .99; 95% CI: .52–1.87; P = .99). Of the 76 patients (7% of total) who had a recurrent infection within 30 days, 14 of these (18%) had subsequent antibiotic-resistant infections. Two were from the 7-day arm, two from the 10-day arm, and ten were from the 14-day arm (P = 0.10). Additionally, an analysis of 7 days versus 14 days of treatment using highly bioavailable agents was completed. There was no difference in odds of recurrent infection between the 7-day and 14-day IPTW cohorts when using IV beta-lactams or other high bioavailability antibiotics (aOR: .76; 95% CI: .38–1.52). Therefore, the findings in this study may suggest that for some bacteremic patients with cUTI, 7 days of highly bioavailable or IV antibiotics may be sufficient for some, whereas 10 days may be more useful for others. Study findings are in concordance with new practice developments across medicine attempting to shorten the standard duration of therapy for various infections, and may be used to further guideline development.
Image: PD
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