Systematic Literature Review of the Prevalence and Prognostic Value of Delta-Like Ligand 3 Protein Expression in Small Cell Lung Cancer

Background: Delta-like ligand 3 (DLL3), a member of the Notch pathway, has been identified as a potential therapeutic target as it is highly expressed in small cell lung cancer (SCLC), a subtype accounting for 15% of lung cancer cases. Objective: A systematic literature review (SLR) was conducted to understand the prevalence and prognostic impact of DLL3 expression on survival of patients with SCLC and treatment response. Patients and Methods: Systematic literature searches were conducted across multiple databases to capture studies of any SCLC population that evaluated DLL3 expression. Specific outcomes of interest included prevalence of DLL3 expression, method of expression analysis, and impact on outcome, including treatment response and survival (overall, progression-free, disease-free) according to varying levels of DLL3 expression/positivity. Standard risk of bias tools were used to evaluate study quality. Results: Among the 30 included studies, the most common DLL3 testing method was immunohistochemistry (N = 26, 86.7%). For comparability, results focused on the 13 (22.3%) studies that used the Ventana DLL3 (SP347) immunohistochemistry assay. The prevalence of DLL3 positivity ranged from 80.0–93.5% for studies using a threshold of ≥ 1% of tumor cells (N = 4) and 58.3–91.1% for studies with a ≥ 25% threshold (N = 4). DLL3 expression was generally categorized as high using cutoffs of ≥ 50% (prevalence range: 45.8–79.5%; N = 6) or ≥ 75% (prevalence range: 47.3–75.6%; N = 5) of cells with positivity. Two studies used an H-score of ≥ 150 to define high DLL3 expression with prevalence ranging from 33.3–53.1%. No consistent associations were seen between DLL3 expression level and patient age, sex, smoking history, or disease stage. Two studies reported change in DLL3 expression category (high versus low) before and after chemotherapy. No statistically significant differences were reported between DLL3 expression groups and survival (overall, progression-free, or disease-free) or treatment response. Conclusions: There is a high prevalence of DLL3 expression in SCLC. Further research and analytical methods may help to characterize different populations of patients with SCLC based on DLL3 expression. While no significant prognostic factor in the included studies was identified, additional cohort studies using standardized methodology, with longer follow-up, are needed to better characterize any potential differences in patient survival or response by DLL3 expression level in SCLC.</p

Evidence of in Vivo Existence of Borrelia Biofilm in Borrelial Lymphocytomas

Lyme borreliosis, caused by the spirochete Borrelia burgdorferi sensu lato, has grown into a major public health problem. We recently identified a novel morphological form of B. burgdorferi, called biofilm, a structure that is well known to be highly resistant to antibiotics. However, there is no evidence of the existence of Borrelia biofilm in vivo; therefore, the main goal of this study was to determine the presence of Borrelia biofilm in infected human skin tissues. Archived skin biopsy tissues from borrelial lymphocytomas (BL) were reexamined for the presence of B. burgdorferi sensu lato using Borrelia-specific immunohistochemical staining (IHC), fluorescent in situ hybridization, combined fluorescent in situ hybridization (FISH)—IHC, polymerase chain reaction (PCR), and fluorescent and atomic force microscopy methods. Our morphological and histological analyses showed that significant amounts of Borrelia-positive spirochetes and aggregates exist in the BL tissues. Analyzing structures positive for Borrelia showed that aggregates, but not spirochetes, expressed biofilm markers such as protective layers of different mucopolysaccharides, especially alginate. Atomic force microscopy revealed additional hallmark biofilm features of the Borrelia/alginate-positive aggregates such as inside channels and surface protrusions. In summary, this is the first study that demonstrates the presence of Borrelia biofilm in human infected skin tissues

Completeness of prescription information in US commercial claims databases

Pharmacy commercial claims databases are widely used for pharmacoepidemiologic research. However, concerns have been raised that these databases may not fully capture claims for generic medication as a result of patients filling outside the context of their insurance. This has implications for many research activities and quality improvement programs. We sought to estimate the percentage of missing drug claims in US commercial claims data using a novel design

Association of primary prophylactic (PP) granulocyte-colony stimulating factor (G-CSF) use with chemotherapy dose modifications and relative dose intensity (RDI) among breast cancer patients receiving high-risk regimens for febrile neutropenia (FN)

314 Background: FN is a primary driver of chemotherapy modification and reduced RDI. Breast cancer patients often receive regimens with high risk ( > 20%) for FN. PP G-CSF use is recommended to decrease incidence of infection, as manifested by FN. Real-world evidence describing the association of G-CSF with reduced RDI in breast cancer patients is lacking. Methods: We retrospectively analyzed Flatiron Health Electronic Health Record data from 2011 to 2019 of adult female breast cancer patients initiating high-risk for FN chemotherapy regimens. PP G-CSF (pegfilgrastim, filgrastim, or biosimilars) use was assessed in the first and subsequent cycles of chemotherapy overall and by modality (on-body injector [OBI] vs. pre-filled syringe [PFS]). Standard dose was defined by NCCN guidelines. RDI was defined with respect to dose and timing of delivery: (delivered dose intensity/standard dose intensity)*100 and categorized as < 85% vs ≥85%. Characteristics were described by G-CSF use and adjusted relative risks (ARRs) were estimated for the association between G-CSF use and RDI, adjusting for age, serum hemoglobin, ECOG, HER2 status, and HR status. Results: There were 27,812 breast cancer patients included with a median age of 57 years. Most (90%) received PP-G-CSF. Four cycles of TC (docetaxel + cyclophosphamide) was the most common regimen prescribed (36%) and 82% of these patients received PP-G-CSF support in the first cycle, with OBI given more often than PFS (62% vs 38%). Second most common was dd AC-T Q1W (doxorubicin + cyclophosphamide followed by paclitaxel) and 98% of these patients received PP G-CSF (59% OBI vs 41% PFS). 80% of G-CSF users (vs 48% of those with no G-CSF) completed 4 or more cycles of chemotherapy (all regimens had ≥4 planned cycles). G-CSF users had a significant reduction in risk of RDI < 85% in Cycle 1 (ARR: 0.60; 95% confidence interval [CI]: 0.43 – 0.85) and Cycle 2 (ARR: 0.76; 95% CI: 0.59 – 0.97). At the overall chemotherapy course level, the risk of RDI < 85% was not significantly different by G-CSF use (ARR: 0.83; 95% CI: 0.63 - 1.08). There was no significant difference in risk of reduced RDI between OBI and PFS (ARR: 1.13; 95% CI: 0.94 - 1.35). Conclusions: This study revealed that 90% of breast cancer patients receiving high-risk for FN chemotherapy received PP-G-CSF support and completed more cycles than those who did not receive G-CSF. G-CSF users had lower risk of a reduced RDI in Cycles 1 and 2

Declining rates of osteoporosis management following fragility fractures in the U.S., 2000 through 2009

Background: Clinical practice recommendations state that patients with fragility fractures should be evaluated for osteoporosis and treated for the disease if it is present. The purpose of this study was to assess osteoporosis evaluation and treatment patterns for patients with fragility fractures and assess whether anti-osteoporosis pharmacotherapy initiated immediately following a fragility fracture is associated with improved adherence to the treatment protocol. Methods: This retrospective cohort study involved data from a large commercially insured population seen in the period from 2001 through 2009. Patients were community-dwelling individuals aged fifty years or older who had a new low-energy fracture at the hip, vertebra, wrist, or humerus with no evidence of a fragility fracture, osteoporosis treatment, malignant disease, or Paget disease for twelve months preceding the fracture. Rates of diagnostic testing and pharmacotherapy for osteoporosis within twelve months post-fracture were evaluated. Patients treated with oral bisphosphonates were evaluated to determine whether twelve-month adherence to the treatment protocol differed between those who had initiated therapy sooner (at zero to ninety days) and those who initiated it later (at ninety-one to 365 days) following the fracture. Results: The 88,571 women and 41,984 men had an average age of 72.3 years and 70.5 years, respectively. Nineteen percent (16,464) of the women and 10% (4014) of the men initiated osteoporosis pharmacotherapy, and 30% (26,481) of the women and 15% (6427) of the men underwent diagnostic testing and/or pharmacotherapy following fracture. Treatment rates were highest following vertebral fracture and lowest following wrist or humeral fracture. Treatment rates significantly decreased over time (from 2001 through 2009). The average twelve-month adherence (medication possession ratio) was 56% and 61% among women and men, respectively. Adherence was similar between patients who had initiated treatment sooner after the fracture and those who had initiated it later after the fracture. Conclusions: Clinical guidelines for evaluation and treatment following fragility fracture were met for less than one-third of women and less than one-sixth of men. While primary fracture prevention remains the ideal, secondary prevention is critical and there is a need to reverse the downward trend in adherence to post-fracture guidelines. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. Copyright © 2014 by the Journal of Bone and Joint Surgery, Incorporated

Declining rates of osteoporosis management following fragility fractures in the U.S., 2000 through 2009

Background: Clinical practice recommendations state that patients with fragility fractures should be evaluated for osteoporosis and treated for the disease if it is present. The purpose of this study was to assess osteoporosis evaluation and treatment patterns for patients with fragility fractures and assess whether anti-osteoporosis pharmacotherapy initiated immediately following a fragility fracture is associated with improved adherence to the treatment protocol. Methods: This retrospective cohort study involved data from a large commercially insured population seen in the period from 2001 through 2009. Patients were community-dwelling individuals aged fifty years or older who had a new low-energy fracture at the hip, vertebra, wrist, or humerus with no evidence of a fragility fracture, osteoporosis treatment, malignant disease, or Paget disease for twelve months preceding the fracture. Rates of diagnostic testing and pharmacotherapy for osteoporosis within twelve months post-fracture were evaluated. Patients treated with oral bisphosphonates were evaluated to determine whether twelve-month adherence to the treatment protocol differed between those who had initiated therapy sooner (at zero to ninety days) and those who initiated it later (at ninety-one to 365 days) following the fracture. Results: The 88,571 women and 41,984 men had an average age of 72.3 years and 70.5 years, respectively. Nineteen percent (16,464) of the women and 10% (4014) of the men initiated osteoporosis pharmacotherapy, and 30% (26,481) of the women and 15% (6427) of the men underwent diagnostic testing and/or pharmacotherapy following fracture. Treatment rates were highest following vertebral fracture and lowest following wrist or humeral fracture. Treatment rates significantly decreased over time (from 2001 through 2009). The average twelve-month adherence (medication possession ratio) was 56% and 61% among women and men, respectively. Adherence was similar between patients who had initiated treatment sooner after the fracture and those who had initiated it later after the fracture. Conclusions: Clinical guidelines for evaluation and treatment following fragility fracture were met for less than one-third of women and less than one-sixth of men. While primary fracture prevention remains the ideal, secondary prevention is critical and there is a need to reverse the downward trend in adherence to post-fracture guidelines. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. Copyright © 2014 by the Journal of Bone and Joint Surgery, Incorporated

Real-world effectiveness of osteoporosis therapies for fracture reduction in post-menopausal women

Summary: Studies examining real-world effectiveness of osteoporosis therapies are beset by limitations due to confounding by indication. By evaluating longitudinal changes in fracture incidence, we demonstrated that osteoporosis therapies are effective in reducing fracture risk in real-world practice settings. Introduction: Osteoporosis therapies have been shown to reduce incidence of vertebral and non-vertebral fractures in placebo-controlled randomized clinical trials. However, information on the real-world effectiveness of these therapies is limited. Methods: We examined fracture risk reduction in older, post-menopausal women treated with osteoporosis therapies. Using Medicare claims, we identified 1,278,296 women age ≥ 65 years treated with zoledronic acid, oral bisphosphonates, denosumab, teriparatide, or raloxifene. Fracture incidence rates before and after treatment initiation were described to understand patients’ fracture risk profile, and fracture reduction effectiveness of each therapy was evaluated as a longitudinal change in incidence rates. Results: Fracture incidence rates increased during the period leading up to treatment initiation and were highest in the 3-month period most proximal to treatment initiation. Fracture incidence rates following treatment initiation were significantly lower than before treatment initiation. Compared with the 12-month pre-index period, there were reductions in clinical vertebral fractures for denosumab (45%; 95% confidence interval [CI] 39–51%), zoledronic acid (50%; 95% CI 47–52%), oral bisphosphonates (24%; 95% CI 22–26%), and teriparatide (72%; 95% CI 69–75%) during the subsequent 12 months. Relative to the first 3 months after initiation, clinical vertebral fractures were reduced for denosumab (51%; 95% CI 42–59%), zoledronic acid (25%; 95% CI 17–32%), oral bisphosphonates (23%; 95% CI 20–26%), and teriparatide (64%; 95% CI 58–69%) during the subsequent 12 months. Conclusion: In summary, reductions in fracture incidence over time were observed in cohorts of patients treated with osteoporosis therapies.</p

Development and Evaluation of a Liquid Bead Microarray Assay for Genotyping Genital Human Papillomaviruses▿ †

We developed a liquid bead microarray (LBMA) assay for genotyping genital human papillomaviruses (HPVs) based on the MY09-MY11-HMB01 PCR system and the reverse line blot (RLB) assay probe sequences. Using individual HPV plasmids, we were able to detect as few as 50 copies per reaction. In two separate retrospective studies, the LBMA assay was compared to the RLB assay and to the Hybrid Capture II (hc2) assay. Testing was performed without knowledge of other assay results. In the first study, 614 cervical swab samples (enriched for HPV infection) from 160 young women were tested for HPV DNA, and 360 (74.8%) type-specific HPV infections were detected by both assays, 71 (14.8%) by the LBMA assay only, and 50 (10.4%) by the RLB assay only. Type-specific agreement for the two assays was excellent (99.1%; kappa = 0.85; 95% confidence interval [95% CI], 0.82 to 0.88). Samples with discrepant LBMA and RLB test results tended to have low viral loads by a quantitative type-specific PCR assay. In the second study, cervical swab samples from 452 women (including 54 women with histologically confirmed cervical-intraepithelial neoplasia grade 2 or worse [≥CIN2]) were tested initially by the hc2 and subsequently by the LBMA assay. The estimated sensitivities for ≥CIN2 were similar for the LBMA and hc2 assays (98.4% [95% CI, 95.0 to 100%] and 95.6% [95% CI, 89.2 to 100%], respectively). The percentages of negative results among 398 women without ≥CIN2 were similar for the LBMA and hc2 assays (45% and 50%, respectively). The repeat test reproducibility for 100 samples was 99.1% (kappa = 0.92; 95% CI, 0.90 to 0.95). We conclude that the new LBMA assay will be useful for clinical and epidemiological research