Cytoreductive therapy in younger adults with polycythemia vera: a meta-analysis of safety and outcomes.

ABSTRACT: Cytoreductive therapy is not routinely recommended for younger patients with polycythemia vera (PV) due to concern that treatment toxicity may outweigh therapeutic benefits. However, no systematic data support this approach. To support objective risk/benefit assessment of cytoreductive drugs in patients with PV aged <60 years (PV<60), this systematic review and meta-analysis was conducted to evaluate toxicity and disease-related complications in PV<60 treated with interferon alfa (rIFN-α) or hydroxyurea (HU). A search of PubMed, Scopus, Web of Science and Embase identified 693 unique studies with relevant keywords, of which 14 met inclusion criteria and were selected for analysis. The weighted average age of patients treated with rIFN-α was 48 years (n = 744 patients; 12 studies) and for HU was 56 years (n = 1397; 8 studies). The weighted average duration of treatment for either drug was 4.5 years. Using a Bayesian hierarchical model, the pooled annual rate of discontinuation due to toxicity was 5.2% for patients receiving rIFN-α (n = 587; 95% confidence interval [CI], 2.2-8.2) and 3.6% for HU (n = 1097; CI, 1-6.2). The average complete hematologic response for rIFN-α and HU was 62% and 52%, respectively. Patients experienced thrombotic events at a pooled annual rate of 0.79% and 1.26%; secondary myelofibrosis at 1.06% and 1.62%; acute myeloid leukemia at 0.14% and 0.26%; and death at 0.87% and 2.65%, respectively. No treatment-related deaths were reported. With acceptable rates of nonfatal toxicity, cytoreductive treatment, particularly with disease-modifying rIFN-α, may benefit PV<60. Future randomized trials prioritizing inclusion of PV<60 are needed to establish a long-term benefit of early cytoreductive treatment in these patients.

Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2.

Obesity, defined as a body mass index (BMI) ≥ 30, is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated BMI is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear because of inconsistent findings from epidemiological studies and a lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelia of women carrying a BRCA mutation is positively correlated with BMI and with biomarkers of metabolic dysfunction. In addition, RNA sequencing showed obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which affected neighboring breast epithelial cells. In breast tissue explants cultured from women carrying a BRCA mutation, we found that blockade of estrogen biosynthesis or estrogen receptor activity decreased DNA damage. Additional obesity-associated factors, including leptin and insulin, increased DNA damage in human BRCA heterozygous epithelial cells, and inhibiting the signaling of these factors with a leptin-neutralizing antibody or PI3K inhibitor, respectively, decreased DNA damage. Furthermore, we show that increased adiposity was associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1+/- mice. Overall, our results provide mechanistic evidence in support of a link between elevated BMI and breast cancer development in BRCA mutation carriers. This suggests that maintaining a lower body weight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.

Times to Diagnosis, Staging, and Treatment of Head and Neck Cancer Before and During COVID-19.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has reduced the demand for, and supply of, head and neck cancer services. This study compares the times to diagnosis, staging, and treatment of head and neck cancers before and during the COVID-19 pandemic. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary academic medical center in New York City (NYC). METHODS: The times to diagnosis, staging, and treatment of head and neck cancer for patients presenting to the clinics of 4 head and neck oncology surgeons with newly diagnosed head and neck cancers were compared between pre-COVID-19 and COVID-19 periods. RESULTS: Sixty-eight patients in the pre-COVID-19 period and 26 patients in the COVID-19 period presented with newly diagnosed head and neck cancer. Patients in the COVID-19 group had a significantly longer time to diagnosis than the pre-COVID-19 group after adjustment for age and cancer diagnosis (P = .02; hazard ratio [HR], 0.54; 95% CI, 0.32-0.92). Patients in the pre-COVID-19 and COVID-19 groups had no statistically significant differences in time to staging (P > .9; HR, 1.01; 95% CI, 0.58-1.74) or time to treatment (P = .12; HR, 1.55; 95% CI, 0.89-2.72). CONCLUSION: This study found that time to diagnosis for head and neck cancers was delayed during a COVID-19 period compared to a pre-COVID-19 period. However, there was no evidence of delays in time to staging and time to treatment during the COVID-19 period. Our results prompt further investigations into the factors contributing to diagnostic delays but provide reassurance that despite COVID-19, patients were receiving timely staging and treatment for head and neck cancers.

Clinical Significance of Circulating Tumor Cells in Hormone Receptor-positive Metastatic Breast Cancer Patients who Received Letrozole with or Without Bevacizumab.

PURPOSE: We evaluated the prognostic and predictive value of circulating tumor cells (CTCs) hormone receptor-positive (HR+) metastatic breast cancer (MBC) patients randomized to letrozole alone or letrozole plus bevacizumab in the first-line setting (CALGB 40503). EXPERIMENTAL DESIGN: Blood samples were collected at pretreatment and three additional time points during therapy. The presence of ≥5 CTCs per 7.5 mL of blood was considered CTC positive. Association of CTCs with progression-free survival (PFS) and overall survival (OS) was assessed using Cox regression models. RESULTS: Of 343 patients treated, 294 had CTC data and were included in this analysis. Median follow-up was 39 months. In multivariable analysis, CTC-positive patients at baseline (31%) had significantly reduced PFS [HR, 1.49; 95% confidence interval (CI), 1.12-1.97] and OS (HR, 2.08; 95% CI, 1.49-2.93) compared with CTC negative. Failure to clear CTCs during treatment was associated with significantly increased risk of progression (HR, 2.2; 95% CI, 1.58-3.07) and death (HR, 3.4; 95% CI, 2.36-4.88). CTC-positive patients who received only letrozole had the worse PFS (HR, 2.3; 95% CI, 1.54-3.47) and OS (HR, 2.6; 95% CI, 1.59-4.40). Median PFS in CTC-positive patients was significantly longer (18.0 vs. 7.0 months) in letrozole plus bevacizumab versus letrozole arm (P = 0.0009). Restricted mean survival time analysis further revealed that addition of bevacizumab was associated with PFS benefit in both CTC-positive and CTC-negative patients, but OS benefit was only observed in CTC-positive patients. CONCLUSIONS: CTCs were highly prognostic for the addition of bevacizumab to first-line letrozole in patients with HR+ MBC in CALGB 40503. Further research to determine the potential predictive value of CTCs in this setting is warranted.

Association of Peripheral Vascular Disease With Complications After Total Ankle Arthroplasty.

BACKGROUND: Despite limited evidence, peripheral vascular disease is often cited as a contraindication for total ankle arthroplasty. The purpose of our study was to identify whether peripheral vascular disease in patients undergoing total ankle arthroplasty increased the rate of infection, postoperative irrigation and debridement, or failure of the implant. METHODS: The PearlDiver Database was used to identify Medicare patients who underwent a total ankle arthroplasty from 2005 to 2014. These data were then analyzed for postoperative infections within 90 days, subsequent irrigation and debridements, and failure of total ankle arthroplasties. A diagnosis of preoperative peripheral vascular disease only included those patients who had peripheral vascular disease as an ICD-9 diagnosis code and underwent a preoperative lower extremity angiogram prior to total ankle arthroplasty. Medical comorbidities were identified using ICD-9 diagnosis codes. Three multivariable logistic regression models were then developed in order to identify risk factors associated with postoperative infections and failure after total ankle arthroplasty. RESULTS: A total of 10 698 Medicare patients who underwent a primary total ankle arthroplasty were identified. There were 334 patients who had a postoperative infection within 90 days of their total ankle arthroplasty, and 95 of those patients required an irrigation and debridement. Regression analysis demonstrated that patients with peripheral vascular disease had the greatest risk of developing a postoperative infection within 90 days (OR 2.85, P < .01), requiring an irrigation and debridement postoperatively (OR 4.87, P < .001), and having a total ankle arthroplasty failure at any time point postoperatively (OR 2.51, P < .001). CONCLUSIONS: Our study suggests that preoperative peripheral vascular disease is a significant risk factor for an acute postoperative infection, postoperative irrigation and debridement, and failure of the implant in Medicare patients undergoing a total ankle arthroplasty. LEVEL OF EVIDENCE: Level III, therapeutic.

Somatic mutations precede acute myeloid leukemia years before diagnosis.

The pattern of somatic mutations observed at diagnosis of acute myeloid leukemia (AML) has been well-characterized. However, the premalignant mutational landscape of AML and its impact on risk and time to diagnosis is unknown. Here we identified 212 women from the Women's Health Initiative who were healthy at study baseline, but eventually developed AML during follow-up (median time: 9.6 years). Deep sequencing was performed on peripheral blood DNA of these cases and compared to age-matched controls that did not develop AML. We discovered that mutations in IDH1, IDH2, TP53, DNMT3A, TET2 and spliceosome genes significantly increased the odds of developing AML. All subjects with TP53 mutations (n = 21 out of 21 patients) and IDH1 and IDH2 (n = 15 out of 15 patients) mutations eventually developed AML in our study. The presence of detectable mutations years before diagnosis suggests that there is a period of latency that precedes AML during which early detection, monitoring and interventional studies should be considered.

Outcomes of Reconstruction of the Stage II Adult-Acquired Flatfoot Deformity in Older Patients.

BACKGROUND: Reconstruction of the stage II adult-acquired flatfoot deformity (AAFD) often requires the use of multiple osteotomies and soft tissue procedures that may not heal well in older patients. The purpose of our study was to determine whether patients older than 65 years with stage II AAFD had inferior clinical outcomes or an increased number of subsequent surgical procedures after flatfoot reconstruction when compared with younger patients. METHODS: One-hundred forty consecutive feet (70 right, 70 left) with stage II AAFD in 137 patients were divided into 3 groups based on age: younger than 45 years (young; n = 21), 45 to 65 years (middle-aged; n = 87), and 65 years and older (older; n = 32). Preoperative and postoperative Foot and Ankle Outcome Scores (FAOSs) at a minimum of 2 years were compared. Hospital records were reviewed to determine if patients underwent a subsequent procedure postoperatively. RESULTS: Patients in the older group did not demonstrate any differences in changes in FAOS subscales compared with patients in the young and middle-aged groups (all P > .15). The older group had significant preoperative to postoperative improvements in all the FAOS subgroups ( P < .01). In addition, patients in the older group were not more likely to undergo a subsequent surgery than were the younger patients (all P > .10). CONCLUSIONS: Our study found that patients older than 65 years with stage II AAFD have improvements in patient-reported outcomes and rates of revision surgery after surgical reconstruction that were not significantly different than those of younger patients. LEVEL OF EVIDENCE: Therapeutic Level III, comparative series.

Development and Validation of an Assessment Tool for Competency in Critical Care Ultrasound.

BACKGROUND: Point-of-care ultrasound is an emerging technology in critical care medicine. Despite requirements for critical care medicine fellowship programs to demonstrate knowledge and competency in point-of-care ultrasound, tools to guide competency-based training are lacking. OBJECTIVE: We describe the development and validity arguments of a competency assessment tool for critical care ultrasound. METHODS: A modified Delphi method was used to develop behaviorally anchored checklists for 2 ultrasound applications: "Perform deep venous thrombosis study (DVT)" and "Qualify left ventricular function using parasternal long axis and parasternal short axis views (Echo)." One live rater and 1 video rater evaluated performance of 28 fellows. A second video rater evaluated a subset of 10 fellows. Validity evidence for content, response process, and internal consistency was assessed. RESULTS: An expert panel finalized checklists after 2 rounds of a modified Delphi method. The DVT checklist consisted of 13 items, including 1.00 global rating step (GRS). The Echo checklist consisted of 14 items, and included 1.00 GRS for each of 2 views. Interrater reliability evaluated with a Cohen kappa between the live and video rater was 1.00 for the DVT GRS, 0.44 for the PSLA GRS, and 0.58 for the PSSA GRS. Cronbach α was 0.85 for DVT and 0.92 for Echo. CONCLUSIONS: The findings offer preliminary evidence for the validity of competency assessment tools for 2 applications of critical care ultrasound and data on live versus video raters.