Magee-Womens Hospital

Saura C., Oliveira M., Feng Y., Dai M., Chen S., Hurvitz S.A., Kim S., Moy B., Delaloge S., Gradishar W., Masuda N., Palacova M., Trudeau M.E., Mattson J., Yap Y.S., et. al.

PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

Zhang H., Ahearn T.U., Lecarpentier J., Barnes D., Beesley J., Qi G., Jiang X., O’Mara T.A., Zhao N., Bolla M.K., Dunning A.M., Dennis J., Wang Q., Ful Z.A., Aittomäki K., et. al.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1–3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10−8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores. Genome-wide analysis identifies 32 loci associated with breast cancer susceptibility, accounting for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade.

Emens L.A., Molinero L., Loi S., Rugo H.S., Schneeweiss A., Diéras V., Iwata H., Barrios C.H., Nechaeva M., Nguyen-Duc A., Chui S.Y., Husain A., Winer E.P., Adams S., Schmid P.

Abstract Background Understanding the impact of the tumor immune microenvironment and BRCA1/2-related DNA repair deficiencies on the clinical activity of immune checkpoint inhibitors may help optimize both patient and treatment selection in metastatic triple-negative breast cancer. In this substudy from the phase 3 IMpassion130 trial, immune biomarkers and BRCA1/2 alterations were evaluated for association with clinical benefit with atezolizumab and nab-paclitaxel (A+nP) vs placebo and nP in unresectable (P+nP) locally advanced or metastatic triple-negative breast cancer. Methods Patients were randomly assigned 1:1 to nab-paclitaxel 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) and atezolizumab 840 mg every 2 weeks or placebo until progression or toxicity. Progression-free survival and overall survival were evaluated based on programmed death-ligand 1 (PD-L1) expression on immune cells (IC) and tumor cells, intratumoral CD8, stromal tumor-infiltrating lymphocytes, and BRCA1/2 mutations. Results PD-L1 IC+ in either primary or metastatic tumor tissue was linked to progression-free survival and overall survival benefit with A+nP. PD-L1 IC+ low (26.9%; 243 of 902 patients) and high (13.9%; 125 of 902 patients) populations had improved outcomes that were comparable. Intratumoral CD8 and stromal tumor-infiltrating lymphocytes positivity (sTIL+) were associated with PD-L1 IC+ status; improved outcomes were observed with A+nP vs P+nP only in CD8+ and sTIL+ patients who were also PD-L1 IC+. BRCA1/2 mutations (occurring in 14.5% [89 of 612 patients]) were not associated with PD-L1 IC status, and PD-L1 IC+ patients benefited from A+nP regardless of BRCA1/2 mutation status. Conclusions Although A+nP was more efficacious in patients with richer tumor immune microenvironment, clinical benefit was only observed in patients whose tumors were PD-L1 IC+.

Urish K.L., Cassat J.E.

Osteomyelitis, or inflammation of bone, is most commonly caused by invasion of bacterial pathogens into the skeleton. Bacterial osteomyelitis is notoriously difficult to treat, in part because of the widespread antimicrobial resistance in the preeminent etiologic agent, the Gram-positive bacterium Staphylococcus aureus . Bacterial osteomyelitis triggers pathological bone remodeling, which in turn leads to sequestration of infectious foci from innate immune effectors and systemically delivered antimicrobials.

Bollag L., Lim G., Sultan P., Habib A.S., Landau R., Zakowski M., Tiouririne M., Bhambhani S., Carvalho B.

The purpose of this article is to provide a summary of the Enhanced Recovery After Cesarean delivery (ERAC) protocol written by a Society for Obstetric Anesthesia and Perinatology (SOAP) committee and approved by the SOAP Board of Directors in May 2019. The goal of the consensus statement is to provide both practical and where available, evidence-based recommendations regarding ERAC. These recommendations focus on optimizing maternal recovery, maternal-infant bonding, and perioperative outcomes after cesarean delivery. They also incorporate management strategies for this patient cohort, including recommendations from existing guidelines issued by professional organizations such as the American College of Obstetricians and Gynecologists and the American Society of Anesthesiologists. This consensus statement focuses on anesthesia-related and perioperative components of an enhanced recovery pathway for cesarean delivery and provides the level of evidence for each recommendation.

Perkins R.B., Wentzensen N., Guido R.S., Schiffman M.

ImportanceEach year in the US, approximately 100 000 people are treated for cervical precancer, 14 000 people are diagnosed with cervical cancer, and 4000 die of cervical cancer.ObservationsEssentially all cervical cancers worldwide are caused by persistent infections with one of 13 carcinogenic human papillomavirus (HPV) genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. HPV vaccination at ages 9 through 12 years will likely prevent more than 90% of cervical precancers and cancers. In people with a cervix aged 21 through 65 years, cervical cancer is prevented by screening for and treating cervical precancer, defined as high-grade squamous intraepithelial lesions of the cervix. High-grade lesions can progress to cervical cancer if not treated. Cervicovaginal HPV testing is 90% sensitive for detecting precancer. In the general population, the risk of precancer is less than 0.15% over 5 years following a negative HPV test result. Among people with a positive HPV test result, a combination of HPV genotyping and cervical cytology (Papanicolaou testing) can identify the risk of precancer. For people with current precancer risks of less than 4%, repeat HPV testing is recommended in 1, 3, or 5 years depending on 5-year precancer risk. For people with current precancer risks of 4% through 24%, such as those with low-grade cytology test results (atypical squamous cells of undetermined significance [ASC-US] or low-grade squamous intraepithelial lesion [LSIL]) and a positive HPV test of unknown duration, colposcopy is recommended. For patients with precancer risks of less than 25% (eg, cervical intraepithelial neoplasia grade 1 [CIN1] or histologic LSIL), treatment-related adverse effects, including possible association with preterm labor, can be reduced by repeating colposcopy to monitor for precancer and avoiding excisional treatment. For patients with current precancer risks of 25% through 59% (eg, high-grade cytology results of ASC cannot exclude high-grade lesion [ASC-H] or high-grade squamous intraepithelial lesion [HSIL] with positive HPV test results), management consists of colposcopy with biopsy or excisional treatment. For those with current precancer risks of 60% or more, such as patients with HPV-16–positive HSIL, proceeding directly to excisional treatment is preferred, but performing a colposcopy first to confirm the need for excisional treatment is acceptable. Clinical decision support tools can facilitate correct management.Conclusions and RelevanceApproximately 100 000 people are treated for cervical precancer each year in the US to prevent cervical cancer. People with a cervix should be screened with HPV testing, and if HPV-positive, genotyping and cytology testing should be performed to assess the risk of cervical precancer and determine the need for colposcopy or treatment. HPV vaccination in adolescence will likely prevent more than 90% of cervical precancers and cancers.

Egemen D., Cheung L.C., Chen X., Demarco M., Perkins R.B., Kinney W., Poitras N., Befano B., Locke A., Guido R.S., Wiser A.L., Gage J.C., Katki H.A., Wentzensen N., Castle P.E., et. al.

The 2019 American Society for Colposcopy and Cervical Pathology Risk-Based Management Consensus Guidelines for the management of cervical cancer screening abnormalities recommend 1 of 6 clinical actions (treatment, optional treatment or colposcopy/biopsy, colposcopy/biopsy, 1-year surveillance, 3-year surveillance, 5-year return to regular screening) based on the risk of cervical intraepithelial neoplasia grade 3, adenocarcinoma in situ, or cancer (CIN 3+) for the many different combinations of current and recent past screening results. This article supports the main guidelines presentation by presenting and explaining the risk estimates that supported the guidelines.From 2003 to 2017 at Kaiser Permanente Northern California (KPNC), 1.5 million individuals aged 25 to 65 years were screened with human papillomavirus (HPV) and cytology cotesting scheduled every 3 years. We estimated immediate and 5-year risks of CIN 3+ for combinations of current test results paired with history of screening test and colposcopy/biopsy results.Risk tables are presented for different clinical scenarios. Examples of important results are highlighted; for example, the risk posed by most current abnormalities is greatly reduced if the prior screening round was HPV-negative. The immediate and 5-year risks of CIN 3+ used to decide clinical management are shown.The new risk-based guidelines present recommendations for the management of abnormal screening test and histology results; the key risk estimates supporting guidelines are presented in this article. Comprehensive risk estimates are freely available online at https://CervixCa.nlm.nih.gov/RiskTables.

Brufsky A.

Coronavirus disease-2019 (COVID-19) infection and its severity can be explained by the concentration of glycosylated severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral particles in the lung epithelium, the concentration of glycosylated angiotensin-converting enzyme receptor 2 (ACE2) in the lung epithelium, and the degree and control of the pulmonary immune response to the SARS-CoV-2 spike protein at approximately day 8 to 10 after symptom onset, which may be related to both. Binding of ACE2 by SARS-CoV-2 in COVID-19 also suggests that prolonged uncontrolled hyperglycemia, and not just a history of diabetes mellitus, may be important in the pathogenesis of the disease. It is tempting to consider that the same mechanism acts in COVID-19 as in SARS, where an overactive macrophage M1 inflammatory response, as neutralizing antibodies to the SARS-CoV-2 spike protein form at day 7 to 10, results in acute respiratory distress syndrome (ARDS) in susceptible patients. It also allows consideration of agents, such as hydroxychloroquine, which may interfere with this overly brisk macrophage inflammatory response and perhaps influence the course of the disease, in particular, those that blunt but do not completely abrogate the M1 to M2 balance in macrophage polarization, as well as viral load, which in SARS appears to be temporally related to the onset of ARDS.

Schiff D.M., Nielsen T., Hoeppner B.B., Terplan M., Hansen H., Bernson D., Diop H., Bharel M., Krans E.E., Selk S., Kelly J.F., Wilens T.E., Taveras E.M.

Importance Racial and ethnic disparities persist across key health and substance use treatment outcomes for mothers and infants. The use of medications, such as methadone or buprenorphine, for the treatment of opioid use disorder (OUD) has been associated with improvements in the outcomes of mothers and infants; however, only half of all pregnant women with OUD receive these medications. The extent to which maternal race or ethnicity is associated with the use of medication to treat OUD, the duration of the use of medication to treat OUD, and the type of medication used to treat OUD during pregnancy are unknown. Objective To examine the extent to which maternal race and ethnicity is associated with the use of medications for the treatment of OUD in the year before delivery among pregnant women with OUD. Design, Setting, and Participants This retrospective cohort study used a linked population-level statewide data set of pregnant women with OUD who delivered a live infant in Massachusetts between October 1, 2011, and December 31, 2015. Of 274 234 total deliveries identified, 5247 deliveries among women with indicators of having OUD were included in the analysis. Maternal race and ethnicity were defined as white non-Hispanic, black non-Hispanic, or Hispanic based on self-reported data on birth certificates. Main Outcomes and Measures Main outcomes were the receipt of any medication for OUD, the consistency of the use of medication (at least 6 continuous months of use before delivery, inconsistent use, or no use) for the treatment of OUD, and the type of medication (methadone or buprenorphine) used to treat OUD. Multivariable models were adjusted for maternal sociodemographic characteristics, comorbidities, and any significant interactions between the covariates and race and ethnicity. Results The sample included 5247 pregnant women with OUD who delivered a live infant in Massachusetts during the study period. The mean (SD) maternal age at delivery was 28.7 (5.0) years; 4551 women (86.7%) were white non-Hispanic, 462 women (8.8%) were Hispanic, and 234 women (4.5%) were black non-Hispanic. A total of 3181 white non-Hispanic women (69.9%) received any type of medication for the treatment of OUD in the year before delivery compared with 228 Hispanic women (49.4%) and 108 black non-Hispanic women (46.2%). Compared with white non-Hispanic women, black non-Hispanic and Hispanic women had a substantially lower likelihood (adjusted odds ratio [aOR], 0.37; 95% CI, 0.28-0.49 and aOR, 0.42; 95% CI, 0.35-0.52, respectively) of receiving any medication for the treatment of OUD. Stratification by maternal age identified greater disparities among younger women. Black non-Hispanic and Hispanic women also had a lower likelihood (aOR, 0.24; 95% CI, 0.17-0.35 and aOR, 0.34; 95% CI, 0.27-0.44, respectively) of consistent use of medication for the treatment of OUD compared with white non-Hispanic women. With respect to the type of medication used to treat OUD, black non-Hispanic and Hispanic women had a lower likelihood (aOR, 0.60; 95% CI, 0.40-0.90 and aOR, 0.77; 95% CI, 0.58-1.01, respectively) than white non-Hispanic women of receiving buprenorphine treatment compared with methadone treatment. Conclusions and Relevance This study found racial and ethnic disparities in the use of medications to treat OUD during pregnancy, with black non-Hispanic and Hispanic women significantly less likely to use medications consistently or at all compared with white non-Hispanic women. Further investigation of patient, clinician, treatment program, and system-level factors associated with these findings is warranted.

Smith S.M., Boppana A., Traupman J.A., Unson E., Maddock D.A., Chao K., Dobesh D.P., Brufsky A., Connor R.I.

Identification of risk factors of severe coronavirus disease 2019 (COVID-19) is critical for improving therapies and understanding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis. We analyzed 184 patients hospitalized for COVID-19 in Livingston, New Jersey for clinical characteristics associated with severe disease. The majority of patients with COVID-19 had diabetes mellitus (DM) (62.0%), Pre-DM (23.9%) with elevated fasting blood glucose (FBG), or a body mass index >30 with normal hemoglobin A1c (HbA1C) (4.3%). SARS-CoV-2 infection was associated with new and persistent hyperglycemia in 29 patients, including several with normal HbA1C levels. Forty-four patients required intubation, which occurred significantly more often in patients with DM as compared with non-diabetics. Severe COVID-19 occurs in the presence of impaired glucose metabolism in patients, including those with DM, preDM, and obesity. COVID-19 is associated with elevated FBG and several patients presented with new onset DM or in DKA. The association of dysregulated glucose metabolism and severe COVID-19 suggests that SARS-CoV-2 pathogenesis involves a novel interplay with glucose metabolism. Exploration of pathways by which SARS-CoV-2 interacts glucose metabolism is critical for understanding disease pathogenesis and developing therapies.