Citations

AbstractBackground:Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Patients with TNBC are primarily treated with neoadjuvant chemotherapy (NAC). Response to NAC is prognostic, with reductions in low overall survival and disease-free survival rates in those patients who do not achieve pathological complete response (pCR). Based on this premise, we focused on patients with residual disease and hypothesized that paired analysis of primary and residual TNBC tumors following NAC could identify unique biomarkers associated with post-NAC recurrence.Methods and Results: We investigated 24 TNBC tumors from 12 patients with pre- and post-NAC data, including four patients who recurred shortly after surgery(<24 months) and eight who remained recurrence-free (> 48 months). These tumors were collected from a prospective NAC breast cancer study (BEAUTY) conducted at the Mayo Clinic. Differential expression analysis of pre-NAC biopsies showed minimal gene expression differences between early recurrent and non-recurrent TNBC tumors; however, post-NAC samples demonstrated a significant alteration in expression patterns in response to intervention. Topological-level differences associated with early recurrence were implicated in 251 gene sets, and an independent assessment of microarray gene expression data from the paired NAC I-SPY1 trial confirmed 56 genesets. Underlying these 56 gene sets, 113 genes were observed to be differentially expressed in the I-SPY1 and BEAUTY post-NAC studies. An independent (n=392) breast cancer data set with relapse-free survival (RFS) data was used to refine our gene list to a 17 gene signature. A three-fold cross-validation analysis of the gene signature with the combined BEAUTY and I-SPY1 data yielded an average AUC of 0.88 for six machine learning models. Due to the limited studies with pre-and post-NAC TNBC tumor data, further validation of the signature is needed.Conclusion:Analysis of multi-omics data from post-NAC TNBC chemoresistant tumors showed downregulation of mismatch repair, purin, and tubulin pathways. Additionally, weidentified a 17 gene signature in TNBC associated with post-NAC recurrence enriched with down-regulation of immune genes.

AbstractBackgroundWe hypothesized full‐thickness chest wall resection (FTCWR) with advanced surgical techniques and modern systemic therapy is safe, provides local control, and good overall survival.MethodsRetrospective review of FTCWR (including rib or part of sternum) for breast cancer between 2000 and 2020. Primary endpoints included 90‐day morbidities and all‐cause mortality. Secondary endpoints were loco‐regional and distant recurrence, DFS and overall survival (OS).ResultsA total of 35 patients met the criteria. 34 FTCWR were for recurrence and the median time to chest wall recurrence was 6 years. Tumor subtype was triple‐negative in 51% and the remainder HR+ Her2−. 58% were palliative resections. FTCWR included rib(s) in 89% and portion of sternum in 57%; 94% required reconstruction and 80% were R0 resections. There were no 90‐day mortalities. Overall morbidity was 10/35(28%). 17(49%) patients received neoadjuvant systemic therapy for their recurrence and three received neoadjuvant radiation. Adjuvant treatment included chemotherapy (8), endocrine therapy (3), and both (8). Ten patients (28%) received adjuvant radiation. The Median follow‐up was 31 months and there were 6 (17%) loco‐regional and 7 (20%) distant recurrences. OS was 86% and 67% at 1 and 3 years, respectively.ConclusionFTCWR was associated with low morbidity, mortality, recurrence rates, and good OS. Selective FTCWR is safe and has acceptable short‐term survival rates.

Case: A 49-year-old highly active man had a direct fall on the left shoulder, causing a chronic locked posterior shoulder dislocation. Radiographic analysis revealed a reverse Hill-Sachs lesion (RHSL) that affected 31% of the articular surface. He was successfully treated with a modified McLaughlin procedure that included a double-row suture anchor as a novel fixation approach to secure the lesser tuberosity transfer and the subscapularis tenodesis. Conclusion: The reported approach for reconstructing the RHSL provides adequate stability, pain reduction, and functional outcomes. It may be considered as an option for joint preservation in extensive humeral head defects.

BackgroundTo evaluate risk factors (treatment‐related, comorbidities, and lifestyle) for breast cancer–related lymphedema (BCRL) within the context of a Prospective Surveillance and Early Intervention (PSEI) model of care for subclinical BCRL.MethodsThe parent randomized clinical trial assigned patients newly diagnosed with breast cancer to PSEI with either bioimpedance spectroscopy (BIS) or tape measurement (TM). Surgical, systemic and radiation treatments, comorbidities, and lifestyle factors were recorded. Detection of subclinical BCRL (change from baseline of either BIS L‐Dex ≥6.5 or tape volume ≥ 5% and < 10%) triggered an intervention with compression therapy. Volume change from baseline ≥10% indicated progression to chronic lymphedema and need for complex decongestive physiotherapy. In this secondary analysis, multinomial logistic regressions including main and interaction effects of the study group and risk factors were used to test for factor associations with outcomes (no lymphedema, subclinical lymphedema, progression to chronic lymphedema after intervention, progression to chronic lymphedema without intervention). Post hoc tests of significant interaction effects were conducted using Bonferroni‐corrected alphas of .008; otherwise, an alpha of .05 was used for statistical significance.ResultsThe sample (n = 918; TM = 457; BIS = 461) was female with a median age of 58.4 years. Factors associated with BCRL risk included axillary lymph node dissection (ALND) (p < .001), taxane‐based chemotherapy (p < .001), regional nodal irradiation (RNI) (p ≤ .001), body mass index >30 (p = .002), and rurality (p = .037). Mastectomy, age, hypertension, diabetes, seroma, smoking, and air travel were not associated with BCRL risk.ConclusionsWithin the context of 3 years of PSEI for subclinical lymphedema, variables of ALND, taxane‐based chemotherapy, RNI, body mass index >30, and rurality increased risk.

Abstract Background Clinical differences between critical illness from influenza infection vs coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients. Methods We compared demographics, clinical characteristics, and outcomes of US children (aged 8 months to 17 years) admitted to the intensive care or high-acuity unit with influenza or COVID-19. Using mixed-effects models, we assessed the odds of death or requiring life support for influenza vs COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity. Results Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median, 5.2 years vs 13.8 years), less likely to be non-Hispanic Black (14.5% vs 27.6%) or Hispanic (24.0% vs 36.2%), and less likely to have ≥1 underlying condition (66.4% vs 78.5%) or be obese (21.4% vs 42.2%), and a shorter hospital stay (median, 5 days vs 7 days). They were similarly likely to require invasive mechanical ventilation (both 30.2%), vasopressor support (19.6% and 19.9%), or extracorporeal membrane oxygenation (2.2% and 2.9%). Four children with influenza (2.2%) and 11 children with COVID-19 (2.9%) died. The odds of death or requiring life support in children with influenza vs COVID-19 were similar (adjusted odds ratio, 1.30; 95% confidence interval, .78–2.15; P = .32). Conclusions Despite differences in demographics and clinical characteristics of children with influenza or COVID-19, the frequency of life-threatening complications was similar. Our findings highlight the importance of implementing prevention measures to reduce transmission and disease severity of influenza and COVID-19.

Background TAILOR‐PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to decreased Clopidogrel Response After Percutaneous Coronary Intervention) studied genotype‐guided selection of antiplatelet therapy after percutaneous coronary intervention versus conventional therapy with clopidogrel. The presence of CYP2C19 loss‐of‐function alleles in patients treated with clopidogrel may be associated with increased risk for ischemic events. We report a prespecified sex‐specific analysis of genotyping and associated cardiovascular outcomes from this study. Methods and Results Associations between sex and major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia) and Bleeding Academic Research Consortium (BARC) bleeding at 12 months were analyzed using Cox proportional‐hazards models. Among 5276 randomized patients, loss‐of‐function carriers were observed in ≈36% of both sexes, and >80% of carriers were heterozygotes. At 12 months, after adjustment for baseline differences, risks of MACE (HR , 1.28 [0.97 to 1.68]; P =0.088) and BARC bleeding (hazard ratio [HR], 1.36 [0.91 to 2.05]; P =0.14) were comparable among women and men. There were no significant interactions between sex and treatment strategy for MACE interaction P value ( P int =0.59) or BARC bleeding ( P int =0.47) nor for sex and genotype (MACE P int =0.15, and BARC bleeding P int =0.60). Conclusions CYP2C19 loss‐of‐function alleles were present in ≈1 in 3 women and men. Women had similar adjusted risks of MACE and bleeding as men following percutaneous coronary intervention. Genotype‐guided therapy did not significantly reduce the risk of MACE or bleeding relative to conventional therapy for both sexes. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01742117.

AbstractAlthough pulmonary hypertension (PH) is widely prevalent in India, care delivery for this condition has unique challenges in a lower middle‐income country (LMIC). To describe care delivery for patients with PH and associated barriers in India. We interviewed physicians across eight healthcare systems in India about PH clinical care using semi‐structured enquiries to understand care delivery and associated challenges in their specific practice as well as the associated health system. Qualitative analysis was performed using content analysis methodology. Physicians reported that common causes for PH in their practice were rheumatic mitral valve disease, coronary artery disease, and congenital heart disease (CHD). No center had a dedicated PH program. Only one center had a specific protocol for PH management. Diagnostic evaluations were limited, and right heart catheterizations were recommended for patients with CHD. Pulmonary vasodilator therapy was used for severe symptoms or markers of severe disease. Agents used to treat PH were widely variable across physicians and prostacyclins are unavailable in India. Barriers included limited training in PH for physicians, lack of consensus guidelines for PH specific to LMIC, and lack of financial incentives for health care systems to organize dedicated PH programs. Other barriers included poor patient health literacy and socioeconomic barriers that limit ability to test and treat PH. PH care delivery in India is variable with widely differing clinical practices. Dedicated training in PH management and establishing guidelines specific to LMIC like India can form the first step forward.

Background: Vascular endothelial growth factor (VEGF) C156S is an engineering variant of VEGF-C that has the potential to promote lymphangiogenesis, activating on VEGF receptor (VEGFR) 3, without promoting angiogenesis (i.e., not acting on VEGFR-2). We conducted a systematic review of publications assessing the use of this growth factor in lymphedema treatment. We hypothesized that VEGF-C156S specificity for VEGFR-3 was an important differential for the lymphangiogenesis promoted by it. Methods and Results: We conducted a comprehensive systematic review of the published literature on PubMed/Medline, Embase, and Cochrane Clinical Answers. Eligibility criteria included articles reporting data on the use of VEGF-C156S in lymphedema treatment. We excluded articles that investigated physiology action of VEGF-C156S and articles that focused on other therapies. From 304 potential articles found in the literature, four studies fulfilled the study eligibility criteria. To date, all studies about this growth factor have been experimental. The effect of VEGF-C156 on lymph node transfer was investigated in half of the experiments. Interestingly, delivery of VEGF-C156S was mostly performed through viral gene transfer, but injection (subcutaneously or intravenously) of it as a protein (liposomal or nonliposomal) was also investigated by one author to assess drug bioavailability. Conclusions: Although authors reported promotion of lymphangiogenesis, VEGF-C156S was correlated with lymphatic hyperplasia or nonstatistically significant lymphangiogenesis compared with controls. Scientific evidence about the use of VEGF-C156S in lymphedema treatment is still limited. However, authors have shown that its lymphangiogenic effect is inferior to VEGF-C.

OBJECTIVES Infectious meningitis (IM) in US children is increasingly rare and new rapid multiplex PCR-based testing is increasingly available. We evaluated the added value of cerebrospinal fluid (CSF) protein and glucose tests to predict IM when compared with information provided by CSF white blood cell count (WBC) and multiplex polymerase chain reaction (PCR). METHODS We retrospectively reviewed CSF results from October 2015 to August 2017 in patients 0 to 18 years at a US children’s hospital. Noninfectious evaluations were excluded. Test characteristics were calculated for CSF WBC, protein, and glucose in isolation and in parallel for prediction of microbiologically confirmed IM. Chart review was performed to identify consideration of protein and glucose in medical decision-making (MDM). RESULTS We identified 735 patients including 446 &lt;2 months; 45 (6.1%) had microbiologically-confirmed IM, including 23 (5.2%) age &lt;2 months. Multiplex PCR and/or CSF WBC identified all IM patients. When added to CSF WBC, measurement of glucose made no contribution to sensitivity, specificity, positive predictive value (PPV) or negative predictive value (NPV), and protein had no impact on sensitivity and decreased the specificity, PPV, and NPV compared with CSF WBC alone. Abnormal protein was documented in MDM in 6 (0.8%) patients, all of whom had elevated WBC counts also cited. Glucose was not mentioned in MDM. CONCLUSIONS Multiplex PCR testing and WBC may be sufficient to predict meningitis in children in low incidence settings. Protein and glucose did not contribute significant additional information. More intentional use of protein and glucose testing in patients with suspected IM may achieve higher value care.