Citations

Abstract An evolutionary perspective provides a unifying explanation for the modifiable risk factors and lifestyle-based interventions for the leading causes of morbidity and mortality globally. Non-communicable diseases develop from an evolutionary mismatch between the prior environment and modern patterns of behavior; however, it is unclear whether an evolutionary mismatch narrative could promote positive behavior change in patients. We hypothesize that educating patients about evolutionary mismatch could augment efforts to improve healthful behavior. Specifically, explaining the ‘why’ behind what is being recommended could promote health literacy and adherence. Furthermore, we offer suggestions of how clinicians could educate patients about evolutionary mismatch for key-lifestyle factors, diet and physical activity, as well as several specific modern diseases. We also consider how to sidestep patients’ skepticism of evolutionary theory. Here, we lay the groundwork for research on how educating patients with an evolutionary mismatch narrative could impact health behaviors and improve outcomes.

AbstractBackgroundEpidemiological studies have demonstrated a positive association between chronic lymphocytic leukaemia (CLL) and non-melanoma skin cancer (NMSC). We hypothesized that shared genetic risk factors between CLL and NMSC could contribute to the association observed between these diseases.MethodsWe examined the association between (i) established NMSC susceptibility loci and CLL risk in a meta-analysis including 3100 CLL cases and 7667 controls and (ii) established CLL loci and NMSC risk in a study of 4242 basal cell carcinoma (BCC) cases, 825 squamous cell carcinoma (SCC) cases and 12802 controls. Polygenic risk scores (PRS) for CLL, BCC and SCC were constructed using established loci. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).ResultsHigher CLL-PRS was associated with increased BCC risk (OR4th-quartile-vs-1st-quartile = 1.13, 95% CI: 1.02–1.24, Ptrend = 0.009), even after removing the shared 6p25.3 locus. No association was observed with BCC-PRS and CLL risk (Ptrend = 0.68). These findings support a contributory role for CLL in BCC risk, but not for BCC in CLL risk. Increased CLL risk was observed with higher SCC-PRS (OR4th-quartile-vs-1st-quartile = 1.22, 95% CI: 1.08–1.38, Ptrend = 1.36 × 10–5), which was driven by shared genetic susceptibility at the 6p25.3 locus.ConclusionThese findings highlight the role of pleiotropy regarding the pathogenesis of CLL and NMSC and shows that a single pleiotropic locus, 6p25.3, drives the observed association between genetic susceptibility to SCC and increased CLL risk. The study also provides evidence that genetic susceptibility for CLL increases BCC risk.

OBJECTIVE Surgical treatment for degenerative spondylolisthesis has been proven to be clinically challenging and cost-effective. However, there is a range of thresholds that surgeons utilize for incorporating fusion in addition to decompressive laminectomy in these cases. This study investigates these surgeon- and site-specific factors by using the Quality Outcomes Database (QOD). METHODS The QOD was queried for all cases that had undergone surgery for grade 1 spondylolisthesis from database inception to February 2019. In addition to patient-specific covariates, surgeon-specific covariates included age, sex, race, years in practice (0–10, 11–20, 21–30, > 30 years), and fellowship training. Site-specific variables included hospital location (rural, suburban, urban), teaching versus nonteaching status, and hospital type (government, nonfederal; private, nonprofit; private, investor owned). Multivariable regression and predictor importance analyses were performed to identify predictors of the treatment performed (decompression alone vs decompression and fusion). The model was clustered by site to account for site-specific heterogeneity in treatment selection. RESULTS A total of 12,322 cases were included with 1988 (16.1%) that had undergone decompression alone. On multivariable regression analysis clustered by site, adjusting for patient-level clinical covariates, no surgeon-specific factors were found to be significantly associated with the odds of selecting decompression alone as the surgery performed. However, sites located in suburban areas (OR 2.32, 95% CI 1.09–4.84, p = 0.03) were more likely to perform decompression alone (reference = urban). Sites located in rural areas had higher odds of performing decompression alone than hospitals located in urban areas, although the results were not statistically significant (OR 1.33, 95% CI 0.59–2.61, p = 0.49). Nonteaching status was independently associated with lower odds of performing decompression alone (OR 0.40, 95% CI 0.19–0.97, p = 0.04). Predictor importance analysis revealed that the most important determinants of treatment selection were dominant symptom (Wald χ2 = 34.7, accounting for 13.6% of total χ2) and concurrent diagnosis of disc herniation (Wald χ2 = 31.7, accounting for 12.4% of total χ2). Hospital teaching status was also found to be relatively important (Wald χ2 = 4.2, accounting for 1.6% of total χ2) but less important than other patient-level predictors. CONCLUSIONS Nonteaching centers were more likely to perform decompressive laminectomy with supplemental fusion for spondylolisthesis. Suburban hospitals were more likely to perform decompression only. Surgeon characteristics were not found to influence treatment selection after adjustment for clinical covariates. Further large database registry experience from surgeons at high-volume academic centers at which surgically and medically complex patients are treated may provide additional insight into factors associated with treatment preference for degenerative spondylolisthesis.

Abstract Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR, ypT0/Tis ypN0). SGN-LIV1A is an investigational antibody drug conjugate consisting of an antibody to LIV1A, a zinc transporter highly prevalent in breast cancer, and a highly potent microtubule inhibitor, monomethyl auristatin E. Retrospective IHC analysis of LIV1A expression levels amongst tumor samples from 100 previous ISPY-2 patients showed 88% of breast tumor samples with moderate to high expression of LIV1A (Yau, C. et al SABCS 2018).Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone-receptor positive (HR+) patients had to have MP high molecular profile. Treatment included SGN-LIV1A 2.5 mg/kg (max dose 250 mg) every 3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. All patients undergo serial MR imaging where response at 3 & 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Analysis set was modified intention to treat with patients who switched to non-protocol therapy counted as non-pCR and not as their pCR status at time of surgery. The goal is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint within signatures defined by HR & HER2 status & MP result. This investigational arm was eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-HER2-. Regimens may also leave the trial for futility (< 10% probability of success), maximum sample size accrual (10% < probability of success <85%), maximum time in trial (2 years) or for safety as recommended by the independent DSMB. Results: Sixty patients were randomized and evaluable to SGN-LIV1A. The study arm was stopped due to reaching the predetermined time limit for patient accrual of 2 yrs. Final estimated pCR rates are below. The estimated pCR rates were similar between the SGN-LIV1A and control arms for any tumor subtype. Preliminary safety events for SGN-LIV1A include increased rates of transaminitis and hyperglycemia and reduced rates of peripheral neuropathy compared to control. One patient was removed from the analysis as she was determined to have angiosarcoma of the breast. Notably, this patient had a dramatic early response and subsequent pCR to SGN-LIV1A treatment. Conclusion: The value of I-SPY 2 is to give insight about the performance of an investigational agent’s likelihood of achieving pCR. SGN-LIV1A delivered every 3 weeks was comparable to paclitaxel for the primary endpoint of pCR in I-SPY2 and may have a similar side effect profile, however, with less peripheral neuropathy. Clinical trials evaluating weekly dosing of SGN-LIV1A are ongoing. A trial of SGN-LIV1A in the treatment of angiosarcoma is under consideration at this time. Final Estimated pCR Rates and Predictive ProbabilitiesEstimated pCR rate(95% prob interval)SignatureSGN-LIV1AControlProbability SGNLIV1A Superior to ControlPredictive Probability of Success in Phase 3HER2-0.16 (0.08-0.24) N= 600.20 (0.16-0.25) N= 3270.180.02HR-/HER2-0.25 (0.12-0.37) N=360.28 (0.21-0.35) N=1460.310.06HR+/HER2-0.09 (0-0.18) N=240.14 (0.09-0.19) N=1810.150.03 Citation Format: Heather Beckwith, Richard Schwab, Christina Yau, Erica Stringer-Reasor, Shi Wei, A. Jo Chien, Kathy S Albain, Kevin Kalinsky, Anne Wallace, Anthony Elias, Douglas Yee, Amy S Clark, Judy C Boughey, Heather Han, Rita Nanda, Claudine Isaacs, Zahi Mitri, Julie E Lang, Alexandra Thomas, Tara Sanft, Angela DeMichele, Jane Perlmutter, Hope S Rugo, Nola M Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, I-SPY 2 Consortium, Amy Wilson, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of SGN-LIV1a followed by AC in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-10.

Abstract Context. —The World Health Organization (WHO) recently published its 4th edition of the classification of tumors of the central nervous system, incorporating a substantial number of important changes to the previous version (WHO 2000). The new WHO classification introduces 7 changes in the grading of central nervous system neoplasms, ranging in significance from minor to major, in categories of anaplastic oligoastrocytomas, meningiomas, choroid plexus tumors, pineal parenchymal tumors, ganglioglioma, cerebellar liponeurocytoma, and hemangiopericytomas. The 4th edition also introduces 10 newly codified entities, variants, and patterns, as well as 1 new genetic syndrome. A number of established brain tumors are reorganized, including medulloblastomas and primitive neuroectodermal tumors, in an attempt to more closely align classification with current understanding of central nervous system neoplasia. Objective. —To summarize and discuss the most significant updates in the 4th edition for the practicing surgical pathologist, including (1) changes in grading among established entities; (2) newly codified tumor entities, variants, patterns, and syndromes; and (3) changes in the classification of existing brain tumors. Data Sources. —The primary source for this review is the WHO Classification of Tumours of the Central Nervous System, 4th edition. Other important sources include the 3rd edition of this book and the primary literature that supported changes in the 4th edition. Conclusions. —The new edition of the WHO blue book reflects advancements in the understanding of brain tumors in terms of classification, grading, and new entities. The changes introduced are substantial and will have an impact on the practice of general surgical pathologists and neuropathologists.