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PURPOSE: To develop guideline recommendations concerning optimal neoadjuvant therapy for breast cancer. METHODS: ASCO convened an Expert Panel to conduct a systematic review of the literature on neoadjuvant therapy for breast cancer and provide recommended care options. RESULTS: A total of 41 articles met eligibility criteria and form the evidentiary basis for the guideline recommendations. RECOMMENDATIONS: Patients undergoing neoadjuvant therapy should be managed by a multidisciplinary care team. Appropriate candidates for neoadjuvant therapy include patients with inflammatory breast cancer and those in whom residual disease may prompt a change in therapy. Neoadjuvant therapy can also be used to reduce the extent of local therapy or reduce delays in initiating therapy. Although tumor histology, grade, stage, and estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) expression should routinely be used to guide clinical decisions, there is insufficient evidence to support the use of other markers or genomic profiles. Patients with triple-negative breast cancer (TNBC) who have clinically node-positive and/or at least T1c disease should be offered an anthracycline- and taxane-containing regimen; those with cT1a or cT1bN0 TNBC should not routinely be offered neoadjuvant therapy. Carboplatin may be offered to patients with TNBC to increase pathologic complete response. There is currently insufficient evidence to support adding immune checkpoint inhibitors to standard chemotherapy. In patients with hormone receptor (HR)-positive (HR-positive), HER2-negative tumors, neoadjuvant chemotherapy can be used when a treatment decision can be made without surgical information. Among postmenopausal patients with HR-positive, HER2-negative disease, hormone therapy can be used to downstage disease. Patients with node-positive or high-risk node-negative, HER2-positive disease should be offered neoadjuvant therapy in combination with anti-HER2-positive therapy. Patients with T1aN0 and T1bN0, HER2-positive disease should not be routinely offered neoadjuvant therapy.Additional information is available at www.asco.org/breast-cancer-guidelines.

In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer (N = 128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N = 34), lapatinib (L; N = 36), or both (TL; N = 58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30-65%) and TL (52%, 95% CI 38-65%), and a lower pCR rate with L (25%, 95% CI 13-43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment (N = 110), after one cycle of HER2-targeted therapy alone (N = 89), and at time of surgery (N = 59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

Caloric restriction (CR) and its related alternatives have been shown to be the only interventions capable of extending lifespan and decreasing the risk of cancer, along with a reduction in burden in pre-clinical trials. Nevertheless, the results from clinical trials have not been as conclusive as the pre-clinical results. Recognizing the challenges associated with long-term fasting, the application of caloric restriction mimetics (CRMs), pharmacological agents that mimic the molecular effects of CR, to harness the potential benefits while overcoming the practical limitations of fasting has resulted in an interesting alternative. This review synthesizes the findings of diverse clinical trials evaluating the safety and efficacy of CR and CRMs. In dietary interventions, a fast-mimicking diet was the most tolerated to reduce tumoral growth markers and chemotherapy side effects. CRMs were well tolerated, and metformin and aspirin showed the most promising effect in reducing cancer risk in a selected group of patients. The application of CR and/or CRMs shows promising effects in anti-cancer therapy; however, there is a need for more evidence to safely include these interventions in standard-of-care therapies. [ABSTRACT FROM AUTHOR]

PurposeTo explore the genetic landscape of tumors from patients enrolled on the BOLERO-2 trial to identify potential correlations between genetic alterations and efficacy of everolimus treatment. The BOLERO-2 trial has previously demonstrated that the addition of everolimus to exemestane prolonged progression-free survival by more than twofold in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer previously treated with nonsteroidal aromatase inhibitors.Patients and methodsNext-generation sequencing was used to analyze genetic status of cancer-related genes in 302 archival tumor specimens from patients representative of the BOLERO-2 study population. Correlations between the most common somatic alterations and degree of chromosomal instability, and treatment effect of everolimus were investigated.ResultsProgression-free survival benefit with everolimus was maintained regardless of alteration status of PIK3CA, FGFR1, and CCND1 or the pathways of which they are components. However, quantitative differences in everolimus benefit were observed between patient subgroups defined by the exon-specific mutations in PIK3CA (exon 20 v 9) or by different degrees of chromosomal instability in the tumor tissues.ConclusionThe data from this exploratory analysis suggest that the efficacy of everolimus was largely independent of the most commonly altered genes or pathways in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. The potential impact of chromosomal instabilities and low-frequency genetic alterations on everolimus efficacy warrants further investigation.

In this paper, we study the n -body problem in the Poincaré upper half-plane ℍ R 2 , where the radius R of the Poincaré disk is fixed. We introduce a new potential to derive the condition for hyperbolic relative equilibria on ℍ R 2 . We analyze the relative equilibrium of positive masses moving along geodesics under the SL (2 , ℝ) group. This result is utilized to establish the existence of relative equilibria for the n -body problem on ℍ R 2 for n = 2 and n = 3. We revisit previously known results and uncover new qualitative findings on relative equilibria that are not evident in an extrinsic context. Additionally, we provide a simple expression for the center of mass of a system of point particles on a two-dimensional surface with negative constant Gaussian curvature. [ABSTRACT FROM AUTHOR]

This was a population-based study to determine the impact of COVID-19 on birth outcomes in the Chicago metropolitan area, comparing pre-pandemic (April–September 2019) versus pandemic (April–September 2020) births. Multivariable regression models that adjusted for demographic and neighborhood characteristics were used to estimate the marginal effects of COVID-19 on intrauterine fetal demise (IUFD)/stillbirth, preterm birth, birth hospital designation, and maternal and infant hospital length of stay (LOS). There were no differences in IUFD/stillbirths or preterm births between eras. Commercially insured preterm and term infants were 4.8 percentage points (2.3, 7.4) and 3.4 percentage points (2.5, 4.2) more likely to be born in an academic medical center during the pandemic, while Medicaid-insured preterm and term infants were 3.6 percentage points less likely (−6.5, −0.7) and 1.8 percentage points less likely (−2.8, −0.9) to be born in an academic medical center compared to the pre-pandemic era. Infant LOS decreased from 2.4 to 2.2 days (−0.35, −0.20), maternal LOS for indicated PTBs decreased from 5.6 to 5.0 days (−0.94, −0.19), and term births decreased from 2.5 to 2.3 days (−0.21, −0.17). The pandemic had a significant effect on the location of births that may have exacerbated health inequities that continue into childhood. [ABSTRACT FROM AUTHOR]

This paper reports on the longitudinal links between first-time mothers (N = 48) Adult Attachment Interviews (AAIs), provided during pregnancy, and their first-born children's AAIs, provided at age 16 years. The AAIs from the adolescents were scored for reflective functioning (RF), and this was found to be significantly linked to whether their mothers' AAI were appraised as free-autonomous/secure as opposed to insecure-dismissing. Discussion concerns the unique influence of mothers upon their first-born children's development of reflective functioning skills, including the understanding of mind and emotion. Fathers, for whom AAIs were also available, appeared to have no influence on this process. RF scores from the adolescents did not differ as a function of either the previously observed infant-mother attachment or the infant-father attachment.

The reduction in opioid use has become a public health priority. We aimed to assess if performing buccal nerve blocks (BNB) at the time of buccal mucosa graft (BMG) harvest impacts post-operative narcotic usage in the inpatient setting. We retrospectively reviewed clinical characteristics and morphine milligram equivalents (MMEs) received for all patients that underwent a BMG urethroplasty at our institution. The primary outcome measure was post-operative MMEs for patients before and after implementing the BNB. We identified 74 patients that underwent BMG urethroplasty, 37 of which were before the implementation of the BNB and 37 of which were after. No other changes were made to the peri-operative pathway between these time points. The mean total MMEs per day, needed post-operatively, was lower in the BNB group (8.8 vs. 5.0, p = 0.12). A histogram distribution of the two groups, categorized by number of MMEs received, showed no significant differences between the two groups. In this retrospective analysis, we report our experience using BNBs at the time of buccal mucosa graft harvest. While there were no significant differences between the number of MMEs received before and after implementation, further research is needed to assess the blocks' impact on pain scores. [ABSTRACT FROM AUTHOR]

The book "Psychoanalytic parent-infant psychotherapy and mentalization: a dialogue in theory and practice" by Tessa Baradon and Chloe Campbell is a valuable resource for understanding the practices of psychoanalytic parent-infant psychotherapy (PPIP) and mentalizing in relation to infancy. The authors, who have extensive experience in their respective fields, provide a theoretical framework for PPIP and mentalization, as well as insights into trauma in the parent-infant relationship and the concept of mentalization in infancy. The book also includes clinical vignettes and research on PPIP, highlighting the importance of dialogue between perspectives and the value of keeping emotions in mind when working with parents and babies. Overall, this book is a valuable addition to the literature on psychoanalytic parent-infant therapy and will be of interest to practitioners and researchers in the field. [Extracted from the article]

Gossypol is a natural disesquiter-pene that blocks the activity of the mammalian facilitative hexose transporter GLUT1. In human HL-60 cells, which express GLUT1, Chinese hamster ovary ceils overexpressing GLUT1, and human erythrocytes, gossypol inhibited hexose transport in a concentration-dependent fashion, indicating that blocking of GLUT1 activity is independent of cellular context. With the exception of red blood cells, the inhibition of cellular transport was instantaneous. Gossypol effect was specific for the GLUT1 transporter since it did not alter the uptake of nicotinamide by human erythrocytes. Gossypol affects the glucose-displaceable binding of cytochalasin B to GLUT1 in human erythrocyte ghost in a mixed noncompetitive way, with a [K.sub.i] value of 20 [micro]M. Likewise, GLUT1 fluorescence was quenched ~80% by gossypol, while Stern-Volmer plots for quenching by iodide displayed increased slopes by gossypol addition. These effects on protein fluorescence were saturable and unaffected by the presence of D-glucose. Gossypol did not alter the affinity of D-glucose for the external substrate site on GLUT1. Kinetic analysis of transport revealed that gossypol behaves as a noncompetitive inhibitor of zero-trans (substrate outside but not inside) transport, but it acts as a competitive inhibitor of equilibrium-exchange (substrate inside and outside) transport, which is consistent with interaction at the endofacial surface, but not at the exofacial surface of the transporter. Thus, gossypol behaves as a quasi-competitive inhibitor of GLUT1 transport activity by binding to a site accessible through the internal face of the transporter, but it does not, in fact, compete with cytochalasin B binding. Our observations suggest that some effects of gossypol on cellular physiology may be related to its ability to disrupt the normal hexose flux through GLUT1, a transporter expressed in almost every kind of mammalian cell and responsible for the basal uptake of glucose. glucose transport; GLUT1 transporter; transporter inhibition

Understanding the types and magnitude of human‐caused mortality is essential for maintaining viable large carnivore populations. We used a database of cause‐specific mortality to examine how hunting regulations and landscape configurations influenced human‐caused mortality of North American gray wolves (Canis lupus). Our dataset included 21 studies that monitored the fates of 3564 wolves and reported 1442 mortalities. Human‐caused mortality accounted for 61% of mortality overall, with 23% due to illegal harvest, 16% due to legal harvest, and 12% the result of management removal. The overall proportion of anthropogenic wolf mortality was lowest in areas with an open hunting season compared to areas with a closed hunting season or mixed hunting regulations, suggesting that harvest mortality was neither fully additive nor compensatory. Proportion of mortality from management removal was reduced in areas with an open hunting season, suggesting that legal harvest may reduce human‐wolf conflicts or alternatively that areas with legal harvest have less potential for management removals (e.g., less livestock depredation). Proportion of natural habitat was negatively correlated with the proportion of anthropogenic and illegal harvest mortality. Additionally, the proportion of mortality due to illegal harvest increased with greater natural habitat fragmentation. The observed association between large patches of natural habitat and reductions in several sources of anthropogenic wolf mortality reiterate the importance of habitat preservation to maintain wolf populations. Furthermore, effective management of wolf populations via implementation of harvest may reduce conflict with humans. Effective wolf conservation will depend on holistic strategies that integrate ecological and socioeconomic factors to facilitate their long‐term coexistence with humans. [ABSTRACT FROM AUTHOR]

Background. Retained ureteral stents can result in significant morbidity and can be surgically challenging to urologists. A multimodal approach is often necessary for removal, potentially including retrograde and antegrade procedures performed over multiple anesthetic sessions. We describe the novel "Tri-Glide" technique for treating retained stents, particularly those with stent shaft encrustation prohibiting safe removal. Case Presentation. Two patients with nephrolithiasis and retained, encrusted ureteral stents were managed with the "Tri-Glide" technique. Patient #1 was a 58-year-old man with a severely calcified ureteral stent, retained for 14 years. After undergoing simultaneous cystolitholapaxy and percutaneous nephrolithotomy to treat proximal and distal encrustations, the stent shaft remained trapped in the ureter due to heavy calcifications. Three hydrophilic guidewires were passed alongside the stent, allowing it to easily slide out of the ureter intact. Patient #2 was a 74-year-old man who after only 3-months of stent dwell time developed severe stent shaft encrustation preventing removal. After multiple maneuvers failed, the "Tri-Glide" technique was used to create a smooth track for stent to slide out intact with gentle traction. Both patients did well postoperatively with no complications. Conclusion. The "Tri-Glide" technique can aid in the management of complex encrusted stent extractions, especially when there is significant shaft encrustation. [ABSTRACT FROM AUTHOR]