MEK inhibition reprograms CD8+ T lymphocytes into memory stem cells with potent antitumor effects.

Regenerative stem cell-like memory (TSCM) CD8+ T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces TSCM that have naive phenotype with self-renewability, enhanced multipotency and proliferative capacity. This is achieved by delaying cell division and enhancing mitochondrial biogenesis and fatty acid oxidation, without affecting T cell receptor-mediated activation. DNA methylation profiling revealed that MEKi-induced TSCM cells exhibited plasticity and loci-specific profiles similar to bona fide TSCM isolated from healthy donors, with intermediate characteristics compared to naive and central memory T cells. Ex vivo, antigenic rechallenge of MEKi-treated CD8+ T cells showed stronger recall responses. This strategy generated T cells with higher efficacy for adoptive cell therapy. Moreover, MEKi treatment of tumor-bearing mice also showed strong immune-mediated antitumor effects. In conclusion, we show that MEKi leads to CD8+ T cell reprogramming into TSCM that acts as a reservoir for effector T cells with potent therapeutic characteristics.

BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors.

BACKGROUND: Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection. METHODS: A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice. RESULTS: Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors. CONCLUSIONS: The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression.

Challenges and Opportunities in Cancer Drug Resistance.

There has been huge progress in the discovery of targeted cancer therapies in recent years. However, even for the most successful and impactful cancer drugs which have been approved, both innate and acquired mechanisms of resistance are commonplace. These emerging mechanisms of resistance have been studied intensively, which has enabled drug discovery scientists to learn how it may be possible to overcome such resistance in subsequent generations of treatments. In some cases, novel drug candidates have been able to supersede previously approved agents; in other cases they have been used sequentially or in combinations with existing treatments. This review summarizes the current field in terms of the challenges and opportunities that cancer resistance presents to drug discovery scientists, with a focus on small molecule therapeutics. As part of this review, common themes and approaches have been identified which have been utilized to successfully target emerging mechanisms of resistance. This includes the increase in target potency and selectivity, alternative chemical scaffolds, change of mechanism of action (covalents, PROTACs), increases in blood-brain barrier permeability (BBBP), and the targeting of allosteric pockets. Finally, wider approaches are covered such as monoclonal antibodies (mAbs), bispecific antibodies, antibody drug conjugates (ADCs), and combination therapies.

Combinatorial approaches for mitigating resistance to KRAS-targeted therapies.

Approximately 15% of all cancer patients harbor mutated KRAS. Direct inhibitors of KRAS have now been generated and are beginning to make progress through clinical trials. These include a suite of inhibitors targeting the KRASG12C mutation commonly found in lung cancer. We investigated emergent resistance to representative examples of different classes of Ras targeted therapies. They all exhibited rapid reactivation of Ras signaling within days of exposure and adaptive responses continued to change over long-term treatment schedules. Whilst the gene signatures were distinct for each inhibitor, they commonly involved up-regulation of upstream nodes promoting mutant and wild-type Ras activation. Experiments to reverse resistance unfortunately revealed frequent desensitization to members of a panel of anti-cancer therapeutics, suggesting that salvage approaches are unlikely to be feasible. Instead, we identified triple inhibitor combinations that resulted in more durable responses to KRAS inhibitors and that may benefit from further pre-clinical evaluation.

Reducing prescribing of antibiotics for acute respiratory infections using a frontline nurse-led EHR-Integrated clinical decision support tool: protocol for a stepped wedge randomized control trial.

BACKGROUND: Overprescribing of antibiotics for acute respiratory infections (ARIs) remains a major issue in outpatient settings. Use of clinical prediction rules (CPRs) can reduce inappropriate antibiotic prescribing but they remain underutilized by physicians and advanced practice providers. A registered nurse (RN)-led model of an electronic health record-integrated CPR (iCPR) for low-acuity ARIs may be an effective alternative to address the barriers to a physician-driven model. METHODS: Following qualitative usability testing, we will conduct a stepped-wedge practice-level cluster randomized controlled trial (RCT) examining the effect of iCPR-guided RN care for low acuity patients with ARI. The primary hypothesis to be tested is: Implementation of RN-led iCPR tools will reduce antibiotic prescribing across diverse primary care settings. Specifically, this study aims to: (1) determine the impact of iCPRs on rapid strep test and chest x-ray ordering and antibiotic prescribing rates when used by RNs; (2) examine resource use patterns and cost-effectiveness of RN visits across diverse clinical settings; (3) determine the impact of iCPR-guided care on patient satisfaction; and (4) ascertain the effect of the intervention on RN and physician burnout. DISCUSSION: This study represents an innovative approach to using an iCPR model led by RNs and specifically designed to address inappropriate antibiotic prescribing. This study has the potential to provide guidance on the effectiveness of delegating care of low-acuity patients with ARIs to RNs to increase use of iCPRs and reduce antibiotic overprescribing for ARIs in outpatient settings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04255303, Registered February 5 2020, https://clinicaltrials.gov/ct2/show/NCT04255303 .

Impact of patient-centered prescription medication labels on adherence in community pharmacy.

BACKGROUND: Prescription medication labels are often constructed in a manner which hinders safe and appropriate use of medicines. The United States Pharmacopeia released voluntary standards to revise medication labels in an effort to support patients' understanding and improve medication use. OBJECTIVE: To examine the impact of label changes on medication adherence before and after pharmacy implementation of the United States Pharmacopeia patient-centered prescription medication label standards. METHODS: This study used a retrospective pre-post cohort design. Prescription fill claims data were obtained from a community health plan serving Medicaid patients for 1 independent community pharmacy organization across 8 retail pharmacy sites. We calculated medication possession ratios (MPR) and proportion of days covered (PDC) for medications used for contraception, asthma, hypertension, and depression from 15 months before to 13 months after implementation of the label changes. RESULTS: Findings showed significant increases in mean MPR for asthma controller (increased by 0.111 [t = 0.290, P<0.0001]), antihypertensives (increased by 0.062 [t = 0.146, P < 0.0002]), and contraceptives medications (increased 0.133 [t = 0.209, P < 0.0001]) from preintervention to postintervention periods. Results also revealed increases in mean PDC for asthma controllers (increased by 0.193 [t = 0.267, P < 0.0001]), antihypertensives (increased by 0.067 [t = 0.175, P = 0.049]), and contraceptives (increased by 0.111 [t = 0.208, P < 0.0119]) from preintervention to postintervention periods. CONCLUSION: We report an association between a change to more patient-centered prescription medication labels and increased medication adherence based on MPR and PDC among Medicaid recipients.

Complication Profile of Total Submuscular Versus Prepectoral Tissue Expander Placement: A Retrospective Cohort Study.

BACKGROUND: We sought to compare the safety profile of prepectoral breast reconstruction with total submuscular tissue expander reconstruction, previously our standard. Primary outcomes of interest in this retrospective cohort study were incidence of infection, hematoma, seroma, mastectomy flap necrosis, and reconstruction loss. METHODS: Total submuscular and prepectoral with acellular dermal matrix reconstructions consecutively performed by a single surgeon (P.D.S.) between January 1, 2016, and December 31, 2019, were compared. Demographic and clinical characteristics, as well as complications and complication types, were extracted for all patients. A t test was used to assess differences in continuous variables. Multivariate logistics regression was used to assess the association between type of reconstruction and complication rate. The statistical significance was set at 0.05 for all comparisons. RESULTS: A total of 133 patients (234 breasts) were included. There was a significantly greater incidence of infection (16.5% vs 5.5%, P < 0.01) in the prepectoral/acellular dermal matrix cohort. However, reconstructive loss was low in both cohorts (2.5% and 3.0%, P = 0.83). Adjusted odds ratio for complications in the prepectoral cohort was 2.26, but this was not statistically significant (adjusted P = 0.24). CONCLUSIONS: Prepectoral breast reconstruction shares an overall complication profile that is not greater than that of total submuscular reconstruction. It is associated with a greater risk of infection; however, the ability to salvage the reconstruction with early, aggressive intervention results in low rates of reconstructive loss, comparable with those of total submuscular reconstruction.

Preservation of the Implant in Nipple-Sparing Mastectomies: A Retrospective Cohort Study.

BACKGROUND: Mastectomies are an integral part of breast cancer treatment for many patients.1 Of those patients, a significant number have previously undergone breast augmentation before being diagnosed with breast cancer. Therefore, we developed the novel technique of performing nipple- and implant-sparing mastectomies (NISMs) for women with prior breast augmentations. This study will assess the plausibility of using NISMs versus nipple-sparing mastectomies (NSMs) in this subgroup of patients by comparing the complication rates. METHODS: Data were collected on age, tumor size, tumor grade, receptors, and the interval between mastectomy and implant exchange for both groups. Descriptive statistics were used to summarize patient characteristics. Independent samples t tests, χ2 tests, and Fisher exact tests were used to compare the NISM and NSM cohorts. Logistic regression was used to assess the association between complications and mastectomy type and was summarized as an odds ratio with a 95% confidence interval. RESULTS: Fifteen patients underwent an NISM and 35 patients underwent an NSM. The overall rate of complications was less in NISM cases than in NSM cases (20% vs 27%). However, this difference was not statistically significant (odds ratio, 0.54; 95% confidence interval, 0.18-1.64; P = 0.278). CONCLUSIONS: The overall complication rate was lower with NISMs compared with NSMs. Nipple- and implant-sparing mastectomy is a novel, viable, and safe option for patients with breast cancer and a history of submuscular breast augmentation.

Increasing system-wide implementation of opioid prescribing guidelines in primary care: findings from a non-randomized stepped-wedge quality improvement project.

BACKGROUND: Clinician utilization of practice guidelines can reduce inappropriate opioid prescribing and harm in chronic non-cancer pain; yet, implementation of "opioid guidelines" is subpar. We hypothesized that a multi-component quality improvement (QI) augmentation of "routine" system-level implementation efforts would increase clinician adherence to the opioid guideline-driven policy recommendations. METHODS: Opioid policy was implemented system-wide in 26 primary care clinics. A convenience sample of 9 clinics received the QI augmentation (one-hour academic detailing; 2 online educational modules; 4-6 monthly one-hour practice facilitation sessions) in this non-randomized stepped-wedge QI project. The QI participants were volunteer clinic staff. The target patient population was adults with chronic non-cancer pain treated with long-term opioids. The outcomes included the clinic-level percentage of target patients with a current treatment agreement (primary outcome), rates of opioid-benzodiazepine co-prescribing, urine drug testing, depression and opioid misuse risk screening, and prescription drug monitoring database check; additional measures included daily morphine-equivalent dose (MED), and the percentages of all target patients and patients prescribed ≥90 mg/day MED. T-test, mixed-regression and stepped-wedge-based analyses evaluated the QI impact, with significance and effect size assessed with two-tailed p < 0.05, 95% confidence intervals and/or Cohen's d. RESULTS: Two-hundred-fifteen QI participants, a subset of clinical staff, received at least one QI component; 1255 patients in the QI and 1632 patients in the 17 comparison clinics were prescribed long-term opioids. At baseline, more QI than comparison clinic patients were screened for depression (8.1% vs 1.1%, p = 0.019) and prescribed ≥90 mg/day MED (23.0% vs 15.5%, p = 0.038). The stepped-wedge analysis did not show statistically significant changes in outcomes in the QI clinics, when accounting for the comparison clinics' trends. The Cohen's d values favored the QI clinics in all outcomes except opioid-benzodiazepine co-prescribing. Subgroup analysis showed that patients prescribed ≥90 mg/day MED in the QI compared to comparison clinics improved urine drug screening rates (38.8% vs 19.1%, p = 0.02), but not other outcomes (p ≥ 0.05). CONCLUSIONS: Augmenting routine policy implementation with targeted QI intervention, delivered to volunteer clinic staff, did not additionally improve clinic-level, opioid guideline-concordant care metrics. However, the observed effect sizes suggested this approach may be effective, especially in higher-risk patients, if broadly implemented. TRIAL REGISTRATION: Not applicable.

Improving health care communication for caregivers: A pilot study.

With the growing older adult population, there will also be more informal caregivers assisting friends and family with their health care. With the increasing complexity of health care, improved caregiver communication skills have the potential to reduce caregiver burden and frustration and improve care recipient health. The primary goal of this project was to develop and refine the content and teaching methods of a small-group behavioral change program to improve communication between caregivers of older adults and health care professionals. The authors developed the Care Talks program for improving communication between caregivers and health care professionals. They conducted a prospective cohort feasibility study of the intervention to assess caregiver communication confidence at baseline and one month postintervention. Six participants were enrolled. Of the 15 participants who answered the question, 15 (100%) would recommend this program to a friend. There was significant improvement in a 10-question composite of communication confidence pre/post scores from 74.1 to 79.6 p = .03. This small-group behavioral change intervention significantly improved communication confidence for this sample of caregivers. Further research is needed to determine the long-term effects of this program on caregivers and care recipients.

In the Age of Breast Augmentation, Breast Reconstruction Provides an Opportunity to Augment the Breast.

BACKGROUND: Augmentation mammoplasty remains the most common cosmetic surgery procedure performed. The objective of this article is to evaluate the impact of augmented volume of the reconstructed breast in patients that undergo nipple-sparing mastectomy and patients previously augmented who undergo mastectomy with tissue expander/implant-based reconstruction. METHODS: Patients undergoing skin-sparing mastectomy, nipple-sparing mastectomy, and mastectomy after previous augmentation followed by tissue expander/implant-based reconstruction between June 2011 and April 2015 by 2 surgeons at the same institution were included. Retrospective chart review of the patients identified using these criteria was performed to record patient characteristics, complications, breast volume, implant volume, and percentage change in volume at the time of reconstruction. Percentage change of breast volume was calculated using the formula (implant breast weight)/(breast weight) for skin-sparing and nipple-sparing mastectomy patients and (final breast implant weight - [breast weight + augmentation breast implant weight])/([breast weight + augmentation breast implant]) for patients undergoing mastectomy following previous augmentation. RESULTS: A total of 293 patients were included in the study with 63 patients who underwent nipple-sparing mastectomy, 166 patients who underwent skin-sparing mastectomy, and 64 patients who underwent previous augmentation with subsequent mastectomy. Mean percentage change in breast volume was 66% in the nipple-sparing mastectomy group, 15% for the right breast and 18% for the left breast in the skin-sparing mastectomy group, and 81% for the right breast and 72% for the left breast in the mastectomy following previous augmentation group. Complication rate for nipple-sparing mastectomy was 27%, mastectomy following previous augmentation was 20.3%, and skin-sparing mastectomy group was 18.7%. CONCLUSION: Patients who undergo nipple-sparing mastectomy or mastectomy following previous augmentation have the ability to achieve greater volume in their reconstructed breast via tissue expander/implant-based reconstruction.

Early Postoperative Complications after Oncoplastic Reduction.

BACKGROUND: Breast-conserving surgery with adjuvant radiation therapy (BCT) has been established as safe oncologically. Oncoplastic breast surgery uses both oncologic and plastic surgery techniques for breast conservation to improve cosmetic outcomes. We evaluated the risk factors associated with complications after oncoplastic breast reduction. METHODS: A single-institution, institutional review board-approved, retrospective review of electronic medical records of female patients with breast cancer who underwent oncoplastic breast reduction from 2008 to 2014. A review of electronic medical records collected relevant medical history, clinical and pathological information, and data on postoperative complications within 6 months stratified into major or minor complications. Categorical variables analyzed with the χ2 exact method; continuous variables were analyzed with the Wilcoxon rank sum test exact method. RESULTS: We identified 59 patients; 4 required re-excision for positive margins, and 1 moved on to completion mastectomy. The overall complication rate was 33.9% (n = 20): 12 major (20.3%) and 8 minor (13.6%). Of the continuous variables (age, body mass index, and tissue removed), increased age was associated with minor complications (P = 0.02). Among the categorical variables (stratified body mass index, prior breast surgery, hypertension, diabetes mellitus, hyperlipidemia, vascular disease, pulmonary disease, and stratified weight of tissue removed), none were associated with overall or major complications. Pulmonary disease was associated with minor complications (P = 0.03). Bilateral versus unilateral oncoplastic breast reduction showed no statistically significant increase in complications. CONCLUSIONS: The overall complication rate after oncoplastic breast reduction was markedly higher than that in nationally published data for breast-conserving surgery. The complication rate resembled more closely the complication rate after bilateral mastectomy with immediate reconstruction. No risk factors were associated with major or overall complications. Age and pulmonary disease were associated with minor complications. Patients should be selected and counseled appropriately when considering oncoplastic breast reduction.

Complications and Recurrence in Implant-Sparing Oncologic Breast Surgery.

BACKGROUND: Patients with a history of prior breast augmentation and newly diagnosed breast cancer represent a rapidly expanding and unique subset of patients. Prior studies have described changes in breast parenchyma and characteristic body habitus of previously augmented patients, as well as increased rates of capsular contracture associated with breast conservation therapy. In our current study, we aimed to study the risk factors contributing to morbidity and whether recurrence rates are higher in patients with prior breast augmentation undergoing lumpectomy or mastectomy for breast cancer and identify differences in complications between these 2 groups. METHODS: Retrospective analysis approved by institutional review board was performed on patients with prior breast augmentation undergoing lumpectomy (N = 52) and mastectomy (N = 64) for breast cancer. RESULTS: Patients with prior breast augmentation undergoing mastectomy had a higher rate of complications compared with those undergoing lumpectomy (20.3% vs 5.9% respectively, P = 0.031), after adjusting for patient-specific factors including body mass index [odds ratio (OR), 0.242; 95% confidence interval (CI), 0.063-0.922; P = 0.0376], tumor stage (OR, 0.257; 95% CI, 0.064-1.036; P = 0.0562), smoking status (OR, 0.244; 95% CI, 0.065-0.918; P = 0.0370), and chemotherapy (OR, 0.242; 95% CI, 0.064-0.914; P = 0.0364). Four patients (7.7%) developed late complications in the lumpectomy group with 2 developing capsular contractures, 1 had fat necrosis and 1 needed complex reconstruction because of flattening of the nipple-areolar complex. There was no difference in recurrence or tumor margins between lumpectomy and mastectomy groups. CONCLUSIONS: Patients with prior breast augmentation undergoing mastectomy have higher complication rates compared with lumpectomy even after adjusting for tumor stage. There appears to be no increased oncologic risk associated with either procedure given our current follow-up. Understanding these operative risks may help in patients' decision-making process with regards to type of oncologic surgery.

Assessing the Effectiveness of the Functional Movement Screen in Predicting Noncontact Injury Rates in Soccer Players.

Smith, PD, and Hanlon, D. Assessing the effectiveness of the functional movement screen in predicting noncontact injury rates in soccer players. J Strength Cond Res 31(12): 3327-3332, 2017-This study assessed if the Functional Movement Screen (FMS) can accurately predict noncontact injury in adult soccer players when normalizing noncontact injury occurrence against match exposure levels. Senior male players (n = 89) from 5 League of Ireland semiprofessional clubs participated in the study (mean age = 23.2 ± 4.4 years; mean height = 179.5 ± 6.6 cm; mean body mass = 77.5 ± 7.8 kg). Participants performed the FMS during preseason, and their injury occurrence rates and match minutes were tracked throughout 1 season. In total, 66 noncontact injuries were recorded. No significant difference was found in FMS composite scores between players receiving noncontact injuries and players not suffering a noncontact injury (p = 0.96). There was no significant difference in exposure-normalized noncontact injury incidence between those scoring 14 or below and those scoring above 14 on the FMS (0.36 vs. 0.29 non-contact injuries per player per 1,000 match minutes). Players scoring 14 or below on the FMS had an odds ratio of 0.63 (p = 0.45; 95% CI = 0.19-2.07) of receiving a noncontact injury. Despite previous research showing links between low FMS composite scores and subsequent injury, these results suggest that the FMS cannot accurately predict a male soccer player's likelihood of receiving a noncontact injury and that a lower FMS composite score does not significantly increase their noncontact injury incidence rate per 1,000 match minutes. Caution should therefore be used when using the FMS as a predictor of noncontact injury, and pain prevalence during the FMS, previous injuries, and training/match exposure levels should also be taken into account.

Adaptation to mTOR kinase inhibitors by amplification of eIF4E to maintain cap-dependent translation.

The mechanistic target of rapamycin (mTOR) protein kinase coordinates responses to nutrients and growth factors and is an anti-cancer drug target. To anticipate how cells will respond and adapt to chronic mTOR complex (mTORC)1 and mTORC2 inhibition, we have generated SW620 colon cancer cells with acquired resistance to the ATP-competitive mTOR kinase inhibitor AZD8055 (SW620:8055R). AZD8055 inhibited mTORC1 and mTORC2 signalling and caused a switch from cap-dependent to internal ribosome entry site (IRES)-dependent translation in parental SW620 cells. In contrast, SW620:8055R cells exhibited a loss of S6K signalling, an increase in expression of the eukaryotic translation initiation factor eIF4E and increased cap-dependent mRNA translation. As a result, the expression of CCND1 and MCL1, proteins encoded by eIF4E-sensitive and cap-dependent transcripts, was refractory to AZD8055 in SW620:8055R cells. RNAi-mediated knockdown of eIF4E reversed acquired resistance to AZD8055 in SW620:8055R cells; furthermore, increased expression of eIF4E was sufficient to reduce sensitivity to AZD8055 in a heterologous cell system. Finally, although the combination of MEK1/2 inhibitors with mTOR inhibitors is an attractive rational drug combination, SW620:8055R cells were actually cross-resistant to the MEK1/2 inhibitor selumetinib (AZD6244). These results exemplify the convergence of ERK1/2 and mTOR signalling at eIF4E, and the key role of eIF4E downstream of mTOR in maintaining cell proliferation. They also have important implications for therapeutic strategies based around mTOR and the MEK1/2-ERK1/2 pathway.

Prospective evaluation of skin and nipple-areola sensation and patient satisfaction after nipple-sparing mastectomy.

BACKGROUND: Sensation and quality of life (QOL) before and after nipple sparing mastectomy (NSM) are poorly understood. METHODS: Women electing mastectomy with immediate reconstruction and eligible for NSM were prospectively enrolled in a sensation and satisfaction/QOL study. Women self-selected skin-sparing mastectomy (SSM) or NSM. Skin sensation testing using Semmes Weinstein monofilaments and patient satisfaction/QOL surveys were administered preoperatively and at 1 year postoperatively. RESULTS: 53 patients were enrolled (n = 38, 72% NSM and n = 15, 28% SSM). Both groups had significant reduction in postoperative skin sensation. For NSM, measurable NAC sensation was preserved in both NAC for 26% of patients and in one NAC for 68%. QOL and satisfaction was similar between groups. Neither group was satisfied with sexual arousal with breast or nipple stimulation after surgery. CONCLUSION: Patients undergoing SSM and NSM have considerable loss in skin and NAC sensation following surgery. Satisfaction and QOL did not differ between groups. J. Surg. Oncol. 2016;114:11-16. © 2016 Wiley Periodicals, Inc.

Comparison of Reconstructive Outcomes in Breast Cancer Patients With Preexisting Subpectoral Implants: Implant-Sparing Mastectomy With Delayed Implant Exchange Versus Immediate Tissue Expander Reconstruction.

BACKGROUND: Women who have undergone prior augmentation mammoplasty represent a unique subset of breast cancer patients with several options available for breast reconstruction. We performed a single institution review of surgical outcomes of breast reconstruction performed in patients with breast cancer with prior history of subpectoral breast augmentation. METHODS: Institutional review board-approved retrospective review was conducted among patients with previously mentioned criteria treated at our institution between 2000 and 2014. Reconstructions were grouped into 2 categories as follows: (1) removal of preexisting subpectoral implant during mastectomy with immediate tissue expander placement and (2) implant-sparing mastectomy followed by delayed exchange to a larger implant. We reviewed demographics, tumor features, and reconstruction outcomes of these groups. RESULTS: Fifty-three patients had preexisting subpectoral implants. Of the 63 breast reconstructions performed, 18 (28.6%) had immediate tissue expander placed and 45 (71.4%) had implant-sparing mastectomy followed by delayed implant exchange. The groups were comparable based on age, body mass index, cancer type, tumor grade, TNM stage at presentation, and hormonal receptor status. No significant difference was noted between tumor margins or subsequent recurrence, mastectomy specimen weight, removed implant volume, volume of implant placed during reconstruction, or time from mastectomy to final implant placement. Rates of complications were significantly higher in the tissue expander group compared to the implant-sparing mastectomy group 7 (38.9%) versus 4 (8.9%) (P = 0.005). CONCLUSIONS: Implant-sparing mastectomy with delayed implant exchange in patients with preexisting subpectoral implants is safe and has fewer complications compared to tissue expander placement. There was no difference noted in the final volume of implant placed, time interval for final implant placement, or tumor margins.

Comparison of Reconstructive Outcomes in Breast Cancer Patients With Preexisting Subpectoral Implants: Implant-Sparing Mastectomy With Delayed Implant Exchange Versus Immediate Tissue Expander Reconstruction.

BACKGROUND: Women who have undergone prior augmentation mammoplasty represent a unique subset of breast cancer patients with several options available for breast reconstruction. We performed a single institution review of surgical outcomes of breast reconstruction performed in patients with breast cancer with prior history of subpectoral breast augmentation. METHODS: Institutional review board-approved retrospective review was conducted among patients with previously mentioned criteria treated at our institution between 2000 and 2014. Reconstructions were grouped into 2 categories as follows: (1) removal of preexisting subpectoral implant during mastectomy with immediate tissue expander placement and (2) implant-sparing mastectomy followed by delayed exchange to a larger implant. We reviewed demographics, tumor features, and reconstruction outcomes of these groups. RESULTS: Fifty-three patients had preexisting subpectoral implants. Of the 63 breast reconstructions performed, 18 (28.6%) had immediate tissue expander placed and 45 (71.4%) had implant-sparing mastectomy followed by delayed implant exchange. The groups were comparable based on age, body mass index, cancer type, tumor grade, TNM stage at presentation, and hormonal receptor status. No significant difference was noted between tumor margins or subsequent recurrence, mastectomy specimen weight, removed implant volume, volume of implant placed during reconstruction, or time from mastectomy to final implant placement. Rates of complications were significantly higher in the tissue expander group compared to the implant-sparing mastectomy group 7 (38.9%) versus 4 (8.9%) (P = 0.005). CONCLUSIONS: Implant-sparing mastectomy with delayed implant exchange in patients with preexisting subpectoral implants is safe and has fewer complications compared to tissue expander placement. There was no difference noted in the final volume of implant placed, time interval for final implant placement, or tumor margins.

Inhibition of MEK confers hypersensitivity to X-radiation in the context of BRAF mutation in a model of childhood astrocytoma.

PURPOSE: Curative therapy for childhood glioma presents challenges when complete resection is not possible. Patients with recurrent low-grade tumors or anaplastic astrocytoma may receive radiation treatment; however, the long-term sequellae from radiation treatment can be severe. As many childhood gliomas are associated with activation of BRAF, we have explored the combination of ionizing radiation with MEK inhibition in a model of BRAF-mutant anaplastic astrocytoma. EXPERIMENTAL DESIGN: The regulation of TORC1 signaling by BRAF was examined in BT-40 (BRAF mutant) and BT-35 (BRAF wild type) xenografts, in a cell line derived from the BT-40 xenograft and two adult BRAF mutant glioblastoma cell lines. The effect of MEK inhibition (selumetinib), XRT (total dose 10 Gy as 2 Gy daily fractions), or the combination of selumetinib and XRT was evaluated in subcutaneous BT-40 xenografts. RESULTS: Inhibition of MEK signaling by selumetinib suppressed TORC1 signaling only in the context of the BRAF-mutant both in vitro and in vivo. Inhibition of MEK signaling in BT-40 cells or in xenografts lead to a complete suppression of FANCD2 and conferred hypersensitivity to XRT in BT-40 xenografts without increasing local skin toxicity. CONCLUSIONS: Selumetinib suppressed TORC1 signaling in the context of BRAF mutation. Selumetinib caused a rapid downregulation of FANCD2 and markedly potentiated the effect of XRT. These data suggest the possibility of potentiating the effect of XRT selectively in tumor cells by MEK inhibition in the context of mutant BRAF or maintaining tumor control at lower doses of XRT that would decrease long-term sequelae.

d(1) Oxosulfido-Mo(V) Compounds: First Isolation and Unambiguous Characterization of an Extended Series.

Reaction of Tp(iPr)Mo(VI)OS(OAr) with cobaltocene in toluene results in the precipitation of brown, microcrystalline oxosulfido-Mo(V) compounds, [CoCp2][Tp(iPr)Mo(V)OS(OAr)] (Cp(-) = η(5)-C5H5(-), Tp(iPr)(-) = hydrotris(3-isopropylpyrazol-1-yl)borate, OAr(-) = phenolate or 2-(s)Bu, 2-(t)Bu, 3-(t)Bu, 4-(s)Bu, 4-Ph, 3,5-(s)Bu2, 2-CO2Me, 2-CO2Et or 2-CO2Ph derivative thereof). The compounds are air- and water-sensitive and display ν(Mo═O) and ν(Mo[Formula: see text]S) IR absorption bands at ca. 890 and 435 cm(-1), respectively, 20-40 cm(-1) lower in energy than the corresponding bands in Tp(iPr)MoOS(OAr). They are electrochemically active and exhibit three reversible cyclovoltammetric waves (E(Mo(VI)/Mo(V)) = -0.40 to -0.66 V, E([CoCp2](+)/CoCp2) = -0.94 V and E(CoCp2/[CoCp2](-)) = -1.88 V vs SCE). Structural characterization of [CoCp2][Tp(iPr)MoOS(OC6H4CO2Et-2)]·2CH2Cl2 revealed a distorted octahedral Mo(V) anion with Mo═O and Mo[Formula: see text]S distances of 1.761(5) and 2.215(2) Å, respectively, longer than corresponding distances in related Tp(iPr)MoOS(OAr) compounds. The observation of strong S(1s) → (S(3p) + Mo(4d)) S K-preedge transitions indicative of a d(1) sulfido-Mo(V) moiety and the presence of short Mo═O (ca. 1.72 Å) and Mo[Formula: see text]S (ca. 2.25 Å) backscattering contributions in the Mo K-edge EXAFS further support the oxosulfido-Mo(V) formulation. The compounds are EPR-active, exhibiting highly anisotropic (Δg 0.124-0.150), rhombic, frozen-glass spectra with g1 close to the value observed for the free electron (ge = 2.0023). Spectroscopic studies are consistent with the presence of a highly covalent Mo[Formula: see text]S π* singly occupied molecular orbital. The compounds are highly reactive, with reactions localized at the terminal sulfido ligand. For example, the compounds react with cyanide and PPh3 to produce thiocyanate and SPPh3, respectively, and various (depending on solvent) oxo-Mo(V) species. Reactions with copper reagents also generally lead to desulfurization and the formation of oxo-Mo(V) or -Mo(IV) complexes.