Unknown Benefit Research Articles

Maternal immunoglobulins are distributed in the offspring’s brain to support the maintenance of cortical interneurons in the postnatal period

It is known that maternal immunoglobulins (Igs) are transferred to the offspring across the placenta. However, receiving maternal Igs, especially before the blood–brain barrier (BBB) is formed in the offspring’s brain, carries the risk of transferring some brain-reactive Igs. It is thus hypothesized that there may be some unknown benefit to the offspring’s brain that overweighs this risk. In this study, we show that the Ig detected in the embryonic/perinatal mouse brain is IgG not produced by the pups themselves, but is basically transferred from the mother across the placenta using the neonatal Fc receptor (FcRn) during embryonic stages. The amount of IgG in the brain gradually decreases after birth, and almost disappears within 3 weeks postnatally. IgG is detected on axon bundles, microglia, and some meningeal cells, including border-associated macrophages (BAMs), endothelial cells, and fibroblasts. Using Fcer1g knock-out (KO) mice, we show that BAMs and microglia receive maternal IgG in an Fc receptor γ chain (FcRγ)-dependent manner, but IgG on other meningeal cells and axon bundles is received independently of the FcRγ. These results suggest that maternal IgG may be used in multiple ways by different mechanisms. In maternal IgG-deficient mice, the number of interneurons in the cerebral cortex is not altered around birth but is reduced postnatally, suggesting that receipt of maternal IgG is necessary for the maintenance of cortical interneurons in the postnatal period. These data suggest that maternal IgG has an important function in the developing brain, where neither obvious inflammation nor infection is observed.

Abstract TP163: Antiplatelet Use And CADASIL: A Multicenter Analysis Of The Trinetx Research Database

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is hallmarked by a mutation in the NOTCH3 receptor resulting in impaired cerebrovascular autoregulation with subsequent vessel fragility and progressive accumulation of cerebral small vessel disease (CSVD). Antiplatelet medications are commonly prescribed for secondary stroke prevention though this is of unknown therapeutic benefit in preventing acute ischemic stroke (AIS). We aimed to identify whether antiplatelet therapy reduced incidence of AIS in those with reported CADASIL. Methods: Data was collected through the TriNetX Research Network database. Those included were adults with the ICD-10 code (I67.850) for CADASIL. The primary outcome was the validated ICD-10 code for AIS (I63) which were linked with hospital admission encounters. Demographic data and medication use was recorded. The primary exposure was use of an antiplatelet medication for at least 1 month prior to admission for AIS. Standard descriptive and regression analyses were used. Results: Our cohort included 455 individuals: mean age 57±14 years, 36% being female and with similar rates of vascular risk factors between the groups. The antiplatelet cohort was older (antiplatelet: 61 ± 12 yrs vs. unexposed: 57±14 yrs, p = 0.034) and included 40 (8.8%) participants. Rate of AIS trended higher in the antiplatelet group but was not significantly different (antiplatelet: 23%, 9/40 vs. unexposed: 14%, 60/415; p=0.18). Age adjusted logistic regression showed higher odds of AIS (OR 1.62, 95%CI 0.73 - 3.60, p = 0.23). Conclusions: In this hypothesis generating study, our data suggests that antiplatelet use did not significantly impact incidence of AIS. It is unclear if the likelihood findings are related to the natural history of the disease, though this model accounted for differences in age. Further studies are needed to improve power for robust statistical analysis to confirm or refute our findings.

The Cost-Effectiveness of Wound Dressings for Infection Prophylaxis in Total Joint Arthroplasty: An Economic Evaluation

Background Periprosthetic joint infection (PJI) is a medical and economical challenge. Specific post-operative wound dressings have been developed to mitigate risk of PJI following total hip arthroplasty (THA) and total knee arthroplasty (TKA), but these come with added cost and unknown benefit. The purpose of this study was to determine which dressings may be economically justifiable. Methods The average added cost of Xeroform with gauze (Xeroform+gauze), Mepilex Border, Aquacel Ag, and Dermabond Prineo dressings compared to standard dressing (Xeroform+gauze) only were obtained from institutional records and contemporary literature. Baseline infection rates following THA and TKA and average costs of PJI treatment were obtained from the literature. A break-even analysis was utilized to determine the absolute risk reduction (ARR) needed in infection rate to make each dressing cost-effective. Results At $3.00, a single Xeroform+gauze is economically justified if the initial infection rate for TKA (1.10%) and THA (1.62%) are reduced by an ARR of 0.01% and 0.009%, respectively. Two to three additional post-operative dressing changes increases the cost of Xeroform+gauze to $9.00-12.00 and increases the required ARR for TKA to 0.04-0.05% and for THA to 0.028-0.038%. Mepilex Border costs $29.00 and requires an ARR of 0.11% for TKA and 0.09% for THA. Aquacel Ag costs $40.00 and requires an ARR of 0.16% for TKA and 0.13% for THA. Dermabond Prineo costs $79.00 and requires an ARR of 0.31% for TKA and 0.25% for THA. Variations in estimation of initial infection rate did not impact ARR for any dressing type. Conclusions Orthopaedic surgeons have multiple options for surgical dressings following total joint replacement. With respect to infection prophylaxis, Xeroform+gauze is the most cost-effective. Other specialized dressings such as Mepilex Border, Aquacel Ag, or Dermabond Prineo, require significantly higher reductions in infection rate to be economically justifiable.

Conceptions of Legacy Among People Making Treatment Choices for Serious Illness: Protocol for a Scoping Review.

Legacy-what one leaves behind and how one hopes to be remembered after death-is an unexplored and important dimension of decision-making for people facing serious illnesses. A preliminary literature review suggests that patients facing serious illness consider legacy when making medical decisions, for example, forgoing expensive treatment with limited or unknown clinical benefit to preserve one's inheritance for their children. To date, very little is known about the conceptual foundations of legacy. No conceptual frameworks exist that provide a comprehensive understanding of how legacy considerations relate to patient choices about their medical care. The objective of this scoping review is to understand the extent and type of research addressing the concept of legacy by people facing serious illness to inform a conceptual framework of legacy and patient treatment choices. This protocol follows the guidelines put forth by Levac et al, which expands the framework introduced by Arksey and O'Malley, as well as the Joanna Briggs Institute Reviewer's manual. This scoping review will explore several electronic databases including PubMed, Medline, CINAHL, Cochrane Library, PsycINFO, and others and will include legacy-specific gray literature, including dissertation research available via ProQuest. An initial search will be conducted in English-language literature from 1990 to the present with selected keywords to identify relevant articles and refine the search strategy. After the search strategy has been finalized, 2 independent reviewers will undertake a 2-part study selection process. In the first step, reviewers will screen article titles and abstracts to identify the eligibility of each article based on predetermined exclusion or inclusion criteria. A third senior reviewer will arbitrate discrepancies regarding inclusions or exclusions. During the second step, the full texts will be screened by 2 reviewers, and only relevant articles will be kept. Relevant study data will be extracted, collated, and charted to summarize the key findings related to the construct of legacy. This study will identify how people facing serious illness define legacy, and how their thinking about legacy impacts the choices they make about their medical treatments. We will note gaps in the literature base. The findings of this study will inform a conceptual model that outlines how ideas about legacy impact the patient's treatment choices. The results of this study will be submitted to an indexed journal. Very little is known about the role of legacy in the treatment decisions of patients across the continuum of serious illness. In particular, no comprehensive conceptual model exists that would provide an understanding of how legacy is considered by people making decisions about their care during serious illness. This study will be among the first to construct a conceptual model detailing how considerations of legacy impact medical decision-making for people facing or living with serious illnesses. DERR1-10.2196/40791.

Abstract 13711: Cardiomyopathy Complicated by Constriction Resulting in Transplant Listing

Introduction We describe a case of severe cardiomyopathy complicated by pericardial constriction resulting from epicardial VT ablation requiring heart transplant listing. Case Presentation A 43-year-old with a history of silent MI, LV aneurysm and thrombus, cardiomyopathy (EF 15%), Stage C heart failure, and VT on amiodarone initially presented with symptomatic VT requiring AICD therapy. He underwent epicardial ablation with no immediate complications. Post-ablation, he developed polymorphic VT prompting LHC revealing new LAD artery stenosis treated with stents. He was discharged on DAPT and warfarin. He subsequently re-presented with worsening dyspnea, lethargy, and edema. Invasive hemodynamics revealed elevated filling pressures and cardiogenic shock with constrictive physiology. Milrinone and aggressive diuresis were initiated with mild improvement in symptoms. Echocardiogram and cardiac MRI confirmed diagnosis of constrictive pericarditis and presence of hemopericardium. Discussion Multidisciplinary discussions were held to determine treatment. Management of constrictive pericarditis with pericardial stripping was considered. The high-risk nature of the procedure with unknown benefit, his age, and now Stage D heart failure made sternotomy a potential increased risk for future cardiac transplant. Ultimately, decision was made for pericardiocentesis, treatment with colchicine, a switch from triple therapy to warfarin and aspirin, and listing for transplant. Surveillance RHC 6 weeks post hospitalization showed resolution of constrictive physiology and normal cardiac output on milrinone.

Internal mammary node involvement in patients with axilla-negative early breast cancer: a narrative review.

Early breast cancer staging involves radiological and pathological evaluation of the tumour and regional lymph nodes. The internal mammary nodes (IMN) are an important site of possible metastasis and influence disease stage and prognosis. However, the recommendation for routine IMN assessment remains unclear. Internal mammary sentinel lymph node biopsy (SLNB) is associated with increased morbidity and an unknown survival benefit. Furthermore, the IMN are traditionally thought to be involved only synchronous with, or following, axillary node (AXN) metastasis. The aim of this review is to determine the prevalence of IMN metastasis in patients with axilla-negative early breast cancer. A narrative review of studies assessing IMN metastasis was performed. The literature search was completed using the database Medline (Ovid). Twenty-two retrospective studies were identified. The studies included data from SLNB, US, MRI, PET/CT and opportunistic biopsy during free-flap reconstruction (FFR). The prevalence of isolated IMN metastasis ranged from 1.2% to 17.9%.

The long walk together: The role of institutionalized socialization in shaping newcomers' future expectations about their networks

Although a future orientation plays an important role in Van Maanen and Schein's (1979) classic conceptualization of organizational socialization tactics, human resource management practices and scholarly research tend to focus on individuals' adjustment to the present. We address this significant gap by investigating how institutionalized socialization facilitates newcomer outcomes via its impact on newcomers' expected long-term friendship and cooperation networks. Based on construal level theory, we argue that expectations about one's long-term networks reflect perceptions of the stable nature of one's current networks. A 4-wave study with two samples of newcomers in diverse Chinese organizations found that institutionalized socialization predicted positive development in the size of newcomers' current and expected networks, which in turn predicted managers' ratings of newcomers' in-role performance and extra-role behaviors in the form of altruistic helping and taking charge. The study thus documents a relatively unknown benefit of socialization on newcomers' future expectations about their social relationships and the impact on newcomers' behaviors.

Acceptability and barriers to adopting physical therapy and rehabilitation as standard of care in hernia disease: a prospective national survey of providers and preliminary data.

Physical therapy (PT) and rehabilitation are widely utilized in a variety of disease processes to improve function, return to activities of daily living (ADLs), and promote overall recovery. However, hernia repair has struggled to adopt this practice despite operations occurring in one of the most dynamic parts of the body - the abdominal core. This study sought to understand perspectives and perceived barriers regarding the incorporation of PT and rehabilitation in hernia care. A standardized rehabilitation protocol was developed by the Abdominal Core Health Quality Collaborative (ACHQC), a national quality improvement initiative specific to hernia disease, and launched in 2019. Empiric data from the ACHQC was then obtained to describe preliminary utilization. A prospective electronic survey was then deployed to all surgeons participating in the ACHQC to aid in interpreting the identified trends. The survey included questions regarding the current use of PT in their practice, as well as further opinions on the functionality, benefit, and barriers to its use. We identified 1,544 patients who were listed as receiving some form of postoperative rehabilitation, of which 992 (64.2%) had a primary diagnosis of ventral hernia and 552 (35.8%) had an inguinal hernia. Among patients who had a ventral hernia, 863 (87.0%) received self-directed rehabilitation exercises compared to 488 (88.4%) of inguinal hernia patients. The subsequent survey exploring these trends was completed by 46 ACHQC surgeons (10.2%). More than half (52%) reported using PT for hernia patients, primarily in abdominal wall reconstruction cases (92%). Of those who did not report using PT, 50% cited unknown clinical benefit and another 27% cited unknown PT resources. PT utilization was typically concentrated to the postoperative period (58%), while 42% reported also using it preoperatively. Despite 72% of respondents citing a perceived benefit of PT in hernia patients, overall use of PT was primarily reported as 'occasional' by 42%, with another 27% reporting 'rarely.' Perceived benefits of PT included increased core strength, stability, mobility, patient satisfaction, education, independence, earlier return to work and ADLs, overall improved recovery, and decreased risk of postoperative issues. Reported barriers to implementing PT in practice or adapting the ACHQC Rehabilitation Protocol included lack of education, lack of evidence of clinical benefit, and difficulties operationalizing the protocol. A national survey of hernia surgeons demonstrated willingness to adopt PT and rehabilitation protocols in their clinical practices and noted a high perceived benefit to patients. However, lack of education and evidence regarding the protocol may represent important barriers to overcome in widely disseminating these resources to patients. These gaps can be addressed through dedicated educational venues and additional studies establishing PT and rehabilitation as critical future adjuncts for the recovery of hernia repair patients.

Initial and supplementary indication approval of new targeted cancer drugs by the FDA, EMA, Health Canada, and TGA

SummaryBackground. Previous research focused on the clinical evidence supporting new cancer drugs’ initial US Food and Drug Administration (FDA) approval. However, targeted drugs are increasingly approved for supplementary indications of unknown evidence and benefit. Objectives. To examine the clinical trial evidence supporting new targeted cancer drugs’ initial and supplementary indication approval in the US, EU, Canada, and Australia. Data and Methods. 25 cancer drugs across 100 indications were identified with FDA approval between 2009–2019. Data on regulatory approval and clinical trials were extracted from the FDA, European Medicines Agency (EMA), Health Canada (HC), Australian Therapeutic Goods Administration (TGA), and clinicaltrials.gov. Regional variations were compared with χ2-tests. Multivariate logistic regressions compared characteristics of initial and supplementary indication approvals, reporting adjusted odds ratios (AOR) with 95% confidence intervals (CI). Results. Out of 100 considered cancer indications, the FDA approved 96, the EMA 92, HC 86, and the TGA 83 (83%, p < 0.05). The FDA more frequently granted priority review, conditional approval, and orphan designations than other agencies. Initial approvals were more likely to receive conditional / accelerated approval (AOR: 2.69, 95%CI [1.07–6.77], p < 0.05), an orphan designation (AOR: 3.32, 95%CI [1.38–8.00], p < 0.01), be under priority review (AOR: 2.60, 95%CI [1.17–5.78], p < 0.05), and be monotherapies (AOR: 5.91, 95%CI [1.14–30.65], p < 0.05) than supplementary indications. Initial indications’ pivotal trials tended to be shorter (AOR per month: 0.96, 95%CI [0.93–0.99], p < 0.05), of lower phase design (AOR per clinical phase: 0.28, 95%CI [0.09–0.85], p < 0.05), and enroll more patients (AOR per 100 patients: 1.19, 95%CI [1.01–1.39], p < 0.05). Conclusions. Targeted cancer drugs are increasingly approved for multiple indications of varying clinical benefit. Drugs are first approved as monotherapies in rare diseases with a high unmet need. Whilst expedited regulatory review incentivizes this prioritization, indication-specific safety, efficacy, and pricing policies are necessary to reflect each indication’s differential clinical and economic value.

Quality over quantity: unraveling the contributions to cytoplasmic incompatibility caused by two coinfecting Cardinium symbionts.

Cytoplasmic incompatibility (CI) is a common form of reproductive sabotage caused by maternally inherited bacterial symbionts of arthropods. CI is a two-step manipulation: first, the symbiont modifies sperm in male hosts which results in the death of fertilized, uninfected embryos. Second, when females are infected with a compatible strain, the symbiont reverses sperm modification in the fertilized egg, allowing offspring of infected females to survive and spread the symbiont to high frequencies in a population. Although CI plays a role in arthropod evolution, the mechanism of CI is unknown for many symbionts. Cardinium hertigii is a common CI-inducing symbiont of arthropods, including parasitoid wasps like Encarsia partenopea. This wasp harbors two Cardinium strains, cEina2 and cEina3, and exhibits strong CI. The strains infect wasps at different densities, with the cEina3 present at a lower density than cEina2, and it was previously not known which strain caused CI. By differentially curing wasps of cEina3, we found that this low-density symbiont is responsible for CI and modifies males during their pupal stage. cEina2 does not modify host reproduction and may spread by 'hitchhiking' with cEina3 CI or by conferring an unknown benefit. The cEina3 strain also shows a unique localization pattern in male reproductive tissues. Instead of infecting sperm like other CI-inducing symbionts, cEina3 cells are found in somatic cells at the testis base and around the seminal vesicle. This may allow the low-density cEina3 to efficiently modify host males and suggests that cEina3 uses a different modification strategy than sperm-infecting CI symbionts.

Aducanumab and the “post-amyloid” era of Alzheimer research?

Aducanumab and the “post-amyloid” era of Alzheimer research?

The Effect of Bolus on Local Control for Patients Treated With Mastectomy and Radiation Therapy.

Bolus use during postmastectomy radiation therapy doubles the risk of grade 2 and 3 skin toxicity. Despite its unknown benefit, bolus is often prescribed during postmastectomy radiation therapy for patients without skin involvement. For women with breast cancer receiving photon 3-dimensional conformal radiation therapy, bolus was used routinely for chest walls but was omitted for breast reconstructions by about half of radiation oncologists from 2007 to 2011. Eligible patients had newly diagnosed invasive breast cancers without skin involvement (pT1-4a, any-N, M0) treated with adjuvant or neoadjuvant radiation therapy. For the bolus and no-bolus groups, we compared the cumulative incidence of local recurrence (LR) and locoregional recurrence (LRR) with distant recurrence and death as competing risks and breast cancer mortality (BCM). Multivariable analysis of LR and BCM included stage, subtype, lymphovascular invasion, grade, margin status, beam energy, bolus use, hormone therapy, chemotherapy, and reconstruction. Systemic therapy was used for 98% of the 1887 patients. The bolus group had 1569 patients and the no-bolus group had 318 patients. Bolus was used in 51% (281/550) of patients treated with reconstruction and 96% (1288/1337) of patients treated without reconstruction. The 10-year outcomes (95% confidence interval) in patients treated with and without bolus were, respectively: LR 1.9% (1.3-2.7) versus 0.9% (0.3-2.6), LRR 3.1% (2.3-4.0) versus 3.2% (1.6-5.5), and BCM 19.4% (17.3-21.6) versus 18.3% (13.9-23.2). On multivariable analysis, bolus use was not associated with better LR (hazard ratio = 1.4 [0.3-6.4]) or BCM (hazard ratio = 0.8 [0.5-1.2]). For patients treated with mastectomy, radiation therapy, and modern systemic therapy, the cumulative incidence of LR was low, with or without bolus. Because bolus use increases toxicity and does not reduce LR or BCM, it should no longer be used routinely for patients without skin involvement who receive systemic therapy.

Inhibitor Screening in Severe Hemophilia a: A Six-Year Single Center Experience

Background : Factor VIII (FVIII) inhibitors comprise the most morbid and expensive complication in severe hemophilia A. Inhibitor risk is known to be highest within the first 50 exposures to FVIII replacement products, with greatest risk during the first 20 exposures. Routine inhibitor screening is typically performed frequently with the first 20 to 50 exposures, but screening after 50 exposures is controversial, given the high cost of testing and unknown benefit. Early inhibitor detection allows effective treatment of bleeding with bypassing agents, and prompt initiation of immune tolerance to eradicate the inhibitor. Here we report inhibitor screening results at the University of Colorado Hemophilia and Thrombosis Center. Methods : This is a retrospective review of inhibitor testing data from study participants with severe hemophilia A enrolled, with Institutional Review Board approved informed consent, in the Hemophilia Prospective Inceptional Cohort Study (HEMO-PICS) from April 1, 2011 through April 1, 2017. A positive inhibitor was defined as modified Nijmegen Bethesda titer ≥0.5 confirmed on 2 separate blood draws. Tolerance was defined as a Bethesda titer <0.5 on two or more samples. The clinical protocol prescribed inhibitor screening in severe hemophilia A patients every 3-5 exposures prior to 50, and annually thereafter in accordance with National Hemophilia Foundation and US Centers for Disease Control recommendations. Results : Of 204 participants with severe hemophilia A in the study cohort, 24 had fewer than 50 factor exposures and were inhibitor negative at the start of the study observation period (“<50 Exposures Group”), 13 participants had a positive inhibitor at the start of the observation period (“+ Inhibitor Group”), and 167 had >50 exposures and a history of either no inhibitor or a tolerized inhibitor (“>50 Exposures Group”). Figure 1 shows inhibitor surveillance rates and results. In participants with < 50 exposures, positive inhibitors were detected in 11/42 screening tests, while participants with > 50 exposures had 0 positive inhibitors in 454 screening tests. In the “<50 Exposures Group”, 11 of 24 (45%) developed an inhibitor, 7 high titer (peak range 16.7 - 185 BU/mL) and 4 low titer (peak range 0.7 - 1.8 BU/mL). Six participants achieved 50 exposures without inhibitor development during the observation period, while the remaining 7 had fewer than 50 factor exposures at the end of the study period. The mean (+/- standard deviation) age of inhibitor development was 14.6 (+/- 6.2 [range 3-22]) months, after a mean of 12.8 (+/- 7.9 [range 1-29]) factor exposures. Six of those who developed inhibitors did so prior to starting prophylaxis, and the other 5 patients developed inhibitors within 2 months of prophylaxis initiation. Of those who did not develop inhibitors, 8 have been on prophylaxis for an average of 36 (+/- 23.8 [range 14-80]) months, 3 are planning to start prophylaxis, and 2 have declined. Of the 13 participants in the “+ Inhibitor Group”, 3 were tolerized during the study. Conclusion : We report a high rate of positive inhibitor surveillance tests in severe hemophilia A patients during the first 50 exposures (1 per 3.8 tests), and very low rates of positive inhibitors in this population following 50 exposures (0/454). While our results reinforce the practice of frequent inhibitor screening in patients with < 50 factor exposures, screening for inhibitors in patients with > 50 exposure days and no change in the bleeding phenotype is unlikely to be clinically relevant and should not be routinely performed. [Display omitted] DisclosuresWarren:CSL Behring Heimburger Award: Research Funding; Bayer Hemophilia Awards Program: Research Funding. Ng:CSL Behring Heimburger Award: Research Funding; Shire: Consultancy. Buckner:Shire: Membership on an entity's Board of Directors or advisory committees; Uniqure: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees.

Opioid-free Anesthesia: Time to Regain Our Balance.

Opioid-free Anesthesia: Time to Regain Our Balance.

Abstract PS10-36: Treatment patterns and clinical outcomes among patients (pts) with HER2- advanced breast cancer (ABC) and somatic BRCA1/2 mutation(s) (sBRCA1/2mut): Results from a US real-world study

Abstract Background: Recently, somatic genetic information is being increasingly usedin clinical decisions for treatment of metastatic diseases, including breastcancer. Somatic mutations in the BRCA1/2 genes are not frequently seen.The poly ADP-ribose polymerases inhibitors (PARPi) have been approved astreatments for patients with germline (gBRCA1/2mut) HER2- ABC. Real-world practice shows that these agents arealso being utilized for patients who have sBRCA1/2mut. While we await data from large clinicaltrials such as MATVH and TAPUR, currently, limited information is available onthe effectiveness of these agents in patients with sBRCA1/2mut andestablishing a reference point is necessary to assess the unknown potentialclinical benefit. We assessed real-world treatment patterns and clinicaloutcomes among patients with HER2- sBRCA1/2mut without associatedgermline mutation and who had received treatment for ABC. Methods: US oncologists retrospectivelyreviewed charts (July 2019-June 2020) of quasi-randomly selected patients ≥18y, who received ≥1 cytotoxic chemotherapy (CT) regimen(s) for ABC between Jan2013-April 2018. Descriptive analyses were performed for patients with sBRCA1/2mut(without associated germline mutation), which included evaluation of treatment patternsand safety events for the first 3 lines of therapy. Clinical outcomes(progression free survival [PFS] and overall survival rates) were estimatedusing the Kaplan-Meier method for 1st line of therapy. Given therelatively recent launch of PARPi, clinical outcomes for these agents wereimmature. Results: 32 patients were included who only had sBRCA1/2mut: 96.9%were female, 68.8% were white, and 28.1% were black. Median age was 53.0 yrs. Advanced triplenegative breast cancer was observed in 40.6% of patients and 59.4% had hormonereceptor (HR)+/HER2- ABC. Common treatments for HR+/HER2- sBRCA1/2mutdisease included: 1st line (n=19), cyclophosphamide + doxorubicin (10.5%);2nd line (n=17), docetaxel (11.8%), PARPi monotherapy (11.8%), CDK4/6i + letrozole (11.8%); 3rd line- (n=7), eribulin (42.9%). Treatments for triplenegative sBRCA1/2mut breast cancer included: 1st line (n=13), cyclophosphamide + doxorubicin (30.8%);2nd line (n=9), PARPi (22.2%); 3rd line (n=7),atezolizumab based (71.4%). Median PFS across both subtypes was 10.8 months,95% CI 8.5 - 15.0. Overall, 78.9% of patients were alive at 2 years after 1stCT. Safety data will be presented. Conclusion: In this analysis of sBRCA1/2mut HER2- ABC, an individualapproach to select treatment regimens such as CT was frequently used, withoutadequate knowledge on best sequential therapy to include tumor genetic directedintervention. Poor clinical outcomes highlight the need for more efficacioustreatment options. Further studies assessingclinical outcomes among patients with sBRCA1/2mut ABC receivingPARPi are warranted. Citation Format: Elias Obeid, Rohan C Parikh, Elizabeth Esterberg, Bhakti Arondekar, Abigail Hitchens, Lillian Shahied Arruda, Alexander Niyazov. Treatment patterns and clinical outcomes among patients (pts) with HER2- advanced breast cancer (ABC) and somatic BRCA1/2 mutation(s) (sBRCA1/2mut): Results from a US real-world study [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 PS10-36.

Unlocking the potential of antibody-drug conjugates for cancer therapy.

Nine different antibody-drug conjugates (ADCs) are currently approved as cancer treatments, with dozens more in preclinical and clinical development. The primary goal of ADCs is to improve the therapeutic index of antineoplastic agents by restricting their systemic delivery to cells that express the target antigen of interest. Advances in synthetic biochemistry have ushered in a new generation of ADCs, which promise to improve upon the tissue specificity and cytotoxicity of their predecessors. Many of these drugs have impressive activity against treatment-refractory cancers, although hurdles impeding their broader use remain, including systemic toxicity, inadequate biomarkers for patient selection, acquired resistance and unknown benefit in combination with other cancer therapies. Emerging evidence indicates that the efficacy of a given ADC depends on the intricacies of how the antibody, linker and payload components interact with the tumour and its microenvironment, all of which have important clinical implications. In this Review, we discuss the current state of knowledge regarding the design, mechanism of action and clinical efficacy of ADCs as well as the apparent limitations of this treatment class. We then propose a path forward by highlighting several hypotheses and novel strategies to maximize the potential benefit that ADCs can provide to patients with cancer.

COVID-19-induced endotheliitis: emerging evidence and possible therapeutic strategies.

The coronavirus disease 2019 (COVID‐19) pandemic, a viral illness caused by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), 1 has produced at the time of this writing nearly 33 million cases of infection, with over a million deaths in 235 countries, 2 causing an unprecedented burden on healthcare systems and a severe global socioeconomic crisis. As the pandemic spreads, knowledge on the disease course, as well as potential risk factors and predictors of severity is increasing daily, and initial data from randomised controlled studies have allowed care providers to refine therapeutic strategies. Nonetheless, mortality is markedly elevated among those presenting with severe disease, long‐term sequelae among survivors are unknown, and vaccine‐based therapies currently remain at early stages of development. Most reported cases are asymptomatic or present with mild symptoms; however, 7–26% of hospitalised patients experience severe disease, often requiring admission to intensive care units (ICUs), with progressive multiple organ dysfunction and high mortality. 3 , 4 , 5 Such differences in clinical outcomes have led physicians to initiate diverse pharmacological therapies at various stages of the disease, generating challenges as to the most appropriate therapeutic choice for COVID‐19. In this context, the use of dexamethasone has significantly reduced mortality rates in critically ill patients requiring supplemental oxygen or mechanical ventilation, 6 and remdesivir has demonstrated clinical benefit in hospitalised patients, but with unknown survival benefit to date 7 ; additional effective treatment options are therefore urgently needed. In an initial attempt to provide a uniform and widely reproducible methodology to guide systematic treatment strategies, a three‐stage classification of COVID‐19 has been proposed. 8 The Stage I or ‘early infection’ occurs at the initial establishment of disease with high viral replication, and commonly presents with a range of complaints that can include mild and often non‐specific influenza‐like signs and symptoms. Stage II is the ‘pulmonary phase’, with preferential viral‐mediated injury of the lung parenchyma and this is characterised by shortness of breath, hypoxia and pulmonary infiltrates with some degree of lung inflammation. Stage III is characterised by an exaggerated host immune‐inflammatory response to the virus, leading to acute respiratory distress syndrome (ARDS) and multi‐organ failure (MOF).

On the Learning Benefits of Resource Flexibility

Resource flexibility, arguably among the most celebrated operational concepts, is known to provide firms facing demand uncertainty with such benefits as risk pooling, revenue-maximization optionality, and operational hedging. In this paper, we uncover a heretofore unknown benefit: we establish that resource flexibility facilitates learning the demand when the latter is censored, which could, in turn, enable firms to make better-informed future operational decisions, thereby increasing profitability. Further, we quantify these learning benefits of flexibility and find that they could be of the same order of magnitude as the extensively studied risk-pooling benefits of flexibility. This suggests that flexibility’s learning benefits could be a first-order consideration and that extant theories, which view flexibility only as the ability to act ex post, could be underestimating its true value when learning the demand is desirable, for example, when it enables managers to make better ex ante capacity, assortment, or pricing decisions in future periods. This paper was accepted by Vishal Gaur, operations management.

Checkpoint Inhibition in the Treatment of Unresectable, Advanced Lymphoepithelioma-like Hepatocellular Carcinoma

Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a very rare neoplasm, with distinct epidemiologic, morphologic and clinical characteristics. Molecular mechanistic insight into the pathogenesis of this carcinoma suggests a pivotal role for the host immune system in the proliferation and progression of this tumor. However, while detailed genomic profiling of these hepatic tumors have revealed an intra-tumoral inflammatory mutational signature that may predispose to immune checkpoint inhibitor efficacy, no published report has described their use in this tumor type. Unfortunately, with near 100 cases of LEL-HCC reported in the literature to date and the majority of cases confined to localized and resectable disease, current evidence-based practices in the unresectable setting are lacking, with unknown benefit of chemotherapy or immunotherapy. We report on the case of a 68 year-old man with unresectable, advanced LEL-HCC who had evidence of disease stability after starting on the immune checkpoint inhibitor nivolumab. His disease response persisted off therapy for over a year and was potentially augmented by radiotherapy at the site of local progression. For this extremely rare tumor subtype, this case highlights the potential efficacy and safety of immune checkpoint blockade in LEL-HCC and reinforces the need for more robust, large-scale analysis of patients with these rare tumors to better evaluate treatment strategies and outcomes.

Transmission, Tropism, and Biological Impacts of Torix Rickettsia in the Common Bed Bug Cimex lectularius (Hemiptera: Cimicidae).

The torix group of Rickettsia have been recorded from a wide assemblage of invertebrates, but details of transmission and biological impacts on the host have rarely been established. The common bed bug (Cimex lectularius) is a hemipteran insect which lives as an obligatory hematophagous pest of humans and is host to a primary Wolbachia symbiont and two facultative symbionts, a BEV-like symbiont, and a torix group Rickettsia. In this study, we first note the presence of a single Rickettsia strain in multiple laboratory bed bug isolates derived from Europe and Africa. Importantly, we discovered that the Rickettsia has segregated in two laboratory strains, providing infected and uninfected isogenic lines for study. Crosses with these lines established transmission was purely maternal. Fluorescence in-situ hybridization analysis indicates Rickettsia infection in oocytes, bacteriomes, and other somatic tissues. We found no evidence that Rickettsia infection was associated with sex ratio distortion activity, but Rickettsia infected individuals developed from first instar to adult more slowly. The impact of Rickettsia on fecundity and fertility resulted in infected females producing fewer fertile eggs. However, we could not find any evidence for cytoplasmic incompatibility associated with Rickettsia presence. These data imply the existence of an unknown benefit to C. lectularius carrying Rickettsia that awaits further research.