Migrant memory B cells secrete luminal antibody in the vagina.

Antibodies secreted into mucosal barriers serve to protect the host from a variety of pathogens, and are the basis for successful vaccines1. In type I mucosa (such as the intestinal tract), dimeric IgA secreted by local plasma cells is transported through polymeric immunoglobulin receptors2 and mediates robust protection against viruses3,4. However, owing to the paucity of polymeric immunoglobulin receptors and plasma cells, how and whether antibodies are delivered to the type II mucosa represented by the lumen of the lower female reproductive tract remains unclear. Here, using genital herpes infection in mice, we show that primary infection does not establish plasma cells in the lamina propria of the female reproductive tract. Instead, upon secondary challenge with herpes simplex virus 2, circulating memory B cells that enter the female reproductive tract serve as the source of rapid and robust antibody secretion into the lumen of this tract. CD4 tissue-resident memory T cells secrete interferon-γ, which induces expression of chemokines, including CXCL9 and CXCL10. Circulating memory B cells are recruited to the vaginal mucosa in a CXCR3-dependent manner, and secrete virus-specific IgG2b, IgG2c and IgA into the lumen. These results reveal that circulating memory B cells act as a rapidly inducible source of mucosal antibodies in the female reproductive tract.

Analysis of Candy Tobacco Imitation Products Available Online in the United States.

INTRODUCTION: Youth tobacco use remains a critical public health concern, and childhood use of candy tobacco imitation products (CTIP) is associated with cigarette use among youth. However, no research has examined the full extent of CTIP available for purchase in the United States. AIMS AND METHODS: We conducted a content analysis of CTIP available on English-language, US-based websites. We identified sites that marketed CTIP utilizing Google and candy retail websites, examining each product for product names, the tobacco product being replicated (eg, cigar and cigarette), manufacturer, candy flavor, images, product rating, pack color, and if the product had packaging that may appeal to youth. RESULTS: We found 66 CTIP available. The most popular CTIP were cigars, with 39 separate products (59%), followed by candy cigarettes-14 products (21%), candy pipes-8 products (12%), and chewing tobacco-5 products (8%). In the 52 products where packaging design was available, 39 (75%) had packaging that may appeal to youth. CONCLUSIONS: CTIP, many of which contain packaging appealing to youth, are widely available for purchase online across the United States. These findings could stimulate policy actions, such as removal of CTIP from popular retail websites, labeling of CTIP as potentially dangerous to youth, or age verification requirements for purchasing CTIP. IMPLICATIONS: CTIP continues to be sold on the internet despite research indicating candy cigarette product use by youth increases their likelihood of smoking. We conducted research to understand the extent to which CTIP are sold on the internet and whether these products are being marketed to youth. The results provide evidence that some of the largest retail companies in the world continue to sell CTIP, and the majority are sold in packaging that likely appeals to youth. The results suggest that further research into the market for these products is needed, and regulatory measures should be considered to prevent CTIP from leading to youth tobacco use.

Impact of Early Hemodynamic Screening on Extremely Preterm Outcomes in a High-Performance Center.

Rationale: Increasing survival of extremely preterm infants with a stable rate of severe intraventricular hemorrhage represents a growing health risk for neonates. Objectives: To evaluate the role of early hemodynamic screening (HS) on the risk of death or severe intraventricular hemorrhage. Methods: All eligible patients 22-26+6 weeks' gestation born and/or admitted <24 hours postnatal age were included. As compared with standard neonatal care for control subjects (January 2010-December 2017), patients admitted in the second epoch (October 2018-April 2022) were exposed to HS using targeted neonatal echocardiography at 12-18 hours. Measurements and Main Results: A primary composite outcome of death or severe intraventricular hemorrhage was decided a priori using a 10% reduction in baseline rate to calculate sample size. A total of 423 control subjects and 191 screening patients were recruited with a mean gestation and birth weight of 24.7 ± 1.5 weeks and 699 ± 191 g, respectively. Infants born at 22-23 weeks represented 41% (n = 78) of the HS epoch versus 32% (n = 137) of the control subjects (P = 0.004). An increase in perinatal optimization (e.g., antepartum steroids) but with a decline in maternal health (e.g., increased obesity) was seen in the HS versus control epoch. A reduction in the primary outcome and each of severe intraventricular hemorrhage, death, death in the first postnatal week, necrotizing enterocolitis, and severe bronchopulmonary dysplasia was seen in the screening era. After adjustment for perinatal confounders and time, screening was independently associated with survival free of severe intraventricular hemorrhage (OR 2.09, 95% CI [1.19, 3.66]). Conclusions: Early HS and physiology-guided care may be an avenue to further improve neonatal outcomes; further evaluation is warranted.

Acute kidney injury surveillance in the high-risk neonatal population following implementation of creatinine screening protocol.

AIM: Acute kidney injury (AKI) in neonates is associated with longer hospital stays and higher mortality rates. However, there is significant variability in prevalence rates of AKI and the true burden is incompletely understood. In November 2020, the University of Iowa Stead Family Children's Hospital Neonatal Intensive Care Unit implemented a creatinine screening protocol to enhance kidney function monitoring. We sought to evaluate adherence to the protocol to determine if increased surveillance led to increased detection of AKI events. METHODS: A retrospective chart review was conducted for neonates born at <30 weeks' gestation admitted between 2015 and 2020. We reviewed 100 charts in both the pre (2015-2016) and post (2020-2021) implementation era of the AKI surveillance protocol. AKI was defined according to neonatal modified KDIGO criteria. RESULTS: Following implementation of the protocol, neonates were significantly more likely to have creatinine checked (p < 0.001). Serum creatinine was drawn according to protocol guidelines 68% of the time, and 42% of patients (34/82) had an 80% or higher adherence to the protocol. There was a significant increase in detection of AKI in the post-protocol cohort (13/82, incidence of 16%) compared to the pre-protocol cohort (5/83, incidence of 6%), (p = 0.047). CONCLUSION: The implementation of a serum creatinine screening protocol increased the frequency of creatinine draws and detection of AKI.

Vitamin B12 and folic acid alleviate symptoms of nutritional deficiency by antagonizing aryl hydrocarbon receptor.

Despite broad appreciation of their clinical utility, it has been unclear how vitamin B12 and folic acid (FA) function at the molecular level to directly prevent their hallmark symptoms of deficiency like anemia or birth defects. To this point, B12 and FA have largely been studied as cofactors for enzymes in the one-carbon (1C) cycle in facilitating the de novo generation of nucleotides and methylation of DNA and protein. Here, we report that B12 and FA function as natural antagonists of aryl hydrocarbon receptor (AhR). Our studies indicate that B12 and FA bind AhR directly as competitive antagonists, blocking AhR nuclear localization, XRE binding, and target gene induction mediated by AhR agonists like 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 6-formylindolo[3,2-b]carbazole (FICZ). In mice, TCDD treatment replicated many of the hallmark symptoms of B12/FA deficiency and cotreatment with aryl hydrocarbon portions of B12/FA rescued mice from these toxic effects. Moreover, we found that B12/FA deficiency in mice induces AhR transcriptional activity and accumulation of erythroid progenitors and that it may do so in an AhR-dependent fashion. Consistent with these results, we observed that human cancer samples with deficient B12/FA uptake demonstrated higher transcription of AhR target genes and lower transcription of pathways implicated in birth defects. In contrast, there was no significant difference observed between samples with mutated and intact 1C cycle proteins. Thus, we propose a model in which B12 and FA blunt the effect of natural AhR agonists at baseline to prevent the symptoms that arise with AhR overactivation.

A molecular mechanism for probabilistic bet hedging and its role in viral latency.

Probabilistic bet hedging, a strategy to maximize fitness in unpredictable environments by matching phenotypic variability to environmental variability, is theorized to account for the evolution of various fate-specification decisions, including viral latency. However, the molecular mechanisms underlying bet hedging remain unclear. Here, we report that large variability in protein abundance within individual herpesvirus virion particles enables probabilistic bet hedging between viral replication and latency. Superresolution imaging of individual virions of the human herpesvirus cytomegalovirus (CMV) showed that virion-to-virion levels of pp71 tegument protein-the major viral transactivator protein-exhibit extreme variability. This super-Poissonian tegument variability promoted alternate replicative strategies: high virion pp71 levels enhance viral replicative fitness but, strikingly, impede silencing, whereas low virion pp71 levels reduce fitness but promote silencing. Overall, the results indicate that stochastic tegument packaging provides a mechanism enabling probabilistic bet hedging between viral replication and latency.

Longitudinal Immune Profiling of a Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection in a Solid Organ Transplant Recipient.

BACKGROUND: The underlying immunologic deficiencies enabling severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection are currently unknown. We describe deep longitudinal immune profiling of a transplant recipient hospitalized twice for coronavirus disease 2019 (COVID-19). METHODS: A 66-year-old male renal transplant recipient was hospitalized with COVID-19 March 2020 then readmitted to the hospital with COVID-19 233 days after initial diagnosis. Virologic and immunologic investigations were performed on samples from the primary and secondary infections. RESULTS: Whole viral genome sequencing and phylogenetic analysis revealed that viruses causing both infections were caused by distinct genetic lineages without evidence of immune escape mutations. Longitudinal comparison of cellular and humoral responses during primary SARS-CoV-2 infection revealed that this patient responded to the primary infection with low neutralization titer anti-SARS-CoV-2 antibodies that were likely present at the time of reinfection. CONCLUSIONS: The development of neutralizing antibodies and humoral memory responses in this patient failed to confer protection against reinfection, suggesting that they were below a neutralizing titer threshold or that additional factors may be required for efficient prevention of SARS-CoV-2 reinfection. Development of poorly neutralizing antibodies may have been due to profound and relatively specific reduction in naive CD4 T-cell pools. Seropositivity alone may not be a perfect correlate of protection in immunocompromised patients.

First intention high-frequency jet ventilation for periviable infants.

PURPOSE OF REVIEW: Ventilation of periviable infants born at 22-23 weeks gestation remains a challenge in neonatology. This review highlights the evidence surrounding the use of first intention high-frequency jet ventilation (HFJV) in infants born near the limits of viability with a review of pulmonary fetal development and a focused overview of HFJV strategies including an in-depth analysis of the management strategies used in the initial randomized trials. RECENT FINDINGS: A paucity of recent trials exists, with no randomized control trials assessing the use of first intention HFJV performed in the last 25 years. A retrospective observational cohort trial of the use of HFJV for infants born at less than 750 g has been recently published demonstrating the efficacy of HFJV for this population even with 2.0-mm endotracheal tubes. SUMMARY: The lack of recent randomized trials contributes to the controversy surrounding the use of first intention HFJV. Although new research is needed in the area, this review includes the ventilation strategy of an experienced center with a focus on the use of first intention HFJV for the care of premature infants born less than 24 weeks gestation.

Acinar Atrophy, Fibrosis and Fatty Changes Are Significantly More Common than Sjogren's Syndrome in Minor Salivary Gland Biopsies.

Background and Objective: Hyposalivation and xerostomia can result from a variety of conditions. Diagnosis is based on a combination of medical history, clinical and serological parameters, imaging, and minor salivary gland biopsy when indicated. The Objective was to characterize microscopic changes in minor salivary gland biopsies taken in patients with xerostomia. Materials and Methods: 10-year retrospective analysis of minor salivary gland biopsies, 2007-2017. Histomorphometric analysis included gland architecture, fibrosis, fat replacement, inflammation and stains for IgG/IgG4, when relevant. Results: 64 consecutive biopsies, of which 54 had sufficient tissue for diagnosis of Sjogren's Syndrome (SS) were included (18 males, 46 females, average age 56 (±12.5) years). Only 12 (22.2%) were microscopically consistent with SS, none stained for IgG4. Medical conditions were recorded in 40 (63%), most frequently hypertension and hyperlipidemia (28% each). Medications were used by 45 (70%), of which in 50% more than one. Xerostomia in non-SS cases was supported by abnormal gland morphology, including acinar atrophy, fibrosis and fatty replacement. All morphological abnormalities are correlated with age, while fatty replacement correlated with abnormal lipid metabolism. Multiple medications correlated with microscopic features which did not correspond with SS. Conclusions: SS was confirmed in a minority of cases, while in the majority fatty replacement, fibrosis and multiple medications can explain xerostomia, and are related to aging and medical conditions. Medical history and auxiliary tests could lead to correct diagnosis in non-SS patients, avoiding biopsy. The necessity of a diagnostic biopsy should be given serious consideration only after all other diagnostic modalities have been employed.

RUNX Binding Sites Are Enriched in Herpesvirus Genomes, and RUNX1 Overexpression Leads to Herpes Simplex Virus 1 Suppression.

Herpes simplex virus 1 (HSV-1) and HSV-2 can efficiently establish lifelong, transcriptionally silent latency states in sensory neurons to escape host detection. While host factors have previously been associated with long-range insulators in the viral genome, it is still unknown whether host transcription factors can repress viral genes more proximately to promote latency in dorsal root ganglion (DRG) neurons. Here, we assessed whether RUNX (runt-related transcription factor) transcription factors, which are critical in the development of sensory neurons, could be binding HSV-1 genome directly to suppress viral gene expression and lytic infection. Using previously published transcriptome sequencing data, we confirmed that mouse DRG neurons highly express Runx1 mRNA. Through computational analysis of HSV-1 and HSV-2 genomes, we observed that putative RUNX consensus binding sites (CBSs) were more enriched and more closely located to viral gene transcription start sites than would be expected by chance. We further found that RUNX CBSs were significantly more enriched among genomes of herpesviruses compared to those of nonherpesviruses. Utilizing an in vitro model of HSV-1 infection, we found that overexpressed RUNX1 could bind putative binding sites in the HSV-1 genome, repress numerous viral genes spanning all three kinetic classes, and suppress productive infection. In contrast, knockdown of RUNX1 in neuroblastoma cells induced viral gene expression and increased HSV-1 infection in vitro In sum, these data support a novel role for RUNX1 in directly binding herpesvirus genome, silencing the transcription of numerous viral genes, and ultimately limiting overall infection.IMPORTANCE Infecting 90% of the global population, HSV-1 and HSV-2 represent some of the most prevalent viruses in the world. Much of their success can be attributed to their ability to establish lifelong latent infections in the dorsal root ganglia (DRG). It is still largely unknown, however, how host transcription factors are involved in establishing this latency. Here, we report that RUNX1, expressed highly in DRG, binds HSV-1 genome, represses transcription of numerous viral genes, and suppresses productive in vitro infection. Our computational work further suggests this strategy may be used by other herpesviruses to reinforce latency in a cell-specific manner.

Asking the Right Questions About Secondhand Smoke.

INTRODUCTION: Despite knowledge about major health effects of secondhand tobacco smoke (SHS) exposure, systematic incorporation of SHS screening and counseling in clinical settings has not occurred. METHODS: A three-round modified Delphi Panel of tobacco control experts was convened to build consensus on the screening questions that should be asked and identify opportunities and barriers to SHS exposure screening and counseling. The panel considered four questions: (1) what questions should be asked about SHS exposure; (2) what are the top priorities to advance the goal of ensuring that these questions are asked; (3) what are the barriers to achieving these goals; and (4) how might these barriers be overcome. Each panel member submitted answers to the questions. Responses were summarized and successive rounds were reviewed by panel members for consolidation and prioritization. RESULTS: Panelists agreed that both adults and children should be screened during clinical encounters by asking if they are exposed or have ever been exposed to smoke from any tobacco products in their usual environment. The panel found that consistent clinician training, quality measurement or other accountability, and policy and electronic health records interventions were needed to successfully implement consistent screening. CONCLUSIONS: The panel successfully generated screening questions and identified priorities to improve SHS exposure screening. Policy interventions and stakeholder engagement are needed to overcome barriers to implementing effective SHS screening. IMPLICATIONS: In a modified Delphi panel, tobacco control and clinical prevention experts agreed that all adults and children should be screened during clinical encounters by asking if they are exposed or have ever been exposed to smoke from tobacco products. Consistent training, accountability, and policy and electronic health records interventions are needed to implement consistent screening. Increasing SHS screening will have a significant impact on public health and costs.

Hypothyroxinemia Detected at 4 Weeks of Life in Preterm Infants Born at Less than 30 Weeks of Gestation.

OBJECTIVE: Data on free thyroxine (FT4) concentrations beyond first 2 weeks of preterm infants are limited. This study was aimed to describe the association between perinatal characteristics and FT4 concentrations and the incidence of hypothyroxinemia at 4 weeks. STUDY DESIGN: Retrospective analysis of serum thyroid function tests at 4 weeks in preterm infants <30 weeks of gestation. Association between FT4 at 4 weeks of life and perinatal characteristics were determined by bivariate analysis and multivariable regression. Incidence of hypothyroxinemia was determined using a gestational age adjusted definition based on in utero levels at the equivalent postmenstrual age. RESULTS: The study cohort consisted of 280 infants. FT4 concentrations at 4 weeks of life were significantly associated with gestational age, birth weight, gender, and maternal history of thyroid disease. Hypothyroxinemia was found in 32.8% of the study cohort. CONCLUSION: Perinatal characteristics are associated with FT4 concentrations at 4 weeks of life. Nearly one-third of infants born <30 weeks had hypothyroxinemia at 4 weeks of life when compared with in utero levels at the equivalent postmenstrual age.

Non-oncologist Physician Knowledge of Radiation Therapy at an Urban Community Hospital.

Radiation therapy (RT) is a crucial part of cancer care, but previous work suggests that many non-radiation oncologist physicians are uncomfortable referring for RT. To evaluate training and understanding of RT, the authors sent invitations to complete an online questionnaire to all physicians at a community hospital in Bronx, NY, which asked about oncology training and self-rated and objective knowledge of RT. Out of 247 invited participants, 87 responded (35%). Among responders, 19 were attending physicians (22%) and 66 (76%) were residents. Seventy-two percent of respondents reported caring for > 5 cancer patients in the past month, but 54% reported never referring patients for RT. Sixty-nine percent of respondents stated they received no radiation oncology training in medical school, and 36% reported no general oncology training. Approximately half believed themselves to be "somewhat knowledgeable" about RT indications (48%), benefits (53%), and side effects (55%). Objective assessment mean score was 6.2/12 (median 7) for all respondents; Respondents with internal medicine specialization scored higher than others (mean 7.7 vs 3.5; p < 0.01). Scores did not differ between attending and resident physicians, resident post-graduate levels, or receiving oncology training in medical school. The factors most commonly cited as affecting RT referral decisions were type of cancer, patient wishes, family wishes, poor functional status, and life expectancy. Many physicians are unaware of RT effectiveness or indications, which may affect referral patterns. Previous oncology training was not associated with higher knowledge scores.

A calibration scheme for non-line-of-sight imaging setups.

The recent years have given rise to a large number of techniques for "looking around corners", i.e., for reconstructing or tracking occluded objects from indirect light reflections off a wall. While the direct view of cameras is routinely calibrated in computer vision applications, the calibration of non-line-of-sight setups has so far relied on manual measurement of the most important dimensions (device positions, wall position and orientation, etc.). In this paper, we propose a method for calibrating time-of-flight-based non-line-of-sight imaging systems that relies on mirrors as known targets. A roughly determined initialization is refined in order to optimize for spatio-temporal consistency. Our system is general enough to be applicable to a variety of sensing scenarios ranging from single sources/detectors via scanning arrangements to large-scale arrays. It is robust towards bad initialization and the achieved accuracy is proportional to the depth resolution of the camera system.

Effect of Treatment Sequencing on the Tumor Response to Combined Treatment With Ultrasound-Stimulated Microbubbles and Radiotherapy.

OBJECTIVES: To investigate whether timing and sequencing of ultrasound-stimulated microbubbles (USMBs) and external beam radiotherapy (XRT) affect the treatment response in a preclinical prostate cancer model. METHODS: Prostate cancer xenografts were treated with ultrasound-stimulated lipid microspheres before and after 8-Gy XRT. Treatments were separated by 0, 3, 6, 12, and 24 hours, with 5 tumors per group. Tumor effects were evaluated by microvessel density (measured by CD31 staining), cell death (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labeling and hematoxylin-eosin staining), and hypoxia (carbonic anhydrase 9 staining). RESULTS: Administering USMBs 6 hours before XRT showed the maximum treatment effect using all 3 assays. At this time, the mean cell death index ± SD was 36% ± 10%, compared with 19% ± 4% for no separation between USMB treatment and XRT; the microvessel density was 9 ± 3 counts per field (19 ± 5 without separation); and the percentage of hypoxic cells was 10% ± 5% (21% ± 4%). The observed treatment effect was greater with USMBs before XRT than when administering XRT first, but these differences were not statistically significant. CONCLUSIONS: The maximum tumor effect was observed with USMBs delivered 6 hours before XRT. The sequencing of treatment did not have a significant effect on the tumor response.

Uncovering the processes of knowledge transformation: the example of local evidence-informed policy-making in United Kingdom healthcare.

BACKGROUND: Healthcare policy-makers are expected to develop 'evidence-based' policies. Yet, studies have consistently shown that, like clinical practitioners, they need to combine many varied kinds of evidence and information derived from divergent sources. Working in the complex environment of healthcare decision-making, they have to rely on forms of (practical, contextual) knowledge quite different from that produced by researchers. It is therefore important to understand how and why they transform research-based evidence into the knowledge they ultimately use. METHODS: We purposively selected four healthcare-commissioning organisations working with external agencies that provided research-based evidence to assist with commissioning; we interviewed a total of 52 people involved in that work. This entailed 92 interviews in total, each lasting 20-60 minutes, including 47 with policy-making commissioners, 36 with staff of external agencies, and 9 with freelance specialists, lay representatives and local-authority professionals. We observed 25 meetings (14 within the commissioning organisations) and reviewed relevant documents. We analysed the data thematically using a constant comparison method with a coding framework and developed structured summaries consisting of 20-50 pages for each case-study site. We iteratively discussed and refined emerging findings, including cross-case analyses, in regular research team meetings with facilitated analysis. Further details of the study and other results have been described elsewhere. RESULTS: The commissioners' role was to assess the available care provision options, develop justifiable arguments for the preferred alternatives, and navigate them through a tortuous decision-making system with often-conflicting internal and external opinion. In a multi-transactional environment characterised by interactive, pressurised, under-determined decisions, this required repeated, contested sensemaking through negotiation of many sources of evidence. Commissioners therefore had to subject research-based knowledge to multiple 'knowledge behaviours'/manipulations as they repeatedly re-interpreted and recrafted the available evidence while carrying out their many roles. Two key 'incorporative processes' underpinned these activities, namely contextualisation of evidence and engagement of stakeholders. We describe five Active Channels of Knowledge Transformation - Interpersonal Relationships, People Placement, Product Deployment, Copy, Adapt and Paste, and Governance and Procedure - that provided the organisational spaces and the mechanisms for commissioners to constantly reshape research-based knowledge while incorporating it into the eventual policies that configured local health services. CONCLUSIONS: Our new insights into the ways in which policy-makers and practitioners inevitably transform research-based knowledge, rather than simply translate it, could foster more realistic and productive expectations for the conduct and evaluation of research-informed healthcare provision.

Locally advanced breast cancer treated with neoadjuvant chemotherapy and adjuvant radiotherapy: a retrospective cohort analysis.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is increasingly used to treat locally advanced breast cancer (LABC). Improved response to NAC correlates with better survival outcomes. The dual purpose of this study is to report recurrence and survival outcomes for LABC patients treated with NAC, surgery and adjuvant radiotherapy and to correlate these outcomes with tumour response after NAC using multiple response assessment methods. METHODS: All LABC patients treated for curative intent with NAC, surgery, and adjuvant radiotherapy at our institute between January 2009 and December 2014 were included for analysis. NAC was mostly anthracycline and taxane-based; radiotherapy consisted of 50 Gy to the breast/chest wall and regional lymph nodes. Response to NAC was categorized using synoptic pathology reports, modified-RECIST and Chevallier scores. Survival curves were generated by the Kaplan-Meier method and compared using the log-rank test. RESULTS: The cohort included 103 patients nearly equally divided between Stage II (n = 53) and Stage III (n = 50). Rates of locoregional control (LRC), recurrence-free survival (RFS), and overall survival (OS) were 99, 98, and 100% at 1 year and 89, 69 and 77% at 5 years, respectively. Responses to NAC did not correlate with LRC (p > 0.05) but did correlate with RFS and OS (p < 0.05), except that the Chevallier score did not predict RFS (p = 0.06). Using bivariate Cox modeling tumour size before (p = 0.003) and after (p < 0.001) NAC, stage group (p = 0.05), and response assessed by synoptic pathology (p = 0.05), modified-RECIST (p = 0.001), and Chevallier score (p = 0.015) all predicted for RFS. No factors predicted for LRC. CONCLUSION: Pathologic response by all tested methods correlated with improved survival but were not associated with decreased LRC.

Pretreatment financial toxicity predicts progression-free survival following concurrent chemoradiotherapy for locally advanced non-small-cell lung cancer.

Aim: Financial toxicity (FT) describes patients' burden from out-of-pocket medical treatment costs. We studied associations between patient-reported pretreatment FT, socioeconomic status and clinical outcomes for locally advanced non-small-cell lung cancer (LA-NSCLC) patients. Methods: Patients received chemoradiotherapy for locally advanced non-small-cell lung cancer and completed the European Organization for the Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) quality of life assessment before treatment. One question asks whether patients experience 'financial difficulties'. We tested FT and socioeconomic status (SES) as predictors of progression-free survival (PFS) and overall survival (OS). Results: A total of 43 patients were included. Median follow-up for surviving patients was 15 months. A total of 19 patients (44%) experienced disease progression and 17 patients (40%) died. Increasing FT was associated with shorter PFS (p = 0.011). FT did not predict overall survival (p = 0.67). Conclusion: Higher pretreatment FT is associated with shorter PFS.

Comparison of central laboratory assessments of ER, PR, HER2, and Ki67 by IHC/FISH and the corresponding mRNAs (ESR1, PGR, ERBB2, and MKi67) by RT-qPCR on an automated, broadly deployed diagnostic platform.

PURPOSE: The methods (IHC/FISH) typically used to assess ER, PR, HER2, and Ki67 in FFPE specimens from breast cancer patients are difficult to set up, perform, and standardize for use in low and middle-income countries. Use of an automated diagnostic platform (GeneXpert®) and assay (Xpert® Breast Cancer STRAT4) that employs RT-qPCR to quantitate ESR1, PGR, ERBB2, and MKi67 mRNAs from formalin-fixed, paraffin-embedded (FFPE) tissues facilitates analyses in less than 3 h. This study compares breast cancer biomarker analyses using an RT-qPCR-based platform with analyses using standard IHC and FISH for assessment of the same biomarkers. METHODS: FFPE tissue sections from 523 patients were sent to a College of American Pathologists-certified central reference laboratory to evaluate concordance between IHC/FISH and STRAT4 using the laboratory's standard of care methods. A subset of 155 FFPE specimens was tested for concordance with STRAT4 using different IHC antibodies and scoring methods. RESULTS: Concordance between STRAT4 and IHC was 97.8% for ESR1, 90.4% for PGR, 93.3% for ERBB2 (IHC/FISH for HER2), and 78.6% for MKi67. Receiver operating characteristic curve (ROC) area under the curve (AUC) values of 0.99, 0.95, 0.99, and 0.85 were generated for ESR1, PGR, ERBB2, and MKi67, respectively. Minor variabilities were observed depending on the IHC antibody comparator used. CONCLUSION: Evaluation of breast cancer biomarker status by STRAT4 was highly concordant with central IHC/FISH in this blinded, retrospectively analyzed collection of samples. STRAT4 may provide a means to cost-effectively generate standardized diagnostic results for breast cancer patients in low- and middle-income countries.