Physicians are Unable to Consistently Predict Patient Health Literacy in a Breast Clinic.

INTRODUCTION: Health literacy (HL) is a patient's capacity to understand health information. Low HL is associated with worse cancer outcomes and adherence to treatment regimens. This study aimed to test physicians' ability to predict their patients' HL after an initial consultation to determine if routine HL screening is valuable. METHODS: From February 2023 through June 2023, patients seen at an academic breast clinic completed a validated, self-reported HL assessment. Surgical and medical oncologists estimated their patients' HL by answering the same HL questionnaire based on their perception of the patient visit. Patient and physician scores were compared using an intraclass correlation coefficient. Linear regression was used to evaluate associations between physicians' ability to predict HL and other variables. RESULTS: The cohort included 210 patient HL scores with corresponding physician scores for each. Most patients (75.7%) had adequate HL. There was moderate agreement between the patient and physician HL scores (intraclass correlation coefficient = 0.677, P < 0.01), meaning physicians could somewhat predict their patient's HL. Physicians were worse at predicting HL when patients had low HL. There was no difference in physicians' ability to predict HL based on patient age (P = 0.09) or race (P = 0.29). Additionally, we found no difference in the ability to predict HL based on the physician's specialty (P = 0.25). CONCLUSIONS: After an initial consultation, physicians cannot accurately predict patient HL, particularly in patients with lower HL. Given the impact of low HL on a patient's ability to make treatment decisions and adhere to treatment plans, using a validated tool to measure HL is necessary.

Implementation of a Breast Intraoperative Oncoplastic Form to Aid Management of Oncoplastic Surgery.

INTRODUCTION: Oncoplastic breast conservation surgery (BCS) uses concurrent reduction and/or mastopexy with lumpectomy to improve aesthetic outcomes. However, tissue rearrangement can shift the original tumor location site in relation to external breast landmarks, resulting in difficulties during re-excision for a positive margin and accurate radiation targeting. We developed the Breast Intraoperative Oncoplastic (BIO) form to help depict the location of the tumor and breast reduction specimen. This study seeks to assess physician perspectives of the implementation outcomes. METHODS: From February 2021 to April 2021, the BIO form was used in 11 oncoplastic BCS cases at a single institution. With institutional review board approval, surgical oncologists (SOs), plastic surgeons (PSs), and radiation oncologists (ROs) were administered a 12-question validated survey on Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM), using a 5-point Likert scale during initial implementation and at 6-month reassessment. RESULTS: Twelve physicians completed the survey initially (4 SOs, 4 PSs, and 4 ROs). The mean scores for Acceptability of Intervention Measure, Intervention Appropriateness Measure, and Feasibility of Intervention Measure were high (4.44, 4.56, and 4.56, respectively). Twelve completed the second survey (5 SOs, 3 PSs, and 4 ROs). The mean scores were marginally lower (4.06, 4.21, and 4.25). There were no significant differences when stratified by number of years in practice or specialty. Free text comments showed that 75% of physicians found the form helpful in oncoplastic BCS. CONCLUSIONS: The data indicate high feasibility, acceptability, and appropriateness of the BIO form. Results of this study suggest multidisciplinary benefits of implementing the BIO form in oncoplastic BCS.

Dendritic cell therapy augments antitumor immunity triggered by CDK4/6 inhibition and immune checkpoint blockade by unleashing systemic CD4 T-cell responses.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are a mainstay treatment for hormone receptor-positive breast cancer. While their principal mechanism is inhibition of cancer cell proliferation, preclinical and clinical evidence suggests that CDK4/6i can also promote antitumor T-cell responses. However, this pro-immunogenic property is yet to be successfully harnessed in the clinic, as combining CDK4/6i with immune checkpoint blockade (ICB) has not shown a definitive benefit in patients. METHOD: We performed an in-depth analysis of the changes in the tumor immune microenvironment and systemic immune modulation associated with CDK4/6i treatment in muring breast cancer models and in patients with breast cancer using high dimensional flow cytometry and RNA sequencing. Gain and loss of function in vivo experiments employing cell transfer and depletion antibody were performed to uncover immune cell populations critical for CDK4/6i-mediated stimulation of antitumor immunity. RESULTS: We found that loss of dendritic cells (DCs) within the tumor microenvironment resulting from CDK4/6 inhibition in bone marrow progenitors is a major factor limiting antitumor immunity after CDK4/6i and ICB. Consequently, restoration of DC compartment by adoptively transferring ex vivo differentiated DCs to mice treated with CDK4/6i and ICB therapy enabled robust tumor inhibition. Mechanistically, the addition of DCs promoted the induction of tumor-localized and systemic CD4 T-cell responses in mice receiving CDK4/6i-ICB-DC combination therapy, as characterized by enrichment of programmed cell death protein-1-negative T helper (Th)1 and Th2 cells with an activated phenotype. CD4 T-cell depletion abrogated the antitumor benefit of CDK4/6i-ICB-DC combination, with outgrowing tumors displaying an increased proportion of terminally exhausted CD8 T cells. CONCLUSIONS: Our findings suggest that CDK4/6i-mediated DC suppression limits CD4 T-cell responses essential for the sustained activity of CD8 T cells and tumor inhibition. Furthermore, they imply that restoring DC-CD4 T-cell crosstalk via DC transfer enables effective breast cancer immunity in response to CDK4/6i and ICB treatment.

Impact of delay in adjuvant therapy for gallbladder adenocarcinoma.

BACKGROUND: Receipt of adjuvant therapy for gallbladder adenocarcinoma (GBAC) is associated with a survival benefit. This study sought to identify whether delays in initiation of adjuvant therapy among patients with resected GBAC impacts long-term survival. METHODS: Patients with stage II and III GBAC who underwent a curative-intent resection followed by adjuvant chemotherapy or chemoradiation between 2004 and 2017 were queried from the National Cancer Data Base. Descriptive statistics and multivariate models were constructed to determine the relationship between timely (<12 weeks) and delayed (>12 weeks) adjuvant therapy and overall survival (OS). RESULTS: A total of 871 patients with GBAC were identified. The median time to receipt of adjuvant chemotherapy was 67 days and the median time to receipt of adjuvant chemoradiation was 69 days. After controlling for all factors, treatment at an Academic/Research center was the only variable associated with timely receipt of adjuvant therapy. However, after controlling for clinically relevant factors, the timing of adjuvant therapy did not impact OS (delayed: HR 0.93, 95% CI: 0.46-1.85; P = .83). CONCLUSION: Current guidelines support the use of adjuvant therapy following resection of GBAC. This national cohort study demonstrates that delays in adjuvant therapy >12 weeks did not impact long-term survival.

Conditional Survival Following Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Surface Malignancies: An Analysis from the US HIPEC Collaborative.

INTRODUCTION: The long-term prognosis of patients who undergo cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal surface malignancies (PSM) varies considerably on the basis of histological and operative factors. While overall survival (OS) estimates are used to inform adjuvant therapy and surveillance strategies, conditional survival may provide more clinically relevant estimates of prognosis by accounting for disease-free time elapsed. PATIENTS AND METHODS: All patients from 12 academic institutions who underwent CRS ± HIPEC for PSM from 2000 to 2017 were retrospectively analyzed. OS and disease-free survival (DFS) rates were calculated using the Kaplan-Meier method while conditional overall (COS) and conditional disease-free survival (CDFS) rates were calculated at 1, 2, or 3 years from surgery for different tumor histologies. RESULTS: Overall, 1610 patients underwent CRS ± HIPEC. Among patients with benign appendiceal mucinous tumors (N = 460), 5-year OS and COS at 3 years were 92.1% and 96.3% (Δ4.2%), respectively. For patients with well-differentiated appendiceal cancers (N = 400), 5-year OS and COS at 3 years were 76.3% and 88.3% (Δ12.0%), respectively. For patients with high-grade appendiceal cancers (N = 258), 5-year OS and COS at 3 years were 43.8% and 75.4% (Δ31.6%), respectively. For patients with colorectal cancers (N = 362), 5-year OS and COS at 3 years were 31.8% and 67.3% (Δ35.5%), respectively. For patients with peritoneal mesothelioma (N = 130), 5-year OS and COS at 3 years were 67.6% and 89.7% (Δ22.1%), respectively. Similar trends were observed for DFS/CDFS. CONCLUSION: The conditional survival of patients undergoing CRS ± HIPEC for PSM is associated with tumor histology. COS and CDFS provide a more accurate, dynamic estimate of survival than OS and DFS, especially for patients with more aggressive histologies.

Prognostic factors in patients receiving surgery and radiation therapy for retroperitoneal sarcoma: A machine-learning analysis.

BACKGROUND: The addition of radiation therapy to surgery for retroperitoneal sarcoma remains controversial. Improved patient selection may help identify optimal candidates for multimodality treatment. The aim of this analysis was to define prognostic factors among patients who receive radiation therapy and surgery to aid in patient selection for multimodal therapy. METHODS: Patients who received radiation therapy and underwent curative-intent resection for retroperitoneal sarcoma between 2004 and 2016 were identified from a national cohort in the United States (National Cancer Database). A machine-based classification and regression tree model was used to generate similar groups of patients relative to overall survival based on preoperative factors. RESULTS: A total of 1,443 patients received radiation therapy in addition to surgery. Median age was 61 years old and 55.0% were female. Most patients (66%) received care at an academic or integrated network cancer program. With a median follow-up of 84 months, receipt of radiation therapy was not associated with improved overall survival (P = .81). Classification and regression tree analysis revealed a significant association between overall survival and American Joint Committee on Cancer stage group, age, tumor histology, and Charlson comorbidity score. Application of these parameters via machine learning stratified patients into 5 cohorts with distinct survival outcomes. In the most favorable cohort (Cohort 1: American Joint Committee on Cancer stage group ≤II, age ≤61, histology including fibrosarcoma, well differentiated liposarcoma, myxoid liposarcoma, and leiomyosarcoma), the 5-year overall survival was 81.7% and median overall survival was not reached; in the least favorable cohort (Cohort 6: American Joint Committee on Cancer stage group >II, age >68) where the 5-year survival was 41.3% and median overall survival was 45.2 months (P < .001 versus Cohort 1). CONCLUSION: In the absence of a defined survival benefit, patients with advanced American Joint Committee on Cancer stage group, older age, and medical comorbidities have relatively unfavorable overall survival after combined modality therapy and therefore stand the least to gain from the addition of radiation therapy to surgery. In contrast, younger patients with good performance status and retroperitoneal sarcoma histologies with a higher propensity for local recurrence may have the greatest opportunity to benefit from radiation therapy.

BCL-xL inhibition potentiates cancer therapies by redirecting the outcome of p53 activation from senescence to apoptosis.

Cancer therapies trigger diverse cellular responses, ranging from apoptotic death to acquisition of persistent therapy-refractory states such as senescence. Tipping the balance toward apoptosis could improve treatment outcomes regardless of therapeutic agent or malignancy. We find that inhibition of the mitochondrial protein BCL-xL increases the propensity of cancer cells to die after treatment with a broad array of oncology drugs, including mitotic inhibitors and chemotherapy. Functional precision oncology and omics analyses suggest that BCL-xL inhibition redirects the outcome of p53 transcriptional response from senescence to apoptosis, which likely occurs via caspase-dependent down-modulation of p21 and downstream cytostatic proteins. Consequently, addition of a BCL-2/xL inhibitor strongly improves melanoma response to the senescence-inducing drug targeting mitotic kinase Aurora kinase A (AURKA) in mice and patient-derived organoids. This study shows a crosstalk between the mitochondrial apoptotic pathway and cell cycle regulation that can be targeted to augment therapeutic efficacy in cancers with wild-type p53.

Smaller parathyroids have higher near-infrared autofluorescence intensity in hyperparathyroidism.

BACKGROUND: Intraoperative parathyroid gland identification can be challenging. Parathyroid glands have an intrinsic autofluorescence when excited by wavelengths in the near-infrared region. Studies using near-infrared cameras to detect parathyroid gland near-infrared autofluorescence have suggested improved identification. The pathologic parathyroid glands in primary hyperparathyroidism have variable near-infrared autofluorescence intensity, but how this correlates with different characteristics of hyperparathyroidism is unknown. Our objective was to correlate the fluorescent intensity of excited glands with clinical variables to enhance a surgeon's ability to identify parathyroid glands. METHODS: The data on patients undergoing surgery for primary hyperparathyroidism were collected. The images were collected intraoperatively with a handheld near-infrared device and analyzed. The data consisted of the ratio of mean parathyroid gland near-infrared autofluorescence over background (white gauze) near-infrared autofluorescence. The variables assessed for correlation with autofluorescence intensity were gland volume and weight, preoperative serum calcium and parathyroid hormone, age, body mass index, and sex. The images were quantified by Image J software (National Institutes of Health, Bethesda, MD). The lasso regression was analyzed by R version 4.1.3 to calculate adjusted P values (R Foundation for Statistical Computing, Vienna, Austria). RESULTS: From 2017 to 2021, 131 patients with primary hyperparathyroidism underwent parathyroidectomies of 151 parathyroid glands. The mean near-infrared autofluorescence intensity of parathyroid glands had a negative correlation with weight with lighter glands fluorescing more (P = .019) and a positive correlation with age with glands from older patients fluorescing more (P = .013). There were no significant correlations with preoperative serum calcium and parathyroid hormone, body mass index, and sex (P > .05). CONCLUSION: In patients with primary hyperparathyroidism, we found that autofluorescence intensity correlated with parathyroid gland weight and patient age. This suggested that near-infrared camera use may be particularly helpful in identifying smaller adenomas and in older patients.

Short- and long-term outcomes following robotic and open resection for intrahepatic cholangiocarcinoma: A national cohort study.

BACKGROUND: Curative-intent liver resection with porta hepatis lymphadenectomy provides the best chance for long-term survival for patients with intrahepatic cholangiocarcinoma (ICC). While the robotic approach has been increasingly utilized, its impact on perioperative and long-term outcomes of patients with ICC are largely unknown. METHODS: Patients with stages I-III ICC who underwent surgical resection between 2004 and 2017 were identified from the National Cancer Database. Descriptive statistics and multivariate models were constructed to examine the association between surgical approach and surgical and oncological outcomes. RESULTS: A total of 1876 patients with ICC who underwent open (n = 1804, 96.2%) and robotic-assisted (n = 72, 3.8%) resection were identified. Following surgery, patients who underwent a robotic-assisted resection had a shorter length of hospital stay yet there was no difference in 30-day readmission or 90-day mortality. Older age, disease stage, and higher comorbidity were associated with worse OS. Patients undergoing robotic-assisted surgery had no difference in long-term risk of death compared with patients who underwent an open procedure. CONCLUSION: This national cohort study demonstrated that the robotic approach for patients undergoing resection for ICC resulted in a shorter hospitalization while not compromising oncological outcomes such as negative margins, postoperative mortality, and long-term survival.

In search of lost time: Delays in adjuvant therapy for pancreatic adenocarcinoma among under-resourced patient populations.

BACKGROUND: The initiation of adjuvant chemotherapy for pancreatic adenocarcinoma within 12 weeks after surgery is recommended by the National Comprehensive Cancer Network. This study seeks to identify factors associated with delayed adjuvant chemotherapy and whether delays impact survival in under-resourced populations. METHODS: Patients with nonmetastatic pancreatic adenocarcinoma who received a definitive resection followed by adjuvant chemotherapy between 2006 and 2017 were queried from the National Cancer Database. Multivariate logistic regression models were constructed to determine the relationship between socioeconomic/clinical variables and delayed adjuvant chemotherapy. Kaplan Meier curves compared survival between under-resourced patients receiving delayed versus timely adjuvant chemotherapy. RESULTS: Among 25,008 patients, timely adjuvant chemotherapy varied by stage (stage 1: 67.9% vs stage 2: 75.8% vs stage 3: 89.2%; P < .001). Older age (odds ratio 1.02, 95% confidence interval 1.02-1.03; P < .001), Non-Hispanic Black race (odds ratio 1.25, 95% confidence interval 1.11-1.41; P < .001), increasing comorbidity score (odds ratio 1.18, 95% confidence interval 1.12-1.23; P < .001), 30-day readmission (odds ratio 1.45, 95% confidence interval 1.28-1.63; P < .001), and undergoing a Whipple (odds ratio 1.30, 95% confidence interval 1.16-1.44; P < .001) were associated with delayed adjuvant chemotherapy. Conversely, the highest neighborhood median income quartile (odds ratio 0.84, 95% confidence interval 0.73-0.97; P = .021), private insurance (odds ratio 0.59, 95% confidence interval 0.46-0.76; P < .001), Medicare (odds ratio 0.68, 95% confidence interval 0.52-0.88; P = .003), and receipt of neoadjuvant therapy (odds ratio 0.05, 95% confidence interval 0.04-0.06; P < .001) were associated with timely adjuvant chemotherapy. Non-Hispanic Black patients and patients with the lowest neighborhood education had worse overall survival when receiving delayed versus timely adjuvant chemotherapy. CONCLUSION: Timely adjuvant chemotherapy for pancreatic adenocarcinoma was only achieved in 73.3% of patients. Age, race, comorbidities, median income, and insurance were identified as barriers. Delayed adjuvant chemotherapy was associated with worse survival among under-resourced populations.

Impact of care fragmentation on the outcomes of patients receiving neoadjuvant and adjuvant therapy for pancreatic adenocarcinoma.

INTRODUCTION: Neoadjuvant therapy (NT) is increasingly used for localized pancreatic ductal adenocarcinoma (PDAC). The impact of care fragmentation during NT on the outcomes of patients with PDAC is unknown. METHODS: Adult patients with Stage I-III PDAC who received NT and patients who underwent surgery first followed by adjuvant therapy (AT) between 2004 and 2016 were queried from the National Cancer Database. Short- and long-term outcomes were compared between patients who received fragmented care (FC; care provided at >1 hospital) versus integrated care (IC; care at a single institution). RESULTS: Among 6522 patients who underwent NT before pancreatectomy, 3755 (57.6%) received FC and 2767 (42.4%) received IC. While patients who received FC had a longer time to initiation of treatment (33.2 vs. 29.7 days, p < 0.001), there was no difference in median overall survival (OS) (26.7 vs. 26.5 months, p = 0.6). Among patients who underwent upfront surgery followed by AT (n = 15 291), patients who received FC had a longer time from diagnosis to undergoing surgery but less time from surgery to AT and no difference in OS (24.0 vs. 24.0 months, p = 0.910). CONCLUSION: Although care fragmentation was associated with slightly longer times to initiate and complete treatment among patients with localized PDAC, long-term survival outcomes were similar.

Pegylated Interferon Treatment for the Effective Clearance of Hepatitis B Surface Antigen in Inactive HBsAg Carriers: A Meta-Analysis.

Background: Expanding antiviral therapy to benefit more populations and optimizing treatment to improve prognoses are two main objectives in current guidelines on antiviral therapy. However, the guidelines do not recommend antiviral therapy for inactive hepatitis B surface antigen (HBsAg) carriers (IHCs). Recent studies have shown that antiviral therapy is effective with good treatment outcomes in IHC populations. We conducted a systematic review and meta-analysis of HBsAg clearance and conversion in IHCs. Methods: We searched PubMed, Embase, Medline, and Web of Science to retrieve articles on HBsAg clearance in IHCs published between January 2000 and August 2021. Data were collected and analysed using the random-effects model for meta-analysis. Results: A total of 1029 IHCs from 11 studies were included in this analysis. The overall HBsAg clearance rate was 47% (95% confidence interval (CI): 31% - 64%), with a conversion rate of 26% (95% CI: 15% - 38%) after 48 weeks of Pegylated interferon (Peg-IFN) treatment. In the control group (including nucleos(t)ide analogue (NA) treatment or no treatment), the overall HBsAg clearance rate was only 1.54% (95% CI: 0.56% - 3.00%), which was markedly lower than that in the Peg-IFN group. Further analysis showed that a low baseline HBsAg level and long treatment duration contributed to a higher HBsAg clearance rate. Conclusion: This study showed that treatment of IHCs can be considered to achieve a clinical cure for chronic hepatitis B virus (HBV) infection. After Peg-IFN treatment, the HBsAg clearance rate was 47%, and the conversion rate was 26%, which are markedly higher than those reported by previous studies on Peg-IFN treatment in patients with chronic hepatitis B (CHB). A low baseline HBsAg level and long treatment duration were associated with HBsAg clearance in IHCs. Therefore, antiviral therapy is applicable for IHCs, a population who may be clinically cured. Systematic Review Registration: http://www.crd.york.ac.uk/PROSPERO, CRD): CRD42021259889.

Regulatory T-cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Regulatory T-cells (Tregs) impair cancer immunosurveillance by creating an immunosuppressive environment that fosters tumor cell survival. Our previous findings demonstrated that neutrophil extracellular traps (NETs), which are involved both in innate and adaptive immunity, are abundant in livers affected by non-alcoholic steatohepatitis (NASH). However, how NETs interact with Tregs in the development of NASH-associated hepatocellular carcinoma (NASH-HCC) is not known. METHODS: A choline-deficient, high-fat diet+diethylnitrosamine mouse model and the stelic animal model were utilized for NASH-HCC and a western diet mouse model was used for NASH development. Treg depletion was achieved using FoxP3-DTR mice. RNA sequencing was used to explore the mechanism by which NETs could regulate Treg differentiation. Bioenergetic analyses of naïve CD4+ T-cells were assessed by Seahorse. RESULTS: Although the absolute number of CD4+ T-cells is lower in NASH livers, the Treg subpopulation is selectively increased. Depleting Tregs dramatically inhibits HCC initiation and progression in NASH. There is a positive correlation between increased NET and hepatic Treg levels. RNA sequencing data reveals that NETs impact gene expression profiles in naïve CD4+ T-cells, with the most differentially expressed genes being those involved in mitochondrial oxidative phosphorylation. By facilitating mitochondrial respiration, NETs can promote Treg differentiation. Metabolic reprogramming of naïve CD4+ T-cells by NETs requires toll-like receptor 4. Blockade of NETs in vivo using Pad4-/- mice or DNase I treatment reduces the activity of Tregs. CONCLUSIONS: Tregs can suppress immunosurveillance in the premalignant stages of NASH. NETs facilitate the crosstalk between innate and adaptive immunity in NASH by promoting Treg activity through metabolic reprogramming. Therapies targeting NETs and Treg interactions could offer a potential strategy for preventing HCC in patients with NASH. LAY SUMMARY: Regulatory T-cells (Tregs) can promote tumor development by suppressing cancer immunosurveillance, but their role in carcinogenesis during non-alcoholic steatohepatitis (NASH) progression is unknown. Herein, we discovered that selectively increased intrahepatic Tregs can promote an immunosuppressive environment in NASH livers. Neutrophil extracellular traps (NETs) link innate and adaptive immunity by promoting Treg differentiation via metabolic reprogramming of naïve CD4+ T-cells. This mechanism could be targeted to prevent liver cancer in patients with NASH.

Full Abstract to Published Manuscript: Evaluation of the Scientific Impact of the American Society of Breast Surgeons Conference.

BACKGROUND: The scientific rigor of the abstracts presented at the American Society of Breast Surgeons (ASBrS) annual meeting has not been recently evaluated. In this study, we sought to determine the rate at which abstracts presented at the 2017 and 2018 ASBrS meetings were published in peer-reviewed journals, and compared the rates with breast abstracts presented at the 2018 Society of Surgical Oncology (SSO) meeting. METHODS: Abstracts from the 2017 and 2018 ASBrS and 2018 SSO conferences were searched in PubMed for published manuscripts using the abstract title and/or first or last author. RESULTS: In 2017, 21.6% of the 268 abstracts presented at the ASBrS conference resulted in full publication, compared with 36.6% of the 273 abstracts presented at the 2018 ASBrS conference, resulting in a significant difference in the publication rate (p < 0.001). Of the 158 abstracts published from the 2017 and 2018 meetings, 75 (47.8%) were published in Annals of Surgical Oncology (ASO). There was no correlation between impact factor and time to publication. Oral presentations and quick shots were more likely to be published than poster presentations, and oral presentations were more likely to be published in higher-impact journals. The 2018 SSO meetings resulted in 54 of 111 (48.6%) breast abstracts leading to full publication. CONCLUSION: Approximately 29.2% of the abstracts presented at the ASBrS 2017 and 2018 conferences resulted in a published manuscript. A higher publication rate in higher impact journals for oral presentations indicates that the abstract review process properly stratifies the research.

Pre-operative exercise therapy triggers anti-inflammatory trained immunity of Kupffer cells through metabolic reprogramming.

Pre-operative exercise therapy improves outcomes for many patients who undergo surgery. Despite the well-known effects on tolerance to systemic perturbation, the mechanisms by which pre-operative exercise protects the organ that is operated on from inflammatory injury are unclear. Here, we show that four-week aerobic pre-operative exercise significantly attenuates liver injury and inflammation from ischaemia and reperfusion in mice. Remarkably, these beneficial effects last for seven more days after completing pre-operative exercising. We find that exercise specifically drives Kupffer cells toward an anti-inflammatory phenotype with trained immunity via metabolic reprogramming. Mechanistically, exercise-induced HMGB1 release enhances itaconate metabolism in the tricarboxylic acid cycle that impacts Kupffer cells in an NRF2-dependent manner. Therefore, these metabolites and cellular/molecular targets can be investigated as potential exercise-mimicking pharmaceutical candidates to protect against liver injury during surgery.

Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors.

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) delay progression of metastatic breast cancer. However, complete responses are uncommon and tumors eventually relapse. Here, we show that CDK4/6i can enhance efficacy of T cell-based therapies, such as adoptive T cell transfer or T cell-activating antibodies anti-OX40/anti-4-1BB, in murine breast cancer models. This effect is driven by the induction of chemokines CCL5, CXCL9, and CXCL10 in CDK4/6i-treated tumor cells facilitating recruitment of activated CD8+ T cells, but not Tregs, into the tumor. Mechanistically, chemokine induction is associated with metabolic stress that CDK4/6i treatment induces in breast cancer cells. Despite the cell cycle arrest, CDK4/6i-treated cells retain high metabolic activity driven by deregulated PI3K/mTOR pathway. This causes cell hypertrophy and increases mitochondrial content/activity associated with oxidative stress and inflammatory stress response. Our findings uncover a link between tumor metabolic vulnerabilities and anti-tumor immunity and support further development of CDK4/6i and immunotherapy combinations.

Disparities in Stage-Specific Guideline-Concordant Cancer-Directed Treatment for Patients with Pancreatic Adenocarcinoma.

BACKGROUND: The utilization of cancer-directed treatment for patients with all stages of pancreatic cancer in the USA is unknown. This study sought to examine national practice patterns and identify patient, hospital, regional, and other factors associated with disparities in the use of guideline-concordant cancer-directed therapy. METHODS: Patients diagnosed with PDAC between 2004 and 2015 were queried from the National Cancer Data Base. Standard of care cancer-directed treatment was defined as surgical resection plus chemotherapy or chemoradiation for patients with stage 1 and 2 disease, chemotherapy for patients with metastatic disease (stage 4), and chemotherapy with or without surgery or chemoradiation for patients with locally advanced stage 3 disease. RESULTS: A total of 336,629 patients with stage 1 (n = 38,443, 11.4%), stage 2 (n = 93,923, 27.9%), stage 3 (n = 37,492, 11.1%), or stage 4 metastatic (n = 166,771, 49.5%) disease were identified. Adherence with stage-specific standard of care treatment occurred in only 45.3% (n = 152,560) of patients among the entire cohort and varied by stage of disease (stage 1: 14.6% vs. stage 2: 39.9% vs. stage 3: 67.6%, vs. stage 4: 50.9%). Older age (OR 0.95, 95%CI 0.94-0.95; p < 0.001), female sex (OR 0.94, 95%CI 0.943-0.97; p < 0.001), African Americans (OR 0.89, 95%CI 0.87-0.91; P < 0.001), and increasing comorbidity burden (Charlson-Deyo score ≥3: OR 0.52, 95%CI 0.50-0.55; P < 0.001) were associated with a lower likelihood of receiving stage-specific standard of care treatment. Conversely, treatment at a high-volume center (quartile 4: OR: 1.13, 95%CI 1.10-1.16; P < 0.001) and higher education level (OR 1.32, 95%CI 1.28-1.36; p < 0.001) was associated with higher likelihood of receiving stage-specific standard of care treatment. Patients who received standard of care treatment had a 47% lower risk of death compared with patients who did not receive standard of care treatment (HR 0.53, 95%CI 0.52-0.53; P < 0.001). CONCLUSION: Pancreatic adenocarcinoma is a complex disease requiring a multi-disciplinary approach for optimal outcomes. Receipt of stage-specific standard of care treatment for PDAC is associated with improved long-term oncological outcomes, but is only achieved in less than half of patients. Further studies are needed to evaluate interventions to address these treatment disparities for patients with PDAC.

Neoadjuvant endocrine therapy use in early stage breast cancer during the covid-19 pandemic.

PURPOSE: Physician treatment preferences for early stage, estrogen positive breast cancer (ER + BC) patients were evaluated during the initial surge of the COVID-19 pandemic in the US when neoadjuvant endocrine therapy (NET) was recommended to allow safe deferral of surgery. METHODS: A validated electronic survey was administered May-June, 2020 to US medical oncologists (MO), radiation oncologists (RO), and surgeons (SO) involved in clinical trials organizations. Questions on NET use included practice patterns for locoregional management following NET. RESULTS: 114 Physicians from 29 states completed the survey-42 (37%) MO, 14 (12%) RO, and 58 (51%) SO. Before COVID-19, most used NET 'rarely' (49/107, 46%) or 'sometimes' (36, 33%) for ER + BC. 46% would delay surgery 2 months without NET. The preferred NET regimen was tamoxifen for premenopausal and aromatase inhibitor for postmenopausal women. 53% planned short term NET until surgery could proceed. Most recommended omitting axillary lymph node dissection (ALND) for one micrometastatic node after 1, 2, or 3 months of NET (1 month, N = 56/93, 60%; 2 months, N = 54/92, 59%; 3 months, N = 48/90, 53%). With longer duration of NET, omission of ALND decreased, regardless of years in practice, percent of practice in BC, practice type, participation in multidisciplinary tumor board, or number of regional COVID-19 cases. CONCLUSION: More physicians preferred NET for ER + BC during the pandemic, compared with pre-pandemic times. As the duration of NET extended, more providers favored ALND in low volume metastatic axillary disease. The Covid-19 pandemic affected practice of ER + BC; it remains to be seen how this may impact outcomes.