Citations

AbstractPelvic organ prolapse (POP) is a dysfunction that affects a large proportion of women. Current support scaffolds’ lack of biocompatibility, biodegradability, and mechanical compliance are associated with surgical complications including erosion and pain, indicating the urgent need for new tissue scaffolds with customizable functions. A new material that uses polyvinyl alcohol (PVA) as the main ingredient and is chemically tuned to possess suitable mechanical properties and degradation rates for the surgical treatment of POP is developed. Specifically, the thiol‐norbornene “click” chemistry enables the sol‐gel transition of the biomaterial under UV‐light without side‐products. Meanwhile, NaOH treatment further toughens the hydrogel with a higher crosslink density. The PVA‐based biocompatible ink can be printed with UV‐facilitated direct ink writing due to the rapidly UV‐initiated chemical crosslink; in situ image analysis and machine learning methods are applied during this procedure to quantify and improve the printing quality. The cell viability results demonstrate the biocompatibility of the POP scaffolds, suggesting the potential for future animal studies and the possibility of clinical research. This study bridges polymer chemistry and manufacturing engineering with a specific tissue engineering application to solve the common disorder of POP, shedding light on individualized medicine and intelligent systems for biomedical engineering.

The relationship between diabetes and coronavirus disease 2019 (COVID-19) is bidirectional: Although individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyperinflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease after influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602K (MSDC), dampened pulmonary inflammation and promoted lung recovery while concurrently reducing blood glucose levels and hyperlipidemia after viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized hypoxia-inducible factor–1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development after SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.

AbstractAimTo examine the impact of socioeconomic status (SES) and postacute care (PAC) locations on the association between hospital safety‐net status and 30‐day postdischarge outcomes (readmission, hospice use, or death).MethodMedicare Current Beneficiary Survey (MCBS) participants during 2006–2011 who were Medicare Fee‐for‐Service beneficiaries aged 65.5 years or older were included. The associations between hospital safety‐net status and 30‐day post‐discharge outcomes were evaluated by comparing the models with and without PAC and SES adjustments. Safety‐net hospital status was defined as being in the top 20% of hospitals ranked by hospital‐level percent of total Medicare patient days. SES was measured using individual‐level SES (dual eligibility, income, and education) and the Area Deprivation Index (ADI).ResultsThis study identified 13,173 index hospitalizations for 6,825 patients; 1,428 hospitalizations (11.8%) were in safety‐net hospitals. The average unadjusted 30‐day hospital readmission rate was 22.6% in safety‐net hospitals versus 18.8% in nonsafety‐net hospitals. Regardless of whether patient SES status was controlled or not, safety‐net hospitals had higher estimated probabilities of 30‐day readmission (ranging from 0.217 to 0.222 vs. 0.184 to 0.189), and lower probabilities for having neither readmission nor hospice/death (0.750–0.763 vs. 0.780–0.785); for models additionally adjusted for PAC types, safety‐net patients had lower rates of hospice use or death (0.019–0.027 vs. 0.030–0.031).ConclusionsThe results suggested that safety‐net hospitals had lower hospice/death rates but higher readmission rates relative to outcomes at nonsafety‐net hospitals. Readmission rate differences were similar regardless of patients' SES status. However, the rate of hospice referral or death rate was related to SES, which suggested that the outcomes were affected by SES and PAC types.

Abstract The immune responses to anti-PD-1 therapy in cancer patients are not completely defined due to lack of reliable biomarkers that identifies responsive and functional T cells. Bim, a molecule of the Bcl-2 family, was recently identified as a downstream signaling molecule of PD-1 pathway in CD8+ T cells and has both pro-apoptotic and effective roles in CD8 T cells. Our clinical data shown that high level of Bim in CD8+ T cells (before checkpoint blockade) was predictive of response in metastatic melanoma whereas in colorectal cancer, low level of Bim was associated with treatment response. Using co-immunoprecipitation, high resolution microscopy and FRET we identified ANT2 (Adenine Nucleotide Translocase 2, an inner membrane protein of mitochondria) as a protein interacting with Bim. Accordingly, we found CD8+ T cells with low and high mitochondrial potential demonstrated different ANT2/Bim ratio, and high ANT2/Bim ratio fall in effector T cells with low mitochondrial potential but high cytotoxic activity. Given the pro-survival of ANT2, our results indicate that ANT2 may function to balance the pro-apoptotic and effective role of Bim in mitochondria in order to preserve effector T cells before contraction. Understanding the molecular mechanism of Bim and ANT2 interaction in CD8+ T cells may provide a novel marker to identify resilient CD8+ T cells responsive to anti-PD-1 therapy, and predict clinical response to the therapy.

TPS780 Background: Pancreatic adenocarcinoma is an aggressive malignancy with a limited number of therapeutic options. One subset of patients (up to 15%) carries germline and/or somatic mutations in homologous recombination repair genes, most notably BRCA1, BRCA2 and PALB2 amongst others, that confer sensitivity to PARP inhibition. Combinations of PARP inhibitors with anti-PD1 immunotherapy have shown activity in breast and ovarian cancer and have not yet been thoroughly studied in pancreatic cancer. Methods: We designed a single-arm phase 2 investigator-initiated study utilizing the combination of niraparib, a highly selective PARP inhibitor and a dostarlimab, an anti PD1 antibody, in the subset of pancreatic cancer patients with germline or somatic mutations in BRCA1/2, PALB2, BARD1, RAD51C, or RAD51D. Additional inclusion criteria include metastatic pancreatic adenocarcinoma, receipt of a platinum agent in 1st or 2nd line unless contraindicated, and at least 1 but not more than 2 prior lines of systemic therapy not including maintenance. Prior PARP inhibition is allowed, but not immediately prior to enrollment. Exclusion criteria include active unstable autoimmune disease or prior malignancy requiring active treatment within 2 years. Patients are treated with niraparib 200 mg orally once daily on days 1 through 21 of a 21 day cycle. Dostarlimab is administered IV 500 mg every 3 weeks for the 1st 4 cycles and then 1000 mg IV every 6 weeks subsequently. The primary endpoint of the study is the disease control rate at 12 weeks using standard iRECIST criteria. Twenty patients will be enrolled to ensure 19 evaluable. The design has 80% power to detected improvement in disease control rate from 25-50% with significance level of 0.10. Descriptive factors include gene mutated for inclusion, germline/somatic, and platinum refractoriness. Given the size of the study along with genetic heterogeneity there will be no interim analysis. Patients are being enrolled at 3 Mayo clinic sites in Rochester Minnesota, Phoenix Arizona, Jacksonville Florida. To date, 13 patients have been enrolled across all 3 sites. Full accrual is anticipated by early 2023. Correlative studies include genomic characterization of baseline tumors, assessment of immune infiltration of tumor microenvironment, tumor collection for organoid/xenograft, and serial circulating cell-free DNA and immune biomarkers. Trial Identifiers: NCT04493060, Mayo: MC1841. Supported by Glaxo Smith Kline. Clinical trial information: NCT04493060 .

61 Background: Although several guideline-recommended colorectal cancer (CRC) screening modalities have been shown to reduce CRC incidence and mortality, adherence remains below U.S. public health goals. Patient navigation services have been shown to improve CRC screening completion. Patient navigation services, including outbound phone, text, and e-mail reminders, and inbound phone support (>200 languages) are included with all mt-sDNA test (Cologuard) orders. A website and financial assistance (upon request and qualification) are also available for patients. We developed a survey, informed by behavioral theory, to identify psychosocial and communication factors associated with completion of mt-sDNA screening including questions to evaluate awareness and use of navigation services. Methods: Adults aged 45-75 years, with a US postal address, who received a valid order for mt-sDNA screening between 5/21-9/21 were eligible for sampling. RTI administered the survey between 3/22-6/22. Participants had the option to complete electronic- or paper-based surveys. We conducted crosstabulation with Chi Square to assess whether awareness and use of navigation services was significantly associated with (a) test completion within 6 months of the order date and (b) likelihood of future mt-sDNA use. Results: 2,973 participants completed the survey (RR= 21.7%; 65.15% by web and 34.85% by paper). Responders and non-responders did not differ significantly by age or sex. For each navigation service, awareness was significantly higher among those who completed the mt-sDNA test compared to those did not. Across all services, awareness was significantly higher among respondents reporting they were ‘very likely’ to complete mt-sDNA if recommended by a healthcare provider in the future than all other responses combined. A significantly higher proportion of completers (vs. non-completers) reported receiving the email reminder, using the Cologuard website, and using the English language inbound phone support. A significantly higher proportion of those “very likely” to complete mt-sDNA screening in the future reported receiving the email reminder, using the Cologuard website, and using the English language inbound phone support. Conclusions: Awareness and use of patient navigation services was associated with higher completion of the mt-sDNA test and with greater likelihood of future mt-sDNA test use. Patient navigation services comprised of evidence-based strategies, such as reminders, support patient adherence to CRC screening.

60 Background: Colorectal cancer (CRC) screening has been shown to reduce CRC incidence and mortality. Several CRC screening modalities are guideline recommended for average-risk adults aged 45-75 years. CRC screening is underutilized in the US and access to facility-based options, such as colonoscopy, represents a potential barrier. Home-based stool tests are guideline-endorsed and offer a convenient, accessible, scalable option for CRC screening. Thus, understanding the factors that influence completion of stool-based CRC screening is important to guide interventions to improve adherence. We developed a survey, informed by behavioral theory, to identify psychosocial, behavioral and communication factors associated with completion of mt-sDNA screening. Methods: The survey instrument was finalized through expert review, quality testing, and cognitive testing. Adults aged 45-75 years, with a US postal address, who received a valid order for mt-sDNA and whose kit was shipped between 5/21-9/21 were eligible for sampling. RTI administered the survey between 3/22-6/22. Participants had the option to complete electronic or paper surveys. We fit a multivariable logistic regression to identify factors significantly associated with mt-sDNA test completion. Results: Of 17,370 individuals invited to participate, 2,973 completed the survey (AAPOR RR3 = 21.7%); 77.3% of the sample completed the mt-sDNA test. Responders and non-responders did not differ significantly by sex or age. Controlling for demographic characteristics and insurance status, the odds of mt-sDNA test completion were significantly higher among participants who reported greater perceived test effectiveness (OR = 1.20), greater ease (OR = 4.06), and greater comfort in test use (OR = 1.18). Odds of test completion were significantly higher among participants who reported their healthcare provider discussed the mt-sDNA test with them (OR = 2.01) and involved them a great deal in decision making about CRC screening (OR = 1.29). Participants who expressed greater worry about developing CRC were less likely to return their mt-sDNA kit (OR = 0.81). Conclusions: To improve population adherence to CRC screening recommendations, efforts are needed to ensure patients understand the attributes and effectiveness of available test options and feel adequately prepared to complete their preferred screening test. Additionally, healthcare providers must be appropriately prepared and resourced to educate and to engage patients in shared decision-making about CRC screening.

489 Background: To determine if SBRT followed by sorafenib (SBRT/S) improves overall survival (OS), progression free survival (PFS) and quality of life (QOL) vs. sorafenib alone (S), in patients (pts) with HCC. Methods: Eligible pts had new or recurrent HCC, unsuitable for surgery, ablation or TACE, with Zubrod performance status (PS) 0-2, Child-Pugh (CP) A, BCLC stage B or C, ≤ 5 HCCs, sum of hepatic HCCs ≤ 20 cm, and distant metastases ≤ 3 cm. Pts were randomized 1:1 to S 400 mg BID vs. SBRT (27.5-50 Gy in 5 fractions) followed by S 200 mg BID, increased to 400 mg BID after 28 days. Primary endpoint was OS; reported secondary endpoints - PFS, adverse events (AEs - CTCAEv4), and QOL (improvement in FACT-Hep score by ≥ 5 points from baseline to 6 months). Planned sample size was 292 pts (238 OS events, HR=0.72, 80% power, 1-sided α=0.05). Accrual closed early, due to a change in HCC standard of care. Statistics were amended to report as of 7/1/2022, projecting 155 OS events, with 65% power and the same α. OS and PFS were estimated by Kaplan-Meier and arms compared using log-rank test. Cox proportional hazards models were used to analyze treatment effect. Secondary endpoints were tested with 2-sided α=0.05. Results: Of 193 pts accrued from April 2013 to March 2021 from 23 sites, 177 eligible pts were randomized to S (n=92) vs. SBRT/S (n=85). Median age was 66 yrs (27-84); 41% had Hep. C; 19% had Hep. B or B/C. 82% were BCLC stage C. 74% had macrovascular invasion (MVI), 63% with VP3 or VP4 MVI. 4% had metastases. Median sum of max diameter of HCCs was 8.2 cm for S and 6.7 cm for SBRT/S; 40% had a single HCC. Median follow-up for all and alive pts was 13.2 and 33.7 mo. 22% of S pts received SBRT after discontinuing S. With 153 OS events, median OS was improved from 12.3 mo. (90% CI 10.6, 14.3) with S to 15.8 mo. (90% CI 11.4-19.2) with SBRT/S (HR=0.77, 1-sided p=0.0554). After adjusting for PS, M stage, CP A5 vs. 6, and degree of MVI, OS was statistically significantly improved for SBRT/S (HR=0.72, 95% CI 0.52-0.99, 2-sided Cox p=0.042). Median PFS was improved from 5.5 mo. (95% CI 3.4-6.3) with S to 9.2 months (95% CI 7.5-11.9) with SBRT/S (HR=0.55, 95% CI 0.40-0.75, 2-sided p=0.0001). 8 grade (G) 3+ bleeds were seen: 5 in S arm (1 G3 variceal, 2 G3 upper GI, 1 G3 hepatic, and 1 G4 abdominal) and 3 post SBRT/S (2 G3 upper GI, 1 G3 lower GI). Treatment-related G3+ AEs were not significantly different (S - 42%; SBRT/S - 47%; p=0.52), with 3 G5 AEs (S - 1 hepatic failure, 1 death NOS; SBRT/S - 1 lung infection). 83 (47%) pts consented to QoL. Of 20 S and 17 SBRT/S pts with QoL assessments at baseline and 6 months, 10% on S improved in FACT-Hep score vs 35% on SBRT/S. Conclusions: Compared to S alone, SBRT improved OS & PFS in patients with HCC, with no observed increase in AEs, and a strong suggestion for QOL benefit at 6 months. Supported by U10CA180868 (NRG Onc. Op., U10CA180822 (NRG Onc. SDMC), UG1CA189867 (NCORP), and U24CA180803 (IROC) from the NCI. Clinical trial information: NCT01730937 .

424 Background: Understanding the impact of anticancer therapies on immune system is critical to successful design and incorporation of immunotherapies. We developed a novel immune monitoring platform that measures the relative amount of circulating effector T cells and antitumor cytotoxicity of circulating immune cells. We previously showed that this assay can differentiate patients’ clinical response to anti-PD-1 therapy. Here, we applied this assay to patients with gastric or gastroesophageal junction adenocarcinoma (GGEA) who received chemoradiation or chemotherapy-based therapies. Methods: Patients underwent peripheral blood collection at baseline and during follow-up. Levels of circulating effector T cells (CX3CR1+NKG7+/CD3+CD8+) were quantified by flow cytometry using peripheral blood mononuclear cells (PBMCs). Antitumor cytotoxicity of circulating immune cells was evaluated by co-culturing CD3/CD28 activated PBMCs with calcein-AM labeled GGEA tumor cells (FLO-1). Antitumor cytotoxicity of individual patients’ PBMCs was calculated based on the amount of calcein released by dead tumor cells. Results: In a pilot study of 8 patients with mismatch repair-proficient (pMMR) GGEA, the changes in the frequency of effector T cells appeared to be associated with radiographic response to treatment based on RECIST (3 partial response [PR], 3 stable disease [SD], and 2 progressive disease [PD]). The median interval between sequential blood collections was 64 days and an increase in effector T cells was observed in patients with PD. Antitumor cytotoxicity was evaluated in 4 patients who did not receive targeted therapies or immune checkpoint inhibitors. Two of these patients (a, b) had blood collected at the time of diagnosis (treatment naïve) and after neoadjuvant therapy. One developed pulmonary metastases after chemoradiation while the other had significant tumor shrinkage after chemotherapy. The decrease in antitumor cytotoxicity of PBMCs was less in the patient with PD (-19.4%) than the one with PR (-48.5%). Two patients (c, d) had blood collected twice while receiving the same chemotherapy for metastatic disease (not treatment naïve). The decrease in antitumor cytotoxicity of PBMCs was less in the patient with SD (-0.3%) than the one with PR (-14.5%). Conclusions: We demonstrated the feasibility of using PBMCs to monitor immune response to anticancer therapies. Our data raise the possibility that the amount of circulating effector T cells and antitumor cytotoxicity of PBMCs may be associated with tumor burden in patients with pMMR solid tumors. [Table: see text]

147 Background: PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 cancer testis antigens (CTAs) frequently expressed in patients with colorectal cancer (CRC). PolyPEPI1018 successfully induced anticancer immunity and triggered recruitment and infiltration of cytotoxic T cells into the tumor of MSS mCRC subjects demonstrating also early evidence of clinical activity, in first-line mCRC. Here we report the initial results of the phase Ib study of PolyPEPI1018 vaccine plus trifluridine/tipiracil (TAS-102) in late-stage mCRC patients. Methods: Patients with MSS mCRC who have progressed on ≤2 lines of prior chemotherapy regimen for mCRC received PolyPEPI1018 subcutaneously on days 1 and 15 and TAS-102 orally twice daily on days 1-5 and 8-12 of a 28-day cycle. Treatment continued for up to 7 cycles until disease progression or unacceptable toxicity. Immunomonitoring was performed at both blood and tumor levels prior to- and on study treatment. The primary endpoint of the study was safety and tolerability. Data on objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and correlation studies will be also presented. Results: 15 patients (67% male) started treatment. At baseline, median age was 55 years (range 31–71), 73% had liver metastases and the primary tumor site was colon-sigmoid in 40% and rectum in 33%. The combination was well-tolerated; most common side effect related to PolyPEPI1018 was Grade (Gr) 1-2 local skin reactions in 93% of patients. Gr 3 events. There were no Gr 4 or 5 events. The ORR was 0% and the DCR was 50%. The mPFS was 2.5 months (95%CI 2.1-NR). At the data cut-off (September 7, 2022), the mOS has not been reached; median follow-up was 4.0 months (95% CI 2.2-4.4). Post-treatment, vaccine-specific T cell responses were detected ex vivo in the PBMC of 4/5 subjects tested. In addition, one subject who had no detectable T cell response at peripheral level, responded at the tumor level with more than 300% increase of both CD3+ and CD8+ tumor-infiltrating lymphocytes compared to baseline. Patients with increased PFS (≥ 16 weeks) had robust vaccine-specific T cell responses. Conclusions: To our knowledge, this is the first phase Ib study investigating combination of a cancer vaccine with TAS-102 chemotherapy in advanced MSS mCRC. Our results show that PolyPEPI1018 plus TAS-102 was well-tolerated with few grade 3 AEs beyond what is expected with TAS-102 monotherapy. PolyPEPI1018 induced immunological responses at both peripheral and tumor level, albeit no objective tumor responses could be detected. The study is on-going for the collection of overall survival data. Clinical trial information: NCT05130060 .