High Response Group Research Articles

Role of endogenous GLP-1 on arterial stiffness and renal haemodynamics following bariatric surgery.

Cardiovascular trials have revealed the positive impact of GLP-1 receptor agonists (GLP-1 RAs) on cardiovascular outcomes in type 2 diabetes (T2D). However, the specific effects of endogenous GLP-1 on arterial stiffness and renal function remain understudied. This study aimed to explore the influence of endogenous GLP-1 response post-bariatric surgery on arterial stiffness and renal haemodynamic. Thirty individuals with morbid obesity and without T2D, scheduled for Roux-en-Y Gastric Bypass (RYGB), were included. Clinical parameters, 3-hour oral glucose tolerance test (OGTT) with serial sampling for glycaemia, GLP-1 and insulin, carotid-femoral pulse wave velocity (cf-PWV), carotid distensibility coefficient (carotid-DC) and renal resistive index (RRI) measurements were conducted pre-surgery and 1-year post-surgery. Participants were categorized into high-response and low-response groups based on their post-surgery increase in GLP-1 (median increase of 104% and 1%, respectively, pre- vs. post-surgery). Post-surgery, high-response group demonstrated a greater reduction in cf-PWV (p = .033) and a greater increase (p = .043) in carotid DC compared to low-response group. These enhancements were observed independently of weight loss or blood pressure changes. High-response group exhibited a reduction in RRI (p = .034), although this association was influenced by improvement in pulse pressure. Finally, a multivariate stepwise regression analysis indicated that the percentage increase of GLP1, Δ-GLP1(AUC)%, was the best predictor of percentage decrease in cf-PWV (p = .014). Elevated endogenous GLP-1 response following RYGB was associated with improved arterial stiffness and renal resistances, suggesting potential cardio-renal benefits. The findings underscore the potential role of endogenous GLP-1 in influencing vascular and renal haemodynamics independent of traditional weight loss.

Higher hepatitis B core-specific T cell response is associated with a lower risk of clinical relapse after discontinuation of oral antiviral treatment

BackgroundHepatitis B virus (HBV)-specific T cell response is a major host immune response to control the virus. However, it is still unclear how it affects long-term outcomes of chronic hepatitis B patients, especially those who stop nucleos(t)ide analogue (NA) therapy. We aimed to explore whether the HBV-specific T cell response at the end of treatment (EOT) was associated with clinical outcomes. MethodsIn a prospective cohort study, 51 HBeAg-negative patients who discontinued NA therapy were enrolled. ResultsIn a mean follow-up of 25.3 months, 25 patients developed clinical relapse. We found that a stronger hepatitis B core (HBc)-specific T cell response at EOT was associated with a lower risk of clinical relapse. Compared to the low-response group, the high-response group had a lower risk of clinical relapse with hazard ratio of 0.21 (95% CI: 0.05–0.88). The high HBc-specific T cell response was associated with reduced surge of HBV DNA and HBcrAg during the first year of follow-up. The T cell response at EOT was comparable between different NA treatments. Notably, the overall HBV-specific T cell response could be partially restored along with clinical relapse; however, such reinvigorated T cell response was not associated with HBsAg seroclearance. ConclusionsA higher HBc-specific T cell response at EOT was associated with lower risk of clinical relapse and reduced surge of HBV DNA and HBcrAg levels off NA therapy.

Identification of DNA Repair-related Genes as Biomarkers Reflecting MSI, TMB, and TIL in Colorectal Cancer.

There are no established biomarkers for immune checkpoint inhibitors (ICI) in colorectal cancer (CRC) with microsatellite stability (MSS) or proficient mismatch repair (pMMR). Therefore, this study aimed to identify biomarkers for ICI benefit in patients with pMMR by analyzing the down-regulated DNA repair-related genes involved in highly immunogenic and immune responses, and comparing their expression levels and clinical features. Mismatch repair (MMR), tumor-infiltrating lymphocytes (TIL), and tumor mutation burden (TMB) were evaluated in 13 CRC cases and mRNA expression levels of 95 DNA repair-related genes were measured. DNA repair-related genes with reduced mRNA expression in the high immunogenicity and high immune response groups were identified. Then, the mRNA expression levels of the identified DNA repair-related genes were measured in 135 patients with CRC. Hierarchical cluster analysis was performed using the mRNA expression levels to compare the clinicopathological characteristics of each cluster. ATR, LIG4, and RAD52 mRNA levels were significantly down-regulated in the high immunogenicity group. GADD45B, SMUG1, and XRCC6 mRNA levels were significantly down-regulated in the high immune response group. Cases in the cluster with reduced mRNA expression of the six genes were pMMR cases. CD8 mRNA expression level was higher in this cluster than in the other clusters. Decreased mRNA expression levels of ATR, LIG4, RAD52, GADD45B, SMUG1, and XRCC6 genes were associated with high cytotoxic T cell and TMB levels, suggesting that these genes could serve as biomarkers for ICI efficacy in pMMR cases.

Impact of Luteinizing Hormone on IVF/ICSI Assisted Reproduction on the Initiation Day of Gonadotropin-releasing Hormone Antagonist Protocol.

The aim of the study was to explore the optimal timing of gonadotropin initiation and the reasonable interval of luteinizing hormone (LH) levels in the gonadotropin-releasing hormone antagonist (GnRH-A) protocol. A retrospective cohort study was conducted to analyze the data concerning the oocyte retrieval cycles from 1,361 cases with the GnRH-A protocol implemented. The ovarian responses (including AMH, AFC) in these patients were divided into the poor ovarian response group (an antral follicle count [AFC] ≤ 6, n = 394), the normal ovarian response group (an AFC > 6 and < 15, n = 570), and the high ovarian response group (an AFC ≥ 15, n = 397), according to the AFC. The patients were sub-grouped according to LH levels on the protocol initiation day, and the clinical outcomes (including dose of Gn initiation, Gn administration days, GnRH-ant administration days, P levels on the HCG day, E2 levels on the HCG day, LH levels on the HCG day, number of embryos transferred, total fertilization rate, embryo implantation rate(%), proportion of 2PN, proportion of good-quality embryos, endometrial thickness on the hCG injection day(mm), moderate to severe OHSS, AFC on the initiation day, proportion of type A endometrium on the hCG injection day, clinical pregnancy rate, biochemical pregnancy rate, early abortion rate, ectopic pregnancy rate) were compared. On the GnRH-A protocol initiation day, among all patients with different ovarian responses, the body mass index (BMI) in those with an LH ≥ 5 IU/L was lower. The differences in pregnancy outcomes between the LH < 5 IU/L group and the LH ≥ 5 IU/L group were not statistically significant across the different ovarian response groups, but the LH < 5 IU/L group had a higher proportion of good-quality embryos (80.3±24.9 vs. 74.8±26.9, P =0.035) than the LH≥5IU/Lgroup in those with poor ovarian response. The total fertilization rate (82.2±18.1 vs 85.4±15.1, P =0.021) and proportion of two pronuclei (2PN) (69.0±20.9 vs 72.7±19.9, P =0.035) were higher in the LH ≥ 5 IU/L group than the LH<5 IU/L group for those with normal ovarian responses. The embryo implantation rate (41.4±41.3 vs 52.6±43.4, P =0.012) was higher in the LH ≥ 5 IU/L group than in the LH<5 IU/L group in those with high ovarian response. The results of the multivariate logistic analysis showed that the age of the female partner, number of embryos transferred, proportion of good-quality embryos, endometrial thickness on the hCG injection day, and moderate- to-severe ovarian hyperstimulation syndrome (OHSS) were independent factors correlated with the outcome of live births (P < 0.05). The LH levels on the gonadotropins (Gn) initiation day in the GnRH-A protocol will not affect pregnancy outcomes.

Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial.

Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge. Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full model. We further validated ISS10 in an independent HCC cohort treated with nivolumab plus ipilimumab. The study identified a significant association between the ISS and treatment response. Among patients classified as high responders, those treated with the atezolizumab plus bevacizumab combination exhibited improved overall and progression-free survival as well as better objective response rate compared to those treated with sorafenib. We also observed a significant correlation between ISS10 and response to nivolumab plus ipilimumab treatment. Analysis of immune cell subpopulations revealed distinct characteristics associated with ISS subtypes. In particular, the ISS10 high subtype displayed a more favorable immune environment with higher proportions of antitumor macrophages and activated T-cells, potentially explaining its better response. Our study suggests that ISS and ISS10 are promising predictive biomarkers for enhanced therapeutic outcomes in HCC patients undergoing combination immunotherapy. These markers are crucial for refining patient stratification and personalized treatment approaches to advance the effectiveness of standard-of-care regimens.

Secretion of IFN-γ by specific T cells in HCMV infection

One major risk for recipients undergoing allogeneic hematopoietic stem cell transplants (allo-HSCTs) is infection with the human cytomegalovirus (HCMV). For HCMV treatment, it is especially crucial to be able to differentiate between recipients who are at high risk of reactivation and those who are not. In this study, HCMV-DNA was collected from 60 HLA-A*02 allo-HSCT recipients before and after transplantation. After transplantation, the release of interferon (IFN)-γ by T cells specific to HCMV was assessed using the enzyme-linked immunospot assay (ELISPOT). The results show that the median viral load (VL) was significantly higher in the HCMV persistent-infection group compared to the non-persistent-infection group (p = 0.002), and that the late-infection rate was considerably higher in the high-VL group compared to the low-VL group (p = 0.014). The uninfected group had a considerably higher median IFN-γ spot‐forming cell (SFC) count than the persistent-infection group (p = 0.001), and IFN-γ SFC counts correlated negatively and linearly with VLs (r = −0.397, p = 0.002). The immune-response groups showed significantly difference in median VL (p = 0.018), and the high immune response group had a reduced late-infection rate than the no/low immune response groups (p = 0.049). Our study showed that allo-HSCT recipients with a high VL at an early transplantation stage were at high risk for late HCMV infection. Further HCMV reactivation can be prevented by HCMV-specific T cells secreting enough IFN-γ.

Acquisition of complement fixing antibodies targeting Plasmodium falciparum merozoites in infants and their mothers in Uganda.

Antibody-mediated complement fixation has previously been associated with protection against malaria in naturally acquired immunity. However, the process of early-life development of complement-fixing antibodies in infants, both in comparison to their respective mothers and to other immune parameters, remains less clear. We measured complement-fixing antibodies in newborns and their mothers in a malaria endemic area over 5 years follow-up and found that infants' complement-fixing antibody levels were highest at birth, decreased until six months, then increased progressively until they were similar to birth at five years. Infants with high levels at birth experienced a faster decay of complement-fixing antibodies but showed similar levels to the low response group of newborns thereafter. No difference was observed in antibody levels between infant cord blood and mothers at delivery. The same result was found when categorized into high and low response groups, indicating placental transfer of antibodies. Complement-fixing antibodies were positively correlated with total schizont-specific IgG and IgM levels in mothers and infants at several time points. At nine months, complement-fixing antibodies were negatively correlated with total B cell frequency and osteopontin concentrations in the infants, while positively correlated with atypical memory B cells and P. falciparum-positive atypical memory B cells. This study indicates that complement-fixing antibodies against P. falciparum merozoites are produced in the mothers and placentally-transferred, and they are acquired in infants over time during the first years of life. Understanding early life immune responses is crucial for developing a functional, long lasting malaria vaccine.

Abstract 16922: One-Year Latent Health Status Trajectories in Patients With Symptomatic Peripheral Artery Disease

Background: Symptomatic peripheral artery disease (PAD) can dramatically impact health status. We aimed to characterize typical health status trajectories following initiation of PAD specialty care and to identify demographic, medical, and psychosocial predictors of suboptimal recovery. Methods: Adults with new or worsening PAD (Rutherford 1-3) presenting to vascular clinics in the US, Australia, and Netherlands 2011-2015 in the PORTRAIT study were included. Demographics, comorbidities, and psychosocial measures including the EQ-5D (generic health status), PHQ-8 (depression), GAD-2 (anxiety), PSS (stress), ESSI (social support) were obtained upon initial evaluation. Peripheral Artery Questionnaires (PAQ; 0-100, higher = better PAD-specific health status) were administered at 0, 3, 6, and 12 months. Latent trajectory modeling was used to identify typical PAQ score trajectories by Bayesian information criterion. Predictors of favorable vs. poor recovery trajectory (&lt;10-point PAQ increase at 1 year) were assessed by logistic regression. Missingness was handled by multiple imputation. Results: The final cohort included 1,204 patients, had a mean age of 67.5 (±9.4) years, was 62.5% male, and 82.1% white. A 5-group model best fit the data (Figure). At 1 year, the High (n=401), Intermediate (n=400), and Sustained Response (n=98) groups demonstrated “favorable” mean PAQ changes of +16.8 , +24.0, and +59.4 points, respectively. The Low (n=150) and Transient Response (n=155) groups demonstrated “poor” recovery of +8.6 and +7.6 points, respectively. Significant predictors of poor recovery included age, nonwhite race, worse EQ-5D, and worse PHQ-8 (all p&lt;0.05). Conclusion: Patients with symptomatic PAD follow predictable health status trajectories after initiating care. Poor recovery trajectory is predicted by age, nonwhite race, worse generic health status, and depressive symptom burden. Further emphasis should be placed on these factors during treatment.

Retrospective study on the trajectories of lower limb volume after outpatient-based complex decongestive therapy in post-operative gynecological cancer patients with lymphedema

PurposeTo determine the effect of outpatient-based complex decongestive therapy in patients with secondary lower limb lymphedema (LLL) after gynecologic cancer surgery using group-based trajectory modeling (GBTM), and to examine factors predictive of the treatment course.MethodsThis retrospective study included participants who underwent surgery for gynecological cancer with pelvic lymph node dissection and subsequently visited the outpatient clinic for the treatment of stage II LLL according to the International Society of Lymphology. The improvement rate of edema at the initial visit and 3, 6, and 12 months later was assessed by calculating the volume of the lower extremity using the circumferential method. For evaluation of the patterns of treatment course, logistic regression analysis was performed after group estimation by the trend of the treatment course using GBTM.ResultsA total of 148 women (mean age 60.6 years (standard deviation: 13.4 years)) were analyzed. Three improvement trajectories were identified: (1) no response group, with worsening rather than improvement (n = 26); (2) moderate response group, with a slow improvement rate (n = 89); and (3) high response group, with a high improvement rate (n = 33). In addition, adherence to compression therapy at 3 months post-intervention was found to be a predictor in the no response group.ConclusionsGBTM estimated that there are three patterns of the treatment course in patients with LLL after gynecologic cancer surgery. Adherence to compression therapy at 3 months post-intervention is a predictor of the treatment effectiveness.

Analysis of relative factors and prediction model for optimal ovarian response with gonadotropin-releasing hormone antagonist protocol.

To explore the relative factors for best ovarian response in patients undergoing assisted reproductive technology with the gonadotropin-releasing hormone antagonist protocol and to establish a nomogram prediction model of ovarian response. A retrospective cohort analysis of the clinical data of 1,944 patients who received assisted reproductive treatment in the Center for Reproductive Medicine of Fujian Maternity and Child Health Hospital from April 1, 2018, to June 30, 2020. According to the number of oocytes obtained, there were 659 cases in the low ovarian response group (no more than five oocytes were retrieved), 920 cases in the normal ovarian response group (the number of retrieved oocytes was >5 but ≤18), and 365 cases in the high ovarian response group (>18 oocytes retrieved). Independent factors affecting ovarian responsiveness were screened by logistic regression, which were the model entry variables, and a nomogram prediction model was established based on the regression coefficients. There were statistically significant differences in age, anti-Mullerian hormone, antral follicle count, the diagnosis of endometriosis, decreased ovarian reserve, polycystic ovary syndrome, basal follicle-stimulating hormone and basal luteinizing hormone among the three groups (P < 0.001). Multifactorial stepwise regression analysis showed that female age (0.95 [0.92-0.97], P = 0.000), decreased ovarian reserve (0.27 [0.19-0.38]), P = 0.000), endometriosis (0.81 [0.56-0.86], P = 0.000), antral follicle count (1.09 [1.06-1.12], P = 0.000), basal follicle-stimulating hormone (0.90 [0.85-0.96], P = 0.001), Anti-Mullerian hormone (1.19 [1.13-1.26], P= 0.000) and luteinizing hormone on trigger day (0.73 [0.66-0.80], P= 0.000), were independent factors for the occurrence of different ovarian responses during ovarian hyperstimulation. The predictive model of ovarian responsiveness was constructed based on the above factors, and the model was verified with 589 patients' data from July 1, 2020, to December 31, 2020, at this center. The predicted ovarian response (number of eggs obtained) of a total of 450 patients was consistent with the actual results, with a coincidence degree of 76.4%, and the consistency index of the model is 0.77. The nomogram model was successfully developed to effectively, intuitively, and visually predict the ovary reactivity in the gonadotropin-releasing hormone antagonist protocol and provide guidance for clinical practice.

Correlation of gut microbiota and metabolic functions with the antibody response to the BBIBP-CorV vaccine

SummaryIncreasing evidence indicates that gut microbiota may play a key role in vaccination immunity. Here, we investigate whether the human gut microbiota and metabolic function correlate with the BBIBP-CorV vaccine response. A total of 207 participants who received the BBIBP-CorV vaccine are enrolled. The gut microbiome and metabolic functions are investigated using metagenomic sequencing and metabolomic assays. We find that BBIBP-CorV vaccination is accompanied by altered microbiome composition and functional pathways, and the gut microbiome and its functional profiles correlate with the vaccine response. The levels of short-chain fatty acids (SCFAs) are much higher in the high antibody response group compared to the low response group, and several SCFAs display a positive correlation with the antibody response. Our study highlights that the gut microbiome and its function is associated with the BBIBP-CorV vaccine response, providing evidence for further exploration of microbiome modulation to improve COVID-19 vaccine efficacy.

Anti–Müllerian hormone and antral follicle count predict ovarian response in women less than 45 years following GnRH antagonist multiple–dose protocol

Objective: To speculate which of the following parameters: antral follicle count (AFC), anti-Müllerian hormone (AMH), follicle- stimulating hormone (FSH) and age can be used as a predictor of ovarian response to gonadotropin-releasing hormone (GnRH) antagonist stimulation multiple-dose protocol in women under 45 years, and to determine the cutoff value of these parameters and their correlations for predicting low and high ovarian response. Methods: This prospective study included 462 women with the mean age of (29.3±6.5) years. All women were subjected to the GnRH antagonist stimulation multiple-dose protocol. On the second day of the menstrual cycle, ultrasonography was conducted to determine AFC in both ovaries. Peripheral blood samples were collected to evaluate the level of estradiol, FSH, luteinizing hormone, prolactin, thyroid-stimulating hormone, and AMH. The women were divided into three groups: low response (AHH&lt;1 ng/mL, n=173), normal response (AMH=1.0-3.5 ng/mL, n=175), and high response (AMH &gt;3.5 ng/mL, n=114). Results: A significant decrease was found in the age and FSH level in the high response group compared to other groups (P&lt;0.001). Conversely, a significant increase was shown in AMH, estradiol on human chorionic gonadotropin (hCG) day, AFC, mature oocytes, fertilized oocytes, and embryos transferred in the high response group compared to the other two groups (P&lt;0.001). The receiver operating characteristic (ROC) curves demonstrated that AFC and AMH had the highest accuracy, followed by basal FSH level and age in the prediction of low ovarian reserves (P&lt;0.001) with cutoff values of ≤4.50 and ≤0.95 for AFC and AMH, respectively. Moreover, the ROC analysis showed that AFC had the highest accuracy, followed by AMH level and age in the prediction of high ovarian reserves with a cutoff value of ≥14.50, ≥3.63, and ≤27.50 years, respectively (P&lt;0.01). A significant decrease was observed in women's age, estradiol level, and oocyte fertilization rate in pregnant women compared to non-pregnant women (P&lt;0.001). Additionally, significant negative correlations were found between the AFC, the number of mature oocytes, fertilized oocytes, embryos transferred, and the age of pregnant women (P&lt;0.001). Conclusions: AFC and AMH predict low and high ovarian response to GnRH antagonist stimulation multiple-dose protocol in women under 45 years.

Maternal cortisol level around conception is associated with offspring sex ratio in captive European wild rabbit (Oryctolagus cuniculus)

The sex ratio of the offspring at birth is usually 1: 1 established by natural selection. The sex allocation model predicts that if parents have adequate resources, they would benefit from differentially allocating maternal investment to that sex having higher fittness under the particular environmental conditions. However, little is known about what mechanisms would result in biased sex ratio. One such mechanism could be the interaction of of stress reactivity and progesterone levels in the mothers around conception. In the present investigation the fecal cortisol and progesterone levels at the day of conception were measured in fifteen European wild rabbit does kept in cages. The does were clustered to low and high cortisol response groups and the sex ratio of their progeny was determined. We found a significant correlation between the progesterone levels of mothers and their stress status measured at the mating. This correlation was also reflected in the sex ratio bias in their litters. Even though the litter size was not different, we found higher progesterone levels and more female offspring in the does with higher cortisol levels indicating that maternal status around conception may affect the litter sex ratio.

Serum miR-181d-5p levels in response to controlled ovarian stimulation: predictive value and biological function.

The response to controlled ovarian stimulation (COS) for in vitro fertilization (IVF) varies dramatically from one patient to another, affecting success rates. A previous large-scale study identified increased serum miR-181d-5p levels in patients with high response to COS prior to stimulation. We aim to evaluate whether the expression of miR-181d-5p differs according to the ovarian response to COS in women undergoing intracytoplasmic sperm injection (ICSI) cycles. Samples collected prior to COS for ICSI were split into three groups depending on the ovarian response to COS: poor response (PR), <4 oocytes retrieved (n=25); normal response (NR), ≥8 and ≤12 oocytes retrieved (n=21); and high response (HR), >25 oocytes retrieved (n=20). miR-181d-5p serum levels were compared among experimental groups. miR-181d-5p levels were increased in the HR group when compared to the PR (p=0.0001) and NR groups (p=0.0079). miR-181d-5p levels correlated with the number of aspirated follicles (p<0.0001), retrieved oocytes (p<0.0001), and mature oocytes (p=0.0002). Increased miR-181d-5p levels independently predict a high response (p=0.006), with Positive and Negative Predictive Values of 66.7% and 69.4%, respectively. miR-181d-5p was also detected in the ovarian tissue in a mouse model. Moreover, computational analysis of miR-181d-5p predicted targets and promoter region suggested that this miRNA might be involved in the regulation of key signaling pathways and biological processes for female reproductive biology. In conclusion, miR-181d-5p is a promising circulating predictor of high stimulation and potential mediator of the hypothalamus-pituitary-gonad axis, providing opportunities for the individualization of COS protocols.

Interspecific variation in wildlife responses to cattle, swine and chicken feed in the forests surrounding poultry farms.

To strengthen farm biosecurity, wildlife behaviors around livestock environments require significant attention. Livestock feed is considered one of essential factors that attract wildlife to the livestock environment. We experimentally studied wildlife response to cattle, swine, and chicken concentrated feeds in the forests surrounding poultry farms. In 14 feeding sites, four feed conditions were established: without feed (control); cattle feed; chicken feed; and swine feed. Wildlife behaviors at each feed point were monitored using infrared cameras. In 3,175 videos, 10 mammals were photographed on 10 or more occasions. Wildlife more frequently appeared at the points with feed than without feed. In addition, the number of videos that captured foraging or interest behaviors was largest for swine feed, followed by chicken feed, then cattle feed. There was a large difference among wildlife in their response to livestock feeds, although each species did not have a strong preference for a specific feed. Livestock feeds invite frequent visits by high and moderate response groups, especially omnivores and carnivores with omnivorous tendencies. Therefore, to protect against such wildlife intrusion, leftover feed and feed storage must be properly managed. This study also suggests that livestock feeds may not cause intrusions by rare response group species; hence, if their intrusions occur, they may be due to factors other than livestock feed. The study situation can partly reflect actual feed-stealing situations. The results will contribute to consider the properly management to protect livestock environments from wildlife intrusions.

Application of ultrasound markers measured at different time points of COH cycle in the prediction of ovarian response for individualised ovulation induction

The purpose of this study was to evaluate the predictive value of ultrasound markers measured at different time points of the controlled ovarian hyperstimulation (COH) cycle on ovarian response and outcome indicators in the IVF-ET cycle. According to the oestrogen level and the number of retrieved oocytes, patients who planned for COH treatment were separated into low-response group, normal and high-response group. The ovarian stromal artery flow parameters on the day of pituitary down-regulation, day 1, day 7, day 10, and the day of hCG injection were collected prospectively. We also have collected the data of cumulus oophorus count on the day of hCG injection by transvaginal sonography. Compared with the low-response group, on the first day of the COH cycle PI, RI, and S/D were lower in the high-response group than they were in the low-response group (p < .05). PSV and EDV were significantly higher in the high-response group than they were in the low-response group (p < .01), and the PSV on the first day of the COH cycle have statistical significance in predicting the number of high-quality embryos. The number of cumulus oophorus on the day of hCG injection has statistical significance in predicting the number of oocytes retrieved and fertilised oocytes. We conclude that the ovarian stromal artery flow parameters on the first day of the COH cycle and cumulus oophorus count on hCG injection day can serve as efficient indicators for an early assessment of ovarian response and individualised ovulation induction. IMPACT STATEMENT What is already known on this subject? AMH, AFC, and the age of the patient are well-known effective parameters for the evaluation of ovarian response, but these are insufficient and full of individual differences. Some researchers have investigated the value of colour Doppler ultrasound and cumulus oophorus in assessing ovarian response, but no definitive conclusion has been reached. What do the results of this study add? The hemodynamic parameters of ovarian stromal artery on the first day of the COH cycle and the number of cumulus oophorus on the day of hCG injection detected by Transvaginal Colour Doppler Sonography (TV-CDS) could be used to predict the ovarian response. What are the implications of these findings for clinical practice and/or further research? Ovarian stromal artery flow parameters and cumulus oophorus detected by TV-CDS can potentially be offered as a complementary parameter for ovarian reserve.

Ex Vivo Drug Sensitivity Assay Correlates with Clinical Response and Identifies Panobinostat and Bortezomib As a Potential Novel Drug Combination for Pediatric AML

BackgroundPediatric acute myeloid leukemia (AML) is a rare disease with roughly 600 cases diagnosed in the United States each year with minimal improvement in clinical outcomes over the last few decades. We previously demonstrated that an ex vivo drug sensitivity assay (DSA) can predict clinical response in myelodysplastic syndrome (Spinner et al. Blood Adv 2020). Here we investigated whether the DSA performed on pre-induction pediatric AML samples correlates with clinical response and can identify potent novel drug combinations.MethodsPre-induction blood or bone marrow samples were assayed from 20 de novo pediatric AML patients diagnosed at Texas Children's between 5/2015 and 10/2020. All patients consented to research (82% enrolled in clinical trial identifier NCT03568994) and received ADE (Cytarabine, Daunorubicin, and Etoposide), and next-generation sequencing was done as part of clinical care. Risk stratification was per AAML1831 guidelines. Drug sensitivity data was analyzed from 13/20 samples that passed quality control with matched treatment conditions: 9/13 (69%) patients had M1/M2 histology, 3/13 (23%) were M4/M5 and 1/13 (8%) was M7 with a median age of 12.3 years. For the ex vivo DSA, samples were incubated in conditioned media and treated with a single dose of up to 25 unique compounds and up to 149 drug combinations. After 72 hours, changes in tumor blast populations were assessed by flow cytometry using an 11-marker panel to identify blasts. For each treatment condition, drug sensitivity was calculated based on the number of blasts remaining after treatment compared to DMSO control. Clinical response data, including minimal residual disease (MRD) percentage by flow cytometry, and 1-year relapse-free survival (RFS), were correlated with drug sensitivity results. Log odds ratios (OR) were calculated with the Haldane-Anscombe correction. ORs were used to quantitatively measure the association between clinical attributes and the DSA to the clinical response data. For evaluation of ORs, a normalized blast score of 70% viability was used to maximize the separation between high and low drug sensitivity.ResultsEx vivo drug sensitivity correlated with both MRD (r=0.63) and 1-year RFS (r=0.59) in the de novo patient subset (Fig A). Three patients with an MRD >1% exhibited low ex vivo sensitivity to ADE, and among these 3 patients, 2 did not achieve 1-year RFS. Results from the DSA predicted increased odds of having an MRD >1% compared to demographic and mutational clinical attributes that showed weaker associations with MRD (Fig B).Of the 77 treatment conditions that were tested in 13 patient samples, Bortezomib in combination with Panobinostat (B/P) was the most efficacious treatment in the DSA, where drug sensitivity ranged from low (>100% blast viability) to high (0% blast viability). Separation of patient samples into two distinct low and high DSA response groups was observed with B/P, whereas ADE and single agents showed a graded distribution (Fig C). Within these response groups, pAML3 showed low sensitivity to ADE in the ex vivo DSA and the patient did not respond to ADE. In contrast, pAML8 showed high sensitivity to ADE ex vivo and the patient responded to ADE treatment. While pAML3 and pAML8 showed similar ex vivo sensitivity to B/P as for ADE (Fig D), pAML4 showed preferential sensitivity to ADE and not B/P, and conversely pAML6 showed sensitivity to B/P and not ADE.ConclusionEx vivo drug sensitivity to ADE correlates with both MRD and 1-year RFS in a cohort of 13 de novo pediatric AML patients. These results suggest that clinical response in pediatric AML may be assessed prior to treatment using an ex vivo drug sensitivity assay. Compared to demographic and mutational clinical characteristics queried, ex vivo drug sensitivity to ADE has the potential to be a more predictive measure compared to clinical attributes alone. Combining genomics with functional ex vivo drug sensitivity data could further enhance precision medicine and biomarker discovery in pediatric AML. The DSA also highlights Bortezomib/Panobinostat as a potential novel drug combination for pediatric AML, and the ability to identify a patient sample that is insensitive to ADE and sensitive to Bortezomib/Panobinostat ex vivo supports the use of the DSA to not only predict clinical response but also to possibly inform treatment decisions for pediatric AML patients. [Display omitted] DisclosuresStrachan: Notable Labs: Current Employment, Current holder of stock options in a privately-held company. Gu: Notable Labs: Current Employment, Current holder of stock options in a privately-held company. Kita: Notable Labs: Current Employment, Current holder of stock options in a privately-held company. Richardson: Notable Labs: Current holder of stock options in a privately-held company, Ended employment in the past 24 months. Anderson: Notable Labs: Current holder of individual stocks in a privately-held company, Ended employment in the past 24 months. Santaguida: Notable Labs: Consultancy, Current holder of individual stocks in a privately-held company, Ended employment in the past 24 months, Patents & Royalties.

Modeling Patient-Reported Swallowing Outcomes With Dose to the Epiglottis

Swallowing is a complex physiologic function and care is needed for its preservation when head and neck (HN) cancer patients receive radiation therapy. The larynx, and especially the epiglottis, is one involved organ. This study's purpose was to investigate whether radiation dose to the epiglottis is more predictive of acute swallowing toxicity than dose to the rest of the larynx or the total larynx.A cohort of 91 HN patients with no prior HN radiation treated at a single institution form 2013-2020 with either protons or photons was studied retrospectively. Patients were selected based on primary-site diagnosis code (nasopharynx, oropharynx, tonsil, and base of tongue) and prescription dose (≥60 Gy). Swallowing outcomes were assessed with patient-reported outcomes (PROs), using the EORTC QLQ H&N35 survey, that were collected prior to (baseline) and following treatment (within 2 weeks of finishing). The post-treatment swallowing-specific PRO scores were used to evaluate acute swallowing toxicity, and patients were stratified into those with high (score > 50) and low (score≤50) responses. The epiglottis, the arytenoid cartilages, and the non-epiglottic larynx were contoured by a single individual (SA); the three substructures were then combined for a total larynx structure. 16 patients with either a larynx disfigured by their disease or high baseline swallowing score were removed from the analysis. A univariate analysis was first performed using a Wilcoxon rank-sum test on the mean doses to the epiglottis, total larynx, and non-epiglottic larynx structures. Next, a random-forest (RF) machine-learning model was trained using 29 patient-specific features with demographic and clinical information (including primary site, chemotherapy, smoking, bi-/unilateral, and HPV/p16), baseline PRO scores, and dose metrics to the total larynx and epiglottis. The model was trained on a 60-patient training set using nested 10-fold cross-validation and then assessed on a 15-patient test set using the area under the receiver-operator curve (AUC).The univariate analyses for the total and non-epiglottic larynx mean doses showed no statistical differences between the two groups (P = 0.56 and 0.86, respectively). That of the epiglottic mean dose, however, showed a significant difference (P = 0.026) with 39.2 [32.7-52.9] Gy and 47.2 [41.1-57.2] Gy for the low- and high-response groups, respectively. The RF had AUC = 0.71 ± 0.22 and 0.70 on the training and test sets, respectively, with the epiglottis volume receiving 30 Gy identified as the most important feature.The univariate analysis and RF model indicate that the dose to the epiglottis is more sensitive for predicting patient-reported acute swallowing toxicity than either the doses to the rest of the larynx or the full larynx. These results suggest that consideration be given to the epiglottic dose during treatment planning.

High ovarian response to ovarian stimulation: effect on morphokinetic milestones and cycle outcomes.

To assess the effect of high ovarian response on oocyte quality and ovarian stimulation cycle outcomes. A retrospective cohort study conducted at three IVF units. The high ovarian response (HOR) and polycystic ovary syndrome (PCOS) with HOR (PCOS HOR) groups included 151 and 13 women who underwent controlled ovarian stimulation (COS) resulting in more than 15 retrieved oocytes, for a total of 1863 and 116 cultured embryos, respectively. The normal ovarian response (NOR) group comprised 741 women with 6-15 retrieved oocytes, resulting in 4907 cultured embryos. Data collected included fresh cycle data and pregnancy rates, in addition to annotation of morphokinetic events from time of pronuclei fading to time of initiation of blastocyst formation of embryos cultured in a time lapse incubator, including occurrence of direct unequal cleavage at first cleavage (DUC-1) (less than 5h from two to three blastomeres). Comparison was made between morphokinetic parameters between the 3 groups. Cycle outcomes were compared in the high vs. normal ovarian response groups. Oocyte maturation rate was significantly lower in the HOR vs. NOR groups (56.5% vs. 90.0%, p < 0.001), while the fertilization rates were similar (60.2% vs. 58.1%, p = 0.397). The prevalence of DUC-1 embryos was higher in the PCOS HOR and the HOR groups as compared to the NOR group (22.7% vs. 16.2% and 12.0%, respectively, p < 0.001). After exclusion of DUC-1 embryos, remaining embryos from the NOR and HOR groups reached the morphokinetic milestones at similar rates, with comparable implantation and clinical pregnancy rates, while the PCOS HOR showed shorter time to 5 blastomeres compared to the NOR and HOR groups. High ovarian response might be associated with decreased oocyte quality, manifested as a higher proportion of immature oocytes and higher rate of direct uneven cleavage embryos, while embryos exhibiting normal first cleavage have similar temporal milestones and implantation potential.

The Role of Pretreatment 18F-FDG PET/CT for Early Prediction of Neoadjuvant Chemotherapy Response in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma

IntroductionTo evaluate the role of maximal standardized uptake values (SUVmax) and total lesion glycolysis (TLG) from serial 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for early prediction of neoadjuvant chemotherapy (NAC) response in locoregionally advanced nasopharyngeal carcinoma (LANPC).MethodsA total of 121 LANPC patients who completed pretreatment 18F-FDG PET/CT between June 2017 and July 2020 were retrospectively included. The median age of all the participants was 50 years old (range: 19–74 years), with 94 (77.7%) males and 27 (22.3%) females. The SUVmax from the primary tumor site (SUVmax-PT) and the total lesion glycolysis from the primary tumor site (TLG-PT) were recorded. Tumor response was calculated according to the Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 Criteria at two-week post-secondary NAC cycle. Patients who achieved an objectively partial or full reaction after two cycles of NAC were defined as ‘responders’, and patients who obtained stability or progression were classified as ‘non-responders’.ResultsAfter two cycles of NAC, 96 patients were categorized as “responders” and 25 patients as “non-responders”. The optimal thresholds of the SUVmax-PT were 11.8 and 38.5 for the TLG-PT. Non-responders were significantly associated with high SUVmax-PT (HR, 3.49; 95% CI, 1.17–10.36; p = 0.024) and TLG-PT (HR, 4.45; 95% CI, 1.44–13.78; p = 0.010) in multivariate analysis. Recursive partitioning analysis (RPA) categorized patients into three prognostic groups based on SUVmax-PT and TLG-PT: high-response group, intermediate-response group, and low-response group, with corresponding favorable response rates of 94%, 80%, and 55%, respectively. Moreover, a nomogram was created based on metabolic parameters that precisely projected an individual’s response of NAC (C-index, 0.787; 95% CI, 0.533–1.000).ConclusionPretreatment 18F-FDG PET/CT to measure SUVmax-PT and TLG-PT could be a useful non-invasive method for early indication of NAC efficacy. The nomogram based on PET/CT parameters may potentially provide direction for treatment decisions based on NAC levels.