Rate Response Research Articles

Effect of zamicastat on blood pressure and heart rate response to cold pressor test: A double-blind, randomized, placebo-controlled study in healthy subjects.

Dopamine beta-hydroxylase (DβH) inhibitors, like zamicastat, hold promise for treating pulmonary arterial hypertension. This study aimed to validate the mechanism of action of zamicastat by studying its effect on the overdrive of the sympathetic nervous system (SNS). A single-centre, prospective, double-blind, randomized, placebo-controlled, crossover study evaluated the effect of 400 mg zamicastat in 22 healthy male subjects. Cold pressor test (CPT) was performed at screening and each treatment period on Days -1 and 10. Plasma and 24 h-urine levels of dopamine (DA), epinephrine (EPI) and norepinephrine (NE), and plasma DβH activity, were measured. Compared to placebo, zamicastat showed a - 4.62 mmHg decrease in systolic blood pressure during the cold stimulus vs. rest phases on Day 10 of CPT (P = .020). Zamicastat decreased mean arterial pressure response to cold stimulus during CPT (-2.62 mmHg; P = .025). At Day 10, zamicastat significantly increased plasma DA, before CPT (12.63 ng/L; P = .040) and after CPT (19.22 ng/L; P = .001) as well as the estimated plasma EPI change from baseline after CPT (P = .040). Inhibition of plasma DβH activity ranged from 19.8% to 25.0%. At Day 10, significant reductions in 24-h urinary excretion of EPI (P = .002) and NE (P = .001) were observed. Zamicastat Cτ geometric mean ± GSD ranged from 45.86 ± 1.46 ng/mL on Day 3 to 58.64 ± 1.52 ng/mL on Day 10, with moderate inter-individual variability (CV: 32.6%-36.6%). Steady state was already achieved on Day 6. Our results demonstrated the effect of zamicastat on the overdrive sympathetic response to cold stimulus, confirming its potential as SNS modulator.

ARIMAX Modelling: Response of Hass Avocado Respiration Rate to Environmental Factors

This research explores how random events influence the respiration rate in Hass avocado beyond deterministic models in order to develop better strategies for extending its shelf life. Understanding these factors can enhance the accuracy of postharvest management strategies. The Autoregressive Integrated Moving Average (ARIMA) model with exogenous variables (ARIMAX) is an alternative stochastic probability model which is capable of modeling complex, externally influenced phenomena such as respiration. This study aimed to elucidate the effect of three exogenous variables, namely temperature, relative humidity, and ambient illumination, on the respiration rate of Hass avocado fruits. Data on the respiration rate and exogenous variables were obtained using sensors coupled to a data acquisition system in a prototype of continuous airflow. The Box–Jenkins methodology was employed to construct the ARIMA models. The temperature, relative humidity, ambient illumination, and respiration rate variables were adjusted to the ARIMA models (3,1,2), ARIMA (1,1,2), ARIMA (1,1,2), and ARIMA (1,1,3), respectively. The ARIMAX (1,1,3) models were obtained from the pre-whitened respiration rate series. The impact detected in the transfer functions indicates increases in the respiration rate of 0.34%, 1.52%, and 0.99% for each unit increase in the temperature, relative humidity, and ambient illumination variables, respectively. In this regard, ARIMAX modeling is reliable for explaining the physiological response of Hass avocado fruits due to external factors. In future research, it is intended to extrapolate this stochastic modeling procedure to measure the effect of dynamic loads on the respiratory metabolism of fruits during transportation, where there is a considerable loss in the quality of fresh products.

An open-label, prospective trial to evaluate the efficacy and safety of ixazomib in combination with cyclophosphamide and dexamethasone in patients with newly diagnosed POEMS syndrome.

This open-label, prospective trial evaluated the combination of ixazomib, cyclophosphamide and dexamethasone (ICD) in 12 newly diagnosed POEMS syndrome patients. The study is registered with the Chinese Clinical Trials Registry (ChiCTR2000030072). The treatment protocol consisted of 12 cycles of the ICD regimen compromising ixazomib (4 mg on Days 1, 8 and 15), oral cyclophosphamide (300 mg on Days 1, 8 and 15) and dexamethasone (20 mg weekly). A total of 12 patients received a median of 10 (range: 3-23) cycles of the ICD regimen. The haematological response could be evaluated in 10 patients. The overall haematological response rate was 80% (8/10), with 30% (3/10) achieving complete haematological response, and the overall serum VEGF response rate and neurological response were 100% and 83.3% respectively. Two patients experienced grade 3/4 AEs, including diarrhoea (n = 1) and leukopenia (n = 1). The combination of ixazomib, cyclophosphamide and dexamethasone demonstrated both efficacy and safety in newly diagnosed POEMS syndrome, making it a viable treatment option.

Blunted brachial blood flow velocity response to acute mental stress in PTSD females.

Post-traumatic stress disorder (PTSD) is associated with increased cardiovascular disease (CVD) risk. Compared with males, females are twice as likely to develop PTSD after trauma exposure, and cardiovascular reactivity to stress is a known risk factor for CVD. We aimed to examine hemodynamic responses to acute mental stress in trauma-exposed females with and without a clinical diagnosis of PTSD. We hypothesized that females with PTSD would have higher heart rate (HR), blood pressure (BP), and lower blood flow velocity (BFV) responsiveness compared with controls. We enrolled 21 females with PTSD and 21 trauma-exposed controls. We continuously measured HR using a three-lead electrocardiogram, BP using finger plethysmography, and brachial BFV using Doppler ultrasound. All variables were recorded during 10 min of supine rest, 5 min of mental arithmetic, and 5 min of recovery. Females with PTSD were older, and had higher BMI and higher resting diastolic BP. Accordingly, age, BMI, and diastolic BP were covariates for all repeated measures analyses. Females with PTSD had a blunted brachial BFV response to mental stress (time × group, p = 0.005) compared with controls, suggesting greater vasoconstriction. HR and BP responses were comparable. In conclusion, our results suggest early impairment of vascular function in premenopausal females with PTSD.

Apnea or normal breathing during repeated high-intensity swimming enhance sprint efficiency and which metabolic disorder?

The aim of this study was to investigate the effect of normal breath and apnea swimming on acid-base balance, physiological responses and performance during high-intensity interval training in swimming. Sixteen swimmers completed 6×50 m intervals of freestyle swimming with normal breath and apnea at maximum intensity, with 1 minute rest. Capillary blood gases (pH, PCO<inf>2</inf>, PO<inf>2</inf>, HCO<inf>3</inf>, Hct, Hb) were collected at four (4) measurement time points: 1) at rest once; 2) at rest just after the 3rd repetition; 3) at finish; and 4) at 10 min of recovery. Heart rate (HR) during swimming, lactate acid (La) concentration and swimming time (t<inf>50</inf>) were measured. Our study showed uncompensated metabolic acidosis due to increased lactic acidosis in both breathing conditions, more pronounced in apnea, and faster swimming times in apnea without different heart rate responses. Apnea during repetitive high intensity long distance interval 50 m freestyle swimming causes uncompensated metabolic acidosis but improves sprint performance.

Effects of Resistance Exercise with and without Blood Flow Restriction on Acute Hemodynamic Responses: A Systematic Review and Meta-Analysis

Low-load intensity resistance exercise with blood flow restriction (BFR) is an alternative method for enhancing strength and muscle mass. However, acute cardiovascular responses to a complete training session remain uncertain compared to high-load intensity resistance exercise (HI). Therefore, the objective of this study to examine acute and post-exercise hemodynamic responses to low-load BFR and HI protocols. This systematic review and meta-analysis (RD42022308697) followed PRISMA guidelines to investigate whether the responses of heart rate (HR), blood systolic (SBP), blood diastolic pressure (DBP), and rate pressure product (RPP) immediately after and up to 60 min post-exercise from BFR were consistent with those reported after resistance exercises performed at HI in healthy individuals. Searches using PICO descriptors were conducted in databases from January 2011 to December 2023, and effect sizes were determined by Hedge’s g. The selected studies involved 160 participants in nine articles, for which the responses immediately after BFR and HI exercises showed no differences in HR (p = 0.23) or SBP (p = 0.57), but significantly higher DBP (p &lt; 0.01) and lower RPP (p &lt; 0.01) responses were found when comparing BFR to HI. Furthermore, the BFR and HI protocols showed no differences regarding SBP (p = 0.21) or DBP (p = 0.68) responses during a 15 to 60 min post-exercise period. Thus, these results indicated that hemodynamic responses are similar between BFR and HI, with a similar hypotensive effect up to 60 min following exercise.

Closed vessel burning rate measurements of composite propellants using microwave interferometry

AbstractBurning rate as a function of pressure is one of the primary evaluation metrics of solid propellants. Most solid propellant burning rate measurements are made at a nearly constant pressure using a variety of measurement approaches. This type of burning rate data is highly discretized and requires many tests to accurately determine the burning rate response to pressure. It would be more efficient to measure burning rate dynamically as pressures are varied. Techniques used to make transient burning rate measurements are reviewed briefly and initial results using a microwave interferometry (MI) technique are presented. The MI method used in tandem with a closed bomb enables nearly continuous measurement of burning rates for self‐pressurizing burns, capturing burning rate data over a wide range of pressures. This approach is especially useful for characterization of propellants with complex burning behaviors (e. g., slope breaks or mesa burning). The burning rates of three research propellants were characterized over a pressure range of 0.101–24.14 MPa (14–3500 psi). One research propellant exhibited a slope break at a pressure of 6.63 MPa (960 psi). Using MI in a closed pressure vessel, 14 propellant strand burns resulted in a nearly continuous burning rate curve over a pressure range of 0.41–24.13 MPa (60–3500 psi) that reasonably matched conventional burning rate measurements. The development of this technique provides an opportunity to quickly characterize the burning rate curve of solid propellants with greater fidelity and efficiency than traditional quasi‐static pressure testing techniques.

Comparison of immunochemotherapy and chemotherapy alone in conversion therapy for locally advanced unresectable esophageal squamous cell carcinoma.

The clinical value of preoperative immunochemotherapy and simple chemotherapy induction regimen in the conversion therapy of locally advanced unresectable esophageal squamous cell carcinoma (ESCC) is still unclear. Retrospective analysis was conducted on patients with unresectable cT4b stage ESCC who underwent conversion surgery in our hospital from January 2020 to December 2022. According to the preoperative induction treatment plan, they were divided into induction immunochemotherapy group (iICT group) and induction chemotherapy group (iCT group). The conversion surgery rate, R0 resection rate, radiological and pathological tumor responses, safety, and short-term survival outcomes were analyzed. The results showed that a total of 199 patients with cT4b locally advanced unresectable ESCC who underwent preoperative induction therapy were included in this study. Among them, there were 64 cases (32.2%) in the iICT group, 135 cases (67.8%) in the iCT group. There was a statistically significant difference in objective response rate (73.5% vs 48.9%) and conversion surgery rate (81.3% vs 66.7%), between the iICT and iCT groups (P=0.001 and P=0.019). Among the two groups of patients who underwent surgery, there were statistically significant differences in R0 resection rate (94.2% vs 82.2%) and pathological complete remission rate (23.1% vs 6.7%) between the iICT and iCT groups (P=0.043 and P=0.004). And there was no statistically significant difference in the incidence of grade 3 and above between two groups (P=0.928). The 2-year EFS of the iICT group and iCT group were 76.4% and 42.4%, respectively, with statistically significant differences (P=0.006). Compared with simple chemotherapy, the combination of PD-1 inhibitors and chemotherapy can achieve better conversion surgery rate, tumor response and event-free survival in the conversion therapy of locally advanced unresectable ESCC.

The dynamic response of Russian exchange rate to precious metals and minerals prices

The dynamic response of Russian exchange rate to precious metals and minerals prices

Fine root production and turnover rate responses to long-term warming and nitrogen addition in a semi-arid grassland

Soil carbon pool is closely linked to fine root production and turnover rate. Lack of knowledge about the effects of nitrogen addition and warming on fine root production and turnover rate limits our ability to accurately predict soil carbon stocks. We studied the responses of fine root production and turnover rate with an 8-year soil warming (ambient +1 °C) and nitrogen addition (ambient + 4.42 g N m−2 yr−1) experiment in a semi-arid grassland on the Loess Plateau of China. Warming significantly decreased fine root production but increased fine root turnover rate due to warming-induced reduction in soil water content. Conversely, nitrogen addition significantly increased fine root production due to decreased soil phosphorus availability. Combined warming and nitrogen addition had no significant effect on fine root production, but decreased fine root turnover rate due to low phosphorus availability caused by nitrogen addition and low soil moisture induced by warming. Our findings have important implications for more accurately predicting the belowground responses of dryland to global changes.

Efficacy and side effects of pembrolizumab plus chemotherapy vs. chemotherapy alone in patients with advanced gastric or gastroesophageal junction adenocarcinoma: A meta‑analysis.

Recently, the treatment plan of pembrolizumab plus chemotherapy was regarded as a promising treatment for patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJC). However, the efficacy and side effects of pembrolizumab plus chemotherapy still lack evidence-based medical evidence to support. Therefore, a meta-analysis was conducted to evaluate the hot issue. By searching PubMed, EMBASE, Cochrane Library, Web of Science, any randomized clinical studies of pembrolizumab plus chemotherapy versus chemotherapy in patients with advanced GC/GEJC met the inclusion criteria were included. The quality of the literature was evaluated and the data was extracted. A correlative software was also used to analyze the data and to draw a conclusion. After screening 14,015 studies, four studies were eligible for the meta-analysis. Compared with chemotherapy alone group, the overall survival (OS) rate was significantly longer. In programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 subgroup and PD-L1 CPS ≥10 subgroup analyses, the results showed that the response rate (RR) and complete response rate (CR) were both higher in pembrolizumab plus chemotherapy group compared with chemotherapy alone group. There were not significant differences in the CR, the treatment-related adverse events, succumbed to drug-related events and succumbed to immune-mediated events between the two groups. However, the effect events such as the treatment-related adverse events led to discontinuation, the 3-5 treatment-related adverse events and the immune-mediated adverse events and infusion reactions were more common in pembrolizumab plus chemotherapy group. In conclusion, the current meta-analysis revealed that, in treating advanced GC/GEJC, pembrolizumab plus chemotherapy had improved therapeutic efficacies than chemotherapy alone, as evidenced by the significantly longer OS. Furthermore, the patients in PD-L1 CPS ≥1 subgroup and PD-L1 CPS ≥10 subgroup appeared to benefit from pembrolizumab plus chemotherapy treatment because of higher RR and CR. However, side effects such as the treatment-related adverse events leading to discontinuation, the 3-5 treatment-related adverse events, and immune-mediated adverse events and infusion reactions deserved more attention.

Performance optimization for an optimal operating condition for a shell and heat exchanger using a multi-objective genetic algorithm approach.

In this study, shell and heat exchangers are optimized using an integrated optimization framework. In this research, A structured Design of Experiments (DOE) comprising 16 trials was first conducted to systematically determine the essential parameters, including mass flow rates (mh, mc), temperatures (T1, t1, T2, t2), and heat transfer coefficients (€, TR, U). By identifying the first four principal components, PCA was able to determine 87.7% of the variance, thereby reducing the dimensionality of the problem. Performance-related aspects of the system are the focus of this approach. Key outcomes (€, TR, U) were predicted by 99% R-squared using the RSM models. Multiple factors, such as the mass flow rate and inlet temperature, were considered during the design process. The maximizing efficiency, thermal resistance, and utility were achieved by considering these factors. By using genetic algorithms, Pareto front solutions that meet the requirements of decision-makers can be found. The combination of the shell and tube heat exchangers produced better results than expected. Engineering and designers can gain practical insight into the mass flow rate, temperature, and key responses (€, TR, U) if they quantify improvements in these factors. Despite the importance of this study, it has several potential limitations, including specific experimental conditions and the need to validate it in other situations as well. Future research could investigate other factors that influence system performance. A holistic optimization framework can improve the design and engineering of heat exchangers in the future. As a result of the study, a foundation for innovative advancements in the field has been laid with tangible improvements. The study exceeded expectations by optimizing shell and heat exchanger systems using an integrated approach, thereby contributing significantly to the advancement of the field.

Comparison of time-motion, heart rate responses, and training load measurement in Brazilian jiu-jitsu heavyweight and lightweight fighters: a cross-sectional study

ABSTRACT This study compares technical-tactical and physiological parameters between lightweight and heavyweight male Brazilian Jiu-Jitsu (BJJ) fighters. We included 11 adult BJJ fighters (lightweight: age = 28 ± 7 years; body mass = 73 ± 2 kg; height = 1.72 ± 0.7 m; body mass index = 25 ± 2 kg/m2; heavyweight: age = 27 ± 3 years; body mass = 95 ± 6 kg; height = 1.87 ± 0.6 m; body mass index = 27 ± 2 kg/m2). Six participants were considered lightweight (71 to 77 kg) and five heavyweight divisions (88 to 101 kg). Initially, sample characteristics and a graded exercise test determined the physiological parameters. A simulated competition (10 minutes maximum) assessed technical-tactical characteristics, Heart Rate (HR), Rate of Perceived Exertion (RPE), TRaining IMPulse based on HR, session-RPE, and time at HR intensity zones (Z1, Z2, and Z3). A comparison test revealed that heavyweight athletes exhibited a higher height, body mass, total time in low-intensity efforts per block, number of standing combat blocks, and less time in high-intensity efforts per block and lower VO2MAX than lightweight (p < 0.05). The HR showed a nonlinear increase throughout each minute of the fights, with the heavyweight division demonstrating predominantly higher HR values. All fighters accumulated more time in training zone 3. The physiological and temporal differences between divisions suggest that BJJ training must be designed specifically for lightweight or heavyweight divisions.

A novel strategy for predicting the efficacy of temozolomide treatment for metastatic pheochromocytomas/paragangliomas.

There are few studies on the efficacy of temozolomide (TMZ) in the treatment of Metastatic pheochromocytoma / paraganglioma (MPP) patients. And it remains unclear which MPP patients may benefit from TMZ treatment. This wasa prospective study. MPP patients were enrolled. Patients were treated with TMZ until disease progression or intolerable toxicities. The primary endpoints were disease control rate (DCR) and objective response rate (ORR). Secondary endpoints included biochemical response rate progression-free survival (PFS) and safety. Wecomparedthe difference between effective and ineffective groups, to explore which patients are more suitable for TMZ treatment. 62 patients with MPP were enrolled and tumor response were evaluated in 54 patients. The DCR was 83% (35/42), and the ORR was 24% (10/41) among the progressive patients. PFSwas 25.2 ± 3.1months. The most common adverse event was nausea(41/55). We found that 92.9% (13/14) of patients with MGMT methylation greater than 7% respond to treatment. For the patients with MGMT methylationless than 7%, Ki-67 index could be used to guide the use of TMZ in these patients. Among the patients with Ki-67 index less than 5%, 66% (8/12) patients showed respond to treatment, and only 33% (4/12) patients with Ki-67 index more than 5% showed respond to TMZ. This study indicated that TMZis a potential choice for the treatment of MPP with the high ability on disease control and well tolerability. Werecommended to MGMT methylation analysis testandKi-67 index to guideTMZ application.

An Overview of Appropriate Medical Practice and Preparedness in Radiation Emergency Response.

Radiation emergencies involving high doses of nuclear radiation pose significant risks from exposure to ionizing radiation in various scenarios. These situations include transportation accidents involving radioactive materials, occupational exposure, nuclear detonations, dirty bombs, and nuclear power plant accidents. In addition to the immediate risks of acute radiation syndrome (ARS) and related diseases, long-term exposure can increase the risk of other health issues such as cardiovascular disease and cancer. Vulnerable populations, including pregnant women and children, face particular concern due to potential impacts on their health and the health of unborn babies. The severity of ARS depends on several factors such as radiation dose, quality, dose rate, exposure uniformity, and individual biological responses. Bioindicators are biological responses or markers that help assess the severity and effects of radiation exposure on an individual. Bioindicators can include physical symptoms such as nausea, vomiting, and diarrhea, or laboratory tests such as changes in blood cell counts and gene expression that can help in assessing and treating exposed individuals. Additionally, early prodromal symptoms such as vomiting, diarrhea, and erythema can provide important clues for diagnosis and treatment. Developing a comprehensive plan for radiation emergencies is vital for safeguarding public health, infrastructure, and the environment. First responders play a critical role in establishing safety perimeters, triage, and coordination with various stakeholders. Education and training are essential for medical personnel and the public. This article provides general recommendations and identifies challenges to effective radiation emergency preparedness and response.

An open, prospective, single arm, phase II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) with neoadjuvant chemotherapy in patients with advanced ovarian cancer: Interim analysis from the AK104-IIT-003 study.

e17552 Background: There is an unmet need to improve neoadjuvant chemotherapy (NAC) to decrease postoperative residual disease (R0 rate: 50%) and improve prognosis in ovarian cancer (OC). R0 rate and histopathological response of interval cytoreductive surgery (IDS) after NAC combined with immune checkpoint blockades were reported to be encouraging. Cadonilimab (AK104) is a tetravalent bispecific antibody targeting PD-1 and CTLA-4. In this study, we report the efficacy and safety of AK104 with NAC in patients with advanced-stage ovarian cancer (NCT05430906). Methods: This study is an open-label, prospective, single arm, phase II study of evaluating the efficacy and safety of cadonilimab combined with chemotherapy as neoadjuvant treatment for advanced ovarian cancer. Patients received neoadjuvant therapy of cadonilimab plus platinum-taxane chemotherapy (3 to 4 cycles) followed by surgery. Surgery would be performed within 30 days of completion of neoadjuvant therapy. The primary endpoint was the R0 rate. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), chemotherapy response score (CRS), pathologic complete response(pCR), progression-free survival (PFS), and safety. A sample size of 35 achieves 80% power to detect a difference of 0.2 using a two-sided Z-test to estimate the standard deviation with a significance level (alpha) of 0.1. And the sample size was expected to be 40 cases to ensure that the FAS set contains 35 cases for analysis. Results: 17 patients were enrolled from Dec 12, 2022, to Dec 6, 2023. The median patient age was 57 years (range 45–70 years), and most patients presented with high-grade serous carcinoma (94.1%) and stage IVa (5.9%), IVb disease (76.5%). 15 (88.2%) patients had undergone IDS, with an R0 resection rate of 66.7%. ORR was 94.1%, with 1patient achieved CR and 15 patients achieved PR. 11.8% achieved pathological complete response, and 17.6% had a chemotherapy response score (CRS) of 3. PFS or OS data are not mature by cut-off date. Safety and adverse event (AE) were analyzed after completion of neoadjuvant therapy. Treatment-related AEs (TRAEs) of any grade were evaluated for all study populations. TRAEs of any grade occurred in 13 (76.5%) patients. Grade ≥3 TRAEs occurred in 3 (17.6%) patients. The most common TRAEs were thyroid dysfunction (23.5%) and bone marrow suppression (17.6%). Grade ≥ 3 irAE (immune⁃mediated colitis) occurred in 1 (5.9%) patient. All of the TRAEs, including severe AEs, were manageable, with no new safety concerns in this study. Conclusions: This study showed promising activity with a durable clinical response, supporting the potential of NAC with bispecific antibody AK104 in advanced-stage ovarian cancer. Meanwhile, long-term efficacy evaluation still needs following up. Clinical trial information: NCT05430906 .

Safety of pressurized intraperitoneal aerosolized chemotherapy (PIPAC) in patients (pts) with biliary tract cancer with peritoneal metastases.

TPS4186 Background: Biliary tract cancers are rare with the majority of pts diagnosed with metastatic disease at initial presentation. Up to 20% of pts will have peritoneal metastases, resulting in symptoms of ascites, abdominal pain, and potential bowel obstruction. Despite advances in standard of care systemic treatments such as combination gemcitabine, cisplatin, and durvalumab (gem/cis/durva), penetration to peritoneal metastases may be poor. While addition of nab-paclitaxel to gem/cis increased objective response in a phase 2 study (1), SWOG 1815 did not demonstrate a significant improvement in survival with the triplet combination compared to gem/cis (2), possibly due to added toxicity. PIPAC directly delivers treatment to the peritoneal space, which could potentially reduce toxicity and improve efficacy. We aim to investigate the safety of PIPAC nab-paclitaxel plus systemic gem/cis/durva in biliary tract cancer pts with peritoneal metastases. Methods: This is an investigator-initiated, non-randomized phase 1 trial enrolling up to 12 evaluable pts using a modified phase 1 queue 3+3 design. Eligible pts must have treatment-naïve histologically or cytologically confirmed intra/extra-hepatic cholangiocarcinoma or gallbladder cancer with documented metastatic disease and visible peritoneal disease on imaging or laparoscopy. Gem/cis (800/25 mg/m2) will be administered on Days 1 and 8 of 3-week cycles; durva (1500 mg) will be administered on Day 1. Pts will receive PIPAC nab-paclitaxel (90 mg/m2) on Day 3 of Cycles 1, 3, and 5. If dose-limiting toxicities (DLTs) occur, nab-paclitaxel may be reduced to 70 mg/m2; the DLT window for each pt is 42 days after the first PIPAC. After eight 3-week cycles, durva (1500 mg) will be continued on Day 1 of 4-week cycles until disease progression or unacceptable toxicity. The primary endpoint is treatment-related adverse events (AEs) graded by NCI Common Terminology Criteria for Adverse Events version (v) 5.0. AEs will be monitored during treatment and for 4 weeks after the last dose of treatment with any agent. Secondary endpoints include objective response per Response Evaluation Criteria in Solid Tumors v1.1, peritoneal regression grading score at each PIPAC, peritoneal carcinomatosis index at time of laparoscopy, post-operative surgical complications, progression-free/overall survival, PIPAC technical failure rate, EQ-5D-5L and MD Anderson Symptom Inventory responses before/during treatment, and number of daily steps taken before/during treatment. Exploratory endpoints include characterization of sub-clonal tumor evolution/tumor microenvironment changes and PIPAC nab-paclitaxel pharmacokinetics/pharmacodynamics. Enrollment began 6/2023 and is ongoing. 1. Shroff et al, JAMA Oncol 2019. 2. Shroff et al, JCO 2023 LBA490. Clinical trial information: NCT05285358 .

Second line immune targeted therapies in relapsed or refractory diffuse large B-cell lymphoma: A network meta-analysis.

e19071 Background: Relapsed or refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) patients undergo multiple lines of burdensome therapies. We conducted a network meta-analysis (NMA) of phase 3 randomized control trials (RCTs) to evaluate the effectiveness of second-line (2L) immune targeted treatments (ITTs), including chimeric antigen receptor (CAR)-T cell therapies in R/R DLBCL patients, focusing on overall survival (OS), event-free survival (EFS), progression-free survival (PFS), overall response rate (ORR) and complete response (CR). Methods: In a systematic review, we searched RCTs from PubMed, Embase and Cochrane Library spanning January 2016 to September 2023.We included studies reporting on adults (≥18 years) DLBCL patients experiencing R/R to first-line anti-CD20 antibody and anthracycline-containing regimen. RCTs comparing ITTs with SOC (2L salvage chemoimmunotherapy regimens followed by stem cell transplantation) were included. Frequentist fixed-effect model was utilized to estimate hazard ratios (HRs) for survival outcomes and odds ratios (ORs) for binary outcomes (ORR and CR) with corresponding 95% confidence intervals (CIs). We ranked treatment effectiveness based on the surface under the cumulative ranking curves (SUCRA). Results: Our search identified 539 records; four RCTs contributed to the NMA: three comparing CAR-Ts, axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), tisagenlecleucel (tisa-cel) with SOC, and one comparing ofatumumab + cisplatin, cytarabine, dexamethasone (O-DHAP) with SOC. Axi-cel significantly improved OS compared to both tisa-cel (HR, 0.59; 95% CI, 0.36-0.96) and SOC (HR, 0.73; 95% CI, 0.55-0.98). For EFS, axi-cel (HR, 0.38; 95% CI, 0.27-0.53) and liso-cel (HR, 0.32; 95% CI, 0.21-0.51) showed significant improvement compared to ODHAP. Axi-cel and liso-cel improved EFS significantly when individually compared to tisa-cel, and SOC.Axi-cel (HR, 0.51; 95% CI, 0.39-0.67) and liso-cel (HR, 0.4; 95% CI, 0.26-0.61) improved PFS significantly when compared to SOC. Axi-cel and liso-cel also significantly improved PFS when individually compared to ODHAP. In terms of ORR, Axi-cel (OR, 5.93; 95% CI, 3.63- 9.68) and Liso-cel (OR, 6.96; 95% CI, 3.37- 14.37) produced significantly higher ORR compared to SOC. Axi-cel and liso-cel had higher CR significantly when individually compared to ODHAP, tisa-cel, and SOC.In the SUCRA rankings, axi-cel was the most effective for OS, liso-cel ranked the most effective for EFS and PFS. Conclusions: Axi-cel was consistently associated with improved OS and EFS when compared to tisa-cel and SOC while liso-cel improved EFS and PFS over ODHAP and SOC. ORR and CR were higher for axi-cel and liso-cel over tisa-cel, ODHAP and SOC. Results are constrained by lack of multiple studies for each treatment comparison.

Updated results of perioperative PD-1 antibody toripalimab plus FLOT chemotherapy for locally advanced resectable gastric or gastro-esophageal junction adenocarcinoma: A one-arm open-table phase II trial.

e16128 Background: Perioperative chemotherapy is the standard treatment for resectable gastric/gastroesophageal junction (GEJ) adenocarcinoma. Immune checkpoint inhibitors have activity in advanced gastric/GEJ cancer. This trial to assess the efficacy of the addition of toripalimab to FLOT for resectable patients and explore the immune microenvironment prospectively related to treatment response of neoadjuvant immunotherapy by multiplex immunohistochemistry. Methods: This is a prospective, single-arm, investigator-initiated phase II trial. Patients with histologically confirmed, resectable, gastric and GEJ adenocarcinoma (≥ cT2 or cN+) were enrolled to receive 4 pre- and post-operative cycles of toripalimab (240mg, q2w) plus FLOT (docetaxel 50 mg/m2; oxaliplatin 85 mg/m2; leucovorin 200 mg/m2; 5-Fu 2600 mg/m2, q2w). The primary endpoint were 3-year disease-free survival rate, overall survival and pathological complete response rate (pCR). Planned sample size of 36 operated patients. if the pCR rate is greater than 16% (n = 6), an additional 20 cases will be added. Multiplex immunohistochemistry is used to quantify in situ biomarker at subcellular resolution. Results: Study accrual completed at August 2022, 55 patients were enrolled, 40M/15F, age 57 (28-76), ECOG 0 (39) and 1 (16). 4 patients had not received surgery were excluded from efficacy analysis (Three patients withdrew consent after two treatment cycles and one refused surgery after 4 cycles pre-operative treatment). Fifty-one had completely neoadjuvant treatment and received surgery. Pathological response was TRG 0/ 1/ 2/ 3 in 10/ 6/ 21/ 14 patients with pCR seen in 10 (19.6%). Major pathologic response (TRG 0 and 1) was seen in 16 (31.4%) patients. At 36.6 (17.6-57.8) months follow up, the median disease-free survival (DFS) and overall survival (OS) were not reached for all patients. DFS rate at 1, 2, and 3 year is 78.4%, 56.9%, and 54.3%. OS rate at 1, 2, and 3 year is 94.1%, 69.5%, and 65.2%. Compared with TRG 2 or 3, patients with MPR showed significant longer survival (p = 0.01). Twenty-four patients underwent immune microenvironment analysis on their pre-treatment specimens by multiplex immunohistochemisty. Compared with TRG 2 or 3 (n = 11), NK cells with positive CD56 expression in tumor parenchyma microenvironment in patients with MPR (n = 13) were significant decreased (p = 0.024). Conclusions: Perioperative toripalimab in combination with FLOT showed promising efficacy with high pCR and MPR rate in patients with resectable gastric/GEJ adenocarcinoma. MPR rate and NK cells in tumor microenvironment have a predictive on therapeutic efficacy, with deserves further study. Clinical trial information: NCT04354662 .

The impact of drought duration on two Potamogeton species with different growth forms

When facing new climate extremes, aquatic plant communities may experience more frequent or increasing durations of water shortages. Aquatic macrophytes of permanently inundated habitats (true hydrophytes) may lack the physiological or morphological characteristics that protect terrestrial plants from drying out. Aquatic hydrophytes with floating or emergent leaves are expected to be more resilient to droughts than completely submerged plants, as they have morphological characteristics adapted to air-exposed conditions. Therefore, we expected the latter to survive longer periods of air exposure and perform better with increasing drought than a completely submerged growing species. Here, we conducted a microcosm experiment and exposed two Potamogeton species—the completely submerged growing Potamogeton perfoliatus and the areal leaf producing Potamogeton nodosus—to different drought conditions (1, 5, and 15 days). We aimed to detect how two species with different growth strategies cope with and respond to increasing air exposures with waterlogged sediment. Both species showed a resistance to 1–5 days of drought but showed high mortality after 15 days. They displayed significant differences in all measured morphological responses (shoot length, side shoot, and leaf counts), plant chemistry (carbon, nitrogen, and phosphate), and the produced biomass (shoot, root, leaves), and reacted significantly to increasing drought durations. Differences in their resistance were observed based on the mortality rate and morphological responses. To prevent long-term droughts and keep mortality low, we recommend to the water managers to identify areas of risk and increase water levels during dry periods.