Days Of Infusion Research Articles

Clinical efficacy of Endostar continuous infusion combined with concurrent chemoradiotherapy in the treatment of oesophageal squamous cell carcinoma.

To evaluate the effectiveness and safety of concurrent chemoradiotherapy using Endostar continuous infusion for treating oesophageal squamous cell carcinoma (OSCC). A total of 62 patients with oesophageal carcinoma were divided into three groups: the Endostar continuous infusion group (n = 27), the Endostar intravenous drip group (n = 21) and the concurrent chemoradiotherapy group (n = 14). All patients underwent oesophageal radiotherapy (56-60 Gy) alongside concurrent chemotherapy (4 mg of raltitrexed +100 mg of oxaliplatin, two cycles). In the Endostar continuous infusion group, 210 mg of Endostar was administered via infusion once every 3 weeks for 72 h, repeated for two cycles. The Endostar intravenous drip group received a dosage of 15 mg/day of Endostar, administered once daily for 14 days, repeated for two cycles. The objective response rate (ORR) (complete remission + partial remission), progression-free survival (PFS), 2-year overall survival (2y-OS) and adverse reactions were observed. In the Endostar continuous infusion, intravenous drip and concurrent chemoradiotherapy groups, the ORR was 100, 95.2 and 78.6%, respectively (p < 0.05). There was a statistically significant difference between the continuous infusion and concurrent chemoradiotherapy groups (p < 0.05). However, there was no statistically significant difference between the continuous infusion and intravenous drip groups or the intravenous drip and concurrent chemoradiotherapy groups (p > 0.05). The continuous infusion and intravenous drip groups had higher PFS rates than the concurrent chemoradiotherapy group (p < 0.05). Regarding the 2y-OS rate, no statistically significant difference was observed among the three groups (p > 0.05). Furthermore, there was no statistically significant difference in adverse reactions among the groups (p > 0.05). Concurrent chemotherapy based on endostatin is effective and safe in the treatment of OSCC. Continuous 3-day Endostar infusion treatment can significantly enhance both short-and long-term therapy efficacy in patients while maintaining a high level of safety.

Development and validation of a nomogram for sleep disorders among stroke patients

BackgroundPrecisely identifying high-risk sleep disorder patients and implementing suitable measures are important for decreasing the incidence of sleep disorders. In this study, a nomogram method was adopted to construct a tool to predict sleep disorders in stroke based on four factors: individual characteristics, treatment-related factors, psychological factors, and family-related factors. MethodsA total of 450 stroke patients were continuously diagnosed at the Affiliated Hospital of Nantong University, and the data on participants were randomly distributed into a training set (n = 315) and a validation set (n = 135). Within the training set, using LASSO regression and random forest methods, five optimal predictors of sleep disorders were identified. Five optimal predictors were used to develop a model. The calibration, discrimination, generalization, and clinical applicability of the model were evaluated using calibration curves, receiver operating characteristic (ROC) curves, internal validation, and decision curve analysis (DCA). ResultsWe found that the place of residence, average daily infusion time, the Hospital Anxiety and Depression Scale (HADS), the Type D Personality Scale-14 (DS14), and the Fatigue Severity Scale (FSS) were crucial factors associated with sleep disorders. The validation data showed an area under the curve (AUC) of 0.903 compared to 0.899 in the training set. There was an approach to the diagonal in the calibration curve of this model, and the results of DCA noted that it is clinically beneficial across a range of thresholds from 5 % to 99 %. ConclusionA model was developed to predict sleep disorders among stroke patients to help hospital staff evaluate the risk among patients and screen high-risk patients.

Chronic central nervous system leptin administration attenuates kidney dysfunction and injury in a model of ischemia/reperfusion-induced acute kidney injury.

In the present study we examined whether chronic intracerebroventricular (ICV) leptin administration protects against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). Twelve-week-old male rats were implanted with an ICV cannula into the right lateral ventricle and 8-10 days after surgery, leptin (0.021 mg/hr, n=8) or saline vehicle (0.5 ml/h, n=8) was infused via osmotic minipump connected to the ICV cannula for 12 days. On day 8 of leptin or vehicle infusion, rats were submitted to unilateral ischemia/reperfusion (UIR) by clamping the left pedicle for 30 min. To control for leptin-induced reductions in food intake, the vehicle-treated group was pair-fed (UIR-PF) to match the same amount of food consumed by leptin-treated (UIR-Leptin) rats. On the 12th day of leptin or vehicle infusion (4th day after AKI), single-left kidney glomerular filtration rate (GFR) was measured, blood samples were collected to quantify white blood cells, and kidneys were collected for histological assessment of injury. UIR-Leptin treated rats showed reduced right and left kidney weights (right: 1040±24 vs. 1281±36 mg; left: 1127±71 vs. 1707±45 mg, for UIR-Leptin and UIR-PF, respectively). ICV leptin infusion improved GFR (0.50±0.06 vs. 0.13±0.03 ml/min/g KW) and reduced kidney injury scores. ICV leptin treatment also attenuated the reduction in circulating adiponectin levels that was observed in UIR-PF rats, and increased circulating white blood cells count compared to UIR-PF rats (16.3±1.3 vs. 9.8±0.6 k/mL). Therefore, we show that leptin, via its actions on the central nervous system, confers significant protection against major kidney dysfunction and injury in a model of ischemia/reperfusion-induced AKI.

Time toxicity of lutetium-177 treatment in gastroenteropancreatic neuroendocrine tumours

Objectives: We aim to investigate the time toxicity of patients with gastroenteropancreatic-neuroendocrine tumours treated with lutetium-177 Dotatate in a single institution. Design: This is a retrospective cohort study. Methods: All patients with gastroenteropancreatic-neuroendocrine tumours treated with lutetium-177 Dotatate in the Alexander Fleming Institute were included. Our primary endpoint was to evaluate time toxicity, which accounted for every day that the patient had contact with any department of any healthcare institution. Results: Our cohort included 21 patients with metastatic disease, female sex 86%, and had a median age of 55 (IQR 44-63). The primary tumour site was small intestine in 47.6% of the cases. The median number of previous systemic treatments for advanced disease was 2 (IQR 2 - 3). The overall response rate was 19%, and 66.6% had disease clinical benefit. The median calculated 'time toxicity' was 11 days (IQR 8-18), representing 5.7% of the total treatment duration. The main contributors to time-toxicity included infusion days, blood draws, radiological scans, and hospitalizations (median 4 days for each). Conclusion: Lutetium-177 Dotatate treatment for gastroenteropancreatic-neuroendocrine tumours was associated with a low time toxicity, excellent tolerability, good response and a prolonged PFS, of which the median was not reached in the short follow-up we present. Newer treatments with different mechanisms of action provide longer survivals and widen the landscape of choices. Understanding new clinical endpoints is important for the transition into a more modern clinical practice, strengthening personalised and patient-oriented strategies.

EASIX-guided risk stratification for complications and outcome after CAR T-cell therapy with ide-cel in relapsed/refractory multiple myeloma

BackgroundChimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release...

Blinatumomab infusion interruptions in pediatric patients rarely lead to readmission.

Blinatumomab is a bispecific T-cell engager administered as a 28-day continuous infusion. Infusions can be associated with interruptions requiring support from clinical staff, but the frequency of interventions with outpatient blinatumomab has not been characterized. This study is a single-center, retrospective review of patients who received blinatumomab between December 3, 2014 and October 31, 2021 to determine frequency and type of interventions. Forty patients received blinatumomab for 69 cycles. Clinical staff intervention was required in 31 (45%) cycles, only six (8.7%) cycles needed readmission. Management of outpatient blinatumomab infusions requires education and training of clinical staff and caregivers to quickly troubleshoot interruptions.

OUTREACH: phase 2 study of lisocabtagene maraleucel as outpatient or inpatient treatment at community sites for R/R LBCL

AbstractLisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB chimeric antigen receptor (CAR) T-cell product approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We present the OUTREACH primary analysis, evaluating the safety and efficacy of outpatient monitoring after liso-cel treatment at community sites in the United States. Adults with R/R LBCL after ≥2 prior lines of therapy received liso-cel. Outpatient vs inpatient monitoring was per investigator discretion. The primary end points were incidence of grade ≥3 cytokine release syndrome (CRS), neurological events (NEs), prolonged cytopenia, and infections. Efficacy was a secondary end point. Eighty-two patients received liso-cel (outpatient monitored, 70%; inpatient monitored, 30%). The median follow-up was 10.6 months (range, 1.0-24.5). In outpatients and inpatients, grade ≥3 CRS occurred in 0% and 0%, NEs in 12% and 4%, infections in 12% and 8%, and prolonged cytopenia in 33% and 32%, respectively. Among outpatients, 25% were never hospitalized after infusion, and 32% were hospitalized ≤72 hours after the day of infusion; the median time to hospitalization was 5.0 days (range, 2-310). The median initial hospitalization duration after liso-cel was 6.0 days (range, 1-28) for outpatients and 15.0 days (range, 3-31) for inpatients. Objective response rate was 80%, complete response rate was 54%, and the median duration of response was 14.75 months (95% confidence interval, 5.0 to not reached). OUTREACH is, to our knowledge, the first and largest study to prospectively assess CAR T-cell therapy with outpatient monitoring in community-based medical centers. Liso-cel demonstrated meaningful efficacy with favorable safety in patients with R/R LBCL. Data support the feasibility of liso-cel administration at community sites with outpatient monitoring. This trial was registered at www.ClinicalTrials.gov as #NCT03744676.

Activity of the hypothalamic neuropeptide Y increases in adult and decreases in old rats.

Middle-aged obesity and aging anorexia with muscle loss (sarcopenia) of old people present public health burden. These alterations may appear both in humans and rodents suggesting the role for regulatory alterations. Previously, we demonstrated that biphasic changes in the weight-reducing (catabolic) effects of neuropeptides of the hypothalamus-adipose tissue axis (e.g. leptin) may contribute to both trends. With regard to the anabolic effects of the hypothalamic neuropeptide Y (NPY) inhibited by leptin, we hypothesized non-linear age-related changes with shifts in the opposite directions. We investigated the orexigenic and hypometabolic effects of intracerebroventricularly administered NPY (hyperphagia induced by NPY injection or changes in food intake, body weight, heart rate, body temperature, locomotor activity during a 7-day NPY infusion), the immunoreactivity and gene expression of NPY in the hypothalamic arcuate nucleus of male Wistar rats of five age groups from young to old. The orexigenic/hypometabolic efficacy and the immunoreactivity of NPY increased in middle-aged animals preceding the peak of adiposity observed in aging rats, then decreased preceding anorexia and weight loss in old rats. These shifts may contribute to the development of both age-related obesity and aging anorexia, sarcopenia, and should be considered in future drug development targeting the NPY system.

The association of azole antifungals with overall survival in patients with non-small cell lung cancer receiving immune checkpoint inhibitors.

Preclinical data suggest antifungal azole derivatives have antitumor efficacy that may modulate response to immune checkpoint inhibitors (ICIs). We aimed to evaluate the association of azole drugs with overall survival (OS) in a population of patients with non-small cell lung cancer (NSCLC) treated with ICI within the Veterans Health Administration (VHA). In this retrospective study, the VA Corporate Data Warehouse was queried for patients diagnosed with NSCLC and treated with ICI from 2010 to 2018. Concomitant oral azole use was defined as dispensation by a VA pharmacy within 90 days of the first ICI infusion. Patients who received azole after 30 days were excluded from the analysis to mitigate immortal time bias. OS was measured from the start of ICI. Cox regression and propensity score matching were used to adjust for confounders. We identified 3413 patients with NSCLC receiving ICI; 324 (9.5%) were exposed to concomitant azoles. As a group, azole use was not associated with OS (hazard ratio [HR] = 0.96; 95% CI, 0.84-1.09; P = .51). After stratification by azole type, clotrimazole had an association with better OS on univariable (HR = 0.75; 95% CI, 0.59-0.96; P = .024) and multivariable analysis (HR = 0.71; 95% CI, 0.56-0.91; P = .007). Propensity score matching of patients who received clotrimazole vs no azole yielded 101 patients per matched cohort. Clotrimazole was associated with improved OS, although this did not meet the threshold for statistical significance (HR = 0.74; 0.54-1.01; P = .058). This observational study demonstrated an association between clotrimazole and OS among patients with advanced NSCLC receiving ICI. These findings build upon preclinical evidence and support further investigation into the potential for clotrimazole as a repurposed FDA drug to improve cancer outcomes.

Intermittent versus continuous intravenous epoprostenol for the treatment of digital ischemia

Digital ischemia can be a painful complication of Raynaud’s phenomenon or systemic sclerosis, which is caused by narrowing of blood vessels in the toes and hands. Epoprostenol is a potent vasodilator that may be used to treat digital ischemia in this patient population. Our institution provides epoprostenol infusion using two different administration techniques: a 30-h continuous infusion option and a 5-day intermittent 6-h infusion. In this retrospective chart review, we compared two administration techniques of intravenous epoprostenol administered to patients with digital ischemia. The primary outcome was to compare the efficacy of intravenous epoprostenol 30-h continuous infusion versus 5-day intermittent infusion, as defined by the presence of treatment failure. Between June 2019 and June 2020, 72 adult patient encounters met the inclusion criteria (intermittent: n = 20; continuous: n = 52). The primary outcome did not achieve a statistically significant difference between the two groups: intermittent 20% versus continuous 33.3% p = 0.390, odds ratio = 0.57 (95% confidence interval = 0.17–1.90). Adverse reactions were documented in 28% of patients across both treatment groups, and there was no difference detected when treatment groups were compared (25% vs 28.8%). Patients who received the 5-day infusion experienced a significantly longer average length of stay, with a mean of 8.9 days versus 3 days for those treated with the continuous 30-h infusion ( p &lt; 0.05; 95% confidence interval = 2.15–9.47). This study determined that the efficacy and safety profiles of the two administration techniques may not be comparable. Each protocol offers advantages over the other, and selection should be guided by patient history and risk factors to optimize management.

Phase III randomized trial comparing neoadjuvant paclitaxel+platinum to 5-fluorouracil+platinum in esophageal/GEJ squamous cell carcinoma.

Standard neoadjuvant chemotherapy (NACT) for locally advanced esophageal/gastroesophageal junction squamous cancer (LAEGSC), 5-fluorouracil (5FU)+platinum, is toxic and logistically challenging; alternative regimens are needed. Phase III randomized open-label non-inferiority trial at Tata Memorial Center, India, in resectable LAEGSC. Patients were randomized 1:1 to three cycles of 3-weekly platinum (cisplatin 75 mg/m2 or carboplatin AUC 6) with paclitaxel 175 mg/m2 (day 1) or 5FU 1000 mg/m2 continuous infusion (days 1-4), followed by surgery. Between August 2014 and June 2022, we enrolled 420 patients; 210 to each arm. Significantly more patients on paclitaxel + platinum (194 (92.3%)] received all 3 chemotherapy cycles than on 5FU+platinum (170 [85.9%]), P = .009. 5FU + platinum caused more grade ≥ 3 toxicities (124 [69.7%]) than paclitaxel + platinum (97 [51.9%]), P = .001. Surgery was performed in 131 (62.4%) patients on 5FU + platinum vs 139 (66.2%) on paclitaxel + platinum, P = .415. Paclitaxel + platinum resulted in higher pathologic primary tumor clearance (33 [25.8%]) vs 17 [15%]; P = .04), and pathologic complete responses in 21.9% compared to 12.4% from 5FU + platinum, P = .053. Median OS was 27.5 months (95% CI, 18.6-43.5) from paclitaxel + platinum, which was non-inferior to 27.1 months (95% CI, 18.8-40.7) from 5FU + platinum; HR, 0.89 (95% CI, 0.72-1.09); P = .346. Neoadjuvant paclitaxel + platinum chemotherapy is safer, and results in similar R0 resections, higher pathologic tumor clearance and non-inferior survival, compared to 5FU + platinum. Paclitaxel + platinum should replace 5FU + platinum as NACT for resectable LAEGSC. CTRI/2014/04/004516.

Invasive procedures and surgery following etranacogene dezaparvovec gene therapy in people with hemophilia B

BackgroundLittle information regarding the management of invasive procedures in people with hemophilia B (HB) after undergoing gene therapy is available. Here, we report the management of invasive procedures in people with severe or moderately severe HB who had previously been treated with etranacogene dezaparvovec in the phase 2b and phase 3 HOPE-B clinical trials (NCT03489291 and NCT03569891). Objectives▪. MethodsThis retrospective analysis included invasive procedures performed within 3 and 2 years following a single infusion of 2 × 1013 gc/kg of etranacogene dezaparvovec in participants in the phase 2b and HOPE-B trials, respectively. Data for factor (F)IX dosing, duration of postoperative FIX use, FIX activity prior to invasive procedures, and postoperative bleeds were collected and analyzed. ResultsThe analysis included 64 procedures in 29 participants: 9 major surgeries, 24 minor surgeries, 11 endoscopies, 3 endoscopies with biopsy/polypectomy, and 17 dental procedures. Uncontaminated endogenous FIX activity corresponded to mild hemophilia or normal levels prior to 98% of all procedures, with a median endogenous FIX activity of 43.8 IU/dL (range, 3.1-113 IU/dL). All major surgeries were managed with exogenous FIX, 67% with ≤4 days of FIX infusion. Most minor surgeries (88%), endoscopies (82%), and dental procedures (94%) were managed with no or a single FIX infusion. Postoperative bleeds occurred after 1 minor surgery and 4 dental procedures. There were no symptomatic thrombotic events or FIX inhibitor developments. ConclusionEtranacogene dezaparvovec has the potential to facilitate perioperative management in people with HB by reducing the need for perioperative exogenous FIX and its associated risks.

O47 THE ROLE OF IL-33 AND ST2 IN THE MODULATION OF TARGET ORGAN DAMAGE IN ANGIOTENSIN II-DEPENDENT HYPERTENSION

Introduction: Hypertension is associated with a chronic inflammatory state and aberrant immune system activity. Interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) signalling axis is important in the modulation of atherosclerosis and cardiovascular fibrosis. We aimed to evaluate the modulation of IL-33 and ST2 in hypertensive mouse models and patients. Methods and Results: Hypertension was induced by a 14-day infusion of Ang-II (490ng/min/kg) in 12-week-old WT C57BL/6, ST2KO, IL33KO mice. IL-33 and ST2 mRNA and protein were evaluated using qPCR and Western blot in WT mice. Ang II-infusion significantly increased IL-33 and ST2 protein expression in target organs related to hypertension, particularly the aorta (1.0±0.1 vs 2.8±0.2, p&lt;0.0001, and 0.963±0.068 vs 2.094±0.231, p=0.002, respectively). Further, mRNA expression of IL-33 and ST2 was elevated in hypertensive aortas when compared with control (1.0±0.053 vs 1.76±0.271, p=0.0185 and 1.0±0.039 vs 1.978±0.221, p=0.0039, respectively). IHC from WT mice illustrated the localisation of IL-33 and ST2 in Ang-II aortas in ECs and SMCs. Further in human hypertensive mammary arteries, the localisation was. In-vivo, IL33KO and ST2KO mice showed no altered BP at baseline or after 14 days of Ang-II compared to WT littermates. ST2KO Ang-II mice showed protection against endothelial dysfunction compared to WT Ang-II mice through isometric tension studies (p=0.0317). Additionally, Ang-II-induced IL33KO and ST2KO mice worsen cardiac fibrosis compared to WT littermates (p=0.0005,p&lt;0.0001, respectively). Conclusion: Both IL-33 and its receptor, ST2 are increased in the vascular and perivascular tissues in hypertension. Additionally, the IL-33/ST2 axis has a role in regulating cardiac fibrosis.

The Relationship Between Serum Lactate Dehydrogenase Enzyme Levels and Myeloid Engraftment in Hematopoietic Stem Cell Transplantation

BackgroundThe early detection of myeloid engraftment after hematopoietic stem cell transplantation (HSCT) is of clinical importance for clinicians. In this study, we evaluated whether serum lactic dehydrogenase enzyme levels are significant predictors in the early detection of successful myeloid engraftment after HSCT. MethodsThe study included 74 patients, all of whom underwent HSCT between February 2014 and June 2020. Serum lactic dehydrogenase (LDH) enzyme and complete blood parameters were evaluated at the start of the preparation regimen, on the day of product infusion, 5 days before myeloid engraftment, on the day of myeloid engraftment, and 5 days after engraftment. ResultsLDH enzyme levels increased statistically significantly 5 days before myeloid engraftment (P = .005), and this increase was observed to continue on the day of engraftment, and 5 days after engraftment, but the differences between the measurements 5 days before engraftment and those on the day of engraftment, and 5 days after engraftment were statistically insignificant (P > .05). There was no significant difference in LDH enzyme levels between the measurements made at the beginning of the preparation regimen and those made on the infusion day (P > .05). ConclusionsIncreased LDH enzyme levels after HSCT are associated with increased myelopoiesis in the bone marrow. The monitoring of serum LDH levels and the detection of the onset of increase in enzyme levels in patients undergoing HSCT may be predictors of engraftment.

BEAM or cyclophosphamide in autologous haematopoietic stem cell transplantation for relapsing-remitting multiple sclerosis

The most widely used conditioning regimens in autologous haematopoietic stem cell transplantation (ASCT) for multiple sclerosis (MS) are BEAM with anti-thymocyte globulin (ATG) and high-dose cyclophosphamide with ATG (Cy/ATG). In this retrospective study, we compare efficacy and safety of these regimens when used for relapsing-remitting MS. We assessed 231 patients treated in Sweden before January 1, 2020. The final cohort comprised 33 patients treated with BEAM/ATG and 141 with Cy/ATG. Prospectively collected data from the Swedish MS registry were used for efficacy, and electronic health records for procedure-related safety. The Kaplan–Meier estimate of ‘no evidence of disease activity’ (NEDA) at 5 years was 81% (CI 68–96%) with BEAM/ATG and 71% (CI 63–80%) with Cy/ATG, p = 0.29. Severe adverse events were more common with BEAM/ATG, mean 3.1 vs 1.4 per patient, p = <0.001. Febrile neutropaenia occurred in 88% of BEAM/ATG patients and 68% of Cy/ATG patients, p = 0.023. Average hospitalisation was 3.0 days longer in BEAM/ATG patients from day of stem-cell infusion, p < 0.001. While both regimens showed similar efficacy, BEAM/ATG was associated with more severe adverse events and prolonged hospitalisation. In the absence of randomised controlled trials, Cy/ATG may be preferable for ASCT in patients with relapsing-remitting MS due to its favourable safety profile.

EFEKTIVITAS SEDUHAN DAUN ASAM JAWA TERHADAP KADAR HOMA-IR DAN HOMA-β PADA PASIEN DIABETES MELLITUS TIPE 2

This study assessed the impact of tamarind leaf tea on HOMA-IR and HOMA-β levels in patients with Type 2 Diabetes Mellitus (DM). Thirty-two patients aged 20-50 years from Sungai Ambawang District Health Center, who were not using any DM medication, participated. They were divided into control (KN) and treatment (KP) groups, with KP receiving a tamarind leaf tea infusion for 7 days. HOMA-IR and HOMA-β levels were calculated using standardized formulas based on fasting insulin and glucose levels. The Wilcoxon signed-rank test revealed a significant decrease in HOMA-IR levels in the KP group (p&lt;0.05), while no significant change was observed in the KN group. Although no significant difference in HOMA-β levels was found between the two groups, the KP group showed a notable increase by 4. These findings suggest that a 7-day tamarind leaf tea infusion effectively reduced HOMA-IR levels in patients with type 2 DM, although it did not significantly affect HOMA-β levels. This study highlights the potential of tamarind leaf tea as a complementary approach for managing insulin resistance in Type 2 DM patients. Further research is needed to explore the long-term effects and mechanisms of action for improving β-cell function. The conclusion of this study is that steeping tamarind leaves for seven days can reduce HOMA-I levels and slightly increase HOMA-β levels in patients with type 2 Diabetes Mellitus.

A case report of fludarabine associated ectopic atrial bradycardia and literature review of fludarabine induced bradycardia

BackgroundFludarabine is a chemotherapeutic agent with lymphodepleting effects that is increasingly used as part of a conditioning regimen prior to allogeneic stem cell transplantation. Fludarabine is generally considered a relatively safe medication with only rare cases of cardiotoxic side effects.Case PresentationHere, we present a case of a 30-year-old woman who was undergoing conditioning for a haploidentical cell transplantation for treatment of Fanconi anemia with a 5-day course of daily fludarabine infusion. After her second fludarabine infusion, she was noted to have ectopic atrial bradycardia that resolved with supportive therapy and completion of fludarabine infusion.ConclusionWe report the first case of ectopic atrial bradycardia associated with fludarabine. Although rare and transient, clinicians should recognize this rare cardiotoxic side effect of fludarabine.

The changes of coagulation profiles in Kawasaki disease and its associations with clinical classification, intravenous immunoglobulin responsiveness and coronary artery involvement

Coagulation disorders are common in Kawasaki disease (KD). The main objectives of the present study were to probe the associations of coagulation profiles with clinical classification, IVIG responsiveness, coronary artery abnormalities (CAAs) in the acute episode of KD. A total of 313 KD children were recruited and divided into six subgroups, including complete KD (n = 217), incomplete KD (n = 96), IVIG-responsive KD (n = 293), IVIG-nonresponsive KD (n = 20), coronary artery noninvolvement KD (n = 284) and coronary artery involvement KD (n = 29). Blood samples were collected within 24-h pre-IVIG therapy and 48-h post-IVIG therapy. Coagulation profiles, conventional inflammatory mediators and blood cell counts were detected. Echocardiography was performed during the period from 2- to 14-day post-IVIG infusion. In addition, 315 sex- and age-matched healthy children were enrolled as the controls. (1) Before IVIG therapy, coagulation disorders were more prone to appear in KD patients than in healthy controls, and could be overcome by IVIG therapy. FIB and DD significantly increased in the acute phase of KD, whereas reduced to normal levels after IVIG therapy. (2) PT and APTT were significantly longer in patients with complete KD when compared with their incomplete counterparts after IVIG therapy. (3) The larger δDD, δFDP and the smaller δPT, δINR predicted IVIG nonresponsiveness. (4) The higher δDD and δFDP correlated with a higher risk for CAAs (DD: r = −0.72, FDP: r = −0.54). Coagulation disorders are correlated with complete phenotype, IVIG nonresponsiveness and CAA occurrence in the acute episode of KD, and can be rectified by synergistic effects of IVIG and aspirin.

Abstract Mo137: Modulation of the Inflammatory and Fibrotic Effects of Angiotensin on Cardiomyocytes through YAP-mediated Transcription.

Introduction: Signaling through the transcriptional co-activator Yes-associated protein (YAP) has been shown to protect the myocardium against ischemic or mechanical stress. Research Question: In light of the critical role of inflammation on adverse cardiac responses we examined the possibility that YAP regulates inflammatory responses to Angiotensin II (AngII)-mediated stress. Approach: Cardiomyocyte specific YAP-KO mice were generated, implanted with AngII minipumps, infused with AngII (1.5 mg/kg/min) or vehicle for periods of 3 hrs to 3 days and hearts collected for analysis. Results: YAP deletion markedly enhanced AngII-induced mRNA expression of pro-inflammatory cytokines and chemokines (e.g. CCL2, CXCL2, IL-6) at 3 or 24 hrs in the cardiomyocyte, but not non-myocyte cell fraction. Expression of mRNA for the hypertrophic genes ANP and MHC-β, in contrast, was decreased in YAP KO mice. After 3 days of AngII infusion there was enhanced mRNA for pro-fibrotic genes (Col1a1, Col3a1 and Periostin) and increased staining for COL1A1 and F4/80, indicative of increased fibrosis and inflammatory cell recruitment in the absence of YAP signaling. Single cell RNA sequencing revealed specific subsets of genes that were upregulated in the cardiomyocyte subcluster from YAP KO mice. These included pro-inflammatory cytokines, cJun family genes, TLR4 and, surprisingly, CaMKIId. Elevated activation of CaMKIIδ in response to AngII in YAP KO hearts was confirmed by increased phosphorylation of phospholamban. Cardiomyocytes expressing siYAP also showed enhanced expression of TLR4 and CaMKIIδ. Conclusion: Upregulated expression of cJun, TLR4 and CaMKII occurs in the absence of YAP and this conspires to create a greatly enhanced inflammatory milieu which fuels adverse responses to external insults. YAP activation serves to suppress these responses and thus temper development of maladaptive inflammation.

Pembrolizumab Plus Carboplatin and Paclitaxel as First-Line Therapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (KEYNOTE-B10): A Single-Arm Phase IV Trial.

Standard-of-care first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is pembrolizumab plus platinum and fluorouracil (FU). However, FU is associated with potential challenges (continuous 4-day infusion, high administration costs, and cardiovascular and gastrointestinal toxicities), creating a clinical need for alternative chemotherapy combinations. We evaluated the efficacy and safety of first-line pembrolizumab plus carboplatin and paclitaxel for R/M HNSCC in the open-label, single-arm, phase IV KEYNOTE-B10 study (ClinicalTrials.gov identifier: NCT04489888). Eligible adults had previously untreated, histologically or cytologically confirmed R/M HNSCC regardless of PD-L1 status, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received pembrolizumab 200 mg intravenously once every 3 weeks for ≤35 cycles and carboplatin AUC 5 mg/mL/min intravenously once every 3 weeks for ≤6 cycles and investigator's choice of paclitaxel 100 mg/m2 on days 1 and 8 or 175 mg/m2 on day 1, intravenously once every 3 weeks. The primary end point was objective response rate per RECIST v1.1 by BICR. Between October 27, 2020, and April 29, 2022, 149 patients were screened and 101 received treatment. As of February 20, 2023, the median follow-up was 18.9 months (range, 9.1-27.0). At this final analysis, 49 (49%) of 101 patients had an objective response (95% CI, 38.4 to 58.7), including seven patients (7%) with a confirmed complete response. Of the 101 treated patients, grade 3-5 and serious treatment-related adverse events occurred in 76 (75%) and 27 (27%), respectively. There were no new safety signals. Pembrolizumab plus carboplatin and paclitaxel showed promising antitumor activity and a manageable safety profile in first-line R/M HNSCC, suggesting this combination may be an alternative option for this patient population.