Decrease In Platelet Count Research Articles

Adjuvant donafenib for patients with hepatocellular carcinoma at high risk of recurrence following radical resection: A multi-center, retrospective study in China.

e15129 Background: The implementation of adjuvant therapy in reducing tumor recurrence of hepatocellular carcinoma (HCC) is an essential approach for extending the prognosis of patients. The exploration of treatment strategies that are both efficacious and secure remains a prominent area of research in recent years. Donafenib is a novel, oral, small-molecule, multikinase inhibitor, and has demonstrated promising efficacy and safety profiles in preclinical and clinical studies. However, there is currently a lack of reported data on the adjuvant donafenib for HCC following radical resection (R0). The present study aimed to explore the efficacy and safety of adjuvant donafenib for HCC patients at high risk of recurrence following R0. Methods: This retrospective study analyzed 196 patients who underwent R0 for HCC between April 2021 and October 2022. All patients exhibited at least one of the following high risk recurrence factors:① single lesion > 5 cm or multiple lesions of any size; ② microvascular invasion (MVI); and ③ satellite nodules. Among these patients, 49 received donafenib, while 147 (control group) did not. In the donafenib group, donafenib was administered at a dose of 100 or 200 mg bid until tumor recurrence and serious adverse events (AEs). The 1-year and 2-year recurrence-free survival (RFS) rates and overall survival (OS) rates were compared between the two groups, as well as the incidence of adverse events (AEs) in the donafenib group. Inverse probability of treatment weighting (IPTW) was used. Results: The patient population consisted of 167 males and 29 females, with a median age of 59 (range 30-83). All patients exhibited a high risk of recurrence (number of tumors single/multiple, 167/29; tumor size within 5.0/above 5.0 cm, 78/118; MVI yes/no, 140/56; satellite nodules yes/no, 39/157). The median follow-up was 21.8 (range 3.8-32.0) months. Before IPTW, the donafenib group exhibited significantly higher 1-year and 2-year RFS rates compared to the control group (83.7%, 68.0% vs 66.7%, 47,6%, p = 0.023), while no significant difference in 1-year and 2-year OS rates (97.8%, 93.9% vs 91.8%, 80.6%, p = 0.120). After IPTW, the 1-year, 2-year RFS rates and OS rates were more favorable for the donafenib group compared to the control group (86.6%, 72.5% vs 64.8%, 45.0%, P = 0.004; 97.9%, 95.6% vs 89.5%, 77.9%, P = 0.043, respectively). In the donafenib group, AEs occurred in 44 patients, including 39 with grade 1 or 2 AEs and 5 with grade 3 AEs. The most common AEs included hand-foot skin reaction, decreased platelet count, and diarrhea. Conclusions: Adjuvant donafenib may improve RFS of HCC patients at high risk of recurrence following R0, while exhibiting favorable safety. This finding deserves further exploration.

Clinical efficacy and safety of cadonilimab immunotherapy in patients with advanced cervical cancer: A retrospective study.

e17519 Background: For patients with recurrent or metastatic cervical cancer, especially those with negative PD-L1 expression, there is a lack of effective treatment and often indicate poor prognosis. A multicenter retrospective study was conducted to evaluate the safety and antitumor activity of cadonilimab in recurrent or metastatic cervical cancer patients. Methods: Patients with metastatic or recurrent cervical cancer, who underwent treatment of cadonilimab at Shenzhen People’s Hospital and Huazhong University of Science and Technology Union Shenzhen Hospital. All patients received immunotherapy of cadonilimab at a dose of 10mg/kg of body weight with/without the combination of chemotherapy/bevacizumab/ radiotherapy. Cadonilimab were repeated every 3 weeks until disease progression or intolerable toxicity. Antitumor activity and safety were assessed in all patients. Results: Since July 2022 to November 2023. A total of 18 patients (Figo stage IB1-IIIC) with recurrent/metastatic cervical cancer, 3 patients with newly diagnosed advanced cervical cancer (Figo stage IVB stage) were included. With a median follow-up of 7.0 months (IQR 1.9–15.4), the number of treatment cycles for cadonilimab ranged from 3 to 17 cycles, with a median of 7 cycles. 6 patients with PD-L1-positive expression, 5 patients with negative expression, and 10 patients were unknown. 8 patients combined of chemotherapy, 7 patients received cadonilimab monotherapy, 4 patients combined of chemotherapy and bevacizumab, 1 patient combined of bevacizumab, 1 patients combined of chemotherapy, bevacizumab and radiotherapy . 2 patients with newly diagnosed advanced disease and 2 patients with recurrent cervical cancer achieved complete response (CR), 11 patients with achieved partial response(PR) and 1 patients were in stable disease(SD). The objective response rate (ORR) was 71.4% (15 of 21 patients). The ORR of patients with the PD-L1-negative expression was 80% (4 of 5 patients).Grade 3–4 treatment-related adverse events occurred in 7 (33.3%) of 21 patients, the most frequent grade 3-4 adverse events were decreased white blood cell count (3 [14.3%]), decreased platelet count (2 [9.5%]) and anemia (2 [9.5%]). Immune-related AEs (irAEs) were all G1-2, and occurred in 2 (9.5%) patients. None of the patients discontinued treatment because of intolerable toxicity. Conclusions: In this study, cadonilimab containing therapies showed promising results in responses and survival outcomes among patients with metastatic or recurrent cervical cancer and have a favorable safety profile. [Table: see text]

A phase I study of highly potent oral ATR inhibitor (ATRi) tuvusertib plus oral PARP inhibitor (PARPi) niraparib in patients with solid tumors.

3018 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase and poly-ADP ribose polymerases (PARPs) are crucial components in the DNA damage response (DDR). Combining tuvusertib and niraparib may synergistically enhance synthetic lethality and increase apoptosis. Part B1 of the DDRiver Solid Tumors 301 study (NCT04170153) assessed this combination. Methods: Part B1 of this open-label multicenter dose-escalation phase Ib trial enrolled unselected patients with metastatic or locally advanced unresectable solid tumors refractory to standard treatment. The primary objective was to determine safety (including maximum tolerable dose and recommended dose(s) for expansion [RDE]). Secondary and tertiary objectives included determination of the pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of different dosing regimens of tuvusertib plus niraparib. Multiple continuous and intermittent schedules were explored with tuvusertib doses ranging from 90–180 mg once-daily (QD) and niraparib doses from 100–200 mg QD. A partial ordering continual reassessment method was used to identify the RDEs. Results: As of 02 January 2024, 43 patients had been enrolled (all with baseline body weight <77kg or platelet count <150,000/mm3); 13 patients remained on treatment. Ten (26.3%) patients had dose-limiting toxicities (DLTs). The most common DLT was grade 3 anemia requiring blood transfusion (n=4; 10.5%); the most frequent grade ≥3 treatment-emergent adverse events were anemia (n=18; 41.9%), platelet count decrease (n=6; 14.0%) and fatigue (n=4; 9.3%). The PK of tuvusertib when combined with niraparib was consistent with that of tuvusertib monotherapy, suggesting a lack of any clinically meaningful mutual drug–drug interactions. Dose-dependent ɣ-H2AX inhibition (proximal PD marker) was observed at tuvusertib doses ≥130 mg QD. Preliminary efficacy data show 5 (15.6%) responses (3 confirmed) by RECIST v1.1 in 32 evaluable patients: 2 in patients with epithelial ovarian cancer (EOC; 1 with BRCA1-mutant [ BRCA1m] PARPi-resistant EOC, 1 with BRCA-wild type homologous recombination deficiency-positive EOC) and 1 each in patients with non-small cell lung cancer, estrogen receptor-positive HER2-negative BRCA1m breast cancer, and BRCA1m PARPi-resistant pancreatic cancer. Tuvusertib 180 mg QD and niraparib 100 mg QD or tuvusertib 90 mg QD and niraparib 200 mg QD, both given in a 1 week on/1 week off schedule, were identified as RDEs. Conclusions: The combination of tuvusertib plus niraparib, each administered on a 1 week on/1 week off schedule, has a manageable safety profile and is suitable for further investigation. A combination study in patients with PARPi-resistant EOC is planned. Clinical trial information: NCT04170153 .

HOPE: Harnessing olaparib, palbociclib, and endocrine therapy for BRCA1/2-associated HR+, HER2- metastatic breast cancer.

10616 Background: Thepoly (ADP-ribose) polymerase inhibitor olaparib yields superior progression-free survival, response rates and patient-reported outcomes compared with chemotherapy in patients with BRCA1- or BRCA2- ( BRCA1/2) associated metastatic breast cancer (MBC). Fulvestrant and palbociclib improve outcomes in patients with hormone receptor-positive (HR+) MBC. HOPE (NCT03685331) is a phase I trial to evaluate combination olaparib (O), fulvestrant (F), and palbociclib (P) in patients with BRCA1/2-associated HR+, HER2 negative MBC. Methods: A 3+3 dose escalation was used to assess safety and preliminary efficacy of O, F and P. Eligible participants (pts) had HR+ MBC, a germline (g) or somatic (s) mutation in BRCA1/2, measurable/evaluable disease, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior PARPi and CDK4/6i were permitted but not in combination. Palbociclib was added after a 28-day safety run-in (Cycle 0) of O + F alone. Fulvestrant dose was 500mg IM on day 1 of each 28-day cycle. Dose level 0 (DL0, starting level) was F, O 300mg orally BID continuously, P 75mg orally daily on days 1-21; DL-1 was F, O 250mg orally BID, P 75mg orally daily on days 1-21. The primary endpoint was MTD (adverse events (AEs) based on CTCAE v5.0). Dose limiting toxicity (DLT) period included Cycles 0 and 1. A 30% DLT rate was acceptable; 6 pts had to be treated at a dose for it to be declared MTD. RECIST v1.1 was used to evaluate response. Results: Eight treated pts (s BRCA1:1 ;g BRCA2:6; s BRCA2:1 ) had median (M) age 47; M 0 (0-2) prior lines of endocrine therapy and 0 (0-1) prior chemotherapies for MBC. Three pts each had received O, F, and CDK4/6i as part of their standard of care treatment before study. At DL0, 2/2 pts had DLT with persistent grade(G) 3 neutropenia. Among 6 pts treated at DL-1, none experienced DLT, but 3 pts missed doses of study treatment due to cytopenias (G3 neutropenia, G3 leukopenia, G3 thrombocytopenia) during the DLT period. Following the DLT period, 1 pt reduced O to 200mg orally daily and 1 discontinued P based on provider discretion due to cytopenias (G3 neutropenia, G3 thrombocytopenia). Grade 3 AEs occurring in >1 pt related to study treatment were: neutrophil count decrease (G3/2, n=5/2); white blood cell decrease (G3/2/1, n=3/2/2); platelet count decrease (G3/2/1, n=2/0/1). Overall related AEs in >50% of pts were anemia (n=7), fatigue (n=6) and nausea (n=5). Best responses were CR/PR/SD/PD in 1/1/5/1 pts. Conclusions: MTDof O, F and P (DL-1) was reached and demonstrated antitumor activity. Although no AEs meeting protocol-specified DLT criteria were observed at MTD, hematologic toxicity at this dose complicated drug delivery and required close monitoring during and after the DLT period. Combinations utilizing PARP1 selective inhibitors, lower doses of therapy or sequential rather than combination therapy may improve feasibility. Clinical trial information: NCT03685331 .

Safety run-in phase of the multi-epitope HER2 peptide vaccine in combination with trastuzumab emtansine in HER2-positive breast cancer with residual disease after neoadjuvant chemotherapy.

550 Background: Residual disease after neoadjuvant chemotherapy (NAC) in HER2-positive breast cancer (BC) confers poor outcomes. Despite additional trastuzumab emtansine (T-DM1) in the adjuvant setting, a significant number of patients with residual disease still develop recurrence. H2NVAC is a multi-epitope T helper cell-activating peptide vaccine that is composed of 4 degenerate HER2-derived HLA-DR epitopes admixed with GM-CSF. Our previous phase I trial showed that this vaccine was safe and generated robust, long-lasting T and B cell immune responses. Methods: Patients with stage II-III HER2+ BC with any amount of residual disease in the breast /axilla after NAC were enrolled in a safety run-in phase of H2NVAC in combination with T-DM1. Patients were treated with H2NVAC and T-DM1 for 6 cycles, followed by 2 boosters at 3 and 12 months. Dose-limiting toxicity (DLT) was defined as any grade (G) ≥ 3 adverse events (AE) occurring within 21 days after the first vaccination. Results: A total of20 patients were enrolled with a median age of 51 years (range 27-69), 80% were White and 15% were Black. Most patients had hormone receptor-positive disease (90%). 40% were premenopausal, 40% were postmenopausal, and 20% were unknown. 14 patients had ypT1, 3 patients ypT2, 3 patients ypT3, 1 patient ypT4, 8 patients ypN0, 9 patients yp N1, 1 patient ypN1mi, and 2 patients ypN2. H2NVAC, in combination with T-DM1, was well tolerated, with no DLT being observed. Only grades 1 and 2 AEs were observed during the DLT period, with fatigue being the most common (G1 60%, G2 5%), followed by peripheral sensory neuropathy (G1 55%, G2 5%) and injection site reaction (G1 50%). Across all treatment cycles, the top 10 most common AEs that were at least possibly related to treatment include injection site reaction (G1 85%, G2 15%), AST increase (G1 65%), ALT increase (G1 45%), fatigue (G1 35%, G2 10%), peripheral sensory neuropathy (G1 35%, G-tube 10%), alk-phos increase (40% G1), nausea (G1 35%, G2 5%), arthralgia (G1 35%), myalgia (G1 25%, G2 5%), and platelet count decrease (G1 30%). There were four patients with G3 AEs at least possibly related to the vaccine observed after the DLT period, including allergic reaction, myositis/skin infection, urticaria, and pruritus/maculopapular rash. Conclusions: H2NVAC, in combination with T-DM1, was safe without DLT observed. The side effect profile was favorable, with the most common AE being the G1 injection site reaction. A multicenter, randomized, placebo-controlled, phase II trial of H2NVAC vs. placebo in combination with trastuzumab emtansine is currently ongoing through the ACCRU consortium. Clinical trial information: NCT04197687 .

Lenvatinib (len) plus pembrolizumab (pembro) in patients with advanced melanoma that progressed on anti–PD-(L)1 therapy: Over 4 years of follow-up from the phase 2 LEAP-004 study.

9559 Background: PD-1 inhibitors such as pembro are a standard-of-care option for advanced melanoma, and effective treatments are needed for disease that progresses on anti–PD-(L)1–based therapy. Previous results from the single-arm, open-label, phase 2 LEAP-004 study (NCT03776136) showed that len + pembro had antitumor activity in patients (pts) with advanced melanoma that progressed on prior anti–PD-(L)1–based therapy. With a median follow-up of 15.3 mo, the ORR was 21.4% and median DOR was 8.3 mo. Results from LEAP-004 led to the inclusion of len + pembro in treatment guidelines for pts with advanced melanoma and confirmed progression on a PD-(L)1 inhibitor. Here, we present results from LEAP-004 with over 4 years of follow-up. Methods: Eligible pts were aged ≥18 years, had unresectable stage III or IV melanoma, had ≥1 measurable lesion, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had confirmed disease progression within 12 weeks of the last dose of anti–PD-(L)1 therapy given alone or in combination for ≥2 doses. All pts received len 20 mg PO QD + ≤35 doses of pembro 200 mg IV Q3W. The primary end point was ORR per RECIST v1.1 by BICR. Secondary end points included DOR and PFS per RECIST v1.1 by BICR, OS, and safety. Results: 103 pts were enrolled and received treatment. Median time from first dose to data cutoff (Oct 11, 2023) was 52.0 months (range, 48.8-55.7). ORR in the overall population was 24.3% (95% CI, 16.4-33.7), with 5 pts (4.9%) having a complete response and 20 (19.4%) a partial response. In key subgroups, ORR was 33.3% (10/30; 95% CI, 17.3-52.8) in pts with progression on prior anti–PD-1 + anti–CTLA-4 therapy and 10.7% (3/28; 95% CI, 2.3-28.2) in pts with BRAF-mutant tumors who received prior BRAF/MEK-directed therapy for metastatic disease. Median DOR in the overall population was 8.5 mo (range, 3.2-40.8) and an estimated 35% of responders remained in response at ≥12 mo. Median PFS was 4.2 mo (95% CI, 3.5-6.3); 24-mo PFS rate was 10.1%. Median OS was 14.0 mo (95% CI, 10.8-18.3); 24-mo OS rate was 29.7%. Efficacy outcomes in pts with mucosal (n = 11) and acral lentiginous (n = 8) melanoma were consistent with the overall population. Any-grade treatment-related AEs occurred in 99 pts (96.1%). Grade 3-5 treatment-related AEs occurred in 51 pts (49.5%). No new treatment-related deaths occurred since prior analysis (1 pt had died because of treatment-related decreased platelet count). Conclusions: With over 4 years of follow up, len + pembrocontinued to show antitumor activity in pts with advanced melanoma and confirmed progression after ≥2 doses of anti–PD-(L)1-based therapy. Safety remained consistent with previous reports, with no new or unexpected safety signals. These results support len + pembro as a potential treatment option for advanced melanoma after anti–PD-(L)1-based therapy. Clinical trial information: NCT03776136 .

Iadademstat in combination with azacitidine in patients with newly diagnosed acute myeloid leukaemia (ALICE): an open-label, phase 2a dose-finding study

Iadademstat is a potent, selective, oral inhibitor of both the enzymatic and scaffolding activities of the transcriptional repressor lysine-specific demethylase 1 (LSD1; also known as KDM1A) that showed promising early activity and safety in a phase 1 trial and strong preclinical synergy with azacitidine in acute myeloid leukaemia cell lines. Therefore, we aimed to investigate the combination of iadademstat and azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukaemia. The open-label, phase 2a, dose-finding ALICE study was conducted at six hospitals in Spain and enrolled patients aged 18 years or older with newly diagnosed acute myeloid leukaemia not eligible for intensive chemotherapy and an ECOG performance status of 0-2. In the dose escalation portion of the trial, patients received a starting dose of iadademstat at 90 μg/m2 per day (with de-escalation to 60 μg/m2 per day and escalation up to 140 μg/m2 per day) orally, for 5 days on, 2 days off weekly, with azacitidine 75 mg/m2 subcutaneously, for seven of 28 days. The primary objectives were safety (analysed in the safety analysis set; all patients who received at least one dose of study treatment) and establishing the recommended phase 2 dose; secondary objectives included response rates in the efficacy analysis set (all patients who had at least one efficacy assessment). This study is registered on EudraCT (EudraCT 2018-000482-36) and has been completed. Between Nov 12, 2018, and Sept 30, 2021, 36 patients with newly diagnosed acute myeloid leukaemia were enrolled; the median age was 76 (IQR 74-79) years, all patients were White, 18 (50%) were male, and 18 (50%) were female, and all had intermediate-risk or adverse-risk acute myeloid leukaemia. The median follow-up was 22 (IQR 16-31) months. The most frequent (≥10%) adverse events considered to be related to treatment were decreases in platelet (25 [69%]) and neutrophil (22 [61%]) counts (all grade 3-4) and anaemia (15 [42%]; of which ten [28%] were grade 3-4). Three patients had treatment-related serious adverse events (one fatal grade 5 intracranial haemorrhage, one grade 3 differentiation syndrome, and one grade 3 febrile neutropenia). Based on safety, pharmacokinetic and pharmacodynamic data, and efficacy, the recommended phase 2 dose of iadademstat was 90 μg/m2 per day with azacitidine. 22 (82%; 95% CI 62-94) of 27 patients in the efficacy analysis set had an objective response. 14 (52%) of 27 patients had complete remission or complete remission with incomplete haematological recovery; of these, ten of 11 evaluable for measurable residual disease achieved negativity. In the safety analysis set, 22 (61%) of 36 patients had an objective response. The combination of iadademstat and azacitidine has a manageable safety profile and shows promising responses in patients with newly diagnosed acute myeloid leukaemia, including those with high-risk prognostic factors. Oryzon Genomics and Spain's Ministerio de Ciencia, Innovacion y Universidades (MICIU)-Agencia Estatal de Investigacion (AEI).

Exploring Acute Kidney Injury Following Aortic Dissection: A Comprehensive Review of Machine Learning Models for Predicting Risk, Management Strategies, Complications, and Racial and Gender Disparities.

Both types of aortic dissection (AD), Stanford type A and type B, can result in complications such as acute kidney injury (AKI) and aortic rupture. Renal complications in AD arise from compromised renal perfusion affecting the renal arteries. Understanding the intricate connection between AD and AKI is crucial for navigating the complexities of tailored treatment and formulating specific management plans. Concerning machine learning models, in patients with type A aortic dissection, factors such as decreased platelet count on admission, increased D-dimer level, longer cardiopulmonary bypass duration, elevated white blood cell levels, the need for blood transfusion, longer aortic clamp time, extended surgery duration, advanced age, and an elevated body mass index were positively associated with the development of AKI. For the risk of AKI after type B aortic dissection, elevated Nt-pro brain natriuretic peptide, prolonged activated partial thromboplastin time, elevated admission systolic blood pressure, and a higher contrast agent requirement during operative repair were found to predict the risk. Male gender was associated with a higher risk of AKI, and nonwhite race was linked to a higher risk of AKI, a greater likelihood of requiring more urgent procedures, and lower levels of insurance coverage. The treatment of AKI following AD requires a multifaceted approach. Identifying and addressing the underlying cause, such as low blood pressure, renal artery involvement, or medication-induced injury, is crucial for effective management and preventing further kidney damage. Maintaining proper fluid balance is essential for improving renal perfusion, but careful monitoring is necessary to avoid complications. The evolving landscape of research, particularly in biomarkers and AI programs, reveals a promising role in predicting the risk for and managing AKI post-AD.

#2275 Beyond glucose control: SGLT2 inhibitors' impact on hematological parameters in lupus nephritis patients

Abstract Background and Aims There is a broad spectrum of hematologic manifestations in SLE including lymphopenia, anemia, thrombocytopenia, or pancytopenia. Anemia worsens the prognosis of many chronic diseases including lupus nephritis. A recent systematic review and metanalysis showed that hemoglobin and hematocrit levels were significantly increased with SGLT2i therapy when compared to placebo. This study aimed to investigate the effect of SGLT2 inhibitors on hematological parameters including iron profile, hepcidin and erythropoietin levels in lupus nephritis patients. Method Double blind randomized controlled trial. The material of the current study included 79 Lupus nephritis patients who were recruited from Nephrology clinic- Urology and Nephrology Center- Mansoura University. Patients with an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m2 had been randomly assigned to 2 groups Study group: included 38 lupus nephritis patients who were randomly assigned to receive dapagliflozin (10 mg once daily) Placebo group: included 41 lupus nephritis who were assigned to receive placebo. The two groups were randomly assigned using computer-generated random tables in a 1:1 ratio and followed up for 12 months. The findings were recorded, tabulated, and analyzed using SPSS22 for windows. Results Both groups had similar ages and gender distribution. BMI, diabetes mellitus, and hypertension rates were comparable between groups. The duration of lupus nephritis and management approaches did not differ. Biopsy results indicated no differences in the class of lupus nephritis. Serum chemistry, including serum creatinine, was similar between groups. The mean hemoglobin levels, MCV and MCH are similar between the control and study groups, with no statistically significant difference (p = 0.5, 0.9 and 0.9 respectively). Regarding iron indices, the median ferritin, TSAT levels show a numerical difference, but it does not reach statistical significance (p = 0.09, 0.05), The mean erythropoietin and hepcidin levels are not significantly different between the groups (p value= 0.1 and 0.9 respectively) also, platelet counts are similar between the groups (p = 0.7). compares hematological investigations before and after the intervention in the study group. There is a statistically significant increase in mean hemoglobin levels post-intervention compared to baseline (p = 0.02) and the mean MCH levels show a numerical increase post-intervention, but the difference is not statistically significant (p = 0.1), but the mean MCV levels do not show a statistically significant change post-intervention (p = 0.7). The median ferritin levels and TSAT values show a numerical increase post-intervention, but the difference is not statistically significant (p = 0.8 and 0.9 respectively). There is a statistically significant decrease in mean hepcidin levels post-intervention (116 ± 15 from baseline 181 ± 76) and (p = 0.001). erythropoietin levels show a numerical increase post-intervention, but the difference is not statistically significant (p = 0.1). there is a slight decrease in platelets counts after intervention but make statistically significant (p = 0.01), but The hematological data after 12 months suggest overall similarity between the control and study groups in terms of hemoglobin, MCV, MCH, ferritin, TSAT, and platelet count, also hepcidin and erythropoietin levels were comparable between both groups (P = 0.7). percentage of participant with anemia (Hgb< 12 g/dl) decreased in study group after intervention from 61% to 42% but with no significant difference with control group (p = 0.3) Conclusion Anemia in lupus nephritis patients is primarily due to iron deficiency, associated with elevated hepcidin levels. Further research is needed to explore these patients' underlying causes of anemia. SGLT2 inhibitors are important add on drugs that has positive effect on varies hematological parameters in lupus nephritis patients in addition to their renal benefits.

Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial.

Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg-1 every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6-62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79-19.12), 8.18 months (95% CI = 6.67-10.48) and 17.48 months (95% CI = 12.35-26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67-not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63-31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027.

Feasibility of hemoperfusion using extracorporeal therapy in the horse.

Develop, implement, and monitor for adverse effects of, a novel hemoperfusion therapy in adult horses. A prospective, observational feasibility study using three healthy adult horses from the North Carolina State University teaching herd. Health status was determined by physical exam, complete blood count, coagulation panel, and serum biochemistry. Each horse was instrumented with a 14 Fr × 25 cm double-lumen temporary hemodialysis catheter and underwent a 240 min polymer-based hemoperfusion session. Horses were administered unfractionated heparin to maintain anti-coagulation during the session. Given the novelty of this therapy in horses, each horse was treated as a learning opportunity that informed an iterative process of protocol development and modification. Our long-term goal is to investigate potential clinical applications of hemoperfusion in horses, including cytokine reduction in horses with severe SIRS/sepsis. Horses were monitored for changes in clinical exam, biochemistry and hematology parameters. Additionally, cytokines were quantified to determine whether extracorporeal hemadsorption therapy alone caused an inflammatory response. Our results show that hemoperfusion therapy was associated with decreased platelet counts and serum albumin concentration. There was no significant change in plasma cytokine concentrations with hemoperfusion therapy. In one horse, the cytokine concentrations decreased, as previously reported with hemoperfusion therapy in humans. We hypothesized that hemoperfusion therapy could be performed in healthy adult horses without significant adverse effects. Polymer-based hemoperfusion is a feasible extracorporeal therapy (ECT) modality for adult horses. Additional studies are needed to further establish clinical protocols, as well as establish efficacy of polymer-based hemoperfusion for treatment of various conditions in horses, including intoxications, immune-mediated conditions, and sepsis.

ACUTE RHABDOMYOLYSIS IN A JUVENILE WITH DENGUE FEVER: A RARE MANIFESTATION BUT BEWARE

Myalgia is a common symptom in patients with Dengue fever. However, acute rhabdomyolysis is a rare manifestation. The precise mechanism of Dengue-associated rhabdomyolysis has not been determined, it is thought likely to be caused by myotoxic cytokines released in response to viral infection, such as TNF and IFN-α. Here we report a case of a 13-year-old boy with Dengue fever, presenting with red urine on day 5 of illness. Together with a decreased platelet count (26 G/L), we initially suspected hematuria but the urinalysis showed no red blood cells. We then thought of rhabdomyolysis causing myoglobinuria, so we ordered diagnostic tests with the following results: CK 1353 U/L, GOT 361 U/L, GPT 90 U/L. The patient was given intravenous fluids and oral oresol to control urine output. Urine color faded and blood CK concentration returned to normal after 13 days. Rhabdomyolysis is rare in dengue fever but requires proper diagnosis and management to prevent acute kidney injury - a life-threatening complication.

Acute liver failure resulting from coinfection with dengue and hepatitis A virus: A case report

Acute liver failure (ALF) is an infrequent and varied condition characterized by severe impairment of liver function that occurs in individuals without any preexisting liver disease. This particular case study presents a distinctive occurrence of ALF resulting from a simultaneous infection of both hepatitis A virus (HAV) and dengue virus, accompanied by dengue hemorrhagic fever. The patient, a 26-year-old male, exhibited symptoms such as fever, nausea, vomiting, abdominal pain, and generalized body aches. Subsequently, the patient developed jaundice, hepatic encephalopathy, acute cholecystitis, and acute pancreatitis. Laboratory tests confirmed the presence of markers for both dengue and HAV, along with decreased platelet count and hemoglobin levels. However, with a treatment plan focused on conservative management, the patient’s condition gradually improved, leading to eventual discharge. This case underscores the potential for coinfection with dengue and HAV to precipitate ALF and emphasizes the significance of early diagnosis and timely intervention to achieve the best possible outcomes for the patient.

Safety of marketed biosimilar monoclonal antibody cancer treatments in the US: a disproportionality analysis using the food and drug administration adverse event reporting system (FAERS) database

ABSTRACT Background By 31 December 2022, the United States Food and Drug Administration (FDA) has approved 12 biosimilar monoclonal antibody cancer treatments. This study detected disproportionate adverse event (AE) reporting signals and compared safety profile of individual biosimilars to their originator biologics and between each pair of biosimilars. Research design and methods The FDA Adverse Event Reporting System data (6/1/2018–12/31/2022) were used to identify AE reports for rituximab, bevacizumab, trastuzumab, and their marketed biosimilars. Reporting odds ratios and empirical Bayesian geometric mean were computed to detect reporting disproportionality in serious, death, and specific AEs between studied biologics/biosimilars and all other drugs. Results Significant AE reporting signals were identified: 1) death for biological rituximab, pruritus for biosimilar rituximab-pvvr, and infusion-related reactions for biological rituximab and biosimilar rituximab-pvvr (significantly higher ROR for rituximab-pvvr than biological rituximab, p < .0001); 2) death for biological bevacizumab and biosimilar bevacizumab-bvzr (significantly higher ROR for bevacizumab-bvzr than biological bevacizumab, p < .0001), hypertension, platelet count decreased (PCD), and proteinuria for biological bevacizumab and biosimilar bevacizumab-awwb (significantly higher ROR of PCD for bevacizumab-awwb than originator bevacizumab, p = .001); and 3) rash for biosimilar trastuzumab-anns. Conclusions Findings call for large, longitudinal studies to examine causality of certain AEs with rituximab-pvvr and bevacizumab biosimilars.

Frequency of Hepatitis C in patients presented with isolated thrombocytopenia.

Objective: HCV-related thrombocytopenia poses challenges in infection and treatment. This study emphasizes screening for early thrombocytopenia as it signals hematological abnormalities, indicating bleeding tendencies and complications. Study Design: Cross-sectional Investigation. Setting: Pathology Department of Allama Iqbal Medical College and Jinnah Hospital. Period: November 2019 to November 2020. Methods: Included 180 participants with platelet counts &lt;100,000/µl, normal hemoglobin, and WBC counts. Exclusions: anemia, leucopenia, prior Hepatitis C treatment, and platelet clumps. Data on age, gender, socioeconomic status, and family history were collected. Platelet counts and HCV detection utilized peripheral smears and venous blood samples, analyzed with SPSS version 25.0. Results: In a study of 180 thrombocytopenic patients of all ages were included with mean age 32. Among 34 HCV-positive cases, 102 had a family history, with age-wise distribution: 18, 14, 2. Gender: 20 males, 14 females. HCV-positive households: 21 positive, 13 negative. Significant p-values for age groups (p=0.000), non-significant for gender (p=0.281), socioeconomic status (p=0.083), and household HCV status (p=0.505). Conclusion: A significant association exists between decreased platelet count and Hepatitis C virus, providing valuable insights for screening in clinical settings.

Abstract PS15-03: Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, plus palbociclib in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: phase 1b cohort

Abstract Background: Vepdegestrant (ARV-471) is an oral PROTAC ER degrader. In a phase 1/2 study (NCT04072952), vepdegestrant monotherapy had a favorable safety profile and encouraging clinical activity, and showed robust ER degradation. The phase 1b cohort of this study is evaluating vepdegestrant in combination with the cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (palbo). In xenograft models, vepdegestrant plus palbo showed substantially greater tumor growth inhibition vs fulvestrant plus palbo, supporting investigation in patients with breast cancer. Methods: Eligible patients for the phase 1b combination cohort had ER+/HER2- locally advanced/metastatic breast cancer and had received ≥1 prior endocrine therapy and ≤2 chemotherapy regimens for advanced disease; prior CDK4/6 inhibitor treatment was permitted. Vepdegestrant was given orally once daily (QD) continuously at doses of 180 mg (n=2), 200 mg (n=21), 400 mg (n=3), or 500 mg (n=20); palbo 125 mg was given orally QD for 21 days followed by 7 days off treatment in 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) in the first cycle and safety (adverse events [AEs] and laboratory abnormalities). Enrollment in these 4 dose levels is complete; we report data as of June 6, 2023. Results: Across 46 patients in the phase 1b cohort, 45 (97.8%) patients were female with a median age of 62.0 y (range: 29–78). Patients had received a median of 4 prior therapies (range: 1–11) in any setting, including 87.0% prior CDK4/6 inhibitors (78.3% prior palbo), 80.4% prior fulvestrant, and 76.1% prior chemotherapy (45.7% in the metastatic setting). There were no DLTs. Treatment-emergent AEs (TEAEs) leading to dose reductions or discontinuation of vepdegestrant occurred in 5 and 4 patients, respectively. TEAEs leading to dose reductions or discontinuation of palbo occurred in 34 and 8 patients, respectively. Grade 3/4 treatment-related AEs (TRAEs) to either vepdegestrant or palbo in ≥10% of patients were neutropenia (89.1%), decreased white blood cell count (15.2%), and decreased platelet count (10.9%); there were no grade 5 TRAEs and no patients had febrile neutropenia. The clinical benefit rate (rate of confirmed complete response, partial response, or stable disease ≥24 wks) in patients treated with vepdegestrant plus palbo was 63.0% (95% CI: 47.5–76.8). The objective response rate in evaluable patients with measurable disease at baseline (n=31) was 41.9% (95% CI: 24.5–60.9). Pharmacokinetics (PK) showed dose-dependent exposure for vepdegestrant, consistent with data for vepdegestrant administered as monotherapy; palbo exposure was similar across dose levels of vepdegestrant and modestly higher compared with historical palbo PK data. Circulating tumor DNA levels were evaluated in patients who received vepdegestrant 200 mg QD plus palbo and demonstrated substantial and sustained decreases in ESR1 mutant allele fraction across multiple treatment cycles. Conclusions: The combination of vepdegestrant plus palbo showed promising clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer who had received extensive prior treatment. The safety profile of vepdegestrant plus palbo was generally consistent with the known safety profiles of the 2 agents except for an increased occurrence of grade 3/4 neutropenia, which was readily managed with laboratory monitoring and dose reductions of palbo. There is an ongoing study lead-in to the global VERITAC-3 study (NCT05909397) that is evaluating 2 doses of palbo (100 mg and 75 mg) in combination with vepdegestrant 200 mg QD to determine the recommended phase 3 combination to compare with letrozole plus palbo as first-line treatment for ER+/HER2- advanced breast cancer. Citation Format: Erika Hamilton, Rinath Jeselsohn, Sara Hurvitz, Dejan Juric, Hyo Han, Melinda Telli, George Zahrah, Rita Nanda, Yuanyuan Zhang, Weiwei Tan, Elizabeth Duperret, Eric Zhi, Cecile Mather, Anne Schott. Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, plus palbociclib in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: phase 1b cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS15-03.

PENGARUH LAMA PENYIMPANAN DARAH TERHADAP JUMLAH TROMBOSIT PADA WHOLE BLOOD SEBELUM DAN SESUDAH DISIMPAN SELAMA 3 HARI DI UNITDONOR DARAH PMI KOTA MEDAN

Blood transfusion is a series of blood transfer process from a donor to a recipient. Blood is stored in the refrigerator with temperature 2-8 °c. In the blood storage process will experience changes in blood components such as platelet count. The researcher aims to determine the effect of long blood storage on platelet count on whole blood before and after being stored for three days at PMI Medan Blood Donor Unit. This research was done by descriptive method of Hematology Analyzer presented in table form. This research took place from 21-23 May 2018 at the Laboratory of Blood Transfusion Unit of Indonesian Red Cross Medan. Thenumber of samples used for the research is 10 samples. The result is the effect of storage duration on the decrease of platelet count where there is a decrease of platelet count in all donor blood samples stored for three days at PMI Medan Blood Donor Unit.Based on existing conclusions, then the suggestion that can be taken is every blood donor unit always do repeat examination for blood component level which will be transfused. For patients who will melaksanakna transfuse, you should use fresh blood. Blood should not be taken out frequently and blood refrigerator do not often open the lid. It is recommended for the same researchers in the future to increase the number of samples so that the results can be more accurate

HUBUNGAN NILAI HEMATOKRIT DAN JUMLAH TROMBOSIT TERHADAP DERAJAT III DAN IV PASIEN DEMAM BERDARAH DENGUE DI RSUD DR. PIRNGADI KOTA MEDAN TAHUN 2022

Dengue Hemorrhagic Fever (DHF) is a disease condition caused by a dengue virus infection. DENV-1, DENV-2, DENV-3, and DENV-4 are serotypes of the virus and are usually transmitted through the bite of mosquitoes from the stegomyia family, such as Aedes aegypti and Aedes albopictus. DHF often results in extraordinary events (KLB) and can lead to death. The disease can be categorized into four different clinical stages: stages I, II, III, and IV. Laboratory examination in DHF usually shows a decrease in platelet count below 100,000/µl and the presence of leaky plasma, which can be seen from the hematocrit that has increased by more than 20%. Objective to determine whether there is a relationship between hematocrit value and platelet count at degrees III and IV in DHF incidence. This type of research uses an observational analytic study with a cross-sectional approach. In the analysis, there is a significant relationship between hematocrit value and clinical degrees III and IV with a value of p = 0.043, and there is a relationship between platelet counts and clinical degrees III and IV with a value of p = 0.000. There is a relationship between hematocrit value and platelet count in clinical degrees III and IV of DHF.

The Value of Warning Signs From the WHO 2009 Dengue Classification in Detecting Severe Dengue in Children.

World Health Organization proposed 7 warning signs to identify the risk of severe dengue in 2009. This study aimed to evaluate the value of these warning signs in detecting severe dengue in children. A cross-sectional study was conducted utilizing data of children with clinical dengue infection obtained from medical records between January 2009 and December 2018 in Jakarta. Children with confirmed dengue were analyzed and stratified into 3 age groups: infants less than 1 year old, children 1-14 years and adolescents 15-18 years of age. Positive predictive value, negative predictive value (NPV), sensitivity and specificity of each warning sign present or absent on admission in detecting severe dengue were computed. Six hundred ninety-nine children with clinical dengue infection were enrolled, among whom 614 (87.8%) had confirmed dengue infection, either by antigen or antibody serological tests. Severe dengue occurred in 211/614 (34.4%) cases. In infants, important warning signs on admission to detect or exclude severe dengue were liver enlargement (NPV 80.8%) and clinical fluid accumulation (NPV 75%). In children and adolescents, warning sign with highest NPV (in children 76.6% and in adolescents 91.9%) was increase in hematocrit concurrent with a rapid decrease in platelet count. Other warning signs with high NPV values in children were abdominal pain (72%), vomiting (70%), clinical fluid accumulation (69.3%), and in adolescents' abdominal pain (80.7%), vomiting (75.7%), clinical fluid accumulation (82.7%). NPVs increase with more than 1 warning sign in all age groups. In infants, liver enlargement or clinical fluid accumulation are important warning signs for severe dengue, when both are absent, severe dengue is unlikely. In older children and adolescents, an increase in hematocrit with the concurrent rapid decrease in platelet count is most discriminative; followed by the absence of abdominal pain, vomiting or fluid accumulation are unlikely severe dengue.

Anti-PD-1 antibody in combination with radiotherapy as first-line therapy for unresectable intrahepatic cholangiocarcinoma

BackgroundUnresectable intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis despite treatment with standard combination chemotherapy. We aimed to evaluate the efficacy and safety of radiotherapy in combination with an anti-PD-1 antibody in unresectable iCCA without distant metastases.MethodsIn this phase II study, patients with histopathologically confirmed unresectable primary or postoperative recurrent iCCA without distant metastases were enrolled. Patients received external radiotherapy with a dose of ≥45 Gy (2-2.5 Gy per fraction), followed by anti-PD-1 immunotherapy (camrelizumab 200 mg once, every 3 weeks) initiated within 7 days after completion of radiotherapy as first-line therapy. The primary endpoint was 1-year progression-free survival (PFS) rate. The secondary end points included safety, objective response rate (ORR), disease control rate (DCR), and overall survival (OS).ResultsFrom December 2019 to March 2021, 36 patients completed radiotherapy and at least one cycle of immunotherapy and were included in efficacy and safety analyses. The median follow-up was 19.0 months (IQR 12.0-24.0), and the one-year PFS rate was 44.4% (95% CI, 30.8-64.0). The median PFS was 12.0 months (95% CI, 7.5-not estimable); the median OS was 22.0 months (95% CI, 15.0-not estimable). The ORR was 61.1% and the DCR was 86.1%. Seventeen of 36 (47.2%) patients experienced treatment-related adverse effects (AEs) of any grade. The most common AE was reactive cutaneous capillary endothelial proliferation (25.0%). Five (13.9%) patients experienced grade ≥3 treatment-related AEs, including decreased lymphocyte (5.6%), bullous dermatitis (2.8%), decreased platelet count (2.8%), and deep-vein thrombosis (2.8%).ConclusionsExternal radiotherapy plus camrelizumab, as first-line therapy, met its primary endpoint and showed antitumor activity and low toxicity levels in patients with unresectable iCCA without distant metastases, warranting further investigation.Trial registrationNCT03898895. Registered 2 April 2019.