Elevated Alkaline Phosphatase Research Articles

The Efficacy and Safety of Anlotinib Plus Etoposide with Cisplatin/Carboplatin in the First-Line Treatment of Lung Cancer: A Phase II Clinical Study.

Background: The primary aim of this phase II clinical study was to assess the safety and efficacy of combining anlotinib, etoposide, and platinum-based drugs as a first-line treatment for ES-SCLC. Methods: Patients underwent the standard chemotherapeutic regimen, consisting of four courses of etoposide plus cisplatin/carboplatin. Additionally, each patient received a 2-week intervention with anlotinib (12 mg/day, once daily). Anlotinib was continued until disease progression, occurrence of unbearable adverse events (AEs), or withdrawal from the research. Progression-free survival (PFS) served as the primary prognostic measure. Secondary measures included the disease control rate (DCR), objective response rate (ORR), overall survival time (OS), and the incidence of AEs. Results: The DCR and ORR were 97.6% and 91.0%, respectively. Estimated PFS and OS were 5.0 months (95% CI: 1.0-10.8 months) and 13.0 months (95% CI: 8.4-18.6 months), respectively. No unexpected adverse effects were reported during the trial. The most common adverse reactions included anemia (42.22%), hypertension (53.33%), alopecia (40.00%), elevated transaminase (24.40%), and elevated alkaline phosphatase (24.44%). Sixteen cases (35.56%) were classified as AEs of grades 3-5. No deaths attributed to treatment-related causes occurred in any patient during the trial. Conclusion: Combination chemotherapy is currently the first-line therapy for extensive small-cell lung cancer (ES-SCLC). Combining anlotinib with conventional platinum-based chemotherapy demonstrated promising therapeutic outcomes and prognosis in the management of ES-SCLC.

Eco-friendly synthesis and assessment of chrysin – primed zinc ferrite nanoparticles against vinyl chloride and 2-acetylaminofluorene model of hepatorenal injury in rats

Co-exposure to environmental toxicants is becoming an emerging problem globally. This study investigated the potential of chrysin-primed zinc-ferrite nanoparticles (ZnFe2O4@Chrysin) to counteract oxidative stress and inflammation in vinyl chloride (VC) and 2-acetylaminofluorene (2-AAF) induced liver and kidney toxicities in male Wistar rats. ZnFe2O4@Chrysin was identified using x-ray diffraction, thermogravimetric analysis, Fourier Transform Infrared spectroscopy, scanning and transmission electron micrographs. Molecular orbital distributions in chrysin were determined using Density Functional Theorem analyses. Forty –two rats were placed in six groups of seven animals each, and orally administered with ZnFe2O4@Chrysin (10, 20, 50 mg/kg), VC (50 mg/kg) and 2-AAF (30 mg/kg) over a period of 28 days. Liver and kidney function, lipid profile, oxidative stress, inflammation, endocrine and cancer parameters were evaluated. Treatment with ZnFe2O4@Chrysin ameliorated the VC + 2-AAF induced elevations in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, triglyceride, urea, uric acid, and sodium and potassium levels. VC + 2-AAF also caused significant elevations in superoxide dismutase, malondialdehyde, nitric oxide, myeloperoxidase levels which were restored by ZnFe2O4@Chrysin. Elevated levels of alpha fetoprotein, C-reactive protein (CRP) and thyroid stimulating hormone in VC + 2-AAF treated rats were significantly reversed by ZnFe2O4@Chrysin. ZnFe2O4@Chrysin also restored the histoarchitecture of the kidney and liver of rats exposed to VC + 2-AAF. This study suggests that ZnFe2O4@Chrysin offered protection against VC and 2-AAF induced alterations in biochemical indices of rats via anti-inflammatory and antioxidant mechanisms.

Enhancing precision: A predictive model for 177Lu-DOTATATE treatment response in neuroendocrine tumors using quantitative 68Ga-DOTATATE PET and clinicopathological biomarkers.

Purpose: This study aims to elucidate the role of quantitative SSTR-PET metrics and clinicopathological biomarkers in the progression-free survival (PFS) and overall survival (OS) of neuroendocrine tumors (NETs) treated with peptide receptor radionuclide therapy (PRRT). Methods: A retrospective analysis including 91 NET patients (M47/F44; age 66 years, range 34-90 years) who completed four cycles of standard 177Lu-DOTATATE was conducted. SSTR-avid tumors were segmented from pretherapy SSTR-PET images using a semiautomatic workflow with the tumors labeled based on the anatomical regions. Multiple image-based features including total and organ-specific tumor volume and SSTR density along with clinicopathological biomarkers including Ki-67, chromogranin A (CgA) and alkaline phosphatase (ALP) were analyzed with respect to the PRRT response. Results: The median OS was 39.4 months (95% CI: 33.1-NA months), while the median PFS was 23.9 months (95% CI: 19.3-32.4 months). Total SSTR-avid tumor volume (HR = 3.6; P = 0.07) and bone tumor volume (HR = 1.5; P = 0.003) were associated with shorter OS. Also, total tumor volume (HR = 4.3; P = 0.01), liver tumor volume (HR = 1.8; P = 0.05) and bone tumor volume (HR = 1.4; P = 0.01) were associated with shorter PFS. Furthermore, the presence of large lesion volume with low SSTR uptake was correlated with worse OS (HR = 1.4; P = 0.03) and PFS (HR = 1.5; P = 0.003). Among the biomarkers, elevated baseline CgA and ALP showed a negative association with both OS (CgA: HR = 4.9; P = 0.003, ALP: HR = 52.6; P = 0.004) and PFS (CgA: HR = 4.2; P = 0.002, ALP: HR = 9.4; P = 0.06). Similarly, number of prior systemic treatments was associated with shorter OS (HR = 1.4; P = 0.003) and PFS (HR = 1.2; P = 0.05). Additionally, tumors originating from the midgut primary site demonstrated longer PFS, compared to the pancreas (HR = 1.6; P = 0.16), and those categorized as unknown primary (HR = 3.0; P = 0.002). Conclusion: Image-based features such as SSTR-avid tumor volume, bone tumor involvement, and the presence of large tumors with low SSTR expression demonstrated significant predictive value for PFS, suggesting potential clinical utility in NETs management. Moreover, elevated CgA and ALP, along with an increased number of prior systemic treatments, emerged as significant factors associated with worse PRRT outcomes.

Xanthogranulomatous Cholecystitis. Case Report and Review of Literature.

Xanthogranulomatous cholecystitis (XGC) is a rare but benign form of chronic cholecystitis representing a small proportion of gallbladder disorders and may mimic carcinoma. The present case is of a 59-year-old male that endorsed a six-month history of vague complaints of diarrhea, anorexia, dark urine, yellowing of his eyes, and recent weight loss without prior work up for his symptoms. Laboratory values showed elevated alkaline phosphatase, gamma-glutamyl transferase (GGT), Cancer antigen 19-9, Chromogranin A, and Lactate Dehydrogenase (LDH). Computer tomography (CT) scan revealed annular-like wall thickening in the body of the gallbladder, wall calcifications in the region of the fundus, and cholelithiasis. Magnetic resonance cholangiopancreatography (MRCP) showed focal narrowing at the mid-gallbladder with restricted diffusion and ill-defined enhancement in this region and a few prominent right upper quadrant lymph nodes. Diagnostic laparoscopy revealed a liver lesion that was resected, and frozen analysis was negative for malignancy. The laparoscopic cholecystectomy was converted to an open procedure due to significant scar tissue in the cystic triangle. The final pathology report revealed xanthogranulomatous cholecystitis (XGC) with no evidence of malignancy identified in the gallbladder or liver parenchyma.

Evaluation of the role of some non-enzymatic antioxidants among Iraqi patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic fat accumulation in individuals consuming little or no alcohol, has become highly prevalent globally. Oxidative stress plays a central role in instigating inflammation and cell death pathways driving NAFLD progression. This case-control study aimed to elucidate the association between circulating levels of the pivotal non-enzymatic antioxidants - coenzyme Q10 and vitamins E and C - and liver injury parameters among 60 Iraqi NAFLD patients versus 30 healthy controls. NAFLD diagnosis entailed over 5% hepatic steatosis on ultrasound excluding other etiologies. Patients spanned three age groups: 20-29, 30-39, and 40-49. Substantially diminished antioxidant levels concurrent with elevated alkaline phosphatase enzyme were unveiled in NAFLD patients relative to controls (all p < 0.001). Age-based analysis reinforced widespread antioxidant depletion and liver enzyme augmentation across NAFLD patients. Significant correlations also emerged between antioxidants and liver parameters. Our novel observations confirm an antioxidant inadequacy likely perpetuating pathogenic oxidative reactions in NAFLD. Restoring such deficits through lifestyle or therapeutic interventions may confer preventative and disease-modifying value.

Improvement of tissue fibrosis in TAFRO syndrome by prednisolone monotherapy

We report the case of a 48-year-old man who presented with fatigue and weight loss. A local physician observed elevated alkaline phosphatase levels, anemia, thrombocytopenia, and renal dysfunction. Fever also appeared, and the patient was admitted to our hospital. Computed tomography revealed hepatosplenomegaly, pleural and ascitic fluid, and left axillary lymphadenopathy. Bone marrow biopsy indicated hyperplasia with increased megakaryocytes and reticulin fibrosis. Axillary lymph node biopsy showed Castleman's disease-like features. Liver biopsy revealed proliferation of reticulin fibrosis. Therefore, TAFRO syndrome was diagnosed and treatment with 1 mg/kg prednisolone was started. Anemia and thrombocytopenia improved, and after 24 weeks of treatment, serum hyaluronic acid and type IV collagen decreased to the normal range. Bone marrow biopsy after 18 weeks of treatment showed decreased reticular fibers. In TAFRO syndrome, improvement of liver and bone marrow fibrosis can be expected with adequate intervention, and serum hyaluronic acid and type IV collagen are useful for evaluating fibrosis.

Clinical significance of preoperative albumin and alkaline phosphatase in colorectal cancer: a systematic review and meta-analysis.

To investigate the association between preoperative serum levels of albumin (ALB) and alkaline phosphatase (ALP) with postoperative outcome in colorectal cancer (CRC) patients. A thorough literature search was conducted across Embase, PubMed, and Cochrane Library databases, identifying 20 eligible studies encompassing 61,296 participants. Studies were primarily observational and case-control in nature, with some randomized controlled trials also included. The random effects model was utilized to synthesize the effect sizes, while study quality was appraised using the Newcastle-Ottawa Scale and the Cochrane Risk of Bias Assessment Tool. Findings revealed that CRC patients with preoperative ALB levels below 3.5 g/dl were at an elevated risk for postoperative complications (OR = 2.56, 95% CI: 2.12-3.08), increased mortality (OR = 4.54, 95% CI: 2.02-10.20), and a poorer prognostic survival risk (HR = 2.09, 95% CI: 1.58-2.77). Additionally, elevated ALP levels were associated with a higher risk of poor overall survival (HR = 1.67, 95% CI: 1.44-1.94). However, publication bias was noted in some studies. Preoperative hypoalbuminemia and elevated ALP levels are significantly linked to adverse postoperative events and reduced survival in CRC patients, suggesting their potential as prognostic biomarkers.

Risk factor analysis and predictive model construction for bone metastasis in newly diagnosed malignant tumor patients.

To identify risk factors for bone metastasis in patients with newly diagnosed malignant tumor and to develop a prediction model. Clinical data from 232 patients with newly diagnosed malignant tumors were analyzed to screen for risk factors associated with bone metastasis. A nomogram prediction model was constructed using R software. The model's performance was evaluated using Receiver Operating Characteristic (ROC) analysis, Bootstrap sampling, and Decision Curve Analysis (DCA). The incidence of bone metastasis in the 232 cases with newly diagnosed malignant tumors was 21.98% (51/232). Multivariate logistic regression analysis revealed that tumor staging III-IV, lymph node metastasis, high Eastern Cancer Collaboration Group Physical Status (ECOG-PS) score, high alkaline phosphatase (ALP) expression, and high SII index were risk factors for bone metastasis at initial diagnosis (all P<0.05). The area under the curve (AUC) of the nomogram model was 0.893. Bootstrap sampling validation showed a small error of 0.017 between predicted and actual probabilities. DCA supported the utility of the model in clinical practice. Bone metastasis in newly diagnosed malignant tumors is associated with advanced tumor staging, lymph node metastasis, high ECOG-PS score, elevated ALP expression, and a high SII index. A nomogram model based on these factors can effectively predict the risk of bone metastasis in these patients.

N-acetyl cysteine and zinc sulphate ameliorated crude oil-induced hepatotoxicity in Wistar rats

Even while crude oil offers many advantages, its toxic chemical composition has been shown to negatively interfere with the body's ability to maintain homeostasis. This investigation examined the effects of crude oil on the liver function of Wistar rats as well as the protective effects of N-acetyl cysteine (NAC) and zinc sulphate (ZnSO4). The experimental group and control group consisted of 42 Wistar rats, which were divided into groups of six each. The experimental group had six groups, while the control group only consumed food and water. In the experimental group, three groups received a diet contaminated with crude oil for two, three, and four weeks, respectively. In addition, another three groups received NAC (100 mg/kg), ZnSO4 (0.5 mg/kg), and a combination of NAC and ZnSo4 for three weeks each. Rats' body weights were recorded both before and after the administration of crude oil. Using commercial kits and histological examinations carried out using conventional histopathological methods, the liver's toxicity was assessed. As a result of eating food contaminated with crude oil, the results showed a significant drop (p &lt; 0.05) in body weight. Additionally, there was liver cell injury. The levels of alkaline phosphatase and alanine transaminase considerably increased. Histological analysis revealed abnormal changes to the liver's typical structure. NAC and ZnSO4 therapy reduced the elevated Alanine transaminase and alkaline phosphatase levels. The study's findings highlight the negative impacts of crude oil and the therapeutic effects of NAC and ZnSO4.

Associated factors with liver fibrosis in rheumatoid arthritis patients treated with methotrexate.

There are conflicting findings on the link between liver fibrosis and cumulative methotrexate dosages. We aimed to determine the frequency of liver fibrosis in rheumatoid arthritis patients treated with methotrexate and to identify its associated factors. We conducted a cross-sectional study over 9 months (April-December 2021), including rheumatoid arthritis patients treated with methotrexate. Demographic and clinical data were collected. Liver stiffness was assessed by FibroScan. Fibrosis and significant liver fibrosis were defined as liver stiffness higher than 6 and 7.2 kPa, respectively. Liver tests, albuminemia, lipid profile, and blood glycemia were measured. Metabolic syndrome was also evaluated. Statistical analyses were performed using SPSS. We included 21 men and 47 women. The mean age was 51.60 ± 1.82 years. The mean disease duration was 8.29 ± 6.48 years. The mean weekly intake of methotrexate was 13.76 ± 3.91 mg. The mean methotrexate duration was 4.67 ± 4.24 years. The mean cumulative dose was 3508.87 ± 3390.48 mg. Hypoalbuminemia and metabolic syndrome were found in 34% and 25% of cases. We noted increased alkaline phosphatase levels in four cases. The mean liver stiffness was 4.50 ± 1.53kPa. Nine patients had liver fibrosis, and four had significant fibrosis. Associated factors with liver fibrosis were as follows: age ≥ 60 years (OR:22.703; 95%CI [1.238-416.487]; p = 0.035), cumulated dose of methotrexate ≥ 3 g (OR: 76.501; 95%CI [2.383-2456.070]; p = 0.014), metabolic syndrome (OR: 42.743; 95%CI [1.728-1057.273]; p = 0.022), elevated alkaline phosphatase levels (OR: 28.252; 95%CI [1.306-611.007]; p = 0.033), and hypoalbuminemia (OR: 59.302; 95%CI [2.361-1489.718]; p = 0.013). Cumulating more than 3 g of methotrexate was associated with liver fibrosis in rheumatoid arthritis patients. Having a metabolic syndrome, higher age, hypoalbuminemia, and elevated alkaline phosphatase levels were also likely to be independently associated with liver fibrosis. Key points • Rheumatoid arthritis patients require monitoring hepatic fibrosis when the cumulated dose of methotrexate is above 3 g. • Metabolic syndrome is a risk factor for liver fibrosis, suggesting that its management is necessary to prevent this complication. • Hypoalbuminemia and elevated alkaline phosphatase levels (twice the upper limit) in rheumatoid arthritis patients treated with methotrexate were associated with liver fibrosis.

Individual Treatment Trial of PIGV-Associated Mabry Syndrome with D-Mannose in a Young Child

We describe the first individual treatment trial with D-mannose in a young girl with PIGV-CDG. PIGV-CDG belongs to the GPI anchor deficiencies leading to intellectual disability, dysmorphic features, epilepsy, and, less frequently, organ malformations. A hallmark of the GPI anchor deficiencies is the elevated serum alkaline phosphatase (AP). Our patient carried the germline homozygous PIGV variant c.1022C&gt;A, p. (Ala341Glu), the most commonly reported pathogenic variant leading to PIGV-CDG so far. We aimed to improve the impaired enzymatic function of PIGV through elevated substrate levels by giving D-mannose orally. We monitored the clinical status, developmental progress as well as serum AP levels. Our patient experienced no side effects. Standardized developmental testing showed better developmental progress during the 21-month treatment period with D-mannose than in the 12 months following the discontinuation of treatment. The D-Mannose treatment might have had a positive effect on the development of our patient with PIGV-CDG.

Sustained delivery of chemically modified mRNA encoding amelogenin from self-assembling hydrogels for periodontal regeneration

Periodontitis is a growing clinical problem worldwide. Despite various approaches that have been devoted to repairing periodontal defects, the clinical outcomes are still limited due to the decline in tissue regenerative potential after periodontitis. Fortunately, chemically modified mRNA (modRNA)-based therapeutics have emerged as a promising strategy to combat incurable diseases. However, the use of modRNA for treating periodontitis is rare and challenging. Herein, a novel therapeutic mRNA platform that allows for sustained delivery and targeted osteogenesis and cementogenesis was developed for periodontal regeneration by combining a self-assembling PLA-PEG-PLA hydrogel and newly synthesized modRNA encoding amelogenin (AMELX) via in vitro transcription. The thermosensitive PLA-PEG-PLA hydrogel significantly prevented modRNA degradation and prolonged the release of encapsulated modRNA by forming an in situ hydrogel depot at 37 °C, resulting in sustained and strong expression of AMELX in human periodontal ligament stem cells (PDLSCs). Moreover, the AMELX modRNA exhibited a great capacity for promoting osteogenesis and cementogenesis of PDLSCs, as evidenced by elevated alkaline phosphatase (ALP) activity, calcium nodule formation, and osteogenesis- and cementogenesis-related gene expression (e.g., ALP, BMP2, CAP, BSP, COL1A1). As a result, after a single local injection, the PLA-PEG-PLA hydrogel enabled AMELX modRNA to persist and release at the defect site, thus successfully regenerating bone and periodontal ligament tissues in periodontal defects of rats. These findings provide a new approach for treating periodontal defects using self-assembling hydrogels to enable safe and effective delivery of AMELX modRNA, thereby offering various possibilities for functional tissue reconstruction with mRNA therapeutics.

Systematic Evaluation of Clinical, Nutritional, and Fecal Microbial Factors for Their Association With Colorectal Polyps.

The identification of risk factors for precursor lesions of colorectal cancer (CRC) holds great promise in the context of prevention. With this study, we aimed to identify patient characteristics associated with colorectal polyps (CPs) and polyp features of potential malignant progression. Furthermore, a potential association with gut microbiota in this context was investigated. In this single-center study, a total of 162 patients with CPs and 91 control patients were included. Multiple variables including information on lifestyle, diet, serum parameters, and gut microbiota, analyzed by 16S-rRNA gene amplicon sequencing and functional imputations (Picrust2), were related to different aspects of CPs. We observed that elevated serum alkaline phosphatase (AP) levels were significantly associated with the presence of high-grade dysplastic polyps. This association was further seen for patients with CRC. Thereby, AP correlated with other parameters of liver function. We did not observe significant changes in the gut microbiota between patients with CP and their respective controls. However, a trend toward a lower alpha-diversity was seen in patients with CRC. Interestingly, AP was identified as a possible clinical effect modifier of stool sample beta diversity. We show for the first time an increased AP in premalignant CP. Furthermore, AP showed a significant influence on the microbial composition of the intestine. Relatively elevated liver enzymes, especially AP, may contribute to the detection of precancerous dysplastic or neoplastic changes in colorectal lesions. The association between elevated AP, premalignant CP, and the microbiome merits further study.

Radical Scavenging, Anti-Inflammatory, and Hepatoprotective Activities of Pentacyclic Triterpene isolated from Rosa webbiana.

Rosa webbiana (RW) Wall Ex. Royle is used in traditional medicine in Pakistan for the treatment of several diseases including jaundice. To date, only neuroprotective potential of the plant has been evaluated. The current study was designed to isolate bioactive compound(s) and investigate its possible radical scavenging, anti-inflammatory and hepatoprotective activities. Column chromatography was done to isolate compounds from the chloroform fraction of RW. The compound was characterized by mass spectrometry, 1H-NMR, and 2D-NMR spectroscopy. Radical scavenging activity was assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydrogen peroxide (H2O2) assays, while anti-inflammatory potential was evaluated via xylene-induced ear edema and carrageenan-induced paw edema models. For hepatoprotection, CCl4-induced model in mice was used. A triterpene compound (3α, 21β-dihydroxy-olean-12-ene) was isolated from RW fruits (ARW1). The compound exhibited DPPH and H2O2 scavenging activities 61 ± 1.31% and 66 ± 0.48% respectively at 500 μg/ml. ARW1 (at 50 mg/kg) exhibited 62.9 ± 0.15% inhibition of xylene-induced ear edema and 66.6 ± 0.17% carrageenan-induced paw edema in mice. In CCl4-induced hepatotoxic mice, ARW1 significantly countered elevation in alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin (T.B), and reduction in total protein (T.P) levels. Liver histomorphological study supported the serum biochemical profile for hepatoprotection. Moreover, ARW1 significantly attenuated the toxic changes in body and liver weight induced by CCl4. The compound ARW1 exhibited anti-radical, anti-inflammatory and hepatoprotective effects. The anti-inflammatory and hepatoprotective activities may be attributed to anti-oxidant potential of the compound.

Alkaline phosphatase and mortality in stroke patients: a systematic review.

Increased plasma levels of alkaline phosphatase (ALP) have been associated to a worse prognosis in several types of diseases. In the present review, the authors aimed to study the relationship between plasma levels of ALP and overall mortality in patients with stroke. A systematic review was carried out, searching two databases: Web of Science and Medline/PubMed. A total of nine studies that included data on overall mortality in stroke patients were selected. The selected studies were published between 2010 and 2022 and were predominantly from Asia. The articles reviewed quantified ALP levels through different methods: highest versus lowest quintiles of plasma ALP (three reports); highest versus lowest quartiles of plasma ALP (four reports); and plasma ALP levels in deceased versus in surviving patients (two reports). All selected studies showed an increased mortality associated to elevated ALP levels, irrespective of stroke type and length of follow-up, from a mean of 10 days to 2.5 years. The studies comparing the highest to the lowest ALP quintiles showed an aggregate value of 1.8 times greater risk of mortality for the former, when compared to the latter. Whereas, the studies comparing the highest to the lowest ALP quartiles showed an aggregate value of 2.4 times greater risk of mortality for the former, when compared to the latter. Elevated ALP levels are associated with increased mortality in stroke patients and provide cost effective prognostic indicators of mortality in stroke.

A Phase II Study of Intermittent Duvelisib Dosing in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Background. Targeting phosphatidylinositol 3-kinase (PI3K) has emerged as an efficacious approach for treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). However, toxicities of the PI3K inhibitors are an important concern limiting their use. Duvelisib is a potent oral inhibitor of both the PI3K-δ and PI3K-γ isoforms with proven efficacy in CLL/SLL. Here we report the results of a phase 2 study evaluating efficacy and safety of duvelisib with intermittent dosing in patients with relapsed/refractory CLL/SLL Methods. This open-label, single arm, phase 2 study enrolled patients with CLL/SLL treated with at least 1 prior line of therapy with active disease as defined by the iWCLL 2008 criteria. Duvelisib was given at a dose of 25 mg PO BID for 28-day cycles for a total of 12 weeks during the induction phase, followed by 75 mg PO BID 2 days on and 5 days off for repeated 28-day cycles during the maintenance phase until death, intolerance or disease progression. The primary endpoint was progression free survival (PFS) at 12 months; secondary endpoints were safety and clinical benefit. The trial was originally planned to enroll 27 patients but was stopped early due to difficulties with enrollment following changing FDA guidance for the use of PI3K inhibitors. Results. Fifteen patients were enrolled. Median age was 74 (59-82) years, 8/15 (53%) were female; patients were primarily Caucasian (13/15; 87%); performance status was 0-1, with 27% (4/15) ECOG 0 and 73% (11/15) ECOG 1. This was a heavily pre-treated patient population with a median of 3 prior lines of therapy (1-6). Among patients where results were available, 79% (11/14) had abnormal FISH results including 36% with TP53 gene loss, 27% del(13q), and 18% del(11q). Sixty-seven percent (8/12) had unmutated IGHV. Of the 15 patients treated, 4 were not evaluable for efficacy due to coming off study early for toxicity (2), development of MDS unrelated to study drug (1) or death due to complications from COVID-19 infection (1). Among the 11 efficacy-evaluable patients, 82% achieved PR, and 18% had stable disease. The 12-month PFS was 43% (95%CI: 18%-66%) and the median PFS was 9.9 months (95% CI: 5.5-NA). Among the 9 responders, the median duration of response (DOR) was 5.3 months (95%CI: 1.9-NA) and 12-month DOR was 22% (95%CI:3%-51%). Five patients (33%) discontinued therapy due to adverse events, which occurred during the induction phase in 4/5 of the patients. Five patients (33%) discontinued due to progressive disease - all during the maintenance phase of treatment. Additionally, 2 patients discontinued due to MD decision; one patient developed MDS which was unrelated to duvelisib; one patient died during treatment due to complications from COVID-19. Treatment was generally well tolerated with the most common grade 3 or higher adverse events being leukocytosis (20%), alanine aminotransferase (ALT) increase (13%), aspartate aminotransferase (AST) increase (13%), oral mucositis (13%) and colitis (13%). The adverse events leading to treatment discontinuation occurred primarily during induction. The most common adverse events of any grade included fatigue in 5 patients (33%), leukocytosis, vomiting, ALT increase, AST increase, diarrhea, and elevation of alkaline phosphatase, which occurred in 4 patients each (27%). Conclusions. We report the results of an open-label, phase 2 study utilizing a continuous dosing induction phase followed by an intermittent dosing maintenance phase of the PI3K inhibitor duvelisib in patients with relapsed/refractory CLL/SLL. Patients who received duvelisib on an intermittent schedule achieved some clinical benefit, however, the desired 12-month PFS goal of 50% was not reached. Adverse events in general were manageable and mainly related to gastrointestinal and liver toxicity, and patient died during treatment from complications from COVID-19 pneumonia. After an initial 12 weeks of continuous duvelisib treatment, the incorporation of intermittent dosing appears to be a viable option for patients with previously treated CLL/SLL.

A Phase 1 Study of Adding Pitavastatin to Venetoclax-Based Therapy in AML and CLL/SLL

Statins (HMG-CoA-reductase inhibitors) are drugs used widely for the treatment of high cholesterol and are generally well-tolerated. There has been increasing interest in repurposing statins for oncology based on the recognition that many cancer cells are “addicted” to the mevalonate biosynthetic pathway (Iannelli et al, 2017; Juarez and Fruman 2021). We have shown that statins increase expression of the pro-apoptotic BCL2 family member PUMA (Lee at al, 2018). We have strong pre-clinical evidence that statins improve responses to the BCL2 inhibitor venetoclax (VEN) in cell line models and ex vivo primary patient specimens from patients with both chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) (Lee et al, 2018). Additionally, retrospective review of patients enrolled into the early clinical trials of VEN in CLL revealed improved responses to VEN (complete remission [CR] and progression-free survival) in the patients who were concurrently on a statin medication (Lee et al, 2018). These retrospective analyses may underestimate the potential of statins for leukemia therapy, as the statin drugs most commonly prescribed for hypercholesterolemia are not pharmacologically optimized for oncology (Abdullah et al., 2018). We developed a phase 1 study of adding pitavastatin (PIT) to VEN-based therapy in patients with AML and CLL/small lymphocytic lymphoma (SLL) (NCT04512105). AML patients were eligible if receiving induction therapy with azacitidine (AZA) and VEN per standard of care. CLL/SLL patients could receive either VEN with obinutuzumab (O) or rituximab. A 3+3 design was employed. Dose level 1 was PIT 2 mg daily, and dose level 2 (DL2) was 4 mg daily. These doses are consistent with the doses used for the treatment of hypercholesterolemia. Those enrolling at DL2 had a creatinine clearance of 60 mL/min or higher based on the prescribing information for pitavastatin. Patients already on statins for the treatment for hypercholesterolemia were allowed; these patients stopped their prescribed statin for 72 hours prior to initiation of PIT. PIT started after patients completed VEN ramp-up and had been on a stable VEN dose for at least 5 days. Primary objectives were assessing safety and tolerability and determining the recommended phase 2 dose of PIT in combination with VEN-based therapies. Secondary objectives included CR rates. Exploratory objectives included performing BH3 profiling on pretreatment and post-treatment blood samples to assess whether add-on treatment with PIT increases apoptotic priming, as seen in preclinical models (Lee et al, 2018). 14 patients signed informed consent. 6 were deemed ineligible. 2 withdrew consent prior to starting PIT therapy. 6 patients received PIT on study. 2 patients had AML and received AZA+VEN. 2 patients had CLL, and 2 patients had SLL. The CLL/SLL patients all received VEN+O. Grade 1 myalgia was reported in one subject on the 4mg PIT dose. 1 patient experienced a grade 1 increase in AST on the 4mg dose. Another patient had grade 1 elevation in bilirubin and alkaline phosphatase at the 4 mg dose. Grade 3-4 toxicities included leukopenia, neutropenia (1 case of febrile neutropenia, grade 3), anemia, and thrombocytopenia. Cycle 1 was defined as the dose-limiting toxicity (DLT) period, and no hematologic toxicities occurred during the DLT period. 1 patient had grade 3 pancreatitis, but this was felt to be unrelated to therapy or disease (also outside the DLT period). No grade 5 toxicities occurred while on study therapy. Toxicities were overall felt to be similar to patients receiving VEN-based therapy in standard clinical practice. All evaluable patients (n=5) achieved clinical CR. 1 patient with SLL is awaiting re-staging at the time of this abstract. Correlative studies are ongoing. In 2 patient peripheral blood samples analyzed, the % blasts (for an AML sample) and % CD5+ B-cells (for a CLL sample) were reduced 24 hours after PIT dosing compared to prior to any treatment and before PIT/after VEN ramp-up. Based on the tolerability of PIT and encouraging clinical outcomes, a phase 2 study is being planned to better assess the efficacy of adding PIT to VEN-based therapies in AML and CLL/SLL.

Longitudinal PET/CT Imaging with Iodine ( 124I) Evuzamitide Reveals Organ Response to Plasma Cell Immunotherapy in a Patient with AL Amyloidosis

Background:Iodine-124-evuzamitide is a novel amyloidophilic peptide (p5+14), labeled with iodine-124, for detecting amyloid by positron emission/x-ray computed tomographic (PET/CT) imaging ( Pharmaceuticals 2023 Apr 21;16(4):629). PET is an inherently quantitative modality and thus 124I-evuzamitide may be useful for monitoring disease progression and response to therapy. Amyloid deposits can impact any organ in patients with light chain-associated amyloidosis (AL); thus, tissue-specific changes in amyloid load, based on PET/CT imaging, may be informative. Currently, response to therapy is assessed by anatomic imaging and measurement of serum or urinary biomarkers. However, the correlation between these metrics and concomitant changes in amyloid load remains enigmatic. Here, we report a case of a patient with AL amyloidosis, on long-term daratumumab therapy, who underwent longitudinal 124I-evuzamitide PET/CT imaging over 4 years (NCT03678259 and NCT05968846). Patient and Methods: A 70-year-old male presented with abnormal liver function tests, notably an elevated serum alkaline phosphatase (ALK) of 465 IU/L. Biopsies of both the liver and celiac nodes revealed the characteristic apple-green birefringence of Congo red stain, indicating the presence of amyloid. The patient began daratumumab immunotherapy 14 months prior to his enrollment in the 124I-evuzamitide imaging study and over the 4-year course of serial imaging. During this time, regular serial serum biomarkers were evaluated as standard of care. PET/CT images were acquired at 0, 23, and 45 months. For each imaging session, the patient received 2 mCi iodine-124-labeled tracer via intravenous injection and was imaged at 5 h post injection. Image data were assessed for visual uptake of radiotracer and quantified by manual 2D region-of-interest analysis where the semi-quantitative mean standard uptake value ratio (SUVR mean) was calculated using blood pool as the reference tissue. Results: Over the 45 months of evaluation, there was a 59% and 73% reduction in 124I-evuzamitide SUVR in the liver and spleen. This was accompanied by decreases in the weight-scaled organ volume (cc/kg) for both the liver (15.2%) and spleen (30.0%) based on segmentation of the organ volume from CT images. This reduction in radiotracer uptake coincided with a sustained decrease in serum FLC, from 38.3 mg/L to 19.1 mg/L, and a positive liver response, where ALK levels dropped from ~200 IU/L to ~120 IU/L. In contrast, renal radiotracer uptake increased slightly in the context of stable creatinine levels, and a modest decline in eGFR. Cardiac uptake of 124I-evuzamitide remained positive and relatively stable, concordant with serum NT-proBNP levels. These data suggest that organ-specific amyloid response, in the context of a sustained hematologic response, may occur independently and at different rates. Conclusion: Previous reports have demonstrated the resolution of AL amyloid. However, this is the first report using an amyloid-binding radiotracer, capable of visualizing all major organs including the heart, demonstrating the complex pattern of organ response and regression of AL amyloid in the context of concurrent biomarker improvement and changes in organ volume. PET/CT imaging using 124I-evuzamitide may, therefore, play a valuable role in both diagnosing amyloidosis and monitoring changes in organ-specific amyloid load. Additional longitudinal imaging studies are needed to support this clinical application.

Persistent Albuminuria and Chronic Kidney Disease in Adults with Sickle Cell Disease: Results from a Multicenter Natural History Study

Background: Patients with sickle cell disease (SCD) are at high risk for developing kidney disease. Albuminuria, an early marker of kidney injury, may be initially transient in patients with SCD. Existing guidelines propose confirming albuminuria at multiple timepoints before intervention. A recent study suggests a urinary albumin-creatinine ratio (UACR) ≥ 100 mg/g correlates highly with persistent albuminuria and subsequent decline in estimated glomerular filtration rate (eGFR). We examined a cohort of patients with SCD to assess those characteristics associated with persistent albuminuria and chronic kidney disease (CKD). Methods During routine clinical visits, we enrolled patients with HbSS or HbSß 0 thalassemia between 18 and 65 years at 4 centers into a prospective study to assess the natural history of kidney disease in SCD. We excluded patients if they had bone marrow transplantation, cancer, connective tissue disease, diabetic nephropathy, other glomerular diseases, hepatitis (B or C), HIV, or were on dialysis. Blood and urine were collected for routine clinical laboratory assessments. Serum cystatin C was measured by commercially available ELISA, and eGFR was calculated using the CKD-EPI-2012 cystatin C equation. We defined CKD as an eGFR &amp;lt; 60 mL/min/1.73m 2 or presence of albuminuria. Glomerular hyperfiltration was defined as an eGFR&amp;gt;130 in females and &amp;gt;140mL/min/1.73m 2 in males, respectively. Persistent albuminuria was considered present if 2 or 3 UACR values were ≥30 mg/g or if initial baseline value was ≥100 mg/g (PMID: 32289161). We utilized generalized linear models adjusting for age and sex to identify characteristics associated with persistent albuminuria and CKD. For multivariable selection, we fit binomial or multinomial LASSO regression models adjusted for age, sex, hemoglobin, %Hemoglobin F, hemoglobinuria, and hydroxyurea to identify those variables associated with outcomes of interest. Results Of 284 enrolled patients, 268 had complete data for UACR, cystatin C and serum creatinine at baseline; 104 (38.8%) of these had persistent albuminuria (Table 1). CKD was present in 40.7% of patients and 26.5% exhibited hyperfiltration. In analyses adjusted for age and sex, several factors were associated with the likelihood of persistent albuminuria. Higher hemoglobin, higher %Hemoglobin F, higher serum bicarbonate and use of NSAIDs were associated with decreased likelihood of persistent albuminuria. Higher systolic and diastolic blood pressure, elevated serum alkaline phosphatase, total bilirubin, and white blood cell count (WBC) were associated with an increased likelihood of persistent albuminuria as were presence of hemoglobinuria and use of angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). In multivariable selection, higher systolic and diastolic blood pressure, ACEi/ARB use, leg ulcers, higher WBC, higher aspartate transaminase (AST) remained associated with higher likelihood of persistent albuminuria. Presence of avascular necrosis, NSAID use, and higher serum bicarbonate were associated with lower likelihood of persistent albuminuria. When evaluating baseline UACR, individuals with UACR≥100 mg/g had similar probability of subsequent albuminuria as compared to those with severe albuminuria (UACR≥300 mg/g) [Table 2]. Conclusion Persistent albuminuria in this cohort was associated with multiple clinical features. Lower use of NSAIDs in this cohort likely represents counseling of patients to avoid these due to their kidney disease. The relationship with serum bicarbonate suggests a propensity for metabolic acidosis in these patients which could exacerbate the underlying SCD. These data confirm the predictive value of a single UACR value ≥100 mg/g for persistent albuminuria, suggesting this may be a sufficient trigger to warrant intervention. CKD, hyperfiltration and albuminuria were extraordinarily common, consistent with prior studies and validate use of this cohort for additional longitudinal assessment of kidney disease in SCD.

Clinical factors associated with illness perception, worry and mental health in sclerosing cholangitis: A single centre prospective study

BackgroundA reduced quality of life and symptoms of depression and anxiety are reported in patients with primary sclerosing cholangitis (PSC), however specific risk factors and the effect of sclerosing cholangitis (SC) with autoimmune features are not known. ObjectiveTo integrate mental wellbeing assessment into routine clinical care for patients with SC, and evaluate factors associated with measures relating to quality of life, illness perception and mental health. MethodsA prospective study of adult non-transplant patients with SC attending the outpatient clinic over a 1 year period. Self-reported questionnaires were sent to patients electronically prior to clinic to assess worry, illness perception, depression and anxiety. Demographic and clinical information was collected. ResultsQuestionnaires were completed in 52/130 (40 %) patients with SC who attended clinic. Worry related to quality of life, mental and physical health, and future health were common. There was no difference in overall worry or illness perception in patients treated with ursodeoxycholic acid; whilst patients with PSC had a higher illness perception (P = 0.04) than those with SC and autoimmune features. Both worry (P = 0.047) and illness perception (P = 0.01) were higher in patients with elevated alkaline phosphatase, whilst there was no difference in patients with and without cirrhosis. There were high screening test scores for both depression (21.1 %) and anxiety (9.6 %), with no association with patient factors. ConclusionsWe integrated an electronic questionnaire for completion prior to clinic for patients with SC with good uptake. We identified a high prevalence of patient worries and symptoms of depression and anxiety, which may be more common in PSC with elevated alkaline phosphatase and without autoimmune features. We recommend the adoption of similar tools into routine clinical practice for patients with SC.