Significant Renal Toxicity Research Articles

The IDH1-R132H mutation aggravates cisplatin-induced acute kidney injury by promoting ferroptosis through disrupting NDUFA1 and FSP1 interaction

AbstractThe IDH1-R132H mutation is implicated in the development of various tumors. Whether cisplatin, a common chemotherapeutic agent, induces more significant renal toxicity in individuals with the IDH1-R132H mutation remains unclear. In this study, we observed that the IDH1-R132H mutation exacerbates mitochondrial lipid peroxidation and dysfunction in renal tubules, rendering the kidneys more susceptible to cisplatin-induced ferroptosis. The IDH1-R132H mutation increases methylation of the Ndufa1 promoter, thereby suppressing NDUFA1 transcription and translation. This suppression disrupts NDUFA1’s interaction with FSP1, reducing its resistance to cisplatin-induced tubular epithelial cell death. As a consequence, ROS accumulates, lipid peroxidation occurs, and ferroptosis is triggered, thereby promoting acute kidney injury. In summary, this study elucidates a novel mechanism underlying cisplatin-induced nephrotoxicity and provides valuable insights for the development of personalized treatment strategies for tumor patients carrying the IDH1-R132H mutation.

Nephroprotective Effect of Bergapten Against Cyclophosphamide-Mediated Renal Stress, Inflammation, and Fibrosis in Wistar Rats: Probable Role of NF-kB and TGF-β1 Signaling Molecules.

Cyclophosphamide (CPM) is a well-established antineoplastic drug with marked clinical outcomes in various types of cancers. Despite being a promising drug, its use is associated with significant renal toxicity and often limits its use, leading to compromised clinical outcomes. Therefore, this study explored the renal protective effect of bergapten (BGP), a natural bioactive compound that showed marked antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. Till now, BGP has not been studied for its renal protective effect in an in vivo model. Animals were divided into control, toxic, BGP-3, BGP-10, and BGP Per se. The control group was treated with normal saline for 2 weeks. To the toxic group, CPM 200 mg/kg was given on day 7 as i.p. To BGP-3, 10, and Per se, BGP-3 and 10 mg/kg, ip was given 2 weeks with a single shot of CPM 200 day 7. To the Per se group, only BGP 10 mg/kg, ip was given from day 1 to day 14. After 14 days, animals were sacrificed, and kidneys were removed and studied for the markers of oxidative stress, inflammation, renal injury, renal fibrosis, and renal damage using biochemical, histopathological, and immunohistochemical studies. We found that BGP-10 effectively reversed the damage toward normal, whereas BGP-3 failed to exhibit a significant renal protective effect. We conclude that bergapten could be a potential renal protective drug, and hence, more detailed cellular molecular-based studies are needed to bring this drug from the bench to the bedside.

Efficacy, Toxicity, and Prognostic Factors of Re-treatment With [177Lu]Lu-DOTA-TATE in Patients With Progressing Neuroendocrine Tumors: The Experience of a Single Center.

Peptide receptor radionuclide therapy (PRRT) is an effective and safe treatment of unresectable or metastatic, progressive neuroendocrine tumours (NETs). However, if progression occurs after the initial PRRT, treatment options remain limited. Our aim was to evaluate the efficacy and safety of a repeat177Lutetium-[DOTA°,Tyr3]octreotate ([177Lu]Lu-DOTA-TATE) PRRT course in patients with progressive NET after the first [177Lu]Lu-DOTA-TATE PRRT (peptide receptor radionuclide therapy first treatment (PRRT1)). This is a nine-year retrospective observational study of 20 patients who were re-treated with PRRT (peptide receptor radionuclide therapy retreatment (PRRTR)) after PRRT1. The median progression-free survival (PFS) following PRRT1 was 32 months (interquartile range (IQR): 16.5-44.5). After PRRT1, all 20 patients progressed. Of the 20 patients included, two were lost during follow-up. The median PFS after PRRTR was 17.5 months (IQR: 7-39). At the time of analysis, 15/18 patients progressed, and 3/18 had stable disease after PRRTR. Among those patients who progressed, the median time to progression was nine months (IQR: 0-17). The median overall survival from the time of the first cycle of PRRT1 was 66 months (IQR: 65-90). No significant renal or liver toxicity was reported, nor was there a drop in haemoglobin. The decrease in platelet count after PRRTR was statistically significant (p=0.03). Two cycles at PRRTR (vs. 1) were associated with a longer PFS (p=0.014) and the presence of metastases pre-PRRTR was associated with a shorter time to progression following PRRTR (p=0.04). Conclusion: Patients who progressed after PRRT1 can achieve good PFS and minor toxicity. Our study reinforces the efficacy and safety of PRRTR and provides an analysis of factors associated with better outcomes, which can aid clinicians in clinical decision-making.

Epigenetic Priming with 5-Azacytidine Prior to Allogeneic Stem Cell Transplantation for Myeloid Malignancies with In Vivo T Cell Depletion: Results of a Phase II Trial

Background: Relapse is the main cause of death in patients who undergo allogeneic hematopoietic stem cell transplantation (HCT) for myeloid malignancies. Recent improvements in survival have been mainly due to reduction in non-relapse mortality (NRM). Acquired abnormalities of DNA methylation are frequent in myeloid malignancies and are particularly observed among patients with adverse risk features. Epigenetic priming with decitabine to induce DNA hypomethylation was investigated in a phase I trial for acute myeloid leukemia (AML) and has proven safe and feasible (Scandura et al Blood 2011). Applying the principle of chemotherapy-sensitization through hypomethylation in myeloid malignancy, we conducted a phase II trial (NCT02497404) of the epigenetic modulator -5-azacytidine given prior to a reduced intensity conditioning (RIC) regimen. Here we report the results of this trial. Methods: We designed an open label phase II study to determine the feasibility and efficacy of epigenetic priming with 5-Azacytidine prior to RIC for HCT with in-vivo T-cell depletion. Inclusion criteria were AML, myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) with an intermediate or poor risk profile by ELN and IPSS-R, respectively, and adequate organ function. Stem cell grafts were GCSF- mobilized peripheral blood stem cells from either a matched related donor (MRD) or matched unrelated donor (MUD), matched for HLA at loci A, B, C, DR, and DQ. The epigenetic priming regimen was 5-Azacytidine 75 mg/m2/daily X 5, given between days -11 to -7 (Dose reduction to 50 mg/m2/daily after 14 patients due to toxicity). The conditioning regimen consisted of Fludarabine 40 mg/m2/daily, days -6 to -3, and Melphalan 140 mg/m2, on day -3. Graft versus host disease (GVHD) - prophylaxis consisted of Alemtuzumab (total dose 60 mg for MUD and 30 mg for MRD), and Tacrolimus for 3-6 months post-transplant. The Primary objectives were overall survival (OS) and progression free survival (PFS) at 1 year. Secondary objectives were incidence of GVHD and NRM. Results: 39 adult patients with AML, MDS, and chronic neutrophilic leukemia (CNL) were enrolled prospectively between 2/2015 and 6/2018. The median age was 60 years (range, 26-74). The majority of patients had AML (33, 85%), or MDS (5, 13%). Nineteen AML patients (58%) had a poor risk karyotype. Nine cases (23%) had mutated TP53. The donor was MUD in 22 (44%), MRD in 17 (56%) of patients. Other patient characteristics are listed in Table 1. The median follow up for survivors is 6.7 years (5.8 - not reached). Thirty-eight patients engrafted neutrophils at a median of 13 days (9-16) and platelets at a median of 16 days (12-102). One patient was not evaluable due to early death on day 9. OS at 1 year was 64% (95% CI 51-81%) and 36% (95% CI 24-55%) at 4 years, (Figure 1). PFS at 1 year was 54% (95% CI 40-72%) and 33% (95% CI 21-52%) at 4 years. At 1 year, relapse was the cause of death in 21% (95% CI 18-22%) and NRM was 15% (95% CI 13-17%). At 4 years, relapse was the cause of death in 41% (95% CI 38-43%), while NRM reached 23% (95% CI 20-25%). The most common cause of NRM was infection in 5 patients (46%), followed by thrombotic microangiopathy and GVHD. The incidence of acute GVHD by day 100 was 29% (95% CI 13-43%) with grade III-IV acute GVHD found in 8% (95% CI 6-9%). The incidence of chronic GVHD at 1 year was estimated at 22% (95% CI 7.4-35%). No new cases of chronic GVHD were seen thereafter. The most common grade 3/4 toxicities were infections in 8 patients (21%) and renal failure (23%). We found 6/14 patients to have grade 3/4 renal toxicity with 2 requiring hemodialysis. After reducing the 5-azacytidine dose to 50 mg/m2/daily, we observed only 3/25 cases of grade 3/4 renal dysfunction. Conclusion: Preconditioning treatment with 5-azacytidine as epigenetic priming is tolerable with a toxicity profile overall similar to conditioning with fludarabine/melphalan. But the addition of azacytidine at 75 mg/m2/daily (total 5 doses) causes significant renal toxicity, which abates with dose reduction. The PFS in this very high-risk population with historically high relapse rates is promising. A larger number of patients is needed to further evaluate the efficacy of this approach. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Anchoring of Nanocomposites Based on Novel Metal Nanocomplexes/Nanocarbonaceous Surfaces and Assessing Their In Vivo Anticancer Effects on Ehrlich Ascites Tumor.

Nanotechnology is the study of materials' unique properties at the nanoscale. Nanomedicine is the application of nanotechnology in medicine, which has been utilized to treat some common diseases, such as cancer. The aim of the present work is to synthesize the cadmium (Cd) nanocomplex using paracetamol as a ligand with a molar ratio of 1:2 M/L that was characterized by different physicochemical methods and to explore the effect of the synthesized Cd nanocomplex on the immune system and the redox status of the body and their anticancer effects on Ehrlich ascites carcinoma (EAC) induced in mice. Eighty female albino mice were separated into Group I: control; Group II: EAC; Group III: EAC treated with a low-dose Cd nanocomplex; and Group IV: EAC treated with a high-dose Cd nanocomplex. Interleukin-6 (IL-6), NLR family pyrin domain containing 3 (NLRP3), and 8-hydroxy 2-deoxyguanosine (8-OHdG) levels were assessed by enzyme-linked immunosorbent assay (ELISA). Peroxynitrite level and glutathione peroxidase activity were assessed by spectrophotometry. NRF2 mRNA expression, cadmium content, and liver and renal toxicity were estimated. Results: There was a significant increase in IL-6, NLRP3, 8-OHdG, peroxynitrite, and NRF2 mRNA expressions and in the glutathione peroxidase activity in EAC treated with low- and high-dose Cd nanocomplexes. However, the EAC treated with high-dose Cd nanocomplex group showed significant liver and renal toxicity. Conclusion: Cadmium nanocomplex has anticancer effects on EAC induced in mice via its effects on the immune system and redox status as well as pyroptosis and epigenetic instability of the body, while high doses of Cd nanocomplex can cause liver and renal toxicity.

Caloric Restriction Ketogenic Diets (KR) Enhance Radiotherapy Responses in Lung Cancer Xenografts

<h3>Purpose/Objective(s)</h3> Dietary interventions can change metabolite levels in the tumor microenvironment, which might then affect cancer cell metabolism to alter tumor growth. Caloric restriction (CR) and ketogenic diet (KD) are often thought to limit tumor progression. <h3>Materials/Methods</h3> Mice bearing Lewis Lung Carcinoma xenografts were randomly divided into ad libitum diet group (AL), radiation group (RT), KR diet group (KR), or KR + RT group (KT). Mice in KR and KT group were fed a KR (KetoCal 4:1 fats: proteins+carbohydrates; 70% of total energy). Mice in RT and KT group were treated with radiation (4Gy*3f). Mice weights, tumor size, blood ketone levels and survival were monitored. <h3>Results</h3> Blood ketone levels were significantly higher for the mice consuming a KR diet compared to standard diet (3.2 mmol/L vs 0.8 mmol/L at week 3, P < .001). Some mice with KR diet lost a significant amount of weight (10%ཞ15% of starting weight) by the end of the treatment. The KR diets combined with radiation resulted in slower tumor growth in Lewis Lung Carcinoma xenografts and longer survival time (P < 0.05), relative to radiation alone. The KR diet also slowed tumor growth and prolonged survival (P < 0.05), relative to control. Hematological and pathological examinations indicated that the KR diet was safe and well tolerated, and no significant cardiac, hepatic and renal toxicity was observed. <h3>Conclusion</h3> Blood ketone levels were significantly higher for the mice consuming a KR diet compared to standard diet (3.2 mmol/L vs 0.8 mmol/L at week 3, P < .001). Some mice with KR diet lost a significant amount of weight (10%ཞ15% of starting weight) by the end of the treatment. The KR diets combined with radiation resulted in slower tumor growth in Lewis Lung Carcinoma xenografts and longer survival time (P < 0.05), relative to radiation alone. The KR diet also slowed tumor growth and prolonged survival (P < 0.05), relative to control. Hematological and pathological examinations indicated that the KR diet was safe and well tolerated, and no significant cardiac, hepatic and renal toxicity was observed.

Expert consensus on the treatment of chronic kidney disease with tuberculosis (2022 version)

China is a country with a high burden of chronic kidney disease(CKD) and tuberculosis. Patients with CKD are at increased risk of Mycobacterium tuberculosis infection, and the prevalence of CKD is also significantly higher in patients with tuberculosis. The coexistence of the two diseases brings great difficulties for clinical treatment. In this consensus, the general situation, clinical characteristics, metabolic characteristics of anti-tuberculous drugs, and the principles of protocol formulation of such patients were discussed and summarized. When making anti-tuberculosis regimen for patients with chronic renal failure, drugs that metabolized through liver, liver and kidney channels or metabolic pathways other than liver and kidney should be selected as far as possible. Drugs with significant renal toxicity and mainly metabolized by the kidney should be avoided. For CKD patients with mild decrease in GFR (60-89 ml·min-1·1.73 m-2), anti-tuberculosis regimen should be carried out according to the national standards and guidelines, without reducing the dose of anti-tuberculosis drugs. For CKD patients with significantly reduced GFR, mainly CKD3b, stages 4-5, and those receiving dialysis, the anti-tuberculosis regimen must be adjusted according to the GFR. For CKD patients with GFR less than 30 ml·min-1·1.73 m-2, this consensus also recommended anti-tuberculous regimen for initial, retreated and multi-drug-resistant tuberculosis patients. This consensus aimed to improve clinicians' understanding of CKD complicated with tuberculosis, standardize the clinical treatment, improve the curative effect, and reduce adverse reactions. Data from previous trials of CKD combined with TB treatment are still scarce. We look forward to further investigation and evidence-based medical research on CKD with tuberculosis in the future, and make positive efforts for the control of CKD and tuberculosis in China.

37-Year-Old Man With Headache and Nasal Congestion

37-Year-Old Man With Headache and Nasal Congestion

Concurrent chemoradiotherapy with cisplatin given once-a-week versus every-three weekly in head and neck squamous cell carcinoma: Non-inferior, equivalent, or superior?

Cisplatin-based concurrent chemoradiotherapy is the contemporary standard-of-care in curative-intent management of loco-regionally advanced head and neck squamous cell carcinoma. The most optimal dose-schedule of concurrent cisplatin remains debatable with widespread variability in clinical practice. High-quality evidence in favour of cisplatin-based chemoradiotherapy is largely based on high-dose cisplatin given as 100 mg/m2 every three-weekly for up to three cycles. However, such dosing is typically associated with high rates of significant acute hematological and renal toxicity prompting the need for alternative lesser toxic dose-schedules. Compliance to three doses of three-weekly high-dose cisplatin is reportedly suboptimal with nearly 40% of patients unable to receive the third cycle thereby achieving cumulative cisplatin dose of 200 mg/m2 which is generally regarded sufficient for beneficial anti-tumor effect. The most common alternative schedule is low-dose (20–50 mg/m2) cisplatin once-weekly during radiotherapy. Such low-dose weekly regimens have undergone less rigorous prospective evaluation versus RT alone but continue to be widely used in co-operative group trials and routine clinical practice. In the last decade, several small prospective randomized controlled trials have reported significantly lesser toxicity and comparable disease-related outcomes with low-dose weekly cisplatin. However, two recent randomized controlled trials have re-ignited the debate globally due to their contradictory results, inferences, and conclusions. Through this commentary, we critically appraise and summarize the existing evidence-base to inform contemporary clinical practice and guide future research. There is increasingly emerging evidence that chemoradiotherapy with once-weekly cisplatin is non-inferior to three-weekly cisplatin for disease-related outcomes in curative-intent management of loco-regionally advanced head and neck cancer.

Phellodendri Chinensis Cortex-Based Nanoparticles Integrated in Dissolvable Microneedles for Ameliorating Psoriasis-Like Inflammation

Psoriasis is a common and highly relapsing skin disease, for which topical treatments are used by approximately 88% of people with psoriasis as their primary therapy. However, in practice, the low convenience and side effects such as skin irritation of current topical treatments limit the application of the therapy. To address these issues, we calcined Phellodendri Chinensis Cortex (PCC) to prepare Phellodendri Chinensis Cortex Nanoparticles (PCC-NPs) which were packed into dissolvable microneedles (MNs) for the treatment of psoriasis. In this study, we revealed that the trace amounts of PCCNPs delivered by MNs could exert therapeutic effects therapeutic effects in the affected skin comparable to those of standard drugs, accompanied with the suppressed psoriasis-like inflammation without significant hepatic or renal toxicity or allergic reactions. These results indicate that dissolvable PCC-NPs MNs may serve as an innovative topical therapy for the inhibition of psoriatic inflammation.

Non-steroidal anti-inflammatory drugs caused an outbreak of inflammation and oxidative stress with changes in the gut microbiota in rainbow trout (Oncorhynchus mykiss)

One of the main contributors to pharmaceutical pollution of surface waters are non-steroidal anti-inflammatory drugs (NSAIDs) that contaminate the food chain and affect non-target water species. As there are not many studies focusing on toxic effects of NSAIDs on freshwater fish species and specially effects after dietary exposure, we selected rainbow trout (Oncorhynchus mykiss) as the ideal model to examine the impact of two NSAIDs – diclofenac (DCF) and ibuprofen (IBP). The aim of our study was to test toxicity of environmentally relevant concentrations of these drugs together with exposure doses of 100× higher, including their mixture; and to deepen knowledge about the mechanism of toxicity of these drugs. This study revealed kidneys as the most affected organ with hyalinosis, an increase in oxidative stress markers, and changes in gene expression of heat shock protein 70 to be signs of renal toxicity. Furthermore, hepatotoxicity was confirmed by histopathological analysis (i.e. dystrophy, congestion, and inflammatory cell increase), change in biochemical markers, increase in heat shock protein 70 mRNA, and by oxidative stress analysis. The gills were locally deformed and showed signs of inflammatory processes and necrotic areas. Given the increase in oxidative stress markers and heat shock protein 70 mRNA, severe impairment of oxygen transport may be one of the toxic pathways of NSAIDs. Regarding the microbiota, an overgrowth of Gram-positive species was detected; in particular, significant dysbiosis in the Fusobacteria/Firmicutes ratio was observed. In conclusion, the changes observed after dietary exposure to NSAIDs can influence the organism homeostasis, induce ROS production, potentiate inflammations, and cause gut dysbiosis. Even the environmentally relevant concentration of NSAIDs pose a risk to the aquatic ecosystem as it changed O. mykiss health parameters and we assume that the toxicity of NSAIDs manifests itself at the level of mitochondria and proteins.

Caloric restriction ketogenic diets (KR) in relation to radiotherapy responses in lung cancer xenografts

e20528 Background: Dietary interventions can change metabolite levels in the tumour microenvironment, which might then affect cancer cell metabolism to alter tumour growth. Caloric restriction (CR) and ketogenic diet (KD) are often thought to limit tumour progression. The current study tests the hypothesis that caloric restriction ketogenic diets (KR) enhance radiotherapy responses in lung cancer xenografts. Methods: Mice bearing Lewis Lung Carcinoma xenografts were randomly divided into ad libitum diet group (AL), radiation group (RT), KR diet group (KR), or KR + RT group (KT). Mice in KR and KT group were fed a KR (KetoCal 4:1 fats: proteins+carbohydrates;70% of total energy). Mice in RT and KT group were treated with radiation (4Gy*3f). Mice weights, tumor size, blood ketone levels and survival were monitored. Results: Blood ketone levels were significantly higher for the mice consuming a KR diet compared to standard diet (3.2 mmol/L vs 0.8 mmol/L at week 3, P &lt; .001). Some mice with KR diet lost a significant amount of weight (10%～15% of starting weight) by the end of the treatment.The KR diets combined with radiation resulted in slower tumor growth in Lewis Lung Carcinoma xenografts and longer survival time (P &lt; 0.05), relative to radiation alone. The KR diet also slowed tumor growth and prolonged survival (P &lt; 0.05), relative to control. Hematological and pathological examinations indicated that the KR diet was safe and well tolerated, and no significant cardiac, hepatic and renal toxicity was observed. Conclusions: These results showed that a KR diet enhanced radiotherapy responses in lung cancer xenografts. Further studies are needed to address the mechanism of this diet intervention.

Donor-Derived Marrow Mesenchymal Stem Cells Co-Transplantation Following Haploidentical Hematopoietic Stem Cell transplantation: a Multicenter Clinical Study in 35 Severe Aplastic Anemia Children

BackgroundHaploidentical hematopoietic stem-cell transplantation (haplo-HSCT) is associated with an increased risk of graft failure and severe graft-versus-host disease (GVHD). Marrow mesenchymal stromal cells (MSCs) have been shown to support in vivo normal hematopoiesis and to display potent immunosuppressive effects. We launched a multi-center clinical study to examine the safety and feasibility of co-transplantation of MSCs (from third party donors) and haploidentical HSCs into 35 children with severe aplastic anemia (SAA).MethodsA total of 35 children with SAA were enrolled in this multi-center study between January 2014 and December 2016. All patients met the criteria of HLA-mismatched with ⩾5/10 HLA-matched loci. The conditioning regimen for haploidentical hematopoietic stem cell transplantation consisted of busulfan (Bu), cyclophosphamide and ATG. BM and peripheral blood CD34+ cells were infused intravenously ⩾5×108 cells/kg and ⩾2×106 cells/kg of recipient weight on day 01 and day 02, respectively. MSCs (1×106cells/kg) were administered by venous infusion within 6 h proceeding stem cell infusion on day 01 then on day +14 (figure 1).ResultsOf the 35 patients,16 (45.71%) were considered to have very severe SAA. The patients' median age was 11.5 years (range 3-18). The median mononuclear cell and CD34+ counts were 15.4 × 108/kg and 3.7 × 106/kg, respectively.All 35 patients (100%) achieved hematopoietic reconstitution and sustained full donor chimerism within 30 days after HSCT. The median time for myeloid engraftment was 14 days (range 10-22 days) and for platelets engraftment 18 days (range 9-36 days).Almost half of patients (17, 48.57%) experienced aGVHD after transplantation, including 8 (22.86%) with grade I, 5 (14.29%) with grade II, 2 (5.71%) with grade III and 2(5.71%)with grade IV. At 100 days after transplantation, the cumulative incidence of grades II-IV aGvHD was 25.71% and that of grades III-IV was 11.42% (Figure 2). The four patients with grade III or IV aGVHD received additional treatment with methylprednisolone (2 mg/kg/day for 5 days), CD25 monoclonal antibody and the immunosuppressant CsA was changed to FK-506. Four patients were cured, but one patient died.All 35 patients survived for more than 100 days after transplantation, the majority of them (25, 71.43%) remained disease-free and 8 patients (22.86%) developed cGVHD. Among these cGVHD patients, 5 patients (14.29%) showed limited cGVHD and 3 patients (8.57%) showed extensive cGVHD (Figure 3).All patients received the conditioning regimen on schedule without encountering any significant transplantation-related, bowel, renal or liver toxicity. No patients experienced infusional toxicity during the infusion of MSCs. Of the 35 patients, 22 developed varying degrees of fever associated with hematopoietic dysfunction which was resolved after treatment with anti-inflammatory medication. In addition, 11 patients developed a CMV infection and 17 developed an EB virus infection and 2 developed an infection with both CMV and EBV. One patient progressed to EBV-associated PTLD and died of viral infection 130 days after transplantation, and another patient progressed to EBV-associated veno-occlusive disease (VOD) and died of viral infection 115 days after transplantation. Two patients developed reversible posterior leukoencephalopathy syndrome (RPLS) died of 120 days and 105 days respectively. Viral infections in the remaining patients were treated with ganciclovir or foscarnet and gamma globulin and, all patients fully recovered.Patients were followed-up for a median of 22 months (range 3.5-37 months). None of the patients were lost to follow-up. Five patients died within the follow-up period. The causes of death included GVHD (1 patient) and infection (4 patients). The mean survival time was 21.4 months (Figure 4). All 30 of the surviving patients (beyond 8 months) achieved a hematologic complete remission(CR).ConclusionsOur results indicate that co-transplantation of MSCs with haplo-HSCT is a relatively safe therapy regime for children with SAA. Despite the lack of a comparative control group and limited cases enrolled in the study, our findings support previous studies showing that alternative donor HSCT combined with MSCs infusion could be an effective approach to improve survival rates for patients with SAA. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Renal Safety of [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Compromised Baseline Kidney Function.

Simple SummaryRadioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is an effective antitumor-treatment in metastatic castration-resistant prostate carcinoma (mCRPC). Concerns of potential nephrotoxicity are based on renal tubular PSMA expression and the resulting radiopharmaceutical retention during RLT, but data confirming clinically significant renal toxicity are still lacking. In this study, n = 22 patients treated within a prospective patient registry (REALITY Study) with significantly impaired baseline kidney function were investigated for treatment-associated nephrotoxicity and the potential relationship with administered activities of [177Lu]Lu-PSMA-617. As opposed to prevailing concerns, glomerular filtration rate (GFR) improved significantly in our cohort of patients and no significant correlation between change in GFR and administered activities were found. As pre-treatment chronic kidney failure did not lead to detectable RLT-induced deterioration of renal function in our study, the nephrotoxic potential of [177Lu]Lu-PSMA-617 RLT may be overestimated. We suggest not to categorically exclude patients from enrolment to PSMA-RLT due to renal impairment.Background: Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is an effective antitumor-treatment in metastatic castration-resistant prostate carcinoma (mCRPC). Concerns of potential nephrotoxicity are based on renal tubular PSMA expression and the resulting radiopharmaceutical retention during RLT, but data confirming clinically significant renal toxicity are still lacking. In this study, patients with significantly impaired baseline kidney function before initiation of therapy were investigated for treatment-associated nephrotoxicity and the potential relationship with administered activities of [177Lu]Lu-PSMA-617. Methods: Twenty-two mCRPC patients with impaired renal function (glomerular filtration rate (GFR) ≤ 60 mL/min) who received more than two cycles of [177Lu]Lu-PSMA-617 RLT (median 5 cycles and median 6-week time interval between consecutive cycles) were analyzed in this study. Patients were treated within a prospective patient registry (REALITY Study, NCT04833517). Cumulative administered activities ranged from 17.1 to 85.6 GBq with a median activity of 6.5 GBq per cycle. Renal function was closely monitored during and after PSMA-RLT. Results: Mean pre-treatment GFR was 45.0 ± 10.7 mL/min. After two (22/22 patients), four (20/22 patients), and six cycles (10/22 patients) of RLT, a significant increase of GFR was noted (each p < 0.05). End-of-treatment GFR (54.1 ± 16.7 mL/min) was significantly higher than baseline GFR (p = 0.016). Only one patient experienced deterioration of renal function (change of CTCAE grade 2 to 3). The remaining patients showed no significant reduction of GFR, including follow-up assessments (6, 9, and 12 months), and even showed improved (10/22 patients) or unchanged (11/22 patients) CTCAE-based renal impairment grades during and after the end of PSMA-RLT. No significant correlation between the change in GFR and per-cycle (p = 0.605) or cumulative (p = 0.132) administered activities were found. Conclusions: As pre-treatment chronic kidney failure did not lead to detectable RLT-induced deterioration of renal function in our study, the nephrotoxic potential of [177Lu]Lu-PSMA-617 RLT may be overestimated and not of clinical priority in the setting of palliative treatment in mCRPC. We suggest not to categorically exclude patients from enrolment to PSMA-RLT due to renal impairment.

Peptide receptor radionuclide therapy in patients with metastatic progressive pheochromocytoma and paraganglioma: long-term toxicity, efficacy and prognostic biomarker data of phase II clinical trials

BackgroundPheochromocytoma and paraganglioma (PPGL) have currently only limited treatment options available for patients in the metastatic phase (mPPGL) in either post-surgery or inoperable settings. However, these rare tumors overexpress somatostatin receptors and can thus be treated with peptide receptor radionuclide therapy (PRRT). We present data about our 10-year experience treating 46 consecutive mPPGL patients with 90Y-DOTATOC or 177Lu-DOTATATE.Patients and methodsAll patients (20 men and 26 women, median age 52 years) showed positive scintigraphic imaging at 111In-octreotide or 68Ga-DOTATOC positron emission tomography/computed tomography (PET/CT). 90Y-DOTATOC was administered in 12 patients, with cumulative dosages ranging from 7.4 to 11 GBq, while 34 patients received 18.5 or 27.5GBq of 177Lu-DOTATATE. We used Southwest Oncology Group Response Evaluation Criteria in Solid Tumors criteria to evaluate treatment efficacy and Common Terminology Criteria for Adverse Events criteria to assess toxicity. The prognostic role of primary tumor site, hormone secretion, succinate dehydrogenase (SDHx) mutation, and metastatic involvement was also evaluated.ResultsBoth 90Y-DOTATOC and 177Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, 177Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy.ConclusionsPRRT is safe and effective for the treatment of patients with progressive mPPGL, especially at higher dosages. The longer mOS of 177Lu-DOTATATE-treated patients in our protocols indicates the former radiopharmaceutical as the better candidate for further clinical application.

The Significance of Urinary RBP and KIM-1 Determination in Cisplatin – Induced Acute Kidney Injury

<i>Objective: </i>Cisplatin is one of the most commonly used and most effective chemotherapy drugs in clinical treatment of solid tumors, because of its strong anti-cancer effect, no cross resistance with other cancer drugs, but cisplatin is one of the significant renal toxicity drugs either, which greatly limits its clinical application. The traditional diagnostic methods for AKI are to measure Scr and changes in urine volume, but these indicators are affected by non-renal factors and cannot reflect renal function in an early and timely manner, which delays the optimal early treatment time for AKI. To discuss the clinical value of detecting urinary retinol binding protein (RBP) and kidney injury molecule 1 (KIM-1) in early diagonsis of cisplatin-induced acute kidney injury. <i>Methods:</i> 48 rats were randomly divided into the cisplatin group (CP group, 42 rats) and the control group (NS group, 6 rats). The urinary RBP and KIM-1, renal pathological changes were observed at each injection time points. <i>Results: </i>Urinary KIM-1 it significantly increased at 12h point (P<0.05), which was higher obviously than NS group. Urinary RBP it significantly elevated at 6h point (P<0.05). It has correlation with Scr. <i>Conclusion:</i> In cisplatin-induced acute kidney injury, urinary RBP and KIM-1 increased obviously earlier than serum creatinine, they were early sensitive markers.

A Novel Amphibian Antimicrobial Peptide, Phylloseptin-PV1, Exhibits Effective Anti-staphylococcal Activity Without Inducing Either Hepatic or Renal Toxicity in Mice.

In order to part address the problem of drug-resistant pathogens, antimicrobial peptides (AMPs) have been proposed as alternatives to traditional antibiotics. Herein, a novel phylloseptin peptide, named phylloseptin-PV1 (PPV1), is described from the defensive skin secretion of the Neotropical white-lined leaf frog, Phyllomedusa vaillantii. The peptide was synthesized by solid phase peptide synthesis (SPPS) and purified by RP-HPLC, prior to assessment of its biological activities. PPV1 not only demonstrated potent antimicrobial activity against planktonic ESKAPE microorganisms and the yeast, Candida albicans, but also inhibited and eradicated Staphylococcus aureus and MRSA biofilms. The antimicrobial mechanism was shown to include permeabilization of target cell membranes. The in vivo antimicrobial activity of the peptide was then evaluated using mice. PPV1 also exhibited antiproliferative activity against the cancer cell lines, H157, MCF-7, and U251MG, but had a lower potency against the normal cell line, HMEC-1. Although, the peptide possessed a moderate hemolytic action on mammalian red blood cells in vitro, it did not induce significant hepatic or renal toxicity in injected infected mice. These studies have thus found PPV1 to be a potent phylloseptin group AMP, which can effectively inhibit staphylococci, both in vitro and in vivo, without eliciting toxicity. These data thus provide support for further evaluation of PPV1 as a novel antimicrobial agent with therapeutic potential.

Abstract CT159: First-in-human dose escalation of AlphaMedixTM for targeted alpha-emitter therapy of neuroendocrine tumors

Abstract Introduction: Peptide Receptor Radioligand Therapy (PRRT) has been shown to be an effective treatment for patients with metastatic somatostatin receptor (SSTR) positive neuroendocrine tumors (NETs), however interest in developing alpha-emitter based therapies remains high. We present the initial safety and preliminary efficacy of this first-in-human (FIH) study of AlphaMedix™ (212Pb-DOTAMTATE), a novel somatostatin analog for Targeted Alpha-emitter Therapy (TAT), in patients with SSTR expressing NETs (FDA IND 135150). Methods: Thirteen adult subjects, 6 men and 7 women, median age 68 (range 27-75), with biopsy-proven unresectable or metastatic SSTR (+) NETs from different primary sites (small bowel, pancreas, and lung) with at least one measurable lesion were treated with a Single, weight-based, Ascending Dose (SAD) of AlphaMedix™. Dose escalation was conducted according to a classic 3+3 design. Once a partial response was observed in the SAD-3 cohort, the Multiple Ascending Dosing (MAD) began at the same dose level (3 cycles dosed every 8-weeks). Subjects who had previously received PRRT were excluded. All patients received amino acid renal protection prior to AlphaMedixTM administration. Response to treatment was measured per RECIST 1.1 and the effect on the quality of life was measured with the EORTC-QLQ-C30 QOL questionnaire. Two SAD cohorts (SAD1 and SAD2) received 30.7 and 40.0 µCi/kg respectively. MAD3 received 52.0 µCi/kg per cycle and MAD4, began dosing at 67.6 µCi/ kg for a total dose ranging from 14.7 to 16.8 mCi, across 3 cycles. Results: All 3 subjects in MAD 4 who received 67.6 µCi/ kg for 3 cycles showed partial response with 73%, 71%, and 33% decrease in size of the index lesions respectively. 68Ga DOTATATE PET/CT revealed almost a complete response in 2 subjects and a partial response in the third. No clinically significant investigational drug-related hematological and renal toxicity was noted. The most common adverse events noted were diarrhea 2/13(23%), nausea 4/13(30%), fatigue 4/13(30%), hyperglycemia 7/13(53%). Moderate hair loss was seen in 2/13 (15%) patients. Quality of life parameters suggest significant improvement in pain, energy, and shortness of breath in the majority of subjects. Conclusion: Dramatic decreases in tumor burden and a positive impact on quality of life were seen in all of the subjects who received three cycles of AlphaMedixTM at the highest dose tested. In addition, AlphaMedixTM was extremely well tolerated with only mild adverse events, most of which were attributable to the AA solution used for renal protection. This FIH study of AlphaMedixTM illustrates that PRRT with 212Pb is feasible, well-tolerated, and provides substantial reduction in tumor burden to patients with unresectable, metastatic SSTR expressing NETs Citation Format: Izabela Tworowska, Ebrahim S. Delpassand, Julien Torgue, Farah Shanoon, Jason Hurt, Rodolfo Nunez. First-in-human dose escalation of AlphaMedixTM for targeted alpha-emitter therapy of neuroendocrine tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT159.

In vitro Antioxidant Activities of Hydroethanolic Extract of Defatted Wonderful Kola (Buchholzia coriacea) Seeds and Its Safety Evaluation in Murine Models

Introduction: Buccholzia coriaceaseed possesses a vast number of therapeutic applications in African traditional medicine. However, there are still limited information on its bioactive constituents, pharmacological actions and safety profile. This study was designed to prepare hydroethanolic extract of (defatted) Buccholzia coriacea seeds (HEBCS), evaluate its total phenols and flavonoids, in vitro antioxidant activity and its safety in rats and mice.&#x0D; Methods: Seeds were defatted with hexane and the residue extracted with 80% ethanol (EtOH). The total phenols and flavonoid content of the lyophilised HEBCS was determined followed by in vitro antioxidant activity against stable free radicals (DPPHŸ, ABTSŸ+) and reactive oxygen species (ŸOH, NO and H2O2). Limit test (at 5000 mg/ kg body weight (bw) and acute toxicity test (at doses of 62.5, 125, 250 and 500 mg/kg bw) was carried out in rats followed by sub chronic toxicity study (at doses of 125 and 250 mg/ kg bw) in mice. Biomarkers of hepatic function (ALT, AST, ALP and total bilirubin) and renal function (urea and creatinine) were assessed.&#x0D; Results: The total phenols and flavonoids content of HEBCS was found to be 31.76 μg GAE/ mg and 22.82 μg QE/ mg respectively. The half-maximal inhibitory concentration (IC50) value for HEBCS when tested against DPPHŸ, ABTSŸ+, ŸOH, H2O2 and NO were found to be 257.85, 496.73, 883.68, 475.68 and 1786.42 μg/mL respectively. The Median Lethality Dose (LD50) for HEBCS in rat was greater than 5000 mg/ kg body weight. HEBCS did not show any significant (P = .05) hepatic or renal toxicity.&#x0D; Conclusion: Data obtained from the present study highlight the safety of HEBCS and its potential role as a source of natural antioxidants.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with Oxaliplatin, Cisplatin, and Doxorubicin in Patients with Peritoneal Carcinomatosis: An Open-Label, Single-Arm, Phase II Clinical Trial.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an innovative approach for treating peritoneal carcinomatosis that applies chemotherapeutic drugs into the peritoneal cavity as an under-pressure airflow. It improves local bioavailability of cytostatic drugs as compared to conventional intraperitoneal chemotherapy. The aim of this study is to prove feasibility, efficacy and safety of this new treatment. Patients included in the analysis underwent at least two single port PIPAC procedures; drugs used were Oxaliplatin for colorectal cancers and Cisplatin + Doxorubicin for ovarian, gastric, and primary peritoneal cancers. The primary endpoint was the Disease Control Rate according to the RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Secondary significant endpoints were overall and progression free survival, tumor regression on histology, and quality of life. Safety and tolerability were assessed according to the Common Terminology Criteria for Adverse Events 4. Sixty-three patients were enrolled in this trial. Forty patients (100 PIPAC) were eligible for analysis. Twenty patients were undergoing systemic chemotherapy. Fourteen patients reported an objective response (35%). Median overall survival was 18.1 months; median progression-free survival was 7.4 months. Minor morbidity was observed in seven procedures. Grade 3 complications occurred in two patients, and grade 4 in one patient submitted to reoperation. Single-port PIPAC is feasible, safe, and easy to perform. The combined treatment based on systemic chemotherapy and PIPAC does not induce significant hepatic and renal toxicity and can be considered a valid therapeutic option in patients with advanced peritoneal disease. Further studies on the use of PIPAC alone, possibly with different drug dosages, may define the real effectiveness of the procedure.