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Journal of Infection in Developing... Nov 2023Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening hematologic disease segregated into familial (primary) and acquired (secondary) subtypes....
INTRODUCTION
Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening hematologic disease segregated into familial (primary) and acquired (secondary) subtypes. Hyperinflammation and HLH occur when the immune system fails to clear activated macrophages and histiocytes. Infections, malignancies, and rheumatologic disorders are the major triggers leading to HLH. Miliary tuberculosis is a serious disease with a lymphohematogenous spread of Mycobacterium tuberculosis, which is known to be one of the causative agents of HLH. Miliary tuberculosis and HLH have atypical presentations which are similar to routine diseases. Hence, physicians may face challenges to diagnose and treat these complications.
CASE REPORT
We report the case of a 60-year-old man with a history of prolonged fever, shortness of breath, jaundice, altered mental status, undiagnosed lower back pain, and overuse of parenteral betamethasone. Miliary tuberculosis was diagnosed by diffuse, vague random micronodules in both lungs and positive acid-fast bacilli in bronchoalveolar lavage and bone marrow aspiration and biopsy. Moreover, compatible presentation and pancytopenia, hypertriglyceridemia, high serum level of ferritin and fibrinogen-derived products, and evidence of hemophagocytosis on bone marrow aspirate led to the diagnosis of HLH. Unfortunately, despite nearly two months of an anti-tuberculosis regimen (standard and salvage) and eight doses of etoposide, he eventually passed away after clinical improvement.
CONCLUSIONS
Irrational and indiscriminate use of glucocorticoids can be a devastating cause of the spread of tuberculosis and its rare complications, such as HLH.
Topics: Male; Humans; Middle Aged; Lymphohistiocytosis, Hemophagocytic; Tuberculosis, Miliary; Pancytopenia; Etoposide; Adrenal Cortex Hormones
PubMed: 38064397
DOI: 10.3855/jidc.17303 -
AAPS PharmSciTech Aug 2023It is hypothesized that meta-iodobenzylguanidine (MIBG) complexation with etoposide (VP-16) will improve drug solubility and specificity towards BE(2)C neuroblastoma...
It is hypothesized that meta-iodobenzylguanidine (MIBG) complexation with etoposide (VP-16) will improve drug solubility and specificity towards BE(2)C neuroblastoma (NB) cells, 90% of which are known to be MIBG avid. After MIBG and VP-16 interaction, the dry complex was analyzed for crystalline structure, surface morphology, solubility, and size distribution by X-ray powder diffraction (P-XRD), scanning electron microscopy (SEM), infrared (FTIR) and UV spectroscopy, and dynamic light scattering. After exposure to the complex, the cell viability and decay rates were assessed by the MTS assay and estimated using exponential decay models (EDM). Multi-factorial ANOVA and an independent t-test were used to assess for cell viability and solubility data, respectively. The resulting (1: 3 w/w) VP-16: MIBG complex had a mean diameter and zeta potential of 458.5 nm and 0.951 mV, respectively. It dramatically increased the drug apparent water solubility (~ 12-folds). This was ascribed to the formation of a VP-16/MIBG nanocrystalline state mainly governed by cation-π interactions, evidenced by FTIR, SEM, and P-XRD data following the complexation. The EDM relating percent cell viability to drug concentration yielded an excellent fit (r > 0.95) and enabled to estimate the IC values of both native drug and its complex: 6.2 μM and 5.23 μM, respectively (indicating a conservation of drug anticancer activity). The statistical results were consistent with those of the exponential decay models, indicating that MIBG does not inhibit the anticancer activity of VP-16. This study indicates that the VP-16/MIBG complexation improves VP-16 solubility without antagonizing its anticancer activity. Moreover, the efficiency of the EDM for drug IC estimation provides alternative mathematical method for such in vitro cytotoxicity studies.
Topics: Etoposide; 3-Iodobenzylguanidine; Cell Survival; Dynamic Light Scattering; Microscopy, Electron, Scanning
PubMed: 37594527
DOI: 10.1208/s12249-023-02599-4 -
Molecules (Basel, Switzerland) Jul 2023The purpose of this study was to evaluate L-cysteine-modified transfersomes as the topical carrier for enhanced epidermal delivery of podophyllotoxin (POD)....
The purpose of this study was to evaluate L-cysteine-modified transfersomes as the topical carrier for enhanced epidermal delivery of podophyllotoxin (POD). L-cysteine-deoxycholic acid (LC-DCA) conjugate was synthesized via an amidation reaction. POD-loaded L-cysteine-modified transfersomes (POD-LCTs) were prepared via a thin membrane dispersion method and characterized for their particle size, zeta potential, morphology, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and in vitro release. Subsequently, in vitro skin permeation and retention, fluorescence distribution in the skin, hematoxylin-eosin staining and in vivo skin irritation were studied. The POD-LCTs formed spherical shapes with a particle size of 172.5 ± 67.2 nm and a zeta potential of -31.3 ± 6.7 mV. Compared with the POD-Ts, the POD-LCTs provided significantly lower drug penetration through the porcine ear skin and significantly increased the skin retention ( < 0.05). Meaningfully, unlike the extensive distribution of the POD-loaded transfersomes (POD-Ts) throughout the skin tissue, the POD-LCTs were mainly located in the epidermis. Moreover, the POD-LCTs did not induce skin irritation. Therefore, the POD-LCTs provided an enhanced epidermal delivery and might be a promising carrier for the topical delivery of POD.
Topics: Animals; Swine; Administration, Cutaneous; Podophyllotoxin; Cysteine; Skin; Epidermis; Particle Size; Drug Carriers; Drug Delivery Systems
PubMed: 37570682
DOI: 10.3390/molecules28155712 -
Thoracic Cancer Oct 2023Combined treatment using anti-programmed death-ligand 1 antibody (anti-PD-L1) and platinum-etoposide is the current standard first-line treatment for patients with...
INTRODUCTION
Combined treatment using anti-programmed death-ligand 1 antibody (anti-PD-L1) and platinum-etoposide is the current standard first-line treatment for patients with extensive-stage (ES) small cell lung cancer (SCLC). However, the best treatment for relapsed ES-SCLC after the first-line treatment remains unclear. There are some approved chemotherapeutic agents that can be used against ES-SCLC, and treatment with irinotecan is well established as both a monotherapy and a combined therapy, in combination with platinum. Therefore, we conduct a phase II study with irinotecan in the second- or later-line setting for patients with ES-SCLC who have been previously treated with combined treatment.
METHODS
Our study will enroll total 30 patients who are diagnosed with ES-SCLC and have experienced disease progression after the combined treatment. Patients will receive irinotecan on days 1, 8, and 15, which will be repeated every 4 weeks. Doses of irinotecan (100/80/60 mg/m ) will be determined according to the type of UGT1A1 gene polymorphism, and the treatment will be discontinued following disease progression, intolerance, withdrawal of patient consent, and based on the investigator's decision. The primary endpoint of the study is the response rate, and the secondary endpoints are overall survival, progression-free survival, and safety.
DISCUSSION
Since the present first-line treatment has been changed to the combined treatment, the second- or later-line treatment should be re-evaluated for patients with relapsed SCLC. Irinotecan is a major chemotherapeutic agent used for SCLC. This study demonstrates and re-evaluates the clinical benefits of irinotecan after combined treatment with anti-PD-L1 and platinum-etoposide for patients with ES-SCLC.
REGISTRATION DETAILS
This study was registered in the Japan Registry of Clinical Trials (no. jRCT s071210090) on November 4, 2021.
Topics: Humans; Small Cell Lung Carcinoma; Irinotecan; Etoposide; Lung Neoplasms; Platinum; Cisplatin; Camptothecin; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Immunotherapy; Disease Progression; Clinical Trials, Phase II as Topic
PubMed: 37675546
DOI: 10.1111/1759-7714.15097 -
The Lancet. Haematology May 2024Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to determine the...
BACKGROUND
Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to determine the safety of anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation (HSCT) in patients with CD30 lymphoma at high risk of relapse.
METHODS
This phase 1 dose-escalation study was performed at two sites in the USA. Patients aged 3 years and older, with classical Hodgkin lymphoma or non-Hodgkin lymphoma with CD30 disease documented by immunohistochemistry, and a Karnofsky performance score of more than 60% planned for autologous HSCT were eligible if they were considered high risk for relapse as defined by primary refractory disease or relapse within 12 months of initial therapy or extranodal involvement at the start of pre-transplantation salvage therapy. Patients received a single infusion of CAR T cells (2 × 10 CAR T cells per m, 1 × 10 CAR T cells per m, or 2 × 10 CAR T cells per m) as consolidation after trilineage haematopoietic engraftment (defined as absolute neutrophil count ≥500 cells per μL for 3 days, platelet count ≥25 × 10 platelets per L without transfusion for 5 days, and haemoglobin ≥8 g/dL without transfusion for 5 days) following carmustine, etoposide, cytarabine, and melphalan (BEAM) and HSCT. The primary endpoint was the determination of the maximum tolerated dose, which was based on the rate of dose-limiting toxicity in patients who received CAR T-cell infusion. This study is registered with ClinicalTrials.gov (NCT02663297) and enrolment is complete.
FINDINGS
Between June 7, 2016, and Nov 30, 2020, 21 patients were enrolled and 18 patients (11 with Hodgkin lymphoma, six with T-cell lymphoma, one with grey zone lymphoma) were infused with anti-CD30 CAR T cells at a median of 22 days (range 16-44) after autologous HSCT. There were no dose-limiting toxicities observed, so the highest dose tested, 2 × 10 CAR T cells per m, was determined to be the maximum tolerated dose. One patient had grade 1 cytokine release syndrome. The most common grade 3-4 adverse events were lymphopenia (two [11%] of 18) and leukopenia (two [11%] of 18). There were no treatment-related deaths. Two patients developed secondary malignancies approximately 2 years and 2·5 years following treatment (one stage 4 non-small cell lung cancer and one testicular cancer), but these were judged unrelated to treatment. At a median follow-up of 48·2 months (IQR 27·5-60·7) post-infusion, the median progression-free survival for all treated patients (n=18) was 32·3 months (95% CI 4·6 months to not estimable) and the median progression-free survival for treated patients with Hodgkin lymphoma (n=11) has not been reached. The median overall survival for all treated patients has not been reached.
INTERPRETATION
Anti-CD30 CAR T-cell infusion as consolidation after BEAM and autologous HSCT is safe, with low rates of toxicity and encouraging preliminary activity in patients with Hodgkin lymphoma at high risk of relapse, highlighting the need for larger studies to confirm these findings.
FUNDING
National Heart Lung and Blood Institute, University Cancer Research Fund at the Lineberger Comprehensive Cancer Center.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Male; Female; Middle Aged; Transplantation, Autologous; Adult; Immunotherapy, Adoptive; Ki-1 Antigen; Aged; Adolescent; Hodgkin Disease; Young Adult; Child; Receptors, Chimeric Antigen; Antineoplastic Combined Chemotherapy Protocols; Melphalan; Lymphoma, Non-Hodgkin; Carmustine; Etoposide; Child, Preschool; Cytarabine
PubMed: 38555923
DOI: 10.1016/S2352-3026(24)00064-4 -
Journal of Biomolecular Structure &... 2023P53 is eminent tumour suppressor protein that plays a prominent role in cell cycle arrest, DNA repair, senescence, differentiation and initiation of apoptosis. P53 is an...
P53 is eminent tumour suppressor protein that plays a prominent role in cell cycle arrest, DNA repair, senescence, differentiation and initiation of apoptosis. P53 is an attractive drug target and the high toxicity of some cancer chemotherapy drugs increase the demand for new anti-cancer drugs from natural products. In this current scenario, identification of promising anticancer compounds from natural sources by repurposing approach is still relevant for the early prevention and effective management of cancer. In present study, we docked natural compounds like podophyllotoxin, quercetin and rutin along standard drugs (MG-132 and Bay 61-3606) against p53 protein. ADME/T analysis predicted toxicity of phytochemicals and drugs. docking analysis of podophyllotoxin, quercetin and rutin gave HDOCK docking scores of -187.87, -148. 97 and -143.85, whereas control drugs MG-132 and Bay 61-3606 showed docking scores of -159.59 and -140.71 against p53 respectively. AutoDock analysis of rutin and MG-132 showed highest binding affinity scores of -7.3 and -6.8 kcal/mol against p53. Molecular dynamic simulation for p53 protein displayed stable conformation and convergence. In this study, P53-rutin complex showed free binding energy score of 11.84 kcal/mol and P53-MG-132 complex reported free energy score of 16.3 kcal/mol. Protein contacts atlas gives non-covalent contacts framework by exploring interfaces of individual subunits and protein-ligand interactions. STRING tool predicts physical and functional interactions between proteins. The results of this study revealed that rutin and MG-132 could be promising inhibitors against targeted p53 protein and this could prove detrimental for molecular therapeutics and drug-designing strategies.Communicated by Ramaswamy H. Sarma.
PubMed: 36281711
DOI: 10.1080/07391102.2022.2137241 -
Oral Oncology Sep 2023Esthesioneuroblastoma and sinonasal neuroendocrine carcinoma (SNEC) are the most common histological subtypes of non-squamous Sinonasal Tumors. A multidisciplinary...
Real world data on long term outcome of neoadjuvant chemotherapy in locally advanced esthesioneuroblastoma and sinonasal tumor with neuroendocrine differentiation - Results from a single centre study.
INTRODUCTION
Esthesioneuroblastoma and sinonasal neuroendocrine carcinoma (SNEC) are the most common histological subtypes of non-squamous Sinonasal Tumors. A multidisciplinary approach is preferred for locally advanced unresectable esthesioneuroblastoma and SNEC.
METHODS
From June 2010 to October 2021, 59 patients with esthesioneuroblastoma and SNEC received NACT. NACT consists of 2-3 cycles of Etoposide-Platinum based chemotherapy. Depending upon response and performance status, subsequent therapy was planned. SPSS descriptive statistics were performed for analysis. Kaplan Meir methods were used for the estimation of Progression Free Survival (PFS) and Overall Survival (OS).
RESULTS
45 (76.3 %) Esthesioneuroblastoma and 14 (23.7 %) SNEC patients received NACT. The median age of the population was 45 years (range 20-81 years). The majority of patients received 2-3 cycles of Platinum (Cisplatin or Carboplatin) + Etoposide as NACT. 28 patients (47.5%) underwent surgery and 20 patients (33.9%) received definitive chemoradiotherapy after NACT. The most common grade 3 or above adverse events were anemia (13.6%), neutropenia (27.1), and hyponatremia (45.8%). At the time of analysis, the median PFS was 56 months (95% CI 31 months to 77 months), and the median OS was 70 months (95% CI 56 months to 86 months). The most common late toxicities noticed were metabolic syndrome (42.4%), hyperglycemia (39%), nasal bleeding (33.9%), hypertension (17%), dyslipidemia (8.5%), and hypothyroidism (5.1%).
CONCLUSION
The study shows that NACT is safe, and can be easily delivered without any life-threatening toxicities, with a favorable response and improved survival in this subset of patients.
Topics: Humans; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Neoadjuvant Therapy; Esthesioneuroblastoma, Olfactory; Etoposide; Retrospective Studies; Cisplatin; Carcinoma, Neuroendocrine; Paranasal Sinus Neoplasms; Nasal Cavity; Nose Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37413771
DOI: 10.1016/j.oraloncology.2023.106486 -
Journal of Cancer Research and Clinical... Dec 2023Bleomycin, etoposide, and cisplatin combination chemotherapy (BEP) improves the survival of patients with testicular cancer, but is associated with potentially... (Randomized Controlled Trial)
Randomized Controlled Trial
Physical exercise in patients with testicular cancer treated with bleomycin, etoposide and cisplatin chemotherapy: pulmonary and vascular endothelial function-an exploratory analysis.
PURPOSE
Bleomycin, etoposide, and cisplatin combination chemotherapy (BEP) improves the survival of patients with testicular cancer, but is associated with potentially life-threatening toxicities like pneumonitis and thromboembolic events. This study explored the effects of physical exercise in patients with testicular cancer during or after BEP-chemotherapy on pulmonary and vascular endothelial toxicity.
METHODS
In this post hoc analysis of a multicenter randomized clinical trial (NCT01642680), patients with metastatic testicular cancer scheduled to receive BEP-chemotherapy were randomized to a 24-week exercise intervention, initiated during (group A) or after BEP-chemotherapy (group B). Endpoints were pulmonary function (forced vital capacity (FVC), forced expiratory volume in one second (FEV1), lung transfer-coefficient and transfer factor for carbon monoxide (KCO, DLCO) and markers of vascular endothelial dysfunction (von Willebrand factor (vWF) and factor VIII).
RESULTS
Thirty patients were included. Post-chemotherapy, patients declined less in FVC, FEV1 and DLCO in group A compared to group B. Post-chemotherapy, vWF and factor VIII were significantly lower in group A compared to group B. After completion of exercise, started either during BEP-chemotherapy or thereafter, no between-group differences were found. At 1-year post-intervention, significant between-group differences were found in favour of group A in DLCO and KCO.
CONCLUSIONS
Patients who exercised during BEP-chemotherapy better preserved FVC, FEV1 and DLCO, measured directly post-chemotherapy and 1-year post-intervention (DLCO, KCO). This coincided with less increase in vWF and factor VIII measured directly post-chemotherapy. These data support a beneficial role of a physical exercise intervention during BEP-chemotherapy on pulmonary and vascular damage in patients with testicular cancer.
TRIAL REGISTRY
Optimal Timing of Physical Activity in Cancer Treatment (ACT) Registry URL: https://clinicaltrials.gov/ct2/show/NCT01642680 .
TRIAL REGISTRATION NUMBER
NCT01642680.
Topics: Male; Humans; Testicular Neoplasms; Cisplatin; Etoposide; Bleomycin; Factor VIII; von Willebrand Factor; Antineoplastic Combined Chemotherapy Protocols; Lung; Exercise
PubMed: 37889308
DOI: 10.1007/s00432-023-05469-5 -
Journal of Orthopaedic Research :... Nov 2023Bone cement is often used in the surgical treatment of Ewing sarcoma (ES). Chemotherapy-impregnated cement (CIC) has never been tested in slowing ES growth. The purpose...
Bone cement is often used in the surgical treatment of Ewing sarcoma (ES). Chemotherapy-impregnated cement (CIC) has never been tested in slowing ES growth. The purpose of the study is to determine if CIC can decrease cell proliferation, and to assess changes in the mechanical qualities of the cement. Chemotherapeutic agents including doxorubicin, cisplatin, etoposide, and SF2523 were mixed with bone cement. ES cells were plated and exposed to cell growth media that had contained CIC or regular bone cement (RBC) as a control, and cell proliferation assays were performed daily for 3 days. Mechanical testing on RBC and CIC was also performed. There was a significant decrease (p < 0.001) in cell proliferation among all cells treated with CIC compared to cells treated with RBC by 48 h postexposure. Additionally, there was a synergistic effectiveness of the CIC noted when multiple antineoplastic agents were combined. Three-point bending tests did not reveal substantial reductions in tolerated maximum bending load and maximal displacement at maximal bending load between CIC and RBC. Statement of Clinical Significance: CIC does appear to be effective at decreasing cell growth and does not appear to substantially alter the mechanical properties of the cement.
Topics: Humans; Sarcoma, Ewing; Bone Cements; Antineoplastic Agents; Etoposide; Doxorubicin; Bone Neoplasms
PubMed: 36971130
DOI: 10.1002/jor.25561 -
Plant & Cell Physiology Dec 2023Tetrahydrofuran ring formation from dibenzylbutyrolactone lignans is a key step in the biosynthesis of aryltetralin lignans including deoxypodophyllotoxin and...
Tetrahydrofuran ring formation from dibenzylbutyrolactone lignans is a key step in the biosynthesis of aryltetralin lignans including deoxypodophyllotoxin and podophyllotoxin. Previously, Fe(II)- and 2-oxoglutarate-dependent dioxygenase (2-ODD) from Podophyllum hexandrum (Himalayan mayapple, Berberidaceae) was found to catalyze the cyclization of a dibenzylbutyrolactone lignan, yatein, to give deoxypodophyllotoxin and designated as deoxypodophyllotoxin synthase (DPS). Recently, we reported that the biosynthesis of deoxypodophyllotoxin and podophyllotoxin evolved in a lineage-specific manner in phylogenetically unrelated plant species such as P. hexandrum and Anthriscus sylvestris (cow parsley, Apiaceae). Therefore, a comprehensive understanding of the characteristics of DPSs that catalyze the cyclization of yatein to deoxypodophyllotoxin in various plant species is important. However, for plant species other than P. hexandrum, the isolation of the DPS enzyme gene and the type of the enzyme, e.g. whether it is 2-ODD or another type of enzyme such as cytochrome P-450, have not been reported. In this study, we report the identification and characterization of A. sylvestris DPS (AsDPS). Phylogenetic analysis showed that AsDPS belonged to the 2-ODD superfamily and shared moderate amino acid sequence identity (40.8%) with P. hexandrum deoxypodophyllotoxin synthase (PhDPS). Recombinant protein assay indicated that AsDPS and PhDPS differ in terms of the selectivity of substrate enantiomers. Protein modeling using AlphaFold2 and site-directed mutagenesis indicated that the Tyr305 residue of AsDPS probably contributes to substrate recognition. This study advances our understanding of the podophyllotoxin biosynthetic pathway in A. sylvestris and provides new insight into 2-ODD involved in plant secondary (specialized) metabolism.
Topics: Podophyllotoxin; Phylogeny; Lignans; Apiaceae
PubMed: 37948767
DOI: 10.1093/pcp/pcad103