A New Approach for Potential Combined Chelation Therapy Using Mono- and Bis-Hydroxypyridinones

Iron (Fe) overload diseases, such as β-thalassemia (thal) major and hemochromatosis, have been treated for several decades by chelating therapy with desferrioxamine (DFO). However, drawbacks associated with that drug led to the development of new chelating drugs. The 3-hydroxy-4-pyridinones emerged as highly effective Fe chelators, and deferiprone (L1) has been approved as a Fe chelating drug. The most recent strategy for Fe overload problems is based on the replacement of monotherapies by a combination therapy with both chelators. Following a similar chelating strategy, we present herein the results of animal tests with a combination of two different hydroxypyridinone-based chelators. Both are of the 3-hydroxy-4-pyridinone (HP) type, but with one and two HP chelating units, and extra functional groups to account for differentiation in their physicochemical and biological properties, namely chelating efficacy and bioavailability. Animal studies have shown that the simultaneous administration of this pair of HP chelators, under appropriate proportion, to metal-loaded mice, could speed up metal excretion. This may be rationalized by adjuvant and eventual synergistic effects, due to complementary accessibility of each chelator to different cellular compartments.     

量子点-RGD探针光动力疗法联合吉西他滨治疗胰腺癌荷瘤裸鼠初探

背景:胰腺癌发病隐匿,进展迅速,预后极差。光动力疗法(PDT)是20世纪80年代发展起来的一种新型抗肿瘤治疗手段。目前关于PDT在体内靶向治疗胰腺癌的研究甚少。目的:探讨以量子点-RGD(QDs-RGD)探针为光敏剂的PDT联合吉西他滨对胰腺癌移植瘤裸鼠的治疗效应。方法:合成QDs-RGD探针,制备胰腺癌移植瘤裸鼠模型。采用小动物活体成像术观察QDs-RGD、QDs探针注射入模型裸鼠体内1、5、10、24 h后的显影情况。取40只造模成功的裸鼠,随机分为5组:对照组(不给予任何治疗);单纯光照组(激光630 nm,120 J/cm2,持续照射20 min);PDT组(QDs-RGD 0.5 nmol+激光照射);吉西他滨组(吉西他滨50 mg/kg);联合治疗组(QDs-RGD 0.5 nmol+激光照射+吉西他滨50 mg/kg)。第18 d处死全部裸鼠,取出瘤体,称重并测量体积,计算抑瘤率。结果:QDs-RGD注射1 h后,肿瘤显影逐渐清晰,注射5 h后显影达高峰,随后逐渐减弱。QDs于瘤体附近的聚集浓度明显低于QDs-RGD,注射10 h后肿瘤部位已无显影。PDT组、吉西他滨组和联合治疗组的瘤重、瘤体积均显著低于对照组和单纯光照组(P0.01),其中联合治疗组又显著低于PDT组和吉西他滨组(P0.05);对照组与单纯光照组间、PDT组与吉西他滨组间瘤重、瘤体积差异均无统计学意义(P0.05)。联合治疗组、吉西他滨组、PDT组的抑瘤率分别为70.5%、43.5%、37.1%。结论:以QDs-RGD探针为光敏剂的PDT联合吉西他滨能明显抑制裸鼠体内胰腺癌移植瘤的生长,为临床治疗胰腺癌提供了一条新思路。     

Use of Immunosuppressive Therapy in the Treatment of IgA-dominant Infection-related Glomerulonephritis

A 51-year-old Japanese man who experienced colon cancer recurrence following primary and metastatic lesion resection was hospitalized due to facial cellulitis with febrile neutropenia and purpura on his lower extremities after chemotherapy. It was complicated by rapidly progressive glomerulonephritis. He was diagnosed with immunoglobulin A (IgA)-dominant endocapillary proliferative glomerulonephritis based on kidney histology. His glomeruli were positive for the nephritis-associated plasmin receptor, plasmin activity and galactose-deficient IgA1 (Gd-IgA1). A skin biopsy immunofluorescence study revealed IgA deposition within perivascular regions but no Gd-IgA1 deposition. The final diagnosis was IgA-dominant infection-related glomerulonephritis (IRGN). The patient''s renal function returned to normal after receiving immunosuppressive therapy that consisted of a glucocorticoid and a cyclophosphamide. Immunosuppressive therapy should be considered in cases of IRGN if the patient''s infection is completely under control.     

Multi-Objective Optimization of Nd: YAG Laser Drilling of Optical-Grade Acrylic Plate Using Taguchi-Based Grey Relational Analysis

This study proposed an effective method for optimizing laser drilling processing (LDP) by using grey relational analysis (GRA) for multiple performance requirements. First, we developed a system using a Quantel Brilliant Neodymium-doped Yttrium Aluminum Garnet (Nd: YAG) laser with a pulse width of 5–6 ns and F-theta lenses to deliver a focused laser beam with a diameter of 0.2 mm. The developed system was first employed to drill holes in a 3-mm-thick optical-grade acrylic polymethyl methacrylate (PMMA) plate on a safe window with a high optical density and a grade of OD 7+ @ 950~1085 nm. To avoid errors in the experimental data due to unstable power, a laser power (energy) meter was used to measure the energy stability of the Quantel Brilliant Pulse Laser. Given the stability of 5.6%, this is an effective method for LDP. Four control factors were investigated, including laser pulse energy, repetition rate, focusing position offset, and drilling time. Then, nine experiments were performed using the Taguchi method with orthogonal arrays in L₉ (3⁴). The experimental results with multiple quality characteristics were measured and used to optimize the control factors by using GRA with equal weighting of the four qualities (roundness, Hillock ratio, taper, and HAZ). The results show that A1B3C1D1 is the optimal combination of the control factors, and the maximal variation of 0.406 is obtained from the control factor B (focusing position offset) which has the greatest contribution to the drilling time. We then performed confirmation experiment and obtained a better result from the combination of the control factors, A1B3C1D1. GRA helps us determine the best laser drilling parameters to meet the desired multiple drilling qualities.     

LDL-Therasorb Immunoadsorption for the Treatment of Severe Hypercholesterolemia Refractory to Conventional Therapy

Abstract: The role of severe hypercholesterolemia (SH) as a major risk factor for coronary heart disease has been well established. Not all patients with SH can be treated sufficiently with diet and drugs. In such circumstances, extracorporeal removal of low-density lipoprotein (LDL) cholesterol is required in patients with existing atherosclerosis. The chronic regular application of extracorporeal cholesterol removal demands an efficient and selective method not influencing other plasma components. Several methods have been developed for the extracorporeal reduction of LDL cholesterol using different approaches to achieve selectivity. Today the most selective approach is the use of specific antibodies directed against apolipopro-tein B-100. For 17 years, this method has been used in the therapy of patients with SH. Numerous publications demonstrate the safety and efficacy of immunoadsorption (IA) with the LDL-Therasorb System. Within an IA treatment, LDL cholesterol is reduced by 60–70%. The system, however, allows for any desired reduction in the cholesterol levels because the double column system can be alternately loaded and regenerated to enable virtually unlimited treatment of plasma. The treatable plasma quantity is not limited by the nonspecific removal of other plasma components, e.g., coagulation factors, fibrinogen, plasminogen, or immunoglobulins. In long-term studies, the influence of LDL-Therasorb IA on coronary and peripheral atherosclerotic disease has been shown to have a favorable influence on the development of stenoses. In the majority of patients, a stop of progression and even a regression of stenoses could be demonstrated.     

New Insights on Solvent Implications in the Design of Materials Based on Cellulose Derivatives Using Experimental and Theoretical Approaches

The current paper presents a strategic way to design and develop materials with properties adapted for various applications from biomedicine to environmental applications. In this context, blends of (hydroxypropyl)methyl cellulose (HPMC) and poly(vinylpyrrolidone) (PVP) were obtained to create new materials that can modulate the membrane properties in various fields. Thus, to explore the possibility of using the HPMC/PVP system in practical applications, the solubility parameters in various solvents were initially evaluated using experimental and theoretical approaches. In this frame, the study is aimed at presenting the background and steps of preliminary studies to validate the blends behavior for targeted application before being designed. Subsequently, the analysis of the behavior in aqueous dilute solution of HPMC/PVP blend offers information about the conformational modifications and interactions manifested in system depending on the structural characteristics of polymers (hydrophilicity, flexibility), polymer mixtures composition, and used solvent. Given this background, based on experimental and theoretical studies, knowledge of hydrodynamic parameters and analysis of the optimal compositions of polymer mixtures are essential for establishing the behavior of obtained materials and validation for most suitable applications. Additionally, to guarantee the quality and functionality of these composite materials in the targeted applications, e.g., biomedical or environmental, the choice of a suitable solvent played an important role.     

Usefulness of Rapid Desensitization Therapy for Severe Rash Caused by Molecularly Targeted Drugs Used in the Treatment of Non-small-cell Lung Cancer

Molecular-targeted drugs (MTDs), such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase inhibitors, are used to treat non-small-cell lung cancer (NSCLC). The incidence of rash caused by EGFR-TKIs and discontinuation of MTDs because of rash are issues. Rapid desensitization therapy (RDT) was performed in five patients who developed severe rash after introduction of MTDs and was successful in four, all of whom showed no rash relapse. RDT may thus be useful for treating rash in patients receiving MTDs for NSCLC.     

Effective Combination Therapy of Deferiprone and deferoxamine for the Rapid Clearance of Excess Cardiac IRON and the Prevention of Heart Disease in Thalassemia. The Protocol of the International Committee on Oral Chelators

The International Committee on Oral Chelators (ICOC) combination therapy protocol involving the administration of deferiprone (L1) during the day (80–110 mg/kg/day) and deferoxamine (DFO) (40–60 mg/kg at least 3 days/week) during the night for 8–12 hours using a pump, or the whole 24 hours using an elastomeric pump infuser, has been tested in 11 thalassemia patients (seven males, four females) over a period of 9–28 months. The patients had variable serum ferritin levels (0.54–4.6 mg/L) and cardiac iron load ranging from normal to severe siderosis levels (MRI T2*: 4.7–45 ms). There was a substantial overall reduction in serum ferritin levels (0.17–2.16 mg/L) and normalization of cardiac iron (MRI T2* >20 ms) in all patients. In two patients with severe and moderate cardiac iron load range levels, cardiac iron normalization was achieved within 9–10 months. Two patients on L1 monotherapy (80–120 mg/kg/day) maintained normal range MRI T2* cardiac iron levels over the same period. The ICOC combination therapy protocol appears to be the most effective and least cumbersome form of chelation treatment for the rapid clearance of excess iron from the heart.     

Treatment results of the thioether lipid ilmofosine in patients with malignant tumours

Summary In a multicentre study patients with liver metastases stratified to the histology of the primary tumour were investigated. A total of 102 patients with colorectal adenocarcinoma, non-small-cell lung cancer, pancreatic cancer, primary liver carcinoma and malignant melanoma were treated with the thioether lipid ilmofosine. The drug was administered orally as a tablet at a dosage of 150–300 mg/day (75 mg/tablet). The tolerability of ilmofosine was poor. There was a dose-limiting gastrointestinal toxicity with nausea, vomiting and loss of appetite (WHO grade II-IV) in 67% of patients. During the period of therapy (1–29 weeks, 8.5 weeks mean) no complete remission and no partial response were observed. We thus conclude that treatment with oral ilmofosine is not effective in patients with liver metastases due to various malignancies.     

Application of Fractal Dimension and Texture Analysis to Evaluate the Effectiveness of Treatment of a Venous Lake in the Oral Mucosa Using a 980 nm Diode Laser—A Preliminary Study

Venous lake (VL) is a common lesion resulting from the enlargement of thin-walled veins surrounded by a thick wall of fibrous tissue. Photocoagulation is becoming one of the basic methods for treating small vascular lesions. The aim of this study was an application of texture analysis (TA) and fractal dimension analysis (FDA) to evaluate VL treatment. Twenty-three VLs were included in the study. We used a 980 nm diode laser, 6 W, 100 ms pulse mode with a 50% duty cycle. The total dose of energy was in a range from 80 J to 600 J. We used the difference of intensity algorithm for FDA and microcontrast and a co-occurrence matrix for TA. A complete therapeutic effect was achieved in 83%, and in 9%, scar formation was observed after three months. No healing was observed in 4%, and there was partial healing in 4%. No differences in FD were observed between the lesions after three months and the healthy mucosa. The fractal dimension and microcontrast of a vascular lesion are mutually coupled. FDA and TA is a useful and objective method of assessing treatment effects for venous lakes. The non-contact mode of the 980 nm diode laser is an effective and safe method for treating a VL.     

Long Term Comparative Studies in Thalassemia Patients Treated with Deferoxamine or a Deferoxamine/Deferiprone Combination. Identification of Effective Chelation Therapy Protocols

For the past 2–6 years, two groups of thalassemia patients, one of 16 patients on deferoxamine (DFO) monotherapy (35–80 mg/kg, 2–5 days/week) and the other group comprising 19 patients on a deferiprone (L1) and DFO combination therapy (L1 75–100 mg/kg/day and DFO 30–60 mg/kg, 1–5 days/week), have been studied and compared before and after the introduction of the combination therapy. The patients on the combination therapy were mainly those not complying or experiencing toxicity with DFO. The effects of chelation therapy on iron load was monitored using regular serum ferritin measurements and also magnetic resonance imaging (MRI) T2* relaxation time measurements at the end of the study. In both groups, cardiac MRI T2* levels were within the normal range (>19 ms) in more than 75% of the patients. There was a substantial improvement in serum ferritin levels and normalization of the MRI T2* levels of the liver in many cases treated with the combination therapy at effective doses by comparison to the DFO group, where the serum ferritin and MRI T2* levels were largely unchanged. It would appear that the major overall determining factor in the rapid clearance of excess iron in thalassemia patients and the maintenance of normal iron stores is the selection and implementation of effective chelation dose protocols. The International Committee on Chelation (ICOC) combination protocol L1 (80–110 mg/kg/day)/DFO (40–60 mg/kg at least 3 days per week) and to a lesser extent, DFO monotherapy at about 50 mg/kg/day, 5 days/week, appears to achieve this goal.     

Oropharyngeal Squamous Cell Carcinoma Treatment in the Era of Immune Checkpoint Inhibitors

While head and neck squamous cell carcinomas (HNSCC) are marginally decreasing due to the reduction in exposure to the major risk factors, tobacco and alcohol, the incidence of high-risk human papillomavirus (HPV)-positive oropharynx squamous cell carcinomas (OPSCC), especially those in the tonsil and base of tongue subsites, are increasing. Patients with the latter are younger, display a longer overall survival, and show a lower recurrence rate after standard-of-care treatment than those with HPV-negative OPSCC. This may reflect an important role for immune surveillance and control during the natural history of the virally driven tumour development. Immune deviation through acquisition of immune-suppressive factors in the tumour microenvironment (TME) is discussed in relation to treatment response. Understanding how the different immune factors are integrated in the TME battleground offers opportunities for identifying prognostic biomarkers as well as novel therapeutic strategies. OPSCC generally receive surgery or radiotherapy for early-stage tumour treatment, but many patients present with locoregionally advanced disease requiring multimodality therapies which can involve considerable complications. This review focuses on the utilization of newly emerged immune checkpoint inhibitors (PD-1/PD-L1 pathway) for treatment of HNSCC, in particular HPV-positive OPSCC, since they could be less toxic and more efficacious. PD-1/PD-L1 expression in the TME has been extensively investigated as a biomarker of patient response but is yet to provide a really effective means for stratification of treatment. Extensive testing of combinations of therapeutic approaches by types and sequencing will fuel the next evolution of treatment for OPSCC.     

Preliminary Evaluation of a New Semi-Closed-Loop Insulin Therapy System Over the Prandial Period in Adult Patients With Type 1 Diabetes: The WP6.0 Diabeloop Study

There is room for improvement in the algorithms used in closed-loop insulin therapy during the prandial period. This pilot study evaluated the efficacy and safety of the Diabeloop algorithm (model predictive control type) during the postprandial period. This 2-center clinical trial compared interstitial glucose levels over two 5-hour periods (with/without the algorithm) following a calibrated lunch. On the control day, the amount of insulin delivered by the pump was determined according to the patient’s usual parameters. On the test day, 50% or 75% of the theoretical bolus required was delivered, while the algorithm, informed of carbohydrate intake, proposed changes to insulin delivery every 15 minutes using modeling to forecast glucose levels. The primary endpoint was percentage of time spent at near normoglycemia (70-180 mg/dl). Twelve patients with type 1 diabetes (9 men, age 35.6 ± 12.7 years, HbA1c 7.3 ± 0.8%) were included. The percentage of time spent in the target range was 84.5 ± 20.8 (test day) versus 69.2 ± 33.9% (control day, P = .11). The percentage of time spent in hypoglycemia < 70 mg/dl was 0.2 ± 0.8 (test) versus 4.4 ± 8.2% (control, P = .18). Interstitial glucose at the end of the test (5 hours) was 127.5 ± 40.1 (test) versus 146 ± 53.5 mg/dl (control, P = .25). The insulin doses did not differ, and no differences were observed between the 50% and 75% boluses. In a semi-closed-loop configuration with manual priming boluses (25% or 50% reduction), the Diabeloop v1 algorithm was as successful as the manual method in determining the prandial bolus, without any exposure to excessive hypoglycemic risk.     

A New Era in Iron Chelation Therapy: The Design of Optimal,Individually Adjusted Iron Chelation Therapies for the Complete Removal of Iron Overload in Thalassemia and other Chronically Transfused Patients

A new era in iron chelation therapy began with the successful removal of excess iron load and the maintenance of normal iron stores in thalassemia patients using the International Committee on Chelation (ICOC) protocols. This achievement was based on two phases, firstly the introduction of deferiprone (L1) (80–100 mg/kg/day) and deferoxamine (DFO) (40–60 mg/kg at least 3 days per week) combination therapy, which appears to progressively remove all excess storage iron and thereafter by the introduction of L1 monotherapy that can maintain physiological range levels of serum ferritin, cardiac and liver magnetic resonance imaging (MRI) T2*. This new development is likely to change current practices and set a new gold standard in the treatment of transfusional iron loaded patients leading to an increased survival and the change of thalassemia from a fatal to a chronic disease. A major aspect of the improved therapies is the ability of L1 to mobilize and remove excess cardiac iron and reduce congestive cardiac failure, which is the main cause of death in thalassemia patients. Further, new developments include the use of alternating sequential chelation therapies and selected dose protocols with L1, DFO and deferasirox (DFRA) for overcoming toxicity and efficacy complications observed in some patients treated with monotherapies or combination therapies. The selection and adjustment of dose protocols is crucial for providing optimum chelation therapy for each individual patient.     

Bilateral Osteonecrosis of the Head of the Femur during Treatment with Retinoic Acid in a Young Patient with Acute Promyelocytic Leukemia

All-trans retinoic acid (ATRA) is the drug of choice for the treatment of acute promyelocytic leukemia (APL). In general, ATRA is well tolerated, but it does have side effects, the most severe of which is ATRA syndrome. We report the case of a young patient with APL treated with ATRA for induction and maintenance therapy who then developed avascular necrosis of both femoral heads. We also review cases of APL patients with osteonecrosis of the femoral head after ATRA therapy.     

Lipoprotein (a) Immunapheresis in the Treatment of Familial Lipoprotein (a) Hyperlipoproteinemia in a Patient with Coronary Heart Disease

Abstract: This paper reports 2 years' experience with lipoprotein (a) (Lp[a]) immunapheresis which was successfully handled on a now 40-year-old patient with familial Lp(a) hyperlipoproteinemia inducing severe coronary heart disease with 2 myocardial infarctions and diffuse coronary sclerosis. Continued treatment by Lp(a) immun-absorption with specific sheep antibodies reduced stenosis in coronary vessels more than 50% and stopped the progression of coronary heart disease. A special apheresis technique and the results of continued absorption effects are described.