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Nephropathic cystinosis is a multisystem autosomal recessive disease caused by cystine accumulation, which is usually treated by oral cysteamine. In order to determine long-term effects of this therapy, we enrolled 86 adult patients (mean age 26.7 years) diagnosed with nephropathic cystinosis, 75 of whom received cysteamine. Therapy was initiated at a mean age of 9.9 years with a mean duration of 17.4 years. By last follow-up, 78 patients had end-stage renal disease (mean age 11.1 years), 62 had hypothyroidism (mean age 13.4), 48 developed diabetes (mean age 17.1 years), and 32 had neuromuscular disorders (mean age 23.3 years). Initiating cysteamine therapy before 5 years of age significantly decreased the incidence and delayed the onset of end-stage renal disease, and significantly delayed the onset of hypothyroidism, diabetes, and neuromuscular disorders. The development of diabetes and hypothyroidism was still significantly delayed, however, in patients in whom therapy was initiated after 5 years of age, compared with untreated patients. The life expectancy was significantly improved in cysteamine-treated versus untreated patients. Thus, cysteamine decreases and delays the onset of complications and improves life expectancy in cystinosis. Hence, cysteamine therapy should be introduced as early as possible during childhood and maintained lifelong.

Purpose The aim of this study was to review the available literature and define clinical practice guidelines for the use of agents for the prevention and treatment of gastrointestinal mucositis. Methods A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guideline possible. Results A total of 251 clinical studies across 29 interventions were examined. Panel members were able to make one new evidence-based negative recommendation; two new evidence-based suggestions, and one evidence-based change from previous guidelines. Firstly, the panel recommends against the use of misoprostol suppositories for the prevention of acute radiation-induced proctitis. Secondly, the panel suggests probiotic treatment containing Lactobacillus spp., may be beneficial for prevention of chemotherapy and radiotherapy-induced diarrhea in patients with malignancies of the pelvic region. Thirdly, the panel suggests the use of hyperbaric oxygen as an effective means in treating radiation-induced proctitis. Finally, new evidence has emerged which is in conflict with our previous guideline surrounding the use of systemic glutamine, meaning that the panel is unable to form a guideline. No guideline was possible for any other agent, due to inadequate and/or conflicting evidence. Conclusions This updated review of the literature has allowed new recommendations and suggestions for clinical practice to be reached. This highlights the importance of regular updates.

Purpose The aim of this study was to review the available literature from 1966 until December 31, 2010 and define clinical practice guidelines for the use of amifostine for the prevention and treatment of oral mucositis in cancer patients. Methods A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. The body of evidence for the use of amifostine, in each cancer treatment setting was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, or no guideline possible. Results Thirty papers were reviewed for evidence on amifostine as an intervention for oral mucositis. No guideline was possible for amifostine in any cancer treatment setting due to inadequate and conflicting evidence. Conclusion Review of the amifostine studies for the prevention and treatment of oral mucositis has found insufficient evidence to support its use in any cancer treatment setting for this purpose. Additional well-designed research is needed to clarify the role of amifostine as an intervention for oral mucositis.

The purpose of this study was two-fold: (1) to formulate γ-tocotrienol (GT3) in a nanoemulsion formulation as a prophylactic orally administered radioprotective agent; and (2) to optimize the storage conditions to preserve the structural integrity of both the formulation and the compound. γ-tocotrienol was incorporated into a nanoemulsion and lyophilized with lactose. Ultra performance liquid chromatography–mass spectroscopy (UPLC–MS) was used to monitor the chemical stability of GT3 over time, the particle size and ζ potential, and scanning electron microscopy (SEM) were used to study the physical stability of the nanoemulsion. Radioprotective and toxicity studies were performed in mice. The liquid formulation exhibited GT3 degradation at all storage temperatures. Lyophilization, in the presence of lactose, significantly reduced GT3 degradation. Both the liquid and lyophilized nanoemulsions had stable particle size and ζ potential when stored at 4 °C. Toxicity studies of the nanoemulsion resulted in no observable toxicity in mice at an oral dose of 600 mg/kg GT3. The nano-formulated GT3 (300 mg/kg) demonstrated enhanced survival efficacy compared to GT3 alone (200 and 400 mg/kg) in CD2F1 mice exposed to total body gamma radiation. The optimal long-term storage of formulated GT3 is as a powder at −20 °C to preserve drug and formulation integrity. Formulation of GT3 as a nanoemulsion for oral delivery as a prophylactic radioprotectant shows promise and warrants further investigation.

Amifostine is a radioprotector with high efficacy but poor safety, short half-life, no oral formulation, and poor compliance, which limits its application. With the increasing risk of exposure to radiation, the development of new radioprotective agents is critical. We previously synthesized a new amifostine derivative, the small molecule compound HL-003. In this study, we focused on evaluating the radioprotective properties of HL-003. Using the in vitro 2,2-diphenyl-1-picrylhydrazyl assay, we initially confirmed HL-003 as a strong antioxidant and demonstrated that its free radical scavenging activity was stronger than that of amifostine. Then, we performed an acute toxicity test, a 28-day toxicity test, a 30-day survival rate test, and a pharmacokinetic study, all of which provided aggregate evidence that HL-003 functioned as a small molecule radioprotector with high efficacy, a favorable safety profile, a long half-life, and oral administration. The intestinal radioprotective mechanism of HL-003 was explored in male C57 mice after abdominal irradiation by analyzing intestinal tissue samples with hematoxylin-eosin staining, immunohistochemistry, TUNEL staining, and immunofluorescence detection. The results showed that HL-003 protected intestinal DNA from radiation damage and suppressed the expression of phosphorylated histone H2AX, phosphorylated p53, and the apoptosis-related proteins caspase-8 and caspase-9, which contributed to maintaining the normal morphology of the small intestine and provided insights into the mechanism of radioprotection. Thus, HL-003 is a small molecule radioprotector with a potential application in radiation medicine.

The radioprotective capacity of a rationally-designed Mn2+-decapeptide complex (MDP), based on Mn antioxidants in the bacterium Deinococcus radiodurans, was investigated in a mouse model of radiation injury. MDP was previously reported to be extraordinarily radioprotective of proteins in the setting of vaccine development. The peptide-component (DEHGTAVMLK) of MDP applied here was selected from a group of synthetic peptides screened in vitro for their ability to protect cultured human cells and purified enzymes from extreme damage caused by ionizing radiation (IR). We show that the peptides accumulated in Jurkat T-cells and protected them from 100 Gy. MDP preserved the activity of T4 DNA ligase exposed to 60,000 Gy. In vivo, MDP was nontoxic and protected B6D2F1/J (female) mice from acute radiation syndrome. All irradiated mice treated with MDP survived exposure to 9.5 Gy (LD70/30) in comparison to the untreated mice, which displayed 63% lethality after 30 days. Our results show that MDP provides early protection of white blood cells, and attenuates IR-induced damage to bone marrow and hematopoietic stem cells via G-CSF and GM-CSF modulation. Moreover, MDP mediated the immunomodulation of several cytokine concentrations in serum including G-CSF, GM-CSF, IL-3 and IL-10 during early recovery. Our results present the necessary prelude for future efforts towards clinical application of MDP as a promising IR countermeasure. Further investigation of MDP as a pre-exposure prophylactic and post-exposure therapeutic in radiotherapy and radiation emergencies is warranted.

We have previously demonstrated that the small molecule octadecenyl thiophosphate (OTP), a synthetic mimic of the growth factor-like mediator lysophosphatidic acid (LPA), showed radioprotective activity in a mouse model of total-body irradiation (TBI) when given orally or intraperitoneally 30 min before exposure to 9 Gy γ radiation. In the current study, we evaluated the effects of OTP, delivered subcutaneously, for radioprotection or radiomitigation from −24 h before to up to +72 h postirradiation using a mouse TBI model with therapeutic doses at around 1 mg/kg. OTP was injected at 10 mg/kg without observable toxic side effects in mice, providing a comfortable safety margin. Treatment of C57BL/6 mice with a single dose of OTP over the time period from −12 h before to +26 h after a lethal dose of TBI reduced mortality by 50%. When administered at +48 h to +72 h postirradiation (LD50/30 to LD100/30), OTP reduced mortality by ≥34%. OTP administered at +24 h postirradiation significantly elevated peripheral white blood cell and platelet counts, increased crypt survival in the jejunum, enhanced intestinal glucose absorption and reduced endotoxin seepage into the blood. In the 6.4–8.6 Gy TBI range using LD50/10 as the end point, OTP yielded a dose modification factor of 1.2. The current data indicate that OTP is a potent radioprotector and radiomitigator ameliorating the mortality and tissue injury of acute hematopoietic as well as acute gastrointestinal radiation syndrome.

While dietary wholegrain Flaxseed (FS) has potent anti-inflammatory, anti-fibrotic and antioxidant properties in murine models of acute and chronic lung injury, the main bioactive ingredient that contributes to these protective effects remains unknown. This study evaluated the lignan complex of FS (FLC) enriched in secoisolariciresinol diglucoside with respect to lung radioprotective and tumor radiosensitizing efficacy using a mouse model of thoracic radiation-induced pneumonopathy. C57/Bl6 mice were fed 0% FS, 10% FS, 10% FLC or 20% FLC for 3 weeks, then irradiated with a single fraction (13.5 Gy) of X-ray radiation treatment (XRT). Mouse survival was monitored for 4 months after irradiation and inflammatory lung parameters were evaluated in bronchoalveolar lavage (BAL) fluid. Gene and protein levels of protective antioxidant and phase II enzymes were evaluated in lung tissue using qPCR and protein levels were verified by immunoblotting. Prolonged administration of the FLC diet was well tolerated and was not associated with any toxicity. Importantly, comparable to the whole grain 10% FS diet, irradiated mice fed 10% and 20% FLC diets displayed improved survival. Improved hemodynamic measurements were also recorded in irradiated mice fed 10% FS or 10% FLC diet compared to irradiated 0% FS fed mice. Flaxseed lignan complex diet also attenuated polymorphonuclear infiltration and overall lung inflammation to levels comparable to those in nonirradiated mice. Flaxseed lignan complex, similarly to FS, up-regulated gene expression as well as protein levels of protective antioxidant enzymes such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Dietary FLC induced radiosensitizing effects in our murine model of metastatic lung cancer. Importantly, protection of normal tissue does not thwart tumor cell death by radiation treatment. The dietary lignan complex of FS, mainly consisting of the phenolic secoisolariciresinol, is protective against radiation pneumonopathy in vivo while not hindering the tumoricidal effects of radiotherapy.

Objective: The objective of this study is to observe the effect of 100-mg melatonin in reducing the levels of double-strand breaks (DSB) induced by 10 mGy and 100 mGy X-ray in peripheral lymphocyte applying H2AX immunofluorescence microscopy and comparing the different efficacies of melatonin ingestion 1 and 2 h before irradiation. Materials and Methods: Informed consent was obtained from five healthy males, nonathlete, and nonsmoking human volunteers aged between 25 and 35 years. Each volunteer was given a single oral dose of 100 mg melatonin at 9 a.m. Blood samples were collected in vacutainer tubes (without any preservative to separate the serum, and with heparin as an anticoagulant for separating leukocytes for in vitro exposure to gamma radiation) 5-10 min before then 1 and 2 h after melatonin ingestion. Afterward, each sample was subdivided into nonirradiated and irradiated groups (10 mGy and 100 mGy). After irradiation, lymphocytes of samples were separated. The isolated lymphocytes in each group were permeabilized for DSB assessment and stained against the phosphorylated histone variant γH2AX. Results: Melatonin ingestion 1 and 2 h before irradiation caused a significant reduction in γH2AX foci. Results further indicate that the change in ingestion of melatonin from 1 to 2 h before exposure had no significant effect. In addition, melatonin administration showed no side effects. Conclusion: The present study showed that melatonin will prove effective in radioprotection against ionizing radiation (IR)-induced DNA damage in human lymphocytes. Our results suggest ingestion of 100-mg melatonin by patients before exposure to IR in radiology.

Purpose The Radiation Therapy Oncology Group (RTOG) conducted a randomized, placebo-controlled trial evaluating the efficacy of GM-CSF in reducing mucosal injury and symptom burden from curative radiotherapy for head and neck (H&N) cancer. Methods Eligible patients with H&N cancer receiving radiation encompassing ≥50 % of the oral cavity or oropharynx received subcutaneous GM-CSF or placebo. Quality of life (QoL) was assessed using the RTOG-modified University of Washington H&N Symptom Questionnaire at baseline 4, 13, 26, and 48 weeks from radiation initiation. Results Of 125 eligible patients, 114 were evaluable for QoL (58 GM-CSF, 56 placebo). Patient demographics, clinical characteristics, and baseline symptom scores were well balanced between the treatment arms. At the end of the acute period (13 weeks), patients in both arms reported negative change in total symptom score indicating increase in symptom burden relative to baseline (mean −18.4 GM-CSF, −20.8 placebo). There was no difference in change in total symptom score (p > 0.05) or change in mucous, pain, eating, or activity domain scores (p > 0.01) between patients in the GM-CSF and placebo arms. Analysis limited to patients treated per protocol or with an acceptable protocol deviation also found no difference in change in total symptom score (p > 0.05) or change in domain scores (p > 0.01) between treatment arms. Provider assessment of acute mucositis during treatment did not correlate with patient-reported mucous domain and total symptom scores (p > 0.05). Conclusion GM-CSF administered concurrently during head and neck radiation does not appear to significantly improve patient-reported QoL symptom burden.