Efficacy of curcumin for amelioration of radiotherapy-induced oral mucositis: a preliminary randomized controlled clinical trial.

BACKGROUND: Oral mucositis (OM) is one of the main problems in almost all patients undergoing head and neck radiotherapy (RT). Owning to the antioxidant and anti-inflammatory properties of curcumin, the effect of both oral and topical formulations of curcumin was assessed on radiation-induced OM (ROM) in this study. METHODS: The safety and efficacy of curcumin mouthwash 0.1% (w/v) and curcumin-nanocapsule were evaluated in ameliorating severity and pain/burning associated with OM during RT. The current randomized, placebo-controlled trial was conducted on 37 patients with head and neck cancers. Patients with grades 1 to 3 of ROM were randomized to receive one of the three interventions: curcumin mouthwash (0.1% w/v); Sinacurcumin soft gel containing 40 mg curcuminoids as nano-micelles (SinaCurcumin®40); or placebo mouthwash with a similar transparent appearance to curcumin mouthwash for 1 min three times daily during RT. Study evaluations were conducted at baseline and weekly thereafter for up to 3 weeks using the Numeric rating scale (NRS) and world health organization (WHO) scale. RESULTS: Among the 45 patients randomized, 37 (mean (SD) age of 53.36 (15.99) years; 14 [37.8%] women) completed the treatment according to the protocol. Patients treated with either oral or topical curcumin showed a significantly reduced severity and burning related to OM during the first 3 weeks after administration (P-Value < 0.001) as compared with the placebo. At study termination, more than 33% of subjects utilizing curcumin mouthwash and 15% of patients utilizing curcumin-nanocapsule remained ulcer free while all of the placebo-receiving subjects had OM. The reduction of NRS and WHO scale between curcumin groups was comparable without significant differences. CONCLUSION: Both curcumin mouthwash and nanocapsule were effective, safe, and well-tolerated in the treatment of radiation-induced OM. Higher doses of curcumin and larger sample sizes can be used for further investigation in future studies. TRIAL REGISTRATION: https://irct.ir/ IRCT20190810044500N17 (13/08/2021).

Prevention of radiotherapy-related oral mucositis with zinc and polyherbal mouthwash: a double-blind, randomized clinical trial.

BACKGROUND: A significant percentage of head and neck cancer (HNCs) patients receiving RT experience oral mucositis (OM). This study aimed to evaluate the effect of the polyherbal (containing chamomile, peppermint oil, Aloe vera, and honey) and zinc mouthwashes in comparison to the control (chlorhexidine) and placebo groups for prevention of radiation-induced OM. METHODS: This study was a double-blinded randomized clinical trial, conducted on 67 patients with HNCs undergoing radiotherapy. The eligible participants were randomized to receive either one of the following; zinc sulfate, polyherbal, chlorhexidine (Vi-one 0.2% CHX), or placebo mouthwash for 6 weeks. Follow-up evaluation of oral hygiene and the checklists of OM and the intensity of pain were filled out according to WHO assessment tool, Oral Mucositis Assessment Scale (OMAS), and Visual Analog Scale (VAS) in all the participants weekly for seven consecutive weeks. RESULTS: The results of present clinical trial demonstrated that the use of either zinc sulfate or polyherbal mouthwash significantly reduced the scores of OM and the severity of pain during weeks 2 to 7 after consumption compared with the CHX or placebo mouthwashes (P < 0.05). According to the post hoc analysis and compared with the placebo, a significantly better result was reported for zinc sulfate and polyherbal mouthwashes at weeks 2 to 7, but not for the CHX mouthwash. CONCLUSION: This study showed that the use of zinc sulfate or polyherbal mouthwashes is effective in prevention of both OM severity scores and pain related to OM intensity at weeks 2 to 7 following consumption in HNCs patients. Trial registration IRCT20190123042475N1 and IRCT20190123042475N2. Registration date: 2019-06-09, 2019-07-26.

Effects of topical timolol for the prevention of radiation-induced dermatitis in breast cancer: a pilot triple-blind, placebo-controlled trial.

INTRODUCTION: Radiation therapy is one of the standard methods in the treatment of breast cancer. Radiotherapy-induced dermatitis (RID) is a common complication of radiotherapy (RT) resulting in less tolerance in RT and even discontinuation of treatment. Timolol is a ß-adrenergic receptor antagonist that presents the best wound healing effects on both chronic and incurable wound healing. Topical forms of timolol could be effective in the prevention of RID due to the role of ß-adrenergic receptors in skin cells and keratinocyte migration, as well as the anti-inflammatory effect of timolol. However, no placebo-controlled randomized trial is available to confirm its role. The current trial aimed to evaluate the efficacy of topical timolol 0.5% (w/w) on the RID severity and patients' quality of life (QOL). METHOD: Patients aged older than 18 years with positive histology confirmed the diagnosis of invasive and localized breast cancer were included. Patients were randomized based on the random number table to receive each of the interventions of timolol 0.5% (w/w) or placebo topical gels from the first day of initiation of RT and for 6 weeks, a thin layer of gel twice daily. Patients were asked to use a thin layer of gel for at least two hours before and after radiation therapy. Primary outcomes were acute radiation dermatitis (ARD) grade using Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale and severity of desquamation based on Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Secondary outcomes were QOL based on Skindex16 (SD-16), maximum grade of ARD, and time of initial RD occurrence. RESULTS: A total of 64 female patients with an age range of 33 to 79 years were included. The means (SD) of age were 53.88 (11.02) and 54.88 (12.48) in the control and timolol groups, respectively. Considering the RTOG/EORTC and CTCAE scores the difference between groups was insignificant (P-Value = 0.182 and P-Value = 0.182, respectively). In addition, the mean (SD) of time of initial RID occurrence in placebo and timolol groups were 4.09 (0.588) and 4.53 (0.983) weeks, respectively (P-Value = 0.035). The maximum grade of RID over time was significantly lower in the timolol group. During the study period, 75.0% of patients in placebo groups had grade 2 of ARD while in the timolol group it was 31.3% (P-Value = 0.002). QoL was not significantly different between groups (P-Value = 0.148). CONCLUSION: Although the topical formulation of timolol, 0.5% (w/w), was found to reduce the average maximum grade of ARD and increase the mean (SD) time of initial RID occurrence, it showed no effect on ARD, severity, and QOL. However, future clinical trials should be performed to assess timolol gel formulation in larger study populations. TRIAL REGISTRATION: https://irct.ir/ IRCT20190810044500N11 (17/03/2021).

Aloe vera for Prevention of Acute Radiation Proctitis in Colorectal Cancer a Preliminary Randomized, Placebo-Controlled Clinical Trial.

OBJECTIVE: To examine the preventive effects of Aloe vera in colorectal cancer patients undergoing radiotherapy. MATERIAL AND METHOD: Twenty colorectal cancer patients, who received radiation, were randomized to receive Aloe vera 3% or placebo ointment, 1 g twice daily for 6 weeks. At weekly visits, acute radiation proctitis (ARP) was evaluated by Radiation Therapy Oncology Group and clinical presentation criteria as the primary endpoint. We also evaluated secondary endpoints of quality of life, psychosocial status, by applying Hospital Anxiety-Depression (HAD) Scale and laboratory measures of quantitative measurement of C-reactive protein (CRP) as a marker for systemic inflammation. RESULTS: There was a significant improvement in the symptom index (before treatment vs. after treatment with Aloe vera) for diarrhea (p = 0.029, median score: 0.5 vs. 0.001). The overall primary and secondary outcomes favored Aloe group, while the measures of toxicity did not achieve a statistical significant difference. The lifestyle score improved significantly with A. vera (p = 004), and they also had a lower depression score in HAD scale (p = 0.008). Furthermore, quantitative CRP decreased significantly during the course of treatment with Aloe vera. CONCLUSION: The use of topical formulation of Aloe vera 3% diminishes the severity of ARP in colorectal cancer patients.

Pharmacological Interventions for the Prevention and Treatment of Kidney Injury Induced by Radiotherapy: Molecular Mechanisms and Clinical Perspectives.

More than half of cancer patients need radiotherapy during the course of their treatment. Despite the beneficial aspects, the destructive effects of radiation beams on normal tissues lead to oxidative stress, inflammation, and cell injury. Kidneys are affected during radiotherapy of abdominal malignancies. Radiation nephropathy eventually leads to the release of factors triggering systemic inflammation. Currently, there is no proven prophylactic or therapeutic intervention for the management of radiation-induced nephropathy. This article reviews the biomarkers involved in the pathophysiology of radiation-induced nephropathy and its underlying molecular mechanisms. The efficacy of compounds with potential radioprotective properties on amelioration of inflammation and oxidative stress is also discussed. By outlining the approaches for preventing and treating this critical side effect, we evaluate the potential treatment of radiation-induced nephropathy. Available preclinical and clinical studies on these compounds are also scrutinized.

Nitric Oxide and Immune Responses in Cancer: Searching for New Therapeutic Strategies.

In recent years, there has been an increasing interest in understanding the mysterious functions of nitric oxide (NO) and how this pleiotropic signaling molecule contributes to tumorigenesis. This review attempts to expose and discuss the information available on the immunomodulatory role of NO in cancer and recent approaches to the role of NO donors in the area of immunotherapy. To address the goal, the following databases were searched to identify relevant literature concerning empirical evidence: The Cochrane Library, Pubmed, Medline, and EMBASE from 1980 through March 2020. Valuable attempts have been made to develop distinctive NO-based cancer therapy. Although the data do not allow generalization, the evidence seems to indicate that low/moderate levels may favor tumorigenesis, while higher levels would exert antitumor effects. In this sense, the use of NO donors could have an important therapeutic potential within immunotherapy, although there are still no clinical trials. The emerging understanding of NO-regulated immune responses in cancer may help unravel the recent features of this "doubleedged sword" in cancer physiological and pathologic processes and its potential use as a therapeutic agent for cancer treatment. In short, in this review, we discuss the complex cellular mechanism in which NO, as a pleiotropic signaling molecule, participates in cancer pathophysiology. We also debate the dual role of NO in cancer and tumor progression and clinical approaches for inducible nitric oxide synthase (iNOS) based therapy against cancer.

The efficacy of teriparatide (Cinnopar®) on bone repair in mandibular fractures: A single blinded randomized clinical trial.

This study focused on the effects of teriparatide (CinnoPar) on healing and postoperative complications in mandibular bone fractures. In this single-blind randomized controlled trial, 30 patients with a mandibular fracture hospitalized for open reduction internal fixation were randomly assigned to the intervention (I) (n = 15) and control (C) (n = 15) groups. Both groups received daily acetaminophen and cephalexin for 1 week. For 1 month, Group I received daily subcutaneous teriparatide injections. The Radiographic Union Scale of the Mandible (RUSM) was used to assess mandibular bone fusion subjectively, and the Hounsfield unit (HU) was used to objectively assess radiodensity in a computed tomography (CT) scan. In both groups, the visual analog scale (VAS) score was used to assess postoperative complications such as pain, swelling, wound opening, pus secretion, and bitter taste. There was no significant difference in bone repair between the two groups in this study (P > 0.05). Teriparatide also had no effect on the postoperative complication rate in the control group (P > 0.05). Within the limitations of the study it seems that in mandibular fractures, teriparatide did not affect bone fusion or postoperative complications, so its use is not recommended for better bone fusion and fewer postoperative complications of mandibular fracture during the first month.

Antibacterial and anti-Trichomonas Vaginalis effects of Rosa Damascena mill petal oil (a persian medicine product), aqueous and hydroalcoholic extracts.

BACKGROUND: Oils in traditional medicine are important products and used routinely for therapeutic purposes. Rose oil (Rosa damascene Mill), a product of Persian medicine, is advised for the treatment of Infectious diseases related to the female genitourinary tract. In the present study, R. damascena petal oil, aqueous, and hydroalcoholic extracts were evaluated for their in vitro antibacterial and anti-Trichomonas vaginalis effects. METHODS: Anti-trichomonas activity evaluation of extracts and oil were assayed by the Homocytometery method. Their antibacterial effects against Escherichia coli, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and clinically isolated Group B Streptococcus were assayed by broth microdilution in 96-well plates. RESULTS: The MIC of hydroalcoholic and aqueous extracts ranged from 25-50 and 25-100 mg/ml, respectively. Rose oil at all administered doses failed to show any antibacterial activity. CONCLUSION: All extracts and oil concentrations showed some degree of growth inhibition activity on T. vaginalis; however, hydroalcoholic extract was more efficient.

Evaluation of adverse effects of chemotherapy regimens of 5-fluoropyrimidines derivatives and their association with DPYD polymorphisms in colorectal cancer patients.

BACKGROUND: 5-Fluorouracil (5-FU) and capecitabine are fluoropyrimidine derivatives that mainly metabolized with dihydropyrimidine dehydrogenase enzyme (DPD). The genetic polymorphism in the genes encoding this enzyme may result in a decrease or loss of enzyme activity which may lead to the accumulation of medicines, their metabolites and potential toxicity. METHOD: This cross-sectional study was conducted on 88 participants with colorectal cancer (CRC). After DNA extraction, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to determine the DPD gene (DPYD) polymorphisms including IVS 14 + 1 G > A, 2846 A > T and 2194 G > A. Chemotherapy-induced side effects were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE Version 5.0). RESULT: Data were collected from 227 chemotherapy cycles of 88 patients with CRC. In a comparison of FOLFOX and FOLFIRI regimens, there was no significant difference in the occurrence of chemotherapy-induced diarrhea, nausea, vomiting and oral mucositis. However, the peripheral neuropathy was more frequent in patients who were treated with FOLFOX (P <  0.001) and hair loss was more common in patients who received FOLFIRI regimen (P = 0.048). Incidence of the DPD IVS14 + 1 G > A polymorphism was observed in four patients (5.5%). There was no association between IVS14 + 1 G > A polymorphism and the occurrence of adverse reactions. CONCLUSION: FOLFOX and FOLFIRI were the most common regimens in CRC patients and their toxicity profile was different in some adverse reactions. Prevalence of IVS14 + 1G > A variant was relatively higher than other similar studies. TRIAL REGISTRATION: Approval code; IR.MAZUMS.REC.95.2480.

The first rare and fatal case of invasive aspergillosis of spinal cord due to Aspergillus nidulans in an Iranian child with chronic granulomatosis disease: review of literature.

BACKGROUND AND PURPOSE: Invasive aspergillosis (IA) of the central nervous system (CNS) is a devastating complication which is rarely reported in immunocompromised children. In this case presentation, we reported a rare and fatal IA with spinal cord involvement in a 10-year-old child with X-linked chronic granulomatosis disease (CGD). CASE REPORT: The child had a previous history of pulmonary tuberculosis. A cervical spine X-ray revealed the involvement of cervical vertebrae (T4/T5) and ribs causing spinal cord compression and epidural abscess. The patient underwent a decompressive laminectomy and mass removal. The histopathology and culture results suggested IA. Despite the aggressive and prolonged therapy, he died within one year. Aspergillus nidulans was identified as the causative agent based on morphological and molecular studies. CONCLUSION: This synopsis represents the aggressive behavior of infection caused by A. nidulans in the CGD patient.

Efficacy and safety of bupropion in cancer-related fatigue, a randomized double blind placebo controlled clinical trial.

BACKGROUND AND OBJECTIVES: Cancer-related fatigue (CRF) is one of the most prevalent complications experienced by cancer patients during and after the process of treatment. Despite conducting a lot of studies, there is no approved therapy to help manage CRF. This study aims to investigate the efficacy of bupropion on CRF. MATERIALS AND METHODS: In this double-blind randomized placebo-controlled clinical trial, a total of 30 eligible cancer patients suffering from fatigue were randomly divided into two groups (15 patients in each group). Bupropion was administered 75 mg/day for the first three days and 150 mg/day (divided in two doses) till the end of the study at week 6. Fatigue as the primary outcome was measured by BFI (Brief Fatigue Inventory) and FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy) scales. Secondary outcomes included HADS (Hospital Anxiety and Depression Scale) and performance status (PS) measured by Karnofsky and ECOG (Eastern Cooperative Oncology Group) scales. Assessments were done at baseline, end of the second and sixth week. RESULTS: There was no significant difference between placebo and bupropion at baseline and the end of second week. Significant difference was seen between two groups at the end of week six (P = 0.006 based on BFI) in favor of bupropion. In-group assessment showed improvement in fatigue levels in both groups during study time (P = 0.000 based on BFI for both bupropion and placebo). Secondary outcomes (e.g., HADS and PS) were not different at baseline and the end of second week. However, at the end of week six, the difference was significant in favor of bupropion. CONCLUSION: A six-week trial of bupropion reduces the CRF and improves the PS of cancer patients. TRIAL REGISTRATION: Current Controlled Trials IRCT20090613002027N12, registration date: 2018-06-01.

Molecular mechanisms of anti-psychotic drugs for improvement of cancer treatment.

Anti-psychotic medications are widely used to treat schizophrenia and bipolar disorder. Besides their medical applications, anti-psychotic drugs have other pharmacological properties which are involved in multiple intracellular functions including metabolism, cell stress, cell-cycle regulation, survival and apoptosis through modulation of cellular signaling pathways such as PI3K/Akt/GSK-3ß, STAT3 and wingless (Wnt)-related intracellular signaling. Also, anti-psychotics counteract the growth of tumor cells by stimulating the cellular immune system and natural killer cells. On the other hand, the positive charge and the lipophilicity of anti-psychotics have significant roles in the inhibition of P-gp pumps resulting in accumulation of chemotherapy drugs as well as increasing the cellular susceptibility to chemotherapy, autophagy, angiogenesis inhibition, stem cells differentiation induction and changing the expression of tumor suppressor genes and oncogenes. Overall, anti-psychotics are able to inhibit the proliferation of cancer cells through modulation of different cellular pathways. Anti-psychotics act as anti-cancer drugs and besides can increase the efficacy of anti-cancer agents in cancer cells. In this study, the anti-cancer effects of different anti-psychotic medicines on various malignant tumor cells and their molecular mechanisms have been discussed.

CYP2D6*3 (A2549del), *4 (G1846A), *10 (C100T) and *17 (C1023T) genetic polymorphisms in Iranian breast cancer patients treated with adjuvant tamoxifen.

There is controversy regarding the efficacy of tamoxifen in breast cancer patients who are carriers of cytochrome P450 2D6 (CYP2D6) gene polymorphisms. Poor metabolizer genotypes may not fully convert tamoxifen to its active metabolite endoxifen and thus have less exposure to anti-estrogen therapy. The present study was conducted to identify the prevalence of CYP2D6 genotypes among Iranian breast cancer patients. A total of 84 estrogen receptor-positive breast cancer patients treated at a referral center in the north of Iran were examined. A peripheral blood sample was obtained from each patient to determine the presence of *3, *4, *10 and *17 single nucleotide polymorphisms of the CYP2D6 gene by polymerase chain reaction-based restriction fragment-length polymorphism analysis. Of the four genotypes assessed, CYP2D6*4 was the most common variant and was identified in 41 (48.8%) patients as heterozygous (G/A) and 3 (3.6%) as homozygous (A/A) alleles. CYP2D6*10 heterozygous mutated alleles (C/T) were also a common genotype that presented in 22 (26.2%) of the study subjects. Variant *17 was less common and was detected only as heterozygous (C/T) in 3 patients (3.6%). No CYP2D6*3 heterozygous or homozygous mutated alleles were observed. In conclusion, the frequency of the CYP2D6 nonfunctional alleles *4 and *10 appeared relatively high in Iranian patients with hormone-sensitive breast cancer. This finding may affect the selection of an optimal hormone therapy, as patients with low CYP2D6 pathway activity may not sufficiently convert tamoxifen to its active metabolite endoxifen.