Homologous platelet gel on radiation-induced dermatitis in a patient receiving head and neck radiotherapy plus cetuximab: A case report.

INTRODUCTION: Acute radiodermatitis is a significant complication of cancer radiotherapy, and platelet-based therapies are emerging as potential new treatments. MAIN SYMPTOMS AND IMPORTANT CLINICAL FINDINGS: In this report, we present the case of a patient with head and neck cancer undergoing radiotherapy combined with the monoclonal antibody cetuximab. After 4 weeks of this treatment, the patient developed cutaneous radiation dermatitis. Despite receiving standard treatment with corticosteroids and emollient cream, the lesion did not improve. MAIN DIAGNOSIS: cutaneous radiation dermatitis on head and neck cancer patient. THERAPEUTIC INTERVENTIONS: Topical application of platelet gel was initiated on the wound. From the second week of radiotherapy to the 4th week, homologous platelet-rich plasma was applied on the dermatitis using a bandage, 4 times a day. OUTCOMES: The topical treatment with homologous platelet gel resulted in complete healing of the radiodermatitis, including restoration of the epidermis, reepithelialization, and reduction in associated pain. CONCLUSION: homologous platelet gel might be an alternative to standard treatment of radiation dermatitis.

Efficacy of topical Calendula officinalis on prevalence of radiation-induced dermatitis: A randomised controlled trial.

OBJECTIVES: A randomised controlled trial was undertaken to compare the efficacy of topical Calendula officinalis (Calendula) versus standard of care (Sorbolene: 10% glycerine in cetomacragol cream) in reducing the prevalence of radiation-induced dermatitis in women undergoing breast cancer radiotherapy. METHODS: A total of 271 women were screened and 82 were randomised. The primary outcome was prevalence of acute radiation-induced dermatitis (RTOG grade 2+) assessed at multiple skin sites. A chi-squared test was conducted for the primary outcome with a worst-case scenario imputation. RESULTS: The recruitment target (n = 178) was not achieved. A total of n = 81 participants were analysed (n = 40 Calendula; n = 41 Sorbolene). There was no detectable difference in prevalence of radiation-induced dermatitis grade 2+ between the Calendula (53%) and Sorbolene (62%) groups (primary analysis OR = 0.87, 95% CI: [0.36, 2.09], P = 0.92; covariate adjusted complete case analysis OR 0.40, 95% CI: [0.13, 1.20], P = 0.10). CONCLUSION: This randomised controlled trial showed no difference between Calendula and standard of care (Sorbolene) for the prevention of radiation-induced dermatitis. However, the study was underpowered (limited recruitment) for the primary comparison.

Uso e efetividade de terapias tópicas no tratamento de radiodermatites: revisão integrativa / Use and affectiveness of topical therapies in radiodermatitis treatment: integrative review / Uso y efectividad de terapias tópicas en el tratamiento de radiodermatitis: revisión integrativa

Objetivo: descrever, a luz da pesquisa bibliográfica, o uso das terapias tópicas no tratamento de radiodermatites. Método: revisão integrativa de ensaios clínicos randomizados nas bases de dados: MEDLINE, LILACS, biblioteca COCHRANE, CINAHL e EMBASE. Após observância dos critérios de inclusão, encontrou-se 1.289 estudos, dos quais, após etapas de exclusão resultaram em 10 estudos. Resultados: foram expostos em categorias num quadro síntese incluindo: dados do estudo, participantes da pesquisa, tipo de terapia tópica utilizada; indicações, contraindicações e resultados. Conclusão: encontraram-se lacunas nos estudos e estas necessitam de investigação. Sugerem-se novos ensaios experimentais a fim de trazer respostas quanto aos tipos de terapias tópicas mais efetivas em radiodermatites, o que trará melhores condições de tratamento e assegurará ao enfermeiro uma assistência de qualidade e ao cliente oncológico uma melhor qualidade de vida

Objective: to describe, in the light of bibliographic research, the use of topical therapies in the treatment of radiodermatitis. Method: integrative review of randomized clinical trials in the databases: MEDLINE, LILACS, COCHRANE, CINAHL and EMBASE. After observing the inclusion criteria, there were 1,289 studies, of which, following exclusion stages, resulted in 10 studies. Results: they were presented in categories in a summary table including: study data, research participants, type of topical therapy used; indications, contraindications and results. Conclusion: gaps have been found in the studies and these need investigation. New experimental trials are suggested in order to provide answers regarding the types of topical therapies more effective in radiodermatites, which will bring better treatment conditions and will ensure the quality of care and the oncological client a better quality of life

Objetivo: describir, a la luz de la investigación bibliográfica, el uso de las terapias tópicas en el tratamiento de radiodermatitis. Método: revisión integrativa de ensayos clínicos aleatorizados en las bases de datos: MEDLINE, LILACS, biblioteca COCHRANE, CINAHL y EMBASE. Después de la observancia de los criterios de inclusión, se encontraron 1.289 estudios, de los cuales, después de etapas de exclusión resultaron en 10 estudios. Resultados: fueron expuestos en categorías en un cuadro síntesis incluyendo: datos del estudio, participantes de la investigación, tipo de terapia tópica utilizada; indicaciones, contraindicaciones y resultados. Conclusión: se ha encontrado lagunas en los estudios y éstas necesitan investigación. Se sugieren nuevos ensayos experimentales a fin de traer respuestas en cuanto a los tipos de terapias tópicas más efectivas en radiodermatitis, lo que traerá mejores condiciones de tratamiento y asegurará al enfermero una asistencia de calidad y al cliente oncológico una mejor calidad de vida

Topical use of Jiawei Simiao Yongan Gao to prevent radiodermatitis in patients with head and neck cancer: A retrospective cohort study.

Radiodermatitis is a common side effect of radiotherapy, but currently there is no standard treatment for its prevention. This study aimed to observe the effect of topical application of a paste based on traditional Chinese medicine, Jiawei Simiao Yongan Gao, on radiodermatitis caused by radiotherapy for patients with head and neck cancer.This was a retrospective cohort study of 40 patients with head and neck cancer evaluated during their radiotherapy. Of these, 20 patients were treated with Jiawei Simiao Yongan Gao on the irradiated skin from the beginning of radiotherapy (JSY group). The other 20 patients were given standard nursing (standard group). Acute skin reactions were classified according to the radiation-induced skin reaction assessment scale (RISRAS) and American radiation therapy oncology group (RTOG) acute toxicity grading criteria every 2 weeks, and adverse effects were recorded until the end of the radiotherapy.The two groups showed differences in severity of radiodermatitis. At 0 to 30 Gy, the skin reactions were similar in the two groups, while above 40 Gy the skin reactions were significantly lower grade in the JSY group (P < .05). At 0 to 20 Gy, there was no statistical significance (P > .05); but above 30 Gy they were lower in the JSY group (P < .05).Jiawei Simiao Yongan Gao effectively alleviated acute radiodermatitis caused by radiotherapy of head and neck cancer patients compared with standard nursing.

Application of red light phototherapy in the treatment of radioactive dermatitis in patients with head and neck cancer.

BACKGROUND: To observe the effect of red light phototherapy (RLPT) on radioactive dermatitis (RD) caused by radiotherapy in patients with head and neck cancer (HNC). METHODS: Sixty patients with HNC admitted to our hospital were randomly divided into experimental group and control group, 30 patients in each group. The control group received routine daily care during radiotherapy treatment. In the experimental group, in addition to routine daily care during radiotherapy treatment, photon therapy apparatus RLPT was added, 10 min/time, 2 times/day, and lasted until the end of radiotherapy. The pain and conditions of the patients' skin were assessed daily, and the skin pain and dermatitis grades of the two groups were compared. RESULTS: In terms of the reaction degree of RD, experimental group was mainly grade 0-2, and control group was mainly grade 2-3, with a significant difference (P < 0.05). In terms of skin pain, according to the pain records at week 2, 3, and 4, the pain degree increased with time. However, the score of wound pain in experimental group was significantly lower than that in control group, and there was a significant difference between the two groups (P < 0.05). CONCLUSIONS: The application of RLPT in the treatment of RD can help accelerate wound healing and significantly shorten healing time. It can not only reduce wounds pain of patients, promote inflammation and ulcer healing, but also ensure the smooth progress of patients' radiotherapy and improve their quality of lives, which is worth popularization and application in the clinical practice.

[Laser and light therapy for treatment of radiation dermatitis]. / Laser- und Lichttherapie zur Behandlung der Strahlendermatitis.

Radiation dermatitis (RD), an inflammatory skin disease that can be an unwanted side effect of medical radiation therapy (RT), most commonly occurs in patients undergoing cancer of the ENT, anal, and vulvar regions. The side effects on the skin and mucous membranes occur within a few weeks after the initiation of RT; however, late side effects can develop months to years after the RT. Therapeutically, various treatment approaches are considered such as pentoxifylline, hyperbaric oxygen therapy, laser therapy, and PBMT. In order to limit the reduced quality of life of patients with RT-induced fibrosis, supportive care consisting of pain therapy, psychological support, and wound care is necessary.

Efficacy of a global supportive skin care programme with hydrotherapy after non-metastatic breast cancer treatment: A randomised, controlled study.

This study investigated the efficacy of post-treatment hydrotherapy as supportive care for management of persistent/long-lasting dermatologic adverse events (dAEs) induced in breast cancer survivors by adjuvant therapy, and its impact on quality of life (QoL). Patients in complete remission after standardised (neo)adjuvant chemotherapy, surgery and radiotherapy combination treatment for infiltrating HR+/HER2-breast carcinoma were enrolled in this randomised, multicentre controlled study 1-5 weeks after completing radiotherapy. The control group (CG, n = 33) received best supportive care and the treatment group (HG, n = 35) received 3-weeks of specific hydrotherapy. The primary criterion was change in QoL (QLQ-BR23) after hydrotherapy. Clinical grading of dAEs, cancer-related QoL (QLQ-C30), dermatologic QoL (DLQI) and general psychological well-being (PGWBI) were assessed. Significant dAEs were found at inclusion in both groups (n = 261). Most items showed significantly greater improvement in the HG versus CG group: QLQ-BR23 (breast [p = .0001] and arm symptoms [p = .0015], systemic therapy side effects [p = .0044], body image [p = .0139]), some dAE grading, DLQI (p = .0002) and PGWBI (p = .0028). Xerosis (88% of patients at inclusion) completely healed in all HG patients. Specific hydrotherapy is an effective supportive care for highly prevalent and long-lasting dAEs occurring after early breast cancer treatment, including chemotherapy, and leads to improved QoL and dermatologic toxicities.

[Hyperbaric oxygen and radiotherapy: From myth to reality]. / Oxygénothérapie hyperbare et radiothérapie : entre mythe et réalité.

Worldwide, more than a million people receive each year a curative radiotherapy. While local control and overall survival are steadily increasing, 5 to 15% of patients still develop above grade 2 late toxicities. Late toxicities treatments are complex. Hyperbaric oxygenation was shown to induce revascularization and healing of injured tissues, but indications are still debated. Through a literature review, we summarized the hyperbaric oxygenation indications in radiation-induced late toxicities. We also studied the knowledge and practice of French local radiation therapists. It seems that hyperbaric oxygen therapy can be a conservative treatment of haemorrhagic cystitis and radiation-induced pain, in case of drug therapies failure. Often associated with a significant morbidity and mortality, surgery could be avoided. The risk of complications in case of tooth extraction in irradiated tissues is also reduced. However, the role of hyperbaric oxygenation for mandibular osteoradionecrosis, radiation-induced proctitis, enteritis, lymphoedema, brachial plexopathy, skin and neurological sequelae seems more questionable since studies results are conflicting. Future outcomes of phase III studies are expected to clarify the role of hyperbaric oxygenation in the management of radio-induced toxicities, including for head and necks complications.

Photobiomodulation for the management of radiation dermatitis: the DERMIS trial, a pilot study of MLS(®) laser therapy in breast cancer patients.

PURPOSE: The aim of this study was to assess the effectiveness and acceptability of photobiomodulation using MLS(®) laser therapy (LT) in the management of acute radiation dermatitis (RD). METHODS: We compared two successive groups of breast cancer patients undergoing identical radiotherapy regimens post-lumpectomy. Both groups received our standard skin care but the second group received six additional LT sessions (beam area 19.635 cm(2), 0.168 W/cm(2), 4 J/cm(2)), starting at fraction 20 of radiotherapy (control and LT group, N = 41 and 38, respectively). The clinical outcomes were the severity of RD (using the Radiation Therapy Oncology Group [RTOG] criteria and the Radiotherapy-Induced Skin Reaction Assessment Scale [RISRAS]) and dermatology-specific quality of life (Skindex-16) before the start of LT and at the end of radiotherapy. Secondary outcomes were patients' ratings of skin care or LT (pleasantness, soothing effect, and global satisfaction). RESULTS: Skin toxicity was equivalent between the groups before the start of LT but significantly differed at the end of radiotherapy, with an aggravation in the control but not in the LT group (e.g., 29 versus 3 % of RTOG grade 2 RD, respectively, P < 0.005). We found no significant group differences with respect to quality of life. However, the RISRAS subjective score decreased in the LT group only, implying a decreased impact of RD on patients' quality of life. Finally, patients' ratings were significantly higher for LT than for standard care. CONCLUSIONS: These findings suggest that LT might be effective to manage acute RD and warrant further research. CLINICAL TRIAL NUMBER: NCT01932073. https://clinicaltrials.gov/ct2/show/NCT01932073 .

A case-control, mono-center, open-label, pilot study to evaluate the feasibility of therapeutic touch in preventing radiation dermatitis in women with breast cancer receiving adjuvant radiation therapy.

BACKGROUND: Therapeutic touch (TT) is a non-invasive commonly used complementary therapy. TT is based on the use of hand movements and detection of energy field congestion to correct imbalances. Improvement in subjective symptoms in a variety of clinical trials has been seen with TT. The effect of TT during radiotherapy for breast cancer is unknown. METHODS: Women undergoing adjuvant radiation for Stage I/II breast cancer post conservative surgery were recruited for this cohort study. TT treatments were administered three times per week following radiation therapy. Feasibility was defined as an a priori threshold of 15 of 17 patients completing all TT treatments. The preventive effectiveness of TT was evaluated by documenting the 'time to develop' and the 'worst grade of radiation' dermatitis. Toxicity was assessed using NCIC CTC V3 dermatitis scale. Cosmetic rating was performed using the EORTC Breast Cosmetic Rating. The quality of life, mood and energy, and fatigue were assessed by EORTC QLQ C30, POMS, and BFI, respectively. The parameters were assessed at baseline, and serially during treatment. RESULTS: A total of 49 patients entered the study (17 in the TT Cohort and 32 in the Control Cohort). Median age in TT arm was 63 years and in control arm was 59 years. TT was considered feasible as all 17 patients screened completed TT treatment. There were no side effects observed with the TT treatments. In the TT Cohort, the worst grade of radiation dermatitis was grade II in nine patients (53%). Median time to develop the worst grade was 22 days. In the Control Cohort, the worst grade of radiation dermatitis was grade III in 1 patient. However, the most common toxicity grade was II in 15 patients (47%). Three patients did not develop any dermatitis. Median time to develop the worst grade in the control group was 31 days. There was no difference between cohorts for the overall EORTC cosmetic score and there was no significant difference in before and after study levels in quality of life, mood and fatigue. CONCLUSION: This study is the first evaluation of TT in patients with breast cancer using objective measures. Although TT is feasible for the management of radiation induced dermatitis, we were not able to detect a significant benefit of TT on NCIC toxicity grade or time to develop the worst grade for radiation dermatitis. In addition, TT did not improve quality of life, mood, fatigue and overall cosmetic outcome.

[Methotrexate-associated photosensitization]. / Photosensibilisierung durch Methotrexat.

BACKGROUND: Methotrexate (MTX), alongside fumaric acid esters, is the most commonly used drug in the systemic therapy of psoriasis in Germany. It is sometimes used in combination with topical therapy and/or phototherapy due to synergistic effects. CASE REPORT: Here we describe a case of phototoxic dermatitis during treatment with MTX. Other cutaneous side effects of MTX include so-called UV recall, radiation recall, and skin tumor formation.

Radiotherapy-induced skin reactions: prevention and cure.

This article describes the prophylactic use of Mepitel Film in three breast-cancer patients undergoing adjuvant radiotherapy. Each patient had significant risk factors for developing severe radiotherapy-induced skin reactions. This article details the experience encountered by these patients through their treatment courses, with observations by the review radiographers responsible for the care and support of these patients during their radiotherapy and the patients themselves. The film was found to be easy to use by the clinical team and resulted in a significant reduction in adverse side effects to the skin, with an associated improvement in patient satisfaction. There was found to be a financial benefit with the use of Mepitel Film when compared to the foam dressings often required for wound management if the patients had suffered moist desquamation.

[The treatment of chronic wounds in the head and neck area after radiotherapy with medical honey]. / Die Behandlung chronischer Wunden im Kopf-Hals-Bereich nach Radiatio mit medizinischem Honig.

BACKGROUND: Wound healing problems and chronic wounds can be a therapeutic challenge are a frequent problem after radiotherapy. They can appear spontaneously or after further surgery. The permanently altered tissue is associated with recurrent bacterial infections with weeping wounds, which cannot be treated sufficiently by conventional conservative wound care. The topical application of medical honey seems to have a positive effect in such cases. The aim of this prospectively study is to check this effectiveness in the treatment of wound healing problems and chronic wounds in the head and neck area of irradiated patients. PATIENTS AND METHODS: In the period of July 2012 until August 2013 nine patients were treated with medical honey. All pa-tients had previously radiotherapy in the head and neck area. 5 patients had protracted wound healing problems after salvage surgery. The remaining 4 cases had spontaneously dehiscenced wounds at the beginning of the study. The wound healing was confirmed by measurement of the wound edges and depth and by adequate photo documentation. RESULTS: In all cases, the conventional wound care was unsuccessfully. In 8 of 9 cases, the wounds could be brought to cure by the application of medical honey over 3-8 weeks. Side effects or allergic reactions to the medical honey were not seen in any -cases. CONCLUSION: Based on our clinical experience we believe that the topical application of medical honey in non-healing or recurrent wounds in the head and neck area after radiotherapy is a reason-able and successful alternative therapy.

[Radio-induced breast morphoea: an unrecognized complication]. / Morphée du sein radio-induite : une complication méconnue.

Morphoea is a localized scleroderma. Since the 1990s, it is described as a complication after irradiation for breast cancer. This complication is unrecognized and underdiagnosed. Irradiation seems to be a factor inducing an autoimmune process. Clinicians should be aware in case of an erythema in a treated area, appearing on average one year after the end of the irradiation. Histology alone can prove the diagnosis and rule out differential diagnoses: principally mastitis (carcinomatous, infectious), chronic radiodermatitis or radiation recall. Treatment of this rare complication is not consensual; it is most often topical steroids. The evolution is marked by a gradual decrease from the initial inflammation. Sclerosis persists, more or less substantially.

[Evaluation and management of acute radiation dermatitis]. / Évaluation et prise en charge de la toxicité cutanée en cours de radiothérapie.

Acute radiation dermatitis remains one of the most commonly observed side effect during radiation therapy leading to complication such as superinfection or treatment disruption. Its management is characterized by a great heterogeneity. Few strategies have demonstrated a benefit in preventing radiation dermatitis, which relies mostly on decreasing dose delivered to the skin and skin care practices. Simple emollients and use of topical steroids can be useful in early stages. The singularity of the skin toxicity seen with cetuximab and radiotherapy warrants a specific grading system and distinctive clinical treatment with use of antibiotics.

Preliminary results of (125)I interstitial brachytherapy for locally recurrent parotid gland cancer in previously irradiated patients.

BACKGROUND: The purpose of this study was to analyze the treatment of recurrent parotid gland cancers with radioactive iodine ((125)I) seed implantation. METHODS: Fifteen patients with recurrent previously irradiated parotid gland cancers were treated with postoperative (125)I seed implantation between April 2004 and June 2009. Local control, survival rates, and side effects were retrospectively reviewed. RESULTS: The 3-year and 5-year local control rates were 67% and 53.6%, and the overall survival rates were 76.2% and 66.7%, respectively. Four patients with House-Brackman (H-B) grade IV cancer recovered to grade II during follow-up. Four patients (26.7%) developed grade IV skin ulceration. Two patients (13.3%) developed moderate fibrosis of the subcutaneous tissues, and 2 patients (13.3%) had hearing loss for 1 year after brachytherapy. CONCLUSION: This study showed excellent local control and a good survival rate in patients who received (125)I brachytherapy. These findings should be interpreted cautiously due to the small number of patients and the relatively short follow-up.

[Treatment and prevention of acute radiation dermatitis]. / Traitement et prévention des radiodermites aiguës.

Acute radiation dermatitis is a common side-effect of radiotherapy which often necessitates interruption of the therapy. Currently, there is no general consensus about its prevention or about the treatment of choice. The goal of this work was to focus on optimal methods to prevent and manage acute skin reactions related to radiation therapy and to determine if there are specific topical or oral agents for the prevention of this acute skin reaction. The prevention and the early treatment are the two focus points of the management of the acute radiation dermatitis.

[Importance of local skin treatments during radiotherapy for prevention and treatment of radio-induced epithelitis]. / Intérêt des applications cutanées en cours de radiothérapie pour la prévention et le traitement des épithéliites radio-induites.

Radio-epithelitis represents a common problem, for which treatments are characterized by a great heterogeneity. The present review of literature focuses on data referenced in Pubmed((c))/Medline((c)) and published in French/English. Despite a real preclinical rationale, aloe vera and trolamine failed to demonstrate any benefit in the prophylactic settings. In a prospective assessment phase III assessment, Calendula Officinalis was shown to be superior to trolamine for the prevention of radio-epithelitis. In the curative settings, sucrafalte failed to demonstrate any benefit. The benefit of dermocorticoids was suggested in terms of erythema and itching. Promising clinical results are available with hyaluronic acid (MA S065D and Ialugen) and silver leaf may reduce the intensity of cutaneous radio-induced side effects. Data from the literature are conflicting, making real the difficulty to adopt from clinical trials any proof-of-principle strategy. Considering these uncertainties, several strategies are allowed. New topics are under investigation. Present data from the literature highlight the need for further trials, in order to propose evidence-based treatments and to harmonize clinical practice.

Homeopathic medicines for adverse effects of cancer treatments.

BACKGROUND: Homeopathic medicines are used by patients with cancer, often alongside conventional treatment. Cancer treatments can cause considerable morbidity and one of the reasons patients use homeopathic medicines is to help with adverse effects. OBJECTIVES: Evaluate effectiveness and safety of homeopathic medicines used to prevent or treat adverse effects of cancer treatments. SEARCH STRATEGY: The following were searched up to November 2008: Cochrane PaPaS Trials Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; CINAHL; BNI; CancerLIT; AMED; CISCOM; Hom-Inform; SIGLE; National Research Register; Zetoc; www.controlled-trials.com; http://clinicaltrials.gov; Liga Medicorum Homeopathica Internationalis (LMHI, Liga) conference proceedings; reference lists of relevant studies were checked; and homeopathic manufacturers, leading researchers and practitioners were contacted. SELECTION CRITERIA: Randomised controlled trials (RCTs) of homeopathic medicines in participants with a clinical or histological diagnosis of cancer where the intervention was aimed at preventing or treating symptoms associated with cancer treatments. All age groups, and all stages of disease were included. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and two review authors extracted data. Three review authors independently assessed trial quality using the Delphi List and the Cochrane Collaboration's tool for assessing risk of bias. Disagreements were resolved by consensus. Where available, data were extracted for analysis. MAIN RESULTS: Eight controlled trials (seven placebo controlled and one trial against an active treatment) with a total of 664 participants met the inclusion criteria. Three studied adverse effects of radiotherapy, three studied adverse effects of chemotherapy and two studied menopausal symptoms associated with breast cancer treatment.Two studies with low risk of bias demonstrated benefit: one with 254 participants demonstrated superiority of topical calendula over trolamine (a topical agent not containing corticosteroids) for prevention of radiotherapy-induced dermatitis, and another with 32 participants demonstrated superiority of Traumeel S (a proprietary complex homeopathic medicine) over placebo as a mouthwash for chemotherapy-induced stomatitis. Two other studies reported positive results, although the risk of bias was unclear, and four further studies reported negative results.No serious adverse effects or interactions were reported attributable to the homeopathic medicines used. AUTHORS' CONCLUSIONS: This review found preliminary data in support of the efficacy of topical calendula for prophylaxis of acute dermatitis during radiotherapy and Traumeel S mouthwash in the treatment of chemotherapy-induced stomatitis. These trials need replicating. There is no convincing evidence for the efficacy of homeopathic medicines for other adverse effects of cancer treatments. Further research is required.