Personalized Radiation Attenuating Materials for Gastrointestinal Mucosal Protection.

Cancer patients undergoing therapeutic radiation routinely develop injury of the adjacent gastrointestinal (GI) tract mucosa due to treatment. To reduce radiation dose to critical GI structures including the rectum and oral mucosa, 3D-printed GI radioprotective devices composed of high-Z materials are generated from patient CT scans. In a radiation proctitis rat model, a significant reduction in crypt injury is demonstrated with the device compared to without (p < 0.0087). Optimal device placement for radiation attenuation is further confirmed in a swine model. Dosimetric modeling in oral cavity cancer patients demonstrates a 30% radiation dose reduction to the normal buccal mucosa and a 15.2% dose reduction in the rectum for prostate cancer patients with the radioprotectant material in place compared to without. Finally, it is found that the rectal radioprotectant device is more cost-effective compared to a hydrogel rectal spacer. Taken together, these data suggest that personalized radioprotectant devices may be used to reduce GI tissue injury in cancer patients undergoing therapeutic radiation.

BMP Antagonists Secreted by Mesenchymal Stromal Cells Improve Colonic Organoid Formation: Application for the Treatment of Radiation-induced Injury.

Radiation therapy is crucial in the therapeutic arsenal to cure cancers; however, non-neoplastic tissues around an abdominopelvic tumor can be damaged by ionizing radiation. In particular, the radio-induced death of highly proliferative stem/progenitor cells of the colonic mucosa could induce severe ulcers. The importance of sequelae for patients with gastrointestinal complications after radiotherapy and the absence of satisfactory management has opened the field to the testing of innovative treatments. The aim of this study was to use adult epithelial cells from the colon, to reduce colonic injuries in an animal model reproducing radiation damage observed in patients. We demonstrated that transplanted in vitro-amplified epithelial cells from colonic organoids (ECO) of C57/Bl6 mice expressing green fluorescent protein implant, proliferate, and differentiate in irradiated mucosa and reduce ulcer size. To improve the therapeutic benefit of ECO-based treatment with clinical translatability, we performed co-injection of ECO with mesenchymal stromal cells (MSCs), cells involved in niche function and widely used in clinical trials. We observed in vivo an improvement of the therapeutic benefit and in vitro analysis highlighted that co-culture of MSCs with ECO increases the number, proliferation, and size of colonic organoids. We also demonstrated, using gene expression analysis and siRNA inhibition, the involvement of bone morphogenetic protein antagonists in MSC-induced organoid formation. This study provides evidence of the potential of ECO to limit late radiation effects on the colon and opens perspectives on combined strategies to improve their amplification abilities and therapeutic effects.

Effectiveness of Low-Level Laser Therapy with a 915 Nm Wavelength Diode Laser on the Healing of Intraoral Mucosal Wound: An Animal Study and a Double-Blind Randomized Clinical Trial.

Background and objectives: Diode laser has been the most popular low-level laser therapy (LLLT) technique in dentistry due to its good tissue penetration, lower financial costs, small size for portable application, and convenience to use. A series of recent studies with 940 nm or 980 nm lasers demonstrated that LLLT showed positive effects after third molar extraction or periodontal flap surgery. However, the effects of LLLT on intraoral mucosal wound healing after surgical incision have not yet been determined in human clinical study. Materials and Methods: The present study was performed to determine the efficacy and safety of 915 nm wavelength low-level laser therapy (LLLT) in mucosal wound healing. A total of 108 Sprague-Dawley rats were used. They were divided into three groups: Abrasive wound group, immediate LLLT once group, and daily LLLT group. As a clinical study, a total of 16 patients with split-mouth design subjected to bilateral mandibular third molar extraction were allocated into the LLLT group and placebo group. The process of LLLT was performed on postoperative days 0, 1, and 7, and parameters related to wound healing were analyzed on days 1, 7, and 14. Results: Repeated laser irradiation promoted mucosal wound healing of the rats. In the clinical study, although there were no significant statistical differences between the LLLT and placebo groups in all inflammatory parameters, the early stage mucosal healing tendency of wound dehiscence was higher in the LLLT group than in the placebo group clinically on postoperative day 1. Conclusions: The present results showed that 915 nm LLLT could be applied safely as an auxiliary therapy for mucosal wound healing.

IMRT-based treatment of unknown primary malignancy of the head and neck: Outcomes and improved toxicity with decreased mucosal dose and larynx sparing.

BACKGROUND: Radiation therapy for squamous cell cancer of the head and neck with unknown primary (head and neck CUP) has been associated with significant levels of swallowing toxicity. We examined the effect of changes in mucosal dose on development of laryngeal strictures and percutaneous endoscopic gastrostomy (PEG) dependence. METHODS: Retrospective analysis of 58 patients with head and neck CUP treated with intensity-modulated radiation therapy (IMRT) at the Dana Farber Cancer Institute from August 2004 through July 2013. RESULTS: There were no significant differences between any recurrences for groups treated to 56 versus ≥60 Gy to the mucosal surfaces. However, mucosal dose and chemotherapy type were associated with stricture on multivariable analysis; median PEG dependence was decreased for patients treated to 56 Gy. A larynx-sparing approach was associated with improved outcomes for strictures and PEG use. CONCLUSION: In this single institution study, a 56 Gy IMRT-based mucosal dose demonstrated significant improvements in swallowing toxicity. Additional benefit was seen with larynx-sparing IMRT.

Blue light-emitting diode in healthy vaginal mucosa-a new therapeutic possibility.

A healthy female genital mucosa has an ecosystem that remains in balance through interactions between endogenous and exogenous factors. The light-emitting diode (LED) is a device that emits light at different wavelengths, with varying color and effects. Blue light in humans is most commonly used for antimicrobial purposes and has been already applied to treat facial acne and gastric bacteria. Although blue LED therapy in humans has been reported, its properties against vaginal infections have not yet been investigated. This study aims to test the safety and effects of 401 ± 5 nm blue LED on healthy vaginal mucosa. Phase I clinical trial involving 10 women between 18 and 45 years old with healthy vaginal mucosa. The participants were illuminated by 401 ± 5 nm blue LED for 30 min and anamnesis, oncotic cytology, and pH measurement were made again after 21/28 days of treatment. In the re-evaluation, adverse effects were investigated. The mean age was 27 ± 5.4 years and one of the women was excluded due to interruption of use of oral contraceptives. Oncotic cytology done before and after therapy showed that the composition of the microflora remained normal in all participants. Vaginal pH remained unchanged in eight of the women and had a reduction in one woman (5.0-4.0). No adverse effects were observed during or after illumination. 401 ± 5 nm blue LED did not generate any adverse effects or pathogenic changes in the microflora and vaginal pH. The effects of 401 ± 5 nm blue LED still need to be tested in vulvovaginal pathogens. Trial registration number: NCT03075046.

Early effects of irradiation on laryngeal mucosa in a gastroesophageal reflux model: an experimental study.

OBJECTIVE: The aim of this study was to evaluate the early histopathological changes of gastroesophageal reflux and irradiation on laryngeal mucosa in rats. STUDY DESIGN: Animal study. SETTING: Experimental animal laboratory, tertiary referral center. SUBJECT AND METHOD: Twenty-four adult female Wistar Albino rats were grouped as: control (n = 6), reflux and irradiation (n = 10), and irradiation (n = 8). Rats were operated to create a reflux model 30 days before irradiation. Ionizing radiation was administered in a single fraction of a 20 Gy to the larynx. Laryngeal tissue samples were taken at the 4th day of irradiation and all specimens underwent histopathological examination. RESULTS: Edema and vascular dilation in lamina propria were higher in the reflux and irradiation, and irradiation groups than control group. Inflammation was higher in the reflux and irradiation group than the control group. Inflammation in squamous epithelium was higher in the reflux and irradiation and irradiation groups compared to the control group. Inflammation in the squamous epithelium of the irradiation group was higher than the reflux and irradiation group. In the respiratory tract epithelium, inflammation was higher in the reflux and irradiation group; additionally, a significant loss of cilia was present in the reflux and irradiation and irradiation groups while pseudostratification was higher in the reflux and irradiation group. CONCLUSION: Ionizing radiation-induced inflammation may increase on previously inflammated area due to gastroesophageal reflux. Therefore, it may be helpful to investigate and treat the reflux in laryngeal cancer patients that will receive ionizing radiation.

Nutritional strategies to prevent gastrointestinal toxicity during pelvic radiotherapy.

Radiotherapy-induced damage to non-cancerous gastrointestinal mucosa has effects on secretory and absorptive functions and can interfere with normal gastrointestinal physiology. Nutrient absorption and digestion may be compromised. Dietary manipulation is an attractive option with sound rationale for intervention. The aim of this review was to synthesise published evidence for the use of elemental formulae, low or modified fat diets, fibre, lactose restriction and probiotics, prebiotics and synbiotics to protect the bowel from gastrointestinal side effects during long-course, radical pelvic radiotherapy. Thirty original studies (recruiting n 3197 patients) were identified comprising twenty-four randomised controlled trials, four cohort studies and two comparator trials. Endpoints varied and included symptom scales (Inflammatory Bowel Disease Questionnaire, Common Technology Criteria for Adverse Events, Radiation Therapy Oncology Group) and Bristol Stool Scale. Dietary and supplement interventions were employed with many studies using a combination of interventions. Evidence from RCT was weak for elemental, low or modified fat and low-lactose interventions and modestly positive for the manipulation of fibre during radiotherapy. Evidence for probiotics as prophylactic interventional agents was more promising with a number of trials reporting positive results but strength and strains of interventions vary, as do methodologies and endpoints making it difficult to arrive at firm conclusions with several studies lacking statistical power. This consolidated review concludes that there is insufficient high-grade evidence to recommend nutritional intervention during pelvic radiotherapy. Total replacement of diet with elemental formula could be effective in severe toxicity but this is unproven. Probiotics offer promise but cannot be introduced into clinical practice without rigorous safety analysis, not least in immunocompromised patients.

Comparative study on the incision healing of the palatal mucosa by using Er:YAG laser or traditional scalpel in the SD rats.

The aim of this study was to compare the histology of wound healing following incisions with the scalpel or the Er:YAG laser in the palatal mucosa of SD rats. Two types of wounds were performed with the stainless steel scalpel or the Er:YAG laser in the palatal mucosa of SD rats, while the adjacent untreated palatal mucosa was chosen as control. Rats were sacrificed on day 1, day 3, day 7, and day 30 post-surgery. Biopsy samples from each wound were examined and the expression of IL-1ß and TGF-ß1 was determined by enzyme-linked immunosorbent assay (ELISA). The early postoperative incision of the scalpel group had obvious bleeding and swelling, while the laser wound mainly covered the surface of white pseudomembrane. The infiltration of neutrophils and lymphocytes in the stroma of the scalpel incision was more than that of the laser group. Compared to the laser group, 1 and 3 days after operation, the TGF-ß1 content of the scalpel group were significantly increased (P = 0.032 and 0.019). Seven days after operation, the TGF-ß1 content of two groups was decreased. TGF-ß1 expression of control group was obviously increased (P > 0.05); 1, 3, and 7 days after operation, the traditional scalpel amount of IL-1ß expression was significantly higher than that of control group (P = 0.000, 0.000, and 0.001). Postoperative day 1, IL-1ß expression of laser group and control group had no significant difference (P = 0.572). Three days after operation, IL-1ß expression of laser incision was increased and was significantly higher than that in control group (P = 0.032), however lower than the scalpel group (P = 0.03). Seven days after operation, the IL-1ß expression of two groups had no significant difference (P = 0.333); however, the IL-1ß expression of two groups were significantly higher than that of the control group (P = 0.02 and 0.001). Compared to the traditional scalpel, the incision of Er:YAG laser has smaller inflammation reaction, more pseudomembrane coverage, and minimal damage of the mucoperiosteal tissue.

Comparison of different treatment planning optimization methods for vaginal HDR brachytherapy with multichannel applicators: A reduction of the high doses to the vaginal mucosa is possible.

PURPOSE: A direct planning approach with multi-channel vaginal cylinders (MVCs) used for HDR brachytherapy of vaginal cancers is particularly challenging. Purpose of this study was to compare the dosimetric performances of different forward and inverse methods used for the optimization of MVC-based vaginal treatments for endometrial cancer, with a particular attention to the definition of strategies useful to limit the high doses to the vaginal mucosa. METHODS: Twelve postoperative vaginal HDR brachytherapy treatments performed with MVCs were considered. Plans were retrospectively optimized with three different methods: Dose Point Optimization followed by Graphical Optimization (DPO + GrO), Inverse Planning Simulated Annealing with two different class solutions as starting conditions (surflPSA and homogIPSA) and Hybrid Inverse Planning Optimization (HIPO). Several dosimetric parameters related to target coverage, hot spot extensions and sparing of organs at risk were analyzed to evaluate the quality of the achieved treatment plans. Dose homogeneity index (DHI), conformal index (COIN) and a further parameter quantifying the proportion of the central catheter loading with respect to the overall loading (i.e., the central catheter loading index: CCLI) were also quantified. RESULTS: The achieved PTV coverage parameters were highly correlated with each other but uncorrelated with the hot spot quantifiers. HomogIPSA and HIPO achieved higher DHIs and CCLIs and lower volumes of high doses than DPO + GrO and surflPSA. CONCLUSIONS: Within the investigated optimization methods, HIPO and homoglPSA showed the highest dose homogeneity to the target. In particular, homogIPSA resulted also the most effective in reducing hot spots to the vaginal mucosa.

Radiation therapy: Managing GI tract complications.

Here's how to recognize radiation-related adverse effects so that you can expedite care and help preserve your patient's quality of life.

Oral mucosal melanoma treated with carbon ion radiotherapy: a case report.

BACKGROUND: Oral mucosal melanoma is a rare disease with a relatively poor prognosis. Carbon ion radiotherapy has been shown to be effective against radiotherapy-resistant tumors owing to its excellent dose concentration and high biological effect. CASE PRESENTATION: Our patient was a 66-year-old Japanese man with oral mucosal melanoma of his right maxillary gingiva (T4aN0M0). He received carbon ion radiotherapy at 57.6 Gy (relative biological effectiveness) in 16 fractions for 4 weeks. Concomitant chemotherapy (dacarbazine + nimustine + vincristine) was administered at the same time as carbon ion radiotherapy initiation. Two courses of adjuvant chemotherapy were given after carbon ion radiotherapy. Although he experienced grade 2 acute oral mucositis, his symptoms improved within a few weeks of undergoing carbon ion radiotherapy. He was alive at the time of reporting, 35 months after treatment, without any recurrence. Late toxicity has not been observed. CONCLUSIONS: Carbon ion radiotherapy for oral mucosal melanoma resulted in a good local effect.

Radiation Therapy Did Not Induce Long-Term Changes in Rectal Mucosa: Results From the Randomized Scandinavian Prostate Cancer Group 7 Trial.

PURPOSE: To investigate long-term changes in the rectal mucosa after curative external beam radiation therapy in the treatment of prostate cancer. METHODS AND MATERIALS: In the Scandinavian Prostate Cancer Group 7 trial, 880 men with locally advanced prostate cancer were randomized to hormonal therapy alone versus hormonal therapy plus radiation therapy to 70 Gy. A subcohort from this trial being randomized at our center (n=178) was invited to a study on late anorectal side effects during 2003-2005, approximately 5 years after treatment, including measuring health-reported quality of life and physician-assessed toxicity score by the Late Effects Normal Tissue Task Force/Subjective, Objective, Management, Analytic (LENT/SOMA) and European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group score. Sixty-seven patients had a rectal mucosa biopsy. Sixty-four biopsies were included in the final analysis, of which 33 patients were randomized to hormonal treatment and 31 to hormonal treatment plus radiation therapy. The presence of fibrosis, number of capillaries, and lymphocyte infiltration was then evaluated by light microscopy. RESULTS: The group receiving radiation therapy had significantly higher LENT/SOMA and function/bother scale scores than the group that only received hormonal treatment, but there was no significant difference in the presence of fibrosis, ectasia, number of capillaries in the lamina propria, or lymphocyte infiltration between the groups. CONCLUSION: Radiation therapy to 70 Gy to the prostate does not induce long-term microscopic mucosal changes in the rectum 5 years after treatment. This is in contrast to the general assumption that structural changes, including fibrosis, seen after radiation therapy include the mucosa. We speculate that the main late effects of radiation therapy on the structure of the rectum are located in the deeper layers of the rectal wall than the mucosa.

Total Mucosal Irradiation with Intensity-modulated Radiotherapy in Patients with Head and Neck Carcinoma of Unknown Primary: A Pooled Analysis of Two Prospective Studies.

AIMS: To determine the clinical outcomes of an intensity-modulated radiotherapy technique for total mucosal irradiation (TM-IMRT) in patients with head and neck carcinoma of unknown primary (HNCUP). MATERIALS AND METHODS: A single-centre prospective phase II trial design was used in two sequential studies to evaluate TM-IMRT for HNCUP. Patients were investigated for primary tumour site using examination under anaesthetic and biopsies, computed tomography ± magnetic resonance imaging (MRI) or 18-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT). Patients received IMRT to the potential primary tumour sites and elective cervical nodes. Concomitant chemotherapy was used in patients who received primary radiotherapy or those with nodal extracapsular extension. RESULTS: Thirty-six patients with HNCUP were recruited; 72% male. Twenty-five patients (69.4%) had p16-positive disease. Two year mucosal and local nodal control rates were 97.1% (95% confidence interval 91.4-100) and 89.8% (78.4-100), respectively. One mucosal primary was detected 7.3 months after TM-IMRT and three patients died from recurrent/metastatic squamous cell carcinoma of the head and neck. Twelve patients (33%) developed grade 3 (Late Effects in Normal Tissue-Subjective, Objective, Management and Analytical; LENT-SOMA) dysphagia with a 1 year enteric tube feeding rate of 2.7%. The high-grade subjective xerostomia rate (LENT-SOMA) at 24 months after IMRT was 15%. CONCLUSIONS: At a median follow-up of 36.1 months, the use of TM-IMRT was associated with good local control. Toxicity was comparable with previously reported TM-IMRT regimens encompassing similar mucosal volumes.

Comparison of International Guidelines on Mucosal Melanoma of the Head and Neck: A Comprehensive Review of the Role of Radiation Therapy.

Mucosal melanomas of the head and neck are rare pathological entities that correlate with poor prognosis due to their high propensity for local failure and distant metastases. The exact role of radiation therapy in the management of mucosal melanoma patients has not yet been fully proven, even though in everyday clinical practice these patients are referred for radiotherapy, in an effort to improve locoregional control. The guidelines of various societies on the role of radiation therapy for the treatment of mucosal melanoma of the head and neck region are very limited. We reviewed and analyzed the guidelines developed in the U.S.A. (National Comprehensive Cancer Network), Canada (Cancer Care Ontario and Canadian Medical Association), Europe (European Society for Medical Oncology and European Society for Radiotherapy and Oncology) and Australia and New Zealand (Cancer Council Australia) and isolated evidence for the management of mucosal melanomas of the head and neck region with radiation therapy worldwide.

Asian expert recommendation on management of skin and mucosal effects of radiation, with or without the addition of cetuximab or chemotherapy, in treatment of head and neck squamous cell carcinoma.

With increasing numbers of patients with unresectable locoregionally advanced (LA) head and neck squamous cell carcinoma (HNSCC) receiving cetuximab/radiotherapy (RT), several guidelines on the early detection and management of skin-related toxicities have been developed. Considering the existing management guidelines for these treatment-induced conditions, clinical applicability and standardization of grading methods has remained a cause of concern globally, particularly in Asian countries. In this study, we attempted to collate the literature and clinical experience across Asian countries to compile a practical and implementable set of recommendations for Asian oncologists to manage skin- and mucosa-related toxicities arising from different types of radiation, with or without the addition of cetuximab or chemotherapy. In December 2013, an international panel of experts in the field of head and neck cancer management assembled for an Asia-Pacific head and neck cancer expert panel meeting in China. The compilation of discussion outcomes of this meeting and literature data ultimately led to the development of a set of recommendations for physicians with regards to the approach and management of dermatological conditions arising from RT, chemotherapy/RT and cetuximab/RT, and similarly for the approach and management of mucositis resulting from RT, with or without the addition of chemotherapy or cetuximab. These recommendations helped to adapt guidelines published in the literature or text books into bedside practice, and may also serve as a starting point for developing individual institutional side-effect management protocols with adequate training and education.

Multichannel vaginal cylinder brachytherapy-Impact of tumor thickness and location on dose to organs at risk.

PURPOSE: Multichannel vaginal cylinder brachytherapy (MCVCB) has the potential to sculpt dose distribution, although this is typically reserved for lesions <5-mm thick. The aim of this study was to investigate the dosimetric consequences of treating lesions with MCVCB of varying locations, ≥5 mm in thickness. METHODS AND MATERIALS: Patients previously treated with MCVCB were randomly selected to each fill one of six categories based on location (lateral, anterior, or vaginal cuff and/or apex) and size of cylinder (2.5 or 3.0 cm). Based on magnetic resonance image, each patient's target lesion was extended circumferentially into theoretical high-risk clinical target volumes measuring 5, 7, and 10 mm in thickness. Image-based brachytherapy treatment plans for each of the six patients' three target volumes were generated. Total 2 Gy per fraction equivalent dosages (EQD2) were calculated using an external beam radiation therapy dose of 45 Gy in 25 fractions in conjunction with a high-dose-rate brachytherapy dose of 25 Gy in five fractions. RESULTS: Maximum EQD2 vaginal surface doses in gray for 5-, 7-, and 10-mm targets were as follows (location-cylinder size): lateral-3.0 cm: 122/153/210, lateral-2.5 cm: 145/195/301, anterior-3.0 cm: 115/135/197, anterior-2.5 cm: 132/173/283, apex-3.0 cm: 173/241/367, and apex-2.5 cm: 349/461/706. Total rectal EQD2 D 2 cc ranged from 53.9 to 67.2 Gy. Total bladder EQD2 D 2 cc ranged from 51.5 to 71.2 Gy. CONCLUSIONS: The vaginal surface dose seems to be the dose-limiting structure for anterior, lateral, and apical vaginal lesions. Caution should be taken when treating lesions >5 mm in depth, with particular attention to vaginal surface dose, especially for apical lesions and with smaller cylinders. In such cases, interstitial brachytherapy should be given strong consideration.

[Mucosal tolerance and low level laser therapy: Is the delegation to radiation technicians possible?]. / Tolérance muqueuse et laser de basse énergie : la délégation aux manipulateurs en radiothérapie est-elle possible ?

Mucositis remains a frequent complication of radiotherapy. Low level laser applications are used to accelerate the healing process. This technique is used routinely in our centre. It is performed by delegation by radiotherapists. The conditions of this delegation of tasks are addressed here.

Microscopic and ultrastructural modifications of postmenopausal atrophic vaginal mucosa after fractional carbon dioxide laser treatment.

Vaginal atrophy occurring during menopause is closely related to the dramatic decrease in ovarian estrogens due to the loss of follicular activity. Particularly, significant changes occur in the structure of the vaginal mucosa, with consequent impairment of many physiological functions. In this study, carried out on bioptic vaginal mucosa samples from postmenopausal, nonestrogenized women, we present microscopic and ultrastructural modifications of vaginal mucosa following fractional carbon dioxide (CO2) laser treatment. We observed the restoration of the vaginal thick squamous stratified epithelium with a significant storage of glycogen in the epithelial cells and a high degree of glycogen-rich shedding cells at the epithelial surface. Moreover, in the connective tissue constituting the lamina propria, active fibroblasts synthesized new components of the extracellular matrix including collagen and ground substance (extrafibrillar matrix) molecules. Differently from atrophic mucosa, newly-formed papillae of connective tissue indented in the epithelium and typical blood capillaries penetrating inside the papillae, were also observed. Our morphological findings support the effectiveness of fractional CO2 laser application for the restoration of vaginal mucosa structure and related physiological trophism. These findings clearly coupled with striking clinical relief from symptoms suffered by the patients before treatment.

Severe retinopathy following radiation therapy with a moderate dose for orbital mucosa-associated lymphoid tissue lymphoma.

Mucosa-associated lymphoid tissue (MALT) lymphoma is a radiosensitive malignancy. We report on a case of severe retinopathy following radiation therapy with a moderate dose for orbital MALT lymphoma. A 69-year-old woman with orbital MALT lymphoma received definitive radiation therapy with a total dose of 36 Gy in 18 fractions. The patient showed complete response but had severe retinopathy along with marked deterioration in visual acuity at 2 years after irradiation. Although the patient underwent treatments for retinopathy, including laser photocoagulation and steroid injection, improvement of the visual acuity was modest. This case developed severe radiation-induced retinopathy after radiation therapy with the moderate dose of 36 Gy that is considered to be usually safe.

TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma.

BACKGROUND: Recently, TERT promoter mutations were identified at high frequencies in cutaneous melanoma tumor samples and cell lines. The mutations were found to have a UV-signature and to lead to increased TERT gene expression. We analyzed a large cohort of melanoma patients for the presence and distribution of TERT promoter mutations and their association with clinico-pathological characteristics. METHODS: 410 melanoma tumor samples were analyzed by Sanger sequencing for the presence of TERT promoter mutations. An analysis of associations between mutation status and various clinical and pathologic variables was performed. RESULTS: TERT promoter mutations were identified in 154 (43%) of 362 successfully sequenced melanomas. Mutation frequencies varied between melanoma subtype, being most frequent in melanomas arising in nonacral skin (48%) and melanomas with occult primary (50%), and less frequent in mucosal (23%), and acral (19%) melanomas. Mutations carried a UV signature (C>T or CC>TT). The presence of TERT promoter mutations was associated with factors such as BRAF or NRAS mutation (P < .001), histologic type (P = .002), and Breslow thickness (P < .001). TERT promoter mutation was independently associated with poorer overall survival in patients with nonacral cutaneous melanomas (median survival 80 months vs 291 months for wild-type; hazard ratio corrected for other covariates 2.47; 95% confidence interval [CI] = 1.29 to 4.74; P = .006). CONCLUSIONS: UV-induced TERT promoter mutations are one of the most frequent genetic alterations in melanoma, with frequencies varying depending on melanoma subtype. In nonacral cutaneous melanomas, presence of TERT promoter mutations is independently associated with poor prognosis.