Comprehensive analysis of body composition features in melanoma patients treated with tyrosine kinase inhibitors.

BACKGROUND: The introduction of tyrosine kinase inhibitors (TKI) has greatly improved the management of metastatic melanoma. Recent studies have uncovered a relationship between the body mass index (BMI) and outcome of patients with metastatic melanoma. However, conflicting results have challenged the relevance of this finding. In the current work, we aim to dissect body composition features of melanoma patients treated with TKI to evaluate their value as biomarkers. PATIENTS AND METHODS: We analyze body composition features via CT scans in a retrospective cohort of 57 patients with non-resectable stage III/IV melanoma receiving first-line treatment with TKI in our department, focusing on the impact of body composition on treatment efficacy and occurrence of adverse events. RESULTS: In uni- and multivariate analyses, we identify an association between the visceral adipose tissue gauge index (VATGI) and survival. We furthermore profile additional body composition features including sarcopenia, which was also associated with a shorter overall survival. Finally, we detected an enrichment of cases with fatigue in patients with low VATGI. CONCLUSIONS: Our study represents the first exploratory study evaluating the suitability of body composition measurements as biomarkers for melanoma patients treated with TKI. Our data suggest a putative use of VATGI as a biomarker predicting patient outcome.

Low skeletal muscle mass predicts melanoma-specific survival in melanoma patients treated with adjuvant immune checkpoint blockade.

PURPOSE: Adjuvant immunotherapy with immune checkpoint blockade(ICB) has greatly reduced the risk of recurrence and metastatic spread in early and advanced melanoma. However, not all patients benefit from adjuvant treatment: many patients show disease recurrence despite therapy, while those without recurrence harbor the risk for potentially irreversible adverse events. Biomarkers to select patients benefitting most from adjuvant therapy are currently lacking. As body composition assessment using CT images has shown promising results as a prognostic biomarker in stage IV melanoma, we aim to study the applicability of body composition parameters also in adjuvant melanoma treatment. METHODS: We analyze body composition features via CT scans in a retrospective cohort of 109 patients with resected stage IIB-IV melanoma receiving an adjuvant first-line treatment with ICB in our department. In this analysis, we focus on the impact of body composition, especially the presence of low skeletal muscle mass (LSMM), on patients' survival and occurrence of adverse events (AEs). RESULTS: In uni- and multivariate analyses, we identify an association between CT-measured LSMM and melanoma-specific survival in patients treated with adjuvant ICB. Furthermore, LSMM is associated with a lower risk for therapy-related AEs, especially hypothyroidism, fatigue, and xerostomia. Conventional serological biomarkers e.g. S100 and LDH and measures of adipose tissue compartments did not show a correlation with survival or the occurrence of AEs. CONCLUSIONS: LSMM constitutes a novel biomarker for melanoma-specific survival in patients treated with adjuvant ICB.

Thermal Effects on Dental Pulp during Laser-Assisted Bleaching Procedures with Diode Lasers in a Clinical Study.

Background In the current cosmetics industry, bleaching is often associated with lasers. However, such treatment also harbors risks. Tooth death is observed at pulpal temperature increases ≥5.6 °C. Therefore, it seems important to investigate the effects of using different lasers. The aim of this study was to determine pulpal temperature increases at different laser parameters during bleaching by modeling a realistic environment and to compare the temperature recording using a thermocouple and thermal camera. The authors assumed that there are laser settings for the lasers used at which the pulpal temperature increases are <5.6 °C and that the temperature recordings with thermocouples and thermal cameras differ only minimally. Methods Human teeth were used, which were extracted for dental reasons. During experiment, teeth were bleached conventionally and by laser activation at 940 nm, 445 nm, and 970 nm. The temperature in the pulp was recorded using thermocouples. In a second setup, longitudinally halved teeth were bleached, while the temperature in the pulp was recorded with a thermocouple and thermal camera. Descriptive statistics were used. The significance level is 0.05. Results In addition to conventional bleaching, temperature increases <5.6 °C were observed for bleaching at 940 nm 1.5 W, at 445 nm 0.3 W, and at 970 nm 0.5 W. For bleaching procedures using 940 nm 7 W, 940 nm 2 W, 445 nm 0.5 W, and 970 nm 1 W, the temperature increase was ≥5.6 °C. Significant differences (p < 0.05) were found in the maximum temperature increases (°C) between all groups. Temperature recordings using a thermocouple and thermal camera differed by about 2.3 °C. The working hypotheses were confirmed. Conclusion With laser bleaching, attention must be paid to the type of laser, its power, and the time in order to avoid excessive overheating of the dental pulp.

Assessment of Fitbit Charge 4 for sleep stage and heart rate monitoring against polysomnography and during home monitoring in Huntington's disease.

STUDY OBJECTIVES: Wearable devices, monitoring sleep stages and heart rate (HR), bring the potential for longitudinal sleep monitoring in patients with neurodegenerative diseases. Sleep quality reduces with disease progression in Huntington's disease (HD). However, the involuntary movements characteristic of HD may affect the accuracy of wrist-worn devices. This study compares sleep stage and heart rate data from the Fitbit Charge 4 (FB) against polysomnography (PSG) in participants with HD. METHODS: Ten participants with manifest HD wore a FB during overnight hospital-based PSG, and for nine of these participants continued to wear the FB for seven nights at home. Sleep stages (30s epochs) and minute-by-minute HR were extracted and compared against PSG data. RESULTS: FB-estimated total sleep and wake times, and sleep stage times were in good agreement with PSG, with intra-class correlations 0.79-0.96. However, poor agreement was observed for Wake After Sleep Onset, and the number of awakenings. FB detected wake with 68.6±15.5% sensitivity and 93.7±2.5% specificity, rapid eye movement (REM) sleep with high sensitivity and specificity (78.7±31.9%, 95.6±2.3%), and deep sleep with lower sensitivity but high specificity (56.4±28.8%, 95.0±4.8%). FB HR was strongly correlated with PSG, and the mean absolute error between FB and PSG HR data was 1.16 ± 0.42 bpm. At home, longer sleep and shorter wake times were observed compared to hospital data, while percentage sleep stage times were consistent with hospital data. CONCLUSIONS: Results suggest the potential for long-term monitoring of sleep patterns using wrist-worn wearable devices as part of symptom management in HD.

Evaluation of tooth color change after a bleaching process with different lasers.

The aim of this in vitro study was to evaluate the efficiency of diode laser-activated bleaching systems for color change of teeth. 75 extracted teeth were studied in five different bleaching protocols. Group 1: diode laser 445 nm, 320 µm fiber, 0.5W, continuous wave mode, dose 53 J/cm2. Group 2: diode laser 970 nm, 320 µm fiber, 1W, continuous wave mode, dose 106.10 J/cm2. Group 3: diode laser 940 nm, bleaching handpiece, 7W, continuous wave mode, dose 105 J/cm2. Group 4: diode laser 940 nm, 300 µm fiber, 2W, continuous wave mode, dose 47.16 J/cm2. Group 5: bleaching process without laser activation. In groups 1, 2 and 5, teeth were bleached with Perfect Bleach Office + and in groups 3 and 4, LaserWhite20 bleaching gel was used. Tooth color was determined immediately after the bleaching process using a spectrophotometer. Color change data on the CIE L * a * b* system was analyzed statistically by the one-way ANOVA and Tukey's HSD test. All bleaching procedures resulted in a change of color. All laser groups (∆E * ab > 3) have statistically larger ∆E * ab values than the control group (∆E * ab = 0.73) (p < 0.05). The diode laser 445 nm has the largest ∆E * ab value (∆E * ab = 4.65) and results in a significantly higher color difference than all other groups. In terms of color score difference in VITA Shades, all laser-activated groups lead to a lightening effect while the control group leads to only a slight lightening effect. The diode laser 445 nm produced the greatest color difference. Laser-activated bleaching is more effective than conventional bleaching without light activation. The diode laser 445 nm performs best in this in vitro study.

Transactivation of Met signaling by oncogenic Gnaq drives the evolution of melanoma in Hgf-Cdk4 mice.

Recent pan-cancer genomic analyses have identified numerous oncogenic driver mutations that occur in a cell-type and tissue-specific distribution. For example, oncogenic mutations in Braf and Nras genes arise predominantly in melanocytic neoplasms of the epidermis, while oncogenic mutations in Gnaq/11 genes arise mostly in melanocytic lesions of the dermis or the uvea. The mechanisms promoting cell-type and tissue-specific oncogenic events currently remain poorly understood. Here, we report that Gnaq/11 hotspot mutations occur as early oncogenic drivers during the evolution of primary melanomas in Hgf-Cdk4 mice. Additional single base substitutions in the Trp53 gene and structural chromosomal aberrations favoring amplifications of the chromosomal region containing the Met receptor gene accumulate during serial tumor transplantation and in cell lines established in vitro. Mechanistically, we found that the GnaqQ209L mutation transactivates the Met receptor. Overexpression of oncogenic GnaqQ209L in the immortalized melanocyte cell line promoted in vivo growth that was enhanced by transgenic Hgf expression in the tumor microenvironment. This cross-signaling mechanism explains the selection of oncogenic Gnaq/11 in primary Hgf-Cdk4 melanomas and provides an example of how oncogenic driver mutations, intracellular signaling cascades, and microenvironmental cues cooperate to drive cancer development in a tissue-specific fashion.

CLSM-Guided Imaging for Quantifying Endodontic Disinfection.

Elimination of microbes in the root canal system is crucial for achieving long-term success in endodontic treatment. Further efforts in study design and standardization are needed in order to improve the validity and comparability of in vitro results on endodontic disinfection procedures, in turn improving clinical outcomes. This study optimizes two models at all steps: tooth selection, pretreatment, inoculation method (by growth or centrifugation), and confocal laser scanning microscopy (CLSM)-guided imaging of LIVE/DEAD-stained specimens. Individual anatomical conditions lead to substantial differences in penetration depth. Sclerosis grading (SCG), a classification system introduced in this study, provides information about the sclerosis status of the dentine and is helpful for careful, specific, and comparable tooth selection in in vitro studies. Sonically activated EDTA for the pretreatment of roots, inoculation of Enterococcus faecalis in an overflow model, 3-4 weeks of incubation, as well as polishing of dentine slices before staining, led to advances in the visualization of bacterial penetration and irrigation depths. In contrast, NaOCl pretreatment negatively affected performance reproducibility and should be avoided in any pretreatment. Nonsclerotized teeth (SCG0) can be used for microbial semilunar-shaped inoculation by centrifugation as a "quick-and-dirty" model for initial orientation. In conclusion, CLSM-guided imaging for quantifying endodontic infection/disinfection is a very powerful method after the fine-tuning of materials and methods.

Wound healing after therapy of oral potentially malignant disorders with a 445-nm semiconductor laser: a randomized clinical trial.

OBJECTIVES: Oral potentially malignant disorders (OPMDs) are the most clinically relevant precursor lesions of the oral squamous cell carcinoma (OSCC). OSCC is one of the 15 most common cancers worldwide. OSCC is with its high rate of mortality an important cause of death worldwide. The diagnosis and therapy of clinically relevant precursor lesions of the OSCC is one of the main parts of prevention of this malignant disease. Targeted therapy is one of the main challenges concerning an oncologically safe tissue removal without overwhelming functional and aesthetic impairment. MATERIALS AND METHODS: In this randomized controlled trial, a newly introduced intraoral 445-nm semiconductor laser (2W; cw-mode; SIROLaser Blue, Dentsply Sirona, Bensheim, Germany) was used in the therapy of OPMDs. Duration and course of wound healing, pain, and scar tissue formation were compared to classical cold blade removal with primary suture by measuring remaining wound area, tissue colorimetry, and visual analogue scale. The study includes 40 patients randomized using a random spreadsheet sequence in two groups (n1 = 20; n2 = 20). RESULTS: This comparative analysis revealed a significantly reduced remaining wound area after 1, 2, and 4 weeks in the laser group compared to the cold blade group (p < 0.05). In the laser group, a significantly reduced postoperative pain after 1 week was measured (p < 0.05). CONCLUSION: Laser coagulation of OPMDs with the investigated 445-nm semiconductor laser is a safe, gentle, and predictable surgical procedure with beneficial wound healing and reduced postoperative discomfort. CLINICAL RELEVANCE: Compared to the more invasive and bloody cold blade removal with scalpel, the 445-nm semiconductor laser could be a new functional less traumatic tool in the therapy of OPMDs. The method should be further investigated with regard to the identification of further possible indications. TRAIL REGISTRATION: German Clinical Trials Register No: DRKS00032626.

Temporary Root Canal Obturation with a Calcium Hydroxide-Based Dressing: A Randomized Controlled Clinical Trial.

Successful bacterial inactivation or elimination is essential for successful outcomes in endodontics. This study investigated the efficacy of a calcium hydroxide paste (Ca(OH)2) as a temporary medical dressing for 1 week after chemomechanical root canal treatment (CMRCT). Microbiological samples from 26 patients were collected after endodontic emergency treatment as follows: (1) removal of the provisional filling material; (2) CMRCT; (3) irrigation with sodium hypochlorite I (3%); (4) medicinal insertion of Ca(OH)2; and (5) irrigation with sodium hypochlorite II (3%). A microbiological examination was carried out after the specimens had been taken from the root canals via saline and sterile paper points. CMRCT resulted in a significant reduction in total bacterial load (TBL) in the root canal (p < 0.05). Additional irrigation (3) resulted in a further significant reduction in TBL (p < 0.05). In contrast, Ca(OH)2 medication did not prevent the bacterial load from returning to the previous level immediately after CMRCT, but did not increase above that level either (p < 0.05). However, the increase in TBL was significant (p < 0.05) in comparison with the disinfection groups (I/II). Administration of Ca(OH)2 for 1 week shows that in combination with an additional disinfection procedure, an increase in TBL must be expected, but not above the level of conditions after CMRCT.

Photobiomodulation therapy assisted orthodontic tooth movement: potential implications, challenges, and new perspectives. / ­­æ¿€å ‰å ‰å­ç”Ÿç‰©è°ƒèŠ‚ç–—æ³•è¾ 助正畸牙齿移动：潜在的作用、挑战与新观点.

Over the past decade, dramatic progress has been made in dental research areas involving laser therapy. The photobiomodulatory effect of laser light regulates the behavior of periodontal tissues and promotes damaged tissues to heal faster. Additionally, photobiomodulation therapy (PBMT), a non-invasive treatment, when applied in orthodontics, contributes to alleviating pain and reducing inflammation induced by orthodontic forces, along with improving tissue healing processes. Moreover, PBMT is attracting more attention as a possible approach to prevent the incidence of orthodontically induced inflammatory root resorption (OIIRR) during orthodontic treatment (OT) due to its capacity to modulate inflammatory, apoptotic, and anti-antioxidant responses. However, a systematic review revealed that PBMT has only a moderate grade of evidence-based effectiveness during orthodontic tooth movement (OTM) in relation to OIIRR, casting doubt on its beneficial effects. In PBMT-assisted orthodontics, delivering sufficient energy to the tooth root to achieve optimal stimulation is challenging due to the exponential attenuation of light penetration in periodontal tissues. The penetration of light to the root surface is another crucial unknown factor. Both the penetration depth and distribution of light in periodontal tissues are unknown. Thus, advanced approaches specific to orthodontic application of PBMT need to be established to overcome these limitations. This review explores possibilities for improving the application and effectiveness of PBMT during OTM. The aim was to investigate the current evidence related to the underlying mechanisms of action of PBMT on various periodontal tissues and cells, with a special focus on immunomodulatory effects during OTM.

Bacteremia Prevention during Periodontal Treatment-An In Vivo Feasibility Study.

The link between periodontitis and systemic diseases has increasingly become a focus of research in recent years. In this context, it is reasonable-especially in vulnerable patient groups-to minimize bacteremia during periodontal treatment. The aim of the present in vivo feasibility study was to investigate the possibility of laser-based bacteremia prevention. Patients with stage III, grade B generalized periodontitis were therefore treated in a split-mouth design either with prior 445 nm laser irradiation before nonsurgical periodontal therapy or without. During the treatments, clinical (periodontal measures, pain sensation, and body temperature), microbiological (sulcus samples and blood cultures before, 25 min after the start, and 10 min after the end of treatment), and immunological parameters (CRP, IL-6, and TNF-α) were obtained. It was shown that periodontal treatment-related bacteremia was detectable in both patients with the study design used. The species isolated were Schaalia georgiae, Granulicatella adiacens, and Parvimonas micra. The immunological parameters increased only slightly and occasionally. In the laser-assisted treatments, all blood cultures remained negative, demonstrating treatment-related bacteremia prevention. Within the limitations of this feasibility study, it can be concluded that prior laser disinfection can reduce bacteremia risk during periodontal therapy. Follow-up studies with larger patient numbers are needed to further investigate this effect, using the study design presented here.

Photobiomodulation therapy assisted orthodontic tooth movement: potential implications, challenges, and new perspectives. / æ¿€å ‰å ‰å­ç”Ÿç‰©è°ƒèŠ‚ç–—æ³•è¾ åŠ©æ­£ç•¸ç‰™é½¿ç§»åŠ¨ï¼šæ½œåœ¨çš„ä½œç”¨ã€æŒ‘æˆ˜ä¸Žæ–°è§‚ç‚¹.

Over the past decade, dramatic progress has been made in dental research areas involving laser therapy. The photobiomodulatory effect of laser light regulates the behavior of periodontal tissues and promotes damaged tissues to heal faster. Additionally, photobiomodulation therapy (PBMT), a non-invasive treatment, when applied in orthodontics, contributes to alleviating pain and reducing inflammation induced by orthodontic forces, along with improving tissue healing processes. Moreover, PBMT is attracting more attention as a possible approach to prevent the incidence of orthodontically induced inflammatory root resorption (OIIRR) during orthodontic treatment (OT) due to its capacity to modulate inflammatory, apoptotic, and anti-antioxidant responses. However, a systematic review revealed that PBMT has only a moderate grade of evidence-based effectiveness during orthodontic tooth movement (OTM) in relation to OIIRR, casting doubt on its beneficial effects. In PBMT-assisted orthodontics, delivering sufficient energy to the tooth root to achieve optimal stimulation is challenging due to the exponential attenuation of light penetration in periodontal tissues. The penetration of light to the root surface is another crucial unknown factor. Both the penetration depth and distribution of light in periodontal tissues are unknown. Thus, advanced approaches specific to orthodontic application of PBMT need to be established to overcome these limitations. This review explores possibilities for improving the application and effectiveness of PBMT during OTM. The aim was to investigate the current evidence related to the underlying mechanisms of action of PBMT on various periodontal tissues and cells, with a special focus on immunomodulatory effects during OTM.

Autumn migration of the migrant hawker (Aeshna mixta) at the Baltic coast.

BACKGROUND: Migratory insects are important for the provision of ecosystem services both at the origin and destination sites but - apart from some iconic species - the migration routes of many insect species have not been assessed. Coastlines serve as a funnel where migrating animals including insects accumulate. Migratory behaviour and captures of dragonflies in bird traps suggest autumn migration of dragonflies along coastlines while the origin and regularity of this migration remain unclear. METHODS: Dragonfly species were caught at the bird observatory Kabli at the Baltic coast in Estonia in 2009, 2010 and 2015. For the 2015 data set, we used a stable hydrogen (H) approach to trace the potential natal origin of the migrant hawker (Aeshna mixta). RESULTS: 1079 (2009), 701 (2010) and 88 (2015) A. mixta individuals were caught during the study periods (35, 37 and 11 days in 2009, 2010 and 2015, respectively). The migration period lasted from end of August to end of September. Based on the results from our stable isotope analysis, we identified two populations of A. mixta: One (range of isotope signatures of non-exchangeable H [δ2Hn wing]: -78‰ to -112‰) had a local likely origin while the other (δ2Hn wing: -113‰ to -147‰) migrated from northerly directions even in headwind from the South. The former showed an even sex ratio whereas the actively migrating population was dominated by males. CONCLUSIONS: Our results suggest a regular southbound autumn migration of A. mixta along the Baltic coast. However, nearly half of the sampled individuals originated from the surroundings suggesting either no, partial or "leap-frog" migration. Contrary to our expectation, A. mixta did not select favourable wind conditions but continued the southbound autumn migration in the flight boundary layer even in case of headwinds. The dominance of males might indicate migration as a result of competition for resources. Further repeated, large-scale studies along the Baltic coast are necessary to pinpoint the migratory pattern and the reason for migration of A. mixta. Such studies should also comprise locations north of the known species range of A. mixta because of the rapid climate-change induced range expansion.

CD4+ T cell-induced inflammatory cell death controls immune-evasive tumours.

Most clinically applied cancer immunotherapies rely on the ability of CD8+ cytolytic T cells to directly recognize and kill tumour cells1-3. These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment4-6. The ability of CD4+ effector cells to contribute to antitumour immunity independently of CD8+ T cells is increasingly recognized, but strategies to unleash their full potential remain to be identified7-10. Here, we describe a mechanism whereby a small number of CD4+ T cells is sufficient to eradicate MHC-deficient tumours that escape direct CD8+ T cell targeting. The CD4+ effector T cells preferentially cluster at tumour invasive margins where they interact with MHC-II+CD11c+ antigen-presenting cells. We show that T helper type 1 cell-directed CD4+ T cells and innate immune stimulation reprogramme the tumour-associated myeloid cell network towards interferon-activated antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4+ T cells and tumouricidal myeloid cells orchestrate the induction of remote inflammatory cell death that indirectly eradicates interferon-unresponsive and MHC-deficient tumours. These results warrant the clinical exploitation of this ability of CD4+ T cells and innate immune stimulators in a strategy to complement the direct cytolytic activity of CD8+ T cells and natural killer cells and advance cancer immunotherapies.

Subcutaneous Fat Abundance and Density Are Associated with an Enhanced Response to Immunotherapy in Metastatic Melanoma: A Retrospective Cohort Study.

RATIONALE AND OBJECTIVES: Despite the impressive efficacy of immune checkpoint inhibitors (ICIs) in the treatment of metastatic melanoma, not all patients respond to therapy. In addition, ICI harbors the risk for serious adverse events (AEs), highlighting the need for novel biomarkers predicting treatment response and occurrence of AEs. Recently, the identification of enhanced response to ICI in obese patients has indicated that body composition might influence treatment efficacy. The aim of the current study is to assess radiologic measurements of body composition as biomarkers for treatment response and AEs to ICI in melanoma. MATERIALS AND METHODS: In the current work, we analyze adipose tissue abundance and density, as well as muscle mass via computed tomography scans in a retrospective cohort of 100 patients with non-resectable stage III/IV melanoma receiving first-line treatment with ICI in our department. From these, we investigate the impact of the subcutaneous adipose tissue gauge index (SATGI) and other parameters of body composition on treatment efficacy and occurrence of AEs. RESULTS: Low SATGI was associated with prolonged progression-free survival (PFS) in univariate and multivariate analyses (hazard ratio 2.56 [95% CI 1.18-5.55], P = .02), as well as an enhanced objective response rate (50.0% vs 27.1%; P = .02). Further analysis with a random forest survival model highlighted a nonlinear relationship between SATGI and PFS with a clear separation into high- and low-risk cohorts separated by the median. Finally, a significant enrichment of cases with vitiligo, but no other AEs, was observed in the SATGI-low cohort (11.5% vs 0%; P = .03). CONCLUSION: We identify SATGI as a biomarker predicting treatment response to ICI without increased risk for severe AEs in melanoma.

A New Mass Spectroscopy-Based Method for Assessing the Periodontal-Endodontic Interface after Intracanal Placement of Biomaterials In Vitro.

Optimizing the interface between biomaterials and dental hard tissues can prevent leakage of bacteria or inflammatory mediators into periapical tissues and thus avoid alveolar bone inflammation. In this study, an analysis system for testing the periodontal-endodontic interface using gas leakage and subsequent mass spectrometry was developed and validated using the roots of 15 single-rooted teeth in four groups: (I) roots without root canal filling, (II) roots with an inserted gutta-percha post without sealer, (III) roots with gutta-percha post and sealer, (IV) roots filled with sealer only, and (V) adhesively covered roots. Helium was used as the test gas, and its leakage rate was found by measuring the rising ion current using mass spectrometry. This system made it possible to differentiate between the leakage rates of tooth specimens with different fillings. Roots without filling showed the highest leakage values (p < 0.05). Specimens with a gutta-percha post without sealer showed statistically significantly higher leakage values than groups with a filling of gutta-percha and sealer or sealer alone (p < 0.05). This study shows that a standardized analysis system can be developed for periodontal-endodontic interfaces to prevent biomaterials and tissue degradation products from affecting the surrounding alveolar bone tissue.

Real-world outcomes using PD-1 antibodies and BRAF + MEK inhibitors for adjuvant melanoma treatment from 39 skin cancer centers in Germany, Austria and Switzerland.

BACKGROUND: Programmed death-1 (PD-1) antibodies and BRAF + MEK inhibitors are widely used for adjuvant therapy of fully resected high-risk melanoma. Little is known about treatment efficacy outside of phase III trials. This real-world study reports on clinical outcomes of modern adjuvant melanoma treatment in specialized skin cancer centers in Germany, Austria and Switzerland. METHODS: Multicenter, retrospective study investigating stage III-IV melanoma patients receiving adjuvant nivolumab (NIV), pembrolizumab (PEM) or dabrafenib + trametinib (D + T) between 1/2017 and 10/2021. The primary endpoint was 12-month recurrence-free survival (RFS). Further analyses included descriptive and correlative statistics, and a multivariate linear-regression machine learning model to assess the risk of early melanoma recurrence. RESULTS: In total, 1198 patients from 39 skin cancer centers from Germany, Austria and Switzerland were analysed. The vast majority received anti PD-1 therapies (n = 1003). Twelve-month RFS for anti PD-1 and BRAF + MEK inhibitor-treated patients were 78.1% and 86.5%, respectively (hazard ratio [HR] 1.998 [95% CI 1.335-2.991]; p = 0.001). There was no statistically significant difference in overall survival (OS) in anti PD-1 (95.8%) and BRAF + MEK inhibitor (96.9%) treated patients (p > 0.05) during the median follow-up of 17 months. Data indicates that anti PD-1 treated patients who develop immune-related adverse events (irAEs) have lower recurrence rates compared to patients with no irAEs (HR 0.578 [95% CI 0.443-0.754], p = 0.001). BRAF mutation status did not affect overall efficacy of anti PD-1 treatment (p > 0.05). In both, anti PD-1 and BRAF + MEK inhibitor treated cohorts, data did not show any difference in 12-month RFS and 12-month OS comparing patients receiving total lymph node dissection (TLND) versus sentinel lymph node biopsy only (p > 0.05). The recurrence prediction model reached high specificity but only low sensitivity with an AUC = 0.65. No new safety signals were detected. Overall, recorded numbers and severity of adverse events were lower than reported in pivotal phase III trials. CONCLUSIONS: Despite recent advances in adjuvant melanoma treatment, early recurrence remains a significant clinical challenge. This study shows that TLND does not reduce the risk of early melanoma recurrence and should only be considered in selected patients. Data further highlight that variables collected during clinical routine are unlikely to allow for a clinically relevant prediction of individual recurrence risk.