Comparison of endovascular strategy versus hybrid procedure in treatment of chronic venous obstructions involving the confluence of common femoral vein.

OBJECTIVE: Treatment of extensive chronic venous obstruction (CVO) with post-thrombotic trabeculation involving the common femoral vein with extension into the femoral vein or deep femoral vein remains a challenge and the best treatment technique for such cases is not clear. In the present study, we compared the results of endovascular alone vs endovascular with additional endophlebectomy (hybrid) procedures for such patients. METHODS: The medical records of 102 consecutive patients (108 limbs) treated between 2015 and 2020 for iliofemoral CVO extending to the femoral confluence were retrospectively reviewed. The patients were divided into two groups: the hybrid procedure (HP) and endovascular treatment (EN) groups. The HP group consisted of those treated with stent implantation and endophlebectomy of the common femoral vein with creation of an arteriovenous fistula. The EN group included those who had undergone stent implantation alone. The patency rates, complications, and clinical outcomes were analyzed. RESULTS: Of the 102 patients, 47 (49 limbs) were in the EN group and 55 (59 limbs) were in the HP group. The demographics of the two groups were similar with no statistically significant differences in cumulative primary, assisted primary, or secondary patency rates at 36 months (33.7% vs 36.3%, P = .839; 59.8% vs 64%, P = .941; 69% vs 72.7%, P = .851; respectively). The patients in the EN group, however, had better clinical improvement with a lower postoperative complication rate (P = .012), shorter procedure duration (P < .001), and shorter hospital stay (P = .025). CONCLUSIONS: The EN and HP both provided similar patency rates for patients with CVO extending into the femoral confluence. The endovascular strategy has the benefit of fewer postoperative complications and a shorter procedure duration and hospital stay compared with the HP.

Intermittent pneumatic compression after varicose vein surgery.

OBJECTIVE: Intermittent pneumatic compression (IPC) is an established treatment option to remove tissue fluid from patients with lymphedema and chronic venous disease. The effects of IPC applied directly after varicose vein surgery performed with high volumes of tumescent local anesthesia have not been investigated. The aim of the present study was to evaluate the use of postoperative IPC concerning its effects on the leg volume and patient comfort after surgery. METHODS: We performed an investigator-initiated, single-center, open-label randomized controlled trial. A total of 186 patients indicated for saphenofemoral junction ligation and great saphenous vein or anterior accessory saphenous vein stripping or great saphenous vein redo surgery were randomly assigned 1:1 to the intervention or control group. The patients in the intervention group were treated with IPC at 40 mm Hg for 45 minutes directly after surgery. The outcome measures were the leg volume changes calculated using an optical three-dimensional scanning system (primary objective), quality of life (QoL; Freiburg Life Quality Assessment for chronic venous disease, short form), pain, and extent of ecchymosis with follow-up examinations on days 1 and 7 after surgery. RESULTS: The patients in both groups had comparable mean leg volume reductions from baseline to day 1 (IPC group, 58.8 mL; control group, 37.4 mL; P = .967) and to day 7 (63.1 mL and 57.0 mL, respectively; P = .546). We also did not observe significant differences between the two groups in QoL and pain. The patients in the IPC group had developed larger areas of ecchymosis compared with the control group (16% vs 13.3% of leg surface, respectively; P = .046), with a tendency toward an increase in pain at 7 days after surgery compared with no IPC application. CONCLUSIONS: The present randomized controlled trial was designed to evaluate the decongestive effects of a single postoperative session of IPC and its effect on QoL, pain, and ecchymosis in patients who had undergone varicose vein surgery under tumescent local anesthesia. Because no evidence for a benefit from IPC could be found in the present study and increased ecchymosis was found, its standard use after varicose vein surgery cannot be recommended.

Short-Term Efficacy of Inguinal Reoperation for Recurrent Saphenofemoral Incompetence using the Stump Suture Technique.

OBJECTIVES: Neovascularization from the saphenofemoral junction (SFJ) is regarded to be an important cause of clinical recurrence. The ideal treatment of SFJ recurrence is still a matter of debate. Barrier strategies have been implemented to improve surgical outcome by reducing neovascularization. This study analyses the value of inguinal reoperation for recurrent SFJ incompetence using a combined approach of stump suture technique, removal of neovasculates, cauterization of free endothelium, and additional tumescent local anesthesia. MATERIALS AND METHODS: Patients who underwent groin reoperation for saphenofemoral recurrence were identified from a prospectively collected database and invited to undergo a follow-up examination. The following study objectives were recorded and descriptively analyzed: duplex ultrasound-detectable repeat reflux at the SFJ, clinical recurrence according to recurrent varicosis after surgery classification, quality of life, clinical severity of venous disease, and side effects. RESULTS: Eighty-three patients (100 legs) attended the follow-up examination after a median time of 16.2 months. A duplex-detected reflux in the groin arising from the common femoral vein was identified in 5% with only 1 leg showing grade 2 neovascularization according to International Union of Phlebology classification. Moderate clinical recurrence (visual analog scale [VAS1-5]: 1.6 ± 0.7) was present in 52%. Same site clinical recurrence originating from the SFJ was detected in 3%. Major complications were not observed, and the procedure was highly accepted by the patients. CONCLUSIONS: This study demonstrates that inguinal reoperation for recurrent saphenofemoral incompetence including a stump suture as barrier has the potential to significantly reduce duplex-detected reflux and same site clinical recurrence accompanied by a high patients' acceptance.

Chemosensitivity-directed therapy compared to dacarbazine in chemo-naive advanced metastatic melanoma: a multicenter randomized phase-3 DeCOG trial.

Chemotherapy still plays an important role in metastatic melanoma, particularly for patients who are not suitable or have no access to highly efficacious new therapies. Pre-therapeutic chemosensitivity testing might be useful to identify optimal chemotherapy regimens for individual patients. This multicenter randomized phase-3 trial was aimed to test for superiority of chemosensitivity-directed combination chemotherapy compared to standard dacarbazine monochemotherapy, and to demonstrate the chemosensitivity test result as prognostic in metastatic melanoma. Chemo-naive patients with advanced melanoma were biopsied from metastatic lesions. Tumor cells were isolated and tested ex-vivo for sensitivity to chemotherapeutic agents using an ATP-based viability assay. Patients with evaluable test results were randomly assigned to receive either chemosensitivity-directed combination chemotherapy (paclitaxel+cisplatin, treosulfan+gemcitabine, treosulfan+cytarabine), or dacarbazine. The primary study endpoint was overall survival (OS). After inclusion of 287 patients and a median follow-up of 26 months, the per-protocol population (n=244) showed no difference in OS between chemosensitivity-directed therapy and dacarbazine (median 9.2 vs 9.0 months, HR=1.08, p=0.64). The disease control rate (CR+PR+SD) tended to be higher in patients treated with chemosensitivity-directed therapy (32.8% vs 23.0%, p=0.088); objective response rates (CR+PR) showed no difference between groups (10.7% vs 12.3%, p=0.90). Patients whose tumors were tested chemosensitive showed no better OS or response rate than patients with chemoresistant tumors. Severe toxicities (CTC grade 3-4) were significantly more frequently observed with chemosensitivity-directed combination chemotherapy than with dacarbazine (40.2% vs 12.3%, p<0.0001). These results indicate, that chemosensitivity-directed combination chemotherapy is not superior to dacarbazine, but leads to significantly more severe toxicities.

Ultraviolet damage, DNA repair and vitamin D in nonmelanoma skin cancer and in malignant melanoma: an update.

Skin exposure with UV radiation (UV) is the main cause of skin cancer development. Epidemiological data indicate that excessive or cumulative UV exposure takes place years and decades before the resulting malignancies arise. The most important defense mechanisms that protect human skin against UV radiation involve melanin synthesis and active repair mechanisms. DNA is the major target of direct or indirect UV-induced cellular damage. Low pigmentation capacity in white Caucasians and rare congenital defects in DNA repair are mainly responsible for protection failures. The important function of nucleotide excision DNA repair (NER) to protect against skin cancer becomes obvious by the rare genetic disease xeroderma pigmentosum, in which diverse NER genes are mutated. In animal models, it has been demonstrated that UVB is more effective to induce skin cancer than UVA. UV-induced DNA photoproducts are able to cause specific mutations (UV-signature) in susceptible genes for squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In SCC development, UV-signature mutations in the p53 tumor suppressor gene are the most common event, as precancerous lesions reveal -80% and SCCs > 90% UV-specific p53 mutations. Mutations in Hedgehog pathway related genes, especially PTCH1, are well known to represent the most significant pathogenic event in BCC. However, specific UV-induced mutations can be found only in -50% of sporadic BCCs. Thus, cumulative UVB radiation cannot be considered to represent the only etiologic risk factor for BCC development. During the last decades, experimental animal models, including genetically engineered mice, the Xiphophorus hybrid fish, the South American oppossum and human skin xenografts, have further elucidated the important role of the DNA repair system in the multi-step process of UV-induced melanomagenesis. An increasing body of evidence now indicates that nucleotide excision repair is not the only DNA repair pathway that is involved in UV-induced tumorigenesis of melanoma and nonmelanoma skin cancer. An interesting new perspective in DNA damage and repair research lies in the participation of mammalian mismatch repair (MMR) in UV damage correction. As MMR enzyme hMSH2 displays a p53 target gene, is induced by UVB radiation and is involved in NER pathways, studies have now been initiated to elucidate the physiological and pathophysiological role of MMR in malignant melanoma and nonmelanoma skin cancer development. Interestingly, increasing evidence now demonstrates an important function of the vitamin D endocrine system (VDES) for prevention of BCC, SCC and melanoma, identifying the vitamin D receptor as a tumor suppressor in the skin.

Comparable effectiveness of endovenous laser ablation and high ligation with stripping of the great saphenous vein: two-year results of a randomized clinical trial (RELACS study).

OBJECTIVE: To compare the clinical efficacy and safety of endovenous laser treatment (EVLT) with high ligation and stripping (HLS) as standard treatment for great saphenous vein (GSV) insufficiency. DESIGN: Two-center randomized controlled trial with 2-year follow-up. SETTING: Interventions were performed on ambulatory and hospitalized patients at 2 vein centers, a university dermatology department (EVLT-treated group), and a specialized vein clinic (HLS-treated group). PATIENTS: Random sample of 400 patients with GSV insufficiency. INTERVENTIONS: Patients were assigned (1:1) to EVLT or HLS of the GSV from September 2004 through March 2007; 185 and 161 patients (limbs), respectively, were treated per protocol. MAIN OUTCOME MEASURES: Clinically recurrent varicose veins after surgery (REVAS classification, primary study objective), duplex-detected saphenofemoral recurrence, clinical venous severity scoring (Homburg Varicose Vein Severity Score), hemodynamics (venous refilling time), quality of life (Chronic Venous Insufficiency Questionnaire 2), adverse effects, and visual analog scale-based evaluations of patients' satisfaction. RESULTS: Clinically recurrent varicose veins after surgery were similarly observed in both groups: 16.2% (EVLT-treated group) vs 23.1% (HLS-treated group); P = .15. Duplex-detected saphenofemoral refluxes occurred significantly more frequently after EVLT (17.8% vs 1.3%; P < .001). Both treatments equally improved medical condition (Homburg Varicose Vein Severity Score) and disease-related quality of life. Endovenous laser treatment caused more adverse effects (phlebitic reaction, tightness, dyspigmentation) but revealed advantages concerning hemodynamics, recovery, and cosmetic outcome. CONCLUSIONS: Both EVLT and HLS are comparably safe and effective procedures to treat GSV incompetence. The significantly higher rate and the course of duplex-detected saphenofemoral recurrences after EVLT remain a matter of further investigations. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN18322872.

Radiofrequency induced thermotherapy (RFITT) of varicose veins compared to endovenous laser treatment (EVLT): a non-randomized prospective study concentrating on occlusion rates, side-effects and clinical outcome.

BACKGROUND: Radiofrequency obliteration (RFO) and endovenous laser treatment (EVLT) are established techniques in varicose therapy. A novel bipolar RFO technique - Radiofrequency Induced Thermotherapy (RFITT) - was introduced in 2007. Comparative studies of RFITT and EVLT with one year follow-up are missing. OBJECTIVE: Comparison of RFITT with EVLT concentrating on occlusion, side-effects, and patients' satisfaction in a prospective non-randomized study. METHODS: 133 patients with incompetent GSV or SSV were treated by RFITT (n=66) or EVLT (n=67). Follow-up at days 1, 7, and months 3, 12 included duplex, digital photoplethysmography (DPPG), assessment of VCSS and patients' satisfaction. RESULTS: Both groups were balanced concerning clinical parameters. Occlusion rates were in trend in favour of EVLT (96.9%) vs RFITT (88.9%), p=0.093, at 12 months follow-up. Functional outcome by DPPG (refilling time: 30.8 vs 31.9 sec.), and side-effects were comparable apart from pain in the first postoperative week, which was more frequent in the EVLT group (0 vs 16.4%, p=0.001). Change in VCSS from baseline was advantageous for EVLT (89.9% vs 79.3%, p=0.005). Major complications did not occur. Both techniques provided excellent satisfaction results. CONCLUSION: After one year RFITT is similarly as effective and safe as EVLT treatment of varicose insufficiency, but needs improvement in treatment parameters.

Construction and evaluation of a multidimensional score to assess varicose vein severity - the Homburg Varicose Vein Severity Score (HVVSS).

To evaluate a novel score (HVVSS) for varicose vein patients combining subjective symptoms, clinical findings and functional data of venous insufficiency. 91 patients (118 legs) with primary varicose veins of the great, small or accessory anterior saphenous vein were treated with conventional surgery. HVVSS was assessed pre- and 3 months postoperatively. The data were compared with established clinical and disease-related life quality scores (VCSS, AVVQ, CIVIQ). Test responsiveness, validity and reliability were determined using correlations with CEAP stage and venous refilling time as hemodynamic parameter, and inter-observer variability was assessed. All scores were highly responsive to varicose vein surgery (p<0.001). HVVSS(0-100) decreased from 34.1 ± 13.0 to 9.6 ± 6.9 postoperatively. The relative score change of HVVSS was superior to VCSS (69.5% vs. 58.8%, p=0.005). HVVSS revealed highly significant correlations with the clinical CEAP stage and was exclusively able to differentiate mild from severe disease as defined by venous refilling time (p=0.009). Inter-observer reliability of HVVSS was confirmed by correlation coefficients of 0.977 and 0.950 pre- and postoperatively (p<0.001). HVVSS is a suitable and reliable tool to assess disease severity in varicose vein patients and to quantify therapeutic effects of varicose vein treatment.

Reciprocal responses of fibroblasts and melanocytes to α-MSH depending on MC1R polymorphisms.

The melanocortin 1-receptor (MC1R) exhibits several variants in form of single nucleotide polymorphisms (SNPs) that are known to differentially regulate melanocyte function. However, whether and how MC1R polymorphisms also affect fibroblast function has not been investigated so far.Therefore we measured intracellular cyclic adenosine monophosphate (cAMP) concentrations and cellular proliferation upon stimulation with alpha-melanocyte stimulating hormone (α-MSH) in eight different human fibroblast and melanocyte cell lines with wild type and different MC1R SNPs.We found that fibroblasts, as well as melanocytes, show differences in MC1R function depending on the MC1R genotype. MC1R stimulation with α-MSH in wild type (MC1R(wt)) melanocytes results in an increase of intracellular cAMP and cellular proliferation. In contrast, MC1R(wt) fibroblasts react with a decrease of intracellular cAMP and proliferation. In MC1R polymorphic fibroblasts (R163Q, R151C and V60L) both effects are significantly alleviated. Similar, but inverse effects could be found in MC1R polymorphic melanocytes (R142H and V92M) with a significantly lower cAMP increase and proliferation rate compared to MC1R(wt) melanocytes.Our results indicate that the MC1R displays reciprocal growth responses in melanocytes and fibroblasts, depending on the MC1R genotype. Thus, the MC1R seems to be not solely important for the skin pigmentary system, but also for the fibroblast function, and might influence different processes of the dermal compartment like wound healing, fibrosis and keloid formation.

Venoarterial flow index steadily improves after endovenous laser treatment of the great saphenous vein.

BACKGROUND: Endovenous laser treatment (EVLT) is a minimally invasive procedure to ablate varicose veins. The venous arterial flow index (VAFI) represents a quantitative duplex ultrasound parameter to characterize venous hemodynamics, which has not been investigated in EVLT so far. OBJECTIVE: To analyze the hemodynamic improvement of EVLT of the great saphenous vein (GSV) according to VAFI measurement. MATERIALS AND METHODS: One hundred thirty-three participants with complete GSV insufficiency were treated with 810-nm EVLT. VAFI as a ratio of venous and arterial flow volumes of the common femoral vessels and digital photoplethysmography (DPPG) were assessed before and 3 (n=129) and 12 months (n=71) after EVLT. RESULTS: EVLT was performed with an energy fluence of 22.5 J/cm², resulting in an occlusion rate of 98.4%. Duplex recurrence rates were 9.4% at 3-month and 15.5% at 12-month follow-up. VAFI significantly improved from 1.395 to 1.242 and 1.167 (p<.001) 3 and 12 months after EVLT. Venous refilling time (DPPG) accordingly increased from 20.0 to 36.9 seconds (p<.001) 3 months postoperatively. CONCLUSION: EVLT improves hemodynamic alterations in people with incompetent GSVs as demonstrated using VAFI and DPPG. VAFI might be a suitable diagnostic tool to quantify venous hemodynamics in people with varicose veins. The authors have indicated no significant interest with commercial supporters.

High-throughput miRNA profiling of human melanoma blood samples.

BACKGROUND: MicroRNA (miRNA) signatures are not only found in cancer tissue but also in blood of cancer patients. Specifically, miRNA detection in blood offers the prospect of a non-invasive analysis tool. METHODS: Using a microarray based approach we screened almost 900 human miRNAs to detect miRNAs that are deregulated in their expression in blood cells of melanoma patients. We analyzed 55 blood samples, including 20 samples of healthy individuals, 24 samples of melanoma patients as test set, and 11 samples of melanoma patients as independent validation set. RESULTS: A hypothesis test based approach detected 51 differentially regulated miRNAs, including 21 miRNAs that were downregulated in blood cells of melanoma patients and 30 miRNAs that were upregulated in blood cells of melanoma patients as compared to blood cells of healthy controls. The tets set and the independent validation set of the melanoma samples showed a high correlation of fold changes (0.81). Applying hierarchical clustering and principal component analysis we found that blood samples of melanoma patients and healthy individuals can be well differentiated from each other based on miRNA expression analysis. Using a subset of 16 significant deregulated miRNAs, we were able to reach a classification accuracy of 97.4%, a specificity of 95% and a sensitivity of 98.9% by supervised analysis. MiRNA microarray data were validated by qRT-PCR. CONCLUSIONS: Our study provides strong evidence for miRNA expression signatures of blood cells as useful biomarkers for melanoma.

Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of >= 1.5 mm tumor thickness: results of a randomized phase III DeCOG trial.

PURPOSE Low-dose (LD) interferon (IFN) alfa (LDI) has demonstrated a consistent disease-free survival benefit for patients with clinically lymph node-negative melanoma in clinical trials. However, the optimal duration of treatment is still under discussion, and no previous trial has evaluated this question specifically. A prolongation of LDI from 18 months to 60 months might be of clinical benefit for patients with intermediate or high-risk melanoma. PATIENTS AND METHODS Eight hundred fifty patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness were included in this prospective randomized, multicenter trial in Germany and Austria. Patients had to be clinically lymph node-negative, and sentinel node biopsy (SLNB) was performed in a majority of cases. They were randomly assigned to receive 3 MU IFNalpha2a three times a week subcutaneously for either 18 months (arm A) or 60 months (arm B). Results Of 850 randomly assigned patients, 840 were eligible for evaluation after a median follow-up of 4.3 years. Tumor thickness and other relevant prognostic factors were well balanced between both groups. SLNB was performed in 635 patients (75.6%), with a positivity rate of 18.0% in arm A and 17.5% in arm B. Neither relapse-free survival (arm A, 75.6% v arm B, 72.6%; P = .72; hazard ratio, 1.05; 95% CI, 0.80 to 1.39) nor distant-metastasis-free survival (81.9% v 79.7%; P = .56; HR, 1.10; 95% CI, 0.80 to 1.52) or overall survival (85.9% v 84.9%; P = .86; HR, 1.03; 95% CI, 0.71 to 1.50) showed significant differences. CONCLUSION A prolongation of conventional LDI therapy from 18 to 60 months showed no clinical benefit in patients with intermediate and high-risk primary melanoma.

Prospective randomized multicenter adjuvant dermatologic cooperative oncology group trial of low-dose interferon alfa-2b with or without a modified high-dose interferon alfa-2b induction phase in patients with lymph node-negative melanoma.

PURPOSE Interferon alfa (IFN-alpha) has shown clinical efficacy in the adjuvant treatment of patients with high-risk melanoma in several clinical trials, but optimal dosing and duration of treatment are still under discussion. It has been argued that in high-dose IFN-alpha (HDI), the intravenous (IV) induction phase might be critical for the clinical benefit of the regimen. PATIENTS AND METHODS In an attempt to investigate the potential role of a modified high-dose induction phase, lymph node-negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness were included in this prospective randomized multicenter Dermatologic Cooperative Oncology Group trial. Six hundred seventy-four patients were randomly assigned to receive 4 weeks of a modified HDI scheme. This schedule consisted of 5 times weekly 10 MU/m(2) IFN-alpha-2b IV for 2 weeks and 5 times weekly 10 MU/m(2) IFN-alpha-2b administered subcutaneously (SC) for another 2 weeks followed by 23 months of low-dose IFN-alpha-2b (LDI) 3 MU SC three times a week (arm A). LDI 3 MU three times a week was given for 24 months in arm B. Results Of 650 assessable patients, there were 92 relapses among the 321 patients receiving high-dose induction as compared with 95 relapses among the 329 patients receiving LDI only. Five-year relapse-free survival rates were 68.0% (arm A) and 67.1% (arm B), respectively. Likewise, melanoma-related fatalities were similar between both groups, resulting in 5-year overall survival rates of 80.2% (arm A) and 82.9% (arm B). CONCLUSION The addition of a 4-week modified HDI induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome.

UV damage and DNA repair in malignant melanoma and nonmelanoma skin cancer.

Exposition of the skin with solar ultraviolet radiation (UV) is the main cause of skin cancer development. The consistently increasing incidences of melanocytic and nonmelanocytic skin tumors are believed to be at least in part associated with recreational sun exposure. Epidemiological data indicate that excessive or cumulative sunlight exposition takes place years and decades before the resulting malignancies arise. The most important defense mechanisms that protect human skin against UV radiation involve melanin synthesis and active repair mechanisms. DNA is the major target of direct or indirect UV-induced cellular damage. Low pigmentation capacity in white Caucasians and rare congenital defects in DNA repair are mainly responsible for protection failures. The important function of nucleotide excision DNA repair (NER) to protect against skin cancer becomes obvious by the rare genetic disease xeroderma pigmentosum, in which diverse NER genes are mutated. In animal models, it has been demonstrated that UVB is more effective to induce skin cancer than UVA. UV-induced DNA photoproducts are able to cause specific mutations (UV-signature) in susceptible genes for squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In SCC development, UV-signature mutations in the p513 tumor suppressor gene are the most common event, as precancerous lesions reveal approximately 80% and SCCs > 90% UV-specific p53 mutations. Mutations in Hedgehog pathway related genes, especially PTCH1, are well known to represent the most significant pathogenic event in BCC. However, specific UV-induced mutations can be found only in approximately 50% of sporadic BCCs. Thus, cumulative UVB radiation can not be considered to be the single etiologic risk factor for BCC development. During the last decades, experimental animal models, including genetically engineered mice, the Xiphophorus hybrid fish, the south american oppossum and human skin xenografts, have further elucidated the important role of the DNA repair system in the multi-step process of UV-induced melanomagenesis. An increasing body of evidence now indicates that nucleotide excision repair is not the only DNA repair pathway that is involved in UV-induced tumorigenesis of melanoma and nonmelanoma skin cancer. An interesting new perspective in DNA damage and repair research lies in the participation of mammalian mismatch repair (MMR) in UV damage correction. As MMR enzyme hMSH2 displays a p53 target gene, is induced by UVB radiation and is involved in NER pathways, studies have now been initiated to elucidate the physiological and pathophysiological role of MMR in malignant melanoma and nonmelanoma skin cancer development.