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Background: Medium, large and giant congenital melanocytic naevi (CMN) can impose a psychosocial burden on patients and families, and are associated with increased risk of developing melanoma or neurological symptoms. Lack of consensus on what outcomes to measure makes it difficult to advise patients and families about treatment and to set up best practice for CMN. Objectives: Fostering consensus among patient representatives and professionals, we aim to develop a core outcome set, defined as the minimum set of outcomes to measure and report in care and all clinical trials of a specific health condition. We focused on the ‘what to measure’ aspect, the so-called core domain set (CDS), following the COMET and CS-COUSIN guidelines. Methods: We conducted a systematic review to identify outcomes reported in the literature. Focus groups with patient representatives identified patient-reported outcomes. All these outcomes were classified into domains. Through e-Delphi surveys, 144 stakeholders from 27 countries iteratively rated the importance of domains and outcomes. An online consensus meeting attended by seven patient representatives and seven professionals finalized the CDS. Results: We reached consensus on six domains, four of which were applied to both care and research: ‘quality of life’, ‘neoplasms’, ‘nervous system’ and ‘anatomy of skin’. ‘Adverse events’ was specific to care and ‘pathology’ to research. Conclusions: We have developed a CDS for medium-to-giant CMN. Its application in reporting care and research of CMN will facilitate treatment comparisons. The next step will be to reach consensus on the specific outcomes for each of the domains and what instruments should be used to measure these domains and outcomes.

In den letzten Jahren hat sich unser Wissensstand zu kongenitalen melanozytaren Navi (KMN) stark erweitert. Die Autoren, eine interdisziplinare Gruppe von Arzten und Arztinnen mit umfangreicher Erfahrung in der Langzeitbetreuung und chirurgischen Therapie von Kindern und Erwachsenen mit KMN (Netzwerk Navuschirurgie, NNC), geben hier eine Stellungnahme zur Indikationsstellung, Planung und Durchfuhrung einer Behandlung unter diesen neuen Pramissen ab. Die Beratung der Eltern zum konservativen und/oder operativen Management von KMN muss im interdisziplinaren Austausch stattfinden und zu einer individuellen Planung des oft mehrstufigen Prozesses fuhren. Hierbei steht das asthetische Langzeitergebnis, nicht die Melanomprophylaxe, im Mittelpunkt. Bei keinem KMN gilt die Pramisse der „Entfernung um jeden Preis“. Mogliche therapiebedingte Nebenwirkungen (Hospitalisation, Wundheilungsstorungen etc.) mussen sorgfaltig mit den Erfolgsaussichten abgewogen werden. Unter diesen Gesichtspunkten ist insbesondere die Methode der Dermabrasion zu hinterfragen. Auf einer Tagung des NNC im September 2018 wurde eine konsentierte Wertung erarbeitet, nach der die Dermabrasion haufig zu Wundheilungsstorungen sowie zu kosmetisch ungunstiger oder hypertropher Narbenbildung fuhren kann und sehr haufig mit einer oft erst Jahre spater auftretenden Repigmentierung assoziiert ist. Zudem ist kein Nutzen im Sinne einer Melanomprophylaxe erkennbar. Daher sollte in Zukunft sorgfaltig auf die moglichen Risiken und den oft limitierten kosmetischen Nutzen der Dermabrasion hingewiesen werden.

In recent years, our knowledge of congenital melanocytic nevi (CMN) has greatly expanded. This has led to a paradigm shift. The present article represents a commentary by an interdisciplinary group of physicians from German-speaking countries with extensive experience in long-term care and surgical treatment of children and adults with CMN (CMN surgery network, "Netzwerk Nävuschirurgie", NNC). The authors address aspects such as the indication for treatment as well as treatment planning and implementation under these new premises. Adequate counseling of parents on conservative and/or surgical management requires an interdisciplinary exchange among physicians and individualized planning of the intervention, which frequently involves a multi-stage procedure. Today, the long-term aesthetic outcome is at the center of any therapeutic endeavor, whereas melanoma prevention plays only a minor role. The premise of "removal at any cost" no longer holds. Potential treatment-related adverse effects (hospitalization, wound healing disorders, and others) must be carefully weighed against the prospects of a beneficial outcome. In this context, the use of dermabrasion in particular must be critically evaluated. At a meeting of the NNC in September 2018, its members agreed on a consensus-based position on dermabrasion, stating that the procedure frequently leads to impaired wound healing and cosmetically unfavorable or hypertrophic scarring. Moreover, dermabrasion is considered to be commonly associated with considerable repigmentation that usually occurs a number of years after the procedure. In addition, the NNC members saw no benefit in terms of melanoma prevention. In the future, physicians should therefore thoroughly caution about the potential risks and often limited cosmetic benefits of dermabrasion.

Melanozytare Navi, also gutartige Proliferationen melanozytarer Zellen der Haut gehoren zu den haufigsten Diagnosen in einer Hautarztpraxis. Die Ahnlichkeit und Verwechslungsmoglichkeit mit einem Melanom ist fur viele Patienten der primare Konsultationsgrund („Ist das was Schlimmes?“). Besondere Aufmerksamkeit erfordern rasch entstandene Pigmentmale.

Melanozytare Navi, also gutartige Proliferationen melanozytarer Zellen der Haut (auch: Muttermale, Leberflecken) gehoren zu den haufigsten Diagnosen in einer Hautarztpraxis. Die Ahnlichkeit und Verwechslungsmoglichkeit mit einem Melanom ist fur viele Patienten der primare Konsultationsgrund („Ist das was Schlimmes?“). Auch Padiater sind regelmasig mit dieser Fragestellung konfrontiert.

Childhood melanoma (ChM) is rare, with clinical and epidemiologic characteristics that differ from those of adult melanomas. The objective of the current study was to systematically identify and analyze case reports and case series of fatal and metastasizing ChM in the medical literature. ChM case reports with a fatal outcome or metastases were identified using a Medline search and subdivided into ChM developing in the absence of a congenital melanocytic nevus (ChM without CMN) and ChM associated with a CMN (ChM with CMN); 258 cases of ChM without CMN (206 cutaneous, 52 noncutaneous) were identified. In cutaneous ChM without CMN with a fatal outcome (n = 155), the mean age at diagnosis was 13.1 years (median 14 yrs). The mean Breslow index in this group was 8.5 mm for children ages 0 to 10 years and 3.7 mm for children ages 11 to 18 years. In ChM with CMN (n = 178; 112 cutaneous, 66 central nervous system [CNS]), the mean age at diagnosis was 5.8 years for cutaneous melanoma (median 3 yrs) and 5.5 years for CMN-associated CNS melanoma (median 3 yrs). The majority of CMN-associated cutaneous melanomas developed in small and giant CMN (vs medium and large); 53.9% of CNS melanomas developed in patients with multiple medium CMN. This study represents the largest and most complete synopsis of ChM case reports in the medical literature. Our analysis supports the view that cutaneous ChM without CMN (or associated with smaller CMN) differs in several important aspects from ChM associated with large or giant CMN.

Background: Predilection sites of melanocytic nevi are highly variable; however, individual patterns (e.g. preponderant involvement of extremities, trunk, etc.) are often noticed. A symmetric appearance of nevi on both sides of the body has not been reported. Objective: Guided by an initial, incidental observation of symmetrically arranged plantar nevi, a prospective survey of palmoplantar nevi was carried out. Methods: Between January 2016, and January 2017, 886 patients underwent a full-body examination for skin cancer screening. Special attention was paid to the pigmentary characteristics of the palms and soles. Results: 12/886 patients exhibited symmetrically or nearly symmetrically distributed plantar nevi (1.35%; mean age 45 years; male-female ratio 1:1). The nevi were mostly situated on the medial part of the plantar arch (9/12 cases; 75%). Remarkably, not a single case of symmetric nevi was identified on the palms. Conclusion: Arguments in favour of the specifity of the finding are: 1) the lack of comparable findings in palmar skin, i.e., in a similar histological compartment and 2) the predominant localization in the foot arch. Symmetric plantar nevi appear to be a rare, but not a random event. Possible underlying causes of this phenomenon are discussed.

Lack of information and misinformation abounds regarding the potential risks of malignancy, management approaches, benefits of surgical intervention, follow-up strategies, and overall prognosis for individuals with congenital melanocytic nevi (CMN). This review is intended to provide answers to questions that frequently arise shortly after the birth of individuals with CMN, especially of larger types.

An unconventional symposium on the subject of pathogenetic, clinical, and therapeutic aspects of large and giant congenital melanocytic nevi and neurocutaneous melanocytosis, was held at the University of Tubingen, Germany, on May 6-7, 2011. Exchanges were made between physicians from a wide range of clinical disciplines, including pathology, dermatology, plastic and pediatric surgery, neurosurgery, pediatric neurology and genetics; basic scientists in cell and developmental biology; psychologists; and an unprecedented gathering of international patient advocacy group representatives. This diversity of outlooks brought fresh perspectives to the discussions about current scientific and therapeutic advances in the field of these rare congenital diseases and their oncogenic associations. A roadmap for future actions sketched out promising therapeutic developments to follow and fostering of interdisciplinary collaboration among all the involved parties.

Summary In 2005, an Internet-based network for the support of patients with congenital melanocytic nevi in German-speaking countries was started (http://www.naevus-netzwerk.de). Along with detailed information for patients and parents, the home-page includes a nevus registry which is based on an electronic questionnaire and which aims at providing data on the long-term course of nevi estimated to reach > 10 cm in largest diameter. In the past, congenital melanocytic nevi have been subject to various mythological interpretations (“Tierfellnavus”, lit.”animal coat nevus”;”Muttermal”). Today an increasing body of reliable scientific data allows a differentiated reflection of the risk of malignant transformation and has led to progress in the diagnostic and therapeutic management. Recent findings from the literature and considerations from scientific meetings are reviewed.

BACKGROUND Congenital melanocytic nevi (CMN) are associated with mental stress as well as medical risks for those affected. The German CMN registry was initiated in 2005. Herein, we present results from an interim analysis focusing on disease course, treatment modalities, and quality of life. PATIENTS AND METHODS One hundred patients enrolled in the registry between 2005 and 2012 were included in this prospective cohort study, and asked to participate in a follow-up survey. In addition, standardized questionnaires were used to collect data on quality of life (dermatology life quality index, DLQI) and perceived stigmatization (perceived stigmatization questionnaire, PSQ; social comfort questionnaire, SCQ). RESULTS Eighty-three percent of patients (or their parents) provided answers to the survey questions (mean patient age: 11.2 years, median: 6 years; mean follow-up: 4.4 years). Overall, four individuals were diagnosed with melanoma, including two pediatric cases with CNS melanoma, one adult with cutaneous melanoma, and one case which later turned out to be a proliferative nodule. Four children were diagnosed with neurocutaneous melanocytosis, three of whom exhibited neurological symptoms. Eighty-eight percent (73/83) of patients underwent surgery. Seventy-eight percent reported no or only minor impact of the CMN on quality of life. In general, perceived stigmatization and impairment of social well-being were also low. CONCLUSIONS Our results provide an overview of the situation of CMN patients in Germany, Austria, and Switzerland. Three percent of patients developed melanoma; 4 % showed CNS involvement.

Purpose Temozolomide (TMZ) has shown efficacy in metastatic melanoma equal to that of dacarbazine (DTIC), the standard chemotherapeutic agent for melanoma. As the combination with interferon-alfa (IFN-α) appears superior to single-agent DTIC regarding response rates, the purpose of this study was to compare TMZ alone and TMZ plus IFN-α in terms of objective response (OR), overall survival, and safety in a prospective, randomized, multicenter trial. Patients and Methods Two hundred ninety-four patients with untreated stage IV metastatic melanoma (American Joint Committee on Cancer staging system) were randomly assigned to receive either oral TMZ alone (200 mg/m2/day; days 1 through 5 every 28 days) or in combination with subcutaneous IFN-α (5 MU/m2; days 1, 3, and 5 every week). Results Two hundred eighty-two patients were eligible for an intent-to-treat analysis, 271 patients were treated per protocol. In the TMZ + IFN-α arm, 33 (24.1%) of 137 patients responded to therapy (partial or complete remission) whereas in the monotherapy arm, in 18 (13.4%) of 134 patients, a response was evident. Thus, the response rate was significantly higher in the combination arm (P = .036). Median survival time was 8.4 months for patients treated with TMZ (95% CI, 7.07 to 9.27) and 9.7 months for those treated with the combination (95% CI, 8.26 to 11.18; P = .16). Dose modifications and interval prolongations due to hematologic toxicity were significantly more frequent in the TMZ + IFN-α arm (P < .001). Conclusion In metastatic melanoma treatment with TMZ + IFN-α leads to a significantly superior OR rate compared to treatment with TMZ alone, which did not translate into prolonged survival in our study population.

We report the case of a 68-year-old female with reactive angioendotheliomatosis (RAE). This case highlights the benign course of this condition and suggests that this entity might be an intravascular histiocytosis.

A new consensus-based classification of congenital melanocytic nevi (CMN) has recently been proposed. It includes categories for projected adult size (PAS) and location, satellite nevi counts, and morphologic characteristics (color heterogeneity, rugosity, nodularity, and hypertrichosis). The objective of the current study was to test the applicability of the new categorization scheme and to correlate classification outcome with the patient's history of melanoma and neurocutaneous melanocytosis (NCM). Children and adults with CMN attending a patient conference in Dallas, Texas, in 2012 were invited to participate in the study. Anamnestical data were collected using a standardized questionnaire. Two dermatologists performed clinical examinations. Of 45 patients enrolled, 33 had a giant CMN (G1 [>40 cm PAS], n = 13; G2 [>60 cm PAS], n = 20), 12 had an NCM (5 symptomatic, 7 asymptomatic), and 1 had a history of melanoma. CMN size was positively correlated with NCM (p < 0.05). The classification system allowed an easy and detailed phenotypic characterization of each individual CMN. CMN size and morphology were difficult to assess in patients after surgical removal, and the number of satellite nevi at birth or during infancy was not always known. Our report provides practical aids for the application of the newly proposed CMN classification. Prospective evaluation of accurately classified patients in CMN registries will reveal the predictive value of the scheme. The small study sample limits meaningful conclusions regarding the correlation between CMN parameters and the risk of NCM and melanoma.

Classic variants of cutaneous borreliosis are erythema chronicum migrans (ECM), lymphadenosis benigna cutis (LBC) and acrodermatitis chronica atrophicans (ACA). Other dermatoses have been reported in the literature as possibly linked to borreliosis. A 59-year old female patient was seen in the late phases of cutaneous borreliosis with histologically confirmed ACA. In addition, prominent livedo racemosa was seen on the legs, also showing tissue changes similar to those of ACA. Borrelia burgdorferi infection was serologically confirmed by the presence of anti-IgM and anti-IgG antibodies. The clinical spectrum of late cutaneous borreliosis should be enlarged to include livedo racemosa.

Radiation-induced acne is a rare, clinically and pathogenetically ill-defined acneiform dermatosis with special features that may occur in irradiated skin areas especially after high doses of deeply penetrating radiation. We report on a patient with an oropharyngeal carcinoma who developed severe radiation-induced acne including comedones and cysts as well as few inflammatory papules and pustules in a skin area irradiated with up to 63 gray of a 6 MeV photon beam. Acnegenic drugs may precipitate the disease; our patient was on longterm therapy with carbamazepine whose acnegenic potency is less well documented than that of testosterone or glucocorticoids. Treatment of radiation-induced acne is comedolytic; topical retinoids are especially valuable.

A case report of recurrent angiolymphoid hyperplasia with eosinophilia (ALHE) in an otherwise healthy 20-year-old female with manifestation of the disease limited to the left arm and hand is presented together with brief evaluation of the literature as well as the features distinguishing ALHE and Kimura's disease. Immunohistochemical investigations support the hypothesis that ALHE represents a reactive inflammatory lesion rather than a benign vascular neoplasm. A viral cause of ALHE (e.g., HHV8 or Epstein-Barr virus (EBV)) could not be demonstrated. The recurrent nature of the disease is shown by this case, which also demonstrates the need for frequent medical and surgical management.

Acute infection with hepatitis C virus (HCV) is often clinically inapparent, but may affect several organ systems in its chronic course. In dermatology, common diseases such as lichen planus, cryoglobulinemic vasculitis and porphyria cutanea tarda have been described in association with HCV infection. A number of other dermatologic disorders, e.g., psoriasis, chronic urticaria, chronic pruritus, pseudo-kaposi sarcoma, necrolytic migratory erythema and Behcet disease, have been associated in case reports with HCV-induced liver disease. In this study we summarize the recent literature reports, present three patients observed by our group and update the topic.

A 76-year-old female patient developed severe manifestations of a kaposi-like acroangiodermatitis (so-called Mali's disease) due to chronic venous insufficiency of the lower extremities. The patient presented with large areas of confluent, violaceous or brown-black papules on both lower legs. Histologically, proliferation of thick-walled capillaries was seen in the upper dermis consisting of fully differentiated endothelial cells, as shown by immunohistochemistry. In contrast to true Kaposi's sarcoma, human-herpes-virus-8 DNA could not be detected by polymerase-chain-reaction in this condition. We review the diagnostic criteria used to distinguish between acroangiodermatitis, also called pseudo-Kaposi's sarcoma, and the true Kaposi's sarcoma.

Die perforierenden Dermatosen bilden eine heterogene Gruppe von Erkrankungen, die durch transepidermale Eliminationsphanomene gekennzeichnet sind. Abzugrenzen sind die primar perforierenden Dermatosen von solchen perforierenden Dermatosen, bei denen Perforation oder Elimination sekundar und als seltenes Teilsymptom bei bestehenden Dermatosen anderer Provenienz auftreten konnen. Zu den primar perforierenden Dermatosen zahlen dabei als Prototypen die Hyperkeratosis follicularis et parafollicularis in cutem penetrans (M. Kyrle), die Elastosis perforans serpiginosa und die perforierende Follikulitis. Die erworbene reaktiv perforierende Dermatose (syn. erworbene reaktiv perforierende Kollagenose) stellt zusammen mit der hereditaren, reaktiv perforierenden Kollagenose eine weitere Variante der primar perforierenden Dermatosen dar. Wir stellen hier eine 84jahrige und eine 96jahrige Patientin mit einer erworbenen reaktiv perforierenden Dermatose vor. Bei beiden Patientinnen lagen eine diabetogene und eine hyperurikamische Stoffwechsellage vor. Eine Therapie mit Allopurinol (100 mg/d) fuhrte bereits nach kurzer Dauer (1 bis 2 Wochen) zu einer weitgehenden Abheilung der disseminierten Lasionen. Uber einen Nachbeobachtungszeitraum von jeweils 6 Monaten befanden sich beide Patientinnen in Vollremission. Diese Beobachtungen belegen erneut die Existenz und Massivitat der Erkrankung und zeigen, das Allopurinol neben der bekannten urikostatischen Wirkung moglicherweise in der Haut immunologische oder differenzierungsmodulierende Effekte vermittelt.

Das Vena-cava-superior-Syndrom ist klinischer Ausdruck einer venosen Stauung im Ableitungsgebiet der oberen Hohlvene. Als Manifestation dieses relativ seltenen Symptomenkomplexes steht eine haufig akut entstehende Gesichtsschwellung im Vordergrund, die den Patienten zunachst zum Dermatologen fuhrt. Weitere klinische Charakteristika des Vena-cava-superior-Syndroms sind Rotung bzw. Zyanose des Gesichts, Stauung der Halsvenen und, bei langerem Bestand, Entwicklung von Kollateralvenen im Brustwandbereich. Die haufigste Ursache des Vena-cava-superior-Syndroms ist heute ein ausgepragter raumfordernder Prozes im Mediastinum, der langsam-progredient oder auch akut-subakut zur oberen Einflus-Stauung fuhrt. Die Erkrankung kann auch einen hochdramatischen, z.T. lebensbedrohlichen Verlauf nehmen, der intensiv-diagnostische bzw. intensiv-therapeutische Masnahmen erfordert. In der vorliegenden Arbeit werden drei eindrucksvolle Falle eines Vena-cava-superior-Syndrom vorgestellt, die a) durch ein Bronchialkarzinom, b) eine bihilare Sarkoidose sowie c) durch ein im Mediastinalraum metastasierendes malignes Melanom bedingt waren. Dabei wird das Krankheitsbild unter besonderer Berucksichtigung der notwendigen diagnostischen und therapeutischen Masnahmen anhand des bisherigen Schrifttums zusammenfassend dargestellt.

An den Augenlidern manifestieren sich unterschiedlichste Erkrankungen. Ein haufiges Symptom dieser Region ist die Schwellung, der wiederum oft ein Odem zugrundeliegt. Neben einer Beschreibung der pathophysiologischen und anatomischen Grundlagen soll im vorliegenden Text vor allem eine praktische Anleitung – unter anderem mit Flusdiagrammen – zum differentialdiagnostischen Vorgehen bei Patienten mit Lidschwellung gegeben werden. Hierbei erweist sich die subjektive Symptomatik (Schmerzen, Juckreiz) als sinnvolles Orientierungskriterium. Die Erkrankungen werden, nach Inzidenz gereiht, in tabellarischer Form charakterisiert. Besonderes Augenmerk gilt den allergischen Ursachen fur Lidschwellungen sowie dem Zusammenhang zwischen Lidschwellung und atrophischen Lidveranderungen.

Background The diameter of congenital melanocytic nevi (CMN) has served as the lone criterion for determining risks of adverse outcomes such as melanoma. A standardized description of additional morphologic features is needed. Objective We sought to develop a consensus-based standardized categorization of cutaneous features of CMN and to test agreement among experts on the proposed scheme. Methods An interdisciplinary group of experts in the field of CMN was surveyed using a detailed questionnaire. Applicability of the expert consensus-based scheme was tested for interobserver agreement. Results The principal variable of the consensus-based categorization is CMN size, based on maximal diameter the CMN is projected to attain by adulthood. CMN size categories include: small ( 10-20 cm); large (L1: >20-30 cm, L2: >30-40 cm); and giant (G1: >40-60 cm, G2: >60 cm). In addition, number of satellite nevi in the first year of life is categorized into none, 1 to 20, more than 20 to 50, and more than 50 satellites. Additional descriptors of CMN include anatomic localization, color heterogeneity, surface rugousity and presence of hypertrichosis (described as none, moderate, marked), and presence of dermal or subcutaneous nodules (none, scattered, extensive). Assessment of consistency among 3 experts showed moderate to excellent interobserver agreement for categorization of the clinical descriptors (kappa values 0.54-0.93). Limitations Applicability of the proposed scheme was tested in a virtual setting and only among experts. Conclusion The proposed categorization scheme for CMN was agreed upon by experts and showed good interobserver agreement. Such standardized reporting of patients with CMN facilitates the development of an international clinical database for the study of large and giant CMN.

The term "melanocytic nevus" comprises a group of clinically and pathologically distinct subtypes. In this prospective clinical study we evaluated the frequency, localization, and age and gender distribution of flat nevi (FN), Miescher nevi (MN), and Unna nevi (UN) in a caucasian population. Nevi were counted in 400 patients, of which 47 had a history of melanoma. Additionally, the patients answered to a detailed UV questionnaire. Flat nevi represented the most common type of melanocytic nevi, with a peak in the 3rd decade of life. They were mostly found on the extremities and on the trunk. Miescher nevi were most common in the 6th decade and were predominantly found in the head and neck region. Unna nevi showed a maximum in the 8th decade and they were mainly situated on the trunk. The counts of all three nevus subtypes were elevated in the melanoma group. Our results confirm that FN, MN, and UN represent melanocytic nevi with distinctive morphological and clinical characteristics. The role of sunlight seems to be more prominent in the pathogenesis of FN. The precise description of FN, MN, and UN may serve as a base for a pathogenetic distinction of subtypes of melanocytic nevi in the future.

Background Therapeutic angiogenesis has become a key technology in experimental and clinical medicine. Only few data are available on the effects of timing and targeting of therapeutic proteins after cell-based gene transfer. This work investigates such effects after temporary expression of vascular endothelial growth factor 165 (VEGF165), the most commonly used angiogenic protein for therapeutic purposes. Methods We established a cell-based gene-transfer model using fibroblasts to temporarily produce VEGF165. Cells were implanted into 40 rats. Protein expression and angiogenic effects were measured by PCR, immunohistology, and microangiography. To determine an improvement for survival of ischemically challenged tissue, cells were implanted in an ischemic flap model at different locations and time points. Results After implantation of modified cells, a temporary increase was found in the target tissue for VEGF165, endothelial cell counts, and capillary network formations. Four wk later, histological alterations in the target tissue area were not different from controls. Implantation of modified cells into flap plus wound margin 1 wk before surgery showed significant improvement of tissue survival demonstrated by planimetric measurements and blood vessels counting in the target tissue. Conclusion In our model, temporary expression of VEGF165 induces therapeutically relevant angiogenesis and improves blood supply only if applied 1 wk before ischemia. It is essential to include the surrounding area for induction of angiogenesis in this model. In contrast, the angiogenic effects are not effective in the target area and its surrounding tissue, if therapeutic gene expression is started during onset of ischemia or 2 wk before ischemia in this model.