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Guidelines
for the Management of
ACTINIC KERATOSES
Developed by the Guideline Subcommittee of the European Dermatology Forum
Subcommittee Members:
(Switzerland) Dr. Rino Cerio, London (UK) Prof. Dr. Bernard Cribier, Strasbourg (France) Prof. Dr. Carlos Ferrándiz Foraster, Badalona (Spain) Prof. Dr. Alberto Giannetti, Modena (Italy) Prof. Dr. Laios Kemény, Szeged (Hungary) Prof. Dr. Helmut Kerl, Graz (Austria) Prof. Dr. Bernt Lindelöf, Stockholm (Sweden) Prof. Dr. Martino Neumann, Rotterdam (The Netherlands) Prof. Dr. Wolfram Sterry, Berlin (Germany) Prof. Dr. Eggert Stockfleth, Berlin (Germany) Members of EDF Guideline
Committee:
Prof. Dr. Martine Bagot, Créteil (France) Prof. Dr. Lasse Braathen, Bern (Switzerland) Prof. Dr. Sergio Chimenti, Rome (Italy) Prof. Dr. José Luis Diaz-Perez, Bilbao (Spain) Prof. Dr. Vladimir Hegyi, Bratislava (Slovak Republic) Prof. Dr. Lajos Kemény, Szeged (Hungary) Prof.Dr. H.C. Korting, Munich (Germany) Prof. Dr. Gillian Murphy, Dublin (Ireland) Prof. Dr. Martino Neumann, Rotterdam (The Netherlands) Prof. Dr. Tony Ormerod, Aberdeen (UK) Prof. Dr. Annamari Ranki, Helsinki (Finland) Prof. Dr. Fenella Wojnarowska, Oxford (UK) Chairman of EDF Guideline Committee: List of conflicts of interest:
is a speaker of symposia sponsored by Shire Prof. Dr. Eggert Stockfleth, Berlin is a speaker for 3M Pharmaceuticals, Shire, (Germany) Guideline for the management of actinic keratoses
This guideline is based on a previous document prepared by E. Stockfleth et al. prepared for the German "Arbeitsgemeinschaft Dermatologische Onkologie - Deutsche Krebsgesellschaft" and has been modified by the Guidelines Committee of the European Dermatology Forum. It reflects the data available at the time the report was written. Future studies may require alterations of the conclusions or recommendations in this report. The level of evidence of published studies is based on the criteria from Sackett (http://www.cebm.net/levels_of_evidence.asp).
Table of contents
Surgical excision, dermabrasion and curettage Disclaimer
This guideline for the management of actinic keratoses (AK) has been prepared by the AK subcommittee of the Guidelines Committee of the European Dermatology Forum. It represents an evidence-based guidance for treatment for actinic keratoses, with identification of the level of evidence available at the time of preparation, and contains a brief overview of epidemiological aspects and clinical management of patients with AK. A variety of different and well-accepted therapeutic modalities are used in the management of AK. This guideline aims to aid in the selection of the most appropriate treatment option for individual patients.
1 Definition and Pathogenesis
Actinic keratoses (AKs) are defined as keratotic macules, papules or plaques with superficial scale on a red base, occurring on areas extensive damage throughsunlight. They should be classified as in situ squamous cell carcinomas (SCC) [Ackerman 2003, Heaphy & Ackerman 2000]. Histopathologically an intraepidermal proliferation of atypical keratinocytes can be observed. AKs are mainly caused by non-ionising radiation, especially through ultraviolet light associated with chronic sun exposure. While UV-A (320 - 400 nm) induced photooxidative stress indirectly induces characteristic DNA mutations, the spectrum of UV-B (290 - 320 nm) irradiation directly results in the formation of cyclobutane (thymin) dimer formation and C ? T or CC ? TT transitions in DNA and RNA. In the absence of appropriate repair mechanisms, these DNAchanges represent the initiation of keratinocyte mutations which can progress into the development of AKs Brash et al. 1996]. Other factors like repeated iatrogenic exposure to UV-A with or without combination with psoralenes, X-rays or radioisotopes are known to induce AKs. Human papilloma-viruses (HPV) play a role as co-carcinogen in the ethiopathogenesis of AKs [Lober & Lober 2000, Stockfleth et al. 2004a]. The association between cutaneous HPV types and skin carcinogenesis is well known since 1978 in patients with epidermodysplasia verruciformis [Orth et al. 1978]. In AKs often cutaneous HPV types and rarely genital types have been detected [Harwood & Proby 2002]. Tumour-inducing effects have been also be shown for viral E6 protein of cutaneous HPVs. E6 interacts with pro-apoptotic Bak-protein and therefore inhibits apoptosis [Jackson & Storey 2000, Jackson et al. 2000]. Other factors include the skin phototype of the individual, genetic factors, chronic immunosupression, history of arsenic exposure. AKs can occur as single lesion or affect an entire field such as sun exposed areas on the forehead or the back of the hand (syn. field cancerisation) [Braakhuis et al. 2003]. Cancer-related molecular alterations are found in both, AK and SCC. This genetic link supports the malignant nature of AKs from its inception. The transformed keratinocytes show a high mutation rate of the tumour-suppressor gene p53 and expression of telomerase [Callen et al. 1997, Mittelbronn et al. 1998]. Additionally, the similar chromosomal aberrations have been described for invasive SCC typical and AK [Ashton et al. 2003].
2 Epidemiology
Epidemiological data show a high occurrence rate of AKs in populations with skinphototype I-III and an increase of AKs in the last decades, worldwide. Regions with higher UV exposure have a higher prevalence of AKs. In Europe a prevalence of 15 % in men and 6 % in women has been documented in a recent report from the U.K. Over the age of 70 years, 34 % of males and 18 % of females were found to have AKs [Memon et al. 2000]. The USA show prevalences between 11 - 26 % [Salasche 2000], and in Australia (Queensland) a very high prevalence of AKs (55 % of men between 30 - 70 years showed AKs, as opposed to 37 % of women) has been reported [Frost et al. 2000]. In addition to sex, gender and age, other risk factors are known. Geographical factors such as altitude and latitude, increased vacational and recreational sunexposure. a history of severe sunburns in childhood, genetic disorders (xeroderma pigmentosum), and immunodeficiency contribute to the development of actinic keratoses. Clinically the affected individual often presents with the characteristic signs of dermatoheliosis such as freckles, solar lentigines and rhytides. High-risk-AKs occur mainly in immunosuppressed patients [Schmook & Stockfleth 2003]. Organ-transplanted patients have a 250 fold higher risk to develop AKs and a 100 fold higher risk to develop invasive SCCs [Stockfleth et al. 2002a, Ulrich et al. 2002]. While about 40 % of immunosuppressed patients develop an invasive SCC only approximately 10 % (6 - 16 %) of immunocompetent patients with AK's show this progression. [Glogau 2000, Stockfleth et al. 2002a]. In conclusion, the incidence of AKs is increasing such that millions of patients are affected worlwide making actinic keratoses the most frequent carcinoma in situ in man.
3 Clinical aspects
Typical AKs are skin-coloured to reddish-brown scaly macules, papules or plaques occurring in areas of chronic sunexposure, especially on face, forehead, scalp, ears, neck, décolleté, arms, dorsum of hands, and lower lips. Lesions size ranges from a few millimetres up to 2 centimetres or more in diameter. AKs rarely develop as solitary lesions; in fact multiple lesions are commonly present (field cancerisation). A clinical classification is illustrated in Table 1. *) Overlapping between subtypes may be observed No distinct clinical boundaries exist between AKs and SCC. It has been reported that before AKs progress to invasive SCC, they may become inflamed and painful [Berhane et al. 2002]. Diagnosis of AKs is based upon the typical clinical aspects. Histological confirmation is necessary, when clinical doubts exist or when special forms of treatment are considered. A biopsy which includes the dermis is required if deeper involvement needs to be excluded. Dermoscopy can be helpful in the differential diagnosis of pigmented actinic keratosis vs. lentigo maligna melanoma and superficial and/or pigemented basal-cell carcinoma. Other techniques, including confocal scanning laser microscopy, have been utilised in serial clinical investigations. [Chung et al. 2004].
4 Histopathology
The histological criteria of AKs are summarized in Table 2. Histopathological features
- Focally atypical keratinocytes (large pleomorphic nuclei, hyperchromatic nuclei) in the basal layer of the epidermis - Alternation of ortho- and parakeratosis - Hyperplasia (or sometimes atrophy) of the epidermis - Rete ridges arranged in buds or columns - Alternation of ortho- and parakeratosis - Neoplastic cells spare both acrosyringia and acrotrichia - Atypical epidermal keratinocytes involve mostly the lower half of the epidermis. Sometimes with focal involvement of the entire thickness of the epidermis - Atypical keratinocytes extend along adnexal epithelia - Dyskeratotic cells and mitotic figures - Lymphocytic infiltrate of variable density The lichenoid subtype of AK is accompanied by dense bandlike infiltrates of lymphocytes in the stratum papillare. Acantholytic dyskeratotic cells above suprabasal clefts are found in acantholytic AKs. The degree of intraepidermal involvement by keratinocytic atypia is graded as mild (AK I), moderate (AK II) or severe (AK III). The classification of AKs takes into consideration that AK is an early stage of cancer and that both, AKs and SCC are stages in the evolution of a continuous process characterised by the proliferation of atypical keratinocytes. On histopathologic grounds alone, AK and SCC are indistinguishable in the epidermal layer, and AKs fulfill all criteria for SCC. Both contain atypical keratinocytes with loss of polarity, nuclear pleomorphism, disordered maturation, and increased numbers of mitotic figures [Ackerman 2003]. AK and SCC are frequently contiguous with one another. It is important to emphasize that in a study of >1000 SCC on sun-damaged skin nearly 100% of these lesions contained histopathologic changes of AK at the periphery [Guenthner et al. 1999]. 5 Treatment options

5.1 Overview
It is impossible to predict which AK will become thicker or more invasive with a potential for destructive growth and risk for metastases, i.e. develop into metastatic squamous cell carcinomas. AKs should therefore be treated. In the decision which therapy should be chosen the following factors play a major role: duration and course of lesions, localisation and extend of disease, solitary or multiple AKs, age, and co-morbidity, mental condition and compliance of the patient, pre-existing (skin) cancer and as well as the presence of other risk factors (especially immuno-suppression). When considering treatment options for actinic keratoses, there is a great variety of accepted methods. When using non-surgical treatment modalities an exemplary probe biopsy for histological diagnosis may be indicated before therapy. The following treatment options are not listed in a ranked order.
5.2 Surgical excision, dermabrasion and curettage
Excision of AKs is not routinely used and only chosen if invasive SCC is suspected or recurrent lesions are present. Shave excision is frequently used for AK. Sutures are not necessary and a histologic diagnosis can be provided [Emmet & Broadbent 1987]. Similarly, curettage may be used alone or in conjunction with electro-surgery or cryotherapy with excellent cure rates [Dinehart 2000]. Curettage may also be combined with zinc chloride as Schreus-method which is also a very effective method for the treatment of field cancerisation [Cerburkovas et al. 2001]. Dermabrasion is especially useful for larger areas of AK on the scalp [Coleman 1996]. All these methods require local anesthesia and may leave epidermal changes or scarring.
5.3 Cryotherapy
Cryotherapy is the most common treatment for AKs, especially for the management
of multiple AKs [Drake et al. 1995, Dinehart 2000, Zouboulis 1999]. Cryotherapy is
available in techniques using liquid nitrogen or as spray or contact-cryotherapy. Field
cancerisation, which describes a chronically sun-damaged area can be treated by
cryo-peeling [Chiarello 2000]. Cryotherapy is not standardised concerning frequency,
duration, intensity and definitive specification of temperature in the frozen tissue. As
a non-specific technique, cryotherapy destroys atypical, but also normal cells by
disruption and separation of the epidermis from the dermis. Pain, redness, edema
and blistering can occur during and after treatment. Scarring and hypo- or
hyperpigmentation is commonly observed.
Though cryotherapy is often used, controlled studies are missing. Complete
responses differ from 75 % to 98 % [Szeimies et al. 2000 - level of evidence 2b,
Graham 2001 - level of evidence 3a]; the recurrence rates of AKs have been
estimated from 1.2 % to 12 % within a 1-year follow up period [Chiarello 2000 -
level of evidence 3a, Lubritz et al. 1982 - level of evidence 3b].
5.4 Chemical peeling
Chemical peeling is a destructive method through the application of caustic agents
like trichloroacetic acid, alpha-hydroxy acids, zinc-chloride or phenolic acid. Chemical
peeling can be a useful alternative for treatment of extensive facial AK [Witheiler
1997 - level of evidence 2c]. The efficacy of chemical peelings depends on the
agent used and is quoted to be round about 75 %; recurrence rates are from 25 - 35
% within one year after therapy. Side effects of chemical peelings include pain,
inflammation, pigmentary alterations, and the risk of scarring [Lawrence et al. 1995 -
level of evidence 2c, Otley & Roenigk 1996, Stone 1998 - level of evidence 3b].
5.5 Laser
Near infrared laser systems like carbon dioxide (CO2) or Erbium-YAG lasers are
indicated in special cases for AKs. Both are ablative laser systems and can be used
for single lesions as well as full face resurfacing. Full face laser resurfacing provides
long-term effective prophylaxis against AKs and may reduce the incidence of AKs
related SCC [Iyer et al 2004]. Adverse events are pain, inflammation, pigmentary
changes and scarring as well as delayed healing and postinflammatory erythema.
Although complete remission is documented from 90 to 91% recurrence rates for
single lesions range from 10 to 15% within 3 to 6 months [Wollina et al. 2001 - level
of evidence 3b, Yu et al. 2003]. Disappointing results reported in earlier literature
maybe related to technical aspects, as the outcomes of full face resurfacing are
strongly user dependend. [Fulton et al. 2000]. The expert opinion is that in skilled
hands there is a place for CO2/Erbium-YAG laser in the management for AKs and the
treatment of actinic cheilitis.
5.6. Radiotherapy
The treatment of AKs with X-rays is considered obsolete due to the cocarcinogenic effect of X-rays.
5.7 Photodynamic therapy
Topical photodynamic therapy (PDT) acts through the selective destruction of atypical
keratinocytes (depth of penetration 3-4 mm) through light activation of a
photosensitiser in the presence of oxygen. The neoplastic cells accumulate more
photosensitiser than normal cells. The photosensitiser generates reactive oxygen
species upon illumination, which results in selective photochemical and photothermal
effects on the irradiated tissue. The most commonly used precursors of
protoporphyrin IX are 5-aminolevulinic acid (ALA) and its derivatives like the new
lipophilic agent methyl aminolevulinate (MAL). MAL-PDT is applied as a cream under
occlusion for 3 hours before illumination with high intensityred light. For Europe, the
European Medical Evaluation Agency (EMEA) labelled MAL as indication for AK. The
clinical experience in AK patients receiving MAL-PDT shows complete response rate of
70-78% after a single treatment session and 90% after two treatment sessions one
week apart. Negative effects of PDT are local pain, risk of photosensitivity (mainly for
ALA) and time delay between application of cream and treatment. Photodynamic
therapy in comparison to cryotherapy shows significantly better cosmetic results -
(evaluation by patients and doctors) [Szeimies et al. 2000 - level of evidence 2b,
Szeimies et al. 2002 - level of evidence 2b, Morton et al. 2002; Pariser et al. 2003
- level of evidence 2b, Schmook & Stockfleth 2003]. Advantages of PDT include the
selective absorption and treatment of sub-clinical lesions and the flourescence of the
photosensitiser can be visualised using Wood´s light before the initiation of therapy
(Freeman et al. 2003). On the other hand, the costs of treatment are considerably
higher compared to cryotherapy.
5.8 Imiquimod
Imiquimod 5%, a member of a novel class of immune response modifiers (IRMs), is a
toll-like receptor (TLR) 7-agonist and stimulates the immune response by induction,
synthesis and release of cytokines. These cytokines increase the cellular immunity.
Therefore it has an indirect antiviral and anti-tumoral potency [Hemmi et al. 2002,
Miller et al. 1999]. Topically applied imiquimod causes a local skin reaction, including
erythema, itching, and burning, that is generally mild to moderate in intensity - also
fever can occur (especially in larger treated areas and/or mucosal application). Apart
from the capability of imiquimod to 'light-up' sub-clinical Aks, Imiquimod is effective
and safe in patients with AKs. Response rates show complete remission in 84 %; a
recurrence rate of 10 % within 1-year follow up and 20 % within 2-years follow up
[Stockfleth et al. 2002b - level of evidence 2b, Stockfleth et al. 2004b - level of
evidence 2b]. A randomised, double-blind, placebo-controlled study in 436 patients
with actinic keratoses showed a complete resolution of all lesions in 45.1 % (vs. 3.2
% placebo) and a partial reduction of actinic keratoses in 59.1 % (vs. 11.8 %
placebo) after a treatment period of 16 weeks (twice per week) [Lebwohl et al. 2004
- level of evidence 2b]. A label for the indication of AK through the EMEA is in
process. Imiquimod is labelled for the indication of superficial basal cell carcinoma in
the USA, Australia and Europe.
5.9 Topical 5-fluorouracil
5-fluorouracil (5-FU) is a topical chemotherapeutic antimetabolite that destroys
clinical foci via interference with DNA and RNA by blocking the methylation reaction
of deoxyuridylic acid to thymidylic acid. Hereby 5-FU interferes with the synthesis of
DNA and, to a lesser extent, inhibits the formation of RNA. 5-FU can be used for the
treatment of multiple lesions and is applied twice a day (2 - 4 weeks). These effects
may cause life-risk complications if dihydropyrimidine-dehydrogenase-deficency
exists [Johnson et al. 1999]. Topical 5-FU can results in severe dermatitis with
wound infections, pruritus, pain and ulceration with scarring and the application is of
limited help in the therapy of extensive AKs. A reduction of severe side effects can be
realised by using intermittent "pulse" 5-FU therapy which is a less intensive way of
employing 5-FU and may be of value in patients unwilling to accept the erosions and
discomfort that accompany the traditional course of daily 5-FU applications [Epstein
1986 - level of evidence 3b]. For localised disease, clearance rates of
approximately 50 % and recurrence rates up to 55 % have been reported with 5-FU
[Gupta 2002, Lawrence et al. 1995 - level of evidence 2c, Levy et al. 2001 - level
of evidence 3b]. Meanwhile, new formulations with different concentrations and
galenics of 5-FU are under clinical investigations. [Jorizzo et al. 2002 - level of
evidence 3a, Levy et al. 2001 - level of evidence 3b, Loven et al. 2002 - level of
evidence 2c, Robins & Gupta 2002].
5.10 Retinoids
Retinaldehyde is a natural derivative of vitamin A; it has effects similar to retinoic
acid [Sass et al. 1996]. Besides counteracting the UV-induced vitamin A deficiency of
the epidermis, topical retinaldehyde may have an antioxidant effect [Sachsenberg-
Studer 1999, Sorg et al. 2001] and decreases the number of sunburn cells. A
placebo-controlled randomised study documents that systemic administered
etretinate reduces AKs in 85 % [Moriarty et al. 1982 - level of evidence 2b]. Some
publications show that the epidemiological characteristics of AKs were not modified
by the application of retinaldehyde and that retinaldehyde has no prophylactic effects
on the development of AKs [Campanelli & Naldi 2002 - level of evidence 3a,
Humphreys et al. 1996 - level of evidence 3a]. Side effects of topically applied
retinoids are increased sensitivity to sunlight, erythema, erosions, pruritus and pain.
Retinoids can be also administered orally especially in patients who develop large
numbers of skin cancers [Berretti & Grupper 1986]. Systemic therapy can be
considered for high risk patients - such as patients with inherited disorders such as
xeroderma pigmentosum (abnormal repair of UV-induced DNA damage), nevoid basal
cell carcinoma syndrome (tumour suppressor gene abnormality) or in after organ-
transplant recipients with chronic immunosuppression [DiGiovanna 2001, McNamara
et al. 2002 - level of evidence 3a]. The use of retinoids for the treatment of AKs is
currently an off-label use.
5.11 Diclofenac in hyaluronic acid gel
Within the last years antineoplastic properties of selective inhibitors of cyclo-
oxygenase 2 (COX-2 have increasingly been investigated). These new agents inhibit
prostaglandin E2 synthesis (PGE2) which is known to suppress the production of
immune-regulatory lymphocytes, T-and B-cell proliferation and the cytotoxic activity
of natural killer cells. Furthermore activation of COX-2 has implications for tumour
angiogenesis through up-regulation of vascular endothelial growth factor (VEGF),
which is a potent angiogenic factor required for tumor growth and metastases [Jung
et al. 2003]. Apart from its affinity to the inducible COX-2, NSAIDs have been
demonstrated to activate peroxisome proliferator-activated-receptor-gamma (PPAR-
gamma) which decreases cancer cell proliferation. Topical diclofenac is applied in
hyaluronic acid (HA). Several randomised, double blind, HA gel vehicle-controlled
clinical studies have evaluated the efficacy of topical diclofenac HA gel in patients
with AK. The 30-day interval between the end of treatment and the evaluation of
efficacy was due to earlier findings stating a significant advantage for diclofenac HA
gel over placebo, when efficacy was evaluated 4 weeks after the end of treatment.
The product significantly reduced lesions when applied for 60 or 90 days bid. A
double-blind, randomised, placebo-controlled multicenter study showed responding
rates of 79 % (verum group) versus 45 % in the placebo group; a complete healing
was seen in 50 % (verum group) versus 20 % in the control group (p<0,001 %)
[Rivers et al. 2002 - level of evidence 2b]. Other controlled studies showed similar
effects [Gebauer et al. 2003 - level of evidence 2b, Wolf et al. 2001 - level of
evidence 2b]. Adverse effects were skin related and mild to moderate in severity
(pruritus, erythema, dry skin, hyp- and paraesthesia). Systemic bioavailability of
diclofenac was demonstrated to be considerably lower after topical application than
after systemic administration and the drug demonstrated a good safety profile.
6 Prevention
Prevention of AKs is an important part in AK-management [Armstrong & Kricker 2001, Thompson 1993]. Education of patients (UV-protection, self-examination, and detection of early lesions) is particularly important. AK is an ongoing disease that requires frequent follow-up (half-yearly to yearly) and long-term management. 7 Summary of Recommendations
It has to be declared that the physician who cares about the patient has always to keep in mind the inidividual needs of the patient. The physician has to respect the individuality of the patient and has to see the guideline as recommendation and supporting device for therapeutical strategies and efforts.
8 Guideline-Procedure
Guideline
Prof. Dr. Lasse R. Braathen, Bern (Switzerland) Prof. Dr. Bernard Cribier, Strasbourg (France) Prof. Dr. Carlos Ferrándiz Foraster, Badalona (Spain) Prof. Dr. Alberto Giannetti, Modena (Italy) Prof. Dr. Laios Kemény, Szeged (Hungary) Prof. Dr. Bernt Lindelöf, Stockholm (Sweden) Prof. Dr. Martino Neumann, Rotterdam (Netherlands) Prof. Dr. Wolfram Sterry, Berlin (Germany) Prof. Dr. Eggert Stockfleth, Berlin (Germany) Guideline development standard operating Procedure of EDF
Foundation of subcommittee for specific guidelines, Identify all existing guidelines for the specific guideline (active process: literature survey plus contact to Select the guidelines with highest quality. Criteria for selection: 1. Availability of strength of evidence2. Availability of strength of recommendation3. Evidence of mechanics of literature review Identification/nomination of additional 50 % EDF members for the EDF-GsubC from amongst the authors of the best guidelines Nomination of chairperson for EDF-GSubC from the Consider involvement of other disciplines and patients´ organisations 1. to decide the author of the first draft and to discuss the present guidelines, their strengths and weaknesses 2. 6 months later to discuss the draft (consensus Circulate the guideline draft to national dermatological societies for comments Circulate final version for approval among members of Deliver final version to EDF guideline chairperson Send guideline for official approval to UEMS (formal Distribute guideline for in advance information to EDF members and National Dermatological Societies Publication 1. on EDF homepage2. in European Journal of Dermatology, British Journal of Dermatology and Journal of Deutsche Dermatologische Gesellschaft
Expiry date
9 References
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Level Therapy/Prevention, Prognosis
Diagnosis
Differential
Economic and
Aetiology/Harm
diagnosis/symptom decision
prevalence study
analyses
homogeneity*) of RCTs homogeneity*) homogeneity*) of homogeneity*) of cohort studies; studies; CDR† with studies CDR† validated 1b studies from in different inception cohort study with good††† study with good follow- clinically sensible evidence; and including multi-way sensitivity analyses value or worse-value analyses †††† homogeneity*) homogeneity*) of homogeneity*) of 2b Level >2 diagnostic and better studies cohort studies or untreated control groups in RCTs (including low quality cohort study or cohort study with study, or poor follow- estimates of data, but including sensitivity analyses incorporating clinically sensible variations. Case-series (and poor Case-series (and Case-control study, Case-series or appraisal, or based on critical appraisal, critical appraisal, or appraisal, or based on critical appraisal, physiology, bench physiology, bench research or "first

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