Vitiligo Physical Vitiligo Physical TreatmentsTreatments

Torello LottiTorello LottiUniversity Unit of DermatologyUniversity Unit of Dermatology

University of FlorenceUniversity of FlorenceFlorence, ItalyFlorence, Italy

Vitiligo: a key conceptVitiligo: a key concept

Melanocytes are not completely absent Melanocytes are not completely absent in the depigmented epidermis in the depigmented epidermis

Comment:Comment: A subpopulation of “resistant” A subpopulation of “resistant”

epidermal melanocytes can persist epidermal melanocytes can persist independent of disease durationindependent of disease duration

Repigmentation can always Repigmentation can always occur independent of occur independent of disease duration and with disease duration and with non-perifollicular pattern non-perifollicular pattern

Should I treat vitiligo?Should I treat vitiligo?

16% of dermatologists in The Netherlands 16% of dermatologists in The Netherlands are in favour of active treatment of vitiligoare in favour of active treatment of vitiligo

Njoo MD et Al, Int J Dermatol 1999;38:866-872Njoo MD et Al, Int J Dermatol 1999;38:866-872

84% of dermatologists in The Netherlands 84% of dermatologists in The Netherlands are reluctant to start any active treatment are reluctant to start any active treatment in vitiligo; 82% in the Mediterranean area in vitiligo; 82% in the Mediterranean area either prescribe placebos or treatments of either prescribe placebos or treatments of cosmetic relevance onlycosmetic relevance only

Lotti T. La vitiligine: nuovi concetti e nuove Lotti T. La vitiligine: nuovi concetti e nuove terapie. UTET – Torino, 2000terapie. UTET – Torino, 2000

I have to treat vitiligo!I have to treat vitiligo!

Positive balance of active treatments of vitiligo Positive balance of active treatments of vitiligo patients*patients*

Topical corticosteroids (max 6 months) Topical corticosteroids (max 6 months) 89%89%

PUVA treatment (max 12 months) PUVA treatment (max 12 months) 16% 16% PUVA treatment (max 9 months) PUVA treatment (max 9 months) 25% 25% UVB treatment (max 6 months) UVB treatment (max 6 months) 87% 87%

(Broad + Narrow Band)(Broad + Narrow Band)

Surgical treatment (one shot + UVB) Surgical treatment (one shot + UVB) 68% 68%

*evaluation made by Dermatologists*evaluation made by Dermatologists• Int J Dermatol 1999;38:866-872

• Arch Dermatol 1999;135:1514-1521

So, how to treat vitiligo?So, how to treat vitiligo?

Cosmetic camouflage (dihydroxyacetone)Cosmetic camouflage (dihydroxyacetone) Depigmentation ( Monobenzyl ether of Depigmentation ( Monobenzyl ether of

hydroquinone, Q-switched ruby laser) hydroquinone, Q-switched ruby laser) Repigmentation (corticosteroids, Repigmentation (corticosteroids, psoralen psoralen

photochemotherapyphotochemotherapy, , UVB phototherapyUVB phototherapy))

The efficacy of UVB in vitiligo therapy is probably The efficacy of UVB in vitiligo therapy is probably due to:due to: Its immunesuppressive effectIts immunesuppressive effect Stimulation of melanocytesStimulation of melanocytes

Psoralen plus UV-A oral Psoralen plus UV-A oral photochemotherapy (PUVA)photochemotherapy (PUVA)

…the classic…the classic Oral assumption of photosensitizers Oral assumption of photosensitizers

(Psoralenes) taken 2 hours before UVA (Psoralenes) taken 2 hours before UVA (320-400 nm) exposure(320-400 nm) exposure

8-Methoxypsoralen (8-MOP) 0.6-0.8 mg/kg, 8-Methoxypsoralen (8-MOP) 0.6-0.8 mg/kg, or 4,5,8-trimethylpsoralen 0.6 mg/kgor 4,5,8-trimethylpsoralen 0.6 mg/kg

Treatments are given 3 times weekly but Treatments are given 3 times weekly but not on two consecutive daysnot on two consecutive days

Best results on the face and neck, worst on Best results on the face and neck, worst on the extremitiesthe extremities

Increased risk of skin cancer induction Increased risk of skin cancer induction photoprotection and maximum amount of photoprotection and maximum amount of treatments are to be consideredtreatments are to be considered

Psoralen plus UV-A oral Psoralen plus UV-A oral photochemotherapy (PUVA)photochemotherapy (PUVA)

Possible side-effects:Possible side-effects: Nausea, vomiting, dizziness, sweatingNausea, vomiting, dizziness, sweating Increased contrast between healthy and Increased contrast between healthy and

affected skinaffected skin BurnsBurns ItchItch Skin cancer inductionSkin cancer induction ……

… The classic

Ideal treatment in vitiligo:Ideal treatment in vitiligo:phocused therapy phocused therapy

EfficacyEfficacy Rapid repigmentationRapid repigmentation Easy and quick esecutionEasy and quick esecution Only the hypopigmented areas are Only the hypopigmented areas are

treatedtreated SafetySafety Pain freePain free

Monochromatic treatment of Monochromatic treatment of vitiligovitiligo

XTRAC XTRAC

Xenon-Chloride Gas Excimer Laser (308 nm)Xenon-Chloride Gas Excimer Laser (308 nm)

EXCILITE EXCILITE

Xenon-Chloride Monochromatic Excimer Light Xenon-Chloride Monochromatic Excimer Light (308 (308 ± 1 nm)± 1 nm)

BIOSKINBIOSKIN

Narrowband UVB (311nm)Narrowband UVB (311nm)

Laser treatment: Technical Laser treatment: Technical specificationsspecifications

XTRAC Excimer LaserXTRAC Excimer Laser

(Photomedex, USA)(Photomedex, USA)•SourceSource XeCl XeCl •WavelengthWavelength 308 nm308 nm•Treatment surfaceTreatment surface 3,2 3,2 cmcm22 •Pulse durationPulse duration 30 ns30 ns•Fluence Fluence 3 3 mJ/cmmJ/cm2 2

•Pulse repetitionPulse repetition 200 Hz200 HzJ Am Acad Dermatol 2002 Jun;46(6):900-6

Monochromatic Excimer Light : Monochromatic Excimer Light : Technical specificationsTechnical specifications

Int J Immunopathol Pharmacol 2002;13(1):11-13

•Source ExcimerSource Excimer•Wavelength 308 nm Wavelength 308 nm 1 1•Treat. Surface 36 x 14 cmTreat. Surface 36 x 14 cm•Irradiance 50 mW/cmIrradiance 50 mW/cm22

•Main supply 230 VMain supply 230 Vacac-12A--12A-50/60Hz50/60Hz•Dimensions 150cm(H)-Dimensions 150cm(H)-50cm(W)-50cm(W)- 105cm(D)105cm(D)•Weight 120 KgWeight 120 Kg

Narrow Band UVB Narrow Band UVB Excimer Laser (XeCl) Excimer Laser (XeCl)

and MELand MEL UVB 308 nmUVB 308 nm Only the hypopigmented areas are Only the hypopigmented areas are

treatedtreated No contrast between normal and No contrast between normal and

hypopigmented skinhypopigmented skin Low dose of irradiationLow dose of irradiation Reduced short-term and long-term side Reduced short-term and long-term side

effectseffects Treatment of limited body areasTreatment of limited body areas

BEFOREBEFORE AFTER 20 AFTER 20 TREATMENTSTREATMENTS

J Korean Med Sci 2005; 20: 273-8J Korean Med Sci 2005; 20: 273-8

Narrow Band UVB and Narrow Band UVB and Microphototherapy - Microphototherapy -

BIOSKINBIOSKIN UVB 311 nmUVB 311 nm Only the hypopigmented areas are Only the hypopigmented areas are

treated treated Particulary effective for the treatment of Particulary effective for the treatment of

limited affected areas and segmental limited affected areas and segmental vitiligo.vitiligo.

Does not increase the colour contrastDoes not increase the colour contrast Low dose of radiationLow dose of radiation Low rates of short-term and long-term Low rates of short-term and long-term

adverse eventsadverse events

BIOSKINBIOSKIN®® device simplified device simplified schemescheme

1) UVB generator

2) Visible and UV

4) Interference Filter

3) Time controlled Leaf Shutter

7) Specific Optical Fiber

5) N.B. UVB

8) Vitiligo patch6) Iris Diaphragm

BIOSKINBIOSKIN® ®

MicrophototherapyMicrophototherapy

BIOSKINBIOSKIN®® emission emission spectrumspectrum

IntensityIntensity10-100 mW/cm10-100 mW/cm22

DEM=40 mW DEM=40 mW × 10 × 10 sec=400mJ/cm2sec=400mJ/cm2

MicrophototherapyMicrophototherapy

This phototherapy permits a differentiated This phototherapy permits a differentiated irradiation.irradiation.

Thus is possible to irradiate i.e. hands and feet Thus is possible to irradiate i.e. hands and feet with a dose 5 or 6 times higher than the dose used with a dose 5 or 6 times higher than the dose used for eyelids.for eyelids.

BIOSKINBIOSKIN®® and and MicrophototherapyMicrophototherapy

UVB narrow band (311 nm) UVB narrow band (311 nm) irradiated on vitiligo patches irradiated on vitiligo patches onlyonly

•Lotti T, Menchini G, Andreassi L. UV-B Lotti T, Menchini G, Andreassi L. UV-B microphototherapy. An elective treatments for microphototherapy. An elective treatments for segmental vitiligo. J Eur Acad Dermatol Venereol. segmental vitiligo. J Eur Acad Dermatol Venereol. 1999;13:102-81999;13:102-8•Menchini G, Comacchi C, Tsoureli E, Lotti T. Menchini G, Comacchi C, Tsoureli E, Lotti T. Microfototerapia BIOSKIN®. In: La vitiligine: nuovi Microfototerapia BIOSKIN®. In: La vitiligine: nuovi concetti e nuove terapie. T. Lotti. 2000 Ed UTET concetti e nuove terapie. T. Lotti. 2000 Ed UTET periodici scientifici srl (MI). pp 108-114periodici scientifici srl (MI). pp 108-114

Results of a study on 734 Results of a study on 734 patients after 2 years of patients after 2 years of

BIOSKINBIOSKIN® ® treatmenttreatment

Microphototherapy vs. Microphototherapy vs. MEL and XTRACMEL and XTRAC

MICROPHOTOTHERAPYMICROPHOTOTHERAPY

UVB 311 nmUVB 311 nm Sessions: every 3 weeksSessions: every 3 weeks Repigmentation after 6 Repigmentation after 6

sessionssessions Permits a differentiated Permits a differentiated

irradiationirradiation

MEL AND XTRACMEL AND XTRAC

UVB 308 nmUVB 308 nm Number of sessions: Number of sessions:

1/week (MEL); 1/week (MEL); 2-3/week (XTRAC)2-3/week (XTRAC)

Repigmentation Repigmentation after 10-20 sessionsafter 10-20 sessions

CONCLUSION?CONCLUSION?

VITILIGOVITILIGOBoth Narrow Band UVB Excimer Laser and Narrow Both Narrow Band UVB Excimer Laser and Narrow

Band UVB Light Band UVB Light show similar results in similar time of treatment even show similar results in similar time of treatment even

if they can be used only in limited skin surfaces.if they can be used only in limited skin surfaces.

Vitiligo therapy & EBM: what is really Vitiligo therapy & EBM: what is really effective?effective?

Several RCTs showed oral psoralen plus UVA (PUVA) and plus Several RCTs showed oral psoralen plus UVA (PUVA) and plus sunlight (PUVAsol) efficacy vs. placebo in achieving >75% sunlight (PUVAsol) efficacy vs. placebo in achieving >75% repigmentation, and one RCT* showed PUVA as more effective repigmentation, and one RCT* showed PUVA as more effective than placebo plus sunlight.than placebo plus sunlight. *Pathak MA, Mosher DB, Fitzpatrick TB. *Pathak MA, Mosher DB, Fitzpatrick TB. Natl Cancer Inst MonogrNatl Cancer Inst Monogr 1984;66:165- 1984;66:165-

7373 Recent RCTs found that NB-UVB is more effective than PUVA Recent RCTs found that NB-UVB is more effective than PUVA

in achieving repigmentation°. in achieving repigmentation°. °Yones SS, Palmer RA, Garibaldinos TM, Hawk JL. °Yones SS, Palmer RA, Garibaldinos TM, Hawk JL. Arch DermatolArch Dermatol 2007;143578- 2007;143578-

8484 Some RCTs showed that combination of different Some RCTs showed that combination of different

phototherapies with both vitamin D analogues and topical phototherapies with both vitamin D analogues and topical corticosteroids may increase the response rates.corticosteroids may increase the response rates. Ermis O, Alpsoy E, Cetin L, Yilmaz E. Ermis O, Alpsoy E, Cetin L, Yilmaz E. Br J DermatolBr J Dermatol 2001;145:472-5 2001;145:472-5

(calcipotriol and PUVA)(calcipotriol and PUVA) Leone G, Pacifico A, Iacovelli P, Paro Vidolin A, Picardo M. Leone G, Pacifico A, Iacovelli P, Paro Vidolin A, Picardo M. Clin Exp DermatolClin Exp Dermatol

2006;31:200-5 (tacalcitol and MEL-UVB)2006;31:200-5 (tacalcitol and MEL-UVB) Westerhof W, Nieuweboer-Krobotova L, Mulder P, Glazenburg EJ. Westerhof W, Nieuweboer-Krobotova L, Mulder P, Glazenburg EJ. Arch Arch

DermatolDermatol 1999;135:1061-6 (fluticasone and UVA) 1999;135:1061-6 (fluticasone and UVA)

Vitiligo therapy & EBM: what is really Vitiligo therapy & EBM: what is really effective?effective?

Topical class 3 corticosteroids have been shown to be Topical class 3 corticosteroids have been shown to be effective in localized vitiligo, while no significative difference effective in localized vitiligo, while no significative difference was shown between class 4 corticosteroids or intralesional was shown between class 4 corticosteroids or intralesional corticosteroids and their respective placebos.corticosteroids and their respective placebos. Njoo MD, Spuls PI, Bos JD, Westerhof W, Bossuyt PM. Njoo MD, Spuls PI, Bos JD, Westerhof W, Bossuyt PM. Arch DermatolArch Dermatol

1998;134:1532-401998;134:1532-40 Combination of topical calcipotriol and betamethasone Combination of topical calcipotriol and betamethasone

dipropionate is more effective than each treatment given dipropionate is more effective than each treatment given alone, reducing side effects.alone, reducing side effects. Kumaran MS, Kaur I, Kumar B. Kumaran MS, Kaur I, Kumar B. J Eur Acad Dermatol VenereolJ Eur Acad Dermatol Venereol 2006;20:269-73 2006;20:269-73

0.1% tacrolimus is as effective as 0.05% clobetasol 0.1% tacrolimus is as effective as 0.05% clobetasol propionate.propionate. Lepe V, Moncada B, Castanedo-Cazares JP, Torres-Alvarez MB, Ortiz CA, Lepe V, Moncada B, Castanedo-Cazares JP, Torres-Alvarez MB, Ortiz CA,

Torres-Rubalcava AB. Torres-Rubalcava AB. Arch DermatolArch Dermatol 2003;139:581-5 2003;139:581-5 Tacrolimus plus excimer laser is more effective than excimer Tacrolimus plus excimer laser is more effective than excimer

laser alonelaser alone Kawalek AZ, Spences JM, Phelps RG. Kawalek AZ, Spences JM, Phelps RG. Dermatol SurgDermatol Surg 2004;30(2 Pt 1):130-5 2004;30(2 Pt 1):130-5

Vitiligo therapy & EBM: what is really Vitiligo therapy & EBM: what is really effective?effective?

One RCT showed that the combination of NB-UVB and One RCT showed that the combination of NB-UVB and tacrolimus is no more effective than NB-UVB alone.tacrolimus is no more effective than NB-UVB alone. Mehrabi D, Pandya AG. Mehrabi D, Pandya AG. Arch DermatolArch Dermatol 2006;142:927-9 2006;142:927-9

One RCT found pimecrolimus to be no more effective One RCT found pimecrolimus to be no more effective than placebo in achieving repigmentation.than placebo in achieving repigmentation. Dawid M, Veensalu M, Grassberger M, Wolff K. J Dawid M, Veensalu M, Grassberger M, Wolff K. J Dtsch Dermatol GesDtsch Dermatol Ges

2006;4:942-62006;4:942-6 There are many reports about the efficacy of melagenine, There are many reports about the efficacy of melagenine,

pseudocatalase, levamisole, and systemic antioxidant pseudocatalase, levamisole, and systemic antioxidant therapy in vitiligo, but RCT evidence is really scarce.therapy in vitiligo, but RCT evidence is really scarce. Souto MG, Manhaes AMH, Milhomens CH, Succi ICB. Souto MG, Manhaes AMH, Milhomens CH, Succi ICB. An Bras DermatolAn Bras Dermatol

1997;72:237-91997;72:237-9 Agarwal S, Ramam M, Sharma VK, et al. Agarwal S, Ramam M, Sharma VK, et al. Br J DermatolBr J Dermatol 2005;153:163-6 2005;153:163-6 Rojas-Urdaneta JE, Poleo-Romero AG. Rojas-Urdaneta JE, Poleo-Romero AG. Invest ClinInvest Clin 2007;48:21-31 2007;48:21-31

Not enough RCT evidence is available nowadays about Not enough RCT evidence is available nowadays about surgical treatments for vitiligo.surgical treatments for vitiligo.

Vitiligo combination therapy:Vitiligo combination therapy:our experienceour experience

Group 1Group 1 BIOSKINBIOSKIN® alone® alone

Group 2Group 2 0.1%Tacrolimus+ BIOSKIN0.1%Tacrolimus+ BIOSKIN® ®

Group 3Group 3 1% Pimecrolimus+BIOSKIN1% Pimecrolimus+BIOSKIN®®

Group 4Group 4 Betamethasone dipropionate 0.05%Betamethasone dipropionate 0.05%+BIOSKIN+BIOSKIN®®

Group 5Group 5 Calcipotriol ointment Calcipotriol ointment 50mcg/g+BIOSKIN50mcg/g+BIOSKIN®®

Group 6Group 6 10% L-phenylalanine+BIOSKIN10% L-phenylalanine+BIOSKIN®®

Group 7Group 7 0.1% Tacrolimus alone 0.1% Tacrolimus alone

Group 8Group 8 Group 1Group 1

Group 9Group 9 Betamethasone dipropionate 0.05%Betamethasone dipropionate 0.05%

Group 10Group 10 Calcipotriol ointment 50mcg/g aloneCalcipotriol ointment 50mcg/g alone

Group 11Group 11 10% L-Phenylalanine alone10% L-Phenylalanine alone

ResultsResults 13 subjects stopped the therapy for 13 subjects stopped the therapy for

personal motivations before the end of personal motivations before the end of the studythe study Of these 4 were on topical corticosteroid Of these 4 were on topical corticosteroid

treatment alonetreatment alone 3 on Tacrolimus 0.1% ointment alone3 on Tacrolimus 0.1% ointment alone 1 on Calcipotriol ointment 50mcg/g alone1 on Calcipotriol ointment 50mcg/g alone 1 on 10% L-phenylalanine cream alone1 on 10% L-phenylalanine cream alone 1 with Pimecrolimus 1% cream alone1 with Pimecrolimus 1% cream alone 2 with BIOSKIN2 with BIOSKIN®+0.05% Betamethasone ®+0.05% Betamethasone

dipropionate creamdipropionate cream 1 with Tacrolimus 0.1% ointment + 1 with Tacrolimus 0.1% ointment +

BIOSKINBIOSKIN®®

Percentage of repigmentation in patients treated with BIOSKINPercentage of repigmentation in patients treated with BIOSKIN®® alone or in alone or in combination, or with active topicals alone.combination, or with active topicals alone.

Treatment (n° of patients)Treatment (n° of patients) Excellent Excellent (>75%)(>75%)

Marked Marked (50-75%)(50-75%)

Moderate Moderate (25-50%)(25-50%)

Minimal Minimal (<25%)(<25%)

Group 1: BIOSKINGroup 1: BIOSKIN®® alone (100) alone (100) 72%72% 19.8%19.8% 4.6%4.6% 3.6%3.6%

Group 2: 0.1% Tacrolimus + BIOSKINGroup 2: 0.1% Tacrolimus + BIOSKIN® ®

(59)(59)76.5%76.5% 18.2%18.2% 3.3%3.3% 2%2%

Group 3: 1% Pimecrolimus + BIOSKINGroup 3: 1% Pimecrolimus + BIOSKIN®® (63)(63)

76.1%76.1% 20.1%20.1% 2.7%2.7% 1.1%1.1%

Group 4: Betamethasone dipropionate Group 4: Betamethasone dipropionate 0.05% + BIOSKIN0.05% + BIOSKIN®® (28) (28)

90.2%90.2% 6.7%6.7% 2.2%2.2% 0.9%0.9%

Group 5: Calcipotriol ointment 50 mcg/g Group 5: Calcipotriol ointment 50 mcg/g + BIOSKIN+ BIOSKIN®® (60) (60)

75.6%75.6% 14.1%14.1% 7.4%7.4% 2.9%2.9%

Group 6: 10% L-Phenylalanine + Group 6: 10% L-Phenylalanine + BIOSKINBIOSKIN®® (60) (60)

74.8%74.8% 11.3%11.3% 10.1%10.1% 3.8%3.8%

Group 7: 0.1% Tacrolimus alone (22)Group 7: 0.1% Tacrolimus alone (22) 61%61% 16.1%16.1% 18.4%18.4% 4.5%4.5%

Group 8: 1% Pimecrolimus alone (19)Group 8: 1% Pimecrolimus alone (19) 54.6%54.6% 18.4%18.4% 21.7%21.7% 5.3%5.3%

Group 9: Betamethasone dipropionate Group 9: Betamethasone dipropionate 0.05% alone (23)0.05% alone (23)

71.2%71.2% 25%25% 2.1%2.1% 1.7%1.7%

Group 10: Calcipotriol ointment 50 Group 10: Calcipotriol ointment 50 mcg/g (18)mcg/g (18)

59.1%59.1% 10.6%10.6% 27.1%27.1% 3.2%3.2%

Group 11: 10% L-Phenylalanine alone Group 11: 10% L-Phenylalanine alone (18)(18)

29.3%29.3% 8.1%8.1% 55%55% 7.6%7.6%

Repigmentation rates: beginning of Repigmentation rates: beginning of repigmentation (weeks) as assessed by clinical repigmentation (weeks) as assessed by clinical

evaluationevaluation

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Treatment Groups

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Group I: Bioskin alone Group II: 0.1% Tacrolimus + Bioskin

Group III: 1% Pimecrolimus + Bioskin Group IV: 0.05% Betamethasone dipropionate + Bioskin

Group V: Calcipotriol ointment 50 mcg/g + Bioskin Group VI: 10% L-Phenylalanine + Bioskin

Group VII: 0.1% Tacrolimus alone Group VIII: 1% Pimecrolimus alone

Group IX: 0.05% Betamethasone dipropionate alone Group X: Calcipotriol ointment 50 mcg/g alone

Group XI: 10% L-Phenylalanine alone

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Group I: Bioskin alone Group II: 0.1% Tacrolimus + Bioskin

Group III: 1% Pimecrolimus + Bioskin Group IV: 0.05% Betamethasone dipropionate + Bioskin

Group V: Calcipotriol ointment 50 mcg/g + Bioskin Group VI: 10% L-Phenylalanine + Bioskin

Group VII: 0.1% Tacrolimus alone Group VIII: 1% Pimecrolimus alone

Group IX: 0.05% Betamethasone dipropionate alone Group X: Calcipotriol ointment 50 mcg/g alone

Group XI: 10% L-Phenylalanine alone

Repigmentation rates and final repigmentation results: visual Repigmentation rates and final repigmentation results: visual comparison of different treatment groups as assessed by comparison of different treatment groups as assessed by

clinical evaluationclinical evaluation

Vitiligo and evidence based Vitiligo and evidence based dermatologydermatology

Dermatologists are prescribing less PUVA in favour of UVB

Growing introduction of combined treatments targeted UVB + “active” topicals

Repigmentation rates show the therapeutic success of focused microphototherapy which is more remarkable when used in combination

Vitiligo and evidence based Vitiligo and evidence based dermatologydermatology

Both BIOSKIN® and Potent topical corticosterod preparations alone are the first line treatment in vitiligo vulgaris affecting less than 10% of the skin surface

Association of these 2 treatments gives better results, with very high repigmentation rate in more than 90% of patients

High repigmentation rates are observed also for other combination treatments, while Tacrolimus and Pimecrolimus but not phenylalanine are relatively active when applied without UVB irradiation

How I treat vitiligoHow I treat vitiligo

Correct diagnosis Correct diagnosis

ComorbiditiesComorbidities

Patient expectationsPatient expectations

Communication issue Communication issue

Thank you for your attentionThank you for your attention

professorprofessor@@torellolotti.ittorellolotti.it

Future combination Future combination treatments are in the pipelinetreatments are in the pipeline