Στοματική κοιλότητα και IBD · Metronidazole Metallic taste, glossitis,...

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Στοματική κοιλότητα και IBD Κωνσταντίνος Χ. Κατσάνος Ιωάννινα, Ιούνιος 2016

Transcript of Στοματική κοιλότητα και IBD · Metronidazole Metallic taste, glossitis,...

Στοματική κοιλότητα και IBD

Κωνσταντίνος Χ. Κατσάνος

Ιωάννινα, Ιούνιος 2016

Στοματική κοιλότητα και IBD

• ΚΑΛΟΗΘΕΙΣ ΕΚΔΗΛΩΣΕΙΣ

• ΠΡΟ-ΝΕΟΠΛΑΣΜΑΤΙΚΕΣ ΕΚΔΗΛΩΣΕΙΣ

• ΝΕΟΠΛΑΣΜΑΤΙΚΕΣ ΕΚΔΗΛΩΣΕΙΣ

ΚΑΛΟΗΘΕΙΣ ΕΚΔΗΛΩΣΕΙΣ

• A significant proportion of patients may have one or more manifestations in the oral cavity and in the perioral skin area.

• The prevalence of oral lesions in IBD has been reported to range from 5-50%.

• oral lesions are more common in CD as compared to UC

• more prevalent in children as compared to adults.

ΙBD & ΣΤΟΜΑΤΚΗ ΚΟΙΛΟΤΗΤΑ

• Oral manifestations may be associated with • the disease itself • with nutritional deficiencies • with complications from therapy.

• may precede IBD diagnosis • may or not be associated with active disease • may involve any part of the oral cavity

• They may cause significant symptoms and disability

ΙBD & ΣΤΟΜΑΤΚΗ ΚΟΙΛΟΤΗΤΑ

• two common clinical scenarios:

• 1) oral lesions associated with altered bowel habits

• 2) established IBD but complaining of new oral lesions.

ΙBD & ΣΤΟΜΑΤΚΗ ΚΟΙΛΟΤΗΤΑ

Oral lesions in CD

• Oral lesions have a prevalence rate between 20-50%.

• higher in proximal gastrointestinal tract and/or perianal involvement.

• Aphthous ulcers, the most common

• preceding GI symptoms in 5%-10% of patients.

Oral lesions in children with CD

• The highest reported rate almost 50%

• 30% may continue to manifest oral lesions despite intestinal disease control.

• Paediatric doctors and dentists play a critical role

Oral manifestations in UC

• Aphthous ulcers in 10% of UC.

• in pediatric patients with UC in up one third and are usually non-specific.

DIAGNOSIS OF ORAL LESIONS IN IBD

• Oral lesions in IBD can be

• specific

• non-specific

1.Specific oral changes or lesions Description

Orofacial Crohn’s disease Granular cheilitis

Pyostomatitis vegetans

Mostly young patients with Crohn’s

Mostly in Crohn’s disease

In ulcerative colitis and in Crohn’s

2. Non-specific oral changes or lesions

-Oral cavity changes Ulcers, cobblestonning, swelling, abscesses, tags, tongue changes, gingival changes etc.

-Lip changes cheilitis, swelling, redness, scaling, fissures, ulcers

-Malabsorption-related oral changes or lesions

Folic acid deficiency Glossitis and/or cheilitis

Iron deficiency Glossitis and/or cheilitis

Zinc deficiency Oral candidiasis, glossitis

Vitamin A deficiency Oral white patches/keratinization

Vitamin B complex deficiency Stomatitis, glossitis, angular cheilitis, burning mouth syndrome, reduced or altered taste

Vitamin C deficiency Scurvy

Vitamin K deficiency Gum and/or oral cavity bleeding

-Medication-related oral changes or lesions

Adalimumab Infections, angioedema, paradoxical reactions

Azathioprine Sicca syndrome

Budesonide Glossitis, dry mouth

Certolizumab pegol Angioedema, Stevens-Jonhson syndrome/toxic epidermal necrolyis, paradoxical reactions

Cholestyramine Glossitis, altered taste,dental changes, gum bleeding

Cyclosporin Gingivitis, gum hyperplasia

Ciprofloxacin Angioedema,Stevens-Jonhson syndrome/ Toxic epidermal necrolyis, oral candidiasis, loss of taste

Infliximab Infections, angioedema, paradoxical reactions

Loperamide Angioedema, Stevens-Jonhson syndrome/ toxic epidermal necrolyis, dry mouth

Mesalazine Stomatitis, dry mouth, altered taste

Methotrexate Stomatitis, gingivitis

Metronidazole Metallic taste, glossitis, stomatitis, candidiasis, dry mouth

(Methyl)prednisolone Oral candidiasis

Mycophenolate mofetil Sicca syndrome

Sulphasalazine Angioedema, stomatitis, Stevens-Jonhson syndrome/toxic epidermal necrolyis, altered taste

Table Specific and non-specific oral changes in patients with IBD.

Oral involvement in IBD Clinical Signs

Orofacial Crohn disease One or more clinical signs of spectrum: perioral erythema, metastatic Crohn’s of skin of the face with ulcers, facial swelling,

mucosal tags, deep linear ulcers, cobblestoning, lip swelling or fissuring, granulomatous cheilitis, mucogingivitis, papules,

nodules, plaques or persistent swelling.

Oral mucosa

[masticatory or lining

(labial / buccal)]

abscesses (mostly in buccal space)

aphthous lesions (minor or major)

aphthous stomatitis

circumferential ulcers

cobblestoning, cobblestone plaques

diffuse oral edema

fissures

IgA pustulosis, leukoplakia, hairy leukoplakia

linear ulcers ,lumps

mucosal tags ,permanent maloformartions / scarring

pseudopolyps

polypoid lesions,pyostomatitis vegetans

swelling and induration

Lip(s) angular cheilitis

fissuring, induration

granulomatous cheilitis ,macrocheilia with or without fissuring

neoformations of the genian mucosa (papilloma,fibroma) ,swelling

Gingiva non specific gingivitis

hyperplastic granular gingivitis

Hard palate palatal ulcer(s)

Teeth parodontal lesions

paraodontosis

reduction of the alveolar bony tissue

Tongue erosions

glossitis

ulcers

Tonsills granulomatous tonsillitis

tonsillar granulomas

Salivary glands Fistula,granulomatous inflammation,

minor salivary gland enlargement reduced salivation

sicca syndrome

Table Clinical signs of oral involvement in IBD by oral anatomic location.

Dental symptoms Discomfort, pain, infections, dental caries, decay,

periodontal involvement

Oral symptoms dry mouth (sicca syndrome), reduced salivation,difficulty

in speaking and/or swallowing, halitosis

Gingiva gingival hypertrophy, swelling, pain, bleeding

Lip changes swelling, macrocheilia, redness, scaling, fissures

Oral mucosa changes ulcer(s), cobblestoning, polypoid tags, buccal swelling,

leukoplakia, mucosal discoloration

Perioral skin changes perioral erythema with scaling, erythema migrans,

swelling, malformations, scarring

Lymphadenopathy persistent submandibular lymphadenopathy

Tongue changes painful tongue, glossitis in top or lateral or whole tongue,

hairy tongue, metallic dysgeusia

Table Oral symptoms in patients with inflammatory bowel disease.

Oral aphthous or ulcerous or edematous lesions Oral granulomatous lesions

Recurrent aphthous stomatitis (RAS) Orofacial granulomatosis (OFG)

Autoimmune rheumatic diseases

(Reiter's syndrome, systemic lupus erythematosus,

Adamandiadis-Behcet's syndrome)

Melkersson-Rosenthal syndrome

Autoimmune bullous diseases, cicatricial pemphigoid,

pemphigus vulgaris, epidermolysis bullosa acquisita

Cheilitis granulomatosa

(Miescher cheilitis)

Infections

(mucobacterial, systemic fungal infections, parasites,

sexually transmitted infections, herpetic gingivostomatitis,

CMV, Coxsackie, oral histoplasmosis) Oral

staphylococcal (S. aureus) mucositis

Foreign body reaction-sarcoid-like

(Polishing-paste-induced silica granuloma,

delayed hypersensitivity to cobalt, oral cavity

piercing)

Lymphatic edema, lymphangioma, vascular edema, Sarcoidosis

Neutropenias Sjögren syndrome

Desquamative gingivitis Wegener’s granulomatosis

Precancerous lesions (lichen planus) Tuberculosis

Cancer (mouth T-cell lymphoma)

Traumas and Allergies

Tuberculoid leprosy

Table Differential diagnosis of oral aphthous and oral granulomatous lesions in patients with inflammatory bowel disease.

Non-specific oral lesions

In IBD and non-IBD patients

-Malabsorption related

-Medication related

-Other

Highly specific

-“Metastatic”

-Orofacial

-Granulomatous

cheilitis

Highly specific

-pyostomatitis

vegetans

Highly suspicious

-Tag-like lesions

-Cobblestoning

-Mucogingivitis

-Lip swelling &

vertical fissuring

-Deep linear oral

ulcers (buccal sulci)

Spectrum of oral manifestations and lesions in inflammatory bowel disease

Crohn’s disease

Ulcerative colitis

a. Highly specific oral lesions

• Highly specific oral lesions are almost pathognomonic for IBD diagnosis

• orofacial and granulomatous cheilitis in CD

• pyostomatitis vegetans in UC and CD

Orofacial Crohn’s disease

• oral ulcers and cobblestoning appearance in the mouth of patients with CD

• “CD of the mouth”.

• Orofacial CD is a specific manifestation of CD (5-15% )

• relapsing aphthous ulceration with coexisting edema of the oral

cavity and of the lips

• Usually the bowel disease develops within a few months of the orofacial condition, but delays of up to nine years have also been reported.

Orofacial Crohn’s disease

• Orofacial CD is clinically and histologically indistinguishable from orofacial granulomatosis (OFG), which occurs in the absence of any bowel disease.

• OFG encompasses two conditions:

• Granulomatous cheilitis (or Miescher cheilitis or cheilitis granulomatosa)

• Melkersson-Rosenthal syndrome

Granulomatous cheilitis

Melkerson-Rosenthal syndrome Orofacial

Crohn’s

(preceeding

bowel

symptoms) Other causes (i.e sarcoidosis, allergy)

Orofacial

Crohn’s

(extraintestinal

manifestation)

Orofacial granulomatosis

Absence of bowel disease Bowel disease

Granulomatous cheilitis

• Granulomatous cheilitis (or cheilitis granulomatosa or Miescher cheilitis)

• Changes are restricted to the lip, mostly focal granulomatous inflammation of the lower lip.

Pyostomatitis vegetans

• Pyostomatitis vegetans (PV) is a rare condition characterized by erythematous and thickened oral mucosa with multiple pustules and superficial erosions.

• PV is associated with IBD in 75% of cases

• Other differential diagnoses include autoimmune

pemphigoid diseases and sometimes infections. •

b. Highly suspicious oral lesions for IBD

• are highly suggestive of underlying IBD, especially CD

• The most common affected portions are the buccal mucosa, gingiva, lips

c. Non-specific lesions in IBD

Recurrent aphthous stomatitis

• Any patient with recurring or insisting oral ulcers should be evaluated medically for the possible presence of a more serious systemic disease.

• Aphthous-like lesions may be seen in 4-5% of patients with IBD.

• Colonic, rather than small intestinal, CD is more often associated with oral

• The list of differential diagnosis is long

Salivary duct and saliva in IBD

• Patients with IBD may complain of dry mouth, similar to the sicca syndrome observed in transplanted patients under immunosuppressive therapy.

• Granulomatous inflammation of minor salivary gland ducts has been suggested as another oral manifestation of active intestinal CD.

Tongue involvement in IBD

• Rare cases of non-neoplastic tongue involvement in IBD have been described

• Alterations of taste (metallic dysgeusia) may be related with

• disease activity,

• nutritional habits

• therapy with metronidazole.

Dental and gingival manifestations in IBD

• dental infections and dental alterations related to malabsorption and to disease activity of IBD.

• Gingival involvement in CD is infrequent.

• Gingival biopsy may be helpful for early diagnosis of an underlying CD.

Oral lesions secondary to nutritional deficiencies

• Nutritional deficiencies may cause oral lesions, the most common being angular cheilitis associated with iron deficiency.

• deficiencies in iron, folic acid, vitamin B12, potassium, calcium, magnesium, vitamin A, vitamin C, vitamin D, zinc and selenium.

Therapy-related oral lesions

• All medications may cause oral lesions or symptoms

• Oral paradoxical reactions to biologicals include oral lichenoid reaction to infliximab and new onset of oral lichen planus during certolizumab pegol use.

MEDICAL TREATMENT OF ORAL MANIFESTATIONS IN IBD

• topical and/or systemic therapies combined

with dietary instructions

• In refractory or intractable cases the algorithms of management may also include surgical treatment

Medical treatment of oral IBD Surgical treatment of oral IBD

Effective treatment of intestinal IBD

Standard treatment (reported)

-Corticosteroids (methlyprednisolone)

-Azathioprine

-Infliximab

-Thalidomide (refractory cases)

-isotretinoin, dapsone (pyostomatitis)

-Long-term p.os antibiotics (tetracycline, erythromycin, penicillin,

metronidazole)

Other possible options (unreported)

-Methotrexate

-Adalimumab

-Certolizumab

Nutrition

-Total enteral nutrition (selected cases)

-Elemental diet (selected cases)

-Elimination diets (special dietary restrictions i.e cinnamate- and benzoate-

free diet)

-Supplementation formulas, vitamins (A,B,C) and trace elements (zinc)

Major surgery

Oral and oropharyngeal surgery

-Oral surgery

-Orthognathic surgery

-Maxillofacial surgery

Plastic facial and lip surgery

-Reconstructive

-Elimination

Colectomy in intractable oral IBD

Minimal or Elective surgery

-small lesion removal

-small fistula repair

-abcess drainage

- oral biopsies (multiple)

Topical treatement

Local intralesional injections

-corticosteroids

- triamcinolone 0.1%

-Infliximab

-analgesics

-lidocaine 2%,

Local ointments

-corticosteroids(1% hydrocortisone)

-tacrolimus

-non-steroidal anti-inflammatory pastes

Mouthwash

-5-aminosalicylic,-corticosteroids,-antiseptic,Elixirs (dexamethasone)

Local dental surgery

(functional repair and cosmetic)

-Dental surgery

-Biopsy of small oral lesion

-Laser for gingival Crohn's disease

Table Treatment of the oral manifestations in inflammatory bowel diseases.

Treatments of oral IBD Type of oral IBD Author/Year Number

of all

patients

Type of trial

(controlled/C

Uncontrolled/U)

Response rates

Oral Crohn’s Plauth et al,30 1991 12 Topical steroids/ U 7 of 12 (58%) patients

Oral Crohn’s Casson et al,142

2000

3 Topical tacrolimus ointment /U Marked improvement in 1-6 months

Orofacial

franulomatosis/ora

l Crohn’s

Mignogna et al,139

2004

7 Triamcinolone injections

/ U

Response (2 or 3 injection

sessions over 14 or 21

days)

Oral Crohn’s Plauth et al,30 1991 26 Azathioprine and/or systemic

steroids / U

13 of 26 (50%) patients

Oral Crohn’s Williams J et al,145

1991

12 Systemic steroids / U Improvement in all, 3

steroid-dependent

Oral Crohn’s Litsas140 ,

2011

1 Systemic prednisone / U Response after 6 months

Resistant oral

Crohn’s

Hegarty et al,153

2003

5 Thalidomide/ U Response

Oral Crohn’s Campbell et al,163

2013

10 Phenolic acid exclusion diet

with micronutrient

supplementation/ U

7 responded

Oral Crohn’s White et al,161 2006 32 Elimination diets

cinnamon- and benzoate-free

diet (CB-free diet) / U

Response after 8 weeks

Oral Crohn’s Cameron et al,159

2003

1 Elemental diet/ U Response but 2 relapses

Granulomatous

cheilitis

Kano et al,70 1992 1 Metronidazole / U Response

Oral Crohn’s Sánchez et al,147 2005

1 Adalimumab+dapsone/ U Response after 5 months

Oral Crohn’s Cardoso et al,149

2006

1 Infliximab/ U Successful treatment

Fistulizing oral

Crohn’s

Staines et al,151

2007

1 Infliximab/ U Successful treatment

Management of oral aphthous ulcers in IBD

(Target in parallel bowel disease remission)

Topical treatment Antibiotics, tacrolimus ointment, corticosteroids (elixirs, ointments, mouthwashes, intralesional injections), analgesics (lidocaine 2%), antiseptic mouthwashes, NSAID pastes

Elimination diets (Cinnamon, benzoate, glutaminate, cocoa) Vitamin and trace element supplementation

Systemic treatment Corticosteroids, azathioprine, methotrexate, tacrolimus

Systemic treatment for refractory cases

Biological therapy, thalidomide, long-term antibiotics

Figure . Algorithm for management for oral aphthous ulcers in IBD.

Management of oral Crohn’s disease

(Target in parallel bowel disease remission)

Topical treatment Antibiotics, tacrolimus ointment, corticosteroids (elixirs, ointments, mouthwashes, intralesional injections), analgesics (lidocaine 2%), antiseptic mouthwashes, NSAID pastes

Food restriction, Enteral / Parenteral nutrition

Elimination diets (Cinnamon, benzoate, glutaminate, cocoa) Vitamin and trace element supplementation

Surgical treatment Head-neck surgery, oral surgery (for local repair and cosmesis) Dental surgery

Systemic treatment Corticosteroids, azathioprine, methotrexate, tacrolimus, biological therapies

Systemic treatment for refractory cases

Switch to a 2nd biological therapy, thalidomide, long-term antibiotics, dapsone, Cyclosporin A (for pyostomatitis)

Figure. Algorithm for recommended management for oral Crohn’s disease.

SURGICAL TREATMENT OF ORAL MANIFESTATIONS IN IBD

• for severe complications refractory to medical therapy. • Minimal or elective surgery • Local dental surgery

• Major surgical interventions include

• oral and oropharyngeal surgery, (orthognathic and/or maxillofacial

surgery) • plastic surgery (reconstructive, elimination i.e for hyperplastic

gingiva). • Colectomy is reserved as an ultimate option for patients with UC

and intractable or highly resistant oral lesions that significantly affect oral feeding and overall quality of life.

ΠΡΟ-ΝΕΟΠΛΑΣΜΑΤΙΚΕΣ ΕΚΔΗΛΩΣΕΙΣ

Environmental factors Sun exposure (UV light), passive smoking(?)

Infections (HPV E6 and E7 oncogenes, HIV, syphilis DNA detected from CMV and EBV in oral cancerous lesions, chronic candidiasis)

Life style (smoking , smokeless tobacco use, pipe smoking, marijuana use, heavy alcohol use, access to medical care or dental care, low consumption of fruits and vegetables)

Drugs (immunosuppressants, anti-TNFa ?, others?)

Alterations in oral homeostasis (xerostomia, reduced salivary flow, candida colonization)

Demographics

(age>40, males, African-American (oral cavity cancer), fair skin (lip cancer)

Education level (Absence of oral screening, no annual oral exam, poor oral hygiene)

Precancerous oral lesions unrecognized and untreated

(leukoplakia, erythroplakia, leukoerythroplakia, chronic candidiasis (?)

Chronic irritation in oral cavity

(traumatic ulcers, poor fitting denture, broken or sharp-edged teeth or fillings)

Underlying conditions (immunodeficiency, transplantation, Plummer-Vinson)

Nutrition deficiencies (low vitamin A, B12, folic acid levels, iron deficiency)

p53 gene alterations-dysplasia-cancer in situ-invasive cancer

Figure. The puzzle of mechanisms and conditions leading to the development of oral precancerous lesions

and oral cancer in inflammatory bowel diseases.

Author Drug Patient Disease Type of

oral lesion

Outcome

Mocciaro et al.54 Certolizumab

pegol

1 Crohn’s Oral lichen

planus

Non evolution

to Ca

Fluckiger et al.55 Azathioprine 1 Ulcerative

colitis

Oral hairy

leukoplakia

Non evolution

to Ca, HIV(-)

Worsnop et al.52 Infliximab 1 Crohn’s Oral lichen

planus

(probable)

Non evolution

to Ca

(Paradoxical

reaction to IFX)

Moss et al.53 Infliximab 1 Crohn’s Oral

lichenoid

reaction to

IFX

Non evolution

to Ca

(Paradoxical

reaction to IFX)

Table. Oral precancerous lesions reported in the form of case reports in patients with inflammatory bowel disease.

a. Typical oral lichen planus (OLP) of the tongue’s right side. (AB)

b. Diffuse OLP, plaque form, of the entire oral mucosa. Note the leukokeratotic aspect to be distinguished from a leukokeratosis. (AB)

c. Cheek’s OL erosive and planus. (AB & ED)

d. Tongue’s atrophic OLP after a long time evolution. Note the typical network of overlapping white striae of the point. (AB)

ΝΕΟΠΛΑΣΜΑΤΙΚΕΣ ΕΚΔΗΛΩΣΕΙΣ

• The incidence and prevalence of oral cancerous and pre-cancerous lesions in IBD is currently unknown.

• No routine oral screening is performed or is advised so far.

• HPV infection!

a.Squamous cell carcinoma (SCC) of the tongue’s point arising on an atrophic oral lichen planus. (ED)

b.SCC of the tongue in a 19-year-old smoker female. The question of the responsability of HPV as cofactors is raised in such a

case. (AB & ED)

c.Typical SCC of the lower lip in a smoker patient arising on a leukokeratosis. (ED)

d.SCC of the lower lip in a young male, rapidly appeared after a kidney transplantation. (ED)

Melanoma of the soft palate in non-IBD non-HIV patient

Kaposi sarcoma of the hard palate in non-IBD non-HIV patient

Author Drug Patient(s) with oral

Ca

Disease Location / Type of

oral cancer

Details

Vilas-Boas et al.61

(case report)

AZA

(9 years)

1 CD Right superior retromollar trigone, SCC /

HPV (-)

Surgery

Li et al.60

(case report)

AZA

(3 years)

1 CD Tongue

SCC (ulcerous in situ)

Surgery

Dulai et al.39

(case report)

IFX+AZA 1 IBD Parotid

Non-Hodgkin lymphoma

Unknown

Biancone et al.26

(multicenter study)

non-biological therapies 1 CD Oropharyngeal

(larynx)

Death

Lichtenstein et al.42

(TREAT cohort registry n=6,773)

IFX

or

Any other therapy

6 CD Oral cavity

(3 patients on IFX)

SIR (95%(CI)

IFX-treated

1.77 (0.37, 5.17)

Any other therapy

1.78 (0.37, 5.21)

Cottone et al.43

(cohort study)

IFX=2,475

ADA=604

1

0

CD Pharyngeal 18 months after IFX

(died)

Pasternak et al.62

(Danish IBD cohort database

n=45,986)

AZA= 5,197 69 IBD Lip/oral cavity/pharynx non-AZA=60

former AZA=4

current AZA=5

RR 95%(CI)

Non-users (referrent)

Former users

1.70 (0.63-4.60)

Users

1.69 (0.57-5.00)

Nyboe- Andersen et al.50

(Danish IBD cohort database)

antiTNF=4,553

non -antiTNF

=51,593

3 IBD Lip/oral cavity/pharynx Crude

1.24 (0.39-3.93)

Adjusted

1.47 (0.43-5.00)

Adjusted for use of azathioprine

1.08 (0.31-3.70)

Colombel et al.44

(Adalimumab cohort trials)

ADA=3,160 1 CD Oral cavity

SCC

1 of total 35 Ca on ADA

<0.1% of the cohort

Sandborn et al.45

(ULTRA cohort study)

ADA=494 1 UC Oral cavity

Beaugerie et al.57 (CESAME cohort

n=17,047)

AZA=7,844 15 IBD 15 ear-nose-throat Ca 3.6% of all Ca (n=428)

Fidder et al.46 (Leuven IFX

cohort n=734 )

AZA (any use pre- or

combo- to IFX)=501

1 IBD Lip SCC patient on combo AZA+IFX

Katsanos et al.47 (EC-IBD

cohort n=681)

AZA=174 2 IBD Lip

(1 BCC in UC on AZA and 1 SCC in UC

not on AZA)

Katsanos et al.48 (Leuven cohort

n=1815)

AZA =725 0 IBD No oral cancer

Fraser et al.49 (Oxford cohort

n=2204)

AZA= 626 2 IBD 1 SCC oral on AZA

1 SCC oral not on AZA

31 Ca in AZA 77 Ca not in AZA

Table. Oral cancers reported in patients with inflammatory bowel disease.

CONCLUSIONS

• The list of oral lesions is extensive.

• may have devastating consequences

• most lesions are easily handled and respond to the treatment of intestinal IBD

• A multidisciplinary approach is essential for the correct diagnosis and management.

The Henry D. Janowitz Division of Gastroenterology at Mt Sinai, NY, USA

+ JAN 12th, 2016