Wednesday, December 13, 2017

An Overview of Chronic Oral Graft-Vs-Host Disease Following Pediatric Hematopoietic Stem Cell Transplantation

Resident’s Name: Michael Hatton                                                           Date: 12/13/2017
Article Title: An Overview of Chronic Oral Graft-Vs-Host Disease Following Pediatric Hematopoietic Stem Cell Transplantation
Authors: Da Fonseca, M; Hong CA
Journal: Pediatric Dentistry
Date: Mar/Apr 2008
Major Topic: Medically compromised patients
Type of Article: Review article
Main Purpose:
Review of the pathogenesis, prevention, and treatment of pediatric chronic GVHD, focusing on its oral manifestation and dental management in children.
Key Points:
1) Mouth can be major or ONLY site of cGVHD presentation – pediatric dentists must be able to recognize conditions.
2) Patients who survive HSCT at least 10 years at 8.3x risk of new solid cancer, mainly squamous cell carcinomas of skin and oral cavity.
3) Research on management of pediatric oral cGVHD almost non-existent.
Overview:
Hematopoetic stem cell transplantation (HSCT) is the treatment of choice for many hematologic, genetic, oncologic, and immunological diseases. It is also one of the most aggressive treatments among the different cancer therapies, and is associated with severe conditioning-related toxicity, which include profound neutropenia, a high level of prophylatic immunosuppression and graft vs host disease (GVHD). GVHD remains a significant complication of HSCT and is a frequent reason for nonrelapse morbidity and mortality following allogenic HSCT.

GVHD is thought to be due to improper recovery of the immune system leading to recognition of T cells as foreign, impaired T and B cell production, impaired antibody production, and functional asplenia; thus clinical manifestations of cGVHD closely resemble that of autoimmune diseases.

Acute Graft-Vs-Host Disease (aGVHD) – distinctive syndrome of dermatitis, hepatitis, and enteritis developing within 100 days of allogeneic HSCT

Chronic Graft-Vs-Host Disease (cGVHD) – tends to be a more pleiotropic (diverse effects) syndrome generally developing after 100 days. 20% of patients receiving matched sibling transplants develop disease, 40% of patients receiving matched unrelated donor recipients develop disease. cGVHD can be categorized as: de novo, quiescent (following acute), or progressive (following acute).

Most significant risk-factors for developing cGVHD:
·        Patient age 10 years or older
·        Donor age 5 years or older
·        Female donor to male recipient
·        Use of total body irradiation as part of transplant conditioning regimen
·        Diagnosis of hematologic malignancy
·        Previous aGVHD

cGVHD course and prognosis:
·        infectious complications, leading to death
·        progressive organ failure from GVHD involvement, leading to death
·        risk of new solid cancers – mainly Squamous Cell Carcinomas of skin and oral cavity

cGVHD prevention and treatment: Best approach to reduce GVHD-related mortality is prevention
·        Interference with T cell activation and function, ie. cyclosporine and tacrolimus
·        Interference with T cell proliferation, ie. methotrexate and mycophenolate mofetil (MMF)
·        Reduction of T cell numbers, ie. Alemtuzumab and antithymocyte globulin
·        Interference with cytokine function, ie. corticosteroids
·        Supportive care: local measures, ie physical therapy, deep tissue massage, optimal oral care, antibiotic prophylaxis, dietary concerns, sunblock

Oral and Dental Aspects:
·        Mouth can be major or ONLY site of cGVHD presentation
·        Oral cGVHD often starts with xerostomia and/or oral sensitivity
·        Risk of development of Oral Squamous Cell Carcinomas
·        Atrophy and erythema or lichenoid lesions of buccal and labial mucosa
·        Oral pain not limited to ulcerations
·        Erosive lesions
·        Jaundice of oral mucosa



Osteoporosis: An Increasing Concern in Pediatric Dentistry

Department of Pediatric Dentistry

Lutheran Medical Center

Resident’s Name: Albert Yamoah, DDS                                                                                     Date: 12/13/2017
Article Title:  
Osteoporosis: An Increasing Concern in Pediatric Dentistry
Author(s):  Marcio A. da Fonseca
Journal: Pediatric Dentistry
Date: 2011
Major Topic: Osteoporosis, Bone Disease, Bone Mineral Density, Treatment and Management of Osteoporosis in Children
Type of Article: Literature Review
Main Purpose:
With increasing numbers of children affected by low bone density and osteoporosis, the topic has become an important issue in contemporary pediatrics.
Key points:
o   Bone fractures are the most common reason for hospitalization between 10 and 14 year olds.
o   Factors, such as lifestyle; diet; chronic illness and medications can affect bone mineral density.
o   Osteoporosis is classically defined in adults as a systemic skeletal disease characterized by:
1.     Low bone mass
2.     Alteration of ultra-structural quality of bone
3.     Deterioration in trabecular architecture
4.     Increased cortical porosity
5.     Reduced cortical thickness
6.     Decreased bone width
o   Osteoporosis is often difficult to define in children as they are constantly changing in size and shape with increases in bone mass and density.
o   Greatest bone mass acquisition tends to mirror height velocity and is greatest during puberty.  
o   Any disruption of this growth would lead to an increased risk of adult osteoporosis and fractures.
o   Excess of deficiencies in GH, TH, PTH, and sex steroids can also lead to decreased bone mineral density.

Primary Bone disorders:
Heritable Disorders of connective tissue:
o   Idiopathic juvenile osteoporosis
o   Osteogenesis imperfecta
o   Marfan syndrome
o   Ehler-Danlos syndrome
o   Bruck syndrome
o   Osteoprosis pseudoglioma syndrome
o   Homocystinuria

Secondary Bone disorders:
Inflammatory Diseases
o   Inflammatory bowel disease
o   Celiac disease
o   Juvenile idiopathic arthritis
o   Cystic Fibrosis
o   Systemic lupus erythematosus
o   Dermatomyositis

Chronic Immobalization
o   Cerebral palsy
o   Neuromuscular disorders
o   Epidermolysis bullosa
o   Spina bifida
o   Spinal cord injury
o   Head Injury

Endocrine Disturbances
o   Turner syndrome
o   Anorexia nervosa
o   Hypogonadism
o   Growth hormone deficiency
o   Juvenile Diabetes Mellitus
o   Hyperthyroidism, Hyperparathyroidism
o   Cushing syndrome
o   Delayed puberty

Hematologic-oncologic disorders
o   Childhood cancer
o   Thalassemia
o   Sickle cell disease

Inborn Errors of Metabolism
o   Protein intolerance
o   Glycogen storage diseases
o   Galactosemia
o   Gaucher disease

Iatrogenic Etiologies
o   Glucocorticoids
o   Anticonvulsants
o   Chemotherapy
o   Cyclosporine
o   Tacrolimus
o   Bone and/or cranial radiation

Others
o    Chronic renal disease
o    Solid organ and hematopoietic stem cell therapy
o    Anorexia nervosa
o    Steroid-dependent asthma

Measuring Bone Mineral Density: 
o   DEXA (dual energy X-ray absorptiometry): Diagnostic tool in the management of adult osteoporosis.
o   DEXA doesn’t distinguish between cortical and trabecular bone
o   DEXA does not differentiate between body types for a certain age (i.e. short kids vs. tall).
o   DEXA is beneficial to use as a monitor during tx.

Treating Osteoporosis in Children:
o   Anticipatory guidance regarding healthy lifestyle  (physical activity, diet, no drugs/alcohol) is of great importance to prevent bone loss and should start from an early age.
o   In severe cases of low bone mineral density, promoting calcium and Vitamin D intake coupled with weight-bearing physical activity can provide benefits with minimal risk.

Implications of Osteoporosis in Dental Treatment: 
o   Getting a full medical history is important.
o   Dentist should be careful when using restraints with child diagnosed with osteoporosis as bone fractures may result.
o   Extractions should be done carefully as to avoid any unnecessary jaw fractures.
o   Dentists should be aware of the patient’s current therapy.
o   Bisphosphonate therapy may lead to BRONJ.
o   Elimination of all potential sources of odontogenic and mucosal infection must be done before the patient starts therapy with bisphosphonates.
o   There are no reported cases of BRONJ developing from primary tooth extraction. However, it is always important to consult with the child’s physician prior to any surgical therapy.
o   Bisphosphonates can also inhibit tooth movement: posing a problem for orthodontic therapy (reduced osteoclasts)
o   It is suggested that orthodontic treatment be avoided in patients with high risk, such as those patients receiving or have received IV Bisphosphonate.
o   Bisphosphonate has also been associated with delayed tooth eruption with OI and with ulcers when pills come in contact with oral mucosa.
Remarks:
Assessment of Article: Very informative
Level of Evidence/Comments: Level III


Monday, December 11, 2017

Old drugs, new uses

Resident’s Name: Brian Darling                                                                     Date: 12/13/17

Article Title: Old drugs, new uses
Author(s): Marcio da Fonseca, Paul Casamassimo
Journal: Pediatric Dentistry
Date: 2011; 33: 67-74
Major Topic: Drugs for pediatric patients
Type of Article: Literature review
Main Purpose: This article reviewed new uses for several medications, methods of action, and concerns for pediatric dental care.
Key Points:  One cannot assume that a certain drug is used only for the indication you learned in school


Drug Class
Original Indications
New Indications
Acetylsalicylic Acid
Analgesic
Antiplatelet therapy
Antiepileptic Drugs
Epilepsy
Neurological conditions, psychiatric disorders, pain syndromes, eating disorders
Bisphosphonates
Postmenopausal and steroid-induced osteoporosis
Primary and secondary osteoporosis, hypercalcemia of malignancy, metastatic bone disease in cancer, multiple myeloma
Botulinum toxin
Strabismus, blephatospasm
Hyperhidrosis, cervical dystonias, facial frown lines, spasticity, hyperlacrimiation, bruxism, rhinitis, hemifacial spasm, Tourette’s syndrome, incontinence, salivary secretory disorder, trismus, myofacial pain, headache
Hydroxurea
Psoriasis, polycythemia vera, cancer, thrombocythemia
Sickle cell disease
Intravenous immunoglobulin
Infections diseases, congenital immunodeficiencies, hypogammaoglobulinemia
Pediatric HIV infections, idiopathic thrombocytopenic purpura, Kawasaki disease, chronic lymphocytic leukemia, prevention of graft-versus-host disease, infections of HSCT, Guillain-Barre syndrome, autoimmune diseases
Methotrexate
Cancer
Juvenile idiopathic arthritis, psoriasis, inflammatory bowel disease, prevention of GVHD in HSCT
Thalidomide
Epilepsy, sedation, antiemetic in pregnancy
Leprosy, multiple myeloma, meylodysplastic syndrome, Behcet’s disease, systetmic lupus erythematosus, aphthous ulcers, erythema multiforme, Crohn’s disease, treatment of post-HSCT GVGD

Anti-epileptic Drugs (Anti-seizure medications)
·      Incidence of psychiatric disorders is higher in epileptic patients
·      Most new anti-epileptic drug claims some efficacy for a psychiatric disorder
·      Used to treat:
o   Neurological conditions
o   Psychiatric disorders
o   Pain syndromes
o   Neuropathic pain
o   Essential tremors
o   Psychiatric disorders
o   Pain syndromes
o   Eating disorders
·      Adverse effects
o   Gingival overgrowth
o   Blood dyscrasias
o   Increased oral secretions or dry mouth
o   Behavior change
o   Liver dysfunction

Thalidomide
·      Affects body immune’s system in several ways – anti-inflammatory and anticancer properties
·      Dose-limiting neutropenia and thrombocytopenia. Risk of thromboembolism

Intravenous Immunoglobulin
·      Increases platelet count
·      Physiologically and pharmacologically the same as immunoglobulin taken from the human body because it is purified from pooled human plasma from healthy donors
·      More than half of clinical IVIG use of “off-label”
·      ~10% of patients have side effects which are usually transient and self-limited – headache, low-grade fever, muscle, back, and joint pain, nausea, vomiting, abdominal pain
·      Very expensive

Hydroxyurea
·      Increases production of fetal hemoglobin containing erythrocytes, which are less likely to sickle and dilutes the number of sickled cells in circulation and may reduce cell adhesion that contributes to vaso-occlusion
·      Dose-related leukopenia, thrombocytopenia, anemia, and oral mucositis
o   All usually resolve within 1-2 weeks
·      Long-term effects may include teratogenic defects, growth delays, cancer

Methotrexate
·      Inhibits dihydrofolate reductase, an enzyme needed for DNA synthesis, repair, and cellular replication
·      Actively proliferating tissues are very sensitive to methotrexate, such as oral mucosa, bone marrow, malignant cells
·      Side effects: mucositis, taste disturbance, nausea, anorexia, headaches, chills, fatigue, pruritus, skin pain, urticarial, alopecia, acute depression, teratogenesis, nephropathy
·      May induce or exacerbate oral lesions like ulcers
·      Opportunistic infections may occur under methotrexate
·      Methotrexate absorption may be reduced with dental drugs of:
o   Nystatin, polymixin B, vancomycin, barbiturates, tranquilizers, NSAIDs, salicylates, penicillins
·      May increase risk of soft tissue necrosis and osteonecrosis when given in combination with radiotherapy

Botulinum Toxin
·      Neurotoxin from Clostridium botulinum, a gram-positive anaerobe, inhibits the release of acetycholine from presynaptic nerve terminals causing local chemodenervation
·      Reduces spasticity in patients with cerebral palsy leading to improvements in gross motor and upper extremity function, gait patterns, and independent ambulation
·      Transient effectiveness

Bisphosphonates
·      Bind strongly to hydroxyapatite crystals and reduce bone resorption by inhibiting cell functions and inducing accelerated osteoclast death
·      Treats primary and secondary osteoporosis
o   Primary osteoporosis: intrinsic skeletal defect seen in osteogenesis imperfect, Marfan syndrome, Ehlers-Danlos syndrome
o   Secondary osteoporosis: sequelae of chronic diseases/conditions
·      Avoid surgical procedures, especially in children being given IV bisphosphonates
·      Insufficient evidence to suggest that implant placement, extraction, and other surgical treatments should be avoided in patients receiving oral bisphosphonates
·      No cases of BRONJ in children to date
·      Ask question about bisphosphonates on medical history because many are taken only every few weeks or months
·      Bisphosphonates may inhibit tooth movement for orthodontics
·      Bisphosphonates may delay tooth eruption

Aspirin (acetylsalicylic acid/ASA)
·      Inhibits COX-1-dependent platelet function (aggregation and vasoconstriction) at low daily doses
·      Also inhibits COX-2-dependent pathophysiologic processes of hyperalgesia and inflammation but requires larger doses to do so
·      Irreversibly inhibits COX-1 and so platelet inhibitory effect lasts entire 8-10 day lifespan of platelet
·      No studies exhibit a causal relationship between Reye Syndrome and aspirin
·      Aspirin has been replaced with acetaminophen often, which bears significant hepatotoxicity potential and may have led to increase in allergic reactions, most notably asthma because it lacks anti-inflammatory activity. Frequent acetaminophen use can cause asthma attacks
·      It is OK to proceed with surgical procedures in patients taking aspirin without any modification of care
·      Anesthesiologists often erroneously defer nasal intubation in patients taking aspirin unless the drug has been stopped for a few days prior to surgery, thus prolonging and complicating dental care under general anesthesia
Remarks:
1-
2-
Assessment of Article:  Level of Evidence/Comments: III