Redonda Gail Miller, M.B.A., M.D.

• President, The Johns Hopkins Hospital
• Associate Professor of Medicine

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0005712/redonda-miller

The nanobiomaterials used in these constructs should be wisely selected to possess superior properties such as high biocompatibility and controllable biodegradation rate women's health issues instructions for authors generic fosamax 70 mg without prescription. Besides the structure the surfaces of the biomaterials in contact with the cells can influence the fate of cells within the environments breast cancer jackets buy discount fosamax 70 mg on line. The surface topography and coating alter the cellular activities of the stem cells and can control the regeneration of different lineages within the musculoskeletal system womens health 06484 order generic fosamax from india. Limited but encouraging in vivo studies in this research field promise that loss or injury in the musculoskeletal tissues can be replaced or healed using regenerative medicine women's health center colonial park fosamax 35 mg order on-line. Response of cells on surface-induced nanopatterns: fibroblasts and mesenchymal progenitor cells pregnancy 4th week buy fosamax 70 mg online. Titanium surface characteristics, including topography and wettability, alter macrophage activation. Nanopillared chitosan/gelatin films: a biomimetic approach for improved osteogenesis. Design, materials, and mechanobiology of biodegradable scaffolds for bone tissue engineering. A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering: the unsolved challenge. Collagen-mimetic peptide-modifiable hydrogels for articular cartilage regeneration. A new composite hydrogel combining the biological properties of collagen with the mechanical properties of a supramolecular scaffold for bone tissue engineering. Naturalbased nanocomposites for bone tissue engineering and regenerative medicine: a review. Development and characterisation of a collagen nano-hydroxyapatite composite scaffold for bone tissue engineering. Fibrin hydrogels functionalized with cartilage extracellular matrix and incorporating freshly isolated stromal cells as an injectable for cartilage regeneration. In situ vascularization of injectable fibrin/poly (ethylene glycol) hydrogels by human amniotic fluidderived stem cells. Elastin based cell-laden injectable hydrogels with tunable gelation, mechanical and biodegradation properties. The effect of elastin on chondrocyte adhesion and proliferation on poly (-caprolactone)/ elastin composites. In vitro ligament­bone interface regeneration using a trilineage coculture system on a hybrid silk scaffold. Hydrogel design for cartilage tissue engineering: a case study with hyaluronic acid. An injectable enzymatically crosslinked carboxymethylated pullulan/chondroitin sulfate hydrogel for cartilage tissue engineering. An injectable calcium phosphate-alginate hydrogel-umbilical cord mesenchymal stem cell paste for bone tissue engineering. Gellan gum-based hydrogel bilayered scaffolds for osteochondral tissue engineering. Gellan gum injectable hydrogels for cartilage tissue engineering applications: In vitro studies and preliminary in vivo evaluation. Bone tissue engineering: scaffold preparation using chitosan and other biomaterials with different design and fabrication techniques. Fabrication and characterization of novel nano-biocomposite scaffold of chitosan­gelatin­ alginate­hydroxyapatite for bone tissue engineering. Extracellular matrix hydrogels from decellularized tissues: structure and function. Recent advancements in decellularized matrix-based biomaterials for musculoskeletal tissue regeneration. Fabrication of anatomically-shaped cartilage constructs using decellularized cartilage-derived matrix scaffolds. Simple and high yielding method for preparing tissue specific extracellular matrix coatings for cell culture. Application of nanoscale materials for regenerative engineering of musculoskeletal tissues. Injectable in situ self-cross-linking hydrogels based on poly (L-glutamic acid) and alginate for cartilage tissue engineering. Fabrication and properties of polycaprolactone composites containing calcium phosphate-based ceramics and bioactive glasses in bone tissue engineering: a review. Calcium and phosphate ions as simple signaling molecules with versatile osteoinductivity. Hydroxyapatite­polymer biocomposites for bone regeneration: a review of current trends. Porous stable poly (lactic acid)/ethyl cellulose/hydroxyapatite composite scaffolds prepared by a combined method for bone regeneration. Facile synthesis of conductive polypyrrole wrinkle topographies on polydimethylsiloxane via a swelling­deswelling process and their potential uses in tissue engineering. Conductive nanofibrous composite scaffolds based on in-situ formed polyaniline nanoparticle and polylactide for bone regeneration. Electrically conductive nanofibers with highly oriented structures and their potential application in skeletal muscle tissue engineering. Electroactive degradable copolymers enhancing osteogenic differentiation from bone marrow derived mesenchymal stem cells. Accelerated osteoblast mineralization on a conductive substrate by multiple electrical stimulation. Carbon based nanomaterials for tissue engineering of bone: building new bone on small black scaffolds: a review. Diels­Alder functionalized carbon nanotubes for bone tissue engineering: in vitro/in vivo biocompatibility and biodegradability. Toxicity and biocompatibility properties of nanocomposites for musculoskeletal tissue regeneration. Multiwalled carbon nanotube-chitosan scaffold: cytotoxic, apoptotic, and necrotic effects on chondrocyte cell lines. Scaffolds containing chitosan, gelatin and graphene oxide for bone tissue regeneration in vitro and in vivo. Thermo-moisture responsive polyurethane shape-memory polymer and composites: a review. Inductively heated shape memory polymer for the magnetic actuation of medical devices. Initiation of shape-memory effect by inductive heating of magnetic nanoparticles in thermoplastic polymers. Delivery of growth factors using a smart porous nanocomposite scaffold to repair a mandibular bone defect. Bio-instructive scaffolds for musculoskeletal tissue engineering and regenerative medicine. Synthetic scaffolds for musculoskeletal tissue engineering: cellular responses to fiber parameters. Effect of polyvinylidene fluoride electrospun fiber orientation on neural stem cell differentiation. Effect of fiber diameter, pore size and seeding method on growth of human dermal fibroblasts in electrospun poly(-caprolactone) fibrous mats. Tuning cell differentiation into a 3D scaffold presenting a pore shape gradient for osteochondral regeneration. Scaffolds and cells for tissue regeneration: different scaffold pore sizes-different cell effects. The effect of mean pore size on cell attachment, proliferation and migration in collagen­glycosaminoglycan scaffolds for bone tissue engineering. Advanced biomaterials for skeletal tissue regeneration: instructive and smart functions. Biomimetic structures: biological implications of dipeptide-substituted polyphosphazene­ polyester blend nanofiber matrices for load-bearing bone regeneration. Integrating biologically inspired nanomaterials and table-top stereolithography for 3D printed biomimetic osteochondral scaffolds. Mineralized biomimetic collagen/alginate/silica composite scaffolds fabricated by a lowtemperature bio-plotting process for hard tissue regeneration: fabrication, characterisation and in vitro cellular activities. Coating electrospun poly(-caprolactone) fibers with gelatin and calcium phosphate and their use as biomimetic scaffolds for bone tissue engineering. Fabrication and characterization of nanobiocomposite scaffold of zein/chitosan/ nanohydroxyapatite prepared by freeze-drying method for bone tissue engineering. A review on polymer nanofibers by electrospinning and their applications in nanocomposites. Colloidal inorganic nanocrystal based nanocomposites: functional materials for micro and nanofabrication. Synthesis and characterization of nanocomposite scaffolds based on triblock copolymer of l-lactide, -caprolactone and nano-hydroxyapatite for bone tissue engineering. Oxygen-tension controlled matrices for enhanced osteogenic cell survival and performance. Various preparation methods of highly porous hydroxyapatite/polymer nanoscale biocomposites for bone regeneration. Surface topography enhances differentiation of mesenchymal stem cells towards osteogenic and adipogenic lineages. Spontaneous differentiation of human mesenchymal stem cells on poly-lactic-co-glycolic acid nano-fiber scaffold. Fiber diameter and seeding density influence chondrogenic differentiation of mesenchymal stem cells seeded on electrospun poly(-caprolactone) scaffolds. Effect of fiber diameter on the spreading, proliferation and differentiation of chondrocytes on electrospun chitosan matrices. Cell orientation and regulation of cell­cell communication in human mesenchymal stem cells on different patterns of electrospun fibers. Mediating human stem cell behaviour via defined fibrous architectures by melt electrospinning writing. Platelet-derived growth-factor-releasing aligned collagen­nanoparticle fibers promote the proliferation and tenogenic differentiation of adipose-derived stem cells. Substrate fiber alignment mediates tendon cell response to inflammatory signaling. The regulation of tendon stem cell differentiation by the alignment of nanofibers. Three dimensional extrusion printing induces polymer molecule alignment and cell organization within engineered cartilage. Hydroxyapatite nanoparticle-containing scaffolds for the study of breast cancer bone metastasis. Characterization of biodegradable and cytocompatible nano-hydroxyapatite/polycaprolactone porous scaffolds in degradation in vitro. Early osteogenic signal expression of rat bone marrow stromal cells is influenced by both hydroxyapatite nanoparticle content and initial cell seeding density in biodegradable nanocomposite scaffolds. Preparation of functionalized gold nanoparticles as a targeted X-ray contrast agent for damaged bone tissue. Nano-composite scaffolds for bone tissue engineering containing silver nanoparticles: Preparation, characterization and biological properties. Embedded silica nanoparticles in poly(caprolactone) nanofibrous scaffolds enhanced osteogenic potential for bone tissue engineering. Chitosan rods reinforced by aligned multiwalled carbon nanotubes via magnetic-field-assistant in situ precipitation. Characterization of electrospun poly(L-lactide) and gold nanoparticle composite scaffolds for skeletal muscle tissue engineering. Slow and continuous application of human recombinant bone morphogenetic protein via biodegradable poly(lactide-co-glycolide) foamspheres. Incorporation of phosphate group modulates bone cell attachment and differentiation on oligo(polyethylene glycol) fumarate hydrogel. Characterization and bioactivity evaluation of (starch/N-vinylpyrrolidone)-hydroxyapatite nanocomposite hydrogels for bone tissue regeneration. The effects of scaffold thickness on tissue engineered cartilage in photocrosslinked poly(ethylene oxide) hydrogels. Cell-induced alignment augments twitch force in fibrin gel­based engineered myocardium via gap junction modification. Investigation of angiogenesis in bioactive 3-dimensional poly(d,l-lactide-co-glycolide)/nanohydroxyapatite scaffolds by in vivo multiphoton microscopy in murine calvarial critical bone defect. Novel nanostructured scaffold for osteochondral regeneration: pilot study in horses. Topography effects of pure titanium substrates on human osteoblast long-term adhesion. Nanotopography modulates mechanotransduction of stem cells and induces differentiation through focal adhesion kinase. Cell contractility arising from topography and shear flow determines human mesenchymal stem cell fate. The effects of nanoscale pits on primary human osteoblast adhesion formation and cellular spreading. TiO2 nanorod array constructed nanotopography for regulation of mesenchymal stem cells fate and the realization of locationcommitted stem cell differentiation. Biofunctionalization of a titanium surface with a nano-sawtooth structure regulates the behavior of rat bone marrow mesenchymal stem cells. The relationship between substrate topography and stem cell differentiation in the musculoskeletal system. Nanotopographic cues and stiffness control of tendon-derived stem cells from diverse conditions. Soft substrates drive optimal differentiation of human healthy and dystrophic myotubes.

Treatment of pustular psoriasis: From the Medical Board of the National Psoriasis Foundation menstruation 4 weeks postpartum buy fosamax with american express. Treatment for palmoplantar pustular psoriasis: Systematic literature review pregnancy announcement ideas fosamax 70 mg order mastercard, evidence-based recommendations and expert opinion menstrual unusual bleeding buy cheap fosamax. Treatment of erythrodermic psoriasis: From the medical board of the National Psoriasis Foundation menopause hormones discount fosamax 70 mg online. Nail psoriasis: A retrospective study on the effectiveness of systemic treatments (classical and biological therapy) zanaflex menstrual cramps cheap 70 mg fosamax otc. Treatment of nail psoriasis: Best practice recommendations from the Medical Board of the National Psoriasis Foundation. Low plasma levels of cholecalciferol and 13-cis-retinoic acid in tuberculosis: Implications in host-based chemotherapy. Retinoic acid therapy attenuates the severity of tuberculosis while altering lymphocyte and macrophage numbers and cytokine expression in rats infected with Mycobacterium tuberculosis. A single blind randomized clinical study: the efficacy of isotretinoin plus narrow band ultraviolet B in the treatment of psoriasis vulgaris. Effectiveness and safety of acitretin in children with plaque psoriasis: A multicenter retrospective analysis. Systemic treatments in childhood psoriasis: A French multicentre study on 154 children. Clinical features of von Zumbusch type of generalized pustular psoriasis in children: A retrospective study of 26 patients in southwestern China. Juvenile generalized pustular psoriasis is a chronic recalcitrant disease: An analysis of 27 patients seen in a tertiary hospital in Johor, Malaysia. Treatment of severe psoriasis in children: Recommendations of an Italian expert group. Statin Use for the Prevention of Cardiovascular Disease in Adults: A Systematic Review for the U. Topical treatment of psoriasis: Questionnaire results on topical therapy accessibility and influence of body surface area on usage. Tazarotene gel, a new retinoid, for topical therapy of psoriasis: Vehiclecontrolled study of safety, efficacy, and duration of therapeutic effect. Tazarotene cream in the treatment of psoriasis: Two multicenter, doubleblind, randomized, vehicle-controlled studies of the safety and efficacy of tazarotene creams 0. Once-daily tazarotene gel versus twice-daily fluocinonide cream in the treatment of plaque psoriasis. Topical therapies for the treatment of plaque psoriasis: Systematic review and network meta-analyses. A phase 2, multicenter, double-blind, randomized, vehicle controlled clinical study to assess the safety and efficacy of a halobetasol/tazarotene fixed combination in the treatment of plaque psoriasis. Efficacy of pulsed dye laser plus topical tazarotene versus topical tazarotene alone in psoriatic nail disease: A single-blind, intrapatient left-to-right controlled study. Role of bexarotene in the treatment of cutaneous T-cell lymphoma: the clinical and immunological sides. All-trans retinoic acid-loaded lipid nanoparticles as a transdermal drug delivery carrier. Nano-lipoidal carriers of tretinoin with enhanced percutaneous absorption, photostability, biocompatibility and anti-psoriatic activity. Development, evaluation and clinical studies of acitretin loaded nanostructured lipid carriers for topical treatment of psoriasis. Desquamation, proliferation, or adherent capacity of the cells are abnormal, and the epidermis may thicken or the skin surface may become xerotic and scaly. Keratinization disorders can be localized or generalized, and various treatment modalities, including topical and systemic retinoids, are used to reduce the clinical symptoms. In this article, we describe the use of retinoids in disorders of keratinization (1). The Ichthyoses Ichthyosis disorders are characterized by dryness with marked desquamation. Current evidence about ichthyosis treatments with oral retinoids including acitretin, isotretinoin and also oral liarozole as retinoic acid metabolism blocking agent is limited. Topical therapies, such as 5% urea, 5% lactic acid, 20% propylene glycol, calcipotriol, and liarozole 5% cream, have demonstrated some therapeutic efficacy in ichthyoses (2­19). Lamellar Ichthyosis and Non-Bullous Ichthyosiform Erythroderma Lamellar ichthyosis shows genetic heterogeneity. It affects both sexes equally, and prevalence of lamellar ichthyosis is less than 1/300,000. Hyperpyrexia and heat intolerance may be a problem in summertime or during exercise. Young children may have increased nutritional requirements due to their rapid growth and desquamation of their skin. Newborns are at risk for hypernatremic dehydration, secondary infection, and sepsis. Newborns require care in the neonatal intensive care unit with a high-humidity chamber, moisturizing, and monitoring of routine biochemistry. Isotretinoin 2 mg/kg/day may be helpful for lamellar ichthyosis and epidermolytic hyperkeratosis with maximum clearing and minimum side effects, according to a multicenter study. The scales and dryness occur mostly on the extensor part of the extremities and palmoplantar creases and less frequently on the flexures. Various topical emollients and keratolytics, including urea, lactic acid, glycolic acid, glycerol, paraffin, propylene glycol, ammonium lactate, salicylic acid, tazarotene, calcipotriol, N-acetyl-cysteine, and a diversity of fatty creams may be useful (5). Systemic retinoids, such as isotretinoin and acitretin, may also be useful, but regularly monitoring for side effects is mandatory. An alternative regimen utilizes apremilast, which was used in a patient with severe ectropion. It effectively controlled the ichthyosis and minimized relapse of the ocular lesions (18). Topical moisturizer ointments and keratolytic agents, such as salicylic acid and alpha-hydroxy acid in petrolatum, topical calcipotriol, and oral retinoids, have been used with favorable results. Topical retinoids including retinoic acid and tazarotene, and oral retinoids such as vitamin A, etretinate, isotretinoin, and acitretin, have been used with good to excellent results. X-Linked Recessive Ichthyosis this uncommon X-linked recessive disorder occurs only in boys, although girl carriers can have or show mild desquamation. The lifelong condition affects about 1/2000­6000 boys with steroid sulfatase enzyme deficiency. There are larger and darker scales, particularly in flexural regions and to a lesser extent the extensor areas; however, palmoplantar regions are unaffected. In laboratory analysis, cholesterol sulfate levels are increased, with elevated mobility of -lipoproteins on electrophoresis. Long-term systemic retinoid therapy is usually avoided to prevent serious side effects. Regular laboratory examination and imaging for calcifications and hyperostosis are mandatory in long-term retinoid therapy (8,14,15). Symmetric Progressive Erythrokeratoderma (Gottron Syndrome) Gottron syndrome is characterized by symmetric, slowly progressive, erythematous, and hyperkeratotic plaques which appear in infancy. Incomplete penetrance and variable expressivity, and sporadic mutations can also be detected. Moisturizers, topical retinoids, topical steroids, calcipotriol, and keratolytic agents, as well as oral retinoids including acitretin and isotretinoin, have been used with positive results. This membrane is shed within a couple of weeks, leaving behind congenital ichthyosis such as non-bullous ichthyosiform erythroderma or lamellar ichthyosis. The principles of treatment include humidification of the skin, prevention of fluid loss, and use of keratolytic agents. Long-term use of systemic retinoids has been reported to cause toxic effects in bone tissue. Cheilitis, dryness of mucous membranes, mild hair loss, and pruritus are the other adverse effects of oral retinoids. The use of a high humidity incubator can treat temperature instability and high water loss problems. The uncommon form, the "Harlequin fetus," is characterized by fissured hyperkeratosis and serious ectropion. High humidity incubators, monitoring of temperature, nutrient and fluid replacement therapies are recommended. To prevent skin and lung infections, antibiotic therapy should be started (14,17). Epidermolytic Hyperkeratosis (Bullous Ichthyosiform Erythroderma) this autosomal dominant disorder is characterized by redness, bullous lesions. The lesions usually become keratotic and verrucous around flexural regions, and erythematous lesions disappear during childhood. Generally, patients do not respond well to topical moisturizing creams or keratolytic therapy (3). The quality of life of these patients is decreased, and they need lifelong therapy. Treatment is symptomatic and antibiotics may be needed if the blisters become infected. Acitretin and isotretinoin may be useful in severe cases by affecting keratin expression. Topical alpha-hydroxy acids, antimicrobial treatment, and systemic retinoids like acitretin can temporarily cause worsening of the lesions; however, dramatic improvement is expected as a result of normalization of epidermal differentiation. Topical retinoids such as tretinoin and tazaroten may be alternative treatments, but patients generally do not respond well to topical retinoids, with high potential for local irritation. There are no reports on serious side effects with short-term systemic retinoids even at higher doses (28­30). Other Ichthyosiform Disorders Ichthyosiform skin lesions can rarely be seen as a part of a syndrome. Refsum syndrome is an autosomal recessive disorder characterized by elevation of phytanic acid, retinal degeneration, peripheral neuropathy, ataxia, and ichthyosis. A multidisciplinary approach Erythrokeratoderma Variabilis this condition is characterized by annular erythematous and scaly lesions that vary in size, shape, and distribution within Retinoids in Keratinization Disorders for eye and neurologic findings, along with emollients and keratolytic agents for ichthyosis, are needed. A phytanic acid-free diet (phytanic acid consumption 10 mg) and plasmapheresis are recommended. Topical therapy, including moisturizing creams, keratolytic agents, and retinoids, should be considered (31,32). Dermatologic treatment includes emollients like soft paraffin, keratolytics, topical retinoids, and vitamin D3 analogs (34). Netherton syndrome is characterized by congenital ichthyosis linearis circumflexa, trichorrhexis invaginata, and atopic predisposition. Water and electrolyte management, emollients such as ammonium lactate lotion, topical tacrolimus, topical steroids, topical retinoids, and keratolytic preparations are recommended. Systemic retinoid treatment is controversial because of its risk of activating the atopic skin lesions during therapy; however, most patients can respond to oral retinoids, narrow-band ultraviolet B, and psoralen plus ultraviolet A therapy (35,36). Different inheritance patterns have been reported including X-linked, recessive, and dominant. Skeletal defects include hypoplasia or aplasia of bones of the arms and legs on the side of the skin lesions. Spinal ligament calcifications and osteophyte formations can be seen in veretebral and facial bones. Surgical interventions for skeletal defects, moisturizers such as 10% urea cream, retinoids, methotrexate, nonsteroidal anti-inflammatory drugs, and keratolytics for skin lesions are recommended. Topical 2% cholesterol and 2% lovastatin cream with or without glycolic acid can improve the treatment (37,38). Conradi-Hunermann disease (Conradi-Hunermann-Happle syndrome; X-linked dominant chondrodysplasia punctata) exhibits X-linked dominant inheritance. It is characterized by whorled-like ichthyosis and atrophoderma vermiculatum lesions, especially on the extremities, alopecia, nail changes, skeletal defects such as hypoplasia, scoliosis, and dysplasia, and eye problems such as cataract, microphthalmia, and optic atrophy. The results of systemic retinoid therapy such as acitretin and isotretinoin are unclear (39,40). Systemic or topical retinoid therapy and topical keratolytic creams are not effective. Orthopedic and physical therapy interventions should be performed for contracture (31,44,45). Photoprotection, prevention of pulmonary infections, application of emollients, keratolytics, and physiotherapy are recommended. Underlying diseases such as Hodgkin lymphoma, other lymphomas, sarcoidosis, leprosy, malabsorption, hypothyroidism, and a poor diet should be investigated if ichthyosis appears suddenly in adulthood period. Primary cutaneous peripheral T-cell lymphoma, present as an acquired ichthyosis, has been treated with oral 300 mg/m2/ day bexarotene monotherapy. Ichthyosis-like scales diminished within 2 months after the administration of bexarotene (48). Topical moisturizers and keratolytics such as lactic, glycolic, and pyruvic acids, lipid-rich lubricants, petrolatum, hydrophilic ointments or heavy creams, salicylic acid, urea, and propylene glycol are recommended (49). Keratoderma of the Palms and Soles Inherited Types Palmoplantar keratodermas can be seen in many genodermatoses as a major manifestation. Diffuse-type palmoplantar keratodermas can present as epidermolytic keratoderma or nonepidermolytic keratoderma. Nonepidermolytic diffuse palmoplantar keratoderma starts at the first year of life.

Given the potential for a prolonged latent period following radiation therapy prior to the development of symptoms breast cancer 77 year old purchase 35 mg fosamax with amex, survivors should be advised to seek medical attention if there is a change in their symptom status and to inform their caregivers of their prior treatments (4) breast cancer x-ray buy fosamax 35 mg amex. Patients with significant prior radiation exposure should be given special consideration and considered as a unique population women's health article on birth control fosamax 70 mg purchase visa, particularly given the potential risk of harm arising because current standard preoperative risk testing grossly underestimates risk of cardiotoxicity pregnancy 31 weeks 70 mg fosamax buy overnight delivery, and because risks with interventions are significantly increased compared to the general population breast cancer uptodate 70 mg fosamax amex. It is hoped that better patient and physician awareness of these issues may lead to a more comprehensive preoperative assessment, improved informed consent, and a better selected surgical population. With increased survivorship comes additional emphasis on efforts to minimize, in particular, longer-term cardiac toxicity. Advances in radiation technology, techniques, dosimetry, precautions, and patient selection have led to reductions in cardiac radiation dose. Given the latency in cardiac sequelae with radiation exposure, the benefits of modern radiation therapy protocols will likely be observed over the next several years. Adjuvant hypofractionated versus conventional whole breast radiation therapy for early-stage breast cancer: Long-term hospital-related morbidity from cardiac causes. International guidelines for management of metastatic breast cancer: Can metastatic breast cancer be cured Effect of breast conservation therapy vs mastectomy on disease-specific survival for early-stage breast cancer. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden. Risk of heart disease in relation to radiotherapy and chemotherapy with anthracyclines among 19,464 breast cancer patients in Denmark. Use of intensity modulated radiation therapy to reduce acute and chronic toxicities of breast cancer patients treated with traditional and accelerated whole breast irradiation. Early cardiac perfusion defects after left-sided radiation therapy for breast cancer: Is there a volume response Breast-conserving radiation therapy using combined electron and intensity-modulated radiotherapy technique. Cardiac dose reduction with deep-inspiratory breath hold technique of radiotherapy for left-sided breast cancer. Prone breast forward intensitymodulated radiotherapy for Asian women with early left breast cancer: Factors for cardiac sparing and clinical outcomes. Pilot study of feasibility and dosimetric comparison of prone versus supine breast radiotherapy. Prone versus supine positioning for whole and partial-breast radiotherapy: A comparison of non-target tissue dosimetry. Postmastectomy radiation therapy technique and cardiopulmonary sparing: A dosimetric comparative analysis between photons and protons with free breathing versus deep inspiration breath hold. Model-based approach for quantitative estimates of skin, heart, and lung toxicity risk for left-side photon and proton irradiation after breast-conserving surgery. Radiation exposure of the heart, lung and skin by radiation therapy References 65 43. Breast-conserving therapy with partial or whole breast irradiation: Tenyear results of the Budapest randomized trial. Definition of stereotactic body radiotherapy: Principles and practice for the treatment of stage I nonsmall cell lung cancer. Dosimetric comparison to the heart and cardiac substructure in a large cohort of esophageal cancer patients treated with proton beam therapy or Intensity-modulated radiation therapy. Mini-review on cardiac complications after mediastinal irradiation for Hodgkin lymphoma. Cardiac inflammation after local irradiation is influenced by the kallikrein-kinin system. Evaluation of left ventricular function in long-term survivors of childhood Hodgkin disease. Increased aorto-mitral curtain thickness independently predicts mortality in patients with radiation-associated cardiac disease undergoing cardiac surgery. Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Mitral and tricuspid valve repair in patients with previous mediastinal radiation therapy. Long-term outcomes of patients with mediastinal radiation-associated severe aortic stenosis and subsequent surgical aortic valve replacement: A matched cohort study. Percutaneous valve replacement in a young adult for radiation-induced aortic stenosis. However, cardiac-related adverse events are common complications and their prevention remains an important challenge for those with or surviving cancer. Prior to initiation of therapy, baseline assessment is crucial to identify patients who are at risk for cardiotoxicity (3). As the use of cardiotoxic treatments increases, dramatic improvements have been made to reduce the incidence of cardiotoxicity for various cancer treatments. This article will provide a brief overview of the evolution of cancer treatment as it pertains to mitigating the effects of cardiotoxic anticancer therapies. The four most common anthracyclines are doxorubicin, daunorubicin, epirubicin, and idarubicin (9,10). Approximately 32% of breast cancer patients (11) and 57%­70% of elderly lymphoma (12,13) patients are treated 67 Table 5. Note: +++ represents >10%; ++ represents 1%-10%; + represents <1% or rare; represents observed but precise incidence not well established; and - represents not well-recognized complication with no/minimal data. It is well documented in the literature that cumulative anthracycline dose is linked to irreversible cardiac dysfunction, left ventricle dysfunction, and heart failure (3,9). Anthracyclinerelated cardiotoxicity can present acutely and/or have a chronic effect, which can occur months, years, or decades after completion of therapy (1). Preventative management of anthracyclineinduced cardiotoxicity is classified into two approaches: (1) reduce cardiotoxic potency; and (2) use a cardioprotective agent concurrently with treatment (15). One way cardiotoxicity is reduced is by replacing bolus administration with slow infusions over 24­96 hours (8). Pharmacodynamic and pharmacokinetic studies in animal models have reported 72 Overview of changes in cancer treatment strategies that increasing infusion duration reduces cardiotoxicity without compromising the oncologic efficacy of anthracycline therapy (8,16). In sarcoma and lymphoma patients, slow continuous doxorubicin infusions between 48 and 72 hours are often used (16). Infusions longer than 96 hours are associated with higher incidence of stomatitis, as well as a need for a prolonged infusion pump and an indwelling catheter (16). Another preventative strategy is using liposomal encapsulation to reduce cardiotoxicity from anthracyclines. By modifying pharmacokinetic and tissue distribution, the risk of cardiotoxicity diminishes without decreasing tumoricidal efficacy (19,20). Liposomal encapsulated doxorubicin has been shown to limit diffusion through the endothelial lining of the cardiac microvasculature (8,9,19). Additional concerns regarding the potential risk of secondary malignancies in childhood lymphoma have led to its restricted use (27). Nonanthracyclines While less common than anthracycline-induced cardiotoxicity, other chemotherapeutic agents used to treat cancer are also associated with cardiotoxicity. Capecitabine, its oral prodrug, is used for colorectal and metastatic breast cancer (3,29). However, this may be underestimated due to differences in the definition of cardiotoxicity and treatment schedules across studies (29). Serious complications are present in 0%­2% of patients and include myocardial infarction, cardiogenic shock, and cardiac arrest (29). Continuous infusion is associated with a higher risk of cardiotoxicities compared to bolus administration (30). Acute asymptomatic bradycardia has been reported in up to 30% of patients, while serious complications are less frequent (32­34). An early case series reported a 5% incidence of serious arrhythmias, ventricular tachycardia, and cardiac ischemia in patients who received paclitaxel (33). Preventative strategies include slow infusion of doxorubicin and paclitaxel, or increased time (24 hours) between doxorubicin and paclitaxel infusions (35,36). The cumulative dose of doxorubicin when combined with paclitaxel should not exceed 360 mg/m2 (37). Pharmacologic cardioprotective strategies during trastuzumab treatment are currently being explored to prevent future toxicity (38). However, these pharmacotherapies did not prevent trastuzumab-mediated left ventricular remodeling, a possible early marker of cardiotoxicity (38,43). Therefore, these results do not provide a solid basis of clinical decision-making, and larger studies are recommended. It is approved for the treatment of gastric, non-small cell lung, and colorectal cancer (52). It is used for a variety of treatments for many advanced solid tumors including colorectal, non-small cell lung, breast, and ovarian cancers (45­48). Bevacizumab is associated with a spectrum of adverse events such as arterial hypertension, heart failure, pulmonary hemorrhage, gastrointestinal bleeding, pulmonary edema, and venous and arterial thromboembolic events (4,6,49). These agents target the 26S proteasome, causing accumulation of protein byproducts within plasma cells and subsequent apoptosis (72­75). Bortezomib is typically used in the first-line setting while carfilzomib is used as second-line therapy in the relapsed setting (72). While relatively rare, proteasome inhibitors are associated with cardiac toxicities including heart failure and hypertension (72,73,76,77). Therefore, careful monitoring and a detailed history for cardiovascular risk factors and prior chemotherapy exposure (with particular attention to anthracyclines) are suggested (73). While there are no standard practice guidelines, Chari and Hajje published a set of recommendations for patients exposed to carfilzomib (83). In brief, screening echocardiograms should be obtained for all patients over the age of 60, with a history of amyloidosis, or other cardiovascular risk factors and repeated every two to three cycles (83). Carfilzomib should be administered slowly over 30 minutes instead of the 2­10 minutes indicated (83). Immunotherapy the role of immunotherapies in oncology has substantially improved the management and survival of several advanced-stage malignancies (84). Although current literature remains limited to case reports and early clinical trials, strategies are proposed to prevent and manage potentially fatal complications. Other strategies include transfer to an intensive care unit to maintain adequate perfusion and treatment of any significant arrhythmias. Tocilizumab and glucocorticoids should be considered as first-line and second-line therapy in the event of cardiotoxicity, respectively (85,88). Studies have observed that patients may be concurrently diagnosed with other immune-related adverse events such as myositis autoimmune thyroiditis and hypophysitis with cardiotoxicity (85,89). From the limited literature, ipilimumab and/or nivolumab-induced myocarditis was reported in 0. Notably, the incidence may be underestimated as cardiac screening is not routinely performed in immunotherapy studies (84,85). Methods of cardiac dose protection and/or avoidance techniques are described in detail in Chapter 4 and are briefly summarized in Table 5. Cardiotoxicity related to radiation therapy is well studied and remains the most common nonmalignant cause of morbidity and mortality in survivors (1,96,98). Elderly patients (>70 years old) are at greater risk due to polypharmacy and use of cardiotoxic therapeutics (103). Studies and case reports have reported an association between high doses of corticosteriods and cardiac events such as atrial fibrillation and hypertension (103,107). This observation was noted in hematological malignancies and suggests that high doses of corticosteroids might mediate potassium outflow from cells, thereby inducing arrhythmias (103,108). New biomarkers such as high-sensitivity cardiac troponin I, C-reactive protein, growth differentiation factor 15, and N-terminal pro-B-type natriuretic peptide have been studied in breast cancer patients receiving anthracycline and trastuzumab therapy (109,112­ 114). However, the studies concluded that further validation is needed before routine clinical use. Both meta-analyses have some limitations and should be interpreted cautiously, as both these studies suffer from patient and treatment heterogeneity. Referral to a cardiologist for routine clinical heart failure (stage B) management is the standard of care. State of the art for cardiotoxicity due to chemotherapy and to targeted therapies: A literature review. The field of cardio-oncology promotes optimal cancer treatment with a focus on limiting collateral cardiac damage (118,119). Along with the collaboration between cardiologists and oncologists, imaging specialists, clinical pharmacologists, nursing support, researchers, and educators are needed in this complex field (1). Cardio-oncology clinics allow clinicians to assess and prescribe appropriate therapeutic management if cardiac risk factors are present or if cardiotoxicity is identified (1). The creation of a specific cardio-oncology training program has been proposed by several experts to further advance this important therapeutic discipline (118). As the number of patients treated with cardiotoxic agents increases, it is imperative that we prevent cancer patients and survivors from becoming cardiac patients. As newer complex targeted therapies are 80 Overview of changes in cancer treatment strategies 13. Management strategies and outcomes for very elderly patients with diffuse large B-cell lymphoma. Cardiac management during adjuvant trastuzumab therapy: Recommendations of the Canadian Trastuzumab working group. Continuous versus bolus infusion of doxorubicin in children with all: Long-term cardiac outcomes. Pegylated liposomal doxorubicin: Metamorphosis of an old drug into a new form of chemotherapy. Stealth liposomes and tumor targeting: One step further in the quest for the magic bullet stealth liposomes and tumor targeting: One step further in the quest for the magic bullet.

Syndromes

• Kisses parents with lips puckered
• Damage to nerves in the foot
• Other urinary problems
• Have a history of bleeding problems
• Fatigue
• Tenderness to the touch
• High blood pressure at a young age
• Parts of the hip bone may not join together at all or in the correct position.
• White blood cell count

Her immediate postoperative recovery was uncomplicated menstruation hygiene cheap fosamax 35 mg visa, and she was discharged on the fourth postoperative day womens health daily magazine order fosamax 35 mg free shipping. At 10 months postmitral valve repair (10 years postanthracycline) breast cancer team names purchase fosamax discount, the patient was admitted to the hospital with exertional shortness of breath and congestive heart failure women health clinic fosamax 70 mg low cost. The patient was instructed to continue valsartan and change atenolol to carvedilol pregnancy xylitol discount 35 mg fosamax with amex. Aldactone was added to her therapy and there was up-titration of her diuretic regimen. Discussion Doxorubicin cardiotoxicity can have an acute, subacute, or late presentation (4). Here, we present a classic example of late presentation valvular disease and cardiomyopathy. Six years after anthracycline exposure and a cumulative dose of 300 mg/ m2, the patient started showing signs of valvular dysfunction, although one can argue that diastolic dysfunction likely preceded this. The most commonly accepted pathophysiological mechanism of anthracycline-induced cardiotoxicity is related to topoisomerase (Top) 2-alpha (8). Cardiotoxicity is cumulative and typically occurs at an average total dose of 400 mg/m2; however, Table 10. Speckle-tracking echocardiography analyses of three apical views in the apical 4, 2-chamber and apical long-axis view with the respective speckle-tracking echocardiography measurements. If the clinical benefit is felt to outweigh the risks, informed and shared decision-making with the patient should occur. Strategies to reduce cardiotoxicity should be considered with liposomal formulation of doxorubicin, continuous infusion or dexrazoxane. For such patients, utilizing a nonanthracycline-based regimen for future treatment cycles may be considered. Late detection of anthracycline induced cardiotoxicity is often irreversible (15). Case summary A 35-year-old Swedish woman presented to our clinic for monitoring of her cardiac function during her cancer treatment. In 2010, while 6 months pregnant, she noticed a breast lump that was red and tender in the inner upper quadrant of the right breast. After completion of her therapy, she underwent a modified radical mastectomy and right breast prosthesis implantation. In May 2014, 3 years after finishing cancer therapy, she was found to have a enlarging left lower lobe nodule on routine imaging with Fluorodeoxyglucose positron emission tomography. She underwent CyberKnife radiation of the lung lesion and was placed on paclitaxel, trastuzumab, and pertuzumab therapy for six cycles. It can be measured in systole or diastole, in three primary directions (longitudinal, radial, and circumferential), and is quantified as a change in length of a myocardial segment in relation to its initial length. This pathway, when stressed with the use of this monoclonal antibody, may cause cardiomyopathy indirectly. Endocardial contour (red) is traced in a series of images encompassing the entire ventricle during cardiac cycle. In this case, we followed current recommendations for cardiac monitoring, which resulted in a favorable outcome in this patient. This risk begins within the first 5 years after radiation 162 Cardio-oncology case studies therapy and continues until the third decade. In August 2013, the patient experienced an episode of left arm and left chest discomfort that awakened him from sleep and prompted a visit to the local emergency room. The pain was sharp, substernal, and had no relation to exertion, food, or emotion. At the hospital, the patient was administered nitroglycerin that did not alleviate his chest pain. The patient was seen in a cardio-oncology clinic for further evaluation of his chest pain. His history and physical examination were unremarkable, and his only cardiac risk factors included his exposure to anterior chest radiation. Lab results indicated a total cholesterol of 252 mg/dL, high-density lipoprotein of 57 mg/dL, low-density lipoprotein of 121 mg/dL, and triglycerides of 79 mg/dL. It characterizes a lesion in the vessel wall as either calcified or noncalcified and helps delineate a lipid core vs. Lifestyle modification with dietary changes, exercise, and weight loss was recommended, but unfortunately the patient was non-compliant. The patient declined bypass surgery and unfortunately owing to statin myopathy the atorvastatin was switched to 5 mg pravastatin daily. His hospital course was complicated by ventricular fibrillation arrest immediately postintervention, which led to intubation and an intra-aortic balloon pump placement. His hospital stay was prolonged, but he was eventually transitioned to optimal medical therapy, including aspirin, pravastatin, clopidogrel bisulfate, furosemide, Ramipril, carvedilol, spironolactone, and a defibrillator vest. The patient called from rehabilitation and came directly to the cardio-oncology clinic for a webinar with image review. Discussion Acute cardiac inflammation can occur at the time of radiotherapy or shortly afterwards, resulting in myocarditis or pericarditis (22). Late cardiovascular effects can manifest clinically years or even decades after treatment resulting in a variety of cardiovascular complications including myocardial fibrosis, valvular heart disease, systolic and diastolic heart failure, coronary artery disease, pericardial disease, and conduction system dysfunction. Radiation induced vasculopathy manifests as both micro- and macrovascular disease and can be rapidly progressive, despite not being clinically apparent until years or even decades after radiotherapy. Radiation-induced endothelial damage may be because of reactive oxygen species, production of 166 Cardio-oncology case studies cytokines (30), and other inflammatory mediators. Lesions are usually longer, concentric, and tubular, making cardiac revascularization more challenging. Newer radiation techniques, including deep inspiration breath-hold gating, accelerated partial breast irradiation, and use of modern 3D planning results in less radiation exposure to the heart, which may ameliorate cardiovascular complications. Medical therapy or revascularization is done depending upon symptoms, cancer stage, comorbidities, and expected survival. However, surgical intervention may be difficult sometimes owing to mediastinal fibrosis. In addition, the internal mammary artery may not be available for graft because of the irradiation of this vessel itself. Nuclear stress interpretations have limitations owing to significant attenuation artifacts, especially breast cancer patients who frequently have breast prothesis implants. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. Sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. Determinants of survival and left ventricular performance after mitral valve replacement. Mitral valve replacement with and without chordal preservation in patients with chronic mitral regurgitation. Comparison between transcatheter and surgical prosthetic valve implantation in patients with severe aortic stenosis and reduced left ventricular ejection fraction. Topoisomerases and anthracyclines: Recent advances and perspectives in anticancer therapy and prevention of cardiotoxicity. Cardiovascular complications of cancer therapy-Best practices in diagnosis, prevention, and management: Part 1. Cardiovascular side effects of cancer therapies: A position statement from the Heart Failure Association of the European Society of Cardiology. Cardiovasc Hematol Agents Med Chem (Formerly Current Med ChemCardiovasc Hematol Agents). Trastuzumab-induced cardiotoxicity: Clinical and prognostic implications of troponin I evaluation. Pathophysiology of anthracycline-and radiation-associated cardiomyopathies: Implications for screening and prevention. Radiation heart disease: Analysis of 16 young (aged 15 to 33 years) necropsy patients who received over 3,500 rads to the heart. Myocardial infarction mortality risk after treatment for Hodgkin disease: A collaborative British cohort study. Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer. Dent, Moira Rushton-Marovac, Heather Lounder, Josee Ivars, Joyce Botros, and Joerg Herrmann 12 Cardio-oncology training Sarju Ganatra and Michael G. Both are complex diseases, sharing risk factors such as age, obesity, smoking, genetics, and various lifestyle factors. The interplay between these two common disease entities necessitates a collaborative and multidisciplinary approach by healthcare providers. There are currently no established guidelines that outline the components and infrastructure needed to establish cardio-oncology clinics or programs. In this article, we utilize the expertise of pioneers in the field of cardio-oncology to outline the components and structure necessary to establish a successful cardio-oncology clinic/program. In order to ensure the success of a clinic, attention to detail in the initial planning stages is crucial. The exact needs at each stage must be identified and met in order to ensure all components are working in unison. Most importantly, any provider involved in the operation of a cardiooncology clinic has to recognize the value and necessity of a cardio-oncology service. Since this is a collaborative specialty, having leaders from oncology as well as cardiology is essential to ensure the success of the clinic. These leaders should develop a proposal for their institution based on local patient needs and provider abilities. Identify a leader to coordinate and pioneer the project Estimate clinical volume and develop a staffing model Once leaders have been identified, they can use their expertise to review local patient data to establish the need for a dedicated cardio-oncology clinic. Concrete information and comprehensive data must be available in order to approach the practice leadership and administration for approval and endorsement. Information on number of patients being referred from oncology to cardiology each year, and delays in cancer therapy while awaiting cardiac assessment, can make a case for establishing a cardio-oncology clinic. Local healthcare providers who have an interest and expertise in managing the cardiac concerns of cancer patients are important in demonstrating the value of a cardio-oncology clinic to healthcare administration. Once need has been established and recognized, the provider in charge of a cardio-oncology service is responsible for exploring and defining the practice landscape, and estimating clinic volume. This includes not only an assessment of how many patients one will encounter, but also which types of questions will be asked and which expectations are to be met. For instance, if cancer patients are repeatedly presenting at a cardiology practice for consultation related to their cancer history and treatment, the need for a joint practice may be more easily recognized and accepted. On the other hand, if the primary reason for cardiology referral is for a pretreatment cardiac optimization, a stronger case could be made for a cardiology clinic focused on cancer patients. At the outset of establishing a new clinic, there should be clear guidance on the appropriate reasons for referral to a cardio-oncology clinic. Once the patient populations are defined, patient volumes and the staffing needs can be estimated. After these steps have been completed, a full clinical proposal can be developed including information on appropriate referrals, staffing requirements, physical space requirements, and cost estimates. In most situations, cardio-oncology programs are established within either a hospital or cancer center. Operation of a cardio-oncology clinic 173 organizations have a leadership structure that has requirements for approval of new clinical programs. Once approval and funding from administration has been granted, operations can commence. At this point it is important to distribute information to local providers in cardiology, oncology, and allied healthcare on the launch of the clinic. This should include referral forms with clearly identified reasons for referral to this clinic. Regular review of clinic performance (number of patients seen, time to referral, etc. Communication between oncology and cardiology is a key element for the establishment of any cardio-oncology clinic. Practitioners can then focus their attention on successfully establishing a cardio-oncology clinic on a small scale, allowing for the identification of any logistical issues that can then be addressed. It may be easier for a scheduling team to successfully adjust to this concept if the scope of the clinic is gradually increased over time. Naturally, the cardio-oncology practice will expand with demand, as other medical services gain interest in this highly collaborative approach. In the former example, communication is paramount to ensure the success of the program. A practical tool to aid communication can be the establishment of multidisciplinary rounds where all involved healthcare providers are invited to discuss cardio-oncology cases. This exchange and sharing of ideas will continually educate and involve all members of the team in current cardio-oncology topics relating to real patient care (8). The cardio-oncology clinic should have timely access to a range of cardiac imaging modalities so that assessments and interventions can be made with minimal disruption to cancer therapy. In many cases, patients may have baseline cardiac disease that needs optimization prior to initiation of cancer therapy, while in others, treatment and management of complications owing to cancer therapy need to be initiated. The main advantage of multidisciplinary care is the interaction among specialists which allows the cardiologist to inform oncologists on best practices to manage cardiac risks and complications, while the oncologist can inform on the relative importance of anticancer therapeutics and absolute benefit to the patient on a case by case basis. Wait times to be assessed in a cardio-oncology clinic need to be balanced with the urgency of impending cancer treatments. The patient receiving active cancer treatment will generally require more urgent access (1­2 weeks), while it might be appropriate for patients not receiving active therapy. Cancer patients should be referred for an urgent consult (within 7 days) if they have symptoms of heart failure, or their cancer treatment has been placed on hold owing to cardiotoxicity. Patients receiving cancer therapy who are at high risk, or who have experienced cancer therapy-related cardiac dysfunction, should be discussed by the cardio-oncology team at multidisciplinary cardio-oncology rounds.

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