Category Archives: Gene Therapy

When gene therapy developer Generation Bio raised $110 million in venture funding in January and then followed up six months later with a $230 million initial public offering, it was as sure asign as any that investors are stoked about the next generation of gene therapies to treat rare diseases.

Their enthusiasm hasnt waned during the year, either, despite challenges ranging from the COVID-19 pandemic delaying clinical trials to regulators pushing back some development timelines so they can gather more data on emerging gene therapies.

And as two FDA-approved gene therapies for rare diseases gain ground in the marketSpark Therapeuticss Luxturna for RPE65 mutation-associated retinal dystrophy and Novartis Zolgensma for spinal muscular atrophy (SMA)the biopharma industry is hard at work on novel approaches to correcting rare disorders caused by errant genes. The advances range from new gene-insertion methods to innovations that allow the therapies to penetrate hard-to-reach tissues in the body.

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Some, like Generation, are directly addressing one big concern that has plagued the first generation of gene therapies: Just how durable are they? Its a question BioMarin faced in August when the FDA declined to approve its hemophilia A gene therapy valoctocogene roxaparvovec after data from a trial showed that levels of factor VIII fell 12 to 18 months after patients received the gene therapy, which is designed to restore the critical blood-clotting protein.

Generations lead gene therapy candidates are designed to treat rare blood disorders hemophilia A and phenylketonuria (PKU), and theyre still in preclinical development. Whats new about the company's approachis the delivery system: Rather than using a virus to insert a gene correction, Generation Biouses an alternative technology that avoids touching off an immune responsea buildup of antibodies to the virus that would normally prevent a second round of treatment.

Generations core technology, called non-viral closed-ended DNA (ceDNA), is carried into the body by a lipid nanoparticle. The potential for the technology to sidestep the immune response thats typical with virus-based gene therapies could be important in diseases like PKU, where the gene correction needs to reach liver cells, or hepatocytes.

The newborn liver divides incredibly quickly, and as it grows, the dose of gene therapy goes down, said Geoff McDonough, M.D., CEO of Generation Bio, in an interview. We dont view that as an existential problem. Well just re-dose.

BioMarin, meanwhile, is working with the FDA to address its request for more data on valoctocogene roxaparvovec, which is an adeno-associated virus (AAV)-based gene therapybut its also looking ahead to innovations that could improve future iterations of the technology. For one thing, it'sinvestigating different capsids that that may reduce the immune response to the first dose, thus allowing re-dosing later.

But that may be only a small part of addressing a decline in response to gene therapy. We also have to understand cellular determinants of expression, because maybe re-dosing isnt actually the answer after all, said Hank Fuchs, M.D., president of research and development at BioMarin, in an interview. To that end, BioMarin is studying liver biopsy tissueto try to understand how individual characteristics may affect the fate of the transgene.

And BioMarin is working with Swiss startup Dinaqor to develop gene therapies to treat heart diseases such as hypertrophic cardiomyopathy. To accomplish that, the companies are making capsids that travel not to the liverthe destination of many gene therapiesbut to the heart. If they succeed, it could be a significant platform play for us, Fuchs said. The morbidity for hypertrophic cardiomyopathy is terrible and 60% of cases are genetic. If we can do cardiac delivery, there are other genetic diseases that could be treated with gene therapy.

In 2019, a group of executives who had pioneered SMA gene therapy Zolgensma launched Taysha Gene Therapies with an ambitious goal: They wanted to correct genetic nervous system disorders by delivering gene therapies directly to the spinal fluid. Now, backed by $125 million in private funding and a $157 million IPO, Taysha is in preclinical testing withthree gene therapies for neurodegenerative diseases.

Tayshas gene therapy for GM2 gangliosidosis, a disease that progressively destroys nerve cells, is distinctive for more than its intrathecal delivery, said CEO RA Session II in an interview.

The therapy uses a single viral vector to deliver not one, but two genes at the heart of the disorderHEXA and HEXB. Theyre linked by a self-cleaving peptide and a promoter, which allows the two genes to be expressed at a one-to-one ratio, mimicking the endogenous system of a healthy cell, Session explained in an interview.

Other gene therapy developers are targeting specific cells in the body with new technology. Encoded Therapeutics, for example, is developing a gene therapy to treat the seizure disorder Dravet syndrome. But rather than replacing the mutated SCN1A gene that causes the disorder, Encoded incorporates pieces of DNA into an AAV vector with the goal of dialing up production of the SCN1A protein thats needed to correct the disorder.

RELATED: Encoded Therapeutics bags $135M to push 'precision gene therapy' into the clinic

Passage Bio is addressing GM1 gangliosidosis using a next-generation viral vector called AAVhu68, which in preclinical trials increased the expression of a needed protein not only in targeted cells, but also in the cerebral spinal fluid. The protein is then taken up by neighboring cells, creating an effect of cross correction that the companys scientists hope will improve developmental milestones and survival in the children who have the disease, said CEO Bruce Goldsmith, Ph.D., in an interview.

In August, Passage Bios planned phase 1/2 trial was placed on a clinical hold by the FDA, which cited concerns about the delivery device planned for the trial. The company is conducting risk assessments and testing the device so it can address the agencys questions, and Goldsmith expects to maintain a close dialogue with the FDA going forward.

Infantile GM1 can occur quite early, so we want to make sure the FDA is a collaborator on defining what developmental scales will be appropriate for measuring outcomes. That means not only primary outcomes but also durabilitywhat theyre looking for in terms of meaningful outcomes, he said. U.K. regulators gave their go-ahead for a clinical trial of the therapy in December.

Improving cross-correction in gene therapy is also a priority for Avrobio, which is developing gene therapies for several rare diseases, including Hunter syndrome and Fabry disease. Its technology platform, called plato, consists of a lentiviral vector and tags that help the therapeutic proteins reach the target cells lysosomesthe organelles inside of cells that orchestrate vital processes in the body.

In diseases like Fabry, all thats needed is cross-correction, where the enzyme in circulation is taken up by the cells and creates a profound effect, correcting a deficiency that causes organ damage, said CEO Geoff MacKay in an interview.The tags aid the uptake of a therapeutic protein. Its like a first-class ticket to the target tissues, like muscles and the central nervous system."

In November, Avrobio announced that in phase 1 and 2 trials of its Fabry genetherapy, the response lasted up to 3.5 years.

RELATED: Avrobio tracks improvements in first patient treated with Gaucher gene therapy

LogicBio Therapeutics approach to moving gene therapy into the future is to harness the power of genome editing.

The companys technology, GeneRide, uses strands of DNA to deliver a functioning copy of a faulty gene into cells nuclei, prompting natural DNA repair mechanisms to insert the good gene exactly where it belongs in the chromosome. The therapeutic gene becomes part of that celland of its daughter cells when it dividespotentially preventing a dilution of effect over time that can occur with other gene therapies.

LogicBios lead program, LB-001 to treat the liver disorder methylmalonic acidemia in children age 3 and older, was hit with a delay in February, when the FDA put a hold on the planned clinical trial so the company could address safety-monitoring concerns.

So LogicBio built in a protocol for caregivers to monitor post-treatment safety at home, and it added survival as a secondary endpoint, said LogicBios chief operating officer Kyle Chiang, Ph.D., in an interview. The company hopes to dose the first patient in the trial in early 2021.

BioMarins Fuchs predicts that each new development in gene therapy will raise more questions for the FDAbut that the delays wont prevent the advances from benefiting patients.

As regulators, its not in their DNA to take risks, Fuchs said. But the quest for gene therapy approvals, he added, will continue to go well, as regulators get more familiar with the technology and developers generate more and more data.

See the article here:
The next generation of gene therapy for rare diseases forges ahead as developers weather hurdles - FierceBiotech

The Wild West. Like changing the engine of acar while driving down the highway.

This was how several cell and gene therapy industry leaders characterized the fields rapidly developing Biomanufacturing and supply chain environment at this years Maryland Tech Council (MTC) BIO Conference held in the BioHealth Capital Region (BHCR).

Cell and gene therapy is so new that itsmanufacturing and supply chain processes and best practices are stillcalcifying, leaving many organizations to learn on the fly as they attempt tobuild the efficiency and standardization necessary for the industry to trulytake off.

Put simply, cell and gene therapy companiesare doing something thats basically never been done before. Only a handful ofcompanies have successfully taken a cell and gene therapy product to market.Gene and cell therapy manufacturing and supply chain is truly a new frontierthat is just starting to be explored and mapped.

Earlier this year at the Bio Innovation Conference during a panel entitled, New Frontiers of Biomanufacturing, had a vigorous discussion about the evolving state of cell and gene therapy manufacturing and innovation. Panelists included Vigenes Chief Manufacturing Officer Jeffrey Hung, Ph.D.; Aaron Vernon, VP of Engineering and Supply Chain at Autolus; John Rowley, Ph.D., Founder, and Chief Product Officer at Rooster Bio; Chris McDonald, VP of Manufacturing at Kite Pharma and Robert Lindblad, Chief Medical Officer at Emmes Corporation, and was moderated by John Walker, Manufacturers Extension Liaison at NIIMBL (National Institute for Innovation in Manufacturing Biopharmaceuticals).

When asked, What keeps you up at night?,Jeffrey Hung of Vigene perfectly captured the conundrum facing those operatingin the cell and gene therapy field: What keeps me awake at night is thecontinued demand for clinical trial materials and commercial product while wekeep having to innovate at a fast pace. Its like trying to change a carsengine while driving it down the highway.

Other panelists cited what seemed likeinherent contradictions faced by a nascient cell and gene therapy industry. Inessence, these companies are learning on the fly without an established set ofrules to follow or even question. Production needs conflict with innovation;personalization is anathema to standardization; and being cutting edge oftenmeans they lack the tools, materials and the well-worn paths to regulatoryapproval already established in other biotech sectors.

As a supporter of manufacturerswhat we see is that everyone wants to innovate but at some point, you have to just bite the bullet and lock down your process to get reliable manufacturing techniques to move it along the regulatory pathway. Every tweak you do requires a lot of other work. You can work on innovation in the second stage of your product, stated Robert Lindblad of Emmes.

In the new frontier space, there are no reagents and no GMP reagents. You cant source GMP reagents so you have to qualify reagents just for your product and your indication, which is not adequate to get a certificate of analysis from the FDA. As you are on the cutting edge, you dont have the equipment to create a closed system, you dont have the reagents you need to have GMP manufacturing, so you have to be creative and work with the agencies to get through the regulatory pathways to commercialization, he added.

The personalized nature of cell and genetherapy also creates challenges for manufacturing standardization and supplychain. The one batch, one patient equation of autologous cell therapy makes ita unique and highly challenging manufacturing process.

When you think about designing and building aplant you cant build inventory. Biologic manufacturing allows for 2 or 3 yearsof inventory. For us, you can never take the plant down, stated Chris McDonaldof Kite Pharma. He added that in many ways building a cell therapymanufacturing plant is a lot easier than running one due to the challengespresented by personalization, constant production, lack of inventory and theoverall newness of the industry.

Rooster Bio has built its business model around solving some of the fields efficiency and standardization issues. Rooster is making great strides in its efforts to standardize parts of the manufacturing and supply chain processes by becoming the Intel of cell banking. By creating off-the-shelf, high-quality media and cells-similar in concept to what the Intel microchip did for the computer industry-Rooster hopes to help standardize an important segment of cell and gene therapy manufacturing process and supply chain, thereby increasing manufacturing efficiency while lowering the cost of cell and gene therapy costs to patients.

One bad reagent going into a cell bank thats supposed to last for a few years can be really debilitating. This is what makes the Rooster Bio business model possible. Innovation cant happen without quality. On the innovation side were in the middle of the process of living cells transitioning from being just a tool for research into technology itself, stated John Rowley of Rooster Bio.

He also cited Moores Law as an apt parallel for whats currently developing in the cell and gene therapy field right now. Moores Law states that the capacity of microchips would likely double every year while computers would decrease in cost. Rowley drew a link between Moores Law, the rapid increase in monoclonal antibody manufacturing capacity and cost reductions of the 1990s and what is going on now in cell and gene therapy manufacturing and supply chain.

While improving the manufacturing and supply chain is critical, Aaron Vernon of Autolus reminded the audience of the real-world impact of cell and gene therapy development failure or success. He emphasized the need for stronger cell and gene therapy manufacturing and supply standardization because of the direct link between personalized therapies and impacts on individual patients.

We have to have zero tolerance for manufacturing failures because of their direct impact on patients. There are a lot of moving parts and things get more complex over time. This doesnt scale easily, he stated. We want to innovate all the time but we dont decisions made early in the research process that hamper supply chain for a very long time.

Because personalized medicine is tailored for specific patients-i.e. one batch, one patient-the stake, while always high in biotech manufacturing, are higher in cell and gene therapy manufacturing and supply chain.

This makes solving the industrysmanufacturing and supply chain questions even more pressing. Having morecompanies successfully commercialize their cell and gene therapy products andincreased information sharing, even among competing companies, are critical tothe industrys future.

Theres a huge amount of knowledge out therebut theres a black box that only gives us information about whats workedand what hasnt really late in the game. We only learn from the FDA after thefact, stated McDonald.

Instead of relying on the FDA, Walker wonderedabout the possibility of sharing successes and failures among cell and genetherapies competing for market share.

Walker offered the following thoughts to thepanel, Different companies know whats working and whats not but because ofIP no one is sharing. As cell therapy is trying to move forward everyone istrying to protect their own space so they are not sharing failures. If youretrying to move the field forward scientifically thats one thing, but right noweveryone is thinking commercially and everyone is in their silo, which istotally understandable

Vernon noted that the Standards Coordinating Body and other organizations are working to develop manufacturing and supply chain standards for the industry and are actively seeking input from companies in the space.

What Ive learned more than anything recentlyis that these organizations need more industry engagement. There are certainthings-how we qualify shipping lanes, logistics, freezing, microbial testing,method validation-that are absolutely inefficient when we are reinventing thewheel all the time at different companies, stated Vernon.

Because this industry is so new-we only have4 or 5 approved cell and gene therapy approved commercial products-its reallyjust too early to be able to standardize, added Hung.

Because it is in fact too early tostandardize, cell and gene therapy organizations find themselves confronting aCatch-22. Manufacturing demand will compete with the need to innovate. Thepersonalized nature of cell and gene therapy will be at odds with the push tostandardize manufacturing and supply chain best practices. The push to beat thecompetition to market will inherently limit the data sharing necessary touplift the entire industry.

While these manufacturing and supplychallenges appear daunting, they always are when it comes to revolutionizingmedicine. Its the energy created by these contradictions that will driveprogress and foment innovation; its the immense challenges of frontierindustries like cell and gene therapy that will ensure the very best of thebest rise to success to pave the way forward for the organizations thatfollow. And its success that will breedmore success, as the conflict between these seemingly opposing forces will onlyresolve itself over time as more companies take therapies to market and thestories of their struggles and successes become public knowledge.

It seems like the Wild West now but conquering new territory is always complex and messy. The car will eventually have time to slow down and get in the shop to fine-tune its engine, offering a smoother, more efficient and faster ride to its destination.

The BHCR regions burgeoning cell and gene therapy cluster, as represented by those on the New Frontiers in Biomanfucturing panel, will clearly play a leading role in fulfilling the promise of cell and gene therapies to deliver high-quality therapies and cures to patients in need while driving down costs over time.

Learn more about working at Kite from Chris McDonald, VP of Manufacturing and Site Lead.

Steve has over 20 years experience in copywriting, developing brand messaging and creating marketing strategies across a wide range of industries, including the biopharmaceutical, senior living, commercial real estate, IT and renewable energy sectors, among others. He is currently the Principal/Owner of StoryCore, a Frederick, Maryland-based content creation and execution consultancy focused on telling the unique stories of Maryland organizations.

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Biomanufacturing and Supply Chain Standardization Key to Success in Cell and Gene Therapy Industry Boom - BioBuzz

Cell Therapy

CellTherapy or Cytotherapy is the transfer of cells into a patient with a goal ofimproving the disease. From beginning blood transfusions were consideredto be the first type of celltherapy to be practiced as routine. Later, Bone marrow transplantation hasalso become a well-established concept which involves treatment of much kind ofblood disorders including anemia, leukemia, lymphoma and rareimmunodeficiencydiseases. Alternativemedical practitioners perform celltherapy in the form of several different names including xeno-transplanttherapy, glandular therapy, and fresh celltherapy. It has been claimed by the proponents of celltherapy that it has been used successfully to repair spinal cord injuries,strengthen weaken immune system, treatsautoimmunediseaseslike AIDS, helppatients with neurological disorders like Alzheimers disease, Parkinsons diseaseand epilepsy.

GeneTherapy

GeneTherapy basically involves the introduction or alteration of geneticmaterial within a cell or organism with an intention of curing the disease.Both celltherapy and gene therapy are overlapping fields of biomedical research withthe goals of repairing the direct cause ofGeneticdiseasesin DNA orcellular population respectively, the discovery of recombinant DNA technologyin the 1970s provided tools to efficiently develop genetherapy. Scientists use these techniques to readily manipulate viralgenomes, isolate genes and identify mutations involved in human disease,characterize and regulategeneexpressions, and engineer variousviral and non-viral vectors. Various long-term treatments for anemia,hemophilia, cystic fibrosis, muscular dystrophy, Gauschers disease, lysosomalstorage diseases, cardiovascular diseases, diabetes and diseases of bones andjoints are resolved through successful gene therapy and are elusivetoday.

StemCell Therapies

CellTherapy is defined as the therapy in which cellular material is injectedinto a patient in order to recover the healthy tissue. Celltherapy is targeted at many clinical indications in multiple organs bymeans of several modes of cell delivery.Stem-CellTherapyis the use ofstem cells to treat or prevent a disease or condition. Stemcells are a class of undifferentiated cells which are able to differentiateinto required or specialized cell types. Adult or somatic stem cells exist throughout the body after embryonic development and arefound available inside the different types of tissue. The stem cell methodologyincludes the phases of Stem cell or progenitor cell engraftment,differentiation followed by long term replacement of damaged tissue.

CellCulture and Bioprocessing

A Stem-Cell line is a group of undifferentiated stem cells which is culturedinvitro and can be propagated indefinitely. While stem cells can propagateindefinitely in culture due to their inherent cellular properties, immortalizedcells would not normally divide indefinitely but have gained this ability tosustain due to mutation. The Immortalized cell lines can be generated from cells by means of isolating cells fromtumors or induce mutations to make the cells immortal. An immortalizedcell line is a population of multicellular organism cells which has notproliferates indefinitely. Due to mutation, the cells evaded normal cellularsenescence and instead undergoing continuous celldivision. A key factor in reducing the production costs ofbiopharmaceuticals is the development of cell lines which in turn produce ahigh yield of product.

TissueScience & Regenerative Medicine

Regenerative Medicine is the branch of translational research deals with the processof replacing, engineering or regenerating human cells, tissues or organs inorder to restore or establish normal functionality of cell. Regenerativemedicine is the combination oftissueengineeringand Molecular Biology. CellTherapy mediate cell repair via five primary mechanisms: providing ananti-inflammatory effect, homing to damaged tissues and recruiting other cellssuch as endothelial progenitor cells for necessary tissue growth, supportingtissue remodeling over scar formation and inhibiting apoptosis programmablecell death and differentiating tissues into bone, cartilage, tendon andligament tissue.

ClinicalTrials on Cell & Gene Therapy

Clinical Trials of Celland Gene Therapy products often varying from the clinical trials design for other types of pharmaceutical products. Thesedifferences in trial design are necessitated by the distinctive features ofthese products. The clinical trials also reflect previous clinical experienceand evidence of medicine. Early experiences with Cell and Gene Therapy products indicate that some CGT products may posesubstantial risks to subjects due to effect at cellular and genetic level. Thedesign of early-phase clinical trials of Cell and Gene Therapy products ofteninvolves the following consideration of clinical safety issues, preclinicalissues and chemistry, manufacturing and controls (CMC) issues that areencountered.

NanoTherapy

Diseases can betreated using viruses as vector to deliver genes inGeneTherapy. Viruses as genevector however, can themselves cause problems in that they may initiateinflammation and the genes may be expressed at too high a level or for too longperiod of exposure. The goal of Nano Technology in genetherapy is delivery of therapeutic genes without a virus, usingnanoparticles as non-viral vector to deliver the genes. The particles canbe made with multiple layers so the outer layer with covering of peptide thatcan target the particles to cells of interest at specific site. The emergent Nanotechnologyin gene therapy is used to develop unique approaches in treating theretinopathies and the development of micro and Nano dimensional artificialantigen presenting cells forcancerimmunotherapy. These antigenpresenting cells mimic the natural signals in immunity that killer T-cellsreceive when there is an invader (bacteria, virus, cancer cell, etc.) in thebody.

AdvancedGene Therapeutics

Functionality ofbiomaterials for these forms is depends upon the chemical reaction such aslocalized or systemic response at the surface tethered moieties or encapsulatedtherapeutic factors such as drugs, genes, cells, growth factors, hormones andother active agents to specific target sites. The application of functional biomaterials is rehabilitation, reconstruction, regeneration, repair,ophthalmic applications and act as therapeutic solutions. It has the propertyof biocompatibility and produce inertness response to the tissue.Thebiomaterial-mediated gene therapy aim to use polymeric gene therapy systems tohalt the progression of neuron loss throughneuroprotectiveroutesand it combine stemcell therapy and biomaterial delivery system in order to enhance regeneration or repairafter ischemic injury.

Geneand Cell Therapy for Rare & Common Diseases

Gene therapy is a superior method to treat uncommon hereditary maladies; fixa solitary quality deformity by presenting a 'right' quality. The main qualitytreatment preliminaries were directed utilizing patients with uncommonmonogenetic issue, however these are presently dwarfed by the clinical testingof quality therapeutics for more typical conditions, for example, malignancy,AIDS and cardiovascular illness. This is halfway because of an inability toaccomplish long haul quality articulation with early vector frameworks, a basicprerequisite for amending numerous innate hereditary deformities. Presently, with the appearance ofadeno-relatedviral(AAV) and lent viral vectors, which show steady qualityarticulation in creature thinks about, this mechanical obstruction, may havebeen survived. These vectors are foreseen to shape the premise of numerous genetherapy protocols for acquired hereditary illnesses.

CellScience and Stem Cell Research

The extract derivedfrom the plant cell culture technology is being harnessed and utilized as anactive ingredient in anti-aging skincare products. In recent years, researchershave identified naturally occurring botanicals with substantial antioxidantactivity proven to protect skin stem cells from UV-induced oxidative stress,inhibit inflammation, neutralize free radicals and reverse the effects ofphoto-aging by means ofanti-oxidantactivity. Consequently,cosmeceutical products containing plant stem cell derived extracts have theability to promote healthy cell proliferation and protect against UV-induced dermatological cellular damage in humans. In contrast to epidermal stem cells,plant stem cells are totipotent that they are capable of regenerating anentirely new, whole plant. Through innovative plant stem cell technology,scientists are able to extract tissue from botanicals and regenerate stem cells can be harnessed for use in humans. The use of stem cellsderived from botanicals plant, rather than human stem cells, avoids thecontroversy surrounding the source or methods of extraction of human stem cellswhile still harnessing the potential of these intriguing cells and its effectin anti-photo aging.

MolecularBasis of Epigenetics

Epigenetics refers to changes in a chromosomewhich has influence on gene activity and expression. It is also used todescribe any heritable phenotypic change that doesn't derive from amodification of the chromosome such as prions.Epigeneticsis the mechanism for storing andperpetuating or continuing indefinitely a memory at the cellular level. Thebasic molecular epigenetic mechanisms that are widely studied at present regulation of chromatin structure of cell through histone post-translationalmodifications and covalent modification of DNA principally through the methodof DNA methylation. Chromatin is a dynamic structure that integrates potentially hundreds ofsignals from the cell surface and has effects of coordinated and appropriate transcriptional response in cell. It is increasingly clear that epigenetic marking ofchromatin and DNA itself is an important component of the cell signalintegration of entire function that is performed by the genome. Moreover, thechanges in the epigenetic state of chromatin in cell can have lasting effectson behavioral changes.

Geneticsand Stem Cell Biology

An undifferentiated mass of cell in amulticellular animal which is prepared for offering rise to uncertain number ofcells of a comparable sort, and from which certain diverse sorts of cell riseby detachment. Undifferentiated life forms can isolate into specific cell creates. Thetwo describing characteristics of an undifferentiated cell are endlessself-restoration and the ability to isolate into a specific adult. There aretwo critical classes of youthful microorganisms: pluripotent that can end upbeing any cell in the adult body, and multipotent that is kept to transforminginto more limited masses of cells.

Regulatoryand Safety Aspects of Cell and Gene Therapy

Celltreatment things require a combination of prosperity examinations.Comparable living being and quality things are heterogeneous substances. Thereare a few zones that particularly ought to be tended to as it is extremely notthe same as that of pharmaceuticals. These range from making group consistency,thing soundness to thing prosperity, quality and sufficiency throughpre-clinical, clinical examinations and displaying endorsement. This reviewplots the present headings/administers in US, EU, India and the relatedchallenges in making SCBP with highlight on clinical point.

Markets& Future Prospects for Cell & Gene Therapy

The immense number of associations related withcell treatment has extended development incredibly in the midst of the pastcouple of years. More than 500 associations have been recognized to be lockedin with cell treatment and 305 of these are profiled 291 co-tasks. Of theseassociations, 170 are related with fundamental microorganisms. The Profiles of72 academic establishments in the US related with cell treatment close by theirbusiness facilitated efforts. Allogeneicdevelopment with in excess of 350 clinical preliminaries is prepared toorder the commercialization of cell medicines in publicize. Advance R&D incell and quality treatment is depended upon to bloom given the normally basedpurposes of intrigue.

CellBiology

Cell biology is the investigation of cell andhow the cell capacities. Cell consist of numerous organelles that performparticular capacities and assume an imperative part in the development andgrowth of an organism. Cells are of 2 composes Prokaryotic Cell and Eukaryotic Cell. Case of aProkaryoticCellincorporates,Bacteria, then again Animal Cell and Plant Cell are portrayed as EukaryoticCells

Geneediting and CRISPR based technologies

CRISPR (Clustered Regularly Interspaced ShortPalindromic Repeats) Technology is a champion among the most fit yet clearmechanical assembly for genome changing. It urges and empowers investigators toeasily change DNA groupings and modify quality limits. It has various potentialapplications that join helping innate disseminates, treating and keeping thespread of diseases and improving yields. CRISPR broadly used as CRISPR-Cas9whereCRISPRsare particular stretches out of DNA andCas9 is the protein which is an aggravate that exhibitions like a few nuclearscissors, fit for cutting DNA strands. The assurance of CRISPR advancementanyway raises moral stresses as it isn't 100% compelling. Regardless, the progressionof CRISPR-Cas9 has disturbed the designed science industry these days, being aclear and great quality changing device.

Genetics& Genomic Medicine

Genetics in Health and Disease in whichtherapy utilizesgenetics, imaging and biological indicators tounderstand predisposition to disease, what constitutes health during childhoodand throughout the life course. Gene and Protein Function are used to develop tools, skills and resources to elucidategene function and to inform development of new therapies using state-of the-arttechnologies. Personalized Medicine and Patient benefit is considered to ensurebasic science discoveries of disease mechanisms and patients genomes are usedto produce best effect to improve patients lives which include betterdiagnostics, identification of biomarkersand targeting of therapies.

BioengineeringTherapeutics

Tissue Engineering or Bioengineering is the combinational usage of cells,Engineering, materials methods, suitable biochemical and physicochemicalfactors in order to improve or replace the infected biological tissues. Thefield includes the development of materials, devices,techniques to detect and differentiate disease states, the treatmentresponse, aid tissue healing, precisely deliver treatments to tissues or cells,signal early changes in health status, and provide implantable bio-artificialreplacement organs for recover or establish of healthy tissue. Techniquesdeveloped here identify and detect biomarkers of disease sub-types,progression, and treatment response, from tissue imaging to genetic testing andSingle cell analysis, that aid the more rapid development of new treatments andguide their clinical applications in treating the disorder. It includes theusage of computational modeling, bioinformatics, andquantitativepharmacologyto integratedata from diverse experimental and clinical sources to discover new drugs andspecific drug targets, as well as to design more efficient and informativepreclinical, clinical safety and efficacy studies.

Immunogenetics& Transplantation

Immunogenetics and Transplantation providesspecialized diagnostic services for allogeneic transplantation and related research. It provides support for blood, bonemarrow, kidney, pancreas, liver, heart, lung, small bowel andcorneatransplantation. Currently Immunogenetics& Transplantation is hot topic of discussion.

Biomarkers

Biomarkersare evolving rapidly in the advance of personalized medicine and individualhealth. The identification & validation of biomarkers in drug discovery,development and in disease prognosis, diagnosis, prevention & treatmentplay an essential role in the genomic era.

Originally posted here:
Genetherapy | Cell Therapy | Conferences | Events | 2019 ...

Sessions/Tracks

Track-1 Cell Therapy:

Cell therapy market investigation gives information about generally accepted clinical and analytical methods that are currently in use for applying cell therapy techniques. It is mainly used mainly in clinics and hospitals. Analysis is done on those companies and products that are actively developing and marketing instrumentation, reagents, and supplies for cell therapy. The cell-based research markets was analysed for 2015, and projected to 2025.They analysed according to therapeutic categories, technologies and geographical areas. The largest expansion will be in diseases of the central nervous system, cancer and cardiovascular disorders. Skin and soft tissue repair as well as diabetes mellitus will be other major markets.

RelatedCell Therapy | Gene Therapy | Cell Therapy Conferences|Gene Therapy Conferences|Conference Series LLC

6th International Conference onTissue Engineering &Regenerative Medicine,Baltimore, USA,Aug 20-22, 2017; 8th World Congress and Expo onCell &Stem Cell Research,Orlando, USA,March 20-22, 2017; 15thWorld Congress onBiotechnologyand Biotech Industries Meet,Rome, Italy,March 20-21,2017; 2nd International Conference onGenetic Counselling andGenomic Medicine,Beijing, China,July 10-12, 2017; International Conference onClinical andMolecular Genetics,Las Vegas, USA,April 24-26, 2017.

Track-2 Cellular Therapy Technologies:

Cell therapy technologies overlap with those of gene therapy,immune therapy cancer vaccines, drug delivery, drug discovery, tissue engineering and regenerative medicine. The cellular therapy technologies and methods, which have already started to play a very important role in the practice of medicine. Cell treatments and immunotherapies are changing the substance of pharmaceutical, empowering specialists, doctors and researchers to address the side effects of a sickness, as well as its basic causes, basically educating the body to recuperate itself. The pace of current advancements in cell treatment and immunotherapy is promising, with a few scientists reporting remarkable clinical results.

RelatedCell Therapy | Gene Therapy | Cell Therapy Conferences|Gene Therapy Conferences|Conference Series LLC

2nd International Conference onMolecular Biology, London, UK,June 22-24, 2017;3rd WorldBioSummit & Expo, Abu Dhabi, UAE,June 19-21, 2017;5th International Conference onIntegrativeBiology, London, UK,June 19-21, 2017;2nd World Congress on HumanGenetics, Chicago, USA,July 24-26, 2017;9th International Conference onGenomicsand Pharmacogenomics, Chicago, USA,July 13-14, 2017.

Track-3 Cell Therapy of Cardiovascular Disorders

Cardiovascular disease implies a range of disease entities whose therapeutic actions differ. Cell therapy is a 21st century approach which is used to treating the cardiovascular disease and now it is being applied worldwide. However, no concerted approach exists for defining the best treatment conditions.Cardio vascular disorders remains the number one cause of morbidity and mortality in the United States and Europe. In the United States alone, 1 million patients are suffering with myocardial infarction every year, with an associated mortality of 26% at 3 years.

RelatedCell Therapy|GeneTherapy|Cell Therapy Conferences|Gene Therapy Conferences|Conference Series LLC

2ndBiotechnologyWorld Convention,London, UK,May 25-27, 2017; International Conference on Animal and HumanCell Culture, Jackson Ville, USA,Sep 25-27, 2017; 9th International Conference onCancerGenomics, Chicago, USA,May 29-31, 2017; 6th International Conference onTissue Engineering &Regenerative Medicine, Baltimore, USA,Aug 20-22, 2017; 8th World Congress and Expo onCell &Stem Cell Research, Orlando, USA,March 20-22, 2017.

Track-4 Cell Therapy for Cancer

A number of cell and gene therapy strategies are being evaluated in patients suffering from cancer and these include manipulating cells to gain or lose function. Clinical trials of cell therapy for many different cancers are currently ongoing. The scientists has recently developed novel cancer therapies by combining both gene and cell therapies.Cancer therapeutics cannot cure cancer and yet in 2014, the overall market for Oncologic therapeutics stood at about $84.3 billion. Any drug that can treat a reasonable survival of more than five years for cancer patients can achieve a blockbuster status. Within oncologic therapeutics, immunotherapeutic drugs have increased worldwide acceptance, because they are targeted drugs targeting only cancer cells.

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Track-5 Cell Therapy for Neurological Disorders

New visions into the biology of neural stem cells (NSCs) have raised expectations for their use in the treatment of neurologic diseases. The truth is that the field is moving forward every year, well thought out clinical trials are being planned and undertaken, but to date none have shown a level of effectiveness that gives hope they may be useful as mainline therapies in 2013. With period, development will be made, but it is only by following the well-established methods of transformation from the laboratory to the clinic that this can happen. If such approaches are abandoned in the rush to get to clinic, then there is a real risk that the whole field will be derailed by a terrible result of an ill thought out treatment. If this were to happen then those treatments being advanced using sound scientific principles and which promise to be of a great use in the future, will instead be lost forever as the unproven, commercially driven cells of today confuse and kill the field. Cell therapy and gene transfer to the diseased or injured brain have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases.

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Track-6 Cell Science & Stem Cell Research:

Stem cell technology is the subject of much discussion and interest across the world. Newspapers and websites frequently report new discoveries, and this fast-paced field has been the focus of hope, excitement and sometimes controversy. Policy makers, regulators, researchers,clinicians and scientists are constantly debating the progress and potential applications of this exciting science. This Stem cell global strategic report will help us to understand unique product opportunities by stem cell type, derive more revenue from products sold to stem cell scientists, and identify new product growth opportunities before the competition. Use the Survey of Stem Cell Scientists & researchers to understand technical requirements, unmet needs, and purchasing preferences of stem cell researchers worldwide.

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Track-7 Cell Culture & Bioprocessing:

Getting cell therapy products onto the market as quickly as possible still remains a key driver in the improve of recombinant therapeutic proteins. Any such advance in bioprocessing is of particular interest to the industry if it considerably shortens the development timeline or improves the end product. In the monoclonal antibody (MAb) area, platform procedures have allowed companies to regulate on particular mammalian cell lines, transfection approaches, process conditions and also downstream processing to shorten the development timeline.

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Track-8 Cell Line Development

The global cell line growth development in the market is segmented on the basis of products, types of cell lines used, the source of cell lines, applications, and geographies. The global cell line development market size was valued at USD 2.38 billion in 2014. The key growth drivers include the increasing demand for monoclonal antibodies, raising demand for effective cancer treatmentsand technical advancements introduced in this field. The global cell line growth market size was valued at USD 2.38 billion in 2014. Key growth drivers include the rising demand for monoclonal antibodies, raising demand for effective cancer therapeutics and technical advancements introduced in this field.

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Track-9 Tissue Science & Regenerative Medicine:

The Global Tissue Science & Regenerative Medicine Market is estimated to observe the highest development coming from the Tissue Engineering segment. By technology type, biomaterial segment presently holds the largest market share of global regenerative medicine market. However, Tissue Engineering segment is expected to be the fastest growing segment over the forecast period. In terms of value, the tissue engineering segment market is anticipated to increase at an outstanding CAGR of 17.5% over the forecast period of 2015-2019, to reach a market value of about US$ 1,070 Mn by 2019. Currently, it accounts for almost 13.2% of the total share of the global regenerative medicine market, which is expected to increase growth potentially by 2019 end.

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Track-10 Gene Therapy

Currently, the concept of gene therapy is being authorized by numerous pharmaceutical companies using clinical data, and there is a increasing interest among venture capitalists to discover the commercial potential of gene therapy. However, the development of the gene therapy market is largely needy on the regulatory environment, and on approvals from industry bodies. Currently, most gene therapy products are still in the clinical trials phase II and phase III, of which a common focuses on the treatment of oncology and heart diseases. The growing popularity of DNA vaccines has positively impacted the development of this market, and there is a high chance of cell and gene therapy being practiced in clinics in the next few years, as encouraging results are developing from the phase II/III trials. Gene therapies market will generate $204m in 2020, according to new visiongain analysis

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Track-11 Cancer Gene Therapy

Initially, scientists followed gene therapy for the administration of genetic material to treat genetic disorders, and it was soon adapted for cancer treatment. Approximately two-thirds of the clinical trials in gene therapy have been designed at the treatment of various types of cancers. Cancer Gene Therapy Marketsize was USD 805.5 million in 2015, with 20.7% CAGR estimation from 2016 to 2024; as per a new global strategic research report. Globally, increasing cancer prevalence will rise demand for gene therapy as the effective personalized treatment choice. According to WHO, cancer incidence is estimated to rise by 50% to reach 15 million by the end of this decade. This increase in number of patients needs this as a potential treatment approach addressing the growing global burden of the disease.

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Track-12 Diabetis Gene Therapy

Recent developments in the field of molecular and cell biology may allow for the growth of novel strategies for the therapy and cure of type 1 diabetes. In particular, it is now possible to predict restoration of insulin secretion by gene or cell-replacement therapy. Diabetes mellitus is growing globally affecting more than 180 million people worldwide . This is mostly type 2 diabetes and, because of the growth in the aging population and massive increase in prevalence of obesity, the incidence is likely to be more than doubled by 2030.

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Track-13 Vectors for Gene Therapy

According to the new research Global strategic report Gene Therapy Market Forecast to 2020, a major focus has been on the on-going clinical trials for the growth of innovative products using different vectors. Increasing number of clinical trials and availability of wide range of genes and vectors used in these trials will enable emergence of new therapy modalities to help make cancer a manageable disease. By the end of 2012, the expected number of clinical trials crossed 1,800 worldwide.

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Track-14 Molecular Epigenetics

The global Epigenetic strategic research market was valued at an estimated$413.24 Millionin 2014. This market is expected to ncrease at a CAGR of 13.64% between 2014 and 2019 to reach$783.17 Millionin 2019. This Market is segmented mainly on the basis of products into enzymes; instruments and consumables; kits; and reagents. Each of these market is further divided into multiple product segments and sub-segments.

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Track-15 Genetics & Genomic Medicine

The National Human Genome Research Institute describesgenomic medicine as"an developing medical discipline that mainly involves using genomic information about an individual as part of their clinical care (e.g., fordiagnostic or therapeutic decision-making) and the health outcomes and policy implications of that clinical use. Geographically, the global Genomic Medicine market is classified into different regions viz. North America, Latin America, Western Europe, Eastern Europe, Asia Pacific Excluding Japan (APEJ), Japan, Middle East and Africa (MEA). Owing to the presence of huge number of academic as well as research institutions in the United States. which are mainly working on genomic medicine to discover next-generation genomic medicines, North America region is expected to lead the global genomic market in terms of value during the forecast period. Also, the presence of several academies offering educational programs coupled with openings in scientific research in the North America and Europe is expected to have positive impact on the regional markets. The genetic & genomic medicine concept still in its nascent stage is yet to receive an drive from the emerging market which are anticipated to hold smaller shares in the global market.

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Track 16 Gene Therapy Commercialization

Themajor theme of this is whether gene therapy can attain commercial success by the early-to-mid 2020s, which types of gene therapy programs have the greatest likelihood of success, and what hurdles might stand in the way of clinical and commercial success of leading gene therapy programs. Asynchrony between the maturation of gene therapy technologies and capital investment in development-focused business models may have stalled the commercialization of gene therapy.

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Track 17 Gene Therapy for rare & Common Diseases

Gene therapy is a logical way to treat rare genetic disorders; and cure a single gene defect by introducing with a 'correct' gene. The first gene-therapy trials were conducted using patients with rare monogenetic disorders, but these are now outstripped by the clinical testing of gene therapeutics for more common conditions, for ex: cancer, AIDS and heart disease. This is partially due to a failure to achieve long-term gene expression with early vector systems, a critical condition for correcting many inborn genetic defects.

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Track 18 Gene Editing Technology

The genome editing market is expected to reach USD 5.54 billion by 2021 from USD 2.84 Billion in 2016, and it wil grow at a CAGR of 14.3% in the next five years (2016 to 2021). The growth of the overall market can be accredited to factors such as increasing government funding and growth in the number of genomics projects, high prevalence rate of infectious diseases and cancer among patients, technological advancements, increasing demand for synthetic genes, growing awareness about genomics, and increasing new product launches by industry players are expected to drive the market in the coming years. Rise in the production of genetically modified crops is also expected to increase the demand for genome editing.

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Track 19 Cell & Gene Therapy Products

The Center for Biologics Evaluation and Research (CBER) controls cellular and gene therapy products and certain devices related to cell and gene therapy.In addition to regulatory oversight of clinical studies, it also provides proactive scientific and supervisory advice to medical and clinical researchers and manufacturers in the area of novel product development.

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Track 20 Ethical Issues in Cell & Gene Therapy

The use of human embryos for research on embryonic stem (ES) cells is currently top on the ethical and political agenda in many countries. Notwithstanding the potential benefit of using human Embryonic Stem cells in the treatment of diseases, their use remains controversial because of their origin from early embryos.

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Track 21 Regulatory & Safety Aspects of Cell & Gene Therapy

Read more:
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Explore the methods for delivering genes into cells.

Space Doctor

You are the doctor! Design and test gene therapy treatments with ailing aliens.

Challenges In Gene Therapy

Researchers hoping to bring gene therapy to the clinic face unique challenges.

Approaches To Gene Therapy

Beyond adding a working copy of a broken gene, gene therapy can also repair or eliminate broken genes.

Gene Therapy Successes

The future of gene therapy is bright. Learn about some of its most encouraging success stories.

Gene Therapy Case Study: Cystic Fibrosis

APA format:

Genetic Science Learning Center. (2012, December 1) Gene Therapy. Retrieved August 31, 2016, from http://learn.genetics.utah.edu/content/genetherapy/

CSE format:

Gene Therapy [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2012 [cited 2016 Aug 31] Available from http://learn.genetics.utah.edu/content/genetherapy/

Chicago format:

Genetic Science Learning Center. "Gene Therapy." Learn.Genetics.December 1, 2012. Accessed August 31, 2016. http://learn.genetics.utah.edu/content/genetherapy/.

Original post:
Gene Therapy: Molecular Bandage - Learn Genetics

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The genetics of skin cancer is an extremely broad topic. There are more than 100 types of tumors that are clinically apparent on the skin; many of these are known to have familial components, either in isolation or as part of a syndrome with other features. This is, in part, because the skin itself is a complex organ made up of multiple cell types. Furthermore, many of these cell types can undergo malignant transformation at various points in their differentiation, leading to tumors with distinct histology and dramatically different biological behaviors, such as squamous cell carcinoma (SCC) and basal cell cancer (BCC). These have been called nonmelanoma skin cancers or keratinocytic cancers.

Figure 1 is a simple diagram of normal skin structure. It also indicates the major cell types that are normally found in each compartment. Broadly speaking, there are two large compartmentsthe avascular cellular epidermis and the vascular dermiswith many cell types distributed in a largely acellular matrix.[1]

Figure 1. Schematic representation of normal skin. The relatively avascular epidermis houses basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for BCC and SCC, respectively. Melanocytes are also present in normal skin and serve as the source cell for melanoma. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.

The outer layer or epidermis is made primarily of keratinocytes but has several other minor cell populations. The bottom layer is formed of basal keratinocytes abutting the basement membrane. The basement membrane is formed from products of keratinocytes and dermal fibroblasts, such as collagen and laminin, and is an important anatomical and functional structure. As the basal keratinocytes divide and differentiate, they lose contact with the basement membrane and form the spinous cell layer, the granular cell layer, and the keratinized outer layer or stratum corneum.

The true cytologic origin of BCC remains in question. BCC and basal cell keratinocytes share many histologic similarities, as is reflected in the name. Alternatively, the outer root sheath cells of the hair follicle have also been proposed as the cell of origin for BCC.[2] This is suggested by the fact that BCCs occur predominantly on hair-bearing skin. BCCs rarely metastasize but can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name rodent ulcer.[3]

Some debate remains about the origin of SCC; however, these cancers are likely derived from epidermal stem cells associated with the hair follicle.[4] A variety of tissues, such as lung and uterine cervix, can give rise to SCC, and this cancer has somewhat differing behavior depending on its source. Even in cancer derived from the skin, SCC from different anatomic locations can have moderately differing aggressiveness; for example, SCC from glabrous (smooth, hairless) skin has a lower metastatic rate than SCC arising from the vermillion border of the lip or from scars.[3]

Additionally, in the epidermal compartment, melanocytes distribute singly along the basement membrane and can transform into melanoma. Melanocytes are derived from neural crest cells and migrate to the epidermal compartment near the eighth week of gestational age. Langerhans cells, or dendritic cells, are a third cell type in the epidermis and have a primary function of antigen presentation. These cells reside in the skin for an extended time and respond to different stimuli, such as ultraviolet radiation or topical steroids, which cause them to migrate out of the skin.[5]

The dermis is largely composed of an extracellular matrix. Prominent cell types in this compartment are fibroblasts, endothelial cells, and transient immune system cells. When transformed, fibroblasts form fibrosarcomas and endothelial cells form angiosarcomas, Kaposi sarcoma, and other vascular tumors. There are a number of immune cell types that move in and out of the skin to blood vessels and lymphatics; these include mast cells, lymphocytes, mononuclear cells, histiocytes, and granulocytes. These cells can increase in number in inflammatory diseases and can form tumors within the skin. For example, urticaria pigmentosa is a condition that arises from mast cells and is occasionally associated with mast cell leukemia; cutaneous T-cell lymphoma is often confined to the skin throughout its course. Overall, 10% of leukemias and lymphomas have prominent expression in the skin.[6]

Epidermal appendages are also found in the dermal compartment. These are derivatives of the epidermal keratinocytes, such as hair follicles, sweat glands, and the sebaceous glands associated with the hair follicles. These structures are generally formed in the first and second trimesters of fetal development. These can form a large variety of benign or malignant tumors with diverse biological behaviors. Several of these tumors are associated with familial syndromes. Overall, there are dozens of different histological subtypes of these tumors associated with individual components of the adnexal structures.[7]

Finally, the subcutis is a layer that extends below the dermis with varying depth, depending on the anatomic location. This deeper boundary can include muscle, fascia, bone, or cartilage. The subcutis can be affected by inflammatory conditions such as panniculitis and malignancies such as liposarcoma.[8]

These compartments give rise to their own malignancies but are also the region of immediate adjacent spread of localized skin cancers from other compartments. The boundaries of each skin compartment are used to define the staging of skin cancers. For example, an in situ melanoma is confined to the epidermis. Once the cancer crosses the basement membrane into the dermis, it is invasive. Internal malignancies also commonly metastasize to the skin. The dermis and subcutis are the most common locations, but the epidermis can also be involved in conditions such as Pagetoid breast cancer.

The skin has a wide variety of functions. First, the skin is an important barrier preventing extensive water and temperature loss and providing protection against minor abrasions. These functions can be aberrantly regulated in cancer. For example, in the erythroderma associated with advanced cutaneous T-cell lymphoma, alterations in the regulations of body temperature can result in profound heat loss. Second, the skin has important adaptive and innate immunity functions. In adaptive immunity, antigen-presenting cells engender a TH1, TH2, and TH17 response.[9] In innate immunity, the immune system produces numerous peptides with antibacterial and antifungal capacity. Consequently, even small breaks in the skin can lead to infection. The skin-associated lymphoid tissue is one of the largest arms of the immune system. It may also be important in immune surveillance against cancer. Immunosuppression, which occurs during organ transplant, is a significant risk factor for skin cancer. The skin is significant for communication through facial expression and hand movements. Unfortunately, areas of specialized function, such as the area around the eyes and ears, are common places for cancer to occur. Even small cancers in these areas can lead to reconstructive challenges and have significant cosmetic and social ramifications.[1]

While the appearance of any one skin cancer can vary, there are general physical presentations that can be used in screening. BCCs most commonly have a pearly rim (see Figure 3) or can appear somewhat eczematous. They often ulcerate (see Figure 3). SCCs frequently have a thick keratin top layer (see Figure 4). Both BCCs and SCCs are associated with a history of sun-damaged skin. Melanomas are characterized by asymmetry, border irregularity, color variation, a diameter of more than 6 mm, and evolution (ABCDE criteria). (Refer to What Does Melanoma Look Like? on NCIs website for more information about the ABCDE criteria.) Photographs representing typical clinical presentations of these cancers are shown below.

Enlarge

Figure 2. Superficial basal cell carcinoma (left panel) and nodular basal cell carcinoma (right panel).

Enlarge

Figure 3. Ulcerated basal cell carcinoma (left panel) and ulcerated basal cell carcinoma with characteristic pearly rim (right panel).

Enlarge

Figure 4. Squamous cell carcinoma on the face with thick keratin top layer (left panel) and squamous cell carcinoma on the leg (right panel).

Enlarge

Figure 5. Melanomas with characteristic asymmetry, border irregularity, color variation, and large diameter.

Basal cell carcinoma (BCC) is the most common malignancy in people of European descent, with an associated lifetime risk of 30%.[1] While exposure to ultraviolet (UV) radiation is the risk factor most closely linked to the development of BCC, other environmental factors (such as ionizing radiation, chronic arsenic ingestion, and immunosuppression) and genetic factors (such as family history, skin type, and genetic syndromes) also potentially contribute to carcinogenesis. In contrast to melanoma, metastatic spread of BCC is very rare and typically arises from large tumors that have evaded medical treatment for extended periods of time. BCCs can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name rodent ulcer. With early detection, the prognosis for BCC is excellent.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types. There are different patterns of sun exposure associated with each major type of skin cancer (BCC, squamous cell carcinoma [SCC], and melanoma).

While there is no standard measure, sun exposure can be generally classified as intermittent or chronic, and the effects may be considered acute or cumulative. Intermittent sun exposure is obtained sporadically, usually during recreational activities, and particularly by indoor workers who have only weekends or vacations to be outdoors and whose skin has not adapted to the sun. Chronic sun exposure is incurred by consistent, repetitive sun exposure, during outdoor work or recreation. Acute sun exposure is obtained over a short time period on skin that has not adapted to the sun. Depending on the time of day and a persons skin type, acute sun exposure may result in sunburn. In epidemiology studies, sunburn is usually defined as burn with pain and/or blistering that lasts for 2 or more days. Cumulative sun exposure is the additive amount of sun exposure that one receives over a lifetime. Cumulative sun exposure may reflect the additive effects of intermittent sun exposure, chronic sun exposure, or both.

Specific patterns of sun exposure appear to lead to different types of skin cancer among susceptible individuals. Intense intermittent recreational sun exposure has been associated with melanoma and BCC,[2,3] while chronic occupational sun exposure has been associated with SCC. Given these data, dermatologists routinely counsel patients to protect their skin from the sun by avoiding mid-day sun exposure, seeking shade, and wearing sun-protective clothing, although evidence-based data for these practices are lacking. The data regarding skin cancer risk reduction by regular sunscreen use are variable. One randomized trial of sunscreen efficacy demonstrated statistically significant protection for the development of SCC but no protection for BCC,[4] while another randomized study demonstrated a trend for reduction in multiple occurrences of BCC among sunscreen users [5] but no significant reduction in BCC or SCC incidence.[6]

Level of evidence (sun-protective clothing, avoidance of sun exposure): 4aii

Level of evidence (sunscreen): 1aii

Tanning bed use has also been associated with an increased risk of BCC. A study of 376 individuals with BCC and 390 control subjects found a 69% increased risk of BCC in individuals who had ever used indoor tanning.[7] The risk of BCC was more pronounced in females and individuals with higher use of indoor tanning.[8]

Environmental factors other than sun exposure may also contribute to the formation of BCC and SCC. Petroleum byproducts (e.g., asphalt, tar, soot, paraffin, and pitch), organophosphate compounds, and arsenic are all occupational exposures associated with cutaneous nonmelanoma cancers.[9-11]

Arsenic exposure may occur through contact with contaminated food, water, or air. While arsenic is ubiquitous in the environment, its ambient concentration in both food and water may be increased near smelting, mining, or coal-burning establishments. Arsenic levels in the U.S. municipal water supply are tightly regulated; however, control is lacking for potable water obtained through private wells. As it percolates through rock formations with naturally occurring arsenic, well water may acquire hazardous concentrations of this material. In many parts of the world, wells providing drinking water are contaminated by high levels of arsenic in the ground water. The populations in Bangladesh, Taiwan, and many other locations have high levels of skin cancer associated with elevated levels of arsenic in the drinking water.[12-16] Medicinal arsenical solutions (e.g., Fowlers solution and Bells asthma medication) were once used to treat common chronic conditions such as psoriasis, syphilis, and asthma, resulting in associated late-onset cutaneous malignancies.[17,18] Current potential iatrogenic sources of arsenic exposure include poorly regulated Chinese traditional/herbal medications and intravenous arsenic trioxide utilized to induce remission in acute promyelocytic leukemia.[19,20]

Aerosolized particulate matter produced by combustion of arsenic-containing materials is another source of environmental exposure. Arsenic-rich coal, animal dung from arsenic-rich regions, and chromated copper arsenatetreated wood produce airborne arsenical particles when burned.[21-23] Burning of these products in enclosed unventilated settings (such as for heat generation) is particularly hazardous.[24]

Clinically, arsenic-induced skin cancers are characterized by multiple recurring SCCs and BCCs occurring in areas of the skin that are usually protected from the sun. A range of cutaneous findings are associated with chronic or severe arsenic exposure, including pigmentary variation (poikiloderma of the skin) and Bowen disease (SCC in situ).[25]

However, the effect of arsenic on skin cancer risk may be more complex than previously thought. Evidence from in vivo models indicate that arsenic, alone or in combination with itraconazole, can inhibit the hedgehog pathway in cells with wild-type or mutated Smoothened by binding to GLI2 proteins; in this way, these drugs demonstrated inhibition of BCC growth in these animal models.[26,27] Additionally, the effect of arsenic on skin cancer risk may be modified by certain variants in nucleotide excision repair genes (xeroderma pigmentosum [XP] types A and D).[28]

The high-risk phenotype consists of individuals with the following physical characteristics:

Specifically, people with more highly pigmented skin demonstrate lower incidence of BCC than do people with lighter pigmented skin. Individuals with Fitzpatrick skin types I or II were shown to have a twofold increased risk of BCC in a small case-control study.[29] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) Blond or red hair color was associated with increased risk of BCC in two large cohorts: the Nurses Health Study and the Health Professionals Follow-Up Study.[30]

Immunosuppression also contributes to the formation of nonmelanoma (keratinocyte) skin cancers. Among solid-organ transplant recipients, the risk of SCC is 65 to 250 times higher, and the risk of BCC is 10 times higher than in the general population.[31-33] Nonmelanoma skin cancers in high-risk patients (i.e., solid-organ transplant recipients and chronic lymphocytic leukemia patients) occur at a younger age and are more common, more aggressive, and have a higher risk of recurrence and metastatic spread than nonmelanoma skin cancers in the general population.[34,35] Among patients with an intact immune system, BCCs outnumber SCCs by a 4:1 ratio; in transplant patients, SCCs outnumber BCCs by a 2:1 ratio.

This increased risk has been linked to the level of immunosuppression and UV exposure. As the duration and dosage of immunosuppressive agents increases, so does the risk of cutaneous malignancy; this effect is reversed with decreasing the dosage of, or taking a break from, immunosuppressive agents. Heart transplant recipients, requiring the highest rates of immunosuppression, are at much higher risk of cutaneous malignancy than liver transplant recipients, in whom much lower levels of immunosuppression are needed to avoid rejection.[31,36] The risk appears to be highest in geographic areas of high UV radiation exposure: when comparing Australian and Dutch organ transplant populations, the Australian patients carried a fourfold increased risk of developing SCC and a fivefold increased risk of developing BCC.[37] This speaks to the importance of rigorous sun avoidance among high-risk immunosuppressed individuals.

Individuals with BCCs and/or SCCs report a higher frequency of these cancers in their family members than do controls. The importance of this finding is unclear. Apart from defined genetic disorders with an increased risk of BCC, a positive family history of any skin cancer is a strong predictor of the development of BCC.

A personal history of BCC or SCC is strongly associated with subsequent BCC or SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these nonmelanoma skin cancers is the mid-60s.[38-43] In addition, several studies have found that individuals with a history of skin cancer have an increased risk of a subsequent diagnosis of a noncutaneous cancer;[44-47] however, other studies have contradicted this finding.[48-51] In the absence of other risk factors or evidence of a defined cancer susceptibility syndrome, as discussed below, skin cancer patients are encouraged to follow screening recommendations for the general population for sites other than the skin.

Mutations in the gene coding for the transmembrane receptor protein PTCH1, or PTCH, are associated with basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. PTCH1, the human homolog of the Drosophila segment polarity gene patched (ptc), is an integral component of the hedgehog signaling pathway, which serves many developmental (appendage development, embryonic segmentation, neural tube differentiation) and regulatory (maintenance of stem cells) roles.

In the resting state, the transmembrane receptor protein PTCH1 acts catalytically to suppress the seven-transmembrane protein Smoothened (Smo), preventing further downstream signal transduction.[52] Stoichiometric binding of the hedgehog ligand to PTCH1 releases inhibition of Smo, with resultant activation of transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E, myc), and regulators of angiogenesis.[53,54] Thus, the balance of PTCH1 (inhibition) and Smo (activation) manages the essential regulatory downstream hedgehog signal transduction pathway. Loss-of-function mutations of PTCH1 or gain-of-function mutations of Smo tip this balance toward constitutive activation, a key event in potential neoplastic transformation.

Demonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested the potential presence of an associated tumor suppressor gene.[55,56] Further investigation identified a mutation in PTCH1 that localized to the area of allelic loss.[57] Up to 30% of sporadic BCCs demonstrate PTCH1 mutations.[58] In addition to BCC, medulloblastoma and rhabdomyosarcoma, along with other tumors, have been associated with PTCH1 mutations. All three malignancies are associated with BCNS, and most people with clinical features of BCNS demonstrate PTCH1 mutations, predominantly truncation in type.[59]

Truncating mutations in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, have been demonstrated in both BCC and medulloblastoma.[60,61] PTCH2 displays 57% homology to PTCH1, differing in the conformation of the hydrophilic region between transmembrane portions 6 and 7, and the absence of C-terminal extension.[62] While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[60,63]

BCNS, also known as Gorlin Syndrome, Gorlin-Goltz syndrome, and nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder with an estimated prevalence of 1 in 57,000 individuals.[64] The syndrome is notable for complete penetrance and extremely variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes.[59,65] The clinical features of BCNS differ more among families than within families.[66] BCNS is primarily associated with germline mutations in PTCH1, but families with this phenotype have also been associated with alterations in PTCH2 and SUFU.[67-69]

As detailed above, PTCH1 provides both developmental and regulatory guidance; spontaneous or inherited germline mutations of PTCH1 in BCNS may result in a wide spectrum of potentially diagnostic physical findings. The BCNS mutation has been localized to chromosome 9q22.3-q31, with a maximum logarithm of the odd (LOD) score of 3.597 and 6.457 at markers D9S12 and D9S53.[64] The resulting haploinsufficiency of PTCH1 in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing heterozygosity for PTCH1.[70] The development of BCC and other BCNS-associated malignancies is thought to arise from the classic two-hit suppressor gene model: baseline heterozygosity secondary to germline PTCH1 mutation as the first hit, with the second hit due to mutagen exposure such as UV or ionizing radiation.[71-75] However, haploinsufficiency or dominant negative isoforms have also been implicated for the inactivation of PTCH1.[76]

The diagnosis of BCNS is typically based upon characteristic clinical and radiologic examination findings. Several sets of clinical diagnostic criteria for BCNS are in use (refer to Table 1 for a comparison of these criteria).[77-80] Although each set of criteria has advantages and disadvantages, none of the sets have a clearly superior balance of sensitivity and specificity for identifying mutation carriers. The BCNS Colloquium Group proposed criteria in 2011 that required 1 major criterion with molecular diagnosis, two major criteria without molecular diagnosis, or one major and two minor criteria without molecular diagnosis.[80] PTCH1 mutations are found in 60% to 85% of patients who meet clinical criteria.[81,82] Most notably, BCNS is associated with the formation of both benign and malignant neoplasms. The strongest benign neoplasm association is with ovarian fibromas, diagnosed in 14% to 24% of females affected by BCNS.[74,78,83] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.[84] Ameloblastomas, aggressive tumors of the odontogenic epithelium, have also been proposed as a diagnostic criterion for BCNS, but most groups do not include it at this time.[85]

Other associated benign neoplasms include gastric hamartomatous polyps,[86] congenital pulmonary cysts,[87] cardiac fibromas,[88] meningiomas,[89-91] craniopharyngiomas,[92] fetal rhabdomyomas,[93] leiomyomas,[94] mesenchymomas,[95] and nasal dermoid tumors. Development of meningiomas and ependymomas occurring postradiation therapy has been documented in the general pediatric population; radiation therapy for syndrome-associated intracranial processes may be partially responsible for a subset of these benign tumors in individuals with BCNS.[96-98] Radiation therapy of medulloblastomas may result in many cutaneous BCCs in the radiation ports. Similarly, treatment of BCC of the skin with radiation therapy may result in induction of large numbers of additional BCCs.[73,74,94]

The diagnostic criteria for BCNS are described in Table 1 below.

Of greatest concern with BCNS are associated malignant neoplasms, the most common of which is BCC. BCC in individuals with BCNS may appear during childhood as small acrochordon-like lesions, while larger lesions demonstrate more classic cutaneous features.[99] Nonpigmented BCCs are more common than pigmented lesions.[100] The age at first BCC diagnosis associated with BCNS ranges from 3 to 53 years, with a mean age of 21.4 years; the vast majority of individuals are diagnosed with their first BCC before age 20 years.[78,83] Most BCCs are located on sun-exposed sites, but individuals with greater than 100 BCCs have a more uniform distribution of BCCs over the body.[100] Case series have suggested that up to 1 in 200 individuals with BCC demonstrate findings supportive of a diagnosis of BCNS.[64] BCNS has rarely been reported in individuals with darker skin pigmentation; however, significantly fewer BCCs are found in individuals of African or Mediterranean ancestry.[78,101,102] Despite the rarity of BCC in this population, reported cases document full expression of the noncutaneous manifestations of BCNS.[102] However, in individuals of African ancestry who have received radiation therapy, significant basal cell tumor burden has been reported within the radiation port distribution.[78,94] Thus, cutaneous pigmentation may protect against the mutagenic effects of UV but not ionizing radiation.

Variants associated with an increased risk of BCC in the general population appear to modify the age of BCC onset in individuals with BCNS. A study of 125 individuals with BCNS found that a variant in MC1R (Arg151Cys) was associated with an early median age of onset of 27 years (95% confidence interval [CI], 2034), compared with individuals who did not carry the risk allele and had a median age of BCC of 34 years (95% CI, 3040) (hazard ratio [HR], 1.64; 95% CI, 1.042.58, P = .034). A variant in the TERT-CLPTM1L gene showed a similar effect, with individuals with the risk allele having a median age of BCC of 31 years (95% CI, 2837) relative to a median onset of 41 years (95% CI, 3248) in individuals who did not carry a risk allele (HR, 1.44; 95% CI, 1.081.93, P = .014).[103]

Many other malignancies have been associated with BCNS. Medulloblastoma carries the strongest association with BCNS and is diagnosed in 1% to 5% of BCNS cases. While BCNS-associated medulloblastoma is typically diagnosed between ages 2 and 3 years, sporadic medulloblastoma is usually diagnosed later in childhood, between the ages of 6 and 10 years.[74,78,83,104] A desmoplastic phenotype occurring around age 2 years is very strongly associated with BCNS and carries a more favorable prognosis than sporadic classic medulloblastoma.[105,106] Up to three times more males than females with BCNS are diagnosed with medulloblastoma.[107] As with other malignancies, treatment of medulloblastoma with ionizing radiation has resulted in numerous BCCs within the radiation field.[74,89] Other reported malignancies include ovarian carcinoma,[108] ovarian fibrosarcoma,[109,110] astrocytoma,[111] melanoma,[112] Hodgkin disease,[113,114] rhabdomyosarcoma,[115] and undifferentiated sinonasal carcinoma.[116]

Odontogenic keratocystsor keratocystic odontogenic tumors (KCOTs), as renamed by the World Health Organization working groupare one of the major features of BCNS.[117] Demonstration of clonal loss of heterozygosity (LOH) of common tumor suppressor genes, including PTCH1, supports the transition of terminology to reflect a neoplastic process.[70] Less than one-half of KCOTs from individuals with BCNS show LOH of PTCH1.[76,118] The tumors are lined with a thin squamous epithelium and a thin corrugated layer of parakeratin. Increased mitotic activity in the tumor epithelium and potential budding of the basal layer with formation of daughter cysts within the tumor wall may be responsible for the high rates of recurrence post simple enucleation.[117,119] In a recent case series of 183 consecutively excised KCOTs, 6% of individuals demonstrated an association with BCNS.[117] A study that analyzed the rate of PTCH1 mutations in BCNS-associated KCOTs found that 11 of 17 individuals carried a germline PTCH1 mutation and an additional 3 individuals had somatic mutations in this gene.[120] Individuals with germline PTCH1 mutations had an early age of KCOT presentation. KCOTs occur in 65% to 100% of individuals with BCNS,[78,121] with higher rates of occurrence in young females.[122]

Palmoplantar pits are another major finding in BCC and occur in 70% to 80% of individuals with BCNS.[83] When these pits occur together with early-onset BCC and/or KCOTs, they are considered diagnostic for BCNS.[123]

Several characteristic radiologic findings have been associated with BCNS, including lamellar calcification of falx cerebri;[124,125] fused, splayed or bifid ribs;[126] and flame-shaped lucencies or pseudocystic bone lesions of the phalanges, carpal, tarsal, long bones, pelvis, and calvaria.[82] Imaging for rib abnormalities may be useful in establishing the diagnosis in younger children, who may have not yet fully manifested a diagnostic array on physical examination.

Table 2 summarizes the frequency and median age of onset of nonmalignant findings associated with BCNS.

Individuals with PTCH2 mutations may have a milder phenotype of BCNS than those with PTCH1 mutations. Characteristic features such as palmar/plantar pits, macrocephaly, falx calcification, hypertelorism, and coarse face may be absent in these individuals.[127]

A 9p22.3 microdeletion syndrome that includes the PTCH1 locus has been described in ten children.[128] All patients had facial features typical of BCNS, including a broad forehead, but they had other features variably including craniosynostosis, hydrocephalus, macrosomia, and developmental delay. At the time of the report, none had basal cell skin cancer. On the basis of their hemizygosity of the PTCH1 gene, these patients are presumably at an increased risk of basal cell skin cancer.

Germline mutations in SUFU, a major negative regulator of the hedgehog pathway, have been identified in a small number of individuals with a clinical phenotype resembling that of BCNS.[68,69] These mutations were first identified in individuals with childhood medulloblastoma,[129] and the incidence of medulloblastoma appears to be much higher in individuals with BCNS associated with SUFU mutations than in those with PTCH1 mutations.[68] SUFU mutations may also be associated with an increased predisposition to meningioma.[91,130] Conversely, odontogenic jaw keratocysts appear less frequently in this population. Some clinical laboratories offer genetic testing for SUFU mutations for individuals with BCNS who do not have an identifiable PTCH1 mutation.

Rombo syndrome, a very rare genetic disorder associated with BCC, has been outlined in three case series in the literature.[131-133] The cutaneous examination is within normal limits until age 7 to 10 years, with the development of distinctive cyanotic erythema of the lips, hands, and feet and early atrophoderma vermiculatum of the cheeks, with variable involvement of the elbows and dorsal hands and feet.[131] Development of BCC occurs in the fourth decade.[131] A distinctive grainy texture to the skin, secondary to interspersed small, yellowish, follicular-based papules and follicular atrophy, has been described.[131,133] Missing, irregularly distributed and/or misdirected eyelashes and eyebrows are another associated finding.[131,132]

Bazex-Dupr-Christol syndrome, another rare genodermatosis associated with development of BCC, has more thorough documentation in the literature than Rombo syndrome. Inheritance is accomplished in an X-linked dominant fashion, with no reported male-to-male transmission.[134-136] Regional assignment of the locus of interest to chromosome Xq24-q27 is associated with a maximum LOD score of 5.26 with the DXS1192 locus.[137] Further work has narrowed the potential location to an 11.4-Mb interval on chromosome Xq25-27; however, the causative gene remains unknown.[138]

Characteristic physical findings include hypotrichosis, hypohidrosis, milia, follicular atrophoderma of the cheeks, and multiple BCC, which manifest in the late second decade to early third decade.[134] Documented hair changes with Bazex-Dupr-Christol syndrome include reduced density of scalp and body hair, decreased melanization,[139] a twisted/flattened appearance of the hair shaft on electron microscopy,[140] and increased hair shaft diameter on polarizing light microscopy.[136] The milia, which may be quite distinctive in childhood, have been reported to regress or diminish substantially at puberty.[136] Other reported findings in association with this syndrome include trichoepitheliomas; hidradenitis suppurativa; hypoplastic alae; and a prominent columella, the fleshy terminal portion of the nasal septum.[141,142]

A rare subtype of epidermolysis bullosa simplex (EBS), Dowling-Meara (EBS-DM), is primarily inherited in an autosomal dominant fashion and is associated with mutations in either keratin-5 (KRT5) or keratin-14 (KRT14).[143] EBS-DM is one of the most severe types of EBS and occasionally results in mortality in early childhood.[144] One report cites an incidence of BCC of 44% by age 55 years in this population.[145] Individuals who inherit two EBS mutations may present with a more severe phenotype.[146] Other less phenotypically severe subtypes of EBS can also be caused by mutations in either KRT5 or KRT14.[143] Approximately 75% of individuals with a clinical diagnosis of EBS (regardless of subtype) have KRT5 or KRT14 mutations.[147]

Characteristics of hereditary syndromes associated with a predisposition to BCC are described in Table 3 below.

(Refer to the Brooke-Spiegler Syndrome, Multiple Familial Trichoepithelioma, and Familial Cylindromatosis section in the Rare Skin Cancer Syndromes section of this summary for more information about Brooke-Spiegler syndrome.)

As detailed further below, the U.S. Preventive Services Task Force does not recommend regular screening for the early detection of any cutaneous malignancies, including BCC. However, once BCC is detected, the National Comprehensive Cancer Network guidelines of care for nonmelanoma skin cancers recommends complete skin examinations every 6 to 12 months for life.[158]

The BCNS Colloquium Group has proposed guidelines for the surveillance of individuals with BCNS (see Table 4).

Level of evidence: 5

Avoidance of excessive cumulative and sporadic sun exposure is important in reducing the risk of BCC, along with other cutaneous malignancies. Scheduling activities outside of the peak hours of UV radiation, utilizing sun-protective clothing and hats, using sunscreen liberally, and strictly avoiding tanning beds are all reasonable steps towards minimizing future risk of skin cancer. For patients with particular genetic susceptibility (such as BCNS), avoidance or minimization of ionizing radiation is essential to reducing future tumor burden.

Level of evidence: 2aii

The role of various systemic retinoids, including isotretinoin and acitretin, has been explored in the chemoprevention and treatment of multiple BCCs, particularly in BCNS patients. In one study of isotretinoin use in 12 patients with multiple BCCs, including 5 patients with BCNS, tumor regression was noted, with decreasing efficacy as the tumor diameter increased.[159] However, the results were insufficient to recommend use of systemic retinoids for treatment of BCC. Three additional patients, including one with BCNS, were followed long-term for evaluation of chemoprevention with isotretinoin, demonstrating significant decrease in the number of tumors per year during treatment.[159] Although the rate of tumor development tends to increase sharply upon discontinuation of systemic retinoid therapy, in some patients the rate remains lower than their pretreatment rate, allowing better management and control of their cutaneous malignancies.[159-161] In summary, the use of systemic retinoids for chemoprevention of BCC is reasonable in high-risk patients, including patients with XP, as discussed in the Squamous Cell Carcinoma section of this summary.

A patients cumulative and evolving tumor load should be evaluated carefully in light of the potential long-term use of a medication class with cumulative and idiosyncratic side effects. Given the possible side-effect profile, systemic retinoid use is best managed by a practitioner with particular expertise and comfort with the medication class. However, for all potentially childbearing women, strict avoidance of pregnancy during the systemic retinoid courseand for 1 month after completion of isotretinoin and 3 years after completion of acitretinis essential to avoid potentially fatal and devastating fetal malformations.

Level of evidence (retinoids): 2aii

In a phase II study of 41 patients with BCNS, vismodegib (an inhibitor of the hedgehog pathway) has been shown to reduce the per-patient annual rate of new BCCs requiring surgery.[162] Existing BCCs also regressed for these patients during daily treatment with 150 mg of oral vismodegib. While patients treated had visible regression of their tumors, biopsy demonstrated residual microscopic malignancies at the site, and tumors progressed after the discontinuation of the therapy. Adverse effects included taste disturbance, muscle cramps, hair loss, and weight loss and led to discontinuation of the medication in 54% of subjects. Based on the side-effect profile and rate of disease recurrence after discontinuation of the medication, additional study regarding optimal dosing of vismodegib is ongoing.

Level of evidence (vismodegib): 1aii

Treatment of individual basal cell cancers in BCNS is generally the same as for sporadic basal cell cancers. Due to the large number of lesions on some patients, this can present a surgical challenge. Field therapy with imiquimod or photodynamic therapy are attractive options, as they can treat multiple tumors simultaneously.[163,164] However, given the radiosensitivity of patients with BCNS, radiation as a therapeutic option for large tumors should be avoided.[78] There are no randomized trials, but the isolated case reports suggest that field therapy has similar results as in sporadic basal cell cancer, with higher success rates for superficial cancers than for nodular cancers.[163,164]

Consensus guidelines for the use of methylaminolevulinate photodynamic therapy in BCNS recommend that this modality may best be used for superficial BCC of all sizes and for nodular BCC less than 2 mm thick.[165] Monthly therapy with photodynamic therapy may be considered for these patients as clinically indicated.

Level of evidence (imiquimod and photodynamic therapy) : 4

In addition to its effects on the prevention of BCCs in patients with BCNS, vismodegib may also have a palliative effect on KCOTs found in this population. An initial report indicated that the use of GDC-0449, the hedgehog pathway inhibitor now known as vismodegib, resulted in resolution of KCOTs in one patient with BCNS.[166] Another small study found that four of six patients who took 150 mg of vismodegib daily had a reduction in the size of KCOTs.[167] None of the six patients in this study had new KCOTs or an increase in the size of existing KCOTs while being treated, and one patient had a sustained response that lasted 9 months after treatment was discontinued.

Level of evidence (vismodegib): 3diii

Squamous cell carcinoma (SCC) is the second most common type of skin cancer and accounts for approximately 20% of cutaneous malignancies. Although most cancer registries do not include information on the incidence of nonmelanoma skin cancer, annual incidence estimates range from 1 million to 3.5 million cases in the United States.[1,2]

Mortality is rare from this cancer; however, the morbidity and costs associated with its treatment are considerable.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types; however, different patterns of sun exposure are associated with each major type of skin cancer. (Refer to the Sun exposure section in the Basal Cell Carcinoma section of this summary for more information.) This section focuses on sun exposure and increased risk of cutaneous SCC.

Unlike basal cell carcinoma (BCC), SCC is associated with chronic exposure, rather than intermittent intense exposure to ultraviolet (UV) radiation. Occupational exposure is the characteristic pattern of sun exposure linked with SCC.[3] A case-control study in southern Europe showed increased risk of SCC when lifetime sun exposure exceeded 70,000 hours. People whose lifetime sun exposure equaled or exceeded 200,000 hours had an odds ratio (OR) 8 to 9 times that of the reference group.[4] A Canadian case-control study did not find an association between cumulative lifetime sun exposure and SCC; however, sun exposure in the 10 years before diagnosis and occupational exposure were found to be risk factors.[5]

In addition to environmental radiation, exposure to therapeutic radiation is another risk factor for SCC. Individuals with skin disorders treated with psoralen and ultraviolet-A radiation (PUVA) had a threefold to sixfold increase in SCC.[6] This effect appears to be dose-dependent, as only 7% of individuals who underwent fewer than 200 treatments had SCC, compared with more than 50% of those who underwent more than 400 treatments.[7] Therapeutic use of ultraviolet-B (UVB) radiation has also been shown to cause a mild increase in SCC (adjusted incidence rate ratio, 1.37).[8] Devices such as tanning beds also emit UV radiation and have been associated with increased SCC risk, with a reported OR of 2.5 (95% confidence interval [CI], 1.73.8).[9]

Investigation into the effect of ionizing radiation on SCC carcinogenesis has yielded conflicting results. One population-based case-control study found that patients who had undergone therapeutic radiation had an increased risk of SCC at the site of previous radiation (OR, 2.94) as compared with individuals who had not undergone radiation treatments.[10] Cohort studies of radiology technicians, atomic-bomb survivors, and survivors of childhood cancers have not shown an increased risk of SCC, although the incidence of BCC was increased in all of these populations.[11-13] For those who develop SCC at previously radiated sites that are not sun-exposed, the latent period appears to be quite long; these cancers may be diagnosed years or even decades after the radiation exposure.[14]

The effect of other types of radiation, such as cosmic radiation, is also controversial. Pilots and flight attendants have a reported incidence of SCC that ranges between 2.1 and 9.9 times what would be expected; however, the overall cancer incidence is not consistently elevated. Some attribute the high rate of nonmelanoma skin cancers in airline flight personnel to cosmic radiation, while others suspect lifestyle factors.[15-20]

The influence of arsenic on the risk of nonmelanoma skin cancer is discussed in detail in the Other environmental factors section in the Basal Cell Carcinoma section of this summary. Like BCCs, SCCs appear to be associated with exposure to arsenic in drinking water and combustion products.[21,22] However, this association may hold true only for the highest levels of arsenic exposure. Individuals who had toenail concentrations of arsenic above the 97th percentile were found to have an approximately twofold increase in SCC risk.[23] For arsenic, the latency period can be lengthy; invasive SCC has been found to develop at an average of 20 years after exposure.[24]

Current or previous cigarette smoking has been associated with a 1.5-fold to 2-fold increase in SCC risk,[25-27] although one large study showed no change in risk.[28] Available evidence suggests that the effect of smoking on cancer risk seems to be greater for SCC than for BCC.

Additional reports have suggested weak associations between SCC and exposure to insecticides, herbicides, or fungicides.[29]

Like melanoma and BCC, SCC occurs more frequently in individuals with lighter skin than in those with darker skin.[3,30] However, SCC can also occur in individuals with darker skin. An Asian registry based in Singapore reported an increase in skin cancer in that geographic area, with an incidence rate of 8.9 per 100,000 person-years. Incidence of SCC, however, was shown to be on the decline.[30] SCC is the most common form of skin cancer in black individuals in the United States and in certain parts of Africa; the mortality rate for this disease is relatively high in these populations.[31,32] Epidemiologic characteristics of, and prevention strategies for, SCC in those individuals with darker skin remain areas of investigation.

Freckling of the skin and reaction of the skin to sun exposure have been identified as other risk factors for SCC.[33] Individuals with heavy freckling on the forearm were found to have a 14-fold increase in SCC risk if freckling was present in adulthood, and an almost threefold risk if freckling was present in childhood.[33,34] The degree of SCC risk corresponded to the amount of freckling. In this study, the inability of the skin to tan and its propensity to burn were also significantly associated with risk of SCC (OR of 2.9 for severe burn and 3.5 for no tan).

The presence of scars on the skin can also increase the risk of SCC, although the process of carcinogenesis in this setting may take years or even decades. SCCs arising in chronic wounds are referred to as Marjolins ulcers. The mean time for development of carcinoma in these wounds is estimated at 26 years.[35] One case report documents the occurrence of cancer in a wound that was incurred 59 years earlier.[36]

Immunosuppression also contributes to the formation of nonmelanoma skin cancers. Among solid-organ transplant recipients, the risk of SCC is 65 to 250 times higher, and the risk of BCC is 10 times higher than that observed in the general population, although the risks vary with transplant type.[37-40] Nonmelanoma skin cancers in high-risk patients (solid-organ transplant recipients and chronic lymphocytic leukemia patients) occur at a younger age, are more common and more aggressive, and have a higher risk of recurrence and metastatic spread than these cancers do in the general population.[41,42] Additionally, there is a high risk of second SCCs.[43,44] In one study, over 65% of kidney transplant recipients developed subsequent SCCs after their first diagnosis.[43] Among patients with an intact immune system, BCCs outnumber SCCs by a 4:1 ratio; in transplant patients, SCCs outnumber BCCs by a 2:1 ratio.

This increased risk has been linked to an interaction between the level of immunosuppression and UV radiation exposure. As the duration and dosage of immunosuppressive agents increase, so does the risk of cutaneous malignancy; this effect is reversed with decreasing the dosage of, or taking a break from, immunosuppressive agents. Heart transplant recipients, requiring the highest rates of immunosuppression, are at much higher risk of cutaneous malignancy than liver transplant recipients, in whom much lower levels of immunosuppression are needed to avoid rejection.[37,45,46] The risk appears to be highest in geographic areas with high UV exposure.[46] When comparing Australian and Dutch organ transplant populations, the Australian patients carried a fourfold increased risk of developing SCC and a fivefold increased risk of developing BCC.[47] This finding underlines the importance of rigorous sun avoidance, particularly among high-risk immunosuppressed individuals.

Certain immunosuppressive agents have been associated with increased risk of SCC. Kidney transplant patients who received cyclosporine in addition to azathioprine and prednisolone had a 2.8-fold increase in risk of SCC over those kidney transplant patients on azathioprine and prednisolone alone.[37] In cardiac transplant patients, increased incidence of SCC was seen in individuals who had received OKT3 (muromonab-CD3), a murine monoclonal antibody against the CD3 receptor.[48]

A personal history of BCC or SCC is strongly associated with subsequent SCC. A study from Ireland showed that individuals with a history of BCC had a 14% higher incidence of subsequent SCC; for men with a history of BCC, the subsequent SCC risk was 27% higher.[49] In the same report, individuals with melanoma were also 2.5 times more likely to report a subsequent SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these nonmelanoma skin cancers is the middle of the sixth decade of life.[26,50-54]

Although the literature is scant on this subject, a family history of SCC may increase the risk of SCC in first-degree relatives (FDRs). Review of the Swedish Family Center Database showed that individuals with at least one sibling or parent affected with SCC, in situ SCC (Bowen disease), or actinic keratosis had a twofold to threefold increased risk of invasive and in situ SCC relative to the general population.[55,56] Increased number of tumors in parents was associated with increased risk to the offspring. Of note, diagnosis of the proband at an earlier age was not consistently associated with a trend of increased incidence of SCC in the FDR, as would be expected in most hereditary syndromes because of germline mutations. Further analysis of the Swedish population-based data estimates genetic risk effects of 8% and familial shared-environmental effects of 18%.[57] Thus, shared environmental and behavioral factors likely account for some of the observed familial clustering of SCC.

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