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Posts Tagged ‘Melanoma’

Imaging-guided cancer treatment


Imaging-guided cancer treatment

Writer & reporter: Dror Nir, PhD

It is estimated that the medical imaging market will exceed $30 billion in 2014 (FierceMedicalImaging). To put this amount in perspective; the global pharmaceutical market size for the same year is expected to be ~$1 trillion (IMS) while the global health care spending as a percentage of Gross Domestic Product (GDP) will average 10.5% globally in 2014 (Deloitte); it will reach ~$3 trillion in the USA.

Recent technology-advances, mainly miniaturization and improvement in electronic-processing components is driving increased introduction of innovative medical-imaging devices into critical nodes of major-diseases’ management pathways. Consequently, in contrast to it’s very small contribution to global health costs, medical imaging bears outstanding potential to reduce the future growth in spending on major segments in this market mainly: Drugs development and regulation (e.g. companion diagnostics and imaging surrogate markers); Disease management (e.g. non-invasive diagnosis, guided treatment and non-invasive follow-ups); and Monitoring aging-population (e.g. Imaging-based domestic sensors).

In; The Role of Medical Imaging in Personalized Medicine I discussed in length the role medical imaging assumes in drugs development.  Integrating imaging into drug development processes, specifically at the early stages of drug discovery, as well as for monitoring drug delivery and the response of targeted processes to the therapy is a growing trend. A nice (and short) review highlighting the processes, opportunities, and challenges of medical imaging in new drug development is: Medical imaging in new drug clinical development.

The following is dedicated to the role of imaging in guiding treatment.

Precise treatment is a major pillar of modern medicine. An important aspect to enable accurate administration of treatment is complementing the accurate identification of the organ location that needs to be treated with a system and methods that ensure application of treatment only, or mainly to, that location. Imaging is off-course, a major component in such composite systems. Amongst the available solution, functional-imaging modalities are gaining traction. Specifically, molecular imaging (e.g. PET, MRS) allows the visual representation, characterization, and quantification of biological processes at the cellular and subcellular levels within intact living organisms. In oncology, it can be used to depict the abnormal molecules as well as the aberrant interactions of altered molecules on which cancers depend. Being able to detect such fundamental finger-prints of cancer is key to improved matching between drugs-based treatment and disease. Moreover, imaging-based quantified monitoring of changes in tumor metabolism and its microenvironment could provide real-time non-invasive tool to predict the evolution and progression of primary tumors, as well as the development of tumor metastases.

A recent review-paper: Image-guided interventional therapy for cancer with radiotherapeutic nanoparticles nicely illustrates the role of imaging in treatment guidance through a comprehensive discussion of; Image-guided radiotherapeutic using intravenous nanoparticles for the delivery of localized radiation to solid cancer tumors.

 Graphical abstract

 Abstract

One of the major limitations of current cancer therapy is the inability to deliver tumoricidal agents throughout the entire tumor mass using traditional intravenous administration. Nanoparticles carrying beta-emitting therapeutic radionuclides [DN: radioactive isotops that emits electrons as part of the decay process a list of β-emitting radionuclides used in radiotherapeutic nanoparticle preparation is given in table1 of this paper.) that are delivered using advanced image-guidance have significant potential to improve solid tumor therapy. The use of image-guidance in combination with nanoparticle carriers can improve the delivery of localized radiation to tumors. Nanoparticles labeled with certain beta-emitting radionuclides are intrinsically theranostic agents that can provide information regarding distribution and regional dosimetry within the tumor and the body. Image-guided thermal therapy results in increased uptake of intravenous nanoparticles within tumors, improving therapy. In addition, nanoparticles are ideal carriers for direct intratumoral infusion of beta-emitting radionuclides by convection enhanced delivery, permitting the delivery of localized therapeutic radiation without the requirement of the radionuclide exiting from the nanoparticle. With this approach, very high doses of radiation can be delivered to solid tumors while sparing normal organs. Recent technological developments in image-guidance, convection enhanced delivery and newly developed nanoparticles carrying beta-emitting radionuclides will be reviewed. Examples will be shown describing how this new approach has promise for the treatment of brain, head and neck, and other types of solid tumors.

The challenges this review discusses

  • intravenously administered drugs are inhibited in their intratumoral penetration by high interstitial pressures which prevent diffusion of drugs from the blood circulation into the tumor tissue [1–5].
  • relatively rapid clearance of intravenously administered drugs from the blood circulation by kidneys and liver.
  • drugs that do reach the solid tumor by diffusion are inhomogeneously distributed at the micro-scale – This cannot be overcome by simply administering larger systemic doses as toxicity to normal organs is generally the dose limiting factor.
  • even nanoparticulate drugs have poor penetration from the vascular compartment into the tumor and the nanoparticles that do penetrate are most often heterogeneously distributed

How imaging could mitigate the above mentioned challenges

  • The inclusion of an imaging probe during drug development can aid in determining the clearance kinetics and tissue distribution of the drug non-invasively. Such probe can also be used to determine the likelihood of the drug reaching the tumor and to what extent.

Note: Drugs that have increased accumulation within the targeted site are likely to be more effective as compared with others. In that respect, Nanoparticle-based drugs have an additional advantage over free drugs with their potential to be multifunctional carriers capable of carrying both therapeutic and diagnostic imaging probes (theranostic) in the same nanocarrier. These multifunctional nanoparticles can serve as theranostic agents and facilitate personalized treatment planning.

  • Imaging can also be used for localization of the tumor to improve the placement of a catheter or external device within tumors to cause cell death through thermal ablation or oxidative stress secondary to reactive oxygen species.

See the example of Vintfolide in The Role of Medical Imaging in Personalized Medicine

vinta

Note: Image guided thermal ablation methods include radiofrequency (RF) ablation, microwave ablation or high intensity focused ultrasound (HIFU). Photodynamic therapy methods using external light devices to activate photosensitizing agents can also be used to treat superficial tumors or deeper tumors when used with endoscopic catheters.

  • Quality control during and post treatment

For example: The use of high intensity focused ultrasound (HIFU) combined with nanoparticle therapeutics: HIFU is applied to improve drug delivery and to trigger drug release from nanoparticles. Gas-bubbles are playing the role of the drug’s nano-carrier. These are used both to increase the drug transport into the cell and as ultrasound-imaging contrast material. The ultrasound is also used for processes of drug-release and ablation.

 HIFU

Additional example; Multifunctional nanoparticles for tracking CED (convection enhanced delivery)  distribution within tumors: Nanoparticle that could serve as a carrier not only for the therapeutic radionuclides but simultaneously also for a therapeutic drug and 4 different types of imaging contrast agents including an MRI contrast agent, PET and SPECT nuclear diagnostic imaging agents and optical contrast agents as shown below. The ability to perform multiple types of imaging on the same nanoparticles will allow studies investigating the distribution and retention of nanoparticles initially in vivo using non-invasive imaging and later at the histological level using optical imaging.

 multi

Conclusions

Image-guided radiotherapeutic nanoparticles have significant potential for solid tumor cancer therapy. The current success of this therapy in animals is most likely due to the improved accumulation, retention and dispersion of nanoparticles within solid tumor following image-guided therapies as well as the micro-field of the β-particle which reduces the requirement of perfectly homogeneous tumor coverage. It is also possible that the intratumoral distribution of nanoparticles may benefit from their uptake by intratumoral macrophages although more research is required to determine the importance of this aspect of intratumoral radionuclide nanoparticle therapy. This new approach to cancer therapy is a fertile ground for many new technological developments as well as for new understandings in the basic biology of cancer therapy. The clinical success of this approach will depend on progress in many areas of interdisciplinary research including imaging technology, nanoparticle technology, computer and robot assisted image-guided application of therapies, radiation physics and oncology. Close collaboration of a wide variety of scientists and physicians including chemists, nanotechnologists, drug delivery experts, radiation physicists, robotics and software experts, toxicologists, surgeons, imaging physicians, and oncologists will best facilitate the implementation of this novel approach to the treatment of cancer in the clinical environment. Image-guided nanoparticle therapies including those with β-emission radionuclide nanoparticles have excellent promise to significantly impact clinical cancer therapy and advance the field of drug delivery.

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Identifying Melanoma by Scent

Author: Tilda Barliya PhD

 

Researchers from the Monell Chemical Center developed a nano-sensor constructed of nano-size carbon nanotubes coated with DNA that could identify melanoma cells by scent (1).

The smell of cancer_MIT Technology

Currently, early detection of skin carcinoma is accomplished primarily through a visual exam,imaging techniques and biopsy of any suspected areas (1).

The biopsy is invasive and usually requires examination by a pathologist,  and the use of reflectance confocal microscopy and dermoscopy in situ for diagnosis of primary melanoma and other skin diseases, require specialized training.  Additionally, proteomics of caner-related biomarkers has also emerged in recent years. The discovery of cancer-related biomarkers using proteomic techniques has primarily focused on prognostic indicators of melanoma, i.e., examining the serum and plasma proteome for biomarkers indicative of metastases to distant sites (2,3).

Volatile cue however, such as those use to detect lung cancer (I), diabetes, COPD etc, have not yet been exploit in detecting melanoma. Rather volatile chemicals are released from melanoma tissues that can be differentiated from those of normal skin, posed a very interestingscientific questions.

Electronic nose that can sniff out cancer

It was no surprising that Dogs can identify by olfaction,melanoma on the skin of patients or melanoma samples hidden on healthy subjects, suggesting that volatile organic compounds (VOCs) from melanoma differ from those of normal skin. (4, 5).

D‘Amico et al. [6] employed gas chromatography/mass spectrometry (GC–MS) and a gas sensor array to investigate whether skin lesions of melanoma and nevi can be differentiated. In his paper, D’Amico had very promising results in which electronic nose sensors have been shown to have good sensitivity (with 80% accuracy) towards volatile organic compounds emitted by skin lesions, and the method seems to be effective for malign lesions identification (6).

Other attempts have been carried out to identify more closely the different VOCs of melanoma lesions compared to normal skin, however, environmental contamination rather than compounds from skin metabolism have failed to yield good detection methodology.

Kwak J et al, created an electronic nose (e-nose)  device employing functionalized DNA-coated carbon nanotube sensors, capable of sensitive and selective detection of compounds emitted from skin (1). These “single walled carbon nanotube field effect transistors (CNT FET’s), functionalized with single stranded DNA (DNACNT), have been shown to respond through a change in source drain current when exposed to VOCs” (7).

“The sensors show rapid response and recovery (seconds), very low signal drift, and chemical responses that are single strand DNA (ss-DNA) base sequence dependent. Single stranded-DNA is chosen for functionalization of the CNTs because it displays recognition for chemical vapors”.

The authors employed SPME and GC–MS to identify the VOCs that differentiate between human melanoma and normal melanocyte cells cultured in vitro, which may provide a model for in vivo human melanomas.  Same analysis were later conducted using GC–MS and DNACNT. Analysis of different normal melanocytes and melanoma cancer cell lines revealed: the growth media for normal melanocytes and cancer cells differed from each other in relative abundance of several compounds:

  • 3-hydroxy-2-butanone (acetoin),
  • 1-hexanol,
  • acetophenone,
  • phenylethyl alcohol
  • phenol

They also noted that dimethylsulfone, which has been reported, in preliminary fashion, as a significant indicator of basal cell carcinoma, was seen in significantly greater amounts in metastatic melanoma cells vs. normal cells.

Summary

It is well known that cancer cells have altered metabolisms, which are expected to yield a different profile of metabolites.The authors presented here suggest significant differences in the “volatile metabolome” of melanoma cells vs. normal melanocytes.

The authors posit that successful development of rapid screening techniques incorporating new e-nose technologies, fitted with nanosensors with high selectivity for endogenous melanoma biomarkers, may effectively scan the complex volatile fingerprints acquired from suspicious lesions and quickly provide an evaluation for the physician, regardless of their geographic location”.

Smelling a disease has also been examined in bladder cancer (8), ovarian cancer (9) as well as Parkinson and Alzheimer disease (10) and it may potentially be used to enable easy, fast and accurate method to scenting a disease.

Ref:

1. Kwak J, Gallagher M, Ozdener MH, Wysocki CJ, Goldsmith BR, Isamah A, Faranda A, Fakharzadeh SS, Herlyn M, Johnson AT, Preti G. Volatile biomarkers from human melanoma cells. Journal of Chromatography B, 931 (2013) 90–96. http://www.ncbi.nlm.nih.gov/pubmed/23770738

2. S.A. Hoffman, W.A. Joo, L.A. Echan, D.W. Speicher, Higher dimensional (Hi-D) separation strategies dramatically improve the potential for cancer biomarker detection in serum and plasma.  J. Chromatogr. B: Analyt. Technol. Biomed. Life Sci. 849 (2007) 43. http://www.ncbi.nlm.nih.gov/pubmed/17140865

3.  J. Solassol, A. Du-Thanh, T. Maudelonde, B. Guillot,  Serum proteomic profiling reveals potential biomarkers for cutaneous malignant melanoma. Int. J. Biol. Markers 26 (2011) 82. http://www.ncbi.nlm.nih.gov/pubmed/21607923

4. H. Williams, A. Pembroke, SNIFFER DOGS IN THE MELANOMA CLINIC? Lancet 333 (1989) 734.  http://www.sciencedirect.com/science/article/pii/S0140673689922575
5. J. Church, H. Williams, Another sniffer dog for the clinic?  Lancet 358 (2001) 930.  http://www.sciencedirect.com/science/article/pii/S0140673601060652

6. D’Amico A, Bono R, Pennazza G, Santonico M, Mantini G, Bernabei M, Zarlenga M, Roscioni C, Martinelli E, Paolesse R, Di Natale C.  Identification of melanoma with a gas sensor array. Skin Res Technol. 2008 May;14(2):226-36.  http://www.ncbi.nlm.nih.gov/pubmed/18412567

7. C. Staii, A.T. Johnson Jr., M. Chen, A. Gelperin, DNA-Decorated Carbon Nanotubes for Chemical Sensing. Nano Lett. 5 (2005) 1774. http://pubs.acs.org/doi/abs/10.1021/nl051261f

8. Written By: Ian Anglin. SMELLING CANCER: DEVICE DETECTS BLADDER CANCER FROM ODOR OF URINE. http://singularityhub.com/2013/07/31/smelling-cancer-device-detects-bladder-cancer-from-odor-of-urine/

9. Horvath G, Chilo J, Lindblad T. Different volatile signals emitted by human ovarian carcinoma and healthy tissue.Future Oncol. 2010 Jun;6(6):1043-1049. http://www.ncbi.nlm.nih.gov/pubmed/?term=Volatile+biomarkers+from+ovarian+cacner

10. Ulrike Tisch, Ilana Schlesinger, Radu Ionescu, Maria Nassar, Noa Axelrod, Dorina Robertman, Yael Tessler, Faris Azar, Abraham Marmur, Judith Aharon-Peretz and Hossam Haick. Detection of Alzheimer’s and Parkinson’s disease from exhaled breath using nanomaterial-based sensors. Nanomedicine January 2013, Vol. 8, No. 1, Pages 43-56   http://www.futuremedicine.com/doi/abs/10.2217/nnm.12.105?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed&

Other open access article in Pharmaceutical Inteliigence

I. By: Tilda Barliya PhD. Diagnosing lung cancer in exhaled breath using gold nanoparticles.  https://pharmaceuticalintelligence.com/2012/12/01/diagnosing-lung-cancer-in-exhaled-breath-using-gold-nanoparticles/

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Reporter/Curator: Stephen J. Williams, Ph.D.

Picture of a human melanoma cell line growing in tissue culture

Cultured human melanocytes .

Nitric oxide (NO), a gas with many biological functions in healthy cells, has also been implicated in the development of pathologies such as cancer.  Nitric oxide may also play a role in chemotherapeutic reisitance. For example it had been known (in the 1996 Melanoma study by Joshi et al. curated below) that nitric oxide synthase activity (the enzyme system which produces NO) was significantly elevated in cultured melanoma cell lines versus normal melanocytes.   Although it is known that many protein and enzymes systems could be directly covalently-modified by nitric oxide, either by S-nitrosylation or NO-NAD+ modifications (one of my earlier postings described one such protein modified by nitric oxide, GAPDH, and the effect these NO-modifications of GAPDH has on the etiology of various pathologies.), the molecular mechanisms by which these modifications affect cellular processes, lead to disease etiology, the proteins which are affected, and mechanisms related to chemotherapeutic sensitivity need to be further characterized. A new study from MIT reveals how NO-induced modifications may reduce cisplatin sensitivity in melanoma cells.  This study focuses on how decreasing nitric oxide levels in melanoma cells increases their cisplatin sensitivity.  The study also describes a possible mechanism for this effect: NO-induced modifications of the proapoptotic enzyme caspace-3 and prolyl-hdroxylase-2 (responsible for targeting prosurvival HIF-1α for proteosomal degradation).  Also, for a description of other cancer-related targets of nitric oxide please see the posting by Dr. Saxena at Crucial role of Nitric Oxide in Cancer on this site.

To read more background on nitric oxide and its role in disease etiology please see our e-book Perspectives on Nitric Oxide in Disease Mechanisms (Biomed e-Books) available on Amazon at:

http://www.amazon.com/Perspectives-Nitric-Disease-Mechanisms-ebook/dp/B00DINFFYC

      It is important, however, to note that most of these relationships between NO-induced protein modification and its relationship to disease mechanisms are causal, meaning that, in general, one notices a nitric-induced modification of a protein/enzyme with concomitant alteration of protein/enzyme function occurring in a disease/phenotype.  However, unlike reversible modifications, which have a cadre of pharmacologic inhibitors, nitric oxide induced modifications are covalent and nonenzymatic, therefore hindering easy cause/effect relationships.

With that said, the following was adapted from the MIT site at http://web.mit.edu/newsoffice/2013/how-melanoma-evades-chemotherapy-0407.html.

  

 

The findings from Dr. Luiz Godoy’s PNAS paper ENDOGENOUSLY PRODUCED NITRIC OXIDE MITIGATES SENSITIVITY OF MELANOMA CELLS TO CISPLATIN,  were presented at the 2013 annual meeting of the American Association for Cancer Research. The prognosis is generally worse for patients whose tumors have high levels of NO, said Luiz Godoy, an MIT research associate and lead author of the study.

Godoy and his colleagues have unraveled the mechanism behind melanoma’s resistance to cisplatin, a commonly used chemotherapy drug, and, in ongoing studies, have found that cisplatin treatment also increases NO levels in breast and colon cancers.

“This could be a mechanism that is widely shared in different cancers, and if you use the drugs that are already used to treat cancer, along with other drugs that could scavenge or decrease the production of NO, you may have a synergistic effect,” said Godoy, who works in the lab of Gerald Wogan, an MIT professor emeritus of biological engineering and senior author of the study.

NO has many roles within living cells. At low concentrations, it helps regulate processes such as cell death and muscle contraction. NO, which is a free radical, is also important for immune-system function. Immune cells, such as macrophages, produce large amounts of NO during infection, helping to kill invading microbes by damaging their DNA or other cell components.

“It’s really a molecule that has a dual effect,” Godoy said. “At low concentrations it can act as a signaling molecule, while high concentrations will be toxic.”

Knocking out NO

In the new study, the researchers treated melanoma cells grown in the lab with drugs that capture NO before it can act. They then treated the cells with cisplatin and tracked cell-death rates. The NO-depleted cells became much more sensitive to the drug, confirming earlier findings.

The MIT team then went a step further, investigating how NO confers its survival benefits. It was already known that NO can alter protein function through a process known as S-nitrosation, which involves attaching NO to the target protein. S-nitrosation can affect many proteins, but in this study the researchers focused on two that are strongly linked with cell death and survival, known as caspase-3 and PHD2.

The role of caspase-3 is to stimulate cell suicide, under the appropriate conditions, but adding NO to the protein deactivates it. This prevents the cell from dying even when treated with cisplatin, a drug that produces massive DNA damage.

PHD2 is also involved in cell death; its role is to help break down another protein called HIF-1 alpha, which is a pro-survival protein. When NO inactivates PHD2, HIF-1 alpha stays intact and keeps the cell alive.

“Now we have a mechanistic link between nitric oxide and the increased aggressiveness of melanoma,” said Douglas Thomas, an assistant professor of medicinal chemistry and pharmacognosy at the University of Illinois at Chicago, who was not part of the research team. “It certainly would be worth exploring whether this mechanism is also present in different tumor types as well.”

The MIT researchers also found in some cancer cells, NO levels were five times higher than normal following cisplatin treatment. Godoy is now investigating how cisplatin stimulates that NO boost, and is also looking for other proteins that NO may be targeting.

Source: http://web.mit.edu/newsoffice/2013/how-melanoma-evades-chemotherapy-0407.html

Melanoma Res. 1996 Apr;6(2):121-6.

Nitric oxide synthase activity is up-regulated in melanoma cell lines: a potential mechanism for metastases formation.

Joshi M, Strandhoy J, White WL.

Source

Department of Dermatology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA.

Abstract

Nitric oxide (NO) may be an important mediator of tumour angiogenesis and metastasis formation. Tumour cell derived NO may be important in the regulation of angiogenesis and vasodilatation of the blood vessels surrounding a tumour. The aims of the present study were, firstly, to determine whether malignant melanoma cells and normal melanocytes had nitric oxide synthase (NOS) activity (measured by the conversion of L-arginine to L-citrulline) and, secondly, to determine whether there was a difference in NOS activity between malignant and normal cell types. This paper assays NOS activity directly in lysates from normal human melanocyte and malignant melanoma cell lines. The enzyme activity was not inducible with bacterial lipopolysaccharide and could be heat denatured. The activity of NOS was demonstrated to be both NADPH- and calcium-dependent and it was inhibitable in a dose-dependent manner by the NOS inhibitor Nw-nitro-L-arginine methyl ester. We conclude that melanoma and melanocyte cells express a constitutive form of NOS. Finally, nitric oxide synthase activity in melanoma cell lines was found to be significantly greater than in normal melanocytes. These findings suggest that NO synthesis is elevated in malignant melanoma. An elevated NO concentration in melanoma is expected to promote metastases by maintaining a vasodilator tone in the blood vessels in and around the melanoma.

Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20373-8. doi: 10.1073/pnas.1218938109. Epub 2012 Nov 26.

Endogenously produced nitric oxide mitigates sensitivity of melanoma cells to cisplatin.

Godoy LC, Anderson CT, Chowdhury R, Trudel LJ, Wogan GN.

Source

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Abstract

Melanoma patients experience inferior survival after biochemotherapy when their tumors contain numerous cells expressing the inducible isoform of NO synthase (iNOS) and elevated levels of nitrotyrosine, a product derived from NO. Although several lines of evidence suggest that NO promotes tumor growth and increases resistance to chemotherapy, it is unclear how it shapes these outcomes. Here we demonstrate that modulation of NO-mediated S-nitrosation of cellular proteins is strongly associated with the pattern of response to the anticancer agent cisplatin in human melanoma cells in vitro. Cells were shown to express iNOS constitutively, and to generate sustained nanomolar levels of NO intracellularly. Inhibition of NO synthesis or scavenging of NO enhanced cisplatin-induced apoptotic cell death. Additionally, pharmacologic agents disrupting S-nitrosation markedly increased cisplatin toxicity, whereas treatments favoring stabilization of S-nitrosothiols (SNOs) decreased its cytotoxic potency. Activity of the proapoptotic enzyme caspase-3 was higher in cells treated with a combination of cisplatin and chemicals that decreased NO/SNOs, whereas lower activity resulted from cisplatin combined with stabilization of SNOs. Constitutive protein S-nitrosation in cells was detected by analysis with biotin switch and reduction/chemiluminescence techniques. Moreover, intracellular NO concentration increased significantly in cells that survived cisplatin treatment, resulting in augmented S-nitrosation of caspase-3 and prolyl-hydroxylase-2, the enzyme responsible for targeting the prosurvival transcription factor hypoxia-inducible factor-1α for proteasomal degradation. Because activities of these enzymes are inhibited by S-nitrosation, our data thus indicate that modulation of intrinsic intracellular NO levels substantially affects cisplatin toxicity in melanoma cells. The underlying mechanisms may thus represent potential targets for adjuvant strategies to improve the efficacy of chemotherapy.

Other posts on this site regarding Nitric Oxide and Cancer include:

Crucial role of Nitric Oxide in Cancer

Nitric Oxide Covalent Modifications: A Putative Therapeutic Target?

Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function

Nitric Oxide Signalling Pathways

In focus: Melanoma therapeutics

Combined anti-CTLA4 and anti-PD1 immunotherapy shows promising results against advanced melanoma

Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease

In focus: Melanoma therapeutics

In focus: Melanoma Genetics

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Author: Tilda Barliya PhD

Photoacoustic Tomography (PAT), also called the optoacoustic or thermoacoustic (TA), is a materials analysis technique based on the reconstruction of an internal photoacoustic source distribution from measurements acquired by scanning ultrasound detectors over a surface that encloses the source under study. Moreover, it is non-ionizing and non-invasive, and is the fastest growing new biomedical method, with clinical applications on the way.

Dr. Lihong Wang, a Distinguished Professor of Biomedical Engineering in the School of Engineering and Applied Science at Washington University in St. Louis, summarizes the state of the art in photoacoustic imaging (1).

The photoacoustic (PA) effect:

The fundamental principle of the PA effect can be simply described: an object absorbs EM radiation energy, the absorbed energy converts into heat and the temperature of the object increases. As soon as the temperature increases, thermal expansion takes place, generating acoustic pressure in the medium. However, a steady thermal expansion (time invariant heating) does not generate acoustic waves; thus, the heating source is required to be time variant.

Dr. Wang explains that “the trick of photoacoustic tomography is to convert light absorbed at depth to sound waves, which scatter a thousand times less than light, for transmission back to the surface. The tissue to be imaged is irradiated by a nanosecond-pulsed laser at an optical wavelength”.

Absorption by light by molecules beneath the surface creates a thermally induced pressure jump that launches sound waves that are measured by ultrasound receivers at the surface and reassembled to create what is, in effect, a photograph.

When comparing to other modalities, PAT has several great advantages:

Table 1 Comparison of imaging modalities.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Dr. Wang is already working with physicians at the Washington University School of Medicine to move four applications of photoacoustic tomography into clinical trials (2).

  • One is to visualize the sentinel lymph nodes that are important in breast cancer staging;
  • A second to monitor early response to chemotherapy;
  • A third to image melanomas;
  • The fourth to image the gastrointestinal tract.

Sentinel node biopsy provides a good example of the improvement photoacoustic imaging promises over current imaging practice. Sentinel nodes are the nodes nearest a tumor, such as a breast tumor, to which cancerous cells would first migrate.

Currently, sentinel node biopsy, includes injection of  a radioactive substance, a dye or both near a tumor. The body treats both substances as foreign, so they flow to the first draining node to be filtered and flushed from the body. A gamma probe or a Geiger counter is used to locate the radioactive particles and the surgeon must cut open the area and follow the dye visually to the sentinel lymph node.

Dr. Wang however, offers a simpler method: injecting an optical dye that shows up so clearly in photoacoustic images that a hollow needle can be guided directly to the sentinel lymph node and a sample of tissue taken through the needle.

Contrast agents:

Most photoacoustic (PA) contrast agents are designed for absorbing laser, especially in the NIR spectral range. However, RF contrast agents are also desirable due to the superior penetration depth of RF in the body (1).  A typical example is indocyanine green (ICG), a dye approved by FDA. ICG has high absorption in the NIR spectral region, and it has already been proved to increase the PA signal when it is injected in blood vessels. Most recently, methyline blue was used as the contrast agent to detect the sentinel lymph node (SLN) (4).

Compared with dyes, nanoparticles possess a high and tunable absorption spectrum, and longer circulation time (1). The absorption peak is tunable by changing the shape and size of the particle. In addition, nanoparticles can be used to target certain diseases by bio-conjugating them with proteins, such as antibodies.  Among different nanoparticles, gold nanoparticles are favored in optical imaging due to their exceptional optical properties in the visible and NIR spectral ranges, including scattering, absorption and photoluminescence. So far, none of the gold nanoparticles have been approved by FDA (1).

One exciting aspect of photoacoustic tomography is that images contain functional as well as structural information because color reflects the chemical composition and chemistry determines function. Photoacoustic tomography, for example, can detect the oxygen saturation of hemoglobin, which is bright red when it is carrying oxygen and turns darker red when it releases it (3), that is important, since almost all diseases, especially cancer and diabetes, cause abnormal oxygen metabolism.  For example see image 1.

Image courtesy of Junjie Yao/Lihong Wang

Image 1: melanoma tumor (MT) cells were injected into a mouse ear on day 1. By day 7, there were noticeable changes in the blood flow rate (top graph, right) and the metabolic rate of oxygen usage (bottom graph, right). Counterintuitively, the tumor did not increase the oxygen extraction fraction (middle graph). The colors correspond to depth, with blue being superficial and red deep (3).

Wang’s team demonstrated that oxygen metabolism betrayed the presence of a melanoma within few days of injections in animal models, where as Oxygen use doubled in a week.

In this aspect: photoacoustic images,  can offer several parameters such as;

  • Vessel cross-section,
  • Concentration of hemoglobin and blood flow speed,
  • and The gradient of oxygen saturation can be used to calculate the oxygen use by a region of tissue.

Analysis of oxygen use is not necessarily new and is frequently measured by positron emission tomography (PET), which requires the injection or inhalation of a radioactively labeled tracer and undesirable radiation exposure.

Photoacoustic Tomography is currently being investigated for (5):

  1. Breast cancer (microvascular).  Additionally, for further information on photoacoustic tomography please read the article by Dr. Venkat Karra (I).
  2. Skin cancer (melanin)
  3. Brain tumors
  4. Cardiac disease – myocardial infraction (6)
  5. Ophthalmology – retinal disease (7)
  6. Ostheoarthrities (8)

Summary

photoacoustic tomography perfectly complements other biomedical imaging modalities by providing unique optical absorption contrast with highly scalable spatial resolution, penetration depth, and imaging speed. In light of its capabilities and flexibilities, PAT is expected to play a more essential role in biomedical studies and clinical practice.

Reference:

1.  Changhui Li and Lihong V Wang. Photoacoustic tomography and sensing in biomedicine. Phys. Med. Biol. 2009 54 R59 doi:10.1088/0031-9155/54/19/R01  http://iopscience.iop.org/0031-9155/54/19/R01 http://iopscience.iop.org/0031-9155/54/19/R01/pdf/0031-9155_54_19_R01.pdf

2. Jiecheny Yin. Photoacoustic tomography in cancer detection. http://bme240.eng.uci.edu/students/08s/jiecheny/index.htm

3. Jim Goodwin. NEW IMAGING TECHNIQUE COULD SPEED CANCER DETECTION. http://www.siteman.wustl.edu/ContentPage.aspx?id=5788

4.  Song K H, Stein E W, Margenthaler J A and Wang L V. Noninvasive photoacoustic identification of sentinel lymph nodes containing methylene blue in vivo in a rat model J. Biomed. Opt. 2008: 13 054033–6.  http://oilab.seas.wustl.edu/epub/SongK_2008_J_Biomed_Opt_13_054033.pdf

5. Junjie Yao and Lihong V Wang.  Photoacoustic tomography: fundamentals, advances and prospects. Contrast Media Mol Imaging. 2011 September; 6(5): 332–345. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205414/

6. Holotta M, Grossauer HKremser CTorbica PVölkl JDegenhart GEsterhammer RNuster RPaltauf GJaschke W. Photoacoustic tomography of ex vivo mouse hearts with myocardial infarction. J. Biomed Opt. 2011 Mar;16(3):036007. doi: 10.1117/1.3556720. http://www.ncbi.nlm.nih.gov/pubmed/21456870

7. Hao F. ZhangCarmen A. Puliafito, and Shuliang Jiao, Photoacoustic Ophthalmoscopy for In Vivo Retinal Imaging: Current Status and Prospects.  Ophthalmic Surg Lasers Imaging. 2011 July; 42(0): S106–S115.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291958/

8. Yao Sun, Eric S. Sobel, and Huabei Jiang. First assessment of three-dimensional quantitative photoacoustic tomography for in vivo detection of osteoarthritis in the finger joints.  Med. Phys. 38, 4009 (2011); http://dx.doi.org/10.1118/1.3598113 . http://online.medphys.org/resource/1/mphya6/v38/i7/p4009_s1?isAuthorized=no

Other articles from our Open Access Journal:

I. By : Venkat Karra. Visualizing breast cancer without X-rays. https://pharmaceuticalintelligence.com/2012/05/08/visualizing-breast-cancer-without-x-rays/

II. By: Dr. Dror Nir. Ultrasound in Radiology – Results of a European Survey. https://pharmaceuticalintelligence.com/2013/07/21/ultrasound-in-radiology-results-of-a-european-survey/

III.  By: Dr. Dror Nir. Causes and imaging features of false positives and false negatives on 18F-PET/CT in oncologic imaging. https://pharmaceuticalintelligence.com/2013/05/18/causes-and-imaging-features-of-false-positives-and-false-negatives-on-18f-petct-in-oncologic-imaging/

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Reporter: Ziv Raviv, PhD

FDA Approves BioMerieux’s BRAF Test as CDx, www.genomeweb.com

The FDA has very recently (May 29, 2013) approved two new drugs to treat unresectable and metastatic melanoma. Both drugs are inhibitors of B-Raf which is frequently mutated in melanoma (1). The new drugs are products of GlaxoSmithKline (GSK): Dabrafenib (marked as Tafinlar), a B-Raf inhibitor aimed to treat melanoma patients harboring V600E mutation (2), and Trametinib (marked as Mekinist), a MEK inhibitor that was shown in phase III clinical trials to be efficient for treating melanoma patients with BRAF V600E or V600K mutations (3). Both drugs are given orally and approved as single agents. About 75,000 new cases of melanoma are being diagnosed in the US and above 9,000 people die from the disease, each year. Until recently metastatic melanoma was considered an incurable disease with very poor prognosis and limited survival rates. These new two drugs are now joining the first two drugs approved in 2011 to treat metastatic melanoma that are already in clinical use – vemurafenib (Zelboraf) which is also a B-Raf inhibitor (4), and ipilimumab (Yervoy). The introduction of the two drugs was co-approved in concert with the THxID BRAF test from BioMérieux. This PCR-based BRAF test is designed to determine whether a melanoma patient harbors the V600E or V600K BRAF gene mutation and will assist directing the correct treatment to be given to patients. This BRAF mutation test is the second companion diagnostic approved for BRAF mutation detection following the approval of Roche’s cobas 4800 BRAF V600 Mutation Test in August 2011. Overall, the association of diagnostics with treatments as approved in this case is another step further in the ongoing efforts invested by pharmaceutical and diagnostic companies toward establishing personalized medicine to treat cancer patients.

Resources:

FDA press release

GenomeWeb report

References

  1. Mutations of the BRAF gene in human cancer. Davies H et al. Nature. 2002 Jun 27;417(6892):949-54.
  2. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomized controlled trial. Hauschild A et al. Lancet. 2012 Jul 28;380(9839):358-65.
  3. Improved survival with MEK inhibition in BRAF-mutated melanoma. Flaherty KT et al. N Engl J Med. 2012 Jul 12;367(2):107-14
  4. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. Chapman PB et al. N Engl J Med. 2011 Jun 30;364(26):2507-16

Related articles on this Open Access Online Scientific Journal

  1. Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease. Author: Ziv Raviv PhD
  2. In focus: Melanoma Genetics. Curator: Ritu Saxena, PhD
  3. In focus: Melanoma therapeutics. Author and Curator: Ritu Saxena, PhD

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Reporter: Aviva Lev-Ari, PhD, RN

 

 

Risk of a Second Primary Cancer after Non-melanoma Skin Cancer in White Men and Women: A Prospective Cohort Study

  • Fengju Song,
  • Abrar A. Qureshi,
  • Edward L. Giovannucci,
  • Charlie S. Fuchs,
  • Wendy Y. Chen,
  • Meir J. Stampfer,
  • Jiali Han mail
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Abstract

Background

Previous studies suggest a positive association between history of non-melanoma skin cancer (NMSC) and risk of subsequent cancer at other sites. The purpose of this study is to prospectively examine the risk of primary cancer according to personal history of NMSC.

Methods and Findings

In two large US cohorts, the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS), we prospectively investigated this association in self-identified white men and women. In the HPFS, we followed 46,237 men from June 1986 to June 2008 (833,496 person-years). In the NHS, we followed 107,339 women from June 1984 to June 2008 (2,116,178 person-years). We documented 29,447 incident cancer cases other than NMSC. Cox proportional hazard models were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). A personal history of NMSC was significantly associated with a higher risk of other primary cancers excluding melanoma in men (RR = 1.11; 95% CI 1.05–1.18), and in women (RR = 1.20; 95% CI 1.15–1.25). Age-standardized absolute risk (AR) was 176 in men and 182 in women per 100,000 person-years. For individual cancer sites, after the Bonferroni correction for multiple comparisons (n = 28), in men, a personal history of NMSC was significantly associated with an increased risk of melanoma (RR = 1.99, AR = 116 per 100,000 person-years). In women, a personal history of NMSC was significantly associated with an increased risk of breast (RR = 1.19, AR = 87 per 100,000 person-years), lung (RR = 1.32, AR = 22 per 100,000 person-years), and melanoma (RR = 2.58, AR = 79 per 100,000 person-years).

Conclusion

This prospective study found a modestly increased risk of subsequent malignancies among individuals with a history of NMSC, specifically breast and lung cancer in women and melanoma in both men and women.

Please see later in the article for the Editors’ Summary

Editors’ Summary

Background

In the United Kingdom and the United States, about one in three people develop cancer during their lifetime and, worldwide, cancer is responsible for 13% of all deaths. Primary cancer, which can develop anywhere in the body, occurs when a cell begins to divide uncontrollably because of alterations (mutations) in its genes. Additional mutations allow the malignancy to spread around the body (metastasize) and form secondary cancers. The mutations that initiate cancer can be triggered by exposure to carcinogens such as cigarette smoke (lung cancer) or the ultraviolet (UV) radiation in sunlight (skin cancers). Other risk factors for the development of cancer include an unhealthy diet, physical inactivity, and alcohol use. In the United States, the most common cancer is non-melanoma skin cancer (NMSC). Although more than 2 million new cases of NMSC occur each year, fewer than 1,000 people die annually in the United States from the condition because the two types of NMSC—basal cell carcinoma and squamous cell carcinoma—rarely metastasize and can usually be treated by surgically removing the tumor.

Why Was This Study Done?

Some studies have suggested that people who have had NMSC have a higher risk of developing primary cancer at other sites than people who have not had NMSC. Such a situation could arise if exposure to certain carcinogens initiates both NMSC and other cancers or if NMSC shares a molecular mechanism with other cancers such as a deficiency in the DNA repair mechanisms that normally remove mutations. If people with a history of NMSC are at a greater risk of developing further cancers, a specific surveillance program for such people might help to catch subsequent cancers early when they can be successfully treated. In this prospective cohort study, the researchers examine the risk of primary cancer according to personal history of NMSC in two large US cohorts (groups)—the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS). The HPFS, which enrolled 51,529 male health professionals in 1986, and the NHS, which enrolled 121,700 female nurses in 1976, were both designed to investigate associations between nutritional factors and the incidence of serious illnesses. Study participants completed a baseline questionnaire about their lifestyle, diet and medical history. This information is updated biennially through follow-up questionnaires.

What Did the Researchers Do and Find?

The researchers identified 36,102 new cases of NMSC and 29,447 new cases of other primary cancers from 1984 in white NHS participants and from 1986 in white HPFS participants through 2008. They then used statistical models to investigate whether a personal history of NMSC was associated with a higher risk of subsequent primary cancers after accounting for other factors (confounders) that might affect cancer risk. A history of NMSC was significantly associated with an 11% higher risk of other primary cancers excluding melanoma (another type of skin cancer that, like NMSC, is linked to overexposure to UV light) in men and a 20% higher risk of other primary cancers excluding melanoma in women; a significant association is one that is unlikely to have happened by chance. The absolute risk of a primary cancer among men and women with a history of NMSC was 176 and 182 per 100,000 person-years, respectively. For individual cancer sites, after correction for multiple comparisons (when several conditions are compared in groups of people, statistically significant differences between the groups can occur by chance), a history of NMSC was significantly associated with an increased risk of breast and lung cancer in women and of melanoma in men and women.

What Do These Findings Mean?

These findings suggest that there is a modestly increased risk of subsequent malignancies among white individuals with a history of NMSC. Although the researchers adjusted for many confounding lifestyle factors, the observed association between NMSC and subsequent primary cancers may nevertheless be the result of residual confounding, so it is still difficult to be sure that there is a real biological association (due to, for example, a deficiency in DNA repair) between NMSC and subsequent primary cancers. Because of this and other study limitations, the findings reported here should be interpreted cautiously and do not suggest that individuals who have had NMSC should undergo increased cancer surveillance. These findings do, however, support the need for continued investigation of the apparent relationship between NMSC and subsequent cancers.

Additional Information

Please access these Web sites via the online version of this summary athttp://dx.doi.org/10.1371/journal.pmed.1​001433.

Citation: Song F, Qureshi AA, Giovannucci EL, Fuchs CS, Chen WY, et al. (2013) Risk of a Second Primary Cancer after Non-melanoma Skin Cancer in White Men and Women: A Prospective Cohort Study. PLoS Med 10(4): e1001433. doi:10.1371/journal.pmed.1001433

Academic Editor: Eduardo L. Franco, McGill University, Canada

 

Received: September 11, 2012; Accepted: March 15, 2013; Published: April 23, 2013

Copyright: © 2013 Song et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by US NIH CA87969 and CA055075. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: AQ declares the following: Pfizer – Questionnaire licensed for clinical trials; research grant. Merck – Questionnaire licensed for clinical trials. Amgen – Research grant. Abbott – Consulting. US Centers for Disease Control – Consulting. Janssen – Consulting. Novartis – Consulting. All other authors have declared that no competing interests exist.

Abbreviations: AR, absolute risk; BCC, basal cell carcinoma; BMI, body mass index; HPFS, Health Professionals Follow-up Study; MV, multivariate; NER, nucleotide excision repair; NHS, Nurses’ Health Study; NMSC, non-melanoma skin cancer; RR, relative risk; SCC, squamous cell carcinoma; UV, ultraviolet

Introduction

Non-melanoma skin cancer (NMSC) is the most common cancer in the United States. It consists mainly of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Its incidence has been rapidly increasing over the past several decades and the incidence rate was about 6,000/100,000 in the year 2006 [1]. NMSC has a low mortality rate of 1/100,000 [2], but its high prevalence and the expense of related treatment make NMSC a major public health problem and place it among the costliest cancers in the United States [3]. Individuals with personal history of NMSC may be at an altered risk for developing other primary cancers[4][11]. One view is that sunlight causes NMSC but also produces vitamin D, which in turn may reduce the risk of other cancers [12]. Another view is that NMSC and other cancers may share common carcinogenic exposures or molecular mechanisms in their etiology, such as DNA repair deficiency and immune suppression, and thus the history of NMSC may indicate an increased risk of subsequent cancer development.

Previous studies suggest a positive association between personal history of NMSC and risk of subsequent cancer at other sites [4][11]. Most previous reports, however, were based on cancer registry data without adjustment for potential confounding lifestyle factors [4][10]. The only cohort study was limited by its sample size and lacked adequate power to assess individual cancer sites [11]. We carried out a cohort analysis to evaluate the association between personal history of NMSC and subsequent malignancy in the Nurses’ Health Study (NHS) and the Health Professionals’ Follow-up Study (HPFS).

Methods

Ethics Statement

Our study was approved by the Human Research Committee at the Brigham and Women’s Hospital with written informed consent from all participants.

Study Population

The NHS was established in 1976, when 121,700 registered nurses aged 30–55 y in 11 US states responded to a baseline questionnaire regarding risk factors for cancer. Participants completed self-administered, mailed follow-up questionnaires biennially with updated information on their lifestyle, diet, and medical history. The HPFS began in 1986 when 51,529 US male health professionals, including dentists, veterinarians, pharmacists, and optometrists aged 40–75 y, completed a baseline questionnaire on lifestyle, diet, and newly diagnosed diseases. The information was updated biennially with follow-up questionnaires. The follow-up rates of the participants in both cohorts exceed 90%. These studies were approved by the Human Research Committee at Brigham and Women’s Hospital. Race was self-identified in this study as White, Asian, African American, and others. Only white participants were included in this study, accounting for 95.6% of the total population in the two cohorts. The rationale for focusing the primary hypothesis on white participants only was that the patterns of incidence (and likely the risk factors) for NMSC differ widely by race.

Identification of NMSC and Other Primary Cancers

We have routinely identified cases of NMSC and other primary cancers in both cohorts (from 1984 in the NHS and from 1986 in the HPFS). Participants reported new diagnoses biennially. With their permission, participants’ medical records were obtained and reviewed by physicians to confirm their self-reported diagnosis. Medical records were not obtained for self-reported cases of BCC, because the validity of BCC self-reports was more than 90% in validation studies in our cohorts in early years [13],[14]. The personal history of pathologically confirmed invasive SCC and self-reported BCC was the exposure in this analysis. The study outcome was the occurrence of the first confirmed primary cancer other than NMSC. All other cancer cases were documented by medical records or death certificates, and only confirmed cases were included in the analysis.

Assessment of Covariates

Covariates in this analysis included age (continuous variable), body mass index (BMI) (<21, 21–23, 23–25, 25–27, 27–29, 29–31, >31), physical activity (quintiles), smoking status (never, past 1–14 cigarettes per day, past 15+ cigarettes per day, current 1–14 cigarettes per day, current 15+ cigarettes per day), multi-vitamin use (yes or no), menopause status and hormone replacement therapy use in women (pre-menopause, post-menopause non-user, post-menopause past user, and post-menopause current user), and physical examination in the last 2 y (yes or no). We asked about the location of residence (US states) at birth and at age of 15 and 30. The 50 states (and the District of Columbia) were divided into three ultraviolet (UV) index groups: 5 or less (low UV index); 6 (medium UV index); and 7 or more (high UV index)[15]. We defined participants in these three groups if they resided in the same UV-index region at birth, age of 15 and 30.

Statistical Analysis

Follow-up began in 1984 for the NHS and 1986 for the HPFS when the diagnosis of NMSC was first routinely collected, and follow-up ended in 2008 for both cohorts. Participants who reported a history of cancer (including NMSC) prior to baseline were excluded. Participants contributed person-time from the date of return of the baseline questionnaire (1984 in NHS and 1986 in HPFS) until date of diagnosis of confirmed primary cancer, date of death, or the end of follow-up (May 31, 2008), whichever came first. For those who were lost to follow-up, we censored them at the return date of the last questionnaire. Cox regression analysis with time-dependent covariates was used to determine the relative risks (RRs) and 95% CIs of second primary malignancies associated with a previous NMSC diagnosis. We calculated age-standardized absolute risks (ARs) of second primary malignancies associated with a previous NMSC diagnosis. NMSC diagnosis could change during the follow-up period. For individuals with no personal history of cancer at baseline who went on to be diagnosed with NMSC as a first cancer diagnosis during follow-up, the follow-up period before the NMSC diagnosis contributed person-time to the non-exposure group, and the follow-up period after the NMSC diagnosis contributed person-time to the exposure group. Age was coded as a continuous variable in all the analyses. We showed overall cancer risk with and without melanoma. We performed several secondary analyses. We excluded those diagnosed with other primary cancers within the first 4 y of NMSC diagnosis to minimize the detection bias. We examined BCC and SCC history separately. We performed stratified analysis according to age (≤60 y, >60 y), UV-index of residence at birth, age 15, and age 30 (≤5, = 6, ≥7), smoking status (never smoker, past smoker, current smoker), and BMI (<25, 25–30, ≥30). We coded these factors as dummy variables and tested their interactions with the history of NMSC individually. We tested multiplicative interaction terms by the likelihood ratio test comparing the model with the cross-product terms with the model containing just the main effects of these factors and the history of NMSC along with the same covariates.

We assessed the association between NMSC diagnosis and risk of developing site-specific cancers that were diagnosed in more than 100 patients in each cohort. For individual cancer sites, the Cox models additionally included risk factors specific for some cancer sites. We included additional covariates in the multivariate models for breast, ovarian, endometrial, prostate cancers, and melanoma. The Bonferroni correction for p-value was applied for multiple comparisons for individual cancer sites among men and women, calculated as 0.05/n (n = 28). Statistical analyses were conducted using SAS software (version 9, SAS Institute). All statistical tests were two-sided.

Results

Characteristics of our study population according to a personal history of NMSC in mid-point of the follow-up (1998) are shown in Table 1. Participants with a history of NMSC were more likely to be older and tended to burn and have more severe sunburns. Participants with history of NMSC diagnosis were more likely to have red or blonde hair and to reside in high UV-index states. Other characteristics were similar between the exposure group and the non-exposure group.

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Table 1. Characteristics according to personal history of non-melanoma skin cancer in 1998.

doi:10.1371/journal.pmed.1001433.t001

We followed the HPFS participants from 1986 to 2008, for a total of 833,496 person-years. During this period, 1,577 cases of SCC, 10,422 cases of BCC, and 10,590 primary cancer cases other than NMSC were recorded. The mean time for the development of a primary cancer after NMSC was 116±47 mo. We followed the NHS from 1984 to 2008 (2,116,178 person-years) during which 2,322 cases of SCC, 21,781 cases of BCC, and 18,857 primary cancer cases other than NMSC were recorded. The mean time for the development of a primary cancer after NMSC was 156±71 mo.

A personal history of NMSC was associated with a higher risk of other primary cancers in men (RR = 1.15; 95% CI 1.09–1.22, p<0.0001) and women (RR = 1.26; 95% CI 1.21–1.31,p<0.0001) (Table 2). The association attenuated slightly when melanoma was excluded from the outcome in the analysis, but remained significant in men (RR = 1.11; 95% CI 1.05–1.18, p= 0.0007) and in women (RR = 1.20; 95% CI 1.15–1.25, p<0.0001). Age-standardized AR was 176 in men and 182 in women per 100,000 person-years. The association remained significant after we excluded those diagnosed with other primary cancers within the first 4 y of NMSC diagnosis in men (RR = 1.15; 95% CI 1.05–1.25) and women (RR = 1.19; 95% CI 1.11–1.28). In men, the association was significant according to BCC diagnosis (RR = 1.17; 95% CI 1.10–1.24) but not SCC diagnosis (RR = 1.01; 95% CI 0.87–1.17). In women, the association was significant for both BCC (RR = 1.25; 95% CI 1.20–1.30) and SCC diagnosis (RR = 1.24; 95% CI 1.10–1.39). We compared people with personal history of SCC with people with personal history of BCC on their risk of developing subsequent cancer, and no significant differences were found (Table S1). In addition, we have compared SCC in situ group with invasive SCC group and the group of SCC or BCC; the results are shown in Table S2. Compared to those with history of invasive SCC or those with history of SCC or BCC, individuals with history of SCC in situ were less likely to develop subsequent cancers. Such risk reduction was significant among women.

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Table 2. Overall and stratified analysis of risks of total subsequent primary cancers according to personal history of non-melanoma skin cancer in men and women.

doi:10.1371/journal.pmed.1001433.t002

No substantial differences were found in the stratified analysis according to age, UV-index, or BMI. When stratified by smoking status, significant associations were found in never-smokers (RR = 1.19; 95% CI 1.08–1.31 in men, and RR = 1.28; 95% CI 1.20–1.38 in women) and past smokers (RR = 1.12; 95% CI 1.03–1.22 in men, and RR = 1.27; 95% CI 1.20–1.35 in women), but not in current smokers (RR = 1.05; 95% CI 0.75–1.46 in men, and RR = 1.10; 95% CI 0.97–1.23 in women). The p-value for interaction was 0.046 for men and women combined.

For individual cancer sites (Table 3), a history of NMSC was associated with an increased risk of prostate cancer in men (RR = 1.11; 95% CI 1.02–1.20, p = 0.01). The age-standardized AR was 137 per 100,000 person-years. The RR was similar for fatal prostate cancer (RR = 1.17; 95% CI 0.89–1.53). A history of NMSC was also associated with an increased risk of melanoma in men (RR = 1.99; 95% CI 1.63–2.43, p<0.0001). The age-standardized AR was 116 per 100,000 person-years. In women, a history of NMSC was associated with an increased risk of breast cancer (RR = 1.19; 95% CI 1.11–1.28, p<0.0001; AR = 87 per 100,000 person-years), lung cancer (RR = 1.32; 95% CI 1.14–1.52, p = 0.0002; AR = 22 per 100,000 person-years), leukemia (RR = 1.30; 95% CI 1.00–1.69, p = 0.05; AR = 7 per 100,000 person-years), kidney cancer (RR = 1.48; 95% CI 1.10–1.99, p = 0.01; AR = 8 per 100,000 person-years), and melanoma (RR = 2.58; 95% CI 2.34 –2.98, p<0.0001; AR = 79 per 100,000 person-years). After taking into account the multiple comparisons for individual cancers (n = 28), the associations with breast cancer, lung cancer in women, and melanoma in both men and women remained significant. We analyzed SCC and BCC history separately for individual cancer sites. We observed different rates for second cancer development according to personal history of SCC and BCC. However, no statistically significant heterogeneity (p for heterogeneity ranged from 0.16 to 0.88) was found for any cancer site between BCC and SCC due to the limited power (Table S3).

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Table 3. Risks of subsequent primary cancers at different sites according to personal history of non-melanoma skin cancer in men and women.

doi:10.1371/journal.pmed.1001433.t003

Discussion

To the best of our knowledge, this is the largest prospective study on this topic. In this study, a total of 36,102 cases of NMSC and 29,447 cases of cancers other than NMSC were documented. Among those with a personal history of NMSC, we found a 15% increased risk in men and a 26% increased risk in women of developing a second primary cancer, compared with those who had no such history. A systematic review summarizing previous studies revealed that NMSC is associated with more than 10% increased risk of subsequent primary cancer in registry-based studies and nearly 50% increased risk in cohort studies [16]. Our study has extended previous findings by adding a prospective analysis in two large US cohorts with more than two decades of follow-up. The unique aspects of our study included stratified analyses by other risk factors, disentanglement of surveillance bias, and comprehensive adjustment for potential confounders.

It was speculated that the association between NMSC and subsequent cancer risk may be different among people living in locations with different UV-indexes. Specifically, southern regions have solar UV-B radiation levels that provide sufficient vitamin D to reduce the risk of cancer incidence, and thus inverse associations were more likely to be found. On the contrary, studies that found positive associations were mostly conducted in northern regions where UV-B radiation levels do not provide sufficient vitamin D [17],[18]. In our analysis stratified by UV-index, no substantial differences were found for the associations between NMSC and cancer risk among locations with different UV-indexes. To the extent that some cancers have been suggested to be reduced with higher vitamin D [19], it might be worth noting the fact that while colorectal cancer was not increased in this study, it was not decreased as would be expected if NMSC were a marker for sunlight and thus vitamin D exposure.

Intensified medical surveillance of persons with a history of NMSC is unlikely to explain the increased cancer incidence observed in our study. In our analysis, we adjusted for physical examination in the last 2 y, and the result changed little. After we excluded those diagnosed with other primary cancers within the first 4 y of NMSC diagnosis, the association remained significant. Compared to those with history of invasive SCC or with history of SCC or BCC, individuals with history of SCC in situ were less likely to develop subsequent cancers. These results suggested that the patients who carried NMSC precursors but did not develop skin cancers might be either less genetically susceptible or have lower exposure. In addition, for prostate cancer, the association remained significant for fatal prostate cancer. Furthermore, several cancers that we observed associations with are not ones that would be detected on routine screening. Moreover, at least one study that assessed deaths rather than cancer incidence also found increased cancer mortality in people with history of NMSC [20].

Several studies have observed an increased risk of NMSC after other cancers. In one study, chronic lymphocytic leukemia patients had an increased risk of death due to NMSC (RR = 17.0, 95% CI 14.4–19.8) [21]. In another study, among 14 different sites for first primary malignancies, 11 of these sites including prostate, breast, and leukemia were followed by an increased risk of skin cancer (for SCC, RR of 14.1 for males and 14.6 for females) [22]. However, while treatment of these primary cancers may predispose to subsequent skin cancers, most of the NMSC cases are cured by surgical excision without any systemic chemotherapy, and radiation, and their concomitant side effects, including possible carcinogenicity. In addition, the similarity between the age-adjusted and multivariate-adjusted RRs demonstrated that the observed association between NMSC and subsequent cancers is unlikely to be explained by confounding from smoking, obesity, vitamin use, exercise, or any of the other measured risk factors that we controlled for.

The link between NMSC and risk of other cancers is likely to represent an etiologic association. For melanoma especially, the link may be due to sun exposure. For other cancers, while there are several explanations [23][28] of the association between NMSC and the risk of subsequent cancer, studies have found that certain genetic markers underlying skin cancer are also associated with other cancer types [29]. It is biologically plausible that deficiencies of pathways responsible for protecting against cellular transformation in multiple tissues, such as DNA repair or immune responses, may act systemically and play a role in cutaneous and internal carcinogenesis.

Humans have evolved several DNA repair pathways dealing with damage [30]. The nucleotide excision repair (NER) pathway is responsible for the repair of a wide variety of DNA damage that leads to distortion of the DNA helix. Such bulky DNA adducts include UV-induced photoproducts, smoking-related benzo(a)pyrene diolepoxide (BPDE)-DNA adducts, and other DNA damage induced by chemical carcinogens. Reduced capacity of the NER has been shown to confer susceptibility to certain cancers in the general population, including melanoma, BCC, SCC, SCC of head and neck, lung cancer, breast cancer, and bladder cancer[31][34]. Personal history of NMSC may be a marker of susceptibility due to reduced DNA repair capacity and it may predict the risk of subsequent cancer development.

The NER activity has been shown to be tissue-specific. For example, relatively low NER efficiency was observed in oral tissues [35]. Both rapidly proliferating tissues (e.g., kidney) and slowly proliferating tissues (e.g., lung) exhibit higher demand for NER capacity upon stimulation to proliferation [36]. The DNA repair system consists of several distinct pathways with many subcomponents, each interacting and overlapping with one another in order to achieve genomic stability and high fidelity. Some tissues, such as breast, lack redundant systems of DNA repair that are present in other tissues [37],[38]. Defects in DNA repair would be expected to have greater impact in such tissues without extensive DNA repair redundancy. In addition, a number of studies have suggested a role of sex hormone (e.g., estrogen and androgen) in the regulation of DNA repair activity in breast and prostate cancers [39]. After correction for multiple comparisons for individual types of cancers, the significant association remained for breast cancer, lung cancer in women, and melanoma in both men and women. Even though the positive associations are biologically plausible, we cannot rule out the possibility of chance findings for each individual cancer site.

In our analysis stratified by smoking status, significant association was found among never and past smokers. Because the NER enzymes recognize bulky DNA adducts including both UV-induced photoproducts and smoking-related BPDE-DNA adducts, the interaction between smoking status and history of NMSC highlights the potential role of the NER pathway in the development of second cancers. However, the effect of inherited insufficient capacity of the NER indicated by history of NMSC is only apparent among non-current smokers and for lung cancer in women. Further mechanistic investigation is warranted.

Sub-optimal immune surveillance could be another common susceptibility factor for both cutaneous and internal cancers. Malignant progression is accompanied by profound immune suppression that interferes with an effective antitumor response and tumor elimination [40]. Impaired immunity has been implicated as a non-site-specific determinant of cancer risk [41]. In addition, UV radiation can also cause immunosuppression. UV exposure adversely affects the skin immune system by diminishing antigen-presenting cell function, inducing immunosuppressive cytokine production, and modulating contact and delayed-type hypersensitivity reactions [42],[43], all of which can reduce the body’s surveillance for tumor cells [44],[45]. UV suppresses immune reactions locally, but can also affect the immune system in a systemic fashion when higher UV doses are given [46],[47]. UV radiation affects immune surveillance by modulating the balance between an effective immune response and immune tolerance of an emerging cancer [41]. We did not observe an association between UV-index and the risk of cancer except for skin cancer in our study, which makes this explanation less likely for our findings.

The identification of BCC cases in this study was based on self-report without pathological confirmation. However, the participants in the two cohorts were nurses and health professionals. The validity of their reports was expected to be high, and it has been proven in our validation studies [13],[14]. In addition, previous studies of BCC in the NHS using the self-reported cases identified both constitutional and sun exposure risk factors as expected, such as lighter pigmentation, less childhood and adolescent tanning tendency, higher tendency to sunburn, and tanning salon attendance [48],[49]. We recently confirmed the MC1R gene as the top BCC risk locus using the NHS and HPFS samples [50]. These data together suggest that the bias due to self-report of BCC is likely to be minimal in our study. Moreover, the potential under-report of BCC diagnosis would be expected to bias observed associations toward the null, and such bias would not explain the positive associations that we found.

The strengths of our study included the prospective cohort design and updated assessment of cancer diagnosis and other risk factors every 2 y, more than two decades of follow-up, and a large number of incident skin cancer cases. We had detailed data on related covariates for stratified analyses and comprehensive adjustment for potential confounders. All the participants were health professionals, minimizing potential confounding by educational attainment or differential access to health care. Nevertheless, we cannot completely exclude residual confounding, and our findings may not assign causality. Although the observed significant associations in breast cancer, lung cancer in women, and melanoma in both men and women remained significant after correction for multiple comparisons, we cannot absolutely rule out chance findings for individual cancer sites, and the underlying mechanism for the associations found in specific cancer sites is not entirely clear. In addition, the significant associations for some individual cancers did not meet the adjusted p-value threshold because of their limited sample size.

We cannot estimate the recurrence rate of NMSC or subsequent cancer risk among people with multiple NMSC because we only recorded the first report of each type of skin cancer in both cohorts. We do not have data for non-whites in this study, and our results cannot be generalized to non-whites owing to the dramatic difference in skin cancer incidence among different races. In summary, we observed a modestly increased risk of other cancers among individuals with a history of NMSC. Because our study was observational, these results should be interpreted cautiously and are insufficient evidence to alter current clinical recommendations. Nevertheless, these data support a need for continued investigation of the potential mechanisms underlying this relationship.

SOURCE:

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001433;jsessionid=55BB9D9B87F79FF1CA7594C56F407F14

 

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Author: Ziv Raviv, PhD

Introduction

Cutaneous melanoma is a type of skin cancer that originates in melanocytes, the cells that are producing melanin. While being the least common type of skin cancer, melanoma is the most aggressive one with invasive characteristics and accounts for the majority of death incidences among skin cancers. Melanoma has an annual rate of 160,000 new cases and 48,000 deaths worldwide. Melanoma affects mainly Caucasians exposed to sun high UV irradiation. Among the genetic factors that characterize the disease, BRAF mutation (V600E) is found in most cases of melanoma (80%).  Awareness toward risk factors of melanoma should lead to prevention and early detection*. There are several developmental stages (I-IV) of the disease, starting from local non-invasive melanoma, through invasive and high risk melanoma, up to metastatic melanoma. As with other cancers, the earlier stage melanoma is being detected, the better odds for full recovery are. Treatment is usually involving surgery to remove the local tumor and its margins, and when necessary also to remove the proximal lymph node(s) that drain the tumor. In high stages melanoma, adjuvant therapy is given in the form of chemotherapy (Dacarbazine and Temozolomide) and immunotherapy (IL-2 and IFN). Until recently no useful treatment was available for metastatic melanoma. However, research efforts had led to the development of two new drugs against metastatic melanoma: Vemurafenib (Zelboraf), a B-Raf inhibitor; and Ipilimumab (Yervoy), a monoclonal antibody that blocks the inhibitory signal of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Both drugs are now available for clinical use presenting good results.

Personalized therapy for melanoma

In an attempt to develop personalized therapies for malignant melanoma, a unique strategy has been taken by the group of Prof. Yardena Samuels at the NIH (now situated at the WIS) to identify recurring genetic alterations of metastatic cutaneous melanoma. The researchers approach employed the collections of hundreds of tumors samples taken from metastasized melanoma patients together with matched normal blood tissues samples. The samples are undergoing exome sequencing for the analysis of somatic mutations (namely mutations that evolved during the progress of the disease to the stage of metastatic melanoma, unlike genomic mutations that may have contribute to the formation of the disease). The discrimination of such tumor related somatic mutations is done by comparison to the exome sequencing of the patient’s matched blood cells DNA. In addition, the malignant cells derived from the removed cancer tissue of each patient are extracted to form a cell line and are grown in culture. These cells are easily cultivate in culture with no special media supplements, nor further genetic manipulations such as hTERT are needed, and are extremely aggressive as determined by various cell culture and in vivo tests. The ability to grow these primary tumor-derived cell lines in culture has a great value as a tool for studying and characterizing the biochemical, functional, and clinical aspects of the mutated genes identified.

In one study [1] Samuels and her colleagues performed this sequencing process for mutation analysis for the protein tyrosine kinase (PTK) gene family, as PTKs are frequently mutated in cancer. Using high-throughput gene sequencing to analyze the entire PTK gene family, the researchers have identified 30 somatic mutations affecting the kinase domains of 19 PTKs and subsequently evaluated the entire coding regions of the genes encoding these 19 PTKs for somatic mutations in 79 melanoma samples. The most frequent mutations were found in ERBB4, a member of the EGFR/ErbB family of receptor tyrosine kinase (RTK), were 19% of melanoma patients had such mutations. Seven missense mutations in the ERBB4 gene were found to induce increased kinase activity and transformation capability. Melanoma derived cell lines that were expressing these mutant ERBB4 forms had reduced cell growth after silencing ERBB4 by RNAi or after treatment with the ERBB inhibitor Lapatinib. Lapatinib is already in use in the clinic for the treatment of HER2 (ErbB2) positive breast cancers patients. Following this study, a clinical trial is now conducted with this drug to evaluate its effect in cutaneous metastatic melanoma patients harboring mutations in ERBB4.

In another study of this group [2], the scientists employed the exome sequencing method to analyze the somatic mutations of 734 G protein coupled receptors (GPCRs) in melanoma. GPCRs are regulating various signaling pathways including those that affect cell growth and play also important role in human diseases. This screen revealed that GRM3 gene that encode the metabotropic glutamate receptor 3 (mGluR3), was frequently mutated and that one of its mutations clustered within one position. Mutant GRM3 was found to selectively regulate the phosphorylation of MEK1 leading to increased anchorage-independent cell growth and cellular migration. Tumor derived melanoma cells expressing mutant GRM3 exhibited reduced cell growth and migration upon knockdown of GRM3 by RNAi or by treatment with the selective MEK inhibitor, Selumetinib (AZD-6244), a drug that is being testing in clinical trials. Altogether, the results of this study point to the increased violent characteristics of melanomas bearing mutational GRM3.

In a third study, melanoma samples were examined for somatic mutations in 19 human genes that encode ADAMTS proteins [3]. Some of the ADAMTS genes have been suggested before to have implication in tumorigenesis. ADAMTS18, which was previously found to be a candidate cancer gene, was found in this study to be highly mutated in melanoma. ADAMTS18 mutations were biologically examined and were found to induce an increased proliferation of melanoma cells, as well as increased cell migration and metastasis. Moreover, melanoma cells expressing these mutated ADAMTS18 had reduced cell migration after RNAi-mediated knockdown of ADAMTS18. Thus, these results suggest that genetic alteration of ADAMTS18 plays a major role in melanoma tumorigenesis. Since ADAMTS genes encode extracellular proteins, their accessibility to systematically delivered drugs makes them excellent therapeutic targets.

Conclusive remarks

The above illustrated research approach intends to discover frequent melanoma-specific mutations by employing high-throughput whole exome and genome sequencing means. For the most highly mutated genes identified, the biochemical, functional, and clinical aspects are being characterized to examine their relevancy to the disease outcomes. This approach therefore introduces new opportunities for clinical intervention for the treatment of cutaneous melanoma. In addition to the discovery of novel highly mutated genes, this approach may also help determine which pathways are altered in melanoma and how these genes and pathways interact. Finding melanoma-associated highly mutated genes could lead to personalized therapeutics specifically targeting these altered genes in individual melanomas. Along with the opportunity to develop new agents to treat melanoma, the approach takes advantage of existing anti-cancer drugs, utilizing them to treat these mutated genes melanoma individuals. In addition to their potential for therapeutics, the discovery of highly mutated genes in melanoma patients may lead to the discovery of new markers that may assist the diagnosis of the disease. The implications of these screenings findings on other types of cancer bearing common pathways similar to melanoma should be examined as well. Finally, this elegant approach should be adopted in research efforts of other cancer types.

* Special review will be published further in the cancer prevention section of Pharmaceutical Intelligence

References

1. Prickett TD, Agrawal NS, Wei X, Yates KE, Lin JC, Wunderlich JR, Cronin JC, Cruz P, Rosenberg SA, Samuels Y (2009) Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet 41 (10):1127-1132

2. Prickett TD, Wei X, Cardenas-Navia I, Teer JK, Lin JC, Walia V, Gartner J, Jiang J, Cherukuri PF, Molinolo A, Davies MA, Gershenwald JE, Stemke-Hale K, Rosenberg SA, Margulies EH, Samuels Y (2011) Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma. Nat Genet 43 (11):1119-1126

3. Wei X, Prickett TD, Viloria CG, Molinolo A, Lin JC, Cardenas-Navia I, Cruz P, Rosenberg SA, Davies MA, Gershenwald JE, Lopez-Otin C, Samuels Y (2010) Mutational and functional analysis reveals ADAMTS18 metalloproteinase as a novel driver in melanoma. Mol Cancer Res 8 (11):1513-1525

Related articles on melanoma on this open access online scientific journal:

1.  In focus: Melanoma Genetics. Curator: Ritu Saxena, Ph.D.

2.  In focus: Melanoma therapeutics. Author and Curator: Ritu Saxena, Ph.D.

3.  A New Therapy for Melanoma.  Reporter- Larry H Bernstein, M.D.

4. Thymosin alpha1 and melanoma. Author, Editor: Tilda Barliya, Ph.D.

5. Exome sequencing of serous endometrial tumors shows recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Reporter and Curator: Dr. Sudipta Saha, Ph.D.

6. How Genome Sequencing is Revolutionizing Clinical Diagnostics. Reporter: Aviva Lev-Ari, PhD, RN.

7. Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. Curator and Reporter: Stephen J. Williams, Ph.D.

 

 

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