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1.  DNA damage response and DNA repair – dog as a model? 
BMC Cancer  2014;14:203.
Background
Companion animals like dogs frequently develop tumors with age and similarly to human malignancies, display interpatient tumoral heterogeneity. Tumors are frequently characterized with regard to their mutation spectra, changes in gene expression or protein levels. Among others, these changes affect proteins involved in the DNA damage response (DDR), which served as a basis for the development of numerous clinically relevant cancer therapies. Even though the effects of different DNA damaging agents, as well as DDR kinetics, have been well characterized in mammalian cells in vitro, very little is so far known about the kinetics of DDR in tumor and normal tissues in vivo.
Discussion
Due to (i) the similarities between human and canine genomes, (ii) the course of spontaneous tumor development, as well as (iii) common exposure to environmental agents, canine tumors are potentially an excellent model to study DDR in vivo. This is further supported by the fact that dogs show approximately the same rate of tumor development with age as humans. Though similarities between human and dog osteosarcoma, as well as mammary tumors have been well established, only few studies using canine tumor samples addressed the importance of affected DDR pathways in tumor progression, thus leaving many questions unanswered.
Summary
Studies in humans showed that misregulated DDR pathways play an important role during tumor development, as well as in treatment response. Since dogs are proposed to be a good tumor model in many aspects of cancer research, we herein critically investigate the current knowledge of canine DDR and discuss (i) its future potential for studies on the in vivo level, as well as (ii) its possible translation to veterinary and human medicine.
doi:10.1186/1471-2407-14-203
PMCID: PMC3995094  PMID: 24641873
Canine and human tumors; DNA damage response; DNA repair
2.  Imagine a world without cancer 
BMC Cancer  2014;14:186.
Background
Since the “War on Cancer” was declared in 1971, the United States alone has expended some $300 billion on research, with a heavy focus on the role of genomics in anticancer therapy. Voluminous data have been collected and analyzed. However, in hindsight, any achievements made have not been realized in clinical practice in terms of overall survival or quality of life extended. This might be justified because cancer is not one disease but a conglomeration of multiple diseases, with widespread heterogeneity even within a single tumor type.
Discussion
Only a few types of cancer have been described that are associated with one major signaling pathway. This enabled the initial successful deployment of targeted therapy for such cancers. However, soon after this targeted approach was initiated, it was subverted as cancer cells learned and reacted to the initial treatments, oftentimes rendering the treatment less effective or even completely ineffective. During the past 30 plus years, the cancer classification used had, as its primary aim, the facilitation of communication and the exchange of information amongst those caring for cancer patients with the end goal of establishing a standardized approach for the diagnosis and treatment of cancers. This approach should be modified based on the recent research to affect a change from a service-based to an outcome-based approach. The vision of achieving long-term control and/or eradicating or curing cancer is far from being realized, but not impossible. In order to meet the challenges in getting there, any newly proposed anticancer strategy must integrate a personalized treatment outcome approach. This concept is predicated on tumor- and patient-associated variables, combined with an individualized response assessment strategy for therapy modification as suggested by the patient’s own results. As combined strategies may be outcome-orientated and integrate tumor-, patient- as well as cancer-preventive variables, this approach is likely to result in an optimized anticancer strategy.
Summary
Herein, we introduce such an anticancer strategy for all cancer patients, experts, and organizations: Imagine a World without Cancer.
doi:10.1186/1471-2407-14-186
PMCID: PMC3995593  PMID: 24629025
Cancer; Carcinogenesis; Multimodal therapy; Cancer classification; Personalized anticancer therapy; Individualized anticancer therapy
3.  Fool’s gold, lost treasures, and the randomized clinical trial 
BMC Cancer  2013;13:193.
Background
Randomized controlled trials with a survival endpoint are the gold standard for clinical research, but have failed to achieve cures for most advanced malignancies. The high costs of randomized clinical trials slow progress (thereby causing avoidable loss of life) and increase health care costs.
Discussion
A malignancy may be caused by several different mutations. Therapies effective vs one mutation may be discarded due to lack of statistical significance across the entire population. Conversely, expensive large randomized trials may have sufficient statistical power to demonstrate benefit despite the therapy only working in subgroups. Non-cost-effective therapy is then applied to all patients (including subgroups it cannot help). Randomized trials comparing therapies with different mechanisms of action are misleading since they may conclude the therapies are “equivalent” despite benefitting different subpopulations, or may erroneously conclude that one therapy is superior simply because it targets a larger subpopulation. Furthermore, minor variances in patient selection may determine study outcome, a therapy may be discarded as ineffective despite substantial benefit in one subpopulation if harmful in another, randomized trials may more effectively detect therapies with minor benefit in most patients vs marked benefit in subpopulations, and randomized trials in unselected patients may erroneously conclude that “shot-gun” combinations are superior to single agents when sequential administration of personalized single agents might work better and spare patients treatment with drugs that cannot help them. We must identify predictive biomarkers early by comparing responding to progressing patients in phase I-II trials. Enriching randomized trials for biomarker-positive patients can markedly reduce required patient numbers and costs despite expensive screening for biomarker-positive patients. Available data support approval of new drugs without randomized trials if they yield single-agent sustained responses in patients refractory to standard therapies. Conversely, new approaches are needed to guide development of drug combinations since both standard phase II approaches and phase II-III randomized trials have a high risk of misleading.
Summary
Traditional randomized clinical trials approaches are often inefficient, wasteful, and unreliable. New clinical research paradigms are needed. The primary outcome of clinical research should be “Who (if anyone) benefits?” rather than “Does the overall group benefit?”
doi:10.1186/1471-2407-13-193
PMCID: PMC3639810  PMID: 23587187
Randomized clinical trials; Gold standard; Phase II trials; Drug combinations; Biomarkers
4.  Human endogenous retroviruses and cancer prevention: evidence and prospects 
BMC Cancer  2013;13:4.
Background
Cancer is a significant and growing problem worldwide. While this increase may, in part, be attributed to increasing longevity, improved case notifications and risk-enhancing lifestyle (such as smoking, diet and obesity), hygiene-related factors resulting in immuno-regulatory failure may also play a major role and call for a revision of vaccination strategies to protect against a range of cancers in addition to infections.
Discussion
Human endogenous retroviruses (HERVs) are a significant component of a wider family of retroelements that constitutes part of the human genome. They were originated by the integration of exogenous retroviruses into the human genome millions of years ago. HERVs are estimated to comprise about 8% of human DNA and are ubiquitous in somatic and germinal tissues.
Physiologic and pathologic processes are influenced by some biologically active HERV families. HERV antigens are only expressed at low levels by the host, but in circumstances of inappropriate control their genes may initiate or maintain pathological processes. Although the precise mechanism leading to abnormal HERVs gene expression has yet to be clearly elucidated, environmental factors seem to be involved by influencing the human immune system.
HERV-K expression has been detected in different types of tumors.
Among the various human endogenous retroviral families, the K series was the latest acquired by the human species. Probably because of its relatively recent origin, the HERV-K is the most complete and biologically active family.
The abnormal expression of HERV-K seemingly triggers pathological processes leading to melanoma onset, but also contributes to the morphological and functional cellular modifications implicated in melanoma maintenance and progression.
The HERV-K-MEL antigen is encoded by a pseudo-gene incorporated in the HERV-K env-gene. HERV-K-MEL is significantly expressed in the majority of dysplastic and normal naevi, as well as other tumors like sarcoma, lymphoma, bladder and breast cancer. An amino acid sequence similar to HERV-K-MEL, recognized to cause a significant protective effect against melanoma, is shared by the antigenic determinants expressed by some vaccines such as BCG, vaccinia virus and the yellow fever virus.
HERV-K are also reactivated in the majority of human breast cancers. Monoclonal and single-chain antibodies against the HERV-K Env protein recently proved capable of blocking the proliferation of human breast cancer cells in vitro, inhibiting tumor growth in mice bearing xenograft tumors.
Summary
A recent epidemiological study provided provisional evidence of how melanoma risk could possibly be reduced if the yellow fever virus vaccine (YFV) were received at least 10 years before, possibly preventing tumor initiation rather than culling melanoma cells already compromised. Further research is recommended to confirm the temporal pattern of this protection and eliminate/attenuate the potential role of relevant confounders as socio-economic status and other vaccinations.
It appears also appropriate to examine the potential protective effect of YFV against other malignancies expressing high levels of HERV-K antigens, namely breast cancer, sarcoma, lymphoma and bladder cancer.
Tumor immune-therapy, as described for the monoclonal antibodies against breast cancer, is indeed considered more complex and less advantageous than immune-prevention. Cellular immunity possibly triggered by vaccines as for YFV might also be involved in anti-cancer response, in addition to humoral immunity.
doi:10.1186/1471-2407-13-4
PMCID: PMC3557136  PMID: 23282240
HERV-K; Cancer prevention; Melanoma; Breast cancer; Ovarian cancer; BCG; Vaccinia; Yellow fever virus vaccine; Epidemiology
5.  Integrative oncology for breast cancer patients: introduction of an expert-based model 
BMC Cancer  2012;12:539.
Background
Malignant breast neoplasms are among the most frequent forms of cancer in the Western world. Conventional treatment of breast cancer may include surgery, hormonal therapy, chemotherapy, radiation and/or immunotherapy, all of which are often accompanied by severe side effects. Complementary and alternative medicine (CAM) treatments have been shown to be effective in alleviating those symptoms. Furthermore, with patient survival rates increasing, oncologists, psychologists and other therapists have to become more sensitive to the needs of cancer survivors that go beyond than the mere alleviation of symptoms. Many CAM methods are geared to treat the patient in a holistic manner and thus are also concerned with the patient’s psychological and spiritual needs.
Discussion
The use of certain CAM methods may become problematic when, as frequently occurs, patients use them indiscriminately and without informing their oncologists. Herbal medicines and dietary supplements, especially, may interfere with primary cancer treatments or have other detrimental effects. Thus, expertise in this highly specialized field of integrative medicine should be available to patients so that they can be advised about the benefits and negative effects of such preparations and practices.
Being a beneficial combination of conventional and CAM care, integrative oncology makes possible the holistic approach to cancer care. The concept of integrative oncology for breast cancer is jointly practiced by the Department of Internal and Integrative Medicine, Kliniken Essen-Mitte, academic teaching hospital of the University of Duisburg-Essen, and the Breast Center at Kliniken Essen-Mitte in Germany. This model is introduced here; its scope is reviewed, and its possible implications for the practice of integrative medicine are discussed.
Summary
Evidence-based integrative care is crucial to the field of oncology in establishing state-of-the-art care for breast cancer patients.
doi:10.1186/1471-2407-12-539
PMCID: PMC3582454  PMID: 23170989
Integrative oncology; Integrative medicine; Complementary and alternative medicine; Holistic care
6.  Natural resistance to cancers: a Darwinian hypothesis to explain Peto’s paradox 
BMC Cancer  2012;12:387.
Background
Peto's paradox stipulates that there is no association between body mass (a surrogate of number of cells and longevity) and cancer prevalence in wildlife species. Resolving this paradox is a very promising research direction to understand mechanisms of cancer resistance. As of present, research has been focused on the consequences of these evolutionary pressures rather than of their causes.
Discussion
Here, we argue that evolution through natural selection may have shaped mechanisms of cancer resistance in wildlife species and that this can result in a threshold in body mass above which oncogenic and tumor suppressive mechanisms should be increasingly purified and positively selected, respectively.
Summary
We conclude that assessing wildlife species in their natural ecosystems, especially through theoretical modeling, is the most promising way to understand how evolutionary processes can favor one or the other pathway. This will provide important insights into mechanisms of cancer resistance.
doi:10.1186/1471-2407-12-387
PMCID: PMC3488527  PMID: 22943484
7.  Has the time to come leave the “watch-and-wait” strategy in newly diagnosed asymptomatic follicular lymphoma patients? 
BMC Cancer  2012;12:210.
Background
Historically, the median overall survival for follicular lymphoma (FL) has been considered to be 9-10 years, and no treatment had ever prolonged this time period. Studies conducted more than 20 years ago demonstrated that treating patients with asymptomatic FL at the onset of the disease did not increase their survival, and that almost 20% of these patients did not need any treatment in the first 10 years of follow-up. Based on these facts, most clinical practice guidelines recommend active surveillance policies for patients with asymptomatic FL.
Discussion
The introduction of antiCD-20 monoclonal antibodies, over the last 15 years, has significantly increased the median survival rate to above 14 years. This improvement was achieved before the combination of rituximab and chemotherapy regimens became extensively used in patients with symptomatic disease. Therefore, this increase in survival may currently be more significant. At present, several clinical trials have evaluated low-toxicity therapies that prolong progression-free periods, among which rituximab monotherapy, radioimmunotherapy or the combination of rituximab with bendamustine are the most relevant. Unfortunately, these clinical trials have included only patients with symptomatic FL. The results of a recently reported clinical trial show that treatment with single-agent rituximab prolongs progression-free survival rates, time to new treatment and the quality of life of asymptomatic patients, as compared with the active surveillance strategy. Longer follow-up of these results and data regarding overall survival are awaited before this treatment can be recommended as the standard initial therapy.
Summary
There are different therapeutic possibilities for asymptomatic FL patients, but no data are currently available to indicate which option is the best. Patients need to understand the risks and benefits of observation versus treatment before a final decision can be made. For patients who want active treatment the administration of four weekly rituximab doses should be considered.
doi:10.1186/1471-2407-12-210
PMCID: PMC3489567  PMID: 22650448

Results 1-7 (7)