Tissue biomarkers for prostate cancer radiation therapy

Prostate cancer is the most common cancer and second leading cause of cancer deaths among men in the United States. Most men have localized disease diagnosed following an elevated serum prostate specific antigen test for cancer screening purposes. Standard treatment options consist of surgery or definitive radiation therapy directed by clinical factors that are organized into risk stratification groups. Current clinical risk stratification systems are still insufficient to differentiate lethal from indolent disease. Similarly, a subset of men in poor risk groups need to be identified for more aggressive treatment and enrollment into clinical trials. Furthermore, these clinical tools are very limited in revealing information about the biologic pathways driving these different disease phenotypes and do not offer insights for novel treatments which are needed in men with poor-risk disease. We believe molecular biomarkers may serve to bridge these inadequacies of traditional clinical factors opening the door for personalized treatment approaches that would allow tailoring of treatment options to maximize therapeutic outcome. We review the current state of prognostic and predictive tissue-based molecular biomarkers which can be used to direct localized prostate cancer treatment decisions, specifically those implicated with definitive and salvage radiation therapy.     

Management of clinically localized prostate cancer

Critics of screening have stated that early detection of prostate cancer does not necessarily reflect a diminishing death rate from the disease. However, several recent reports have demonstrated that the death rate from prostate cancer is decreasing, representing the most compelling validation for aggressive screening. Prostate cancer can be halted only if there is no evidence of systemic or regional metastases and the disease is confined to the surgical field or the radiation template. Surgeons and radiation oncologists must make a concerted effort to exclude men with regional and systemic metastases who are unlikely to benefit from treatment. With the widespread acceptance of prostate-specific antigen screening, a greater proportion of men are being diagnosed with clinically localized prostate cancer. Both radical prostatectomy and radiation therapy are able to halt disease spread in this significant subset of men, but survival outcomes indicate that radical prostatectomy is a more reliable treatment than radiation therapy for clinically localized prostate cancer. Overall, the immediate treatment-related morbidity of radical prostatectomy and radiation therapy in the modern era is quite low. Radical prostatectomy and radiation therapy appear to have a similar impact on continence and erectile function. There is a need for neoadjuvant and adjuvant therapies that can be utilized in those cases where radical prostatectomy and radiation are less likely to completely eradicate or destroy the cancer.     

Vascular Targeted Photodynamic Therapy for Localized Prostate Cancer

Survival for men diagnosed with prostate cancer directly depends on the stage and grade of the disease at diagnosis. Prostate cancer screening has greatly increased the ability to diagnose small and low-grade cancers that are amenable to cure. However, widespread prostate-specific antigen screening exposes many men with low-risk cancers to unnecessary complications associated with treatment for localized disease without any survival advantage. One challenge for urological surgeons is to develop effective treatment options for low-risk disease that are associated with fewer complications. Minimally invasive ablative treatments for localized prostate cancer are under development and may represent a preferred option for men with low-risk disease who want to balance the risks and benefits of treatment. Vascular targeted photodynamic therapy (VTP) is a novel technique that is being developed for treating prostate cancer. Recent advances in photodynamic therapy have led to the development of photosynthesizers that are retained by the vascular system, which provides the opportunity to selectively ablate the prostate with minimal collateral damage to other structures. The rapid clearance of these new agents negates the need to avoid exposure to sunlight for long periods. Presented herein are the rationale and preliminary data for VTP for localized prostate cancer.Key words: Prostate cancer, localized; Minimally invasive ablative treatment for prostate cancer; Photodynamic therapy; WST-09; WST-11; Vascular targeted photodynamic therapy; Padoporfin; Palladium bacteriopheophorbideProstate cancer represents the second most common cause of cancer-related deaths in American men; it is estimated that 27,000 men in the United States died from the disease in 2007.¹ Survival for men with prostate cancer directly depends on the stage and grade of the disease at the time of diagnosis.² These sobering mortality statistics and the more favorable prognosis associated with early detection provide the primary justification for prostate cancer screening, which is performed by measuring the level of serum prostate-specific antigen (PSA) and conducting a digital rectal examination (DRE). It is estimated that 50% of men over the age of 50 years are screened annually for prostate cancer.³Despite widespread acceptance, prostate cancer screening is debated,^4,5 and recommendations for prostate cancer screening are inconsistent. Screening protagonists emphasize that radical prostatectomy increases prostate cancer survival in men with localized disease,⁶ and that the recently observed progressive and significant decline in prostate cancer mortality rates is the direct result of PSA screening and aggressive intervention.⁷ Screening antagonists emphasize the indolent natural history of most prostate cancers detected by screening,⁸ and that the vast majority of men who are treated for prostate cancer do not recognize any survival advantage from early detection and are simply left suffering the ravages of treatment.⁹Both sides of the screening debate have valid arguments. In the absence of widespread screening, many men are denied an opportunity to cure their disease. These men will experience the otherwise preventable consequences of disease progression, which include the development of androgen-insensitive disease¹⁰ and death. However, widespread screening exposes many men to unnecessary complications associated with treatment for localized disease. The challenges are to identify and treat only those cancers that have the biological potential to cause serious and preventable consequences, or to develop treatment options that are associated with fewer complications.     

Selecting treatment for high-risk, localized prostate cancer: the case for radical prostatectomy

The most common treatment options for men with clinically localized prostate cancer include radical prostatectomy and radiation therapy. The choice between these options is often controversial, and selecting the optimal treatment poses a great challenge for patients and physicians. Factors important to the decision include age and life expectancy of the patient, the natural history of the prostate cancer, how curable the disease is, and the morbidity of treatment. Use of these criteria to select treatment for a healthy, 70-year-old man presenting with a nonpalpable tumor, stage T1c disease, serum prostate-specific antigen of 12 ng/mL, and an adenocarcinoma with a Gleason score of 8 that is present in 2 of 12 biopsy cores would lead to the choice of radical prostatectomy over radiation therapy. Data show that such a patient has a life expectancy of more than 12.3 years if the prostate cancer can be cured and a high probability of dying from the disease if it is not cured. Data further show that radical prostatectomy in such a patient would confer a survival advantage over radiation therapy without resulting in greater complications or reduction in quality of life.     

Focus: A Multifaceted Battle Against Cancer: Basal Cell Carcinoma: Pathogenesis,Epidemiology, Clinical Features,Diagnosis, Histopathology,and Management

Basal cell carcinoma (BCC) is the most common malignancy. Exposure to sunlight is the most important risk factor. Most, if not all, cases of BCC demonstrate overactive Hedgehog signaling. A variety of treatment modalities exist and are selected based on recurrence risk, importance of tissue preservation, patient preference, and extent of disease. The pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management of BCC will be discussed in this review.     

Bicalutamide adjuvant to radical prostatectomy

Prostate cancer recurrence affects up to 50% of men in the first 10 years after radical prostatectomy for clinically localized disease. New treatment approaches that reduce this risk are needed. Current published data on the use of adjuvant hormonal therapy in the post-radical prostatectomy setting are limited. New data from the bicalutamide (Casodex) Early Prostate Cancer program show that bicalutamide 150 mg/d, given as immediate adjuvant treatment, produces clear benefits with respect to both progression-free survival and prostate-specific antigen progression when compared with standard management with radical prostatectomy. The greatest improvement of progression-free survival was observed in patient subgroups at highest risk.     

Nuclear matrix proteins as biomarkers in prostate cancer

The nuclear matrix (NM) is the structural framework of the nucleus that consists of the peripheral lamins and pore complexes, an internal ribonucleic protein network, and residual nucleoli. The NM contains proteins that contribute to the preservation of nuclear shape and its organization. These protein components better known as the NM proteins have been demonstrated to be tissue specific, and are altered in many cancers, including prostate cancer. Alterations in nuclear morphology are hallmarks of cancer and are believed to be associated with changes in NM protein composition. Prostate cancer is the most frequently diagnosed cancer in American men and many investigators have identified unique NM proteins that appear to be specific for this disease. These NM protein changes are associated with the development of prostate cancer, as well as in some cases being indicative of cancer stage. Identification of these NM proteins specific for prostate cancer provides an insight to understanding the molecular changes associated with this disease. This article reviews the role of NM proteins as tumor biomarkers in prostate cancer and the potential application of these proteins as therapeutic targets in the treatment of this disease.     

Prepubertal testis tumors

Because prepubertal testis tumors are rare, their management has historically been based on experience with the more common adult testis tumors. However, recent studies highlighting the natural history of these tumors and their response to therapy have resulted in a modern management algorithm that optimizes testicular preservation and minimizes the morbidity of adjuvant therapies. Many prepubertal testis tumors are benign and can be managed with testis-sparing tumor excision. Localized malignant tumors (yolk sac tumors) may be managed with excision alone. Recurrent tumors and metastatic disease can almost always be treated successfully with platinum-based chemotherapy.     

Place de la prostatectomie radicale dans le traitement du cancer de prostate

The screening of the prostate cancer with PSA has dramatically modified the circumstances of diagnosis. Nowadays, most of the patients have a localized disease. The treatment is based on prognostic factors and the spreading of the tumor. If the cancer is localized, some treatments are available. Among them, the radical prostatectomy can be performed either laparoscopically or by an open approach. Surgical treatment of prostate cancer is proven to be an effective way to decrease the occurrence of locoregional extension and metastatic disease. It has been proven that it allowed diminishing the mortality in patients who have a life expectancy more than 10 years. The side effects of the radical prostatectomy consist of impotency and incontinence which can be rehabilitated. The treatment of locally advanced cancer is a controversial issue that can consist in surgery as a unique treatment or in a multimodal treatment. This text summaries the recommendations of the French association of Urology.     

Molecular therapeutics in prostate cancer

The purpose of this review is to provide information on the molecular basis of prostate cancer biology and to identify some of the targets for therapy, and highlight some potential strategies for molecular treatment. Here we give a synopsis of what we have learned regarding molecular biology of cancer in general and the directions research might take in the future in order to impact prostate cancer specifically. This work is certainly not encyclopedic in nature and we apologize in advance to colleagues whose work we were no able to include. Hope lies in learning to utilize some of these molecular workings for better prevention, diagnosis, and treatment of the most common solid organ cancer in men. Prostate cancer is a formidable disease and at current rates of diagnosis will affect one-in-six men living in the United States (Greenlee et al., 2000) Many of these men are diagnosed at an early stage of the disease and can be effectively treated by surgery or radiation. However, a significant fraction of men are diagnosed with later stage disease or progress despite early curative therapeutic attempts. Unfortunately, many of these men succumb to prostate cancer, as management options are limited and not always successful. Through an understanding of the molecular processes that occur in the development and progression of prostate cancer, novel therapies will arise that will provide longer survival, better quality of life, and a chance for cure in men afflicted with this disease.     

N-Octanoyl Dopamine,a Non-Hemodyanic Dopamine Derivative,for Cell Protection during Hypothermic Organ Preservation

Background

Although donor dopamine treatment reduces the requirement for post transplantation dialysis in renal transplant recipients, implementation of dopamine in donor management is hampered by its hemodynamic side-effects. Therefore novel dopamine derivatives lacking any hemodynamic actions and yet are more efficacious in protecting tissue from cold preservation injury are warranted. We hypothesized that variation of the molecular structure would yield more efficacious compounds avoid of any hemodynamic effects.

Methodology/Principal Findings

To this end, we assessed protection against cold preservation injury in HUVEC by the attenuation of lactate dehydrogenase (LDH) release. Modification of dopamine by an alkanoyl group increased cellular uptake and significantly improved efficacy of protection. Further variation revealed that only compounds bearing two hydroxy groups in ortho or para position at the benzene nucleus, i.e. strong reductants, were protective. However, other reducing agents like N-acetyl cysteine and ascorbate, or NADPH oxidase inhibition did not prevent cellular injury following cold storage. Unlike dopamine, a prototypic novel compound caused no hemodynamic side-effects.

Conclusions/Significance

In conclusion, we demonstrate that protection against cold preservation injury by catecholamines is exclusively governed by strong reducing capacity and sufficient lipophilicity. The novel dopamine derivatives might be of clinical relevance in donor pre-conditioning as they are completely devoid of hemodynamic action, their increased cellular uptake would reduce time of treatment and therefore also may have a potential use for non-heart beating donors.     

Progranulin Gene Delivery Protects Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by tremor, rigidity and akinesia/bradykinesia resulting from the progressive loss of nigrostriatal dopaminergic neurons. To date, only symptomatic treatment is available for PD patients, with no effective means of slowing or stopping the progression of the disease. Progranulin (PGRN) is a 593 amino acid multifunction protein that is widely distributed throughout the CNS, localized primarily in neurons and microglia. PGRN has been demonstrated to be a potent regulator of neuroinflammation and also acts as an autocrine neurotrophic factor, important for long-term neuronal survival. Thus, enhancing PGRN expression may strengthen the cells resistance to disease. In the present study, we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of PGRN gene delivery as a therapy for the prevention or treatment of PD. Viral vector delivery of the PGRN gene was an effective means of elevating PGRN expression in nigrostriatal neurons. When PGRN expression was elevated in the SN_C, nigrostriatal neurons were protected from MPTP toxicity in mice, along with a preservation of striatal dopamine content and turnover. Further, protection of nigrostriatal neurons by PGRN gene therapy was accompanied by reductions in markers of MPTP-induced inflammation and apoptosis as well as a complete preservation of locomotor function. We conclude that PGRN gene therapy may have beneficial effects in the treatment of PD.     

Prostate cancer radiation therapy: A physician’s perspective

Prostate cancer is the second most common cancer in men and a major cause of cancer deaths worldwide. Ionizing radiation has played a substantial role in the curative treatment of this disease. The historical evolution of radiotherapy techniques through 3D-conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and image-guided radiotherapy (IGRT) has allowed more accurate and precise treatments toward significant improvements in the therapeutic ratio. The addition of androgen deprivation therapy has significantly improved overall survival becoming the standard therapy for intermediate- and high-risk disease. Many randomized controlled trials have shown improved local control with dose escalation, and hypofractionated RT has been consolidated with proven efficacy and safe clinical results. However, several questions remain open in the radiotherapeutic management of prostate cancer patients and hopefully ongoing studies will shed light on these uncertainties. More individualized approaches are essential through better prognostic and novel predictive biomarkers of prostate radiotherapy response. Clinicians should critically interpret the evolving technologies in prostate cancer radiotherapy with important optimism but balancing the costs and the actual magnitude of clinical benefit. This article provides an overview of the basic aspects of radiotherapy treatment in localized prostate cancer from a physician’s perspective.     

Fluid preservation causes minimal reduction of parasite detectability in fish specimens: A new approach for reconstructing parasite communities of the past?

Long‐term datasets are needed to evaluate temporal patterns in wildlife disease burdens, but historical data on parasite abundance are extremely rare. For more than a century, natural history collections have been accumulating fluid‐preserved specimens, which should contain the parasites infecting the host at the time of its preservation. However, before this unique data source can be exploited, we must identify the artifacts that are introduced by the preservation process. Here, we experimentally address whether the preservation process alters the degree to which metazoan parasites are detectable in fluid‐preserved fish specimens when using visual parasite detection techniques. We randomly assigned fish of three species (Gadus chalcogrammus, Thaleichthys pacificus, and Parophrys vetulus) to two treatments. In the first treatment, fish were preserved according to the standard procedures used in ichthyological collections. Immediately after the fluid‐preservation process was complete, we performed parasitological dissection on those specimens. The second treatment was a control, in which fish were dissected without being subjected to the fluid‐preservation process. We compared parasite abundance between the two treatments. Across 298 fish individuals and 59 host–parasite pairs, we found few differences between treatments, with 24 of 27 host–parasite pairs equally abundant between the two treatments. Of these, one pair was significantly more abundant in the preservation treatment than in the control group, and two pairs were significantly less abundant in the preservation treatment than in the control group. Our data suggest that the fluid‐preservation process does not have a substantial effect on the detectability of metazoan parasites. This study addresses only the effects of the fixation and preservation process; long‐term experiments are needed to address whether parasite detectability remains unchanged in the months, years, and decades of storage following preservation. If so, ecologists will be able to reconstruct novel, long‐term datasets on parasite diversity and abundance over the past century or more using fluid‐preserved specimens from natural history collections.     

Prostate cancer in elderly men

Due to increasing life expectancy and the introduction of prostate-specific antigen (PSA) screening, a rising number of elderly men are diagnosed with prostate cancer. Besides PSA serum levels and Gleason score, age is considered to be a key prognostic factor in terms of treatment decisions. In men older than 70 years, treatment without curative intent may deprive the frail patient of years of life. Modern radical prostatectomy techniques are associated with low perioperative morbidity, excellent clinical outcome, and documented long-term disease control. Thus, radical prostatectomy should be considered because local treatment of organ-confined prostate cancer potentially cures disease. The huge extent of PSA screening programs may lead to overdiagnosis of prostate cancer. Not every man who is diagnosed with prostate cancer will develop clinically significant disease. This has led to the concept of expectant management for screen-detected, small-volume, low-grade disease, with the intention of providing therapy for those men with disease progression.     

The Ethics of Fertility Preservation in Transgender Body Modifications

In some areas of clinical medicine, discussions about fertility preservation are routine, such as in the treatment of children and adolescents facing cancer treatments that will destroy their ability to produce gametes of their own. Certain professional organizations now offer guidelines for people who wish to modify their bodies and appearance in regard to sex traits, and these guidelines extend to recommendations about fertility preservation. Since the removal of testicles or ovaries will destroy the ability to have genetically related children later on, it is imperative to counsel transgender people seeking body modifications about fertility preservation options. Fertility preservation with transgender people will, however, lead to unconventional outcomes. If transgender men and women use their ova and sperm, respectively, to have children, they will function as a mother or father in a gametic sense but will function in socially reversed parental identities. There is nothing, however, about fertility preservation with transgender men and women that is objectionable in its motives, practices, or outcomes that would justify closing off these options. In any case, novel reproductive technologies may extend this kind of role reversal in principle to all people, if sperm and ova can be derived from all human beings regardless of sex, as has happened with certain laboratory animals.     

Cancer of the prostate.

Prostate cancer presents a growing health problem in Western societies as longevity increases. It is characteristically a disease of elderly men associated with the development of osteoblastic bone metastases and initial hormone responsiveness to androgen deprivation. Previously regarded as a Cinderella of cancers, there is currently more controversy concerning the detection and management of both localised and metastatic disease than for any other common malignancy. A balance needs to be drawn between the potential gains of more aggressive management and the disadvantages in terms of increased treatment side effects and cost, taking into account both the natural course of the disease and the life expectancy of patients.     

Liver disease in women. Alcohol,autoimmunity, and gallstones.

Some liver diseases, such as autoimmune liver disease, affect women far more often than men. Others, such as alcohol-related disease, progress more rapidly in women than in men. An increased index of suspicion will lead to improved diagnosis and earlier treatment of women with liver disease.     

Therapeutic Strategies for Localized Prostate Cancer II: Perineal Prostatectomy, X-Rays, Protons, Neutrons, and Combination Brachytherapy

Application of improved imaging, diagnostic, and computer techniques is beginning to have an impact on the management of localized prostate cancer. It is possible to perform a range of surgical and radiation procedures with less morbidity than in the past. The changes in therapy for patients with localized disease derive from better knowledge of anatomy for invasive procedures and optimization of virtual planning for noninvasive methods. Perineal prostatectomy and combinations of beam and seed radiation offer both patient and physician reasonable therapeutic options.     

Sex differences in ischemic heart disease and heart failure biomarkers

Since 1984, each year, more women than men die of ischemic heart disease (IHD) and heart failure (HF), yet more men are diagnosed. Because biomarker assessment is often the first diagnostic employed in such patients, understanding biomarker differences in men vs. women may improve female morbidity and mortality rates.Some key examples of cardiac biomarker utility based on sex include contemporary use of “unisex” troponin reference intervals under-diagnosing myocardial necrosis in women; greater use of hsCRP in the setting of acute coronary syndrome (ACS) could lead to better stratification in women; and greater use of BNP with sex-specific thresholds in ACS could also lead to more timely risk stratification in women.Accurate diagnosis, appropriate risk management, and monitoring are key in the prevention and treatment of cardiovascular diseases; however, the assessment tools used must also be useful or at least assessed for utility in both sexes. In other words, going forward, we need to evaluate sex-specific reference intervals or cutoffs for laboratory tests used to assess cardiovascular disease to help close the diagnostic gap between men and women.