Radio-chemotherapy in anal cancer: Institutional experience at a large radiation oncology center in Chile

Aim

In this article the aim is to provide a concise narrative review and inform the institutional experience at a referral center in Chile with the use of radio-chemotherapy in anal cancer.

Background

Cancer of the anus and anal canal is mainly a loco-regional disease. For years the standard of care has been concomitant radio-chemotherapy, which permits organ preservation and better local control than alternative surgical procedures.

Materials and methods

A retrospective analysis of 44 patients treated between 2002 and 2010 was performed. Local recurrence, distant recurrence and overall survival were analyzed with the Kaplan–Meier method. Relevant groups where compared with the log-rank test and univariate analysis were done with the Cox proportional hazards model.

Results

Median follow-up of the cohort was 56 months, with a minimum follow-up of at least 24 months. There was a significant difference between clinical stages in disease free survival (log-rank trend p < 0.001), and a significant difference in overall survival (OS) when comparing clinical stages that were grouped in stage I–IIIa and IIIB (log-rank p = 0.001). On univariate analysis, age older than 60, having received full treatment and dose above 45 Gy were all significantly related to OS (p < 0.05). An overall survival of 45% and disease free survival of 45% at 5 years were found in our series.

Conclusions

Our findings show that results at the Instituto de Radiomedicina in Chile are comparable to published literature. Dismal results in stage IIIb cases indicate much work remains in therapies to achieve loco-regional control in locally advanced cases.     

Medicinal mushrooms: a rapidly developing area of biotechnology for cancer therapy and other bioactivities

Historically, medicinal mushrooms (basidiomycetes) have been shown to have profound health promoting benefits and recent studies, which are reviewed here, are now confirming their medical efficacy and identifying many of the bioactive molecules. Methods of large-scale cultivation by solid substrate and liquid culture fermentations are also briefly described.     

Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer

Aldehyde dehydrogenase 1 (ALDH1) has been considered to be a marker for cancer stem cells. However, the role of ALDH1 in head and neck squamous cell carcinoma (HNSCC) has yet to be determined. In this study, we isolated ALDH1-positive cells from HNSCC patients and showed that these HNSCC-ALDH1⁺ cells displayed radioresistance and represented a reservoir for generating tumors. Based on microarray findings, the results of Western blotting and immunofluorescent assays further confirmed that ALDH1⁺-lineage cells showed evidence of having epithelial-mesenchymal transition (EMT) shifting and endogenously co-expressed Snail. Furthermore, the knockdown of Snail expression significantly decreased the expression of ALDH1, inhibited cancer stem-like properties, and blocked the tumorigenic abilities of CD44⁺CD24⁻ALDH1⁺ cells. Finally, in a xenotransplanted tumorigenicity study, we confirmed that the treatment effect of chemoradiotherapy for ALDH1⁺ could be improved by Snail siRNA. In summary, it is likely that ALDH1 is a specific marker for the cancer stem-like cells of HNSCC.     

A simple system for monitoring biodiversity in protected areas of a developing country

The achievements of initiatives to strengthen biodiversity conservation in developing countries may be difficult to assess, since most countries have no system for monitoring biodiversity. This paper describes a simple and cost-effective, field-based biodiversity monitoring system developed specifically for areas where specialist staff is lacking. We discuss the preliminary lessons learned from protected areas in the Philippines. Whilst the monitoring system aims to identify trends in biodiversity and its uses so as to guide management action, it also promotes the participation of local people in the management, stimulates discussions about conservation amongst stakeholders and builds the capacity of park staff and communities in management skills. In addition, it seeks to provide people with direction regarding the aims of protected areas, and reinforces the consolidation of existing livelihoods through strengthening community-based resource management systems. The field methods are: (1) standardised recording of routine observations, (2) fixed point photographing, (3) line transect survey, and (4) focus group discussion. Both bio-physical and socio-economic data are used and given equal importance. The system can be sustained using locally available resources. The approach is useful in countries embarking on shared management of park resources with local communities, where rural people depend on use of natural ecosystems, and where the economic resources for park management are limited. We hope this paper will encourage other countries to develop their own biodiversity monitoring system, letting its development become a means for capacity building whilst at the same time supporting the creation of ownership.     

Displacements of fiducial markers in patients with prostate cancer treated with image guided radiotherapy: A single-institution descriptive study

Aim

To describe daily displacements when using fiducial markers as surrogates for the target volume in patients with prostate cancer treated with IGRT.

Background

The higher grade of conformity achieved with the use of modern radiation technologies in prostate cancer can increase the risk of geographical miss; therefore, an associated protocol of IGRT is recommended.

Materials and methods

A single-institution, retrospective, consecutive study was designed. 128 prostate cancer patients treated with daily on-line IGRT based on 2D kV orthogonal images were included. Daily displacement of the fiducial markers was considered as the difference between the position of the patient when using skin tattoos and the position after being relocated using fiducial markers. Measures of central tendency and dispersion were used to describe fiducial displacements.

Results

The implant itself took a mean time of 15 min. We did not detect any complications derived from the implant. 4296 sets of orthogonal images were identified, 128 sets of images corresponding to treatment initiation were excluded; 91 (2.1%) sets of images were excluded from the analysis after having identified that these images contained extreme outlier values. If IGRT had not been performed 25%, 10% or 5% of the treatments would have had displacements superior to 4, 7 or 9 mm respectively in any axis.

Conclusions

Image guidance is required when using highly conformal techniques; otherwise, at least 10% of daily treatments could have significant displacements. IGRT based on fiducial markers, with 2D kV orthogonal images is a convenient and fast method for performing image guidance.     

A Sarcocystid Misidentified as Hepatozoon didelphydis: Molecular Data from a Parasitic Infection in the Blood of the Southern Mouse Opossum (Thylamys elegans) from Chile

ABSTRACT. The blood of 21 adult South American mouse opossums (Thylamys elegans) captured from April through August of 2005 in central Chile was examined for parasites. Light microscopic analysis of blood smears initially suggested that a highly pleomorphic Hepatozoon species typical of American opossums was infecting erythrocytes. Unexpectedly, amplification by PCR and sequencing of a DNA fragment of the small subunit rDNA combined with phylogenetic analyses indicated that the parasite is not a member of the suborder Adeleorina, which includes the Haemogregarina and Hepatozoon species, but that it is a clearly distinct member of the suborder Eimeriorina, which includes the cyst‐forming family Sarcocystidae. Therefore, a reclassification of this unusual intraerythrocytic apicomplexan will require additional life cycle, microscopic, and molecular analyses.     

Mortality and incidence of new primary cancers in men with prostate cancer: A Danish population-based cohort study

Background: Prostate cancer (PC) survivors may have an increased risk of new primary cancers (NPCs) due to shared risk factors or PC-directed treatments. Methods: Using Danish registries, we conducted a cohort study of men with (n = 30,220) and without PC (n = 151,100) (comparators), matched 1:5 on age and PC diagnosis/index date. We computed incidence rates of NPCs per 10,000 person years (PY) and associated 95% confidence intervals (CI), and used Cox proportional hazards regression to compute hazard ratios (HRs) and 95%CI, adjusting for comorbidities. In order to obviate any impact of shorter survival among prostate cancer patients, we censored comparator patients when the matched prostate cancer patient died or was censored. Results: Follow-up spanned 113,487 PY and 462,982 PY in the PC and comparison cohorts, respectively. 65% of the cohorts were aged >70 years at diagnosis. Among PC patients, 51% had distant/unspecified stage, and 63% had surgery as primary treatment. The PC cohort had lower incidence of NPCs than their comparators. The adjusted HR of NPC among men with PC versus the comparators was 0.84 (95%CI = 0.80, 0.88). Lowest HRs were among older men, those with distant stage, and were particularly evident for cancers of the brain, liver, pancreas, respiratory, upper gastrointestinal, and urinary systems. Conclusions: We find no evidence of an increased risk of NPCs among men with PC. The deficit of NPCs among men with PC may be a true effect but is more likely due to lower levels of risk factors (e.g., smoking) in PC patients versus comparators, clinical consideration of cancers at new organs as metastases rather than new primaries, or under-recording/under-reporting of NPCs among PC patients.     

Human Papillomavirus and the use of nanoparticles for immunotherapy in HPV-related cancer: A review

Human Papillomavirus (HPV) remains one of the most commonly contracted sexually transmitted diseases around the world. There are a multitude of HPV types, some of which may never present any symptoms. Others, however, are considered high-risk types, which increase the chance of the person infected to develop cancer. In recent years, the utilization of nanotechnology has allowed researchers to employ and explore the use of nanoparticles in immunotherapies.The new nanoparticle frontier has opened many doors in this area of research as a form of prevention, diagnosis, and treatment in cancers resulting from HPV. This review will provide a brief background of HPV, its relationship to head and neck cancer (HNC) and present some insight into the field of immunotherapeutic nanoparticles.     

Advances in ovarian cancer screening: health and medicine for women: a multidisciplinary, evidence-based review of mid-life health concerns

Early detection is imperative for improving survival from ovarian cancer, the leading cause of death from gynecological cancer in the United States. At the Health and Medicine for Women continuing medical education (CME) conference at Yale in September 2010, Dr. Gil Mor, a researcher in the Department of OB/GYN at Yale, presented recent advances on the pathophysiology of ovarian cancer. These advances, and particularly our growing understanding of cancer stem cells, may help overcome the limitations of current ovarian cancer detection and treatment methods.     

Ligation of prostate cancer cell surface GRP78 activates a proproliferative and antiapoptotic feedback loop: a role for secreted prostate-specific antigen

GRP78, a well characterized chaperone in the endoplasmic reticulum, is critical to the unfolded protein response. More recently, it has been identified on the cell surface, where it has many roles. On cancer cells, it functions as a signaling receptor coupled to proproliferative/antiapoptotic and promigratory mechanisms. In the current study, we demonstrate that ligation of prostate cancer cell surface GRP78 by its natural ligand, activated α(2)-macroglobulin (α(2)M*), results in a 2-3-fold up-regulation in the synthesis of prostate-specific antigen (PSA). The PSA is secreted into the medium as an active proteinase, where it binds to native α(2)M. The resultant α(2)M·PSA complexes bind to GRP78, causing a 1.5-2-fold increase in the activation of MEK1/2, ERK1/2, S6K, and Akt, which is coupled with a 2-3-fold increase in DNA and protein synthesis. PSA is a marker for the progression of prostate cancer, but its mechanistic role in the disease is unclear. The present studies suggest that PSA may be involved in a signal transduction-dependent feedback loop, whereby it promotes a more aggressive behavior by human prostate cancer cells.     

Liquid chromatographic methods for the determination of endogenous nucleotides and nucleotide analogs used in cancer therapy: A review

Endogenous ribonucleotides and deoxyribonucleotides play a crucial role in cell function. The determination of their levels is of fundamental interest in numerous applications such as energy metabolism, biochemical processes, or in understanding the mechanism of nucleoside analog compounds. Nucleoside analogs are widely used in anticancer therapy. Their mechanisms of action are related to their structural similarity with natural nucleotides. Numerous assays have been described for the determination of endogenous nucleotides or anticancer nucleotide analogs in different matrices such as cellular cultures, tissue or peripheral blood mononuclear cells. The determination of these compounds is challenging due to the large difference of concentrations between ribonucleotides and deoxyribonucleotides, the presence of numerous endogenous interferences in complex matrices and the high polarity of the molecules due to the phosphate moiety. The extraction was generally performed at low temperature and was based on protein precipitation using acid or solvent mixture. This first phase could be coupled with extraction or cleaning step of the supernatant. Liquid chromatography coupled with UV detection and based on ion-exchange chromatography using non-volatile high salt concentrations was largely described for the quantification of nucleotides. However, the development of LC–MS and LC–MS/MS during the last ten years has constituted a sensitive and specific tool. In this case, analytical column was mostly constituted by graphite or C18 stationary phase. Mobile phase was usually based on a mixture of ammonium buffer and acetonitrile and in several assays included a volatile ion-pairing agent. Mass spectrometry detection was performed either with positive or negative electrospray mode according to compounds and mobile phase components. The purpose of the current review is to provide an overview of the most recent chromatographic assays (over the past ten years) developed for the determination of endogenous nucleotides and nucleotide analogs used in cancer therapy. We focused on sample preparation, chromatographic separation and quantitative considerations.     

Role of mitochondria in the immune response to cancer: a central role for Ca2+

This study demonstrates that Ca²⁺ stimulates mitochondrial energy metabolism during spleen lymphocyte activation in response to the ascitic Walker 256 tumor in rats. Intracellular Ca²⁺ concentrations, phosphorylated protein kinase C (pPKC) levels, Bcl-2 protein contents, interleukin-2 (IL-2) levels, mitochondrial uncoupling protein-2 (UCP-2) contents and reactive oxygen species (ROS) were significantly elevated in these activated lymphocytes. Mitochondria of activated lymphocytes exhibited high free Ca²⁺ concentrations in the matrix and enhanced oligomycin-sensitive oxygen consumption, indicating an increased rate of oxidative phosphorylation. The production of ROS was largely decreased by diphenylene iodinium in the activated lymphocytes, suggesting that NADPH oxidase is the prevalent source of these species. Accumulation of UCP-2 and the anti-apoptotic protein Bcl-2 is probably important to prevent mitochondrial dysfunction and cell death elicited by the sustained high levels of intracellular Ca²⁺ and ROS and may explain the observed higher resistance from activated lymphocytes against the opening of the mitochondrial membrane permeability pore (MPT). All these changes were blocked by pretreatment of the rats with verapamil, an L-type Ca²⁺ channel antagonist. These data demonstrate a central role of Ca²⁺ in the control of mitochondrial bioenergetics in spleen lymphocytes during the immune response to cancer.     

Circulating tumour cells and cancer stem cells: A role for proteomics in defining the interrelationships between function,phenotype and differentiation with potential clinical applications

Research on the discovery and implementation of valid cancer biomarkers is one of the most challenging fields in oncology and oncoproteomics in particular. Moreover, it is generally accepted that an evaluation of cancer biomarkers from the blood could significantly enable biomarker assessments by providing a relatively non-invasive source of representative tumour material. In this regard, circulating tumour cells (CTCs) isolated from the blood of metastatic cancer patients have significant promise. It has been demonstrated that localised and metastatic cancers may give rise to CTCs, which are detectable in the bloodstream. Despite technical difficulties, recent studies have highlighted the prognostic significance of the presence and number of CTCs in the blood. Future studies are necessary not only to detect CTCs but also to characterise them. Furthermore, another pathogenically significant type of cancer cells, known as cancer stem cells (CSCs) or more recently termed circulating tumour stem cells (CTSCs), appears to have a significant role as a subpopulation of CTCs.     

Trends in incidence and survival analysis in non-melanoma skin cancer from 1994 to 2012 in Girona,Spain: A population-based study

IntroductionWe present an epidemiological study focused on Non-melanoma skin cancers (NMSC), including squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Merkel cell carcinoma (MCC), dermatofibrosarcoma protuberans (DFS) and adnexal and skin appendages neoplasm (ASAN), a neoplasm understudied in cancer registries.Material and methodsWe analyze trends of incidence and survival of NMSC registered with the Cancer Registry of Girona, Spain.ResultsWe found 14389 cases of NMSC, accounting 3,474 SCC, 10729 BCC, 33 MCC, 61 DFSP and 71 ASAN. Incidence increased significantly in SCC and BCC with annual percentage of change of 1.6 and 1.5, respectively, but not in MCC, DFS or ASAN. Five-year relative survival for both sexes was 90.1% in SCC, 99.8% in BCC, 44.2% in MCC, 93.7% in DFS and 84% in ASAN.ConclusionsOur study confirms the increasing incidence and good survival of SCC and BCC and enhances knowledge on the epidemiology of the less incidental NMSC.     

Structural transition of kidney cystatin in dimethylnitrosamine-induced renal cancer in rats: identification as a novel biomarker for kidney cancer and prognosis

In our study, renal cancer is induced in rats making use of dimethylnitrosamine (DMN). G1 – Group 1 were control rats and G2 – Group 2 rats were given a single intra-peritoneal injection of DMN of 50 mg/kg body weight resulting in 100% incidences of renal tumors after 12 months. SEM and histopathology confirmed the presence of renal cancer in the DMN-treated rats. Making use of ammonium sulfate precipitation and gel filtration chromatography on Sephacryl S-100HR column, a thiol protease inhibitor was isolated from kidney of control rats known as Rat kidney Cystatin (RKC) as well as from kidney of cancerous rat called as Cancerous Rat Kidney Cystatin (CRKC). Both these inhibitors were characterized, and interestingly, it was found that CRKC showed greater anti-papain activity and also it was stable in a broad pH and temperature range thus implying that CRKC is more stable as compared to RKC. UV and fluorescence spectroscopy point out in structural difference between RKC and CRKC which was further confirmed by Circular dichroism (CD) and FTIR spectroscopy. Our study clearly showed that kidney cystatin is structurally modified in the case of renal cancer and performs its role in a more efficacious manner.     

A precursor microRNA in a cancer cell nucleus: Get me out of here!

In line with their broad-based effects, microRNAs (miRNAs), small non-coding RNA molecules ∼22 nucleotides long that silence target mRNAs, are thought to act as oncogenes or tumor suppressor genes based on their inhibition of tumor-suppressive and oncogenic mRNAs, respectively. We and others previously showed that global downregulation of miRNAs, a common feature of human tumors, is functionally relevant to oncogenesis as impairment of miRNA biogenesis enhanced transformation in both cancer cells and a K-Ras-driven model of lung cancer. The dysregulation of miRNA biosynthesis in cancer emerges as a cancer-specific mechanism that enhances its tumorigenic capacity. These observations are further supported by the fact that frameshift mutations of TARBP2 occur in sporadic and hereditary carcinomas with microsatellite instability and that DICER1 mutations are associated with familial pleuropulmonary blastoma. Accordingly, it was reported that reduced expression of miRNA-processing factors is associated with poor prognosis in lung cancer and ovarian cancer. Recently we have also demonstrated the presence of Exportin 5 (XPO5) inactivating mutations in tumors with microsatellite instability. This observed genetic defect is responsible for nuclear retention of pre-miRNAs, thereby reducing miRNA processing. The characterized mutant form of the XPO5 protein lacks a C-terminal region that contributes to the formation of the pre-miRNA/XPO5/Ran-GTP ternary complex and the protein itself, as well as pre-miRNAs accumulating in the nucleus of cancer cells. Most importantly, the restoration of XPO5 function reverses the impaired export of pre-miRNAs and has tumor suppressor features. Our data suggest a cancer-specific mechanism to guide the subcellular distribution of miRNA precursors and prevent them from being processed to the active mature miRNA. The control of the miRNA biosynthesis pathway is emerging as an important mechanism in defining the spatiotemporal pattern of miRNA expression in cancer cells.     

Polymorphisms associated with the risk of lung cancer in a healthy Mexican Mestizo population: Application of the additive model for cancer

Lung cancer is the leading cause of cancer mortality in Mexico and worldwide. In the past decade, there has been an increase in the number of lung cancer cases in young people, which suggests an important role for genetic background in the etiology of this disease. In this study, we genetically characterized 16 polymorphisms in 12 low penetrance genes (AhR, CYP1A1, CYP2E1, EPHX1, GSTM1, GSTT1, GSTPI, XRCC1, ERCC2, MGMT, CCND1 and TP53) in 382 healthy Mexican Mestizos as the first step in elucidating the genetic structure of this population and identifying high risk individuals. All of the genotypes analyzed were in Hardy-Weinberg equilibrium, but different degrees of linkage were observed for polymorphisms in the CYP1A1 and EPHX1 genes. The genetic variability of this population was distributed in six clusters that were defined based on their genetic characteristics. The use of a polygenic model to assess the additive effect of low penetrance risk alleles identified combinations of risk genotypes that could be useful in predicting a predisposition to lung cancer. Estimation of the level of genetic susceptibility showed that the individual calculated risk value (iCRV) ranged from 1 to 16, with a higher iCRV indicating a greater genetic susceptibility to lung cancer.     

Excess mortality in persons with severe mental disorders: a multilevel intervention framework and priorities for clinical practice,policy and research agendas

Excess mortality in persons with severe mental disorders (SMD) is a major public health challenge that warrants action. The number and scope of truly tested interventions in this area remain limited, and strategies for implementation and scaling up of programmes with a strong evidence base are scarce. Furthermore, the majority of available interventions focus on a single or an otherwise limited number of risk factors. Here we present a multilevel model highlighting risk factors for excess mortality in persons with SMD at the individual, health system and socio‐environmental levels. Informed by that model, we describe a comprehensive framework that may be useful for designing, implementing and evaluating interventions and programmes to reduce excess mortality in persons with SMD. This framework includes individual‐focused, health system‐focused, and community level and policy‐focused interventions. Incorporating lessons learned from the multilevel model of risk and the comprehensive intervention framework, we identify priorities for clinical practice, policy and research agendas.