Recurrence patterns of pancreatic cancer treated with adjuvant intensity modulated radiotherapy

BackgroundThe aim of this study was to investigate the recurrence patterns in pancreatic cancer patients treated with adjuvant intensity modulated radiotherapy (IMRT) and to correlate the sites of locoregional recurrence with radiotherapy target volumes.Materials and methodsThirty-eight patients who had undergone resection and adjuvant chemoradiation for pancreatic cancer were evaluated. Radiotherapy (RT) was started after 1–3 cycles of adjuvant chemotherapy (CHT). Clinical target volume (CTV) was contoured according to the RTOG guideline. All patients were treated with IMRT with a dose of 45–50.4 Gy. Computerized tomography (CT) images at the time of recurrence were correlated with radiotherapy plans. Locoregional recurrences were classified as in-field, out-field and marginal.ResultsMedian overall survival (OS) was 19 months. One- and 2-year OS rates were 73.6% and 37.1%, respectively. Locoregional recurrence and distant metastases were observed in 11 (28.9%) and 23 (60.5%) patients, respectively. For the 11 locoregional recurrences, 7 were in-field, 1 was marginal, and 3 were out-of-field. One patient had isolated local, 2 patients had isolated regional and 15 (57.6%) patients had only distant failures. The first presentations of failures were mostly distant (58%). On multivariate analysis, tumor size ≥ 3 cm (p = 0.011) and positive vascular invasion (p = 0.014) predicted for worse OS rate.ConclusionsThe majority of locoregional recurrences were in the radiation field among pancreatic cancer patients treated with postoperative IMRT. However, failures were predominantly distant, and improvement of systemic control may be of particular interest.     

Molecular classification as prognostic factor and guide for treatment decision of pancreatic cancer

Clinico-pathological factors fail to consistently predict the outcome after pancreatic resection for pancreatic ductal adenocarcinoma (PDAC). PDACs show a high level of inter- and intra- tumor genetic heterogeneity. A molecular classification should help sort patients into less heterogeneous and more appropriate groups regarding the metastatic risk and the therapeutic response, with the consequences of better predicting evolution and better orienting the treatment. PDAC can be classified based on mutational subtypes and 18gene alterations. Whole-genome sequencing identified mutational signatures, mutational burden and hyper-mutated tumors with specific DNA repair defects. Their overlap/similarities allow the definition of molecular subtypes. DNA and RNA classifications can be used in prognosis assessment. They are useful in therapeutic choice for they allow the design of approaches that can predict the respective drug sensitivity of each molecular subtype. This review provides a comprehensive analysis of available molecular classifications in PDAC and how this can help guide clinical decisions.     

Risk factors for pancreatic cancer

In the United States, the cumulative mortality or lifetime risk of dying from pancreatic cancer is about 1-2%, but although this form of cancer is rare, nearly all patients die from the disease within one to two years. Because of its lethality, pancreatic cancer now ranks fourth as a cause of death from cancer. There are country-specific differences in rates, perhaps explained by differences in life-style factors or diet. African-Americans in the USA have rates that are about 50% higher than Caucasians. Smoking is the major known risk factor for this cancer, explaining 20-30% of all cases. Another 5-10% of causes are caused by germline mutations, with mutations in BRCA2 being the most frequent. Two background diseases increase the risk of pancreatic cancer-pancreatitis, and diabetes. Major challenges presented by this cancer are: 1) determination of the molecular pathways that make this cancer so aggressive; 2) development of new modalities, perhaps based on proteomics, to enhance early detection.     

Troxacitabine prodrugs for pancreatic cancer

Troxacitabine is a cytotoxic deoxycytidine analogue with an unnatural L-configuration, which is activated by deoxycytidine kinase (dCK). The configuration is responsible for differences in the uptake and metabolism of troxacitabine compared to other deoxynucleoside analogues. The main drawback in the use of most nucleoside anticancer agents originates from their hydrophilic nature, which property requires a high and frequent dosage for an intravenous administration. To overcome this problem several troxacitabine prodrugs modified in the aminogroup with a linear aliphatic chain with a higher lipophilicity were developed. To determine whether these prodrugs have an advantage over Troxacitabine pancreatic cancer cell lines were exposed to Troxacitabine and the lipophilic prodrugs. The addition of linear aliphatic chains to troxacitabine increased sensitivity of pancreatic cancer cell lines to the drug > 100-fold, possibly due to a better uptake and retention of the drug.     

Physician attitudes towards pharmacological cognitive enhancement: safety concerns are paramount

The ethical dimensions of pharmacological cognitive enhancement have been widely discussed in academic circles and the popular media, but missing from the conversation have been the perspectives of physicians - key decision makers in the adoption of new technologies into medical practice. We queried primary care physicians in major urban centers in Canada and the United States with the aim of understanding their attitudes towards cognitive enhancement. Our primary hypothesis was that physicians would be more comfortable prescribing cognitive enhancers to older patients than to young adults. Physicians were presented with a hypothetical pharmaceutical cognitive enhancer that had been approved by the regulatory authorities for use in healthy adults, and was characterized as being safe, effective, and without significant adverse side effects. Respondents overwhelmingly reported increasing comfort with prescribing cognitive enhancers as the patient age increased from 25 to 65. When asked about their comfort with prescribing extant drugs that might be considered enhancements (sildenafil, modafinil, and methylphenidate) or our hypothetical cognitive enhancer to a normal, healthy 40 year old, physicians were more comfortable prescribing sildenafil than any of the other three agents. When queried as to the reasons they answered as they did, the most prominent concerns physicians expressed were issues of safety that were not offset by the benefit afforded the individual, even in the face of explicit safety claims. Moreover, many physicians indicated that they viewed safety claims with considerable skepticism. It has become routine for safety to be raised and summarily dismissed as an issue in the debate over pharmacological cognitive enhancement; the observation that physicians were so skeptical in the face of explicit safety claims suggests that such a conclusion may be premature. Thus, physician attitudes suggest that greater weight be placed upon the balance between safety and benefit in consideration of pharmacological cognitive enhancement.     

Human pancreatic cancer stem cells: implications for how we treat pancreatic cancer

Pancreatic cancer has the worst prognosis of any major malignancy, with an annual death rate that approximates the annual incidence rate. Delayed diagnosis, relative chemotherapy and radiation resistance and an intrinsic biologic aggressiveness all contribute to the abysmal prognosis associated with pancreatic cancer. Answers to the frustrating effort to find effective therapies for pancreatic cancer may be gained through a renewed perspective on tumorigenesis as a process governed by a select population of cells, termed cancer stem cells (CSCs). Cancer stem cells, like their normal counterparts, have the properties of self-renewal and multilineage differentiation and possess inherently heightened DNA damage response and repair mechanisms that make them difficult to eradicate. Initially discovered in leukemias, researchers have identified CSCs in several solid-organ malignancies including breast, brain, prostate, and colon cancers. We have recently identified a CSC population in human pancreatic cancers. These pancreatic CSC represent 0.5% to 1.0% of all pancreatic cancer cells and express the cell surface markers CD44, CD24, and epithelial-specific antigen. Pancreatic CSCs have been shown to be resistant to standard chemotherapy and radiation, and devising specific therapies to target this distinct cell population is likely needed to identify effective therapies to treat this dismal disease.     

Targeting pancreatic cancer stem cells for cancer therapy

Pancreatic cancer (PC) is the fourth most frequent cause of cancer death in the United States. Emerging evidence suggests that pancreatic cancer stem cells (CSCs) play a crucial role in the development and progression of PC. Recently, there is increasing evidence showing that chemopreventive agents commonly known as nutraceuticals could target and eliminate CSCs that have been proposed as the root of the tumor progression, which could be partly due to attenuating cell signaling pathways involved in CSCs. Therefore, targeting pancreatic CSCs by nutraceuticals for the prevention of tumor progression and treatment of PC may lead to the development of novel strategy for achieving better treatment outcome of PC patients. In this review article, we will summarize the most recent advances in the pancreatic CSC field, with particular emphasis on nutraceuticals that target CSCs, for fighting this deadly disease.     

Women in medicine: practice patterns and attitudes.

Increasing numbers of women are entering medicine in Canada. In 1959 women accounted for 6% of the medical school graduates, but by 1989 they accounted for 44%. Although there has been little systematic investigation of the impact of this increase on Canada''s health care system, there are grounds for believing that female physicians bring with them distinctive values and interests, which may be reflected in the way they conduct their professional practices. We used data from a recent national survey of 2398 Canadian physicians to examine differences between women and men in their practices and their attitudes toward health care issues. Significant differences were found in the organization and management of the practices. Women preferred group over solo practice and were overrepresented in community health centres, health service organizations and centres locaux de services communautaires in Quebec. One-third of the women, as compared with half of the men, were in specialties. Even after adjusting for differences in workloads the incomes of the women were significantly lower than those of the men. Only minor differences were observed in the assessment of the health care system and alternative modes of organizing health care services. We believe that the differences were due to the double workload of women as professionals and family caregivers and the powerful socialization effects of medical education. As women overcome their minority status in the medical profession, differences between the sexes may become more apparent. Thus, the extent and effects of the progressive increase in the number of women in Canadian medicine should be assessed on an ongoing basis.     

Leveraging immunochemotherapy for treating pancreatic cancer

The refractory response of pancreatic ductal adenocarcinoma(PDAC) to multiple treatment regimens can be attributed to the presence of a desmoplastic stroma toge...     

Proteomic patterns for cancer diagnosis--promise and challenges

Proteomic patterns have been discovered for a variety of cancers and cancer related diseases. The platforms used have been both mass spectrometry and microarrays and the incorporation of computer informatics has resulted in innovative possibilities for novel diagnostics.     

CD40 immunotherapy for pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and lethal cancer which is poorly responsive to standard therapies. Although the PDA tumor microenvironment is considered especially immunosuppressive, recent data mostly from genetically engineered and other mouse models of the disease suggest that novel immunotherapeutic approaches hold promise. Here, we describe both laboratory and clinical efforts to target the CD40 pathway for immunotherapy in PDA. Findings suggest that CD40 agonists can mediate both T-cell-dependent and T-cell-independent immune mechanisms of tumor regression in mice and patients. T-cell-independent mechanisms are associated with macrophage activation and the destruction of PDA tumor stroma, supporting the concept that immune modulation of the tumor microenvironment represents a useful approach in cancer immunotherapy.