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The Eph and Ephrin proteins, which constitute the largest family of receptor tyrosine kinases, are involved in normal tissue development and cancer progression. Here, we examined the expression and role of the B-type Eph receptor EphB2 in breast cancers. By immunohistochemistry using a progression tissue microarray of human clinical samples, we found EphB2 to be expressed in benign tissues, but strongly increased in cancers particularly in invasive and metastatic carcinomas. Subsequently, we found evidence that EphB2, whose expression varies in established cell breast lines, possesses multiple functions. First, the use of a DOX-inducible system to restore EphB2 function to low expressers resulted in decreased tumor growth in vitro and in vivo, while its siRNA-mediated silencing in high expressers increased growth. This function involves the onset of apoptotic death paralleled by caspases 3 and 9 activation. Second, EphB2 was also found to induce autophagy, as assessed by immunofluorescence and/or immunoblotting examination of the LC3, ATG5 and ATG12 markers. Third, EphB2 also has a pro-invasive function in breast cancer cells that involves the regulation of MMP2 and MMP9 metalloproteases and can be blocked by treatment with respective neutralizing antibodies. Furthermore, EphB2-induced invasion is kinase-dependent and is impeded in cells expressing a kinase-dead mutant EphB2. In summary, we identified a mechanism involving a triple role for EphB2 in breast cancer progression, whereby it regulates apoptosis, autophagy, and invasion., (© 2013 Published by Elsevier Inc.)

Common cancers may arise from several different mutations, and each causative mutation may require different treatment approaches. There are also several mechanisms by which malignancies may become resistant to therapy, and each mechanism will also require a different therapeutic strategy. Hence, the paradigm of devising therapies based on tumor type is suboptimal. Each common malignancy may now be regarded as a collection of morphologically similar but molecularly distinct orphan diseases, each requiring unique approaches. Current strategies that employ randomized clinical trials (RCTs) in unselected patients carry a high risk of misleading results. Available data suggest that it is reasonable to grant marketing approval for new anticancer agents based solely on high single-agent response rates in small phase I-II studies involving molecularly-defined patient groups where benefit from other therapies is unlikely. This could markedly speed patient access to important therapies while reducing health care costs by slashing drug development costs. Feasible post-approval surveillance procedures could provide ongoing monitoring of drug safety. While assessment of drug combinations would be more complex due to variable contributions of each component, new strategies have been proposed. In addition to savings from more efficient clinical trials methods, it is essential that we also markedly reduce costs of complying with clinical research regulations. Compliance is too cumbersome and expensive, and current regulatory inflexibility markedly slows progress while escalating health care costs. This requires urgent attention. Regulatory approaches intended to enhance safety may instead potentially cost far more life-years than they save by delaying approval of effective therapies.

Purpose: To determine whether the use of statins after prostate cancer diagnosis is associated with a decreased risk of cancer-related mortality and all-cause mortality and to assess whether this association is modified by prediagnostic use of statins., Patients and Methods: A cohort of 11,772 men newly diagnosed with nonmetastatic prostate cancer between April 1, 1998, and December 31, 2009, followed until October 1, 2012, was identified using a large population-based electronic database from the United Kingdom. Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% CIs of mortality outcomes associated with postdiagnostic use of statins, lagged by 1 year to account for latency considerations and to minimize reverse causality, and considering effect modification by prediagnostic use of statins., Results: During a mean follow-up time of 4.4 years (standard deviation, 2.9 years), 3,499 deaths occurred, including 1,791 from prostate cancer. Postdiagnostic use of statins was associated with a decreased risk of prostate cancer mortality (HR, 0.76; 95% CI, 0.66 to 0.88) and all-cause mortality (HR, 0.86; 95% CI, 0.78 to 0.95). These decreased risks of prostate cancer mortality and all-cause mortality were more pronounced in patients who also used statins before diagnosis (HR, 0.55; 95% CI, 0.41 to 0.74; and HR, 0.66; 95% CI, 0.53 to 0.81, respectively), with weaker effects in patients who initiated the treatment only after diagnosis (HR, 0.82; 95% CI, 0.71 to 0.96; and HR, 0.91; 95% CI, 0.82 to 1.01, respectively)., Conclusion: Overall, the use of statins after diagnosis was associated with a decreased risk in prostate cancer mortality. However, this effect was stronger in patients who also used statins before diagnosis.

Great advances in analytical technology coupled with accelerated new drug development and growing understanding of biological challenges, such as tumor heterogeneity, have required a change in the focus for biobanking. Most current banks contain samples of primary tumors, but linking molecular signatures to therapeutic questions requires serial biopsies in the setting of metastatic disease, next-generation of biobanking. Furthermore, an integration of multidimensional analysis of various molecular components, that is, RNA, DNA, methylome, microRNAome and post-translational modifications of the proteome, is necessary for a comprehensive view of a tumor's biology. While data using such biopsies are now regularly presented, the preanalytical variables in tissue procurement and processing in multicenter studies are seldom detailed and therefore are difficult to duplicate or standardize across sites and across studies. In the context of a biopsy-driven clinical trial, we generated a detailed protocol that includes morphological evaluation and isolation of high-quality nucleic acids from small needle core biopsies obtained from liver metastases. The protocol supports stable shipping of samples to a central laboratory, where biopsies are subsequently embedded in support media. Designated pathologists must evaluate all biopsies for tumor content and macrodissection can be performed if necessary to meet our criteria of >60% neoplastic cells and <20% necrosis for genomic isolation. We validated our protocol in 40 patients who participated in a biopsy-driven study of therapeutic resistance in metastatic colorectal cancer. To ensure that our protocol was compatible with multiplex discovery platforms and that no component of the processing interfered with downstream enzymatic reactions, we performed array comparative genomic hybridization, methylation profiling, microRNA profiling, splicing variant analysis and gene expression profiling using genomic material isolated from liver biopsy cores. Our standard operating procedures for next-generation biobanking can be applied widely in multiple settings, including multicentered and international biopsy-driven trials.

Objectives: To determine the association between self-rated health (SRH) and functional status, comorbidity, toxicity of treatment and mortality in older patients with newly-diagnosed cancer., Materials and Methods: Patients aged 65 and over, newly diagnosed were recruited at the Jewish General Hospital, Montreal, Canada. SRH and functional status [instrumental activities of daily living (IADL), basic activities of daily living (ADL), Eastern Cooperative Oncology Group performance status (ECOG PS), frailty markers and number of comorbid conditions] were evaluated prior to the start of treatment, and at 3, 6 and 12 months (SRH only). Treatment toxicity and mortality data were abstracted from the chart. Logistic regression was also used to examine the relationship between functional status, comorbidity and SRH at baseline. Logistic and Cox regression were used to examine the association between baseline SRH and treatment toxicity/time to death., Results: There were 112 participants enrolled on this study (median age 74.1). At baseline, 74 patients (66.1%) had a good SRH and 38 patients (33.9%) had poor SRH. Only an increasing number of comorbid conditions was associated with poor SRH at baseline in both univariate and multivariable analysis. We found no association between SRH and toxicity or mortality., Conclusion: A substantial proportion had poor SRH prior to and during cancer treatment. An increasing number of comorbidities was associated with poor SRH at baseline. SRH did not predict toxicity or mortality. Attention to comorbid conditions in older patients with cancer is warranted considering their impact on SRH in this population., (© 2013.)

The burden of cancer for Canadian citizens and society is large. New technologies have the potential to increase the use of genetic information in clinical decision-making, furthering prevention, surveillance, and safer, more effective drug therapies for cancer patients. Personalized medicine can have different meanings to different people. The context for personalized medicine in the present paper is genetic testing, which offers the promise of refining treatment decisions for those diagnosed with chronic and life-threatening illnesses. Personalized medicine and genetic characterization of tumours can also give direction to the development of novel drugs. Genetic testing will increasingly become an essential part of clinical decision-making. In Canada, provinces are responsible for health care, and most have unique policies and programs in place to address cancer control. The result is inconsistency in access to and delivery of therapies and other interventions, beyond the differences expected because of demographic factors and clinical education. Inconsistencies arising from differences in resources, policy, and application of evidence-informed personalized cancer medicine exacerbate patient access to appropriate testing and quality care. Geographic variations in cancer incidence and mortality rates in Canada-with the Atlantic provinces and Quebec having higher rates, and British Columbia having the lowest rates-are well documented. Our purpose here is to provide an understanding of current and future applications of personalized medicine in oncology, to highlight the benefits of personalized medicine for patients, and to describe issues and opportunities for improvement in the coordination of personalized medicine in Canada. Efficient and more rapid adoption of personalized medicine in oncology in Canada could help overcome those issues and improve cancer prevention and care. That task might benefit from the creation of a National Genetics Advisory Panel that would review research and provide recommendations on tests for funding or reimbursement, guidelines, service delivery models, laboratory quality assurance, education, and communication. More has to be known about the current state of personalized cancer medicine in Canada, and strategies have to be developed to inform and improve understanding and appropriate coordination and delivery. Our hope is that the perspectives emphasized in this paper will stimulate discussion and further research to create a more informed response.

Background: Before its regulatory approval in Canada, bevacizumab to treat patients with colorectal cancer (crc) was accessed through the Bevacizumab Expanded Access Trial and a special-access program at the Jewish General Hospital. We retrospectively evaluated patient outcomes in that large cohort., Methods: All patients (n = 196) had metastatic crc, were bevacizumab-naïve, and received bevacizumab in combination with chemotherapy at the Jewish General Hospital between 2004 and 2009. We collected patient demographics and clinical characteristics; relevant medical history, disease stage and tumour pathology at diagnosis; type, duration, and line of therapy; grades 3 and 4 adverse events (aes), time to disease progression (ttp), and overall survival (os) from diagnosis., Results: Median follow-up was 36.0 months. Median ttp was 8.0 months [95% confidence interval (ci): 7.0 to 9.0 months). Median os was 41.0 months (95% ci: 36.0 to 47.0 months). Of the 40 grades 3 and 4 bevacizumab-related aes experienced by 38 patients (19.4%), the most common were thrombocytopenia (n = 17), deep-vein thrombosis (n = 6), pulmonary embolism (n = 4), and hypertension (n = 3)., Conclusions: In an expanded access setting, our data reflect the efficacy and safety of bevacizumab-based therapy in the controlled post-registration clinical trial setting.

The majority of samples in existing tumour biobanks are surgical specimens of primary tumours. Insights into tumour biology, such as intratumoural heterogeneity, tumour-host crosstalk, and the evolution of the disease during therapy, require biospecimens from the primary tumour and those that reflect the patient's disease in specific contexts. Next-generation 'omics' technologies facilitate deep interrogation of tumours, but the characteristics of the samples can determine the ultimate accuracy of the results. The challenge is to biopsy tumours, in some cases serially over time, ensuring that the samples are representative, viable, and adequate both in quantity and quality for subsequent molecular applications. The collection of next-generation biospecimens, tumours, and blood samples at defined time points during the disease trajectory--either for discovery research or to guide clinical decisions--presents additional challenges and opportunities. From an organizational perspective, it also requires new additions to the multidisciplinary therapeutic team, notably interventional radiologists, molecular pathologists, and bioinformaticians. In this Review, we describe the existing procedures for sample procurement and processing of next-generation biospecimens, and highlight the issues involved in this endeavour, including the ethical, logistical, scientific, informational, and financial challenges accompanying next-generation biobanking.

In the last half of the century, advances in the systemic therapy of cancer, including chemotherapy, hormonal therapy, targeted therapy, and immunotherapy have been responsible for improvements in cancer related mortality in developed countries even as the population continues to age. Although such advancements have yet to benefit all cancer types, systemic therapies have led to an improvement in overall survival in both the adjuvant and metastatic setting for many cancers. With the pressure to make therapies available as soon as possible, the side-effects of systemic therapies, in particular long-term side-effects are not very well characterized and understood. Increasingly, a number of cancer types are requiring long-term and even lifelong systemic therapy. This is true for both younger and older patients with cancer and has important implications for each subset. Younger patients have an overall greater expected life-span, and as a result may suffer a greater variety of treatment related complications in the long-term, whereas older patients may develop earlier side-effects as a result of their frailty. Because the incidence of cancer in the world will increase over the next several decades and there will be more people living with cancer, it is important to have an understanding of the potential side-effects of new systemic therapies. As an introductory article, in this review series, we begin by describing some of the major advances made in systemic cancer therapy along with some of their known side-effects and we also make an attempt to describe the future of systemic cancer therapy.

Background: Glutathione (GSH) and related enzymes are critical to cell protection from toxins, both endogenous and environmental, including a number of anti-cancer cytotoxic agents., Scope of Review: Enhancing GSH and associated enzymes represents a longtime and persistent aim in the search for cytoprotective strategies against cancer, neurologic degeneration, pulmonary and inflammatory conditions, as well as cardiovascular ailments. The challenge is to identify effective GSH analogues or precursors that generate mimic molecules with glutathione's cellular protective effects. This review will provide an update on these efforts. Much effort has also been directed at depleting cellular GSH and related cytoprotective effects, in order to sensitize established tumors to the cytotoxic effects of anti-cancer agents. Efforts to deplete GSH have been limited by the challenge of selectivity doing so in tumor and not in normal tissue so as to avoid enhancing the toxicity of anti-cancer drugs. This review will also provide an update of efforts at overcoming the challenge of targeting the desired GSH depletion to tumor cells., Major Conclusions: This chapter provides a brief background and update of progress in the development and use of GSH analogues in the therapeutic setting, including the pharmacological aspects of these compounds., General Significance: This is an area of enormous research activity, and major advances promise the advent of novel therapeutic opportunities in the near future. This article is part of a Special Issue entitled Cellular functions of glutathione., (Copyright © 2012 Elsevier B.V. All rights reserved.)

To examine the significance of intratumor genetic heterogeneity (ITGH) of the androgen receptor (AR) gene in breast cancer, patient-matched samples of laser capture microdissected breast tumor cells, adjacent normal breast epithelia cells, and peripheral blood leukocytes were sequenced using a novel next generation sequencing protocol. This protocol measured the frequency of distribution of a variable AR CAG repeat length, a functional polymorphism associated with breast cancer risk. All samples exhibited some degree of ITGH with up to 30 CAG repeat length variants identified. Each type of tissue exhibited a different distribution profile of CAG repeat lengths with substantial differences in the frequencies of zero and 18-25 CAG AR variants. Tissue differences in the frequency of ARs with each of these CAG repeat lengths were significant as measured by paired, twin t-tests. These results suggest that preferential selection of 18-25 CAG repeat length variants in breast tumors may be associated with breast cancer, and support the observation that shorter CAG repeats may protect against breast cancer. They also suggest that merely identifying variant genes will be insufficient to determine the critical mutational events of oncogenesis, which will require measuring the frequency of distribution of mutations within cancerous and matching normal tissues., (© 2013 Wiley Periodicals, Inc.)

Background: Panitumumab is a fully human monoclonal antibody, directed against the epidermal growth factor receptor, that was shown to be effective in third-line metastatic colorectal cancer. We performed a retrospective analysis of patients with chemo-refractory non-KRAS-mutated metastatic colorectal cancer, who received panitumumab at the Jewish General Hospital in Montreal, Canada, between 2009 and 2012., Methods: This chart review included 44 patients (median age: 60 years; performance status: 0-3), of whom 50% had already received three lines of treatment. The primary endpoint was progression-free survival (pfs). Secondary endpoints were overall survival and safety. Tumour progression was determined by radiologic assessments performed once every 3 months per clinical guidelines or by clinical deterioration as determined by the clinician-investigator., Results: In our sample, median pfs was 21.86 ± 5.23 weeks (95% confidence interval: 12.9 to 36.9 weeks) and overall survival was 35.14 ± 7.75 weeks (95% confidence interval: 25.6 to 73.4 weeks) with a median of 5 cycles of panitumumab treatment. The most frequently reported toxicities with panitumumab were skin toxicity (16.2% grade 3) and hypomagnesemia (10.8% grade 3). No infusion reactions were reported., Conclusions: Despite a small sample size from a single institution, our survival and efficacy data are encouraging and comparable to results obtained from the registration panitumumab trial. Our findings suggest that panitumumab can be effective and tolerable in a real-world setting.

Tailoring medical treatment to individual patients requires a strong foundation in research to provide the data necessary to understand the relationship between the disease, the patient, and the type of treatment advocated for. Non-therapeutic oncology clinical trials studying therapeutic resistance require the participation of patients, yet only a small percentage enroll. Treating physicians are often relied on to recruit patients, but they have a number of ethical obligations that might be perceived as barriers to recruiting. Concepts such as voluntariness of consent and conflicts of interest can have an impact on whether physicians will discuss clinical trials with their patients and how patients perceive the information. However, these ethical obligations should not be prohibitive to physician recruitment of patients - precautions can be taken to ensure that patients' consent to research participation is fully voluntary and devoid of conflict, such as the use of other members of the research team than the treating physician to discuss the trial and obtain consent, and better communication between researchers, clinicians, and patients. These can ensure that research benefits are maximized for the good of patients and society.

Background: Melanoma is the fastest growing tumor of the skin, which disproportionately affects younger and middle-aged adults. As melanomas are visible, recognizable, and highly curable while in early stages, early diagnosis is one of the most effective measures to decrease melanoma-related mortality. Skin self-examination results in earlier detection and removal of the melanoma. Due to the elevated risk of survivors for developing subsequent melanomas, monthly self-exams are strongly recommended as part of follow-up care. Yet, only a minority of high-risk individuals practices systematic and regular self-exams. This can be improved through patient education. However, dermatological education is effective only in about 50% of the cases and little is known about those who do not respond. In the current literature, psychosocial variables like distress, coping with cancer, as well as partner and physician support are widely neglected in relation to the practice of skin self-examination, despite the fact that they have been shown to be essential for other health behaviors and for adherence to medical advice. Moreover, the current body of knowledge is compromised by the inconsistent conceptualization of SSE. The main objective of the current project is to examine psychosocial predictors of skin self-examination using on a rigorous and clinically sound methodology., Methods/design: The longitudinal, mixed-method study examines key psychosocial variables related to the acquisition and to the long-term maintenance of skin self-examination in 200 patients with melanoma. Practice of self-exam behaviors is assessed at 3 and 12 months after receiving an educational intervention designed based on best-practice standards. Examined predictors of skin self-exam behaviors include biological sex, perceived self-exam efficacy, distress, partner and physician support, and coping strategies. Qualitative analyses of semi-structured interviews will complement and enlighten the quantitative findings., Discussion: The identification of short and long-term predictors of skin self-examination and an increased understanding of barriers will allow health care professionals to better address patient difficulties in adhering to this life-saving health behavior. Furthermore, the findings will enable the development and evaluation of evidence-based, comprehensive intervention strategies. Ultimately, these findings could impact a wide range of outreach programs and secondary prevention initiatives for other populations with increased melanoma risk.

Purpose: Little is known about the incidence of falls in cancer patients receiving cancer treatment. The aims were to explore the number of falls older adults report in the 6 months after cancer diagnosis, and if those with a fall were more frail than those who did not fall., Methods: Secondary data analysis of a prospective pilot study that recruited patients aged 65 and older with a new cancer diagnosis. At each interview (baseline, 3- and 6-month follow-up), participants were asked if they had a fall in the previous 3 months. The frailty markers and functional status were obtained at baseline, 3- and 6-month follow-up. Chi-square and t tests were used to compare those who had a fall to those who had no fall. Univariate logistic regression analysis was conducted to explore the association between sociodemographic and health characteristics and reporting a fall., Results: Seventeen participants (18.7%) reported one or more falls in the first 6 months after cancer diagnosis. Fifteen participants reported one or more falls in the 3 months prior to the cancer diagnosis. Those who had a fall and those with no fall were not different in terms of health and functioning. None of the sociodemographic and health characteristics including the frailty markers were associated with a fall., Conclusion: A fall is common in cancer patients. More research is needed to examine the risk factors for a fall in older adults receiving cancer treatment.

Connexin43 (Cx43) expression is lost in cancer cells and many studies have reported that Cx43 is a tumor suppressor gene. Paradoxically, in a cellular NIH3T3 model, we have previously shown that Ha-Ras-mediated oncogenic transformation results in increased Cx43 expression. Although the examination of transcriptional regulation revealed essential regulatory elements, it could not solve this paradox. Here we studied post-transcriptional regulation of Cx43 expression in cancer using the same model in search of novel gene regulatory elements. Upon Ras transformation, both Cx43 mRNA stability and translation efficiency were increased. We investigated the role of Cx43 mRNA 3' and 5'Untranslated regions (UTRs) and found an opposing effect; a 5'UTR-driven positive regulation is observed in Ras-transformed cells (NIH-3T3(Ras)), while the 3'UTR is active only in normal NIH-3T3(Neo) cells and completely silenced in NIH-3T3(Ras) cells. Most importantly, we identified a previously unknown regulatory element within the 3'UTR, named S1516, which accounts for this 3'UTR-mediated regulation. We also examined the effect of other oncogenes and found that Ras- and Src-transformed cells show a different Cx43 UTRs post-transcriptional regulation than ErbB2-transformed cells, suggesting distinct regulatory pathways. Next, we detected different patterns of S1516 RNA-protein complexes in NIH-3T3(Neo) compared to NIH-3T3(Ras) cells. A proteomic approach identified most of the S1516-binding proteins as factors involved in post-transcriptional regulation. Building on our new findings, we propose a model to explain the discrepancy between the Cx43 expression in Ras-transformed NIH3T3 cells and the data in clinical specimens.

Background: Mapping patient and work flow and cost analysis studies can help determine the most efficient and cost effective way of providing health services while still maintaining the best standards of care. This study used both time and motion methodology and hospital data to assess the contribution of staff time and facility usage to the overall cost of cancer care during patient visits to a comprehensive cancer centre in Quebec, using metastatic colorectal cancer as a model., Methods: A workflow diagram was created mapping direct and indirect steps involved during a patient's physician or treatment (FOLFOX/bevacizumab or XELOX/bevacizumab) visit. Staff were timed as they performed each task and this data together with compensation amounts were used to calculate personnel costs. Mean work times and 95% confidence intervals (CI) were calculated. Operation and maintenance (O&M) costs for the Centre were calculated using information from hospital databases. All costs were presented in constant Canadian dollars for the 2010-2011 fiscal year period., Results: For physician visits, direct and indirect personnel costs were $9.25 (95%CI:$7.00-$11.51) and O&M costs were $60.21, for a total of $69.46 (95%CI:$67.21-$71.72). For treatment visits, personnel and O&M costs were $71.91 (95%CI:$45.53-$98.29) and $62.00 respectively for a total of $133.91 (95%CI:$107.53-$160.29). When calculated for treatment alone, the total cost was $136.06 (95%CI:$109.16-$162.95) for FOLFOX/bevacizumab and $119.94 (95%CI:$96.89-$142.99) for XELOX/bevacizumab. The highest cumulative personnel costs were for the pharmacists and nurses ($38.87 and $34.82 respectively). Regarding patient flow, total time in between steps was 77.6 and 49.5 minutes for a physician or treatment visit respectively., Conclusions: This study from a health care provider's perspective, demonstrated that in the context of increasingly expensive therapies, costs associated with staff time and facility usage do not contribute greatly to the overall cost of treating cancer at this cancer centre. It also illustrated the need for improvements in patient and work flow to reduce wait times in the clinic.

Therapeutic resistance remains a major cause of cancer-related deaths. Resistance can occur from the outset of treatment or as an acquired phenomenon after an initial clinical response. Therapeutic resistance is an almost universal phenomenon in the treatment of metastatic cancers. The advent of molecularly targeted treatments brought greater efficacy in patients whose tumors express a particular target or molecular signature. However, resistance remains a predictable challenge. This article provides an overview of somatic genomic events that confer resistance to cancer therapies. Some examples, including BCR-Abl, EML4-ALK, and the androgen receptor, contain mutations in the target itself, which hamper binding and inhibitory functions of therapeutic agents. There are also examples of somatic genetic changes in other genes or pathways that result in resistance by circumventing the inhibitor, as in resistance to trastuzumab and BRAF inhibitors. Yet other examples results in activation of cytoprotective genes. The fact that all of these mechanisms of resistance are due to somatic changes in the tumor's genome makes targeting them selectively a feasible goal. To identify and validate these changes, it is important to obtain biopsies of clinically resistant tumors. A rational consequence of this evolving knowledge is the growing appreciation that combinations of inhibitors will be needed to anticipate and overcome therapeutic resistance.

Introduction: The concept of frailty may be useful to characterize vulnerability. The aim of this pilot study was to explore the association between frailty/functional status and treatment toxicity at 3 months and mortality at 6 months., Methods: Patients aged ≥65 years referred to the Jewish General Hospital, Montreal, with a new cancer diagnosis. Seven frailty markers and 4 functional status measures were examined. Logistic regression was used to examine the association between frailty/functional status and toxicity, and Cox models for time to death., Results: 112 participated, median age 74.1, 31 had toxicity and 15 died. At baseline, 88% had ≥1 frailty marker. Low grip strength predicted toxicity (OR 8.47, 95%CI: 1.3-53.6), ECOG performance status and ADL disability predicted time to death., Conclusion: The majority had ≥1 frailty marker. Low grip strength predicted toxicity, none of the functional measures did. Further researcher investigating the usefulness of frailty markers is needed., (2010 Elsevier Ireland Ltd. All rights reserved.)

Background: The aim of this prospective study was to report the quality of life (QoL) of older cancer patients during the first year after diagnosis and factors influencing QoL., Patients and Methods: Newly diagnosed patients aged ≥65 years were recruited for a pilot prospective cohort study at the Jewish General Hospital, Montreal, Canada. Participants were interviewed at baseline, and at 1.5, 3, 4.5, 6, and 12 months. QoL was assessed at each interview using the European Organization for the Research and Treatment of Cancer Quality of Life Core Questionnaire with 30 items. Logistic regression was conducted to determine which sociodemographic, health, and functional status characteristics were associated with decline in global health status/QoL between baseline and 12-month follow-up., Results: There were 112 participants at baseline (response rate 72%), median age of 74.1, and 70% were women. Between baseline and 12-month follow-up (n=78), 18 participants (23.1%) declined ≥10 points in global health status/QoL, while 34 participants (43.6%) remained stable and 23 participants (33.3%) improved ≥10 points. None of the sociodemographic, health, and functional status variables were associated with decline in logistic regression analyses., Conclusion: Almost 25% of older adults experienced clinically relevant decline in their QoL. Further research is needed on which factors influence decline in QoL in older adults., (© The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Introduction: The management of older cancer patients is often suboptimal. This study aims to understand the management of older cancer patients who may receive chemotherapy., Methods: A questionnaire was mailed in 2006-2007 to 181 medical oncologists and hematologists practicing in the Province of Quebec, Canada. Physicians, involved in treatment decisions regarding chemotherapy in cancer patients aged 70 years and older, were eligible., Results: The response rate was 45.7%. Treatment toxicity (24.4%), comorbidities (20.5%), and lack of social support (10.9%) were reported as challenges when caring for older cancer patients. Comorbidities and functional status were reported as principal factors when making treatment decisions regarding chemotherapy; 77.5% of respondents expressed interest in collaborating with geriatricians., Conclusions: The concerns of respondents about comorbidities, functional status, and social support, along with their interest to collaborate with geriatricians, support the need for a partnership between these two disciplines., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Comorbidities and risk factors likely to complicate treatment are common in elderly cancer patients. Anthracyclines remain the cornerstone of first-line therapy for non-Hodgkin's lymphoma (NHL) and metastatic and early breast cancer but can cause congestive heart failure. Elderly patients are at increased risk of this event and measures to reduce it should be considered., Methods: A committee of experts in breast cancer and NHL met under the auspices of the International Society for Geriatric Oncology to review the literature and make recommendations, based on level of evidence, for the assessment, treatment and monitoring of elderly patients requiring anthracyclines., Results and Recommendations: Use of anthracycline-based chemotherapy illustrates many of the dilemmas facing elderly cancer patients. Age in itself should not prevent access to potentially curative treatment or treatment that prolongs life or improves its quality. The risk of cardiotoxicity with conventional anthracyclines is increased by the following factors: an existing or history of heart failure or cardiac dysfunction; hypertension, diabetes and coronary artery disease; older age (independent of comorbidities and performance status); prior treatment with anthracyclines; higher cumulative dose of anthracyclines and short infusion duration. The fact that cumulative and irreversible cardiotoxicity is likely to be greater in this population than among younger patients calls for effective pretreatment screening for risk factors, rigorous monitoring of cardiac function and early intervention. Use of liposomal anthracycline formulations, prolonging the infusion time for conventional anthracyclines and cardioprotective measures should be considered. However, when treatment is being given with curative intent, care should be taken to ensure reduced cardiotoxicity is not achieved at the expense of efficacy.

Breast cancer is a prevalent disease and a major cause of morbidity and cancer-related deaths among women worldwide. A significant number of patients at the time of primary diagnosis present metastatic disease, at least to locoregional lymph nodes, which results in somewhat unpredictable prognosis that often prompts adjuvant systemic therapies of various kinds. The time course of distant recurrence is also unpredictable with some patients sustaining a recurrence within months after diagnosis, even during adjuvant treatments, while others can experience recurrence years or decades after initial diagnosis. To date, clinically approved therapeutics yielded marginal benefits for patients with systemic metastatic breast disease, since despite high clinical responses to various therapies, the patients virtually always become resistant and tumor relapses. Molecular profiling studies established that breast cancer is highly heterogeneous and encompasses diverse histological and molecular subtypes with distinct biological and clinical implications in particular in relation to the incidence of progression to metastasis. The latter has been recognized to result from late genetic events during the multistep progression proposed by the dominant theory of carcinogenesis. However, there is evidence that the dissemination of primary cancer can also be initiated at a very early stage of cancer development, originating from rare cell variants, possibly cancer stem-like cells (CSC), with invasive potential. These precursor metastatic cancer cells with stem-like properties are defined by their ability to self-renew and to regenerate cell variants, which have high plasticity and intrinsic invasive properties required for dissemination and tropism toward specific organs. Equally relevant to the CSC hypothesis for metastasis formation is the epithelial-mesenchymal transition (EMT) process, which is critical for the acquisition of cancer cell invasive behavior and for selection/gain of CSC properties. These exciting concepts have led to the formulation of various approaches for targeting precursor metastatic cells, and these have taken on greater priority in therapeutic drug discovery research by both academia and pharmaceuticals. In this review, we focus on current efforts in medicinal chemistry to develop small molecules able to target precursor metastatic cells via interference with the CSC/EMT differentiation program, self-renewal, and survival. It is not meant to be comprehensive and the reader is referred to selected reviews that provide coverage of related basic aspects. Rather, emphasis is given to promising molecules with CSC/EMT signaling at the preclinical stage and in clinical trials that are paving the way to new generations of anti-metastasis drugs.

Many agents are being studied for the treatment of metastatic breast cancer (MBC), yet few studies have demonstrated longer overall survival (OS), the primary measure of clinical benefit in MBC. This paper examines the key endpoints in clinical trials and U.S. Food and Drug Administration (FDA) approvals of drugs for MBC. PubMed was searched (1980 to October 2009) for reports of phase III trials investigating chemotherapy and/or targeted therapy agents in MBC. FDA approval histories (1996-2009) for cytotoxic and biological agents indicated for MBC were reviewed. Of the 73 phase III MBC trials reviewed, a strikingly small proportion of trials demonstrated a gain in OS duration (12%, n = 9). OS gains were less frequently noted in first-line trials (8%) than in trials of second-line plus other lines of therapy (22%). Few trials were designed with the capacity to detect OS effects. Among 37 phase III trials conducted in the last 15 years, only three systemic therapies were approved for first-line use and nine were approved for use as second-line or other lines of therapy. Of these, only four were supported by results showing longer survival times. There is substantial discordance among the design and conduct of clinical trials, FDA drug approval, and the current view of OS as the ultimate measure of clinical benefit. There is an urgent need to reassess standards for clinical benefit in MBC and to establish guidelines for study design and conduct and drug approval. In the end, what matters most is ensuring rapid access to safe and effective oncology treatments.

Research on the use of health care by older newly-diagnosed cancer patients is sparse. We investigated whether frailty predicts hospitalization, emergency department (ED) and general practitioner (GP) visits in older cancer patients in a prospective pilot study. Newly-diagnosed cancer patients aged 65 years and over were recruited in the Segal Cancer Centre, Jewish General Hospital, Montreal, Canada. One hundred ten patients participated, mean age 74.1, 70% women. During 1 year follow-up, 52 patients (47.3%) had cancer-related hospitalizations, 23 patients (20.9%) had ED visit and 17 patients (15.5%) had GP visit. No frailty marker predicted hospitalization or visits to the GP. Cognitive impairment suspicion was the only frailty marker that predicted ED visits (odds ratio 4.97; 95%CI 1.14-21.69). Although health care use was considerable in this sample, most frailty markers were not associated with health care use in this pilot study., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKI) in patients with nonsmall cell lung cancer (NSCLC)., Methods: The authors tested the possibility that nucleotide sequencing may be poorly suited for detection of mutations in tumor samples and found that denaturing high-performance liquid chromatography (dHPLC) was an efficient and more sensitive method for screening., Results: These results suggested that some reports based on standard DNA sequencing techniques may have underestimated mutation rates. In the present report, the authors examined the relationship between the presence and type of EGFR mutations detected by dHPLC and various clinicopathologic features of NSCLC, including response to therapy with EGFR-TKI. Among 251 patients with advanced disease, 100 individuals received EGFR-TKI. Those whose tumors harbored a detectable EGFR kinase mutation were much more likely to have a partial response (PR) or stable disease (SD) with EGFR-TKI therapy than patients whose tumor contained no mutation (80% vs 35%; P = .001). Among the individual genotype subgroups, the frequency of a PR or SD was significantly different between patients with an exon 19 deletion compared with those with no detectable mutation (86% vs 35%; P < .001). Furthermore, patients whose tumors expressed an exon 19 mutant EGFR isoform exhibited a trend toward better EGFR-TKI response (86% vs 67%; P = .171) and improved survival compared with patients whose tumors expressed an exon 21 mutation., Conclusions: Our findings warrant confirmation in large prospective trials and exploration of the biological mechanisms of the differences between mutation types., (© 2010 American Cancer Society.)

Nrf2 is a key transcription factor, which induces a cytoprotective gene array. Nrf2 is regulated at the posttranslational level through proteasomal degradation through an interaction with the adapter protein Keap1. High levels of Nrf2, resulting from a loss of function mutation in Keap1, were reported in chemoresistant non-small cell lung cancer. We observed very low levels of Nrf2 and of Nrf2-regulated detoxification proteins as a frequent phenotype in the more chemosensitive breast cancer, and when engineering increased Nrf2 levels, we found resistance to both doxorubicin and paclitaxel. We here show that basal Nrf2 levels in different cell lines correlate with their respective sensitivity to a common cytotoxic chemotherapy. Nrf2 and its regulated genes and proteins are the targets of a major strategy in cancer prevention. Molecules that interfere with the Nrf2-Keap1-Cul3 protein-protein interactions result in higher levels of Nrf2. Both naturally occurring and synthetic molecules with this effect have been suggested as clinical chemopreventive agents, including molecules derived from cruciferous vegetables such as the isothiocyanate sulforaphane and even green tea polyphenols. Here, we determine the impact of these putative chemopreventive agents on the sensitivity of established cancer cell lines to chemotherapy. We confirmed that these molecules do increase Nrf2 and detoxification enzyme levels in breast cancer cell lines with very low basal Nrf2 levels, and this is associated with significant chemoresistance to cytotoxic drugs. Both effects are less in another breast cancer cell line with intermediate Nrf2, and in lung cancer cells with high Nrf2, these same molecules have no effect on Nrf2 but do actually enhance chemoresistance. While the details of dose and schedule of these agents require further study in in vivo models, these data sound a cautionary note for the use of these agents in patients with established cancers who are undergoing chemotherapy treatment.

Purpose: With the aging of the population, there will be an increase in the number of older adults diagnosed with cancer. Little is known about the characteristics of older newly diagnosed cancer patients who refuse cancer treatment and how often they refuse. The aim of this paper was to describe the health and functional status characteristics of patients who refused cancer treatment., Methods: A prospective pilot study on health and vulnerability in older newly diagnosed cancer patients was conducted in the Segal Cancer Centre, Jewish General Hospital, Montreal, Canada. One hundred-twelve patients agreed to participate (response 72%). Health and functional status were assessed during the baseline interview; information on cancer treatment was obtained from the medical chart at baseline, 3 and 6 months follow-up. Descriptive techniques such as frequencies and means were used to describe the health and functional status of patients who refused treatment., Results: Of the 112 participants, 17 (15.2%) refused cancer treatment partially or completely. Of those 17, 15 were women and 2 men. Fifteen participants refused a part of their treatment upfront. Two refused all further treatment after severe toxicity. The majority of participants refusing cancer treatment were women with breast cancer and they mostly refused adjuvant chemotherapy. Participants who refused often lived alone, were less often married/living common-law, had activities of daily living disability, and often had early disease., Conclusion: The majority of older newly diagnosed cancer patients underwent the recommended cancer treatment but partial or complete cancer treatment refusal in older newly diagnosed cancer patients was not uncommon.

Cutaneous melanoma still represents a paradox among all solid tumors. It is the cancer for which the best prognostic markers ever identified in solid tumors are available, yet there is very little understanding of their biological significance. This review focuses on recent biological data that shed light on the clinical-biological correlations underlining the 2010 American Joint Committee on Cancer (AJCC) melanoma staging system. A major challenge is to replace outcome clustering based on artificial biomarker breakpoints by a continuous multidimensional prognostic model. Major improvement will come from shared computerized tools that allow the generation of continuous likelihood scores for diagnosis, prognosis, and response prediction. This will lead to the development of platforms which can be used by scientists from different fields to integrate and share high-quality data in the pre-competitive setting and generate new probabilistic causal models.

Objective: To examine the impact of an 8-week cancer multimedia informational intervention on health-related outcomes among individuals newly diagnosed with cancer., Methods: Using a pre-/post-quasi-experimental design, participants with breast or prostate cancer (n=250) were conveniently recruited from four oncology ambulatory clinics and completed questionnaires at three points (enrolment, 1-2 weeks post-intervention, and 3 months later)., Results: Repeated-measure analyses showed that, when compared to controls, the intervention significantly improved satisfaction with cancer information over time for women (p<.001), prevented deterioration in functional quality of life (p=.030) and marginally improved perceived oncologist informational support (p=.051). There were no significant differences in psychosocial adjustment among men. Unlike previously suggested, the intervention did not have a differential impact according to levels of personal resources (self-esteem, mastery, and optimism). However, for all outcomes and regardless of group, participants high in personal resources reported better adjustment across time., Conclusion: Even though the hypotheses were only partially supported, the findings provide preliminary evidence that multimedia interventions can be supportive., Practice Implications: With increasing numbers of new cancer diagnoses, cancer survivors and more limited health care resources, further research is needed to evaluate potential benefits of health information technology in providing support to individuals facing cancer., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Older cancer patients are possibly at an increased risk of medication-related problems because, typically, they receive many medications during their cancer treatment, both for the cancer itself and for supportive care., Objectives: The aim of this study was to describe the number and severity of potential medication problems during treatment of cancer in the first year after diagnosis. We also sought to examine whether patients receiving systemic cancer treatment had more medication-related problems at 3, 6 and 12 months than those not receiving systemic cancer treatment., Methods: This was a prospective pilot cohort study on health and vulnerability in older newly diagnosed cancer patients with 1-year follow-up. The study was conducted at Segal Cancer Centre, Jewish General Hospital, Montreal, Canada. Of 156 eligible patients, 112 agreed to participate (response 71.8%). The patients were aged >or=65 years and were newly diagnosed with breast, colorectal or lung cancer, lymphoma or multiple myeloma. Patients were asked for permission to obtain their list of medications from their pharmacist. The cancer treatment information was abstracted from the medical chart. Vigilance Santé software was used to identify the presence, type and severity of potential medication problems., Results: The median number of medications was five at baseline, seven at 3 months and six at 6 and 12 months. At baseline, 247 potential medication problems were identified, followed by 273 at 3 months, 229 at 6 months and 188 at 12 months. About half of the patients at each follow-up had one or more moderate or severe potential medication problem. Patients receiving systemic cancer treatment had significantly fewer potential problems at 3 months than patients not receiving systemic cancer treatment, but no differences were observed at 6 and 12 months. The most common warnings were contraindications, interactions and miscellaneous warnings, and the cancer treatment was involved in 12% of all potential problems., Conclusion: This study showed that the majority of older newly diagnosed cancer patients take prescribed medication and about two-thirds have potential medication problems, of which about half are of at least moderate severity. The cancer treatment was involved in only a small proportion of all potential drug problems.

Importance of the Field: Connexins (Cxs) and gap junctional intercellular communications (GJICs) play roles in cancer development, growth and metastasis. Experimental studies suggest that targeting Cxs may be a novel technique, either to inhibit tumor cell growth directly or to sensitize to various therapies., Areas Covered in This Review: A brief introduction to the role of Cxs in cancer. The focus is mainly on data available in the literature regarding therapeutic aspects., What the Reader Will Gain: This article reviews the various strategies that take advantage of gap junctions and connexins to eliminate cancer cells, including use of the bystander effect (BE) in gene therapy, the effect of connexins on chemosensitization, the role of apoptotic processes and interactions with the microenvironment. Attempts to restore connexin expression at the transcriptional and post-transcriptional levels are described, as well as promising strategies recently explored. The potential and limitations of the approaches are discussed., Take Home Message: Connexins have multiple facets, singly, in hemichannel complexes, in gap junctions or interacting with different proteins. The regulation of their expression is not fully resolved and selective manipulation of Cxs expression is therefore a challenge. Although the therapeutic potential of connexins is undeniable, more effort is needed to study the regulation and functions of these proteins.

Transcription factor Nrf2 regulates a battery of genes encoding detoxifying enzymes. Under basal conditions, Nrf2 is sequestered in the cytoplasm by a protein known as Keap1. In response to oxidative stress, Keap1-mediated ubiquitination of Nrf2 is decreased significantly and the Nrf2 pathway is turned on. Residues C273 and C288 at the intervening region (IVR) domain of Keap1 are necessary for Keap1 to repress Nrf2, indicating a critical role of the IVR domain in the functional interaction of Keap1 with Nrf2. To identify chemical modulator targeting the IVR domain of Keap1, we built a 3D structural model of the Keap1 IVR domain and demonstrated this structural model is effective in retrieving novel Nrf2 inducers from chemical databases, BM10, 31, and 40 increase concentration of nuclear Nrf2, with a potency comparable to that of sulforaphane. We showed C297S mutation partially abolished the Nrf2-inducing effect of BM31, suggesting BM31 may target C297 in the IVR domain of Keap1. Further, BM31 and BM40 potently induce expression of ARE-regulated enzyme gamma-glutamylcysteine synthetase. We demonstrated that BM31 provides protections for the MCF-7 cells from cytotoxic damage of carcinogen benzo[a]pyrene.

Introduction: Cancer is an important health problem in older persons. The aim of this study was to explore how cancer specialists and geriatricians manage the treatment of older patients with cancer., Methods: Interviews using semi-structured open-ended questions., Sample: physicians working in oncology and geriatric medicine at McGill affiliated hospitals., Analysis: Grounded-theory approach., Results: 24 cancer specialists and 17 geriatricians participated. There was considerable variability with regard to assessment, treatment plan, and follow-up care and little collaboration between both specialists. The cancer specialists have more older cancer patients in their practice and collaborate with geriatricians mostly to deal with complications of cancer treatment. However, both groups of specialists expressed a desire to collaborate more and had similar research priorities., Conclusions: There was considerable variability in the management of older patients with cancer. Care for older patients with cancer might be improved by more collaboration between cancer specialists and geriatricians., (2009 Elsevier Ireland Ltd. All rights reserved.)

Purpose of Review: Cutaneous melanoma still represents a paradox among all solid tumors. It is the cancer for which the best prognostic markers ever identified in solid tumors are available, yet there is very little understanding of their biological significance. This review focuses on recent biological data that shed light on the clinico-biological correlations that support the 2010 AJCC melanoma staging system., Recent Findings: E-cadherin is a keratinocyte-melanoma adhesion molecule whose loss is required for the acquisition of an invasive phenotype. Recent data showed that this loss is mediated by the transcription factor Tbx3 which is also involved in suppressing melanocytes senescence. CCN3 is present in melanoma cells close to the epidermal-dermal interface, but not in melanoma cells that have invaded deep into the dermis. It has been recently demonstrated that CCN3 decreases the transcription and activation of matrix metalloproteinases and suppresses the invasion of melanoma cells. These results suggest that the absence of CCN3 in advanced melanoma cells contributes to their invasive phenotype and that ulceration modifies the microenvironment allowing CCN3-depleted melanoma cells to invade., Summary: A major challenge is to replace outcome clustering based on artificial biomarker breakpoints by a continuous multidimensional prognostic model. Major improvement will come from shared computerized tools allowing to generate continuous likelihood scores for diagnosis, prognosis and response prediction. This will lead to the development of platforms which can be used by scientists from different fields to integrate and share high-quality data in the precompetitive setting and generate new probabilistic causal models.

EphB2 is a tyrosine kinase receptor that has been shown to be a tumor suppressor gene in various cancers. However the mechanisms of this function are unknown. We report that EphB2 induces a form of cell death that does not involve the formation of apoptotic bodies or nuclear fragmentation and is instead accompanied by extensive vacuolization. Transmission electron microscopy demonstrates cytoplasmic vacuoles in EphB2-overexpressing cells that resembled autophagosomes. Using an EYFP-LC3 fusion protein and immunoblotting, we detected LC3 aggregation and conversion from form I to form II, both hallmarks of autophagy, in EphB2-transfected cells. Silencing of the autophagy regulating genes ATG5 or ATG7 using shRNAs, strongly prevented EphB2-induced cell death, further confirming its autophagic nature. EphB2 expression results in mitochondrial depolarization and translocation of cytochrome c from the mitochondria to the cytosol. Mapping of signaling pathways revealed novel information about the mechanisms of action of EphB2. We demonstrated that the MAPK pathway is important in the pro-death action of EphB2, through ERK1/2 phosphorylation and inhibition of this pathway using PD98059 counters EphB2-driven cell death. In addition, we found that inhibition of class III PI3K pathway, using the autophagy inhibitor 3MA, but not class I PI3K inhibition using LY294002, also effectively blocks EphB2- induced cell death. Finally, EphB2 expression inactivates Akt, which is a known inhibitor of autophagy. In conclusion, the EphB2 receptor induces an autophagic cell death that is mediated through the ERK1/2 and PI3K/Akt pathways.

Preliminary experiments showed that MC-1 magnetotactic bacteria (MTB) could be used for the delivery of therapeutic agents to tumoral lesions. Each bacterium can provide a significant thrust propulsion force generated by two flagella bundles exceeding 4pN. Furthermore, a chain of single-domain magnetosomes embedded in the cell allows computer directional control and tracking using a magnetic resonance imaging (MRI) system. Although these embedded functionalities suggest that MTB when under the influence of an external computer could be considered as biological microrobots with the potential of targeting tumors, little is known about their level of penetration in tumoral tissues. In this paper, in vitro experiments were performed to assess the capability of these bacteria to penetrate tumor tissue for the delivery of therapeutic agents. Multicellular tumor spheroids were used since they reproduce many properties of solid tumors. The results show the ability of these MTB when submitted to a directional magnetic field to penetrate inside a 3D multicellular tumor spheroid through openings present in the tissue.

Background: There have been few prospective observational studies which recruited older newly-diagnosed cancer patients, and of these only some have reported information on the number needed to screen to recruit their study sample, and the number and reasons for refusal and drop-out. This paper reports on strategies to recruit older newly-diagnosed cancer patients prior to treatment into an observational prospective pilot study and to retain them during a six-month period., Methods: Medical charts of all patients in the Segal Cancer Centre aged 65 and over were screened and evaluated for inclusion. Several strategies to facilitate recruitment and retention were implemented. Reasons for exclusion, refusal and loss to follow-up were recorded. Descriptive statistics were used to report the reasons for refusal and loss to follow-up. A non-response analysis using chi-square tests and t-tests was conducted to compare respondents to those who refused to participate and to compare those who completed the study to those who were lost to follow-up. A feedback form with open-ended questions was administered following the last interview to obtain patient's opinions on the length of the interviews and conduct of this pilot study., Results: 3060 medical charts were screened and 156 eligible patients were identified. Of these 112 patients participated for a response rate of 72%. Reasons for refusal were: feeling too anxious (40%), not interested (25%), no time (12.5%), too sick (5%) or too healthy (5%) or other reasons (5%). Ninety-one patients participated in the six-month follow-up (retention 81.3%), seven patients refused follow-up (6.2%) and fourteen patients died (12.5%) during the course of the study. The median time to conduct the baseline interview was 45 minutes and 57% of baseline interviews were conducted at home. Most patients enjoyed participation and only five felt that the interviews were too long., Conclusion: It was feasible to recruit newly-diagnosed cancer patients prior to treatment although it required considerable time and effort. Once patients were included, the retention rate was high despite the fact that most were undergoing active cancer treatment.

Nrf2 is the key transcription factor for cytoprotective gene programs. Nrf2 is normally maintained at very low concentrations by proteasomal degradation, through its interaction with the adapter protein Keap1 and the Cul3 E3 ligase. Increased Nrf2 concentration resulting from loss of function Keap1 mutations has been described in chemoresistant non-small cell lung cancer. Previous studies in breast cancer showed low levels of some Nrf2-regulated detoxification genes, but the mechanism has not been systematically examined. We found that half of the breast cancer cell lines examined have decreased concentration of Nrf2 compared with normal mammary epithelial cell lines, associated with variable but detectable levels in Keap1 levels, and consistently increased Cul3 mRNA and protein. Immunochemistry showed that 7 of 10 breast cancer specimens examined also have low Nrf2 levels and increased Cul3. Keap1 protein levels are variable. We found no C23Y mutation in Keap1 of any of the cell lines. Using siRNA, we silenced Cul3 in MCF-7 breast cancer cells, and microarray analysis reveals the induction of GCL, NQO1, AKR1C1, UGDH, and TXN by at least 2-fold. The Nrf2-regulated ABCC1 drug transporter was also found to be increased. These Cul3-silenced MCF7 cells are highly resistant to oxidative stress induced by H(2)O(2,) to the carcinogen benzo(a)pyrene, and to both Doxorubicin and Paclitaxel. This high Cul3/low Nrf2 signature may be key to cellular sensitivity to both chemical carcinogeneic stimuli as well as to cytotoxicity of commonly used chemotherapeutic drugs in established breast cancers.

Background: This was an open-label, nonrandomized, multicenter, 2-stage phase I trial of safety and preliminary efficacy of nonpegylated liposomal doxorubicin (NLD) in combination with trastuzumab in advanced breast cancer, with emphasis on cardiac toxicity., Patients and Methods: Forty patients (median age, 48 years; range, 30-74 years) with HER2/neu 2+ or 3+ tumors (by immunohistochemistry) were recruited December 1999 to November 2002. Patients were eligible if they received or= 1 cycle. Cardiac safety was assessed after completing >or= 4 full treatment cycles., Results: Thirty out of 40 patients (75%) received >or= 4 treatment cycles and were evaluable for cardiac safety. Five patients (13%), 4 who were doxorubicin pretreated, developed left ventricular ejection fraction reductions to < 50%, and 2 (5%) of these patients experienced clinical cardiac toxicity. Fifty percent of the patients had objective tumor responses; median progression-free survival was approximately 21 weeks. Twenty-six patients (65%) had grade 3/4 neutropenia; 2 patients experienced febrile neutropenia., Conclusion: Nonpegylated liposomal doxorubicin plus trastuzumab is active in HER2-positive patients with advanced breast cancer and is associated with a lower risk of cardiac toxicity than conventional doxorubicin plus trastuzumab.

Connexin43 (Cx43) is often deregulated in breast cancer tissue compared with normal adjacent tissue. Stable reexpression of Cx43 in cancer slows growth and renders the cells more sensitive to cytotoxic chemotherapeutics. Pseudogenes are often considered nonfunctional copies of DNA. The Cx43 pseudogene (PsiCx43) possesses all the features of an expressed gene and is exclusively transcribed in breast cancer cell lines and not in normal cells. PsiCx43 can be translated in vivo, and its protein exhibits growth-suppressive behavior similar to Cx43. We showed that PsiCx43 binds to the polyribosomes in breast cancer cells and that exogenous expression of PsiCx43 induces translational inhibition of Cx43. Furthermore, PsiCx43 is translated and binds more efficiently to the translational machinery than does Cx43 in an in vitro system. Following knockdown of PsiCx43 in breast cancer cells, we observed an increase in Cx43 RNA and protein. This results in increased cellular sensitivity to cytotoxic chemotherapy. Our results show that PsiCx43 acts as a posttranscriptional regulator of Cx43 in breast cancer cells, and that this represents an example of the regulation of genes by pseudogenes with potential therapeutic implications in cancer.

We report the SAR studies of 43 ionone-based chalcones that demonstrate substantial in vitro anti-proliferative activities in LNCaP, MDA-PCa-2b, 22Rv1, C4-2B and PC-3 prostate cancer cell lines. Compound 25 with an IC(50) value of 0.74 microM in LNCaP cells potently antagonizes DHT-induced transactivation of the wild type and the clinically relevant T877A, W741C and H874Y mutated androgen receptors, representing a novel chalcone as pan-antagonist of androgen receptor.

Purpose: CPX-1 is a novel, liposome-encapsulated formulation of irinotecan and floxuridine designed to prolong in vitro optimized synergistic molar ratios of both drugs postinfusion. This open-label, single-arm, dose-escalating phase I study was designed to determine the maximum tolerated dose and pharmacokinetics of CPX-1 in patients with advanced solid tumors., Experimental Design: Patients received CPX-1 at 30, 60, 100, 150, 210, or 270 units/m(2) (1 unit = 1 mg irinotecan + 0.36 mg floxuridine) infused over 90 minutes every 14 days in 28-day cycles. Pharmacokinetic samples were collected on days 1 and 15 of cycle 1., Results: Thirty-three patients were enrolled, treated, and evaluated for safety; 30 patients were evaluated for response. A 1:1 plasma irinotecan to floxuridine molar ratio was maintained for 8 to 12 hours. Grade 3/4 toxicities included diarrhea (24.2%), neutropenia (12.1%), and hypokalemia (12.1%); 1 patient (270 units/m(2)) died of persistent diarrhea, which led to dehydration and renal failure (grade 5). Partial response occurred in 3 (12%) of the 25 subjects evaluated through Response Evaluation Criteria in Solid Tumors. Progression-free survival lasting >6 months occurred in 9 patients, 6 with colorectal cancer. Among 15 colorectal cancer patients (10 with prior irinotecan), the calculated median progression-free survival was 5.4 months; 11 patients (72.7%) achieved disease control and 2 patients (13%) had partial response., Conclusions: Outpatient CPX-1 was well tolerated and antitumor activity was shown in patients with advanced solid tumors. The recommended dose for future studies is 210 units/m(2). This is the first clinical evaluation of fixed drug ratio dosing designed to maintain synergistic molar ratios for enhanced therapeutic benefit.

Background: Prescribing for older patients is challenging and complex. Cancer patients are at a considerable increased risk of drug-related problems because they typically receive a large number of medications during their cancer treatment, both for the cancer itself and for supportive care. Few studies have examined the scope of this problem in older newly diagnosed cancer patients., Objective: To investigate the number and severity of potential drug problems and factors associated with the occurrence of potential drug problems in older newly diagnosed cancer patients., Methods: This prospective pilot study was conducted in newly diagnosed cancer patients aged > or =65 years recruited in the Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada. Vigilance Santé software was used to identify the presence and type of potential drug problems. Logistic regression analyses were used to identify factors associated with the presence of one or more severe or moderately severe potential drug problems., Results: There were 112 participants with a mean age of 74.2 years, and 70% were women. A total of 103 patients (92%) were taking medications. The median number of medications per patient was 5 (interquartile range 3-9) and a total of 247 potential drug problems were identified. Sixty-four patients (62.1%) had a potential drug problem of any level of severity and 49 patients had a potential moderate/severe drug problem identified (47.6%). Two (0.8%) potential drug problems of the most severe level were identified, 122 warnings (49.4%) of all potential problems were of moderate severity and 123 warnings (49.8%) were at the least severe level. Factors associated with having one or more moderate/severe potential drug problems were taking five or more drugs and age > or =76 years., Conclusion: The majority of older newly diagnosed cancer patients in this study were taking at least one medication and the median number of medications per patient was 5. Published studies have shown that medication problems are common in community-dwelling older persons, but they are mostly of low severity. In this group of older newly diagnosed cancer patients, potential medication problems were also found to be common; however, half of the potential problems identified were of moderate severity.

The McGill University Department of Oncology has changed and expanded since its inception in 1990, responding to the move to interdisciplinary clinical care, teaching, and research. Although the traditional Divisions have been maintained to correspond to University and Royal College interfaces, the department has steadily been generating a variety of cross-departmental and interdisciplinary programs in which new insights into clinical care and biology are being generated. In research areas ranging from psychosocial and fundamental to translational and clinical therapeutics, interdisciplinarity and an emphasis on clinician-scientists are critical features.

Background: Older cancer patients seen in an oncology clinic seem to be healthier and less disabled than traditional geriatric patients. Choosing the most sensitive tools to assess their health status is a major issue. This cross-sectional study explores the usefulness of frailty markers in detecting vulnerability in older cancer patients., Methods: The study included cancer patients >or=70 years old referred to an oncology clinic for chemotherapy. Information on comorbidities, disability in instrumental activities of daily living (IADL) and activities of daily living (ADL), and seven frailty markers (nutrition, mobility, strength, energy, physical activity, mood, and cognition) was collected. Patients were classified into four hierarchical groups: 1- No frailty markers, IADL, or ADL disability; 2- Presence of frailty markers without IADL or ADL disability; 3- IADL disability without ADL disability; 4- ADL disability., Results: Among the 50 patients assessed, 6 (12.0%) were classified into Group 1, 21 (42.0%) into Group 2, 15 (30.0%) into Group 3, and 8 (16.0%) into Group 4. In Group 2, 7 patients (33.3 %) had one frailty marker, and 14 (66.7%) had two or more. The most prevalent of the frailty markers were nutrition, mobility, and physical activity., Conclusion: The assessment of seven frailty markers allowed the detection of potential vulnerability among 42% of older cancer patients that would not have been detected through an assessment of IADL and ADL disability alone. A longitudinal study is needed to determine whether the use of frailty markers can better characterize the older cancer population and predict adverse outcomes due to cancer treatment.

Glutathione (GSH) plays an important role in protecting cells against injury, particularly during oxidative stress. Alterations in GSH metabolism are becoming the focus of attention in many diseases such as cancer, neurodegeneration, and AIDS. As such, a rapid assessment of GSH levels in a clinical setting is of increasing importance. We tested the efficacy of the thiol-labeling fluorescent dye CM-SNARF in its ability to measure variations in GSH concentration using a visible-light flow cytometer. GSH levels in I83, Jurkat, and primary lymphocytes were depleted with buthionine sulfoximine (BSO) or diamide, or increased with N-acetylcysteine (NAC). Following each treatment, cells were divided and either labeled with CM-SNARF followed by flow cytometry analysis, or assayed for GSH using a biochemical method. BSO treatment caused a maximal 87-90% decrease in GSH and 68-76% decrease in fluorescence units. Diamide depleted GSH 91-95%, corresponding to a fluorescence decrease of 85-88%. NAC treatment increased GSH levels 27% and fluorescence 12-19%. The overall correlation (R2) between mean GSH concentration and mean fluorescence was 0.80-0.88. CM-SNARF can be used to semi-quantitatively and rapidly determine intracellular variations in GSH concentration in the range of 10-150 nmoles GSH/mg protein., (Copyright (c) 2007 International Society for Analytical Cytology.)

Glutathione depletion represents a potentially important strategy to sensitize tumors to cytotoxic drugs. l-Buthionine-(R,S)-sulfoximine (l-BSO) has been studied in both preclinical and early clinical trials, but limitation on its access has led to a search for alternatives. Using a 3D molecular model of human gamma-glutamylcysteine synthetase (gamma-GCS(H)), the major subunit of the rate-limiting GSH synthetic enzyme, we virtually screened the National Cancer Institute chemical database to identify compounds that could bind to and potentially inhibit gamma-GCS(H). We identified 51 test chemicals, all with structures very distinct from l-BSO. We subjected these compounds to biological assays measuring gamma-GCS(H) inhibition and glutathione (GSH) depletion. Among 10 novel gamma -GCS inhibitors identified, 4 compounds depleted glutathione in cells, and 2 with related structures sensitized tumor cells to melphalan treatment. This work validates the use of model-based database mining and identified inhibitors of gamma-GCS(H) with novel chemical structures.