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Introduction: Patients with locally advanced breast cancer (LABC) have a 5-year survival rate of 50% using standard treatment that includes neo-adjuvant chemotherapy, surgery and adjuvant radiation. Given this poor prognosis, we proposed use of an adjuvant regimen in the neoadjuvant setting, involving radiation with docetaxel for radiosensitization. Pathological complete response (pCR) at surgery (the best surrogate for overall survival) was the primary end-point of this single-arm prospective Phase II trial. Given that dose-dependent reductions in tumour RNA integrity mid-treatment were correlated with post-treatment pCRs in similar patients in the NCIC-CTG-MA.22 clinical trial (Breast Cancer Research and Treatment 119:347-56), we also assessed whether changes in tumour RNA integrity and concentration could be observed following this regimen. Methodology: Thirty-two patients with stage III non-metastatic LABC were enrolled at a single institution from 2009-2011. They were treated with neoadjuvant 5-Fluoro-uracil, Epirubicin, and Cyclophosphamide (FEC) q3 weekly for 4 cycles followed by weekly Docetaxel (35 mg/m²) concurrently with regional radiation (45 Gy with 16 Gy boost in 25 & 5 fractions) for the first 6 of 9 weeks (D/R). Serial 14 gauge tumour core biopsies were taken from the patients pre-, mid - and post-treatment and 1 mm³ samples used to assess RNA quantity and quality using an Agilent 2100 Bioanalyzer. This was followed by a modified radical mastectomy. Results: Treatment-related toxicities included grade 3 resolving pneumonitis (6 patients), grade 3 dermatitis (6 patients) and one treatment-related death. The pCR rate was 23%-about twice the provincial rate for LABC. At a mean 21 months follow-up, the relapse-free survival was 100% in the pCR cohort and 65% among partial responders (PRs). While biopsies were not normalized for mass, little difference in RNA concentration was observed between pre-treatment and post-FEC tumour biopsies (means of 50 ± 15 nanograms/microliter and 50 ± 12 nanograms/microliter, respectively). In contrast, the mean tumour RNA concentration was reduced to 10 ± 2.1 nanograms/microliter post-D/R. While the post-treatment biopsies often yielded insufficient RNA for assignment of tumour RNA integrity (RIN) values, treatment response appeared to be associated with low tumour RNA integrity, since patients with disease progression or stable disease had higher RIN values than patients exhibiting PRs or pCRs. Conclusions: This is the first study to use a full chemotherapy regimen with radiation in the neo-adjuvant setting for LABC. Although not without toxicity, the regimen appeared to significantly improve the pCR rate for this high-risk group, resulting in a much-improved outcome even at short-term follow-up. In addition, the FEC →D/R regimen produced reductions in tumour RNA concentration, and treatment response appeared to be associated with reduced RNA integrity. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic is highlighting the harm perpetuated by gender-blind programs for marginalized citizens, including sexual and gender minorities (SGMs) and cisgender women. Gender-blind programs are known to augment harms associated with violence and structural stigmatization by reinforcing rather than challenging unequal systems of power. The intersecting marginalization of these populations with systems of class, race, and settler-colonialism is exacerbating the impact that policies such as physical distancing, school closures, and a realignment of healthcare priorities are having on the wellbeing of these populations. The overarching reasons why women and SGM are marginalized are well known and stem from a hegemonic, patriarchal system that fails to fully integrate these groups into planning and decision making regarding public health programming-including the response to COVID-19. In this perspective, we aim to highlight how the exclusion of cisgender women and SGM, and failure to use a gender redistributive/transformative approach, has (i) hampered the recovery from the pandemic and (ii) further entrenched the existing power structures that lead to the marginalization of these groups. We also argue that COVID-19 represents a once-in-a-century opportunity to realign priorities regarding health promotion for cisgender women and SGM by using gender redistributive/transformative approaches to the recovery from the pandemic. We apply this framework, which aims to challenge the existing power structures and distribution of resources, to exemplars from programs in health, housing, employment, and incarceration to envision how a gender redistributive/transformative approach could harness the COVID-19 recovery to advance health equity for cisgender women and SGM., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: Conflicts of interest: No conflicts of interest exist due to financial and personal relationships that could potentially bias our work.

A 51-year-old man diagnosed with high-grade, high-volume metastatic castration-sensitive prostate adenocarcinoma received pelvic radiation, androgen deprivation therapy, and intravenous docetaxel. Serum prostate-specific antigen became undetectable following treatment. Within a year, his cancer progressed to castration-resistant disease, and he was treated with oral abiraterone acetate 1000 mg and prednisone 10 mg daily. Despite this, the serum prostate-specific antigen rose from 0.03 to 1.39 μg/L, and F-DCFPyL and F-FDG PET/CT showed progression. While F-DCFPyL uptake may be seen in aggressive disease, F-FDG portends poor prognosis. Despite intravenous platinum-based chemotherapy, the patient died of respiratory failure 20 months after his initial diagnosis.

Purpose: Female patients with breast cancer frequently develop arthralgia when treated with aromatase inhibitors (AI). Although the mechanism of AI-induced arthralgia is unknown, potential biomarkers have been identified. The purpose of this study was to investigate the clinical and genetic predictors of AI-induced arthralgia in a prospective cohort of patients with estrogen receptor-positive breast cancer., Methods: One hundred and ninety-six patients were enrolled at initiation of AI therapy with either letrozole or anastrozole. Patients completed two validated self-report questionnaires assessing pain, stiffness, and physical function at baseline, and repeated the questionnaires at two and at six months after the initiation of treatment with an AI. Germline DNA of all patients was genotyped for seven single-nucleotide polymorphisms (SNPs) previously identified by genetic screens and genome-wide association studies as associated with AI-induced arthralgia., Results: More than 50% of the study group experienced arthralgia symptoms. Genetic analysis revealed that four SNPs, in CYP19A1 (rs4775936) and ESR1 (rs9322336, rs2234693, rs9340799), were associated with the development of arthralgia (adjusted P = 0.016, 0.018, 0.017, 0.047). High body mass index (BMI) was also associated with the development of arthralgia symptoms (adjusted P = 0.001). Patients prescribed letrozole were significantly more likely to develop arthralgia than patients on anastrozole (P = 0.018), and also more likely to discontinue AI therapy due to arthralgia. The CYP19A1 (rs4775936) SNP was significantly associated with discontinuation of therapy due to intolerable arthralgia., Conclusions: Our results suggested that BMI and AI drug (letrozole versus anastrozole) were clinical predictors of arthralgia, while genetic variants rs4775936, rs9322336, rs2234693, and rs9340799 were genetic predictors of AI-induced arthralgia. Significantly, rs4775936 was also a predictor of discontinuation of therapy.

Background: Direct observation is necessary for specific and actionable feedback, however clinicians often struggle to integrate observation into their practice. Remotely audio-monitoring trainees for periods of time may improve the quality of written feedback given to them and may be a minimally disruptive task for a consultant to perform in a busy clinic., Methods: Volunteer faculty used a wireless audio receiver during the second half of students' oncology rotations to listen to encounters during clinic in real time. They then gave written feedback as per usual practice, as did faculty who did not use the listening-in intervention. Feedback was de-identified and rated, using a rubric, as strong/medium/weak according to consensus of 2/3 rating investigators., Results: Monitoring faculty indicated that audio monitoring made the feedback process easier and increased confidence in 95% of encounters. Most students (19/21 respondents) felt monitoring contributed positively to their learning and included more useful comments. 101 written evaluations were completed by 7 monitoring and 19 non-monitoring faculty. 22/23 (96%) of feedback after monitoring was rated as high quality, compared to 16/37 (43%) (p < 0.001) for monitoring faculty before using the equipment (and 20/78 (26%) without monitoring for all consultants (p < 0.001)). Qualitative analysis of student and faculty comments yielded prevalent themes of highly specific and actionable feedback given with greater frequency and more confidence on the part of the faculty if audio monitoring was used., Conclusions: Using live audio monitoring improved the quality of written feedback given to trainees, as judged by the trainees themselves and also using an exploratory grading rubric. The method was well received by both faculty and trainees. Although there are limitations compared to in-the-room observation (body language), the benefits of easy integration into clinical practice and a more natural patient encounter without the observer physically present lead the authors to now use this method routinely while teaching oncology students.

Introduction: Intensified chemotherapy improved outcomes for men with poor-prognosis metastatic germ cell cancer (GCC) and unfavorable tumor marker decline after one cycle of bleomycin, etoposide, and cisplatin (BEP) chemotherapy in the GETUG-13 trial. Herein, we report our experience to date using a similar approach., Methods: Patients were identified from our electronic GCC database. Men with poor-prognosis GCC and unfavorable tumor marker decline were offered intensified chemotherapy consisting of T-BEP (three cycles) plus paclitaxel, ifosfamide, and cisplatin (TIP) (one cycle), along with prophylactic granulocyte-colony stimulating factor (G-CSF) and resection of residual masses. Cisplatin, etoposide, and ifosfamide (PEI) replaced the last cycle of T-BEP for bleomycin pulmonary concerns. Serious toxicities, progression-free survival, and overall survival were evaluated retrospectively., Results: Ten patients with poor-prognosis GCC were identified from May 2012 to April 2016. Eight patients had unfavorable tumor marker decline. Six were offered and received intensified chemotherapy (two T-BEPx3 + TIP and four T-BEPx2 + PEI + TIP). Serious toxicities included neutropenic sepsis, deep venous thrombosis, and C. difficile colitis, but there were no toxic deaths. One patient died of synchronous metastatic adenocarcinoma ex teratoma. The remaining five patients achieved marker-negative partial response, two had residual mature teratoma excised, and four have no evidence of disease after surgery. All are alive at a median of 63.5 months (range 46.3-65.6); one patient has grade 2 peripheral sensory neuropathy, and one patient has grade 2 cognitive disturbance. Of four patients treated with standard BEP, two have died of disease and two are alive at 51.4 and 53.6 months., Conclusions: Our experience with intensified chemotherapy for men with poor-prognosis GCC and unfavorable tumor marker decline confirms that it is feasible, reasonably safe, and appears to provide results similar to those reported in GETUG-13.

Objectives: Pre-clinical data suggest metformin might enhance the effect of chemotherapy in breast cancer (BC). We conducted a Phase II randomized trial of chemotherapy plus metformin versus placebo in metastatic breast cancer (MBC)., Material and Methods: In this double blind phase II trial we randomly assigned non-diabetic MBC patients on 1st to 4th line chemotherapy to receive metformin 850 mg po bid or placebo bid. Primary outcome was progression-free survival (PFS); secondary outcomes included overall survival (OS), response rate (RR), toxicity and quality of life (QOL). With 40 subjects and a type-one error of 0.2 (one-sided), a PFS hazard ratio (HR) of 0.58 could be detected with 80% power., Results: 40 patients were randomized (22 metformin, 18 placebo) with a mean age of 55 vs 57 years and ER/PR positive BC in 86.4% vs 83.3% off metformin vs placebo, respectively. Mean BMI was 27kg/m2 in both arms. The majority of patients were on 1st line chemotherapy. Grade 3-4 toxicity occurred in 31.8% (metformin) vs 58.8% (placebo). Best response: Partial response 18.2% metformin vs 25% placebo, stable disease 36.4% metformin vs 18.8% placebo, progressive disease 45.4% metformin vs 56.2% placebo. Mean PFS was 5.4 vs 6.3 months (metformin vs placebo), HR 1.2 (95% CI 0.63-2.31). Mean OS was 20.2 (metformin) vs 24.2 months (placebo), HR 1.68 (95% CI 0.79-3.55)., Conclusion: In this population metformin showed no significant effect on RR, PFS or OS. These results do not support the use of metformin with chemotherapy in non-diabetic MBC patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: The aromatase inhibitor (AI) letrozole is a first-line drug in the adjuvant treatment of breast cancer in postmenopausal women. Adherence to AI therapy, including letrozole, remains problematic due to the development of debilitating AI-induced arthralgia. Letrozole is metabolized in the liver by CYP2A6. It remains unknown if plasma letrozole levels or CYP2A6 genetic variation is associated with the development of arthralgia., Methods: We enrolled 126 female breast cancer patients initiated on letrozole therapy and prospectively collected blood samples at baseline and two follow-up time points to determine letrozole plasma concentrations and CYP2A6 genotype. At each visit, participants completed two validated questionnaires to assess the severity of arthralgia symptoms., Results: More than half (55%) of patients experienced a significant increase in their arthralgia symptoms after initiation of treatment. The clinical variables of body mass index (P = 0.0003) and age (P = 0.0430) were negatively and positively associated with plasma letrozole concentrations, respectively. CYP2A6 genotype was significantly associated with letrozole levels (P < 0.0001), and increased plasma letrozole levels were observed in patients with CYP2A6 reduced-function genotypes. Plasma levels of letrozole and CYP2A6 genotype were not significantly associated with a change in pain score from baseline., Conclusions: CYP2A6 genotype was a significant predictor of letrozole plasma levels, but was not associated with the development of arthralgia.

Background: Pelareorep is an oncolytic virus with activity in many cancers including prostate. It has in vitro synergism with microtubule-targeted agents. We undertook a clinical trial evaluating pelareorep in mCRPC patients receiving docetaxel., Patients and Methods: In this randomized, open-label phase II study, patients received docetaxel 75mg/m 2 on day 1 of a 21-day cycle and prednisone 5mg twice daily, in combination with pelareorep (arm A) or alone (arm B). The primary endpoint was 12 weeks lack of disease progression rate (LPD)., Results: Eighty-five pts were randomized. Median age was 69, ECOG performance status was 0/1/2 in 31%/66%/3% of patients. Bone/regional lymph node/liver metastases were present in 98%/24%/6%. The median prognostic score was slightly higher in Arm A (144 vs. 129 p= 0.005). Adverse events were as expected but more prevalent in arm A. The 12-week LPD rate was 61% and 52.4% in arms A/B (p=0.51). Median survival was 19.1 on Arm A and 21.1 months on Arm B (HR 1.83; 95% CI 0.96 to 3.52; p=0.06). No survival benefit of pelareorep was found., Conclusion: Pelareorep with docetaxel was tolerable with comparable LPD in both arms but response and survival were inferior and so this combination does not merit further study., Competing Interests: CONFLICTS OF INTEREST LS declares the receipt of institutional support for the conduct of this study from Oncolytics Biotech, Inc. All other authors declare that they have no conflicts of interest.

Purpose: To evaluate whether concurrent neoadjuvant radiation added to standard chemotherapy could increase the pathologic complete response (pCR) to treatment for locally advanced breast cancer (LABC)., Methods and Materials: This prospective phase 2 trial recruited 32 LABC patients from 2009 to 2011. Patients received neoadjuvant every-3-weekly 5-fluorouracil (500 mg/m 2 ), epirubicin (100 mg/m 2 ), and cyclophosphamide (500 mg/m 2 ) for 3 cycles, followed by weekly docetaxel (35 mg/m 2 ) for 9 cycles. Regional radiation (45 Gy/25 plus 5.4 Gy/5) was delivered concurrently with docetaxel, then modified radical mastectomy. Patients were matched post hoc by a blinded statistician to a concurrent cohort treated with neoadjuvant chemotherapy, modified radical mastectomy, and adjuvant regional radiation., Results: Thirty of 32 patients completed treatment. Twenty-seven were successfully matched by propensity score to 81 control patients by age, stage, and molecular subtype. The concurrent chemoradiation produced a significant increase in pCR (14% vs 22%, P<.001) but no statistically significant difference in disease-free and overall survival at 3 years (respectively, 69% vs 81%, P=.186, hazard ratio 0.51; and 74% vs 89%, P=.162, hazard ratio 0.46). Toxicity included 25% of patients with grade 3 pneumonitis and 25% of patients with dermatitis, and 1 death., Conclusions: Concurrent neoadjuvant radiation added to radiosensitizing chemotherapy significantly improved pCR. A prospective randomized clinical trial is warranted to exploit the improved response seen with concurrent therapy but using another radio-sensitizing taxane, to better minimize treatment-related toxicity and determine its impact on overall survival., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: While radical cystectomy is the gold standard for muscle-invasive bladder cancer (MIBC), in octogenarians cystectomy results in a higher perioperative mortality rate (6.8-11.1%) than in younger patients (2.2%). Trimodality therapy is a bladder-sparing regimen composed of transurethral resection of bladder tumour (TURBT) and chemoradiotherapy, with intent for salvage cystectomy, and has a 62.5-90% initial complete response rate. In this study, we evaluate TURBT and chemoradiotherapy without salvage cystectomy in medically inoperable octogenarian patients., Methods: We identified a retrospective cohort of patients aged 80-89 years with invasive urothelial carcinoma who received combination chemoradiotherapy between 2008 and June 2014. Outcomes were evaluated by Kaplan-Meier (KM) and Cox regression., Results: In 40 patients, the mean age was 84.5 years (interquartile range [IQR] 83-86). Seventeen patients received hypofractionated, low-dose radiotherapy (LD) (37.5-40 Gy), while 23 received conventionally fractionated radiotherapy (high-dose [HD]) (50-65 Gy). Mean overall survival (OS) was 20.7 months (IQR 12.75-23.25), while mean recurrence-free survival (RFS) was 13.75 months (IQR 3.75-16.5). Patients receiving HD radiotherapy showed improved OS and local RFS (LRFS) without significant differences in Grade 3-4 toxicities. Univariate Cox regression identified hydronephrosis as a predictor of worse OS and local recurrence and HD radiotherapy as a predictor of improved OS and local recurrence rates. Multivariate Cox regression identified hydronephrosis to be a significant predictor of LRFS., Conclusions: Primary chemoradiotherapy for inoperable patients with MIBC resulted in a three-year OS of 54.9% (comparable to cystectomy) and three-year RFS of 42.3%. Superior outcomes were associated with more aggressive chemoradiotherapy treatment. The results of the local control subanalyses in this study are hypothesis-generating due to the limited patient numbers in the cohort.

The co-occurrence of semantic impairment and surface dyslexia in the semantic variant of primary progressive aphasia (svPPA) has often been taken as supporting evidence for the central role of semantics in visual word processing. According to connectionist models, semantic access is needed to accurately read irregular words. They also postulate that reliance on semantics is necessary to perform the lexical decision task under certain circumstances (for example, when the stimulus list comprises pseudohomophones). In the present study, we report two svPPA cases: M.F. who presented with surface dyslexia but performed accurately on the lexical decision task with pseudohomophones, and R.L. who showed no surface dyslexia but performed below the normal range on the lexical decision task with pseudohomophones. This double dissociation between reading and lexical decision with pseudohomophones is in line with the dual-route cascaded (DRC) model of reading. According to this model, impairments in visual word processing in svPPA are not necessarily associated with the semantic deficits characterizing this disease. Our findings also call into question the central role given to semantics in visual word processing within the connectionist account., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In murine models, overexpression of the MET receptor transgene induces tumors with human basal gene expression characteristics supporting MET inhibition as a treatment strategy for triple-negative breast cancer (TNBC). Foretinib is an oral multi-kinase inhibitor of MET, RON, AXL, TIE-2, and VEGF receptors with anti-tumor activity in advanced HCC and papillary renal cell cancer. Patients with centrally reviewed primary TNBC and 0-1 prior regimens for metastatic disease received daily foretinib 60 mg po in a 2-stage single-arm trial. Primary endpoints were objective response and early progression rates per RECIST 1.1. In stage 2, correlative studies of MET, PTEN, EGFR, and p53 on archival and fresh tumor specimens were performed along with enumeration of CTCs. 45 patients were enrolled with 37 patients having response evaluable and centrally confirmed primary TNBC (cTNBC). There were 2 partial responses (ITT 4.7 % response evaluable cTNBC 5.4 %) with a median duration of 4.4 months (range 3.7-5 m) and 15 patients had stable disease (ITT 33 %, response evaluable cTNBC 40.5 %) with a median duration of 5.4 months (range 2.3-9.7 m). The most common toxicities (all grades/grade 3) were nausea (64/4 %), fatigue (60/4 %), hypertension (58/49 %), and diarrhea (40/7 %). Six serious adverse events were considered possibly related to foretinib and 4 patients went off study due to adverse events. There was no correlation between MET positivity and response nor between response and PTEN, EGFR, p53, or MET expression in CTCs. Although CCTG IND 197 did not meet its primary endpoint, the observation of a clinical benefit rate of 46 % in this cTNBC population suggests that foretinib may have clinical activity as a single, non-cytotoxic agent in TNBC (ClinicalTrials.gov number, NCT01147484).

Background and Objectives: For hormone-sensitive breast cancers, treatment with breast-conserving surgery, tamoxifen, or aromatase inhibitors, along with adjuvant radiation, is the mainstay of therapy. The ideal timing of hormonal and radiation treatment is not well defined, and there is a significant degree of practice variability between concurrent and sequential treatment regimes. This variability can cause confusion amongst the clinical team resulting in contradictory recommendations, loss of patient trust, and the potential for missed initiation of hormonal therapy., Methods: To address this question, a systematic review of the literature was conducted and presented to the breast cancer multidisciplinary team at the London Regional Cancer Center. A three-round modified Delphi method was used to obtain a consensus on a series of a priori determined statements., Results: With the currently available evidence, the consensus was that hormonal therapy should be given sequentially after radiation. This will limit potential overlapping adverse effects between hormonal therapy and radiation that may decrease completion of treatment. The sequential approach has not been associated with any harm in clinical outcomes, and there is some suggestion of increased toxicity with concurrent use. However, in patients at high risk of distant recurrence, they felt it would be reasonable to consider concurrent treatment to avoid any delay in therapy., Conclusion: The consensus of our institution to utilize a sequential approach will standardize the treatment decisions and reduce the risk of failing to initiate hormonal therapy. Despite the lack of level 1 evidence, the Delphi methodology did provide a high level of confidence for our group to choose the sequential approach. The consensus was developed after a review of the literature revealed that there was no clear superiority of one schedule over the other and evidence that concurrent treatment may increase adverse events.

Background and Objectives: Adjuvant hormonal therapy is frequently used in the treatment of women with estrogen receptor (ER)/progesterone receptor (PR) positive breast cancer. When radiotherapy is given, hormone therapy may be delivered in a concurrent or sequential manner. Hormonal blockade with tamoxifen or aromatase inhibitors is thought to arrest hormonally dependent cancer cells in the early G1 phase of the cell cycle. This has been theorized to reduce the efficacy of radiation, which is known to be more effective in cells that are actively dividing. Therefore, there has been a reluctance by many to treat with concurrent hormonal and radiation therapy., Methods: We performed a search of the Medline database that led to the identification of 39 studies. Abstract and full-text review of these studies led to the identification of seven English non-review studies in peer-reviewed literature between 1995 and 2015 that addressed the question of timing of radiation and hormonal therapy. Outcome measures were captured from each of the studies., Results: No difference in survival or local-regional recurrence was identified between concurrent versus sequential treatment. Furthermore, no difference in cosmetic outcome or adverse effects was noted for either approach. However, when comparing radiation alone or radiation and hormonal therapy, there was an increased risk of breast and lung fibrosis with combined treatment., Conclusions: Hormone therapy, concurrent or sequential, with radiation results in comparable disease-related outcomes, including survival and recurrence. However, given the theoretical reduction in efficacy and increased rates of fibrosis with concurrent use, it is reasonable to support the use of sequential therapy.

Introduction: Most men with metastatic castration-resistant prostate cancer (CRPC) have biochemical response to docetaxel, but the objective response rate is low. Liver metastases are uncommon with CRPC and associated with shorter survival. More active treatment might benefit these patients. Epirubicin, cisplatin and flurouracil (ECF) is a standard regimen for gastric cancer and response in CRPC liver metastases has been reported. We reviewed our experience with ECF in CRPC with the primary objective of determining its anti-tumour activity in patients with liver metastatic CRPC., Methods: Men with CRPC treated with ECF were identified from electronic databases and data were extracted from medical records. Men with tumours showing neuroendocrine features were excluded., Results: In total, we identified 14 CRPC patients treated with ECF were identified, of which 8 had liver metastases. The median age was 56 (range: 42-76) and all had multiple poor prognostic features. A median of 6 cycles of ECF were administered (range: 1-10) and toxicities were similar to previous reports. Of the 8 patients with liver metastases, 5 had partial remission., Conclusions: ECF was highly active in this small selected group of younger men with liver metastases from CRPC and multiple poor prognostic features. Despite important limitations, this is the third report of high objective response rates with ECF in CRPC. Objective response rates are low with current monotherapies. A higher probability of ORR is preferred for critical organ disease, therefore the anti-tumour activity should encourage testing of ECF in comparison to the most active current therapies.

Tamoxifen is a widely utilized adjuvant anti-estrogen agent for hormone receptor-positive breast cancer, known to undergo CYP2D6-mediated bioactivation to endoxifen. However, little is known regarding additional genetic and non-genetic determinants of optimal endoxifen plasma concentration. Therefore, 196 breast cancer patients on tamoxifen were enrolled in this prospective study over a 24-month period. Blood samples were collected for pharmacogenetic and drug-level analysis of tamoxifen and metabolites. Regression analysis indicated that besides CYP2D6, the recently described CYP3A4*22 genotype, seasonal variation, and concomitant use of CYP2D6-inhibiting antidepressants were significant predictors of endoxifen concentration. Of note, genetic variation explained 33 % of the variability while non-genetic variables accounted for 13 %. Given the proposed notion of a sub-therapeutic endoxifen concentration for predicting breast cancer recurrence, we set the therapeutic threshold at 18 nM, the 20th percentile for endoxifen level among enrolled patients in this cohort. Nearly 70 % of CYP2D6 poor metabolizers as well as extensive metabolizers on potent CYP2D6-inhibiting antidepressants exhibited endoxifen levels below 18 nM, while carriers of CYP3A4*22 were twofold less likely to be in sub-therapeutic range. Unexpectedly, endoxifen levels were 20 % lower during winter months than mean levels across seasons, which was also associated with lower vitamin D levels. CYP3A4*22 genotype along with sunshine exposure and vitamin D status may be unappreciated contributors of tamoxifen efficacy. The identified covariates along with demographic variables were integrated to create an endoxifen concentration prediction algorithm to pre-emptively evaluate the likelihood of individual patients falling below the optimal endoxifen concentration.

Background and Aims: Chronic visceral pain is frequent, extremely debilitating, and generally resistant to pharmacological treatment. It has been shown that chronic visceral inflammation, through altered afferent visceral sensory input, leads to plastic changes in the central nervous system that ultimately sustain pain. Therefore approaches aiming at modulation of brain activity are attractive candidates to control visceral pain., Methods: Here we report findings of a phase II, sham-controlled clinical trial assessing the clinical effects and brain metabolic correlates of a 10-day course of daily sessions of slow-frequency, repetitive transcranial magnetic stimulation (rTMS) targeting the right secondary somatosensory cortex (SII) in patients with chronic pancreatitis and severe visceral pain., Results: Our results show a significant reduction in pain after real rTMS that lasted for at least 3 weeks following treatment. These clinical changes were correlated with increases in glutamate and N-acetyl aspartate (NAA) levels--neurometabolites associated with cortical activity and brain damage--as measured by in vivo single-voxel proton magnetic resonance spectroscopy (1H-MRS). Adverse effects in the real rTMS group were mild and short-lasting., Conclusions: Our results support preliminary findings showing that modulation of right SII with rTMS is associated with a significant analgesic effect and that this effect is correlated with an increase in excitatory neurotransmitter levels such as glutamate and NAA., (Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

Objective: To provide a current and evidence-based clinical review of practical value to primary care physicians encountering men with hormone-refractory prostate cancer (HRPC) in their practice., Methods: Evidence-based narrative review by two expert clinicians incorporating results of systematic reviews and randomized trials whenever available., Results: HRPC represents the final common pathway to death from prostate adenocarcinoma, the single most prevalent cancer in Canadian men. However, primary care physicians will not encounter these patients with a frequency adequate to develop confidence in their care. HRPC is defined by progressive disease despite castration, and biologically is a characterized by androgen hypersensitivity. It is important to understand that HRPC is a disease spectrum ranging from asymptomatic patients with only a rising prostatic-specific antigen (PSA) level and a prognosis measured in years to extremely symptomatic patients with widespread metastases requiring end-of-life care. Numerous effective management options are now available for HRPC and are selected based on the phase of the disease natural history, and patient comorbidities and preferences., Conclusions: Men with HRPC have therapeutic options that can improve and maintain both the quality and quantity of their lives. A co-management approach including a medical oncologist and the patient's urologist and primary care physician is preferred.

Canadian per capita drug expenditures increased markedly in recent years and have become center stage in the debate on health care cost containment. To inform public policy, these costs must be compared with the benefits provided by these drugs. This paper measures the statistical relationship between drug spending in Canadian provinces and overall health outcomes. The analysis relies on more homogenous data and includes a more complete set of controls for confounding factors than previous studies. Results show a strong statistical relationship between drug spending and health outcomes, especially for infant mortality and life expectancy at 65. This relationship is almost always stronger for private drug spending than for public drug spending. The analysis further indicates that substantially better health outcomes are observed in provinces where higher drug spending occurs. Simulations show that if all provinces increased per capita drug spending to the levels observed in the two provinces with the highest spending level, an average of 584 fewer infant deaths per year and over 6 months of increased life expectancy at birth would result., (Copyright (c) 2004 John Wiley & Sons, Ltd.)

The success of researchers in developing innovative and effective medicines has produced a healthier and older population, as well as an observable shift in expenditure towards pharmaceuticals. In contrast to drug expenditures, patented drug prices have actually shown an average annual decrease of 0.5% since 1988. While we agree cost-effectiveness evaluation is a useful input into the decision-making process of drug benefit managers, it is but one consideration, and it is imperative that governments look beyond drug budgets to the broader benefits of innovative drug therapy to Canadians, both economically and clinically. The lead paper makes a number of suggestions regarding clinical trials that would lead to an increased demand on the developers of innovative medicines, all of which would raise the development costs of drugs while reducing the spectrum of available agents. This commentary argues that focusing greater attention on ensuring the appropriate use of medicines, with less concentration on restricting Canadians' access to effective drugs available in other countries, will yield the greatest benefits to the health of our population. Patient health management is a strategy that deserves a closer look to achieve this goal.

The Ottawa General Hospital (OGH) is one of a growing number of institutions that has implemented a cost accounting system. The ability to track costs on a patient-specific basis provides an exciting avenue for reviewing the use of resources. With the accumulation of a complete fiscal year of data, the hospital recently embarked on a review process to identify opportunities for more detailed review with practitioners. This will support the OGH's surgical approach of targeting cuts, rather than making across-the-board reductions. The objective is to allow the hospital to maintain the highest levels of quality and service as the eroding funding situation allows. This paper describes the comprehensive approach taken by the review team to identify populations of patients that were relatively homogeneous and yet showed the greatest practice pattern variances between physicians. The method described provides a template for others to summarize large amounts of data and stratify patient groups for more detailed analysis of the patient care delivery process.

The Ottawa General Hospital is one of 13 Ontario hospitals participating in the Ontario Case Cost Project. The hospital has been collecting clinical and financial information based on the patient-specific use of products and services since April 1, 1993. The resulting decision-support database that is evolving enhances the traditional utilization review process. The author presents the analysis and conclusions regarding laparoscopic cholecystectomy patients as an example of the hospital's use of the data in utilization review activities.