A phase I dose-escalation study of apatorsen (OGX-427), an antisense inhibitor targeting heat shock protein 27 (Hsp27), in patients with castration-resistant prostate cancer and other advanced cancers.

BACKGROUND: Heat shock protein 27 (Hsp27) is a chaperone protein that regulates cell survival via androgen receptor and other signaling pathways, thereby mediating cancer progression. Apatorsen (OGX-427) is a 2'-methoxyethyl-modified antisense oligonucleotide that inhibits Hsp27 expression. This study evaluated the safety profile and recommended phase II dosing of apatorsen in patients with advanced cancer. PATIENTS AND METHODS: Patients with castration-resistant prostate (CRPC), breast, ovary, lung, or bladder cancer were enrolled to this phase I dose-escalation study. Apatorsen was administered i.v. weekly in 21-day cycles following 3 loading doses and over 5 dose levels (200-1000 mg). Apatorsen plasma concentrations, circulating tumor cells (CTCs) and CTC Hsp27 expression, and serum Hsp27 levels were evaluated. RESULTS: Forty-two patients were accrued, of which 52% had CRPC. Patients were heavily pretreated, with 57% having had ≥3 prior chemotherapy regimens. During the loading dose/cycle 1 and overall study period, 93% and 100% of patients (N = 42) experienced treatment-related adverse events, respectively; most were grade 1-2 and included chills, pruritus, flushing, prolonged aPTT, lymphopenia, and anemia. One patient experienced a dose-limiting toxicity at the 600 mg dose level (intracranial hemorrhage in a previously undiagnosed brain metastasis). A maximum tolerated dose was not defined. Apatorsen Cmax increased proportionally with dose. Decreases in tumor markers and declines in CTCs were observed, with a prostate-specific antigen decline >%50% occurring in 10% of patients with CRPC; 29/39 assessable patients (74%) had reductions from ≥5 CTC/7.5 ml at baseline to <5 CTC/7.5 ml post-treatment. Twelve patients had stable measurable disease as best response. CONCLUSIONS: Apatorsen was tolerated at the highest dose evaluated (1000 mg). Single-agent activity was suggested by changes in tumor markers, CTC, and stable measurable disease. Phase II studies evaluating apatorsen are underway. CLINICALTRIALSGOV ID: NCT00487786.

Code status communication training in postgraduate oncology programs: a needs assessment.

Background: Discussions with patients with cancer about cardiopulmonary resuscitation directives (code status) are often led by residents. This study was carried out in Canada to identify current educational practices and gaps in training for this communication skill. Methods: Canadian medical and radiation oncology residents and program directors (pds) were surveyed about teaching practices, satisfaction with current education, and barriers to teaching code status discussion skills. Relative frequencies of categorical and ordinal responses were calculated. Results: Between November 2016 and February 2017, 95 (58.6%) of 162 residents and 17 (63%) of 27 pds completed surveys. Only 54.1% and 48.3% of medical and radiation oncology residents, respectively, had received any code status communication training before entering an oncology program. While 41% of residents expected to receive formal teaching on this topic during residency, 47.1% of pds endorsed inclusion of this topic in curricula. Only 20% of residents reported receiving formal evaluation of this skill while 41.2% of pds indicated that evaluations are provided. The importance of this communication skill in oncology was strongly supported. Among residents, 88% desired more training, and 82.3% of pds identified the need for new educational resources. Lack of time, resources, and evaluation tools were among the most commonly identified barriers to teaching. Conclusions: Oncology residency pds and trainees feel that code status communication is important, but teaching and evaluation of this skill are limited. Barriers to teaching and skill-building have been identified. Further work is underway to develop novel educational resources for code status communication training.

Implementing changes to a residency program curriculum before competency-based medical education: a survey of Canadian medical oncology program directors.

Background: Postgraduate medical education is undergoing a paradigm shift in many universities worldwide, transitioning from a time-based model to competency-based medical education (cbme). Residency programs might have to alter clinical rotations, educational curricula, assessment methods, and faculty involvement in preparation for cbme, a process not yet characterized in the literature. Methods: We surveyed Canadian medical oncology program directors on planned or newly implemented residency program changes in preparation for cbme. Results: Prior to implementing cbme, all program directors changed at least 1 clinical rotation, most commonly making hematology/oncology (74%) entirely outpatient and eliminating radiation oncology (64%). Introductory rotations were altered to focus on common tumour sites, and later rotations were changed to increase learner autonomy. Most program directors planned to enhance resident learning with electronic teaching modules (79%), new training experiences (71%), and academic half-day changes (50%). Most program directors (64%) planned to change assessment methods to be entirely based on entrustable professional activities. All programs had developed a competence committee to review learner progress, and most (86%) had integrated academic coaches. Conclusions: Transitioning to cbme led to major structural and curricular changes within medical oncology training programs. Identifying these commonly implemented changes could help other programs transition to cbme.

Surgical attitudes toward preoperative breast magnetic resonance imaging in women with early-stage breast cancer.

Background: Preoperative breast magnetic resonance imaging (mri) is commonly requested by surgeons in the initial workup of women with breast cancer; however, its use is controversial. We performed a survey of breast cancer surgeons across Canada to investigate current knowledge about, attitudes to, and self-reported use of preoperative breast mri in a publicly funded health care system in light of the limited evidence to support it. Methods: All identified general surgeons in Canada were mailed a survey instrument designed to probe current practice and knowledge of published trials. Results: Of 403 responding surgeons, 233 (58%) indicated that they performed breast cancer surgery. Of those 233, 218 (94%) had access to breast mri and completed the entire survey. Overall, 54.6% of responding surgeons felt that breast mri was useful in surgical planning, and more than half (58.3%) indicated that their frequency of use was likely to increase over the next 5 years. Surgeons found preoperative mri most useful in detecting mammographically occult disease (71.5% of respondents) and in planning for breast-conserving surgery (57.3%). The main limitations reported were timely access to mri (51%) and false positives (36.7%). Responses suggest a knowledge gap in awareness of published trials in breast mri. Conclusions: Our study found that, in early-stage breast cancer, self-reported use of mri by breast cancer surgeons in Canada varied widely. Reported indications did not align with published data, and significant gaps in self-reported knowledge of the data were evident. Our results would support the development and dissemination of guidelines to optimize use of mri.

An evaluation of the safety of continuing trastuzumab despite overt left ventricular dysfunction.

Background: The major limitation in the use of trastuzumab therapy is cardiotoxicity. We evaluated the safety of a strategy of continuing trastuzumab in patients with breast cancer despite mild, asymptomatic left ventricular impairment. Methods: Charts of consecutive patients referred to a cardio-oncology clinic from January 2015 to March 2017 for decline in left ventricular ejection fraction (lvef), defined as a fall of 10 percentage points or more, or a value of less than 50% during trastuzumab therapy, were reviewed. The primary outcome of interest was change in lvef, measured before and during trastuzumab exposure and up to 3 times after initiation of cardiac medications during a median of 9 months. Results: All 18 patients referred for decline in lvef chose to remain on trastuzumab and were included. All patients were treated with angiotensin converting-enzyme inhibitors or beta-blockers, or both. After initiation of cardiac medications, lvef increased over time by 4.6 percentage points (95% confidence interval: 1.9 percentage points to 7.4 percentage points), approaching baseline values. Of the 18 patients, 17 (94%) were asymptomatic at all future visits. No deaths occurred in the group. Conclusions: Many patients with mildly reduced lvef and minimal heart failure symptoms might be able to continue trastuzumab without further decline in lvef, adverse cardiac events, or death when treated under the supervision of a cardiologist with close follow-up.

The need for additional safeguards in the informed consent process in schizophrenia research.

The process of obtaining informed consent to participate in a clinical study presents many challenges for research conducted in a population of patients with schizophrenia. Morally valid, informed consent must include information sharing, decisional capacity, and capacity for voluntarism. This paper examines the unique features of schizophrenia that may threaten each of these elements of informed consent, and it proposes additional safeguards in the process of gaining informed consent from individuals with schizophrenia in order to maximise the decision-making potential of this patient population.

Interrelationship between plasma and ovarian cholesterol in a teleost fish.

The profiles of plasma and ovarian cholesterol altered similarly as a result of seasonal influence. Fish pituitary extract and LH significantly depleted plasma and ovarian free cholesterol only, esterified cholesterol remaining unaltered. Findings indicated that plasma cholesterol was the primary source of sterol for ovarian steroidogenesis.

Sertraline-induced hypoglycemia.

OBJECTIVE: To report a case of hypoglycemia that occurred in a patient treated with the selective serotonin-reuptake inhibitor, sertraline. CASE SUMMARY: An 82-year-old white woman with mild cardiovascular disease and no history of glucose intolerance was seen in the emergency department for a presyncopal episode associated with a blood glucose of 32 mg/dL as measured by the ambulance attendant. She had similar symptoms the day before. Despite repeated administration of oral and intravenous glucose, the patient had recurrent episodes of hypoglycemia and was hospitalized for four days. She had started taking sertraline 50 mg once daily for mild depression 25 days prior to presentation. Other medications included furosemide 20 mg/d, ramipril 5 mg/d, clopidogrel 75 mg/d, nitroglycerin patch 0.4 mg/h, and lorazepam 1 mg taken occasionally for agitation. She had never been prescribed any oral hypoglycemic agents. Serum sertraline and desmethylsertraline concentrations measured two, three, and four days after discontinuing sertraline were within the expected range, but the rate of decline was consistent with a moderately prolonged half-life. DISCUSSION: Sertraline has been shown to blunt postprandial hyperglycemia in rats and to potentiate the hypoglycemic effects of sulfonylurea agents in humans. It has not been reported to cause hypoglycemia independently, but in this case, a nondiabetic patient experienced multiple episodes of hypoglycemia that resolved after discontinuation of sertraline. CONCLUSIONS: This report and another implicating fluoxetine in a case of hypoglycemia suggest that healthcare professionals should consider these medications among the possible causes of hypoglycemia occurring in patients receiving selective serotonin-reuptake inhibitors.