Pan-urologic cancer genomic subtypes that transcend tissue of origin

AbstractUrologic cancers include cancers of the bladder, kidney, prostate, and testes, with common molecular features spanning different types. Here, we show that 1954 urologic cancers can be classified into nine major genomic subtypes, on the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy number, and RNA and protein expression). Tissue dominant effects are first removed computationally in order to define these subtypes, which reveal common processes—reflecting in part tumor microenvironmental influences—driving cellular behavior across tumor lineages. Six of the subtypes feature a mixture of represented cancer types as defined by tissue or cell of origin. Differences in patient survival and in the manifestation of specific pathways—including hypoxia, metabolism, NRF2-ARE, Hippo, and immune checkpoint—can further distinguish the subtypes. Immune checkpoint markers and molecular signatures of macrophages and T cell infiltrates are relatively high within distinct subsets of each cancer type studied. The pan-urologic cancer genomic subtypes would facilitate information sharing involving therapeutic implications between tissue-oriented domains.</jats:p

Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1 inhibitors: a case series

Background: Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained increasing attention across many solid tumors and hematologic malignancies due to their efficacy and favorable toxicity profile. With more than 1 agent now FDA-approved in a wide variety of tumor types, and with others in clinical trials, it is becoming more common that patients present to clinic for potential treatment with a second PD-1/PD-L1 inhibitor. Case presentation: In this report, we present two patients with renal cell carcinoma and one with melanoma who received PD-1/PD-L1 inhibitors. Upon progression on their first-line PD-1/PD-L1 inhibitors, these patients received a different PD-1 inhibitor (nivolumab in all cases) and all had progressive disease as their best response to the subsequent PD-1 inhibitor. The reported clinical information focuses on the course of the disease and the responses to all treatment regimens. Conclusions: Clinicians should refrain from using multiple PD-1/PD-L1 inhibitors sequentially outside of clinical trials until there is sufficient data to support this practice routinely. Prospective studies that allow prior treatment with PD-1/PD-L1 are needed to validate the efficacy and safety of these drugs in the second line or later setting. Furthermore, ongoing efforts that aim to identify mechanisms of resistance to immunotherapy will be informative and may ultimately assist physicians in select the optimal treatment following progression on PD-1/PD-L1 inhibitor

Étude de la mécanique respiratoire par la technique des oscillations forcées au cours de la ventilation liquidienne totale

Background : This study aimed to implement low-frequency forced oscillation technique (LFFOT) in neonatal total liquid ventilation (TLV) and to provide the first insight into respiratory impedance under this new modality of ventilation. Method. Thirteen newborn lambs weighing 2.5 « 0.4 kg (mean « SD) were premedicated, intubated, anesthetized, and then placed under TLV using a specially-design liquid ventilator and a perfluorocarbon. The respiratory mechanics measurements protocol was started immediately after TLV initiation. Three blocks of measurements were first performed: one during initial respiratory system adaptation to TLV, followed by two others series during steady state conditions. Lambs were then divided into two groups prior to undergoing another three blocks of measurements: the first group received a 10-min i v infusion of salbutamol (1.5 [micro]g/kg/min) after continuous infusion of methacholine (9 [micro]g/kg/min) while the second group of lambs were chest-strapped. Respiratory impedance was measured using serial single-frequency tests at frequencies ranging between 0.05-2 Hz and then fitted with a constant-phase model. 0.2 Hz harmonic test signals were also launched every ten minutes throughout the measurement protocol. Results. Airway resistance and inertance were starkly increased in TLV compared to gas ventilation with a resonant frequency [less than or equal to] 1.2 Hz. 0.2 Hz resistance and reactance were sensitive to bronchoconstriction and dilation as well as during compliance reduction. Conclusions. We report successful implementation of LFFOT to neonatal total liquid ventilation and present the first insight into respiratory impedance under this new modality of ventilation. We show that LFFOT is an effective tool to track respiratory mechanics under TLV

Étude de la mécanique respiratoire par la technique des oscillations forcées au cours de la ventilation liquidienne totale

Background : This study aimed to implement low-frequency forced oscillation technique (LFFOT) in neonatal total liquid ventilation (TLV) and to provide the first insight into respiratory impedance under this new modality of ventilation. Method. Thirteen newborn lambs weighing 2.5 « 0.4 kg (mean « SD) were premedicated, intubated, anesthetized, and then placed under TLV using a specially-design liquid ventilator and a perfluorocarbon. The respiratory mechanics measurements protocol was started immediately after TLV initiation. Three blocks of measurements were first performed: one during initial respiratory system adaptation to TLV, followed by two others series during steady state conditions. Lambs were then divided into two groups prior to undergoing another three blocks of measurements: the first group received a 10-min i v infusion of salbutamol (1.5 [micro]g/kg/min) after continuous infusion of methacholine (9 [micro]g/kg/min) while the second group of lambs were chest-strapped. Respiratory impedance was measured using serial single-frequency tests at frequencies ranging between 0.05-2 Hz and then fitted with a constant-phase model. 0.2 Hz harmonic test signals were also launched every ten minutes throughout the measurement protocol. Results. Airway resistance and inertance were starkly increased in TLV compared to gas ventilation with a resonant frequency [less than or equal to] 1.2 Hz. 0.2 Hz resistance and reactance were sensitive to bronchoconstriction and dilation as well as during compliance reduction. Conclusions. We report successful implementation of LFFOT to neonatal total liquid ventilation and present the first insight into respiratory impedance under this new modality of ventilation. We show that LFFOT is an effective tool to track respiratory mechanics under TLV

Clinician-Scientist Trainee: A German Perspective

Clinician-scientists are particularly well positioned to bring basic science findings to the patient’s bedside; the ultimate objective of basic research in the health sciences. Concerns have recently been raised about the decreasing workforce of clinician-scientists in both the United States of America and in Canada; however, little is known about clinician-scientists elsewhere around the globe. The purpose of this article is two-fold: 1) to feature clinician-scientist training in Germany; and 2) to provide a comparison with the Canadian system. In a question/answer interview, Rory E. Morty, director of a leading clinician-scientist training program in Germany, and Katrin Milger, a physician and graduate from that program, draw a picture of clinician-scientist training and career opportunities in Germany, outlining the place of clinician-scientists in the German medical system, the advantages and drawbacks of this training, and government initiatives to promote training and career development of clinician-scientists. The interview is followed by a discussion comparing the German and Canadian clinician-scientist development programs, focusing on barriers to trainee recruitment and career progress, and efforts to eliminate the barriers encountered along this very demanding but also very rewarding career path

What Attributes Matter Most in Physicians? Exploratory Findings from a Single-Centre Survey of Stakeholder Priorities in Cancer Care at a Canadian Academic Cancer Centre

Background: Limited research exists regarding how healthcare stakeholders prioritize the importance of differing physician attributes in oncologists. Identifying these priorities can help ensure that Canadian cancer care continues to meet the needs of its patients. In our previous research, compassion and empathy were identified as important physician attributes, with answers like knowledge, professionalism or communication less common. We hypothesized that respondents may have been assuming other, underlying qualities in their oncologists when they prioritized “compassion” and “empathy”. To test this, the current study asks respondents to rank important physician attributes. Methods: With ethics approval, we asked healthcare stakeholders (physicians, nurses, patients, caregivers, medical students, and allied healthcare providers) to rank the eight most popular qualities or attributes. We identified differences between which characteristics each group valued most in physicians. Results: 375 respondents participated in the survey. “Knowledge” and “competence” were the most popular answers in the current study among all groups except medical students. Conclusion: Previously, we identified compassion as a highly valued attribute; however, this survey suggests that this may be with the assumption that a physician is knowledgeable and competent. Future research will use semi-structured interviews to investigate respondents’ rationales for making their choices and help interpret our findings in this study

Scientific Overview of the CSCI-CITAC 2009 Conference

From September 21st-23rd 2009, the Clinical Investigator Trainee Association of Canada – Association des cliniciens-chercheurs en formation du Canada (CITAC-ACCFC) and the Canadian Society for Clinician Investigators (CSCI), held their annual conference in Ottawa. Participants included clinician investigators and trainees from across the country. The conference featured many excellent guest speakers including this year’s recipient of the Henry G. Friesen International Prize in Health Research, Sir John Bell. There were several forums focusing on professional development, with topics such as “sustaining the clinician investigator in Canada”, “succeeding as a clinician investigator”, and “collaborating internationally with MD+ trainees”, alongside networking opportunities to help establish relationships with potential mentors and collaborators. Further, the CSCI-CITAC annual conference featured some of the cutting edge research that MD+ trainees throughout Canada are engaged in. Trainees presented their research either at the Young Investigators Forum poster session or at the oral plenary. This scientific overview aims to highlight some of the research presented by trainees at the annual conference. The broad themes of scientific interest included topics from both basic science and clinical research. In this article, we summarize some of the major research questions that are being investigated by clinician-investigator trainees in the following areas: neurological sciences, cell biology, medicine, immunology, obstetrics, gynecology, neonatology, orthopedics, rheumatology, and public health

Survol du programme scientifique du congrès annuel de la SCRC-ACCFC 2009

Du 21 au 23 septembre 2009 a eu lieu à Ottawa le congrès annuel de l’Association des cliniciens-chercheurs en formation du Canada – Clinical Investigator Trainee Association of Canada (ACCFC-CITAC) et de la Société canadienne de recherche clinique (SCRC). Parmi les participants se trouvaient des cliniciens-chercheurs et des étudiants en provenance des quatre coins du pays. Cette conférence mettait à l’avant-plan des invités de marque, dont le récipiendaire actuel du Prix international de la recherche en santé Henry G. Friesen, Sir John Bell. Plusieurs tables rondes entourant le développement professionnel s’y tenaient, avec des sujets tels que « le support des cliniciens-chercheurs canadiens », « le succès des cliniciens-chercheurs » et « la collaboration internationale des MD+ en formation », tout en donnant l’opportunité d’établir des liens avec des mentors et collaborateurs potentiels. De plus, le congrès annuel de l’ACCFC-CITAC mettait en vedette plusieurs recherches impliquant des MD+ en formation à travers tout le Canada, dans le cadre de la séance de présentation par affiches du Forum des jeunes chercheurs ou lors de la séance plénière. Ce survol vise à mettre en évidence certaines des recherches présentées par les chercheurs en formation lors de la conférence annuelle, autant sur le plan de la recherche fondamentale que de la recherche clinique. Dans cet article, nous résumons les principales questions de recherche abordées par ces cliniciens-chercheurs en formation dans les disciplines suivantes : neurosciences, biologie cellulaire, médecine, immunologie, obstétrique, gynécologie, néonatalogie, orthopédie, rhumatologie et santé publique