The most important attribute: stakeholder perspectives on what matters most in a physician.

Background: Most people can think of important attributes that they believe physicians should have. The canmeds framework defines domains of attributes in medical training (Leader, Medical Expert, Scholar, Communicator, Advocate, Collaborator, and Professional). Whether some are more valued by various stakeholders is unknown. Previous research has shown that patients can receive suboptimal care if physician and patient expectations of a health care encounter differ. In the present study, we sought to identify what various stakeholders identified as the single most important attribute for a physician to possess. Methods: A simple survey asked the question "What is the single most important attribute a physician should have?" at a single academic teaching hospital and affiliated medical school. The survey was administered to medical students, doctors, nurses, patients, and caregivers. Age and sex were also collected. Responses were assigned to domains and analyzed to identify trends. The primary outcome is a descriptive analysis of the findings. Results: From 362 individuals who responded, 109 different responses were obtained. The single most common answer was "compassion" (n = 86). Responses were categorized into these 5 domains: Caring, n = 209; Professional or Collaborator, n = 58; Medical Expert, n = 54; Communicator, n = 32; and Other, n = 9. Compared with men, women chose attributes in the Caring domain more frequently (64% vs. 49%), although that domain was the most popular for both sexes. Medical students were less likely to highly value Communicator attributes. Conclusions: All stakeholder group identified attributes in the Caring domain as being most important. Although all canmeds roles are important, our research highlights the priorities of stakeholders.

Eastern Canadian Gastrointestinal Cancer Consensus Conference 2018.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference was held in Halifax, Nova Scotia, 20-22 September 2018. Experts in radiation oncology, medical oncology, surgical oncology, and pathology who are involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics in the management of pancreatic cancer, pancreatic neuroendocrine tumours, hepatocellular cancer, and rectal and colon cancer, including ■ surgical management of pancreatic adenocarcinoma,■ adjuvant and metastatic systemic therapy options in pancreatic adenocarcinoma,■ the role of radiotherapy in the management of pancreatic adenocarcinoma,■ systemic therapy in pancreatic neuroendocrine tumours,■ updates in systemic therapy for patients with advanced hepatocellular carcinoma,■ optimum duration of adjuvant systemic therapy for colorectal cancer, and■ sequence of therapy in oligometastatic colorectal cancer.

Immune checkpoint inhibitors in MITF family translocation renal cell carcinomas and genetic correlates of exceptional responders.

BACKGROUND: Microphthalmia Transcription Factor (MITF)family translocation renal cell carcinoma (tRCC) is a rare RCC subtype harboring TFE3/TFEB translocations. The prognosis in the metastatic (m) setting is poor. Programmed death ligand-1 expression was reported in 90% of cases, prompting us to analyze the benefit of immune checkpoint inhibitors (ICI) in this population. PATIENTS AND METHODS: This multicenter retrospective study identified patients with MITF family mtRCC who had received an ICI in any of 12 referral centers in France or the USA. Response rate according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. Genomic alterations associated with response were determined for 8 patients. RESULTS: Overall, 24 patients with metastatic disease who received an ICI as second or later line of treatment were identified. Nineteen (82.6%) of these patients had received a VEGFR inhibitor as first-line treatment, with a median PFS of 3 months (range, 1-22 months). The median PFS for patients during first ICI treatment was 2.5 months (range, 1-40 months); 4 patients experienced partial response (16,7%) and 3 (12,5%) had stable disease. Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (PBRM1 and BRD8) had a clinical benefit. Resistant clones in a patient with exceptional response to ipilimumab showed loss of BRD8 mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 × 10- 6). CONCLUSIONS: MITF family tRCC is an aggressive disease with similar responses to ICIs as clear-cell RCC. Mutations in bromodomain-containing genes might be associated with clinical benefit. The unexpected observation about parallel evolution of genes involved in O-glycosylation as a mechanism of resistance to ICI warrants exploration.

Eastern Canadian Colorectal Cancer Consensus Conference 2017.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2017 was held in St. John's, Newfoundland and Labrador, 28-30 September. Experts in radiation oncology, medical oncology, surgical oncology, and cancer genetics who are involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics in the management of gastric, rectal, and colon cancer, including ■ identification and management of hereditary gastric and colorectal cancer (crc);■ palliative systemic therapy for metastatic gastric cancer;■ optimum duration of preoperative radiation in rectal cancer-that is, short- compared with long-course radiation;■ management options for peritoneal carcinomatosis in crc;■ implications of tumour location for treatment and prognosis in crc; and■ new molecular markers in crc.

Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016 was held in Montreal, Quebec, 5-7 February. Experts in radiation oncology, medical oncology, surgical oncology, and infectious diseases involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics: ■ Follow-up and survivorship of patients with resected colorectal cancer■ Indications for liver metastasectomy■ Treatment of oligometastases by stereotactic body radiation therapy■ Treatment of borderline resectable and unresectable pancreatic cancer■ Transarterial chemoembolization in hepatocellular carcinoma■ Infectious complications of antineoplastic agents.

Palliative chemotherapy for patients 70 years of age and older with metastatic colorectal cancer: a single-centre experience.

BACKGROUND: Metastatic colorectal cancer (mcrc) commonly affects elderly people, an understudied subset of patients. We analyzed the survival impact of the first and subsequent lines of chemotherapy in eligible non-trial patients 70 years of age and older with mcrc treated between 2004 and 2012. METHODS: This single-centre retrospective analysis estimated overall survival (os) and progression-free survival (pfs) using the Kaplan-Meier method. Multivariate analysis was used to adjust for age, sex, Eastern Cooperative Oncology Group performance status, score on the Charlson comorbidity index, dependency in activities of daily living, and exposure to 1 or more chemotherapy doublets, capecitabine alone, or best supportive care (bsc). RESULTS: Of 109 patients identified, 29 elected bsc, and 80 received chemotherapy. In multivariate analysis, age was not associated with os [hazard ratio (hr): 0.99; 95% confidence interval (ci): 0.92 to 1.05], but a performance status of 2 or higher was associated with a decreased likelihood of survival (hr: 3.12; 95% ci: 1.87 to 5.76), and exposure to 1 or more doublets was associated with improved survival (hr: 0.33; 95% ci: 0.17 to 0.66). In univariate analysis, a trend toward improved os was observed for first-line doublet chemotherapy compared with capecitabine (hr: 0.66; 95% ci: 0.41 to 1.07), and pfs was superior (hr: 0.46; 95% ci: 0.26 to 0.84). Compared with exposure to 1 doublet, exposure to the 3 potential cytotoxic chemotherapies was not associated with improved os (hr: 0.77; 95% ci: 0.41 to 1.43). The incidence of neutropenia with first-line folfiri was 40%; the incidences of bevacizumab-related arterial and venous thrombosis were both 8%. CONCLUSIONS: Exposure to 1 or more doublet chemotherapies for mcrc was associated with better outcomes in non-trial patients 70 years of age and older. Elderly patients treated with palliative chemotherapy and bevacizumab should be monitored carefully for arterial and venous thrombotic events.

Severe anaphylaxis caused by orally administered vancomycin to a patient with Clostridium difficile infection.

We report the first case of anaphylaxis to oral vancomycin in a cystic fibrosis patient with severe and relapsing Clostridium difficile infection (CDI) refractory to metronidazole. The patient's colitis has been successfully treated with a combination of intravenous metronidazole and tigecycline.

[Treatment of chemotherapy-induced nausea and vomiting with 5-hydroxytryptamine type 3 receptor antagonists]. / Antiemetische Therapie mit 5-HT(3)-Antagonisten in der onkologischen Praxis.

BACKGROUND AND OBJECTIVE: 5-hydroxytryptamine 3 (5-HT3) receptor antagonists have proved to be highly efficacious in the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV). However, several questions remain concerning the relative efficacy of various approved anti-emetics, especially with respect to dosage, duration and timing of administration, as well as differences in toxicity profiles. Thus it seemed appropriate to assess the current therapeutic results in routine daily practice, when applying antiemetic therapy according to established guidelines. PATIENTS AND METHODS: Within LINO e.V., a group of medical oncologists in private ambulant practice (LINO: Association of private-practice medical oncologists in Bavaria), a total of 738 cycles of moderately or highly emesis-inducing chemotherapy were randomly assigned to three treatment options: (1)granisetron 1 mg (GRA1). (2) 3 mg (GRA3), and (3) ondansetron 8 mg (OND8), each combined with 8 mg dexamethasone. Incidence and severity of acute (day 1) and delayed CINV (day 2-5) and the subjective assessment of efficacy were documented on questionnaires filled in by the patients. RESULTS: All of the three regimens adequately prevented vomiting in the majority of the patients. However, all measured effects showed an uniform trend towards slightly decreased efficacy with 8 mg of ondansetron. These differences were predominantly detected with respect to delayed CINV on days 2 to 5, especially after chemotherapy with anthracyclin/cyclophosphamide combination therapy. CONCLUSION: Granisetron, at two different dosage regimens, and ondasetron showed adequate reduction in chemotherapy-induced nausea and vomiting, but ondansetron worked slightly less so.

High efficacy of gemcitabine and cisplatin in patients with predominantly anthracycline- and taxane-pretreated metastatic breast cancer.

BACKGROUND: Effective and tolerable regimens are sought specifically in patients who have been pretreated with anthracyclines and taxanes. Gemcitabine and cisplatin demonstrated synergistic activity in vitro and provides a new mechanism of drug interaction. PATIENTS AND METHODS: Previously treated patients with metastatic breast cancer (MBC) were enrolled in a multicentre phase II study. Treatment consisted of gemcitabine (750 mg/m(2)) and cisplatin (30 mg/m(2)) given on day 1 and 8 every 3 weeks. RESULTS: Thirty-eight patients were recruited, all of whom had previously received chemotherapy (35 pretreated with taxanes, 33 pretreated with anthracyclines). A median of 5 cycles of the study treatment was delivered. There were 2 complete and 13 partial responses, for an overall response rate of 40% (95% confidence interval: 23-56%). Thirteen patients (35%) had stable disease. Tumour response appeared independent of previously applied chemotherapy. Median time-to-progression was 6 months and median overall survival was 13.5 months. Main toxicities were leucopenia and thrombocytopenia (grade 3/4 in 26 and 16% of cycles, respectively). Non-haematological toxicity was rarely severe. CONCLUSIONS: Combination chemotherapy with gemcitabine and cisplatin given on 2 out of 3 weeks is well tolerated and active in heavily pretreated patients with MBC, even after prior exposure to anthracyclines and taxanes.

Cellular immunity in healthy volunteers treated with an octavalent conjugate Pseudomonas aeruginosa vaccine.

Humoral immunity in response to an octavalent O-polysaccharide-toxin A conjugate Pseudomonas aeruginosa vaccine is well studied, and a phase III clinical study in cystic fibrosis (CF) patients is currently ongoing. In contrast, little is known about cellular immunity induced by this vaccine. Fifteen healthy volunteers were immunized on days 1 and 60. Parameters of cellular immunity were studied before vaccination on day 1, and on day 74. Analyses included flow cytometry of whole blood and antigen-induced proliferation of and cytokine production by lymphocyte cultures. The effects of immunization on the composition of peripheral blood lymphocytes as determined by flow cytometry were minor. In contrast, after immunization a highly significant increase of proliferation in response to stimulation with detoxified toxin A was noted: the stimulation index rose from 1.4 on day 1 to 42.2 on day 74 (restimulation with 0.4 microg/ml; P = 0.003). Immunization led to significant production of interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha by antigen-stimulated lymphocytes. In contrast, no significant induction of interleukin (IL)-4 or IL-10 was observed. In conclusion, immunization of healthy volunteers led to activation of cellular immunity including strong antigen-specific proliferation and cytokine production. In CF patients priming of the cellular immune system towards a Th1-like pattern would be of potential advantage. Therefore, confirmatory analyses in immunized CF patients with and without chronic infection with P. aeruginosa are foreseen.

Cellular immunity in healthy volunteers treated with an octavalent conjugate Pseudomonas aeruginosa vaccine.

Humoral immunity in response to an octavalent O-polysaccharide-toxin A conjugate Pseudomonas aeruginosa vaccine is well studied, and a Phase III clinical study in cystic fibrosis (CF) patients is currently ongoing. In contrast, little is known about cellular immunity induced by this vaccine. Fifteen healthy volunteers were immunized on days 1 and 60. Parameters of cellular immunity were studied before vaccination on day 1, and on day 74. Analyses included flow cytometry of whole blood, and antigen-induced proliferation of and cytokine production by lymphocyte cultures. The effects of immunization on the composition of peripheral blood lymphocytes as determined by flow cytometry were minor. In contrast, after immunization a highly significant increase of proliferation in response to stimulation with detoxified toxin A was noted: the stimulation index rose from 1.4 on day 1 to 42.2 on day 74 (restimulation with 0.4 microg/ml; P = 0.003). Immunization led to significant production of interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha by antigen-stimulated lymphocytes. In contrast, no significant induction of interleukin (IL)-4 or IL-10 was observed. In conclusion, immunization of healthy volunteers led to activation of cellular immunity including strong antigen-specific proliferation and cytokine production. In CF patients priming of the cellular immune system towards a Th1-like pattern would be of potential advantage. Therefore, confirmatory analyses in immunized CF patients with and without chronic infection with P. aeruginosa are foreseen.

Aerosolized amphotericin B inhalations as prophylaxis of invasive aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial.

We performed a prospective, randomized, multicenter trial to evaluate the effectiveness of prophylactic inhalations with aerosolized amphotericin B (aeroAmB) to reduce the incidence of invasive aspergillus (IA) infections in patients after chemotherapy or autologous bone marrow transplantation and an expected duration of neutropenia of at least 10 days. From March 1993 until April 1996, 382 patients with leukemias, relapsed high-grade non-Hodgkin lymphomas, or solid tumors were randomized with a 13:10 ratio to receive either prophylactic aeroAmB inhalations at a dose of 10 mg twice daily or no inhalation prophylaxis in an unblinded fashion. The incidence of proven, probable, or possible IA infections was 10 of 227 (4%) in patients who received prophylactic aeroAmB. This did not differ significantly from the 11 of 155 (7%) incidence in patients who received no inhalation prophylaxis (P =.37). Moreover, no differences in the overall mortality (13% v 10%; P =.37) or in the infection-related mortality (8% v 7%; P =.79) were found. In contrast to other nonrandomized trials, we observed no benefit from prophylactic aeroAmB inhalations, but the overall incidence of IA infections was low.

Enhanced pulmonary accumulation of liposomal amphotericin B (AmBisome) in acute liver transplant failure.

Plasma and tissue concentrations of amphotericin B were determined in a patient treated with liposomal amphotericin B during liver transplant failure. A cumulative rise in amphotericin B plasma concentrations was observed accompanied by an enhanced pulmonary deposition of the drug. Failure of the liver as a major component of the reticuloendothelial system may cause elevated plasma concentrations of liposomal amphotericin B and may consequently enhance deposition of liposomes in the lungs as a substitutive clearing organ.

Pharmacokinetics of liposomal amphotericin B (Ambisome) in critically ill patients.

The liposomal formulation of amphotericin B (AmBisome) greatly reduces the acute and chronic side effects of the parent drug. The present study describes the pharmacokinetic characteristics of AmBisome applied to 10 patients at a dose of 2.8 to 3.0 mg/kg of body weight and compares them to the pharmacokinetics observed in 6 patients treated with amphotericin B deoxycholate at the standard dose of 1.0 mg/kg. Interpatient variabilities of amphotericin B peak concentrations (Cmax) and areas under concentration-time curves (AUC) were 8- to 10-fold greater for patients treated with AmBisome than for patients treated with amphotericin B deoxycholate. At the threefold greater dose of AmBisome, median Cmaxs were 8.4-fold higher (14.4 versus 1.7 microg/ml) and median AUCs exceeded those observed with amphotericin B deoxycholate by 9-fold. This was in part explained by a 5.7-fold lower volume of distribution (0.42 liters/kg) in AmBisome-treated patients. The elimination of amphotericin B from serum was biphasic for both formulations. However, the apparent half-life of elimination was twofold shorter for AmBisome (P = 0.03). Neither hemodialysis nor hemofiltration had a significant impact on AmBisome pharmacokinetics as analyzed in one patient. In conclusion, the liposomal formulation of amphotericin B significantly (P = 0.001) reduces the volume of drug distribution, thereby allowing for greater drug concentrations in serum. The low toxicity of AmBisome therefore cannot readily be explained by its serum pharmacokinetics.

Serum pharmacology of amphotericin B applied in lipid emulsions.

Application of amphotericin B in lipid emulsions (AmB/L) reduced membrane toxicity in vitro and decreased amphotericin B-associated toxic side effects in vivo when compared to that of amphotericin B applied in 5% glucose (AmB/G). Therefore, a comparative analysis of the pharmacological parameters of AmB/L and AmB/G was performed. Thirteen patients were analyzed, and nine of these patients received a subsequent treatment with AmB/G and AmB/L. In patients in both treatment groups amphotericin B showed a biphasic elimination from serum, with a prolonged terminal half-life of approximately 27 h. Patients treated with AmB/L showed significantly lower peak concentrations (44.2%; P = 0.008) and correspondingly lower area under the drug concentration-time curve (AUC) values (64.3%; P = 0.015) compared to the values for the same patients treated with AmB/G at a dose range of 0.6 to 1.5 mg/kg of body weight. The enhanced clearance of AmB/L may be due to a faster initial elimination of amphotericin B-lipid aggregates by the reticuloendothelial system. Lower peak concentrations and AUC values in serum and a correspondingly faster deposition of AmB/L in tissues may at least partly explain the lower toxicity of AmB/L. A comparative pharmacokinetic analysis with data for a single patient treated with AmB/L demonstrated that hemodialysis did not significantly affect the disposition of amphotericin B.

Treatment of arthritis in Lewis rats by a monoclonal antibody against alpha beta T cell receptor: differential sensitivity of Yersinia-induced arthritis versus adjuvant arthritis.

Lewis rats experimentally infected with Yersinia enterocolitica develop sterile arthritis similar to Yersinia-associated reactive arthritis in humans. To investigate the putative role of alpha beta T cells in the pathogenesis of Yersinia-induced arthritis (YIA) rats were treated with the monoclonal antibody (mAb) R73 mAb directed against the rat alpha beta T cell receptor. In spite of reduction of alpha beta T cells in peripheral blood and in liver lesions of Yersinia-infected rats this serotherapy had no suppressive effect on YIA. Moreover, R73 mAb treatment had no influence on the number of alpha beta T cells in the inflammed synovial tissue. In contrast, R73 mAb serotherapy in Mycobaterium tuberculosis-immunized rats blocked development of adjuvant arthritis (AA) and suppressed the presence of alpha beta T cells in the synovial tissue. These results suggest fundamental differences between the immunopatho-mechanism of YIA caused by bacterial infection and AA induced by bacterial immunization and known to be T cell mediated. These data might have consequences for putative serotherapy of arthritis in humans.

Selective inhibition of adhesion molecule expression by edelfosine (ET-18-OCH3) on human umbilical vein or microvascular endothelium.

An abundance of data is accumulating that suggest that if one can block endothelial cell-leukocyte binding or inhibit cell adhesion molecules (CAM), inflammatory events can be greatly diminished. In this report, we demonstrate that an alkyl-lysophospho-lipid compound (ET-18-OCH3) can decrease adhesion molecule expression on cultured human micro- and macrovascular endothelial cell lines. ET-18 selectively decreased CAM expression; CD31 was decreased, however. Vascular CAM-1 tumor necrosis factor-alpha-induced expression was not altered. Intercellular adhesion molecule 1 expression was decreased, but endoglin expression was not affected. Thus, we have demonstrated nontoxic downmodulation of vascular CAM expression in vitro. Whether this compound will have anti-inflammatory properties needs to be clarified in animal models.

Characterization of expression and modulation of cell adhesion molecules on an immortalized human dermal microvascular endothelial cell line (HMEC-1).

We have recently reported the creation of the first immortalized cell line derived from human dermal microvascular endothelial cells (HMEC-1). In preliminary studies this line was found to closely resemble microvascular endothelial cells in regard to many phenotypic characteristics. Because two key functional features of endothelial cells are their ability to bind to peripheral blood leukocytes and extracellular matrix proteins via cell adhesion molecules, we have now characterized HMEC-1 in terms of expression and regulation of cell adhesion molecules of the integrin, immunoglobulin gene superfamily, and selectin families. HMEC-1 can either constitutively express or can be induced to express key integrins, including alpha-1, -2, -3, -4, -5, -6, and -V, as well as beta-1, -3, -4, and -5. They also express or are capable of expressing immunoglobulin gene superfamily molecules, such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and a member of the selectin family, E-selectin. A number of important cell adhesion molecules that are either constitutively expressed or that must be induced are regulated in a time- and dose-dependent fashion by selected cytokines. Experiments comparing the phenotypic characteristics of HMEC-1 with human dermal microvascular endothelial cells or human umbilical vein endothelial cells reveal HMEC-1 to have features of both small- and large-vessel endothelial cells.

Inhibition of induced angiogenesis in a human microvascular endothelial cell line by ET-18-OCH3.

Alkyl-lysophospholipids are a group of anti-cancer compounds that have previously been shown to have the unique feature of being selectively toxic to neoplastic tissues. One of these compounds, ET-18-OCH3, has been used for purging bone marrow of cancer cells in phase I clinical trials. Tumor-induced angiogenesis has been directly correlated with tumor growth and metastasis. In this study, we examined the effect ET-18-OCH3 has on a human microvascular endothelial cell line (HMEC-1), including the following functions: angiogenesis, cell-adhesion molecule expression, and cell-junction integrity. We found that ET-18-OCH3 (in vitro) reversibly inhibited induced angiogenesis at levels that did not affect viability. At lower concentrations, ET-18-OCH3 down-regulated the expression of cell-adhesion molecules and affected the integrity of cell-to-cell junctions. This observation demonstrates this versatile family of compounds to have additional targets of action.