Predictive factors of diagnostic and therapeutic divergence in a nationwide cohort of patients seeking second medical opinion.

OBJECTIVES: The aim of this study was to describe the profile of patients who sought a second medical opinion (SMO) on their therapeutic or diagnostic strategy using nationwide data from a French physician network dedicated to SMOs. METHODS: An observational cohort study was conducted and the study population consisted of patients residing in France or in the French overseas territories who submitted a request for an SMO through a dedicated platform between January 2016 and October 2020. Patient characteristics were compared between convergent and divergent SMOs. The divergent rate for all patients excluding those with mental diseases were described. Logistic regression was used to estimate the probability of a divergent SMO according to patient characteristics. RESULTS AND DISCUSSION: In total, 1,552 adult patients over several French regions were included. The divergence rate was 32.3 % (n = 502 patients). Gynecological [Odds Ratio (OR) and 95 % CI: 5.176 (3.154 to 8.494)], urological [OR 4.246 (2.053 to 8.782)] and respiratory diseases [OR 3.639 (1.357 to 9.758)] had the highest probability of a divergent SMO. Complex cases were also associated with a significantly higher risk of a divergent opinion [OR 2.78 (2.16 to 3.59)]. Age, sex, region and profession were not found to be predictive of a divergent second opinion. CONCLUSIONS: Policymakers should encourage new research on patient outcomes such as mortality and hospitalization rates after a SMO. When proven effective, SMO networks will have the potential to benefit from specific public funding or even play a key role in national healthcare quality improvement programs.

Evolving characteristics and outcome of secondary acute promyelocytic leukemia (APL): A prospective analysis by the French-Belgian-Swiss APL group.

BACKGROUND: Reports of patients with secondary acute promyelocytic leukemia (APL) have increased in recent years, particularly for those who received treatment with mitoxantrone, and retrospective studies have suggested that their characteristics and outcomes were similar to those of patients with de novo APL. METHODS: The authors investigated patients with de novo and secondary APL who were included in the ongoing APL-2006 trial. Patients with secondary APL who were included in that trial also were compared with a previous retrospective cohort of patients with secondary APL. RESULTS: In the APL-2006 trial, 42 of 280 patients (15%) had secondary APL. Compared with the retrospective cohort, patients with secondary APL in the APL-2006 trial had a lower incidence of prior breast carcinoma (35.7% vs 57%; P = .03) and a higher incidence of prior prostate carcinoma (26.2% vs 4.7%; P < .001). Treatment of the primary tumor in the APL-2006 trial less frequently included combined radiochemotherapy (28.6% vs 47.2%; P = .044) and no mitoxantrone (0% vs 46.7%; P = .016) but more frequently included anthracyclines (53.3% vs 38.3%; P = .015). In the APL-2006 trial, patients who had secondary APL, compared with those who had de novo APL, were older (mean, 60.2 years vs 48.7 years, respectively; P < .0001) but had a similar complete response rate (97.6% vs 90.3%, respectively), cumulative incidence of relapse (0% vs 1.8%, respectively), and overall survival (92.3% vs 90.9%, respectively) at 18 months. CONCLUSIONS: Although the incidence of secondary APL appears to be stable over time, evolving strategies for the treatment of primary cancers have reduced its occurrence among breast cancer patients but have increased its incidence among patients with prostate cancer. The current results confirm prospectively that patients with secondary APL have characteristics and outcomes similar to those of patients with de novo APL.

Long-term follow-up of European APL 2000 trial, evaluating the role of cytarabine combined with ATRA and Daunorubicin in the treatment of nonelderly APL patients.

All-trans retinoic acid (ATRA) combined to anthracycline-based chemotherapy is the reference treatment of acute promyelocytic leukemia (APL). Whereas, in high-risk patients, cytarabine (AraC) is often considered useful in combination with anthracycline to prevent relapse, its usefulness in standard-risk APL is uncertain. In APL 2000 trial, patients with standard-risk APL [i.e., with baseline white blood cell (WBC) count <10,000/mm(3) ] were randomized between treatment with ATRA with Daunorubicin (DNR) and AraC (AraC group) and ATRA with DNR but without AraC (no AraC group). All patients subsequently received combined maintenance treatment. The trial had been prematurely terminated due to significantly more relapses in the no AraC group (J Clin Oncol, (24) 2006, 5703-10), but follow-up was still relatively short. With long-term follow-up (median 103 months), the 7-year cumulative incidence of relapses was 28.6% in the no AraC group, compared to 12.9% in the AraC group (P = 0.0065). In standard-risk APL, at least when the anthracycline used is DNR, avoiding AraC may lead to an increased risk of relapse suggesting that the need for AraC is regimen-dependent.

Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience.

Acute promyelocytic leukemia (APL) is highly curable with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT), but very long-term results of this treatment, when CT should be added to ATRA and the role of maintenance treatment, remain uncertain. In our APL93 trial that included 576 newly diagnosed APL patients, with a median follow-up of 10 years, 10-year survival was 77%. Maintenance treatment significantly reduced 10-year cumulative incidence of relapses, from 43.2% to 33%, 23.4%, and 13.4% with no maintenance, maintenance using intermittent ATRA, continuous 6 mercaptopurine plus methotrexate, and both treatments, respectively (P < .001). Maintenance particularly benefited patients with white blood cell (WBC) count higher than 5 x 10(9)/L (5000/microL). Early addition of CT to ATRA significantly improved 10-year event-free survival (EFS), but without significant effect on overall survival (OS). The 10-year cumulative incidence of deaths in complete response (CR), resulting mainly from myelosuppression, was 5.7%, 15.4%, and 21.7% in patients younger than 55, 55 to 65, and older than 65 years, respectively, supporting the need for less myelosuppressive treatments, particularly for consolidation therapy. This study is registered at http://clinicaltrials.gov as NCT00599937.

PML-RARA-targeted DNA vaccine induces protective immunity in a mouse model of leukemia.

Despite improved molecular characterization of malignancies and development of targeted therapies, acute leukemia is not curable and few patients survive more than 10 years after diagnosis. Recently, combinations of different therapeutic strategies (based on mechanisms of apoptosis, differentiation and cytotoxicity) have significantly increased survival. To further improve outcome, we studied the potential efficacy of boosting the patient's immune response using specific immunotherapy. In an animal model of acute promyelocytic leukemia, we developed a DNA-based vaccine by fusing the human promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARA) oncogene to tetanus fragment C (FrC) sequences. We show for the first time that a DNA vaccine specifically targeted to an oncoprotein can have a pronounced effect on survival, both alone and when combined with all-trans retinoic acid (ATRA). The survival advantage is concomitant with time-dependent antibody production and an increase in interferon-gamma (IFN-gamma). We also show that ATRA therapy on its own triggers an immune response in this model. When DNA vaccination and conventional ATRA therapy are combined, they induce protective immune responses against leukemia progression in mice and may provide a new approach to improve clinical outcome in human leukemia.

Adverse events in medicine: easy to count, complicated to understand, and complex to prevent.

The performance of patient safety initiatives has not met expected targets for reasons that are gradually being understood. They have been too hospital-centered and too process- and "silo"-driven in their search for the causes of adverse events (AEs). Information technology could help overcome many obstacles, but only if the tools developed are based on a relevant safety model. We have applied the distinction between easy, complicated, and complex problems and strategies in healthcare to changes that need to be made in the detection and analysis of AEs. We propose a triple shift: (i) adopting an outcome-driven rather than a process-driven policy when defining and counting AEs (relatively easy), (ii) applying a patient- and not silo-driven approach and extending the timeframe when analyzing AEs (more difficult), and (iii) taking a systemic view of all care delivered to a patient during their life-span in order to erect barriers against the risks identified (highly complex).

In vivo activation of cAMP signaling induces growth arrest and differentiation in acute promyelocytic leukemia.

Differentiation therapy for acute myeloid leukemia uses transcriptional modulators to reprogram cancer cells. The most relevant clinical example is acute promyelocytic leukemia (APL), which responds dramatically to either retinoic acid (RA) or arsenic trioxide (As(2)O(3)). In many myeloid leukemia cell lines, cyclic adenosine monophosphate (cAMP) triggers growth arrest, cell death, or differentiation, often in synergy with RA. Nevertheless, the toxicity of cAMP derivatives and lack of suitable models has hampered trials designed to assess the in vivo relevance of theses observations. We show that, in an APL cell line, cAMP analogs blocked cell growth and unraveled As(2)O(3)-triggered differentiation. Similarly, in RA-sensitive or RA-resistant mouse models of APL, continuous infusions of 8-chloro-cyclic adenosine monophosphate (8-Cl-cAMP) triggered major growth arrest, greatly enhanced both spontaneous and RA- or As(2)O(3)-induced differentiation and accelerated the restoration of normal hematopoiesis. Theophylline, a well-tolerated phosphodiesterase inhibitor which stabilizes endogenous cAMP, also impaired APL growth and enhanced spontaneous or As(2)O(3)-triggered cell differentiation in vivo. Accordingly, in an APL patient resistant to combined RA-As(2)O(3) therapy, theophylline induced blast clearance and restored normal hematopoiesis. Taken together, these results demonstrate that in vivo activation of cAMP signaling contributes to APL clearance, independently of its RA-sensitivity, thus raising hopes that other myeloid leukemias may benefit from this therapeutic approach.

Suitability of three indicators measuring the quality of coordination within hospitals.

BACKGROUND: Coordination within hospitals is a major attribute of medical care and influences quality of care. This study tested the validity of 3 indicators covering two key aspects of coordination: the transfer of written information between professionals (medical record content, radiology exam order) and the holding of multidisciplinary team meetings during treatment planning. METHODS: The study was supervised by the French health authorities (COMPAQH project). Data for the three indicators were collected in a panel of 30 to 60 volunteer hospitals by 6 Clinical Research Assistants. The metrological qualities of the indicators were assessed: (i) Feasibility was assessed using a grid of 19 potential problems, (ii) Inter-observer reliability was given by the kappa coefficient () and internal consistency by Cronbach's alpha test, (iii) Discriminatory power was given by an analysis of inter-hospital variability using the Gini coefficient as a measure of dispersion. RESULTS: Overall, 19281 data items were collected and analyzed. All three indicators presented acceptable feasibility and reliability (, 0.59 to 0.97) and showed wide differences among hospitals (Gini, 0.08 to 0.11), indicating that they are suitable for making comparisons among hospitals. CONCLUSION: This set of 3 indicators provides a proxy measurement of coordination. Further research on the indicators is needed to find out how they can generate a learning process. The medical record indicator has been included in the French national accreditation procedure for healthcare organisations. The two other indicators are currently being assessed for inclusion.

Relative effectiveness assessment of listed drugs (REAL): a new method for an early comparison of the effectiveness of approved health technologies.

OBJECTIVES: Post-listing assessment of pharmaceuticals depends on national habits. In England, the assessment is based on estimates of cost per quality-adjusted life-year. These are made some considerable time after listing (negative list). In France, effectiveness, and then efficiency, is assessed immediately after listing (positive list). We propose a new formal method--the REAL method--that can help make early comparisons of the effectiveness of medical treatments. METHODS: Relative efficacies are first obtained from randomized controlled trials (RCTs). Members of the Transparency Committee (French National Authority for Health) are then consulted by questionnaire on the transposability of these results to real life. The RCT results and experts' ratings are entered into an effect model to obtain estimates of relative effectiveness, using unidimensional scaling, and bootstrap procedures. RESULTS: Application of the REAL method to the example of a new drug to treat Parkinson's disease and three comparators used in the same indication provided graphs of the distributions of their relative efficacy and relative effectiveness. The new drug was found to provide no added value. CONCLUSIONS: The REAL method is a rational, transparent, and practical procedure for comparing the effectiveness of pharmaceuticals in an immediate post-listing setting.

The "zero risk" concept for hospital-acquired infections: a risky business!

Nosocomial infections represent a serious public health problem. Some recent studies, most of which used strong educational programs, showed a dramatic decrease in the rates of nosocomial infections, particularly catheter-related infections in the intensive care unit. Thus, the concept of "zero risk" is flourishing in the recent literature, and some insurance networks have decided to limit reimbursement for treatment of some of the health care-associated infections, on the grounds that most of them are preventable. This viewpoint article emphasizes the risk of such a position and enumerates the reasons why such a philosophy could be counterproductive. In particular, this philosophy does not fit with the concept of self-declaration of severe adverse events and could push clinicians to underreport those events.

[Self-medication, patients as actors in their own health]. / Automédication: le patient acteur de sa santé.

The patient-doctor relationship has changed in recent years. Patients are gradually becoming actors in their own health, in their own care, as they gain access to medical knowledge. This raises a number of thorny issues. Indeed, where does medical care begin--especially the specific role of healthcare professionals? Who should take responsibility for patient education, and who should hold to account for possible mistakes in self-medication? Profound changes in attitudes are needed to help patients become actors in their own health.

Molecular target-based treatment of human cancer: summary of the 10th international conference on differentiation therapy.

The 10th International Conference on Differentiation Therapy was held between April 29 and May 3, 2004, in Shanghai, China. In the tradition of previous conferences from this series, which have been held biannually since the first meeting organized 20 years ago by Samuel Waxman and Giovanni Rossi in Sardinia, the organizers of the 10th International Conference on Differentiation Therapy aimed to gather basic and clinical cancer investigators in a setting of plenary sessions, workshops, and poster presentations to maximize the effective exchange of information and foster the establishment of collaborative interactions. Approximately 300 scientists attended the meeting with a mission to discuss targeted approaches to cancer treatment, which stem from our understanding of basic biological processes and the mechanisms of their deregulation during tumorigenesis.

[The French National Authority for Health]. / Séance consacrée à la santé publique.

The French National Authority of Health (HAS) is an independent and scientific public body assessing healthcare technologies and procedures for reimbursement and pricing. It also produces tools (guidelines, certificates, agreements and labels) designed to help healthcare professionals provide treatments of better quality and efficiency.

Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia.

PURPOSE: Arsenic trioxide (ATO) is capable of inducing a high hematologic response rate in patients with relapsed acute promyelocytic leukemia (APL). Preclinical observations have indicated that all-trans-retinoic acid (ATRA) may strongly enhance the response to ATO. PATIENTS AND METHODS: Between 1998 and 2001, we conducted a randomized study of ATO alone versus ATO plus ATRA in 20 patients with relapsed APL, all previously treated with ATRA-containing chemotherapy. The primary objective was to demonstrate a significant reduction in the time necessary to obtain a complete remission (CR) in the ATO/ATRA group compared with the ATO group. Secondary objectives were safety and molecular response. RESULTS: The CR rate after one ATO with or without ATRA induction cycle was 80%. Clinical and pharmacokinetic observations indicated that the main mechanism of action of ATO in vivo was the induction of APL cell differentiation. Hematologic and molecular response, time necessary to reach CR, and outcome were comparable in both treatment groups. Of 16 CR patients, three patients who reached a molecular remission after one induction cycle had all received chemotherapy for a treatment-induced hyperleukocytosis. Three additional patients who received further additional ATO with or without ATRA cycles converted later to molecular negativity. CONCLUSION: ATRA did not seem to significantly improve the response to ATO in patients relapsing from APL. Other potential combinations, including ATO plus chemotherapy, have to be tested.

Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia.

Valproic acid (VPA) has been demonstrated to be able to inhibit histone deacetylase activity and to synergize with all-trans retinoic acid (ATRA) in inducing the differentiation of acute myeloid leukemia (AML) cells. A pilot study of the VPA/ATRA combination was performed in 11 elderly patients with de novo AML (median age, 82 years). Complete marrow response was observed in 3 patients, including 1 complete remission. Two additional patients had hematologic improvement.