How useful is intraoperative cone beam computed tomography in maxillofacial surgery? An overview of the current literature.

Intraoperative imaging is increasingly used by surgeons and has become an integral part of many surgical procedures. This study was performed to provide an overview of the current literature on the intraoperative use of cone beam computed tomography (CBCT) imaging in maxillofacial surgery. A bibliographic search of PubMed was conducted in March 2020, without time limitation, using "intraoperative imaging" AND "maxillofacial surgery" AND "cone beam computed tomography" as key words. Ninety-one articles were found; after complete reading, 16 articles met the eligibility criteria and were analysed. The results showed that the majority of the indications were related to maxillofacial trauma, particularly zygomaticomaxillary complex fractures. Final verification with intraoperative CBCT before wound closure was the most common use of this device. However, innovative uses of intraoperative CBCT are expanding, such as CBCT coupling with mirror computational planning, and even the combined use of initial intraoperative CBCT acquisition with navigation. Immediate, fast, and easy evaluation of bone repositioning to avoid the need for further surgical revision is the main advantage of this technique. Imaging quality is comparable to that of multi-slice computed tomography, but with lower radiation exposure. Nevertheless, CBCT is still not widely available in maxillofacial centres, probably because of its cost, and perhaps because not everyone is aware of its advantages and versatility, which are reported in this review.

Emerging therapies for the treatment of relapsed or refractory diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (dlbcl) is an aggressive non-Hodgkin lymphoma, accounting for approximately 30% of lymphoma cases in Canada. Although most patients will achieve a cure, up to 40% will experience refractory disease after initial treatment, or relapse after a period of remission. In eligible patients, salvage therapy followed by high-dose therapy and autologous stem-cell transplantation (asct) is the standard of care. However, many patients are transplant-ineligible, and more than half of those undergoing asct will subsequently relapse. For those patients, outcomes are dismal, and novel treatment approaches are a critical unmet need. In this paper, we present available data about emerging treatment approaches in the latter setting and provide a perspective about the potential use of those approaches in Canada.

Canadian evidence-based guideline for the first-line treatment of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (cll) is the most common adult leukemia in North America. In Canada, no unified national guideline exists for the front-line treatment of cll; provincial guidelines vary and are largely based on funding. A group of clinical experts from across Canada developed a national evidence-based treatment guideline to provide health care professionals with clear guidance on the first-line management of cll. Consensus recommendations based on available evidence are presented for the first-line treatment of cll.

The GBA p.Trp378Gly mutation is a probable French-Canadian founder mutation causing Gaucher disease and synucleinopathies.

Biallelic GBA mutations cause Gaucher disease (GD), and heterozygous carriers are at risk for synucleinopathies. No founder GBA mutations in French-Canadians are known. GBA was fully sequenced using targeted next generation and Sanger sequencing in French-Canadian Parkinson disease (PD) patients (n = 436), rapid eye movement (REM)-sleep behavior disorder (RBD) patients (n = 189) and controls (n = 891). Haplotype, identity-by-descent (IBD) and principal component analyses (PCA) were performed using single nucleotide polymorphism-chip data. Data on GD patients from Toronto and Montreal were collected from patients' files. A GBA p.Trp378Gly mutation was identified in two RBD and four PD patients (1% of all patients combined), and not in controls. The two RBD patients had converted to DLB within 3 years of their diagnosis. Haplotype, IBD and PCA analysis demonstrated that this mutation is from a single founder. Out of 167 GD patients screened, 15 (9.0%) carried the p.Trp378Gly mutation, all in trans with p.Asn370Ser. Three (20%) of the GD patients with the p.Trp378Gly mutation had developed Parkinsonism, and 11 patients had family history of PD. The p.Trp378Gly mutation is the first French-Canadian founder GBA mutation to be described, which leads to synucleinopathies and to GD type 1 when in compound heterozygosity with p.Asn370Ser.

Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma.

BACKGROUND: Copanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α- and δ-isoforms. PATIENTS AND METHODS: This phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis. RESULTS: Thirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib. Follicular lymphoma (48.5%) and peripheral T-cell lymphoma (33.3%) were the most common histologic subtypes. Most patients (78.6%) had received prior rituximab and 54.8% were rituximab-refractory. Median duration of treatment was 23 and 8 weeks in the indolent and aggressive cohorts, respectively (overall range 2-138). Eighty patients were evaluated for efficacy. The objective response rate was 43.7% (14/32) in the indolent cohort and 27.1% (13/48) in the aggressive cohort; median progression-free survival was 294 days (range 0-874) and 70 days (range 0-897), respectively; median duration of response was 390 days (range 0-825) and 166 days (range 0-786), respectively. Common adverse events included hyperglycemia (57.1%; grade ≥3, 23.8%), hypertension (54.8%; grade ≥3, 40.5%), and diarrhea (40.5%; grade ≥3, 4.8%), all generally manageable. Neutropenia occurred in 28.6% of patients (grade 4, 11.9%). Molecular analyses showed enhanced antitumor activity in tumors with upregulated phosphatidylinositol 3-kinase pathway gene expression. CONCLUSION: Intravenous copanlisib demonstrated promising efficacy and manageable toxicity in heavily pretreated patients with various subtypes of indolent and aggressive malignant lymphoma. Subtype-specific studies of copanlisib in patients with follicular, peripheral T-cell, and mantle cell lymphomas are ongoing. This trial is registered with ClinicalTrials.gov number NCT01660451 (Part A).

Emerging therapies for the treatment of relapsed or refractory follicular lymphoma.

With no treatment standard having been established for relapsed and refractory follicular lymphoma, a number of therapeutic approaches are used in Canada. In patients who relapse early or who eventually become resistant to subsequent treatment, prognosis is poor, and new approaches are needed. A number of novel therapies are being examined in this setting, including monoclonal antibodies, immunoconjugates, immunomodulatory agents, and signal transduction inhibitors. With the body of evidence for those emerging therapies accumulating and the standard upfront treatment changing from rituximab and chop (cyclophosphamide-doxorubicin-vincristine-prednisone) or rituximab and cvp (cyclophosphamide-vincristine-prednisone) to bendamustine and rituximab, treatment decisions in the relapsed and refractory setting have become more complex. The choice of subsequent treatment must consider type of upfront treatment; duration of remission; and patient-related factors such as age, comorbidities, and treatment preferences. This paper summarizes the evidence for novel therapies and proposes recommendations for subsequent treatment options by remission duration after induction and maintenance.

Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma.

Ixazomib is an investigational proteasome inhibitor that has shown preclinical activity in lymphoma models. This phase 1 study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary activity of intravenous (IV) ixazomib in relapsed/refractory lymphoma patients who had received ⩾ 2 prior therapies. Thirty patients with a range of histologies received ixazomib 0.125-3.11 mg/m(2) on days 1, 8 and 15 of 28-day cycles. Patients received a median of two cycles (range 1-36). MTD was determined to be 2.34 mg/m(2). Most common drug-related adverse events (AEs) included fatigue (43%), diarrhea (33%), nausea, vomiting and thrombocytopenia (each 27%). Drug-related grade ⩾ 3 AEs included neutropenia (20%), thrombocytopenia (13%) and diarrhea (10%). Drug-related peripheral neuropathy occurred in four (13%) patients; no grade ⩾ 3 events were reported. Plasma exposure increased dose proportionally from 0.5-3.11 mg/m(2); terminal half-life was 4-12 days after multiple dosing. Of 26 evaluable patients, five achieved responses: 4/11 follicular lymphoma patients (one complete and three partial responses) and 1/4 peripheral T-cell lymphoma patients (partial response). Sustained responses were observed with ⩾ 32 cycles of treatment in two heavily pretreated follicular lymphoma patients. Results suggest weekly IV ixazomib is generally well tolerated and may be clinically active in relapsed/refractory lymphoma.

Monitoring response and resistance to treatment in chronic myeloid leukemia.

Chronic myeloid leukemia (cml) results from expression of the constitutive tyrosine kinase activity of the Bcr-Abl oncoprotein. Imatinib, a tyrosine kinase inhibitor (tki), is highly effective in the treatment of cml. However, some patients treated with imatinib will fail to respond, will respond suboptimally, or will relapse because of primary or acquired resistance or intolerance. Research activities focusing on the mechanisms that underlie imatinib resistance have identified mutations in the BCR-ABL gene, clonal evolution, and amplification of the BCR-ABL gene as common causes. Cytogenetic and molecular techniques are currently used to monitor cml therapy for both response and relapse. With multiple and more potent therapeutic options now available, monitoring techniques can permit treatment to be tailored to the individual patient based on disease characteristics-for example, according to BCR-ABL mutation profile or to patient characteristics such as certain comorbid conditions. This approach should benefit patients by increasing the potential for better long-term outcomes.

Phase I clinical trial of i.v. ascorbic acid in advanced malignancy.

BACKGROUND: Ascorbic acid is a widely used and controversial alternative cancer treatment. In millimolar concentrations, it is selectively cytotoxic to many cancer cell lines and has in vivo anticancer activity when administered alone or together with other agents. We carried out a dose-finding phase I and pharmacokinetic study of i.v. ascorbic acid in patients with advanced malignancies. PATIENTS AND METHODS: Patients with advanced cancer or hematologic malignancy were assigned to sequential cohorts infused with 0.4, 0.6, 0.9 and 1.5 g ascorbic acid/kg body weight three times weekly. RESULTS: Adverse events and toxicity were minimal at all dose levels. No patient had an objective anticancer response. CONCLUSIONS: High-dose i.v. ascorbic acid was well tolerated but failed to demonstrate anticancer activity when administered to patients with previously treated advanced malignancies. The promise of this approach may lie in combination with cytotoxic or other redox-active molecules.

Hormone replacement therapy use and variations in the risk of breast cancer.

OBJECTIVE: To determine the effect of different types and formulations of hormone replacement therapy (HRT) on the risk of breast cancer in postmenopausal women. DESIGN: Population-based case-control study. SETTING: UK, 1988-2004. PARTICIPANTS: Women 50-75 years between 1998 and 2004. MAIN OUTCOME MEASURES: Breast cancer incidence to estimate the rate ratio (RR) associated with use of various HRTs over a 30-year period. RESULTS: We identified 6347 incident cases of breast cancer that were matched with 31,516 controls. Cases were on average 61 years at diagnosis and 22% had undergone a hysterectomy. The rate of breast cancer was increased with the use of opposed estrogens in oral form (adjusted RR 1.38; 95% CI 1.27-1.49) in contrast to patch form (RR 1.08; 95% CI 0.81-1.43). This rate was similarly elevated with both continuous (RR 1.29; 95% CI 1.07-1.56) and sequential (RR 1.33; 95% CI 1.21-1.46) forms of opposed estrogen. The rate of breast cancer was not increased among exclusive users of unopposed estrogens (RR 0.97; 95% CI 0.86-1.09) or of tibolone (RR 0.86; 95% CI 0.65-1.13). Users of tibolone who had switched from opposed estrogens, however, had an elevated rate (RR 1.29; 95% CI 1.09-1.52). The rate of breast cancer increased by 25% (95% CI 20-30%) with every ten prescriptions of orally administered opposed estrogen. CONCLUSIONS: The risk of breast cancer varies with the formulation and preparation of HRT. Opposed estrogens (progesterone-estrogen) in oral form are associated with an increased risk of breast cancer, which increases with use. Transdermal opposed estrogens, unopposed estrogens and tibolone do not increase this risk. However, this study is an observational study that carries risks of various biases, and thus the findings need to be interpreted with caution.

[Evaluation of continuing medical training in private sector French cardiologists in 1999]. / Evaluation des pratiques de formation médicale continue des cardiologues libéraux francais en 1999.

The authors present the results of a retrospective national enquiry which took place in 1999 and was mailed and faxed to the 3,800 cardiologists practising in the private sector in order to assess the different types of continuous, individual and collective postgraduate training which they had benefited from in the preceding 12 months. The data was analysed by comparison with that obtained from an individualized representative sample in a panel of private sector cardiologists. The results were then compared with the criteria of a yardstick proposed by the National Committee of Continuous Medical Education of 1997, according to the April 25th 1996 decree. The meeting of these criteria would require carrying out 114,000 to 76,000 hour-equivalents of continuous education whereas the present offer is about 100,000 hour-equivalents. The different forms of individual or collective training were compared in the 327 questionnaires which were exploitable following adhesion to the French Society of Cardiology, to the Cardiologists' Union, to local cardiological societies, by age, gender and type of practice. The average number of annual hours of collective education was 52.2 +/- 60.1 hours (25% quartile = 25 hours, 75% = 60 hours). The average value of hours of individual education was 89.7 +/- 89.3 hours (25% quartile = 25 hours; 75% = 120 hours). This evaluation indicates that about 15% of cardiologists practising in the private sector have inadequate continuous medical education and that 68% would satisfy the criteria laid down in 1997. Moreover, the present offer would seem to be adequate providing the criteria of accreditation have been met.

Simulation of non-enzymatic template-directed synthesis of oligonucleotides and peptides.

A simulation model is proposed for the template- and sequence-directed (TSD) condensation of two trideoxyribonucleotide 3'-phosphate molecules into a hexameric template with palindromic sequence studied experimentally by von Kiedrowski (1986;Angew. Int. Ed. Engl.25, 932--935). The model simulates reasonably well the kinetics of synthesis of both the template, and the pyrophosphate product which is not directly involved in the autocatalytic reaction. It offers quantitative approximation of the different rate constants of the processes involved in the reaction. The model simulates and gives predictions for the influence of factors such as the initial concentrations of the trimers and the template, and gives predictions for the effect of temperature on the dynamics of the autocatalytic reaction. The model also simulates well the production rate of a different self-replicating system (coiled coil peptide) used in the experiments of Lee et al. (1997;Nature390, 591--594). Comparing the different rate constants, it seems that chain elongation occurs at higher rates in the peptide system (at 23 degrees C) than in the nucleotide one (at 0 degrees C), but that the relative contribution of template-directed synthesis is significantly larger with the nucleotides.

Modeling the Disordered Dense Phase in the Packing of Binary Mixtures of Spheres.

A new, probabilistic approach is applied to the case of dense random packings of binary mixtures of spheres, assuming gapless packing. The model describes correctly the dependence of the porosity of the packing on mixture composition and size ratio for the disordered dense "phase" of the binary mixture. The volumes of the voids are calculated accurately by means of a Monte Carlo integration instead of being evaluated by kissing spheres. The results, in term of the porosity/sphere-fraction relationship, are compared with those of a previous model, also based on the gapless packing approximation. Copyright 1998 Academic Press.

Children who can't smell the coffee: isolated congenital anosmia.

Two children with isolated congenital anosmia, a rare syndrome of deficient restricted neuronal migration, are presented with early diagnosis confirmed by standardized smell testing and detailed neuroimaging studies. Recognition of this disorder and its spectrum of presentations provides important insights into the molecular mechanisms underlying the development of the olfactory system.

Perceived parental social support and academic achievement: an attachment theory perspective.

The study tested the extent to which parental social support predicted college grade point average among undergraduate students. A sample of 418 undergraduates completed the Social Provisions Scale--Parent Form (C.E. Cutrona, 1989) and measures of family conflict and achievement orientation. American College Testing Assessment Program college entrance exam scores (ACT; American College Testing Program, 1986) and grade point average were obtained from the university registrar. Parental social support, especially reassurance of worth, predicted college grade point average when controlling for academic aptitude (ACT scores), family achievement orientation, and family conflict. Support from parents, but not from friends or romantic partners, significantly predicted grade point average. Results are interpreted in the context of adult attachment theory.

Mechanical inventiveness: a three-phase study.

This paper focuses on mechanical inventiveness, the conception and development of new devices which require use of mechanical principles. In Phase 1 of the three-phase investigation, we studied 34 inventors who received between three and 82 agricultural and industrial patents. These inventors formed the original criterion group of mechanical inventors. Phase 2 of the investigation was the development of an inventiveness measure. From the criterion group of adult mechanical inventors, the Iowa Inventiveness Inventory (III) was developed to measure attitudes and characteristics of inventors. Subjects for Phase 3 of the study were 90 young inventors (40 males, 50 females), students (grades five to eight) who won local and regional invention contests and reached the state convention of Invent Iowa. In Phase 3, Invent Iowa state finalists in grades five to eight (n = 90) were administered the III and the Mechanical Reasoning test of the Differential Aptitude Tests. Characteristics of the young inventors, as delineated by these assessments, are provided.

[Long-term results of aortic valve replacement with a prosthesis]. / Résultats à long terme des remplacements valvulaires aortiques par prothèse

A long term evaluation of prosthetic replacement of the aortic valve by various types of prosthesis has been carried out; 530 patients from various centres of cardiology were studied. The average annual mortality after the first two postoperative years was about 2.5% and half of the patients undergoing surgery were still alive after 10 years. The functional improvement is usually marked and is generally to be expected, although with an increased risk, even in patients who underwent surgery at stage IV of the NYHA classification. In this study, the prostheses which were associated with the best long term results were the Starr-Edwards 1260, the Smeloff-Cutter, and the Björk. The commonest complications after the first month were dehiscence of the prosthesis (11.8%), thromboembolic episodes (11.2%), coronary complicatons (11.1%) and cardiac failure (7.1%). The most serious is infection of the prosthesis, which is almost invariably fatal. Deterioration in the substance of the prosthesis has become very rare, but there must be reservations in this respect with the SE2400, which has still not been in use long enough. Revision operations were carried out on 7.6% of the survivors at one month, with a mortality of 18.4%. Sudden death remains a constant threat. A study of the actuarial survival graphs for operated and non-operated cases shows that surgery should be advised in all poorly tolerated valve defects, and even for an uncomplicated tight aortic stenosis. Bearing in mind the progressive lowering of operative mortality, surgical treatment is also justified in cases with marked or gross aortic incompetence which is well tolerated if flow-up studies show a progressive increase in cardiac volume.