Consensus statement: summary of the Quebec Lung Cancer Network recommendations for prioritizing patients with thoracic cancers in the context of the COVID-19 pandemic.

Background: The emergence of covid-19 has the potential to change the way in which the health care system can accommodate various patient populations and might affect patients with non-covid-19 problems. The Quebec Lung Cancer Network, which oversees thoracic oncology services in the province of Quebec under the direction of the Ministère de la Santé et des Services sociaux, convened to develop recommendations to deal with the potential disruption of services in thoracic oncology in the province of Quebec. The summary provided here has been adapted from the original document posted on the Programme québécois du cancer Web site at: https://www.msss.gouv.qc.ca/professionnels/documents/coronavirus-2019-ncov/PJ1_Recommandations_oncologie-thoracique-200415.pdf. Methods: Plans to optimize the health care system and potentially to prioritize services were discussed with respect to various levels of activity. For each level-of-activity scenario, suggestions were made for the services and treatments to prioritize and for those that might have to be postponed, as well as for potential alternatives to care. Results: The principal recommendation is that the cancer centre executive committee and the multidisciplinary tumour board always try to find a solution to maintain standard-of-care therapy for all patients with thoracic tumours, using novel approaches to treatment and the adoption of a network approach to care, as needed. Conclusions: The effect of the covid-19 pandemic on the health care system remains unpredictable and requires that cancer teams unite and offer the most efficient and innovative therapies to all patients under the various conditions that might be forced upon them.

Adherence to guidelines in requesting Oncotype DX in a publicly funded health care system.

Background: Oncotype dx [odx (Genomic Health, Redwood City, CA, U.S.A.)] is an approved prognostic tool for women with node-negative, hormone receptor-positive, her2-negative breast cancer. Because of cost, optimal use of this test is crucial, especially in a publicly funded health care system. We evaluated adherence with our provincial guidelines for odx requests, the management of patients with an intermediate recurrence score (rs), and the cost impact of odx. Methods: This retrospective study included 201 consecutive patients with an odx request from two university institutions in Quebec between May 2012 and December 2014. Concordance with provincial guidelines was estimated, with its 95% confidence interval (ci). For patients with an intermediate rs, factors influencing the final treatment decision were assessed. The cost impact of odx was derived from the proportion of patients for whom chemotherapy was not recommended. Results: In 93.0% of patients (95% ci: 89.5% to 96.6%), odx was ordered according to guidelines. The concordance was similar in both institutions (92.7%; 95% ci: 88.1% to 97.3%; and 93.6%; 95% ci: 88.2% to 99.0%). In 112 (55.7%), 78 (38.8%), and 9 (4.5%) patients, the rs suggested low, intermediate, and high risk respectively. In the intermediate-risk group, most patients (n = 58, 74.4%) did not receive chemotherapy, mainly because of patient preference and the absence of a clear proven benefit. Savings of CA$100,000 for the study period (2.5 years) were estimated to be associated with odx use. Conclusions: In our experience, the use of odx was concordant with published recommendations and had a positive cost impact.

Magnetic therapeutic delivery using navigable agents.

For treating cancer in particular, therapeutic agents have evolved in complexity in an effort to enhance targeting efficacy. So far, efforts towards the synthesis alone of new therapeutics have attracted most attention. However, present cancer treatments frequently fail because of severe side effects related to the fact that the drug accumulates in insufficient concentration at the tumor site, while being distributed over healthy tissues and organs. More recently, advanced engineering principles have been considered for the development of platforms and drug-loaded vehicles to deliver payloads to the area to be treated by navigating them using the most direct route in order to improve tumor killing effects while minimizing toxic side effects caused by drug activity in nontargeted regions. If the introduction of engineering and principles of robotics to provide complementary techniques in targeted cancer therapy prove to be beneficial, it could influence future delivery methods and the synthesis of therapeutic carriers.

In vivo MR-tracking based on magnetic signature selective excitation.

A novel magnetic resonance (MR)-tracking method specifically developed to locate the ferromagnetic core of an untethered microdevice, microrobot, or nanorobot for navigation or closed-loop control purpose is described. The tracking method relies on the application of radio-frequency (RF) excitation signals tuned to the equipotential magnetic curves generated by the magnetic signature of the object being tracked. Positive contrast projections are obtained with reference to the position of the magnetic source. A correlation function performed on only one k-space line for each of the three axes and corresponding to three projections, is necessary to obtain a 3-D location of the device. In this study, the effects of the sphere size and the RF frequency offset were investigated in order to find the best contrast noise ratio (CNR) for tracking. Resolution and precision were also investigated by proper measurement of the position of a ferromagnetic sphere by magnetic resonance imaging (MRI) acquisition and by comparing them with the real position. This method is also tested for a moving marker where the positions found by MRI projections were compared with the ones taken with a camera. In vitro and in vivo experiments show the operation of the technique in tortuous phantom and in animal models. Although the method was developed in the prospect of new interventional MR-guided endovascular operations based on miniature untethered devices, it could also be used as a passive tracking method using tools such as catheters or guide wires.

[Diagnosis and classification of pulmonary arterial hypertension]. / Diagnostic et classification des hypertensions artérielles pulmonaires.

The clinical classification of types of pulmonary hypertension has made it possible to better standardize the approach to the diagnosis and treatment of patients, to perform clinical studies among homogeneous patients, and to discover common laboratory abnormalities that may serve as markers or help elucidate mechanisms of disease. Pulmonary arterial hypertension groups together different diseases that affect the small-caliber pulmonary arteries and lead to a progressive increase in pulmonary arterial resistance and right heart failure. A specific diagnosis of pulmonary arterial hypertension is generally based on a detailed and methodical clinical evaluation. Pulmonary biopsy is rarely indicated. Work-up in a center specialized in the management of this disease is frequently appropriate when the cause of the hypertension is not clear or when a specific treatment is envisaged.

FLRG, an activin-binding protein, is a new target of TGFbeta transcription activation through Smad proteins.

The FLRG gene encodes a secreted glycoprotein that binds to activin and is highly homologous to follistatin, an activin ligand. We cloned the promoter region of the human FLRG gene, and defined the minimal region necessary for transcription activation in a reporter-system assay. We showed that the fragment between positions -130 and +6, which consists of multiple consensus Sp1-binding sites, is required for the constitutive expression of the FLRG gene. We demonstrate here that FLRG mRNA expression is rapidly induced by TGFbeta or by transfection with Smad protein expression vectors in human HepG2 cells. We investigated the transcription-regulation mechanism of FLRG expression in HepG2 cells following treatment with TGFbeta. By deletion and point-mutation analysis of the FLRG promoter, we identified a Smad-binding element involved in the TGFbeta-inducible expression of the FLRG gene. Moreover, transactivation of the FLRG promoter by TGFbeta was compromised by dominant-negative mutants of Smad3 and Smad4 proteins. In addition, gel electrophoresis mobility-shift assays demonstrated the specific interaction of Smad3 and Smad4 proteins with the Smad-binding element consensus motif found in the FLRG promoter. Taken together, our data imply that Smad proteins participate in the regulation of expression of FLRG, a new target of TGFbeta transcription activation.

Expression of FLRG, a novel activin A ligand, is regulated by TGF-beta and during hematopoiesis [corrected].

OBJECTIVE: The human gene FLRG, identified from a B-cell chronic lymphocytic leukemia bearing a t(11;19) translocation, encodes a secreted glycoprotein highly homologous with follistatin. Activin A is a TGF-beta family member involved in the regulation of growth and differentiation of various types of cells, such as those of the hematopoietic system. Its biological activity is antagonized by binding with follistatin. We investigated the binding of FLRG to activin A and the expression pattern of FLRG, follistatin, and activin A during hematopoiesis. MATERIALS AND METHODS: The binding of FLRG with activin A was investigated by immunoprecipitation and Far-Western blot analysis. Gene expression was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and Northern Blot in purified hematopoietic populations. RESULTS: We demonstrate that FLRG, like follistatin, is able to bind to activin A. In bone marrow stromal cells, both mRNA and protein FLRG levels were found to be dramatically increased by TGF-beta. FLRG and activin A are expressed in the same cells, with a higher level of expression in the myeloid cells compared with the erythroid and megakaryocytic cells. FLRG and follistatin expression were different in the hematopoietic subpopulations tested. Moreover, we observed that FLRG and activin A expression was up-regulated during hematopoiesis. CONCLUSION: FLRG and activin A are expressed in the same hematopoietic cells and regulated by TGF-beta. Moreover, FLRG interacts with activin A, suggesting that FLRG, like follistatin, participates in the diverse regulatory functions of activin A, such as those in hematopoiesis.

Airway hyperresponsiveness, inflammation, and subepithelial collagen deposition in recently diagnosed versus long-standing mild asthma. Influence of inhaled corticosteroids.

This study aimed at documenting airway inflammation and subepithelial collagen deposition in patients using only inhaled beta(2)-agonists with either recently diagnosed asthma (RDA: /= 13 yr, n = 16) and at the influence of an intense inhaled corticosteroid (ICS) treatment on these parameters, in relation to changes in airway responsiveness. Patients had a methacholine inhalation test and a bronchoscopy with bronchial biopsies before and after an 8-wk treatment with inhaled fluticasone propionate (FP), 1,000 microgram/day. Baseline FEV(1) (mean +/- SEM) was normal and similar in both groups (RDA: 98.1 +/- 2.7, LSA: 94.5 +/- 4.6%). Geometric mean methacholine PC(20) was lower in LSA than in RDA (0.44 versus 3.37 mg/ml) at baseline and improved similarly by 1.85 and 1.86 double concentrations with FP treatment. PC(20) normalized (>/= 16 mg/ml) in five patients with RDA and two patients with LSA. Baseline mean bronchial cell counts (per mm(2) connective tissue surface) for CD3(+), CD4(+), CD8(+), CD25(+), EG1(+), CD45ro(+), and AA1(+) cells were similar in both groups. With FP, EG1(+) (p < 0.001), EG2(+) (p = 0.018), and AA1(+) counts (p = 0.009) decreased significantly in both groups while CD45ro(+) (p = 0.02) counts decreased only in LSA. Baseline type 1 and type 3 collagen deposition underneath the basement membrane was similar in RDA and LSA and did not change significantly after FP. This study shows that recent compared to long-standing mild asthma is associated with a similar degree of airway inflammation and subepithelial fibrosis, and a similar improvement in airway hyperresponsiveness after 8 wk on high-dose ICS. It also indicates that once asthma becomes symptomatic, airway responsiveness cannot normalize in most subjects over such a time period, even with a high dose of ICS.

AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14).

In haematopoietic malignancies the MLL gene, located on chromosome 11q23, is frequently disrupted by chromosome rearrangement, generally resulting in fusion to various partner genes. We have previously reported a t(11;15)(q23;q14) in a case of acute myeloblastic leukaemia. Here, we report the cloning of a novel MLL partner, AF15q14, at chromosome 15q14. In this translocation, the breakpoint occurred in exon 8 of MLL and exon 10 of AF15q14. The normal AF15q14 transcripts of approximately 8.5 kb in size, are expressed in different tumoral cell lines, in a variety of normal tissues, and in all the foetal tissues tested. Sequencing of AF15q14 cDNA revealed a putative open reading frame of 1833 amino acids that had no homology with any other known protein. The C-terminal end of the putative AF15q14 contained a bipartite nuclear localization site. The translocation t(11;15) preserved the open reading frame between MLL and the 3' end of AF15q14. The contribution of AF15q14 to the fusion protein was only 85 amino acids. Immunofluorescence staining experiments with expression vectors encoding these 85 amino acids confirmed the functionality of the predicted nuclear localization site.

FLRG (follistatin-related gene), a new target of chromosomal rearrangement in malignant blood disorders.

We report here the molecular study of a t(11;19)(q13;p13) translocation observed in a case of B-cell chronic lymphocytic leukemia. This translocation leads to the juxtaposition of the CCND1 gene on chromosome 11 to a new transcriptional unit on chromosome 19. The cDNA of this new evolutionarily conserved gene (named FLRG for Follistatin-Related Gene) codes for a secreted glycoprotein of the follistatin-module-protein family. FLRG is expressed in a wide range of human and murine adult tissues and its expression seems to be tightly regulated during murine embryogenesis. Its transcripts could not be detected in hematopoietic cells from all lineages and in particular in cells from lymphoid B and T lineage except in the t(11;19)-carrying leukemia described here. A great variability of expression is observed among the other tumoral cell lines analysed. Besides the t(11;19)-carrying leukemia described in this work, structural rearrangements of the FLRG locus have been found in a non-Hodgkin lymphoma, suggesting that it may play a role in leukemogenesis.

Metallothionein expression in human lung and its varying levels after lung transplantation. Toulouse Lung Transplantation Group.

The aim of this study was to determine the lung levels of metallothionein (MT), a free radical scavenger, because oxygen-derivated free radicals (ODFRs) have been involved both in reperfusion injury of transplanted lungs and in cardiac or renal allograft destruction. First, MT localization was evaluated in 14 normal human lung biopsy specimens. Then, in lung transplant recipients, MT content in BAL fluid (BALF) and its transcription rate in alveolar macrophages (AMs) were determined. The BALFs of 69 patients were separated into six groups: lung transplant recipients in clinically stable condition (CSR), those with acute rejection (AR), asymptomatic cytomegalovirus infection (ACMV), cytomegalovirus pneumonitis (CMVP), bronchiolitis obliterans syndrome (BOS), and patients without transplants who served as control subjects (NTCs). In normal lungs, 83% of AMs were positively stained. MT staining was also observed in pleural endothelial cells and basal cells from bronchial epithelium. In lung transplant recipients, MT levels in BALF were significantly higher in patients with CSR, AR, ACMV, and CMVP compared with NTCs, while during BOS, MT had a significantly lower level compared with other lung transplant groups. However, no difference among groups was found concerning MT-II messenger RNA expression in AMs, showing that, as in normal lung, AMs are not the only cells that produce MT. These data report for the first time to our knowledge MT cell distribution in human lung with specific emphasis on its enhanced levels after lung transplantation, even in the absence of complication. Possible correlation among MT levels, ODFRs, cytokine levels, and corticosteroid treatment during complications of lung transplantation are discussed.

Cancer trends from 1972-1991 for Registered Indians living on Manitoba Reserves.

BACKGROUND: The objectives of this study were to determine if the incidence of and mortality from cancer have increased between 1972-1991, and to describe the distribution of cancer sites and survival for Registered Indians living on-reserves. METHODS: Cancer cases and deaths on-reserve were obtained from the provincial cancer registry, using a postal code match. Treaty Status was verified using a population registry kept by Health Canada. Population figures on-reserve were obtained from the federal Department of Indian Affairs. RESULTS: The average annual number of cases and deaths increased by 64% and 122%, respectively, between 1972-76 and 1987-91 (NS). The age and sex standardized incidence and mortality rates increased by 7% and 50% (NS). Males had a 1.1 times higher incidence and 1.4 times higher death rate than females. The entire excess male incidence and mortality occurs after age 50. Females have 1.1 to 6.2 times the incidence and mortality between ages 20-49. CONCLUSIONS: Cancer incidence and mortality appear to be increasing on-reserve. The distribution of leading sites and pattern of survival are similar to that of the rest of the population, with the exception of a higher proportion of cases and mortality caused by cervical and gallbladder cancer in females and kidney cancer in both sexes. The lung cancer rate is increasing in women and is the leading cause of cancer mortality for both sexes. It is likely that these trends will continue for some time unless there is reduction in the high rate of smoking, dietary change, and implementation of more widespread and effective Pap screening on-reserves.

[Lung pathology in heart, liver and kidney transplantation in adults]. / Pathologies pulmonaires dans la transplantation cardiaque, hépatique et rénale chez l'adulte.

Currently transplantation constitutes the only treatment for terminal heart, liver or renal failure. Post-transplantation complications remain numerous and sometimes fatal. The rejection of the organ, acute or chronic, and secondary infections due to immunosuppression are the most frequent complications that are observed. Added to this are the complications of the surgery itself and also the non-infectious complications of the immunosuppressive drugs. Pulmonary complications contribute an important factor to the post-graft morbidity and mortality. The majority of heart and liver transplants develop pulmonary complications principally in the first six months after graft. The immediate post-operative complications such as atelectasis, pleural effusion and pulmonary oedema are the most frequent but the infectious complications are much the most serious and are responsible for a significant part of the mortality. In renal transplantation pulmonary complications are above all infectious and are much less common than in cardiac or hepatic transplantation. An early diagnosis of the type of complication constitutes a major prognostic factor in immunodepressed patients. Thus, the practising pneumologist must thoroughly know the principal respiratory complications of solid organ transplant.

Tumour necrosis factor-alpha gene expression by alveolar macrophages in human lung allograft recipient with recurrence of sarcoidosis. Toulouse Lung Transplantation Group.

Recurrence of sarcoidosis in lung allografts is an interesting model to study the pathogenesis of this disease. We report a case of sarcoidosis recurrence in a single lung allograft recipient 2 years after transplantation. The expression of tumour necrosis factor-alpha (TNF-alpha) gene by alveolar macrophages was monitored. The TNF-alpha gene was not expressed at the time of recurrence of sarcoidosis, but only later when prominent granulomas were observed.

[Alveolar lavage cytological data in lung transplants free of bronchial superinfection. Toulouse Lung Transplantation Group]. / Données cytologiques du lavage alvéolaire chez le transplanté pulmonaire indemne de surinfection bronchique. Groupe de Transplantation Pulmonaire de Toulouse.

Total and differential cells counts from 173 bronchoalveolar lavages (BAL) carried out in 19 lung transplanted recipients have been analysed. The patients were separated into seven groups: (a) those without detectable complications (86 BAL); (b) those with acute rejection (AR) (26 BAL); (c) those with bronchiolitis obliterans (BO) (21 BAL); (d) those with intra-alveolar cytomegalovirus (CMV) but asymptomatic (11 BAL); (e) those with an associated intra-alveolar CMV and AR (7 BAL); (f) those with CMV pneumonia (11 BAL); (g) those with infectious pneumonia excluding CMV (11 BAL). The alveolar cytological data were compared to those from control subjects who were smokers (7 BAL) or non-smokers (8 BAL). Excluding the BO group, the total cell count from the BAL of transplanted patients was significantly higher than in the non-smoking controls and was approaching that of the smoking controls. The lymphocytes count was significantly higher in transplanted patients without complication and in the AR group than in the controls, but there was no significant difference between the two groups. There was a significantly greater eosinophilia at the time of AR than either before or after. Eosinophilia was also higher in grade 3 AR than in grade 1 or 2 AR. These data stress the absence of any correlation between the lymphocyte count in the BAL and the existence of AR. Alternatively, the alveolar eosinophilia observed at the time of AR does not allow the possibility of an infection to be elimitated with certainty.