Impact of Radiation Therapy Modalities on Loco-regional Control in Inflammatory Breast Cancer.

PURPOSE: In inflammatory breast cancer, radiation therapy intensification is considered a standard of care by some teams, although the level of evidence remains low. We sought to analyze the impact of radiation therapy modalities on the risk of loco-regional and distant relapse. METHODS AND MATERIALS: This retrospective multicenter study included patients with localized inflammatory breast cancer treated between 2010 and 2017. Standard postmastectomy radiation therapy consisted of daily fractions to a total dose of 50 Gy equivalent without a boost or bolus, while intensified radiation therapy referred to the use of a boost or bolus. The cumulative incidence curves of locoregional and distant recurrence were displayed using the competing risk method. RESULTS: Of the 241 included patients, 165 were treated with standard and 76 with intensified radiation therapy. There was significantly more nodal involvement in the intensified group. With a median follow-up of 40 months postradiation therapy, there was no difference between standard versus intensified radiation therapy regarding the cumulative incidence of locoregional (P = .68) or distant recurrence (P = .29). At 5 years, the risks of locoregional and distant recurrence were 12.1% (95% CI, 7.5; 17.7) and 29.4% (95% CI, 21.8; 37.3) for patients treated with standard radiation therapy and 10.4% (95% CI, 4.4; 19.3) and 21.4% (95% CI, 12.6; 31.9) for those treated with intensified radiation therapy. In multivariate analyses, triple-negative subtype and absence of complete pathologic response were associated with a higher risk of loco-regional recurrence. Radiation therapy intensification had no significant impact on locoregional and distant recurrence. For patients with a non-complete pathologic response (n = 172, 71.7%), no significant differences were observed between the 2 groups for loco-regional (P = .80) and distant (P = .39) recurrence. Severe toxicity rates were similar in both groups. CONCLUSIONS: Contrary to other important series, this large retrospective multicentric study did not show a locoregional or distant control benefit of intensified radiation therapy. Pooled prospective studies and meta-analyses of intensified radiation therapy are warranted to endorse this approach.

Prognostic value of circulating short-length DNA fragments in unresected glioblastoma patients.

BACKGROUND: Liquid biopsy application is still challenging in glioblastoma patients and the usefulness of short-length DNA (slDNA) fragments is not established. The aim was to investigate slDNA concentration as a prognostic marker in unresected glioblastoma patients. METHODS: Patients with unresected glioblastoma and treated by radiochemotherapy (RT/TMZ) were included. Plasmas were prospectively collected at three times: before (pre-) RT, after (post-) RT and at the time of progression. Primary objective was to investigate the impact on survival of slDNA concentration [slDNA] variation during RT/TMZ. Secondary objectives were to explore the association between tumor volume, corticosteroid exposition and [slDNA]; and the impact of slDNA detection at pre-RT on survival. RESULTS: Thirty-six patients were analyzed: 11 patients (30.6 %) experienced [slDNA] decrease during RT/TMZ, 22 patients (61.1 %) experienced increase and 3 patients (8.3 %) had stability. Decrease of [slDNA] during RT/TMZ was associated with better outcome compared to increase or stability: median OS, since end of RT, of 13.2 months [11.4 - NA] vs 10.1 months [7.8 - 12.6] and 6.8 months [4.5 - NA], p = 0.015, respectively. slDNA detection at pre-RT time was associated with improved OS: 11.7 months in the slDNA(+) group versus 8.8 months in the slDNA(-) group, p = 0.004. [slDNA] was not associated with corticosteroids exposition or tumor volume. No influence on survival was observed for both whole cfDNA concentration or slDNA peak size. CONCLUSION: [slDNA] decrease during radiochemotherapy phase is a favorable prognostic marker on OS for unresected glioblastoma patients. Larger and independent cohorts are now required. TRIAL REGISTRATION: ClinicalTrial, NCT02617745. Registered 1 December 2015, https://clinicaltrials.gov/ct2/show/NCT02617745?term=glioplak&draw=2&rank=1.

High PDL1/PDL2 gene expression correlates with worse outcome in primary mediastinal large B-cell lymphoma.

Primary mediastinal B-cell lymphoma (PMBL) is an uncommon entity of aggressive B-cell lymphoma with an unusually good prognosis, except for 10-15% of chemotherapy-refractory cases. To identify earlier these higher risk patients, we performed molecular characterization of a retrospective multicenter cohort of patients treated with firstline immunochemotherapy. The traits of the patients with gene-expression profiling data (n = 120) were as follows: median age of 34 years (range, 18-67 years); female sex, 58.3%; elevated lactate dehydrogenase, 82.5%; Eastern Cooperative Oncology Group performance status score of 0 to 1, 85.7%; Ann Arbor stage I/II, 55%; International Prognostic Index score of 1 to 2, 64.4%; and median metabolic tumor volume, 290.4 cm3 (range, 15.7-1147.5 cm3). Among all 137 markers tested for correlation with survival data, only programmed death-ligand (PDL) 1 and PDL2 expression showed a prognostic impact. Overall, both PDL1 and PDL2 genes were highly expressed in 37 patients (30.8%; PDL1high/PDL2high). The baseline clinical characteristics of patients with PDL1high/PDL2high were similar to those of other patients. In univariate analysis, PDL1high/PDL2high status was associated with poor progression-free survival (PFS) (hazard ratio [HR], 4.292) and overall survival (OS; HR, 8.24). In multivariate analysis, PDL1high/PDL2high status was an independent prognostic factor of adverse outcomes (PFS: HR, 5.22; OS: HR, 10.368). We validated these results in an independent cohort of 40 patients and confirmed the significant association between PDL1high/PDL2high status and inferior PFS (HR, 6.11). High PDL1/PDL2 gene expression defines a population with strong immune privilege and poorer outcomes from standard chemotherapy who might benefit from firstline checkpoint inhibitor therapy.

Evaluation of the capability and reproducibility of RECIST 1.1. measurements by technologists in breast cancer follow-up: a pilot study.

The evaluation of tumor follow-up according to RECIST 1.1 has become essential in clinical practice given its role in therapeutic decision making. At the same time, radiologists are facing an increase in activity while facing a shortage. Radiographic technologists could contribute to the follow-up of these measures, but no studies have evaluated their ability to perform them. Ninety breast cancer patients were performed three CT follow-ups between September 2017 and August 2021. 270 follow-up treatment CT scans were analyzed including 445 target lesions. The rate of agreement of classifications RECIST 1.1 between five technologists and radiologists yielded moderate (k value between 0.47 and 0.52) and substantial (k value = 0.62 and k = 0.67) agreement values. 112 CT were classified as progressive disease (PD) by the radiologists, and 414 new lesions were identified. The analysis showed a percentage of strict agreement of progressive disease classification between reader-technologists and radiologists ranging from substantial to almost perfect agreement (range 73-97%). Analysis of intra-observer agreement was strong at almost perfect (k > 0.78) for 3 technologists. These results are encouraging regarding the ability of selected technologists to perform measurements according to RECIST 1.1 criteria by CT scan with good identification of disease progression.

High prevalence of pre-existing sarcopenia in critically ill patients with hematologic malignancies admitted to the intensive care unit for sepsis or septic shock.

BACKGROUND & AIMS: We aimed to evaluate body composition (BC) by computed tomography (CT) in hematologic malignancy (HM) patients admitted to the intensive care unit (ICU) for sepsis or septic shock. METHODS: We retrospectively assessed BC and its impact on outcome of 186 patients at the 3rd lumbar (L3) and 12th thoracic vertebral levels (T12) using CT-scan performed before ICU admission. RESULTS: The median patient age was 58.0 [47; 69] years. Patients displayed adverse clinical characteristics at admission with median [q1; q3] SAPS II and SOFA scores of 52 [40; 66] and 8 [5; 12], respectively. The mortality rate in the ICU was 45.7%. Overall survival rates at 1 month after admission in the pre-existing sarcopenic vs. non pre-existing sarcopenic patients were 47.9% (95% CI [37.6; 61.0]) and 55.0% (95% CI [41.6; 72.8]), p = 0.99), respectively, at the L3 level and 48.4% (95% CI [40.4; 58.0]) vs. 66.7% (95% CI [51.1; 87.0]), p = 0.062), respectively, at the T12 level. CONCLUSIONS: Sarcopenia is assessable by CT scan at both the T12 and L3 levels and is highly prevalent in HM patients admitted to the ICU for severe infections. Sarcopenia may contribute to the high mortality rate in the ICU in this population.

Quantitative MRI to Characterize Hypoxic Tumors in Comparison to FMISO PET/CT for Radiotherapy in Oropharynx Cancers.

Intratumoral hypoxia is associated with a poor prognosis and poor response to treatment in head and neck cancers. Its identification would allow for increasing the radiation dose to hypoxic tumor subvolumes. 18F-FMISO PET imaging is the gold standard; however, quantitative multiparametric MRI could show the presence of intratumoral hypoxia. Thus, 16 patients were prospectively included and underwent 18F-FDG PET/CT, 18F-FMISO PET/CT, and multiparametric quantitative MRI (DCE, diffusion and relaxometry T1 and T2 techniques) in the same position before treatment. PET and MRI sub-volumes were segmented and classified as hypoxic or non-hypoxic volumes to compare quantitative MRI parameters between normoxic and hypoxic volumes. In total, 13 patients had hypoxic lesions. The Dice, Jaccard, and overlap fraction similarity indices were 0.43, 0.28, and 0.71, respectively, between the FDG PET and MRI-measured lesion volumes, showing that the FDG PET tumor volume is partially contained within the MRI tumor volume. The results showed significant differences in the parameters of SUV in FDG and FMISO PET between patients with and without measurable hypoxic lesions. The quantitative MRI parameters of ADC, T1 max mapping and T2 max mapping were different between hypoxic and normoxic subvolumes. Quantitative MRI, based on free water diffusion and T1 and T2 mapping, seems to be able to identify intra-tumoral hypoxic sub-volumes for additional radiotherapy doses.

Cardiovascular outcomes of patients treated for non-Hodgkin lymphoma with first-line doxorubicin-based chemotherapy.

We conducted a single-center retrospective study to assess cardiovascular (CV) toxicity and treatment discontinuation for CV toxicity in diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) patients treated with immunochemotherapy (R-CHOP-like). Between 2006 and 2017, 433 patients were included (DLBCL: n = 345, FL: n = 88). The median age was 63 years (50-73). We defined three types of CV toxicity: early-onset cardiovascular toxicity (the event occurred within 6 months following treatment start); subacute toxicity (the event occurred between 6 months and 1 year after treatment start) and late toxicity (the event occurred 1 year or more after treatment start). Forty-eight (11.1%) patients experienced at least one anthracycline-related CV event. Seven patients experienced treatment discontinuation due to CV toxicity. Early-onset and subacute cardiac events were primarily acute heart failure (34.3%) and atrial fibrillation (28.6%). History of ischemic heart disease (p = 0.02) and valvular heart disease (p = 0.03) were associated with a higher risk of anthracycline-related CV event occurrence.

Circulating tumor DNA in primary mediastinal large B-cell lymphoma versus classical Hodgkin lymphoma: a retrospective study.

Few data exist concerning circulating tumor DNA (ctDNA) relevance in primary mediastinal B-cell lymphoma (PMBL). To explore this topic, we applied a 9-gene next-generation sequencing pipeline to samples from forty-four PMBL patients (median age 36.5 years). The primary endpoint was a similarity between paired biopsy/plasma mutational profiles. We detected at least one variant in 32 plasma samples (80%). The similarity between the biopsy and ctDNA genetic profiles for the 30 patients with paired mutated biopsy/plasma samples was greater than or equal to 80% in 19 patients (63.3%). We then compared PMBL ctDNA features with those of a cohort of Hodgkin lymphoma patients (n = 60). The top three mutated genes were SOCS1, TNFAIP3, and B2M in both lymphoma types. PMBL displayed more alterations in TNFAIP3 (71.9% vs. 46.3%, p = 0.029) and GNA13 (46.9% vs. 17.1%, p = 0.013) than cHL. Our 9-gene set may delineate tumor genotypes using ctDNA samples from both lymphoma types.

Chronic Low-Dose Exposure to Xenoestrogen Ambient Air Pollutants and Breast Cancer Risk: XENAIR Protocol for a Case-Control Study Nested Within the French E3N Cohort.

BACKGROUND: Breast cancer is the most frequent cancer in women in industrialized countries. Lifestyle and environmental factors, particularly endocrine-disrupting pollutants, have been suggested to play a role in breast cancer risk. Current epidemiological studies, although not fully consistent, suggest a positive association of breast cancer risk with exposure to several International Agency for Research on Cancer Group 1 air-pollutant carcinogens, such as particulate matter, polychlorinated biphenyls (PCB), dioxins, Benzo[a]pyrene (BaP), and cadmium. However, epidemiological studies remain scarce and inconsistent. It has been proposed that the menopausal status could modify the relationship between pollutants and breast cancer and that the association varies with hormone receptor status. OBJECTIVE: The XENAIR project will investigate the association of breast cancer risk (overall and by hormone receptor status) with chronic exposure to selected air pollutants, including particulate matter, nitrogen dioxide (NO2), ozone (O3), BaP, dioxins, PCB-153, and cadmium. METHODS: Our research is based on a case-control study nested within the French national E3N cohort of 5222 invasive breast cancer cases identified during follow-up from 1990 to 2011, and 5222 matched controls. A questionnaire was sent to all participants to collect their lifetime residential addresses and information on indoor pollution. We will assess these exposures using complementary models of land-use regression, atmospheric dispersion, and regional chemistry-transport (CHIMERE) models, via a Geographic Information System. Associations with breast cancer risk will be modeled using conditional logistic regression models. We will also study the impact of exposure on DNA methylation and interactions with genetic polymorphisms. Appropriate statistical methods, including Bayesian modeling, principal component analysis, and cluster analysis, will be used to assess the impact of multipollutant exposure. The fraction of breast cancer cases attributable to air pollution will be estimated. RESULTS: The XENAIR project will contribute to current knowledge on the health effects of air pollution and identify and understand environmental modifiable risk factors related to breast cancer risk. CONCLUSIONS: The results will provide relevant evidence to governments and policy-makers to improve effective public health prevention strategies on air pollution. The XENAIR dataset can be used in future efforts to study the effects of exposure to air pollution associated with other chronic conditions. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15167.

A new trajectory approach for investigating the association between an environmental or occupational exposure over lifetime and the risk of chronic disease: Application to smoking, asbestos, and lung cancer.

Quantifying the association between lifetime exposures and the risk of developing a chronic disease is a recurrent challenge in epidemiology. Individual exposure trajectories are often heterogeneous and studying their associations with the risk of disease is not straightforward. We propose to use a latent class mixed model (LCMM) to identify profiles (latent classes) of exposure trajectories and estimate their association with the risk of disease. The methodology is applied to study the association between lifetime trajectories of smoking or occupational exposure to asbestos and the risk of lung cancer in males of the ICARE population-based case-control study. Asbestos exposure was assessed using a job exposure matrix. The classes of exposure trajectories were identified using two separate LCMM for smoking and asbestos, and the association between the identified classes and the risk of lung cancer was estimated in a second stage using weighted logistic regression and all subjects. A total of 2026/2610 cases/controls had complete information on both smoking and asbestos exposure, including 1938/1837 cases/controls ever smokers, and 1417/1520 cases/controls ever exposed to asbestos. The LCMM identified four latent classes of smoking trajectories which had different risks of lung cancer, all much stronger than never smokers. The most frequent class had moderate constant intensity over lifetime while the three others had either long-term, distant or recent high intensity. The latter had the strongest risk of lung cancer. We identified five classes of asbestos exposure trajectories which all had higher risk of lung cancer compared to men never occupationally exposed to asbestos, whatever the dose and the timing of exposure. The proposed approach opens new perspectives for the analyses of dose-time-response relationships between protracted exposures and the risk of developing a chronic disease, by providing a complete picture of exposure history in terms of intensity, duration, and timing of exposure.

Long-term airborne dioxin exposure and breast cancer risk in a case-control study nested within the French E3N prospective cohort.

BACKGROUND: Dioxins, Group 1 carcinogens, are emitted by industrial chlorinated combustion processes and suspected to increase breast cancer risk through receptor-mediated pathways. OBJECTIVES: We estimated breast cancer risk associated with airborne dioxin exposure, using geographic information system (GIS) methods and historical exposure data. METHODS: We designed a case-control study (429 breast cancer cases diagnosed between 1990 and 2008, matched to 716 controls) nested within the E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale) cohort. Airborne dioxin exposure was assessed using a GIS-based metric including participants' residential history, technical characteristics of 222 dioxin sources, residential proximity to dioxin sources, exposure duration and wind direction. Odds ratios (OR) and 95% confidence intervals (CI) associated with quintiles of cumulative exposure were estimated using multivariate logistic regression models. RESULTS: We observed no increased risk of breast cancer for higher dioxin exposure levels overall and according to hormone-receptor status. We however observed a statistically significant OR for Q2 versus Q1 overall (1.612, 95% CI: 1.042-2.493) and for estrogen-receptor (ER) positive breast cancer (1.843, 95% CI: 1.033-3.292). CONCLUSIONS: Overall, as well as according to hormone-receptor status, no increased risk was observed for higher airborne dioxin exposure. The increased risk for low exposure levels might be compatible with non-monotonic dose-response relationship. Confirmation of our findings is required. Our GIS-based metric may provide an alternative in absence of ambient dioxin monitoring and may allow assessing exposure to other pollutants.

Time-dependent effect of intensity of smoking and of occupational exposure to asbestos on the risk of lung cancer: results from the ICARE case-control study.

OBJECTIVE: To estimate the impact of intensity of both smoking and occupational exposure to asbestos on the risk of lung cancer throughout the whole exposure history. METHODS: Data on 2026 male cases and 2610 male controls came from the French ICARE (Investigation of occupational and environmental causes of respiratory cancers) population-based, case-control study. Lifetime smoking history and occupational history were collected from standardised questionnaires and face-to-face interviews. Occupational exposure to asbestos was assessed using a job exposure matrix. The effects of annual average daily intensity of smoking (reported average number of cigarettes smoked per day) and asbestos exposure (estimated average daily air concentration of asbestos fibres at work) were estimated using a flexible weighted cumulative index of exposure in logistic regression models. RESULTS: Intensity of smoking in the 10 years preceding diagnosis had a much stronger association with the risk of lung cancer than more distant intensity. By contrast, intensity of asbestos exposure that occurred more than 40 years before diagnosis had a stronger association with the risk of lung cancer than more recent intensity, even if intensity in the 10 years preceding diagnosis also had a significant effect. CONCLUSION: Our results illustrate the dynamic of the effect of intensity of both smoking and occupational exposure to asbestos on the risk of lung cancer. They confirm that the timing of exposure plays an important role, and suggest that standard analytical methods assuming equal weights of intensity over the whole exposure history may be questionable.

Dose-time-response association between occupational asbestos exposure and pleural mesothelioma.

OBJECTIVES: Early occupational exposure to asbestos has been shown to be associated with an increased risk of pleural mesothelioma (PM), which suggests that the timing of exposure might play a role in the dose-response relationship. However, none studies has evaluated the relative impact of increasing the annual intensity of occupational exposure to asbestos at each time of the whole exposure history. Yet such evaluation would allow the comparison of the risks of PM associated with different longitudinal profiles of occupational exposure to asbestos. Our objective was to estimate the time-dependent relative impact of asbestos exposure intensity over the whole occupational history and to compare the resulting estimated risks of PM associated with different profiles of exposure, using data from a large French case-control study. METHODS: This study included 1196 male cases recruited in 1987-2006 and 2369 matched controls on birth year. Occupational exposure to asbestos was assessed using a job exposure matrix and represented in logistic regression models using a flexible weighted cumulative index of exposure. RESULTS: Due to much stronger weights of early doses of asbestos exposure, subjects who accumulated 20 fibres/mL over their entire job history with high doses during the first years and low doses thereafter were at higher risk of PM than those who accumulated most of the doses later (OR=2.37 (95% CI 2.01 to 2.87)). CONCLUSION: This study provides new insights on the dose-time-response relationship between occupational asbestos and PM and illustrates the importance of considering timing of exposure in its association with cancer risk.

Air pollution and activation of mobile medical team for out-of-hospital cardiac arrest.

BACKGROUND: The association between air pollution exposure and cardiovascular events is well established, and the effect of short-term exposure on out-of-hospital cardiac arrest (OHCA) has received some attention. The effect of air pollution exposure and the activation of mobile intensive care units (MICUs) for cardiac arrest have never been studied. OBJECTIVE: We analyzed associations between air pollutants and MICU activation for OHCA. METHOD: This is a retrospective study including 4558 patients with OHCA and MICU activation from 2007 to 2012. A time-stratified case crossover design was used. Particulate matter (PM) of median aerodynamic diameter less than 2.5 µm (PM2.5), less than 10 µm, and ozone were the 3 main pollutants used to determine the effects of pollution exposure on the event. RESULTS: A daily average increase of 27.6 µg/m(3) in ozone was associated with an increase of MICU activation for OHCA the following day (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.03-1.22). For women, a daily average increase of 27.6 µg/m(3) in ozone was associated with an increase of MICU activation for OHCA the following day (OR, 1.19; 95% CI, 1.01-1.37). An hourly average increase of 10.5 µg/m(3) in PM2.5 was associated with an increase of MICU activation for OHCA in the current hour (OR, 1.11; 95% CI, 1.02-1.19). For men, an increase in PM2.5 was associated with an increase in MICU activation for OHCA the current hour (OR, 1.10; 95% CI, 1.01-1.20). No association was found with PM of median aerodynamic diameter less than 10 µm. CONCLUSION: An association was found between air pollution and MICU activation for OHCA (ozone and PM2.5).