Brachytherapy: An overview for clinicians.

Brachytherapy is a specific form of radiotherapy consisting of the precise placement of radioactive sources directly into or next to the tumor. This technique is indicated for patients affected by various types of cancers. It is an optimal tool for delivering very high doses to the tumor focally while minimizing the probability of normal tissue complications. Physicians from a wide range of specialties may be involved in either the referral to or the placement of brachytherapy. Many patients require brachytherapy as either primary treatment or as part of their oncologic care. On the basis of high-level evidence from randomized controlled trials, brachytherapy is mainly indicated: 1) as standard in combination with chemoradiation in patients with locally advanced cervical cancer; 2) in surgically treated patients with uterine endometrial cancer for decreasing the risk of vaginal vault recurrence; 3) in patients with high-risk prostate cancer to perform dose escalation and improve progression-free survival; and 4) in patients with breast cancer as adjuvant, accelerated partial breast irradiation or to boost the tumor bed. In this review, the authors discuss the clinical relevance of brachytherapy with a focus on indications, levels of evidence, and results in the overall context of radiation use for patients with cancer.

Fluid Intake in Critically Ill Patients: The "Save Useless Fluids For Intensive Resuscitation" Multicenter Prospective Cohort Study.

OBJECTIVES: Patients at risk of adverse effects related to positive fluid balance could benefit from fluid intake optimization. Less attention is paid to nonresuscitation fluids. We aim to evaluate the heterogeneity of fluid intake at the initial phase of resuscitation. DESIGN: Prospective multicenter cohort study. SETTING: Thirty ICUs across France and one in Spain. PATIENTS: Patients requiring vasopressors and/or invasive mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All fluids administered by vascular or enteral lines were recorded over 24 hours following admission and were classified in four main groups according to their predefined indication: fluids having a well-documented homeostasis goal (resuscitation fluids, rehydration, blood products, and nutrition), drug carriers, maintenance fluids, and fluids for technical needs. Models of regression were constructed to determine fluid intake predicted by patient characteristics. Centers were classified according to tertiles of fluid intake. The cohort included 296 patients. The median total volume of fluids was 3546 mL (interquartile range, 2441-4955 mL), with fluids indisputably required for body fluid homeostasis representing 36% of this total. Saline, glucose-containing high chloride crystalloids, and balanced crystalloids represented 43%, 27%, and 16% of total volume, respectively. Whatever the class of fluids, center of inclusion was the strongest factor associated with volumes. Compared with the first tertile, the difference between the volume predicted by patient characteristics and the volume given was +1.2 ± 2.0 L in tertile 2 and +3.0 ± 2.8 L in tertile 3. CONCLUSIONS: Fluids indisputably required for body fluid homeostasis represent the minority of fluid intake during the 24 hours after ICU admission. Center effect is the strongest factor associated with the volume of fluids. Heterogeneity in practices suggests that optimal strategies for volume and goals of common fluids administration need to be developed.

Identification and Management of Pelvic Fractures in Prehospital and Emergency Department Settings.

INTRODUCTION: This study aims to describe the characteristics of patients with a pelvic fracture treated at a level 1 trauma center, the proportion of prehospital undertriage and the use of pelvic circumferential compression device (PCCD). METHODS: This is a retrospective cohort study. Prehospital and inhospital medical records of adults (≥16 y old) with a pelvic fracture who were treated at Hopital de l'Enfant-Jesus-CHU de Québec (Quebec City, Canada), a university-affiliated level 1 trauma center, between September 01, 2017 and September 01, 2021 were reviewed. Isolated hip or pubic ramus fracture were excluded. Data are presented using proportions and means with standard deviations. RESULTS: A total of 228 patients were included (males: 62.3%; mean age: 54.6 [standard deviation 21.1]). Motor vehicle collision (47.4%) was the main mechanism of injury followed by high-level fall (21.5%). Approximately a third (34.2%) needed at least one blood transfusion. Compared to those admitted directly, transferred patients were more likely to be male (73.0% versus 51.3%, P < 0.001) and to have a surgical procedure performed at the trauma center (71.3% versus 46.9%, P < 0.001). The proportion of prehospital undertriage was 22.6%. Overall, 17.1% had an open-book fracture and would have potentially benefited from a prehospital PCCD. Forty-six transferred patients had a PCCD applied at the referral hospital of which 26.1% needed adjustment. CONCLUSIONS: Pelvic fractures are challenging to identify in the prehospital environment and are associated with a high undertriage of 22.6%. Reducing undertriage and optimizing the use of PCCD are key opportunities to improve care of patients with a pelvic fracture.

Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): an updated individual patient data network meta-analysis.

BACKGROUND: The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis. METHODS: For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524. FINDINGS: The network comprised 28 trials and included 8214 patients (6133 [74·7%] were men, 2073 [25·2%] were women, and eight [0·1%] had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2-13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59-0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69-0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75-1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%). INTERPRETATION: The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma. FUNDING: Institut National du Cancer and Ligue Nationale Contre le Cancer.

Locoregional treatment of primary tumor in synchronous metastatic head and neck squamous cell carcinomas.

PURPOSE: Patients with synchronous metastatic head and neck squamous cell carcinomas (mHNSCC) are at risk of locoregional progression associated with significant morbidity and mortality. The aim of this study is to assess whether the addition of aggressive locoregional treatment to systemic therapy could be associated with an improved overall survival (OS) compared to systemic therapy alone in upfront mHNSCC patients. MATERIAL AND METHODS: This retrospective study included patients presenting with previously untreated mHNSCC who underwent first-line systemic therapy at a single institution between 1998 and 2018. Locoregional treatment was defined as either exclusive locoregional radiotherapy (RT) or surgery with or without adjuvant RT. RESULTS: One hundred forty-eight patients were included. Eighty patients were treated with systemic therapy alone and 68 patients were treated with a combination of locoregional treatment and systemic therapy. Median overall survival (OS) was 13 months [10.7-15] and median progression free survival (PFS) was 7.7 month [6.5-8.9]. The addition of a locoregional treatment to systemic therapy compared to systemic therapy alone was associated with improved survival (1-year OS, 65.8% vs. 41.1%, p < .001, and 1-year PFS, 42.5% vs. 18.5%, p < .001). Moreover, RT dose equal to 70 Gy was associated with even longer OS compared to a RT dose below 70 Gy and to no locoregional treatment (23.4 vs. 12.7 vs 7.5 months respectively). In a subgroup analysis on 75 patients presenting with a responding or stable metastatic disease after first-line systemic therapy, oropharyngeal primary tumor site and the addition of a locoregional treatment, especially a high radiation dose of 70 Gy, were evidenced as independent prognostic factors for improved OS. CONCLUSION: The addition of a high-dose RT locoregional treatment to systemic therapy is associated with prolonged OS in patients with synchronous mHNSCC and should be discussed for patients who respond to or have a stable disease after first-line systemic therapy.

Post-therapeutic surveillance of HPV-driven oropharyngeal cancers: are we ready to change our practices?

PURPOSE: Although HPV-positive and negative oropharyngeal cancers are two distinct diseases, Post-Therapeutic Surveillance (PTS) modalities are similar. Adjusting PTS strategies to HPV status will represent a massive practice change that raises the issue of its acceptability, by both physicians and patients. METHODS: Two distinct surveys were designed and submitted, respectively, to HPV-positive patients and physicians (surgeons, radiation and medical oncologists) involved in head and neck cancer treatment. RESULTS: 133 patients and 90 physicians have participated to the study. Most patients were reluctant to embrace new PTS options (remote consultations, nurse consultations and smart phone applications). However, 84% of patients would be favorable to use HPV Circulating DNA (HPV Ct DNA) measurement to guide surveillance modalities. 57% of physicians acknowledged that our current PTS strategy is improvable and most of them would accept the use of new monitoring options from the third year of follow-up. 87% of physicians would be interested to participate to a trial comparing the current PTS strategy to a new approach, where monitoring modalities (number of visits, imaging prescription) would depend on HPV Ct DNA level. CONCLUSIONS: Patients and physicians are aware that PTS modalities should depend on HPV status. Their adhesion is a prerequisite to any potential changes. Strategies based on HPV Ct DNA measurement should be assessed within a randomized clinical trial.

A Canadian consensus-based list of urgent and specialized in-hospital trauma care interventions to assess the accuracy of prehospital trauma triage protocols: a modified Delphi study.

BACKGROUND: Injury severity scales have traditionally been used to assess the performance of prehospital trauma triage protocols, but they correlate weakly with the urgent needs of specialized trauma care interventions. This study aimed to develop a list of in-hospital urgent and specialized trauma care interventions that require direct transport to the highest-level trauma centre within the catchment area. METHODS: Based on a list of potential participants we obtained using data on training, experience, geographic location, affiliations and role within key trauma organizations, we recruited multidisciplinary trauma experts (including prehospital, emergency, surgery and intensive care clinicians, epidemiologists and clinician/decision-makers) from across Canada to complete a 3-round modified Delphi survey. We conducted a literature review of the criteria used to define urgent and specialized trauma care, and included all diagnostic and therapeutic interventions presented in previously published studies in the list of interventions to present to the panellists. The final list was determined by our advisory committee, 5 clinicians with experience in trauma care. Participants were asked to rate their level of agreement for potentially including the 38 items as urgent and specialized trauma care interventions on a 9-point Likert scale. Interventions were retained if more than 67% of participants moderately or strongly agreed (7-9 on the Likert scale). Interventions that did not reach consensus were presented again in the subsequent round. RESULTS: Twenty-three panellists were recruited. The response rate was 91%, 96% and 83% for the 3 rounds. After the Delphi process, 30 of the 38 interventions, including endotracheal intubation, blood product administration and angioembolization, and abdominal, thoracic, neurosurgical, spinal and/or orthopedic operations (excluding hip or limb surgery, and toe or finger amputation), were selected. Hospital admission to the intensive care unit and/or for observation of brain, spinal, thoracic or abdominal injuries were also retained. CONCLUSION: We developed a Canadian consensus-based list of urgent and specialized in-hospital trauma care interventions requiring direct transportation to a major trauma centre. This list should help standardize assessments of current protocols and derive new triage tools.

Twitter as a Medical Media Among French Young Oncologists: Results from a National Survey.

Since its launch in 2006, Twitter has become a commonly used platform for sharing medical information, especially in the field of oncology. However, its role and impact on young oncologists' education remain unclear. Moreover, COVID-19 and congress virtualization is likely to have modified Twitter use by the medical society.We conducted a national survey (27 questions) in France among medical oncology, hematology, and radiation therapy young doctors to help better understand the role played by Twitter on their medical education. One hundred eighty-three young oncologists participated in our survey. A majority does not use Twitter (72.1%), mostly to reduce their time spent on social media. Participants using Twitter (27.9%) often use it more than once a week, mostly by scrolling on their news feed. Interestingly, they rarely express their own opinion on Twitter: a majority of them (75.5%) tweet less than once a month while the rest of them mostly retweet others' tweets. They mainly follow English-speaking experts, scientific societies, and medical journals. Pharmaceutical laboratories' accounts are of less significance. Overall Twitter usage seems increasing since COVID-19 pandemic and the consequent digitalization of congresses. No statistical difference was observed between the baseline characteristics of Twitter users and non-users.This survey shows that Twitter is a relevant mean of continuous medical education used by around a third of French young oncologists, especially since COVID-19 pandemic and the virtualization of congresses. This media should be considered and evaluated for its educational advantages or potential biases.

Feasibility of a repositioning schedule on pressure ulcer prevention in a French Intensive Care Unit: A pre and post-intervention pilot study.

AIMS: As a prerequisite of a multicentre study, we conducted a pilot study to assess the feasibility of a daily repositioning schedule in critically ill patients. The schedule was adapted to the patient's clinical condition, and the estimated risk for developing a pressure ulcer using the Braden scale. DESIGN: A single-center pre and post-intervention pilot study in a French Intensive Care Unit of a university teaching hospital. This study followed TREND guidelines. METHODS: During the first period (March to May 2018), pressure ulcer prevention was performed according to usual care. During the second period (June to August 2018), the repositioning schedule was adapted to the estimated risk for developing a pressure ulcer according to the Braden scale. Eligible patients had no pressure ulcer at baseline, were intubated within 24 hours of admission and expected to receive mechanical ventilation for at least 24 hours. The primary outcome was the rate of pressure ulcer development at 28 days of hospitalization or at discharge or death, as compared with usual care. Secondary outcomes included the feasibility and safety of the schedule, as assessed by caregivers' adherence and workload, and the rate of adverse events. RESULTS: In the pre-intervention period 20 participants were included, and 14 patients were included in the post-intervention period. There was no decrease in the pressure ulcers incidence with the intervention (25% vs. 28.6%; P = 1). The number of daily repositioning performed increased from 3.3 [IQR 3.0; 3.9] during the pre-intervention period to 4.3 [IQR 3.8; 5.2] during the post-intervention period (P < 0.05), where it differed from the number scheduled by 0.6 [IQR 0.1; 1.4] per day, indicating satisfactory adherence of caregivers to the protocol. Adverse events rate did not differ between the two periods (55.9% vs. 57.1%; P = 0.90). CONCLUSION: A personalised daily repositioning schedule in critically ill patients is feasible and safe. The efficacy of such a strategy, together with its economic impact, need to be assessed in a multicentre randomized trial.

2011-2021 rising prevalence of HPV infection among oropharyngeal carcinoma in France.

BACKGROUND: The objective of our study was to investigate changes over the past decade in patient age and the prevalence of HPV in the population of patients with oropharyngeal carcinoma (OPC) treated at our center. METHODS: We performed a retrospective cohort study of patients treated at our cancer center for OPC between 2011 and 2021. Tissue biopsies were assessed for HPV status based on p16 staining for all patients. RESULTS: There were 1,365 treated patients. The proportion of p16-positive patients increased from 43% in 2011 to 57.3% in 2021 (p = 0.01). The sex ratio was 3.6 M/1F for p16-positive and 3.7 M/1F for p16-negative patients (p = 0.94). The mean age increased from 60.2 y in 2011 to 63.6 y in 2021. The mean ages were 61.9 y for p16-positive and 61.7 y for p16-negative patients (p = 0.71), but there was a broader age distribution for the p16-positive patients (p = 0.03). The proportion of patients older than 70 y increased from 11% in 2011 to 28.2% in 2021, and this aging was similar between p16-positive (30.7% in 2021) and p16-negative (26.3% in 2021) patients. The 2-year and 5-year OS rates were 73.7% and 56.5% for the entire cohort. p16-positive patients had 2-year and 5-year OS rates of 86.8% and 77.4%, respectively, whereas p16-negative patients had 2-year and 5-year OS rates of 63.9% and 40.5%. CONCLUSIONS: Assessment of the change over the past decade in the population of patients with OPC at our center showed that HPV-positive OPC now appear to have overtaken HPV-negative cases in France, with 57.3% in 2021, and showed significant aging, with almost thirty percent of patients now older than 70 years. Those combined changes emphasize some of the challenges to be addressed in future OPC management.

Penalized Poisson model for network meta-analysis of individual patient time-to-event data.

Network meta-analysis (NMA) allows the combination of direct and indirect evidence from a set of randomized clinical trials. Performing NMA using individual patient data (IPD) is considered as a "gold standard" approach as it provides several advantages over NMA based on aggregate data. For example, it allows to perform advanced modeling of covariates or covariate-treatment interactions. An important issue in IPD NMA is the selection of influential parameters among terms that account for inconsistency, covariates, covariate-by-treatment interactions or nonproportionality of treatments effect for time to event data. This issue has not been deeply studied in the literature yet and in particular not for time-to-event data. A major difficulty is to jointly account for between-trial heterogeneity which could have a major influence on the selection process. The use of penalized generalized mixed effect model is a solution, but existing implementations have several shortcomings and an important computational cost that precludes their use for complex IPD NMA. In this article, we propose a penalized Poisson regression model to perform IPD NMA of time-to-event data. It is based only on fixed effect parameters which improve its computational cost over the use of random effects. It could be easily implemented using existing penalized regression package. Computer code is shared for implementation. The methods were applied on simulated data to illustrate the importance to take into account between trial heterogeneity during the selection procedure. Finally, it was applied to an IPD NMA of overall survival of chemotherapy and radiotherapy in nasopharyngeal carcinoma.

Accuracy of Prehospital Trauma Triage to Select Older Adults Requiring Urgent and Specialized Trauma Care.

INTRODUCTION: This study aims to assess the sensitivity and specificity of a 5-step prehospital trauma triage protocol to identify older adults who require urgent and specialized trauma care using different age cut-offs to define an older adult (≥55, ≥65, and ≥75 y old). METHODS: Prehospital and in-hospital medical records were reviewed for injured patients transported by an ambulance to an emergency department (ED) between November 11, 2016 and March 3, 2017 in Quebec City, Canada. Sensitivities and specificities were calculated to assess the accuracy of our prehospital trauma triage protocol to identify patients who required at least one urgent in-hospital trauma intervention. RESULTS: A total of 822 patients were included of which 62.9% were ≥55 y old and 56.3% were female. Fall (65.8%) was the main trauma mechanism. Seventy-six (9.2%) patients required urgent trauma care. This proportion was similar regardless of age (8.9%-9.5%). The proportion of patients who needed to be transported to the level-1 trauma center as per the triage protocol tended to decrease with increasing age (20.6% [whole cohort], 15.3% [≥55 y old], 11.4% [≥65 y old], and 9.0% [≥75 y old]). The sensitivity of the protocol for steps 1, 2, and 3 was 56.6% (whole cohort) and 30.0% for patients aged ≥75 y. The specificity ranged between 83.1% (whole cohort) and 93.1% (≥75 y old). CONCLUSIONS: Our prehospital trauma triage protocol has insufficient sensitivity to identify patients with urgent trauma care needs, particularly in older adults.

Disease-free time stratification in locally recurrent head and neck carcinoma after definitive radiotherapy or chemoradiotherapy.

PURPOSE: There is no standard definition of disease-free interval before local recurrence after treatment in head and neck carcinoma (HNSCC). We evaluated an easy-to-use stratification and its association with survival in a large cohort of patients. METHODS: We performed a retrospective cohort analysis of prognostic variables in 325 HNSCC patients with a local recurrence after definitive radiotherapy or concurrent chemoradiotherapy. Endpoints were overall survival (OS) and post-recurrence survival (PRS). RESULTS: Variables associated with the survival were the patient age (OS p < 0.0001, PRS p < 0.0001), the initial disease stage (OS p = 0.24, PRS p = 0.0358), localization (OS p = 0.012, PRS p = 0.0002), a complete initial response to treatment (OS p < 0.0001, PRS p = 0.019), synchronous regional or distant metastatic disease (OS p = 0.0094, PRS p < 0.0001), a salvage surgery (OS p < 0.0001, PRS p < 0.0001) and time to recurrence (OS p = 0.0002, PRS p = 0.0029). Time to recurrence could be stratified between specific prognostic time categories that comprised disease persistence, early recurrence (< 12 months), standard recurrence (12 months-5 years) and late recurrence (> 5 years). CONCLUSION: In HNSCC patients, time to local recurrence is a prognostic variable that can be defined using an easy-to-use stratification.

Personal resources used by nurses enrolled in an advanced practice curriculum during the COVID-19 pandemic in France: Sequential mixed research / Ressources personnelles utilisées par les infirmiers inscrits dans un cursus en pratique avancée lors de la pandémie de coronavirus en France : une recherche mixte séquentielle

Introduction: At the beginning of 2020, a public health emergency was declared in France following the emergence of the SARS-CoV-2 pandemic. Context: Nurses involved in an advanced practice mobilized their specific skills during this health crisis by drawing on the available resources. Objectives: To analyze personal resources used by those nurses in the process of skill mobilization during the pandemic. Method: Sequential mixed research, first quantitative and then qualitative, concerning nurses or students enrolled in an advanced practice curriculum. Results: Our analysis highlighted two groups of activity for those nurses: frontline workers against COVID-19 or coordination. Coordination seemed to present more opportunities to use the specific skills of advance practice nursing. Discussion: Adjustment strategies for stress (coping and hardiness) boost nurses' commitment to their professional practice. Disciplinary knowledge contributes to the enrichment of the knowledge necessary for the mobilization of skills. Conclusion: Future research should explore resources and the mobilization of skills in the implementation of advance practice nursing.

Introduction: Début 2020, l'état d'urgence sanitaire est déclaré en France suite à l'émergence d'une pandémie au SARS-CoV-2. Contexte: Les infirmiers inscrits dans un parcours de pratique avancée ont mobilisé leurs compétences pendant cette crise en s'appuyant sur les ressources disponibles. Objectifs: Analyser les ressources personnelles utilisées par ces infirmiers dans le processus de mobilisation des compétences, lors de la crise sanitaire. Méthode: Recherche mixte séquentielle quantitative puis qualitative auprès des infirmiers français inscrits dans un cursus de pratique avancée. Résultats: Il émerge deux groupes d'activité pour ces infirmiers : en première ligne en service Covid, et la coordination. Il semble y avoir plus d'opportunités d'utiliser les compétences spécifiques à la pratique avancée en coordination. Discussion: Les stratégies d'ajustement au stress (coping et hardiesse) favorisent l'engagement des infirmiers dans leur pratique professionnelle. Les savoirs disciplinaires participent à l'enrichissement des connaissances nécessaires à la mobilisation des compétences. Conclusion: De futures recherches devraient explorer les ressources et la mobilisation des compétences dans l'implantation des infirmiers en pratique avancée.

Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.

BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

Post-Radiation Grade 3 Neuroendocrine Carcinoma: A New Entity?

BACKGROUND: Cancer survivors have a 14% increased risk of developing a malignancy compared with the general population. Second radiation-induced malignancies with different histologies have been described in different organs. Based on individual observations, we hypothesized that neuroendocrine carcinoma (NEC) could arise in irradiated organs. METHODS: In a retrospective analysis of Gustave Roussy database of NEC patients (small cell lung cancer excluded) diagnosed as a second cancer, we looked for the frequency of grade 3 NEC that arose in patients who had received previous radiation therapy for a first cancer. Radiation therapy for the first cancer, dose, location of radiation therapy, pathological characteristics, overall survival, and response to treatment of secondary NEC were analyzed. RESULTS: From January 1995 to December 2017, 847 cases of NEC were seen at Gustave Roussy. Among them, 95 (11.2%) patients had a history of previous malignancy of which 36 (4%) had been treated with radiation therapy. Out of these 36 patients, 12 (1.4% of all NEC patients) developed a NEC within the previous irradiated organ (median dose of 50 Gy, range 36-67.5). Most frequent first cancers were breast cancer (n = 4) and Hodgkin lymphoma (n = 3). NEC arose within a median time of 21.7 years (range 5.1-36.4) from radiation in the thorax (n = 5), digestive tract (n = 3), and other sites. Five large cell NEC, 3 small cell NEC, 1 mixed neuroendocrine neoplasm and 3 not otherwise specified NEC were diagnosed. Ten patients had stage IV disease at diagnosis; median overall survival was 37.8 months (95% CI [17.6 to NA]). Three patients (25%) achieved complete response with multimodal treatment. CONCLUSIONS: NEC can arise from previously irradiated organs and may have a better outcome in this setting. Other risk factors should be investigated to explain the high rate of previous cancer in this population of neuroendocrine neoplasm.

QualFatigue study: which factors influence the use of specific interventions for breast cancer survivors with fatigue? A cross-sectional exploratory study.

PURPOSE: International guidelines recommend specific interventions to reduce cancer-related fatigue (CRF). Evidence suggests underutilization of these interventions among breast cancer survivors. The QualFatigue study aimed to explore the potential factors influencing the use of specific interventions, for relief, in patients with CRF through qualitative analyses. METHODS: Patients with stage I-III breast cancer, and CRF ≥4 on a 10-point numerical scale were recruited within 6-24 months at the end of their primary treatment. Semi-structured interviews were performed. Emergent themes were identified using a stepped content analysis (QDA Miner software). RESULTS: Data saturation was achieved with 15 interviews. Four main themes emerged as potential sources of influence in the participants' use of specific interventions: (1) expectations regarding the management of CRF, (2) representations of the benefits provided by the interventions, (3) individual physical and psychological conditions, and (4) social and environmental situations. Six key levers came out transversally to optimize the use of specific interventions to relieve CRF: (1) listening and recognition of the individual difficulties and needs; (2) individual and global health assessments; (3) information and advice on how to manage CRF; (4) discussion groups focused on the management of CRF; (5) group activities; and (6) professional and personalized guidance. CONCLUSION: This study calls for multi-level action to address many persistent barriers and exploit levers in the management of CRF.

Predictors of neurosurgical intervention in complicated mild traumatic brain injury patients: a retrospective cohort study.

OBJECTIVES: To determine the predicting demographic, clinical and radiological factors for neurosurgical intervention in complicated mild traumatic brain injury (mTBI) patients. METHODS: Design: retrospective multicenter cohort study. Participants: patients aged ≥16 presenting to all level-I trauma centers in Quebec between 09/2016 and 12/2017 with mTBI(GCS 13-15) and complication on initial head CT (intracranial hemorrhage/skull fracture). Procedure: Consecutive medical records were reviewed and separated into two groups: no neurosurgical intervention and neurosurgical intervention (NSI). Main outcome: neurosurgical intervention. Analysis: multiple logistic regression model. RESULTS: Four hundred and seventy-eight patients were included and 40 underwent NSI. One patient had radiological deterioration but no clinical deterioration prior to surgery. Subdural hemorrhage ≥4 mm width (OR:3.755 [95% CI:1.290-10.928]) and midline shift (OR:7.507 [95% CI: 3.317-16.989]) increased the risk of NSI. Subarachnoid hemorrhage was associated with a lower risk of NSI (OR:0.312 [95% CI: 0.136-0.713]). All other intracranial hemorrhages were not associated with NSI. CONCLUSION: Radiological deterioration was not associated with the incidence of NSI. Subdural hemorrhage and midline shift should be predicting factors for neurosurgery. Some patients with isolated findings such as subarachnoid hemorrhage could be safely managed in their original center without being transferred to a level-I trauma center.

Nasopharyngeal carcinoma.

Nasopharyngeal carcinoma is characterised by distinct geographical distribution and is particularly prevalent in east and southeast Asia. Epidemiological trends in the past decade have shown that its incidence has declined gradually but progressively, and mortality has been reduced substantially. These findings probably reflect lifestyle and environmental changes, enhanced understanding of the pathogenesis and risk factors, population screening, advancements in imaging techniques, and individualised comprehensive chemoradiotherapy strategies. In particular, plasma Epstein-Barr virus (EBV) DNA has been used for population screening, prognostication, predicting treatment response for therapeutic adaptation, and disease surveillance. Moreover, the widespread application of intensity-modulated radiotherapy and optimisation of chemotherapy strategies (induction, concurrent, adjuvant) have contributed to improved survival with reduced toxicities. Among the existing developments in novel therapeutics, immune checkpoint therapies have achieved breakthroughs for treating recurrent or metastatic disease and represent a promising future direction in nasopharyngeal carcinoma.

ß1 Syntrophin Supports Autophagy Initiation and Protects against Cerulein-Induced Acute Pancreatitis.

Syntrophins are a family of proteins forming membrane-anchored scaffolds and serving as adaptors for various transmembrane and intracellular signaling molecules. To understand the physiological roles of ß1 syntrophin, one of the least characterized members, we generated mouse models to eliminate ß1 syntrophin specifically in the endocrine or exocrine pancreas. ß1 syntrophin is dispensable for the morphology and function of insulin-producing ß cells. However, mice with ß1 syntrophin deletion in exocrine acinar cells exhibit increased severity of cerulein-induced acute pancreatitis. Reduced expression of cystic fibrosis transmembrane conductance regulator and dilation of acinar lumen are potential predisposition factors. During the disease progression, a relative lack of autophagy is associated with deficiencies in both actin assembly and endoplasmic reticulum nucleation. Our findings reveal, for the first time, that ß1 syntrophin is a critical regulator of actin cytoskeleton and autophagy in pancreatic acinar cells and is potently protective against cerulein-induced acute pancreatitis.