Lenalidomide in combination with R-ESHAP in patients with relapsed or refractory diffuse large B-cell lymphoma: A phase 2 study from GELTAMO.

Diffuse large B-cell lymphoma (DLBCL) patients with relapsed or refractory (RR) disease have poor outcomes with current salvage regimens. We conducted a phase 2 trial to analyse the safety and efficacy of adding lenalidomide to R-ESHAP (LR-ESHAP) in patients with RR DLBCL. Subjects received 3 cycles of lenalidomide 10 mg/day on days 1-14 of every 21-day cycle, in combination with R-ESHAP at standard doses. Responding patients underwent autologous stem-cell transplantation (ASCT). The primary endpoint was the overall response rate (ORR) after 3 cycles. Centralized cell-of-origin (COO) classification was performed. Forty-six patients were included. The ORR after LR-ESHAP was 67% (35% of patients achieved complete remission). Patients with primary refractory disease (n = 26) had significantly worse ORR than patients with non-refractory disease (54% vs. 85%, p = 0.031). No differences in response rates according to the COO were observed. Twenty-eight patients (61%) underwent ASCT. At a median follow-up of 41 months, the estimated 3-year PFS and OS were 42% and 48%, respectively. The most common grade ≥3 adverse events were thrombocytopenia (70% of patients), neutropenia (67%) and anaemia (35%). There were no treatment-related deaths during LR-ESHAP cycles. In conclusion, LR-ESHAP is a feasible salvage regimen with promising efficacy results for patients with RR DLBCL.

[Limits of dose constraint definition for organs at risk specific to stereotactic radiotherapy]. / Limites de la définition des contraintes de dose pour les organes à risque spécifiques à la radiothérapie stéréotaxique.

Stereotactic radiotherapy is a very hypofractionated radiotherapy (>7.5Gy per fraction), and therefore is more likely to induce late toxicities than conventional normofractionated irradiations. The present study examines four frequent and potentially serious late toxicities: brain radionecrosis, radiation pneumonitis, radiation myelitis, and radiation-induced pelvic toxicities. The critical review focuses on the toxicity scales, the definition of the dose constrained volume, the dosimetric parameters, and the non-dosimetric risk factors. The most commonly used toxicity scales remain: RTOG/EORTC or common terminology criteria for adverse events (CTCAE). The definition of organ-at-risk volume requiring protection is often controversial, which limits the comparability of studies and the possibility of accurate dose constraints. Nevertheless, for the brain, whatever the indication (arteriovenous malformation, benign tumor, metastasis of solid tumors...), the association between the volume of brain receiving 12Gy (V12Gy) and the risk of cerebral radionecrosis is well established for both single and multi-fraction stereotactic irradiation. For the lung, the average dose received by both lungs and the V20 seem to correlate well with the risk of radiation-induced pneumonitis. For the spinal cord, the maximum dose is the most consensual parameter. Clinical trial protocols are useful for nonconsensual dose constraints. Non-dosimetric risk factors should be considered when validating the treatment plan.

Neoadjuvant treatment of pancreatic adenocarcinoma: Chemoradiation or stereotactic body radiation therapy?

Despite recent advances, the prognosis of pancreatic adenocarcinomas remains poor, even for patients with resectable tumors. For these latter, new approaches based on neoadjuvant treatment have been developed. Two components are used: chemotherapy and radiation therapy (RT). Indeed, pre-operative RT has many advantages in terms of efficacy and tolerance. It increases notably the chances of subsequent complete tumor resection. Several prospective trials are currently ongoing to clarify its place in the therapeutic arsenal. Another crucial question is to know which is the best RT technique: conventional normofractionated chemoradiotherapy or hypofrationated stereotactic body RT?

Radiotherapy of anal canal cancer.

We present the update of the recommendations of the French society for radiation oncology on external radiotherapy and brachytherapy of anal canal carcinoma. The following guidelines are presented: indications, treatment procedure, as well as dose and dose-constraints objectives, immediate postoperative management, post-treatment evaluation, and long-term follow-up.

Radiation therapy of pancreatic cancers.

We present the update of the recommendations of the French society of oncological radiotherapy on radiotherapy of pancreatic tumors. Currently, the use of radiation therapy for patients with pancreatic cancer is subject to discussion. In the adjuvant setting, the standard treatment is six months of chemotherapy with 5-fluorouracile, irinotecan and oxaliplatin. Chemoradiation may improve the survival of patients with incompletely resected tumours (R1). This remains to be confirmed by a prospective trial. Neoadjuvant chemoradiation is a promising treatment especially for patients with borderline resectable tumours. For patients with locally advanced tumours, there is no standard. An induction chemotherapy followed by chemoradiation for non progressive patients reduces the rate of local relapse. Whereas in the first trials of chemoradiation large fields were used, the treated volumes have been reduced to improve tolerance. Tumour movements induced by breathing should be taken in account. Intensity modulated radiation therapy allows a reduction of doses to the organs at risk. Whereas widely used, this technique has poor evidence-based recommendation. Stereotactic body radiation therapy is also being studied, as a neoadjuvant or exclusive treatment.

Rectal cancer radiotherapy.

We present the updated recommendations of the French society of oncological radiotherapy for rectal cancer radiotherapy. The standard treatment for locally advanced rectal cancer consists in chemoradiotherapy followed by radical surgery with total mesorectal resection and adjuvant chemotherapy according to nodal status. Although this strategy efficiently reduced local recurrences rates below 5% in expert centres, functional sequelae could not be avoided resulting in 20 to 30% morbidity rates. The early introduction of neoadjuvant chemotherapy has proven beneficial in recent trials, in terms of recurrence free and metastasis free survivals. Complete pathological responses were obtained in 15% of tumours treated by chemoradiation, even reaching up to 30% of tumours when neoadjuvant chemotherapy is associated to chemoradiotherapy. These good results question the relevance of systematic radical surgery in good responders. Personalized therapeutic strategies are now possible by improved imaging modalities with circumferential margin assessed by magnetic resonance imaging, by intensity modulated radiotherapy and by refining surgical techniques, and contribute to morbidity reduction. Keeping the same objectives, ongoing trials are now evaluating therapeutic de-escalation strategies, in particular rectal preservation for good responders after neoadjuvant treatment, or radiotherapy omission in selected cases (Greccar 12, Opera, Norad).

Chronic Kidney Disease Progression and Transition Probabilities in a Large Preventive Cohort in Colombia.

BACKGROUND: Variability in chronic kidney disease (CKD) progression is a well-known phenomenon that underlines the importance of characterizing the said outcome in specific populations. Our objectives were to evaluate changes in the estimated glomerular filtration rate (eGFR) over time and determine the frequency of dialysis admission and factors associated with this outcome, to estimate the rate of program's loss-to-follow-up and the probability of transition between CKD stages over time. METHODS: The study type was an observational analytic retrospective cohort in patients treated in a CKD prevention program in Bogota, Colombia, between January 1, 2009, and December 31, 2013, with follow-up until December 31, 2018. Adult participants of 18 years of age or older with diagnosed CKD stages G3 or G4 were enrolled into a prevention program. For each patient, the rate of progression of CKD in ml/min/1.73 m2/year was estimated using the ordinary least-squares method. Dialysis initiation and program's loss-to-follow-up rates were calculated. Heat maps were used to present probabilities of transitioning between various CKD stages over time. Survival model with competing risks was used to evaluate factors associated with dialysis initiation. RESULTS: A total of 2752 patients met inclusion criteria and contributed with 14133 patient-years of follow-up and 200 dialysis initiation events, which represents a rate of 1.4 events per 100 patient-years (95% CI 1.2 to 1.6). The median change of the eGFR for the entire cohort was -0.47 ml/min/1.73 m2 per year, and in the diabetic population, it was -1.55 ml/min/1.73 m2 per year. The program's loss-to-follow-up rate was 2.6 events per 100 patient-years (95% CI 2.3 to 2.9). Probabilities of CKD stage transitions are presented in heat maps. Female sex, older age, baseline eGFR, and serum albumin were associated with lower risk of dialysis initiation while CKD etiology diabetes, cardiovascular disease history, systolic blood pressure, blood urea nitrogen, and LDL cholesterol were associated with a higher likelihood of dialysis initiation. CONCLUSIONS: A CKD secondary prevention program's key indicator is reported here, such as dialysis initiation, progression rate, and program drop-out; CKD progression appears to be correlated with diabetic status and timing of referral into the preventive program.

[Gastric and pancreatic cancers: Will neoadjuvant (chemo)radiotherapy replace adjuvant chemoradiotherapy?] / Cancers gastriques et pancréatiques : la (chimio)radiothérapie néoadjuvante remplacera-t-elle la chimioradiothérapie adjuvante ?

For many years, adjuvant chemoradiotherapy remained essential in the therapeutic management of gastric and pancreatic adenocarcinomas. For these tumours, surgical excision, the only hope of offering the patient prolonged survival, is only possible in 20% of cases. The median survival of operated patients is only 12 to 20 months due to the frequency of locoregional and/or metastatic recurrences. For stomach cancers, adjuvant chemoradiotherapy is justified by the results of the phase III trial Intergroup 0116 published by MacDonald et al. The gain in survival was at the cost of significant toxicity. This treatment was supplanted in the early 2000s by perioperative chemotherapy. Currently, neoadjuvant chemoradiotherapy clinical studies are ongoing with the aim of improving treatments observance and tolerance. For pancreatic cancers, the role of adjuvant chemoradiotherapy has long been discussed because of trials with contradictory results. Neoadjuvant radiotherapy has many advantages in terms of efficacy and tolerance. It increases the chances of subsequent complete tumour resection. Several prospective trials are currently ongoing to clarify its place in the therapeutic arsenal.

Impact of pre-radiation therapy quality of life in lung cancer survival: a prospective, intention-to-treat, multicenter study.

PURPOSE: Lung cancer (LC) has a significant impact on patients' health-related quality of life (HRQoL). We investigate the correlations between pre-radiation therapy HRQoL and survival. MATERIALS AND METHODS: A prospective, intention-to-treat, multicentre study of 437 patients with LC recruited at the radiation oncology departments of three different institutions was conducted between 2012 and 2016. QoL was assessed using the EORTC-QLQ-C30 (v3.0) and EORTC-QLQ-LC13 questionnaires. Global health status (GHS), physical (PF), role functioning (RF), emotional (EF), cognitive (CF), and social functioning (SF) as well as symptoms scores were evaluated in univariate and multivariate analyses. RESULTS: The cohort consisted of 376 men (86%) and 61 women, with a median age of 66 years (range 31-88). Histology was: 72% (n = 315) non-small cell lung cancer and 28% small cell lung cancer. The most common stage was III (80%) and the median follow-up for alive patients was 30 months (range 7-76). Multivariate analysis showed that RF was associated with a lower risk of mortality (HR: 0.693; p = 0.008) and recurrence (HR: 0.737; p = 0.040). Additionally, lower scores on EF and PF were associated with higher mortality (HR: 0.696; p = 0.003 and HR: 0.765; p = 0.044, respectively). Appetite loss, constipation, and dysphagia were associated with a higher risk of mortality (HR: 1.985; p < 0.001, HR: 1.373; p = 0.036, and HR: 1.659; p = 0.002, respectively), while appetite loss was the only symptom associated with a higher risk of recurrence (HR: 1.525; p = 0.014). CONCLUSIONS: Pre-radiation therapy scores on RF, EF, and PF and symptoms like appetite loss, dysphagia, and constipation were associated with the risk of mortality. This information could be added to other prognostic factors to guide our treatment decisions.

Scientific AI in Materials Science: a Path to a Sustainable and Scalable Paradigm.

Recently there has been an ever-increasing trend in the use of machine learning (ML) and artificial intelligence (AI) methods by the materials science, condensed matter physics, and chemistry communities. This perspective article identifies key scientific, technical, and social opportunities that the materials community must prioritize to consistently develop and leverage Scientific AI (SciAI) to provide a credible path towards the advancement of current materials-limited technologies. Here we highlight the intersections of these opportunities with a series of proposed paths forward. The opportunities are roughly sorted from scientific/technical (e.g. development of robust, physically meaningful multiscale material representations) to social (e.g. promoting an AI-ready workforce). The proposed paths forward range from developing new infrastructure and capabilities to deploying them in industry and academia. We provide a brief introduction to AI in materials science and engineering, followed by detailed discussions of each of the opportunities and paths forward.

Outcomes of vaginal squamous cell carcinoma of patients treated with radiation therapy: a series of 37 patients from a single expert center.

INTRODUCTION: The aim is to assess the outcome of patients treated for vaginal carcinoma with radiation therapy in terms of long-term tolerance and survival. MATERIALS AND METHODS: This single-center retrospective study included patients with squamous cell carcinoma of the vagina treated with pelvic external beam radiation therapy (EBRT) with or without vaginal brachytherapy (VB) between 1990 and 2013. RESULTS: Thirty-seven patients were included with stage I (24%), II (60%), III (8%), or IV (8%) vaginal tumors. Median age was 66 years (range 27-86 years). Median tumor size was 4 cm (range 0.7-12 cm). Seven patients underwent first intention surgery. The 37 patients received pelvic EBRT (45 Gy) with inguinal irradiation in 57% of cases. Fifteen (41%) received concurrent chemotherapy. Low-dose supplemental VB was performed in 31 patients (84%) (median dose: 20 Gy). Median follow-up was 59 months (range 7-322 months). Four patients (11%) had late grade 3-4 complications. Relapse occurred in 11 patients (30%), five of them locally. The 5-year relapse-free and cancer-specific survival rates were 68% and 76%, respectively. Surgery and concurrent chemotherapy did not seem to have an impact on the course of the disease. CONCLUSION: In our experience, pelvic EBRT leads to prolonged survival with acceptable long-term toxicity in patients with squamous cell carcinoma of the vagina.

Whole brain radiotherapy with concurrent temozolomide in multifocal and/or multicentric newly diagnosed glioblastoma.

The standard medical care of glioblastoma (GBM) patients with good performance status is based on focal brain radiotherapy (40-60 Gy) with concurrent temozolomide (TMZ) followed by adjuvant TMZ. Newly diagnosed multifocal and/or multicentric GBM (M/M GBM) cases are usually treated with TMZ alone: whole brain chemoradiotherapy (CRT) is avoided for safety reasons. To our knowledge, no study has investigated the safety and efficacy of whole-brain radiotherapy (WBRT) with concurrent TMZ in M/M GBM patients. This retrospective study sought to assess the role of WBRT associated with concurrent TMZ followed by TMZ alone in this population. Eleven patients with pathologically proven M/M GBM (≥3 lobes) were treated with WBRT between April 2009 and September 2017. The median age was 50 years [34-74]. The median dose of radiotherapy was 45 Gy at 1.8 Gy per fraction over 37 days [29-41], with concurrent daily TMZ at the dose of 75 mg/m2. This treatment was followed by adjuvant monthly TMZ (150 mg/m2-D1-D5). All pathology slides and radiology images were reviewed. The median overall and progression-free survival times for all patients were 10 months [4-25] and 5 months [3-21], respectively. There was no grade 3-4 toxicity due to radiotherapy. One patient stopped the TMZ during the radiochemotherapy period and 9 patients received adjuvant TMZ with a median number of 5 cycles [2-8]. Our study supports the safety and the efficacy of WBRT with TMZ in newly diagnosed M/M GBM. Larger prospective studies are needed to support our results.

Correction: Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Partial versus whole breast irradiation: Side effects, patient satisfaction and costs.

PURPOSE: Since accelerated partial breast irradiation has demonstrated non-inferiority to whole breast irradiation regarding recurrence rate in patients with early stage breast cancer, our objective was to compare its impact on short-term adverse events, patient satisfaction and costs. MATERIALS AND METHODS: Patients with early stage breast cancer treated by breast-conserving surgery between 2007 and 2012 were included: 48 women who received three-dimensional conformal accelerated partial breast irradiation in a multicentre phase-II trial were paired with 48 patients prospectively treated with whole breast irradiation. Adverse events, and patients' opinions concerning cosmesis, satisfaction and pain, were gathered 1 month after treatment. Direct and indirect costs were collected from the French National Health Insurance System perspective until the end of radiotherapy. RESULTS: When comparing its impact, skin reactions occurred in 37% of patients receiving three-dimensional conformal accelerated partial breast radiotherapy and 60% of patients receiving whole breast irradiation (P=0.07); 98% were very satisfied in the group three-dimensional conformal accelerated partial breast radiotherapy versus 46% in the group treated with whole breast irradiation (P<0.001); direct costs were significantly lower in the group treated with partial breast irradiation (mean cost: 2510€ versus 5479€/patient), due to less radiation sessions. CONCLUSION: In patients with early-stage breast cancer, partial irradiation offered a good alternative to whole breast irradiation, as it was less expensive and satisfactory. These, and the clinical safety and tolerance results, need to be confirmed by long-term accelerated partial breast irradiation results in on-going phase III trials.

Cardiovascular disease and survival in non-small cell lung cancer: a multicenter prospective assessment.

PURPOSE: Chronic inflammation contributes to cancer development via multiple mechanisms. We hypothesized that cardiovascular diseases (CVD) are also an independent risk factor for survival in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Prospective multicenter data from 345 consecutive NSCLC patients treated from January 2013 to January 2017 were assessed. Median follow-up for all patients was 13 months (range 3-60 months). There were 109 patients with baseline heart disease (HD 32%), 149 with arterial hypertension (43%), 85 with diabetes mellitus (25%), 129 with hyperlipidemia (37%) and 45 with venous thromboembolism events (VTE 13%). A total of 289 patients (84%) were treated with platinum-based chemotherapy (CT), 300 patients (87%) received thoracic radiation therapy (RT; median radiation dose: 60 Gy [range 12-70]); and 50 (15%) patients underwent surgery. RESULTS: Our cohort consisted of 305 men (88%) and 40 (12%) women, with a median age of 67 years (range 31-88 years). Seventy percent had a Karnofsky performance status (KPS) ≥ 80. Multivariate analyses showed a lower OS and higher risk of distant metastasis in patients with advanced stages (p = 0.05 and p < 0.001, respectively) and HD (HR 1.43, p = 0.019; and HR 1.49, p = 0.025, respectively). Additionally, patients with VTE had lower local control (HR 1.84, p = 0.025), disease-free survival (HR 1.64, p = 0.020) and distant metastasis-free survival (HR 1.73, p = 0.025). CONCLUSIONS: HD and VTE are associated with a higher risk of mortality and distant metastasis in NSCLC patients. Chronic inflammation associated with CVDs could be an additional pathophysiologic factor in the development of distant metastasis.

Outcome and toxicity of intensity-modulated radiotherapy with simultaneous integrated boost in patients with pharyngo-laryngeal cancer.

PURPOSE: The present work aims at evaluating intensity-modulated radiation therapy with simultaneous integrated boost (IMRT-SIB) in squamous cell carcinomas (SCC) of the larynx and hypopharynx. METHODS/PATIENTS: We performed a single institutional retrospective analysis on 116 pharyngo (29%)-laryngeal (71%) SCC patients (93% male) treated with IMRT-SIB to 66-69.96 Gy in 33 fractions between 2008 and 2016. Those who underwent surgery (54%) received adjuvant radiation of 66 Gy at 2 Gy/fraction to the surgical bed. 16 patients (14%) were treated for a local recurrence after prior surgery. High-risk lymph node regions received 59.4 Gy at 1.8 Gy/fraction and low risk regions 54.12 Gy at 1.64 Gy/fraction. The median age was 60 years and 95% of patients had an ECOG performance status 0-2. Most had advanced stage disease (III 22%, IV 74%). Chemotherapy was delivered in 74% of cases. RESULTS: Median follow-up was 32 months. Two and three-year overall survival for all patients was 87% and 82%, respectively. There were 28 (24%) locoregional recurrences and 19 (16%) distant failures. Grade 3 mucositis, dermatitis, and xerostomy were observed in 12%, 10%, and 3%, respectively. A longer IMRT-SIB overall treatment time was associated with a higher risk of mortality (HR 1.09, CI 1.01-1.17, P = 0.02). Postoperative IMRT-SIB associated with a significantly lower risk of any recurrence (HR 0.34, CI 0.18-0.64, P = 0.001) and higher local control (HR 0.06, CI 0.01-0.24, P < 0.01). Additionally, it associated with a lower risk of mucositis (P = 0.029) compared with definitive radio (chemo) therapy. CONCLUSIONS: IMRT-SIB is a safe and feasible radiation treatment technique for pharyngo-laryngeal SCC patients with a tolerable acute toxicity profile.

Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue.

Background: Gene expression profiling (GEP) studies recognized a prognostic role for tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL), but the routinely adoption of prognostic stromal signatures remains limited. Patients and methods: Here, we applied the computational method CIBERSORT to generate a 1028-gene matrix incorporating signatures of 17 immune and stromal cytotypes. Then, we carried out a deconvolution on publicly available GEP data of 482 untreated DLBCLs to reveal associations between clinical outcomes and proportions of putative tumor-infiltrating cell types. Forty-five genes related to peculiar prognostic cytotypes were selected and their expression digitally quantified by NanoString technology on a validation set of 175 formalin-fixed, paraffin-embedded DLBCLs from two randomized trials. Data from an unsupervised clustering analysis were used to build a model of clustering assignment, whose prognostic value was also assessed on an independent cohort of 40 cases. All tissue samples consisted of pretreatment biopsies of advanced-stage DLBCLs treated by comparable R-CHOP/R-CHOP-like regimens. Results: In silico analysis demonstrated that higher proportion of myofibroblasts (MFs), dendritic cells, and CD4+ T cells correlated with better outcomes and the expression of genes in our panel is associated with a risk of overall and progression-free survival. In a multivariate Cox model, the microenvironment genes retained high prognostic performance independently of the cell-of-origin (COO), and integration of the two prognosticators (COO + TME) improved survival prediction in both validation set and independent cohort. Moreover, the major contribution of MF-related genes to the panel and Gene Set Enrichment Analysis suggested a strong influence of extracellular matrix determinants in DLBCL biology. Conclusions: Our study identified new prognostic categories of DLBCL, providing an easy-to-apply gene panel that powerfully predicts patients' survival. Moreover, owing to its relationship with specific stromal and immune components, the panel may acquire a predictive relevance in clinical trials exploring new drugs with known impact on TME.

Holocene evolution of Portus Pisanus, the lost harbour of Pisa.

The ancient harbour of Pisa, Portus Pisanus, was one of Italy's most influential seaports for many centuries. Nonetheless, very little is known about its oldest harbour and the relationships between environmental evolution and the main stages of harbour history. The port complex that ensured Pisa's position as an economic and maritime power progressively shifted westwards by coastal progradation, before the maritime port of Livorno was built in the late 16th century AD. The lost port is, however, described in the early 5th century AD as being "a large, naturally sheltered embayment" that hosted merchant vessels, suggesting an important maritime structure with significant artificial infrastructure to reach the city. Despite its importance, the geographical location of the harbour complex remains controversial and its environmental evolution is unclear. To fill this knowledge gap and furnish accurate palaeoenvironmental information on Portus Pisanus, we used bio- and geosciences. Based on stratigraphic data, the area's relative sea-level history, and long-term environmental dynamics, we established that at ~200 BC, a naturally protected lagoon developed and hosted Portus Pisanus until the 5th century AD. The decline of the protected lagoon started at ~1350 AD and culminated ~1500 AD, after which time the basin was a coastal lake.

[Role of radiation therapy in the management of pancreatic cancer]. / Quelle place pour la radiothérapie dans la prise en charge des cancers du pancréas localisés ?

At diagnosis, about 15% of patients with pancreatic cancer present with a resectable tumour, 50% have a metastatic tumour, and 25% a locally advanced tumor (non-metastatic but unresectable due to vascular invasion) or borderline resectable. Despite the technical progress made in the field of radiation therapy and the improvement of the efficacy of chemotherapy, the prognosis of these patients remains very poor. Recently, the role of radiation therapy in the management of pancreatic cancer has been much debated. This review aims to evaluate the role of radiation therapy for these patients.