Are charged particles a good match for combination with immunotherapy? Current knowledge and perspectives.

Charged particle radiotherapy, mainly using protons and carbon ions, provides physical characteristics allowing for a volume conformal irradiation and a reduction of the integral dose to normal tissue. Carbon ion therapy additionally features an increased biological effectiveness resulting in peculiar molecular effects. Immunotherapy, mostly performed with immune checkpoint inhibitors, is nowadays considered a pillar in cancer therapy. Based on the advantageous features of charged particle radiotherapy, we review pre-clinical evidence revealing a strong potential of its combination with immunotherapy. We argue that the combination therapy deserves further investigation with the aim of translation in clinics, where a few studies have been set up already.

[The role of endoscopy in exploration of the mediastinum, indications and results]. / Place de l'endoscopie dans l'exploration du médiastin, indications et résultats.

Since 2005, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as a standard pulmonological tool. The procedure is safe and well tolerated by patients, with minimal morbidity and almost no mortality. A previous review on the technique was published in 2012. However, over the last ten years, a number of new studies have been published on "benign" (sarcoidosis, tuberculosis…) as well as "malignant" diseases (lung cancer, metastases of extra-thoracic cancers, search for mutations and specific oncogenic markers…). These developments have led to expanded indications for EBUS-TBNA, with which it is indispensable to be familiar, in terms of "staging" as well as "diagnosis". In view of optimizing lymph node sampling, several publications have described and discussed EBUS exploration by means of newly available tools (biopsy forceps, larger needles…), and proposed interpretation of the images thereby produced. Given the ongoing evolution of linear EBUS, it seemed indispensable that information on this marvelous tool be updated. This review is aimed at summarizing the novel elements we have found the most important.

Postoperative spino-pelvic stereoradiography to predict adjacent segment disease.

PURPOSE: The purpose of this study was to identify sagittal spinopelvic parameters predictive of adjacent segment disease (ASD) on postoperative whole spine weight-bearing stereoradiography. MATERIALS AND METHODS: A total of 84 patients with previous spinal fusion surgery and documented radiological follow-up with early weight-bearing postoperative whole spine stereoradiography (EOS® Imaging System) were retrospectively included. A pathological group of 42 patients (9 men, 33 women; mean age, 63.1±11.5 [SD] years) who developed documented ASD (mean follow-up, 76.75 months; range: 31.5-158.5 months) was compared with a control group of 42 asymptomatic patients (7 men, 35 women; mean age, 60.9±11.8 [SD] years) (mean follow-up, 115 months; range: 60-197 months) based on sagittal balance evaluation and routinely used spino-pelvic parameters. Comparisons were made using uni- and multivariate analyses. RESULTS: At univariate analysis, patients with ASD had an anteriorly displaced sagittal vertical axis (CAM plumb line) and an inadequate lumbar lordosis (LL) in reference to pelvic incidence (PI) compared to controls. They also had higher C7 slope and C2-C7 offset. At multivariate analysis, C2-C7 offset (OR=1.152; 95% CI: 1.056-1.256; P=0.001) and a lack of LL (OR=5.063; 95% CI: 1.139-22.498; P=0.033) were significantly associated with ASD. CONCLUSION: Anterior cervical imbalance, reflected by an increase in C2-C7 offset and insufficient restoration of LL are postoperative predictive factors of ASD on stereoradiography.

Tumor de células gigantes (osteoclastoma) multicentrico, diagnóstico incidental de adenoma paratiroideo reporte de caso / Multicenter giant cell tumor (osteoclastoma), incidental diagnosis of parathyroid adenoma case report

Los tumores de células gigantes (TDG) llamados también osteoclastomas o tumores pardos cuando se hallan dentro la esfera endocrinológica, son uno de los tumores menos frecuentes, más controversial y menos predecible en su comportamiento. Se producen como consecuencia del exceso de la actividad osteoclastica, como ocurre en el caso del hiperparatiroidismo, mismo que es un desorden endocrino común, por lo general asintomático y diagnosticado por el hallazgo fortuito de hipercalcemia. El diagnóstico de los osteoclastomas suele ser un reto, el alto índice de sospecha es esencial y la biopsia es el estándar de oro para el diagnóstico. Presentamos el caso de un hombre de 42 años quien presentó fracturas patológicas de radio derecho y tibia izquierda, gammagrama óseo con Tc ­ 99m con múltiples lesiones óseas , hormona paratiroidea (PTH) elevada, hipercalcemia, gammagrama de paratiroides con MIBI con presencia de adenoma paratiroideo, la biopsia de las lesiones óseas con presencia de células gigantes multinucleadas correspondientes a osteoclastomas; se llevó a cabo paratiroidectomia y el examen histopatológico confirmó la presencia de un adenoma paratiroideo.

Giant cell tumors (TDG), also called osteoclastomas or brown tumors when they are within the endocrinological sphere, are one of the least frequent, most controversial and least predictable tumors in their behavior. They occur as a consequence of excess osteoclastic activity, as occurs in the case of hyperparathyroidism, which is a common endocrine disorder, generally asymptomatic and diagnosed by the fortuitous finding of hypercalcemia. Diagnosing osteoclastomas is usually challenging, the high index of suspicion is essential, and biopsy is the gold standard for diagnosis. We present the case of a 42-year-old man who presented pathological fractures of the right radius and left tibia, a bone scan with Tc-99m with multiple bone lesions, elevated parathyroid hormone (PTH), hypercalcemia, parathyroid scan with MIBI with the presence of parathyroid adenoma, the biopsy of the bone lesions with the presence of multinucleated giant cells corresponding to osteoclastomas; parathyroidectomy was performed and histopathological examination confirmed the presence of a parathyroid adenoma.

Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

Diagnostic of mediastinal lymphadenopathy in extrathoracic cancer: A place for EBUS-TBNA in real life practice?

INTRODUCTION: Mediastinal lymphadenopathy in patients with extrathoracic malignancy is common. To obtain tissue proof of metastatic spread, EBUS-TBNA is an alternative to mediastinoscopy or thoracoscopy, but there are limited data about its diagnostic performance. The aim of this study was to determine the diagnostic accuracy of EBUS-TBNA for the evaluation of mediastinal lymphadenopathy in patients with extrathoracic cancers. METHODS: We performed a multicenter retrospective study based on an online questionnaire to collect data from January 2011 to December 2012 in all patients with proven extrathoracic malignancy (current or past) and suspected mediastinal lymph node metastases who underwent EBUS-TBNA for diagnosis. RESULTS: Hundred and eighty-five patients were included. Extrathoracic malignancies observed were urological (43), breast (35), gastrointestinal (33), head and neck (30), melanoma (11), lymphoma (6), and others (27). EBUS-TBNA confirmed malignancy in 93 patients (50.3%): concordant metastases in 67 (36.2%); new lung cancer in 25 (13.5%); and 1 unidentified cancer. The diagnostic accuracy, sensitivity, specificity, negative predictive value, and positive predictive value were respectively 54.6%, 68.4%, 100%, 53.3%, and 100%. CONCLUSION: Mediastinoscopy remain the reference, but EBUS-TBNA may be considered as first line investigation in patients with suspected mediastinal lymph node metastases and extrathoracic malignancy. It prevented a surgical procedure in 50.3% of patients.

[Transbronchial cryobiopsy in diffuse interstitial lung diseases]. / Cryobiopsies trans-bronchiques au cours des pneumopathies interstielles diffuses ­ expériences préliminaires.

INTRODUCTION: In the diagnostic approach to interstitial lung disease (ILD), the use of transbronchial cryobiopsy (TBC) may offer an alternative to surgical lung biopsy (SLB). We report the diagnostic effectiveness and the safety of TBC in ILD based on the preliminary experience in two French university centers. METHODS: Twenty four patients underwent TBC for the diagnosis of ILD in the operating room between 2014 and 2017. All the histological diagnoses obtained were then reviewed and validated during multidisciplinary discussions (MDD). RESULTS: Patients had an average of 3 TBC.TBC samples were analyzable in 22/24 (91.7%) patients. In these, samples allowed a histological diagnosis to be made in 14/22 (63.6%) patients and a diagnosis with certainty in 13/22 (59%) after MDD. The overall diagnostic yield from TBC was 13/24 (54.2%). Nine (37.5%) patients had a pneumothorax. Five (20.8%) patients had a bleeding. There were no deaths. Taking into account a possible initial learning curve and considering only the 15 patients who had their TBC after 2015, we note that a diagnosis could be made after MDD for 12 of them, that is, 80%. CONCLUSION: A prospective randomized study is needed to evaluate the technique in France in order to specify its diagnostic performance and its safety profile in comparison to SLB.

Claudin-1, miR-122 and apolipoprotein E transductions improve the permissivity of SNU-182, SNU-398 and SNU-449 hepatoma cells to hepatitis C virus.

Hepatitis C virus (HCV) is a human hepatotropic virus, but many hepatoma cell lines are not permissive to this virus. In a previous study, we observed that SNU-182, SNU-398 and SNU-449 hepatoma cell lines were nonpermissive to HCV. To understand the nonpermissivity, we evaluated the ability of each cell line to support the different steps of HCV life cycle (entry, replication and production of infectious particles). Using retroviral pseudoparticles pseudotyped with HCV envelope proteins and recombinant HCV produced in cell culture, we observed that low level or absence of claudin-1 (CLDN1) expression limited the viral entry process in SNU-182 and SNU-398 cells, respectively. Our results also showed that supplementation of the three cell lines with miR-122 partly restored the replication of a JFH1 HCV replicon. Finally, we observed that expression of apolipoprotein E (ApoE) was very low or undetectable in the three cell lines and that its ectopic expression permits the production of infectious viral particles in SNU-182 and SNU-398 cells but not in SNU-449 cells. Nevertheless, the supplementation of SNU-182, SNU-398 and SNU-449 cells with CLDN1, miR-122 and ApoE was not sufficient to render these cells as permissive as HuH-7 cells. Thus, these cell lines could serve as cell culture models for functional studies on the role of CLDN1, miR-122 and ApoE in HCV life cycle but also for the identification of new restriction and/or dependency host factors essential for HCV infection.

[Oncogenic drivers in daily practice improve overall survival in patients with lung adenocarcinoma]. / Bénéfice à l'évaluation moléculaire en routine pour les cancers bronchiques métastatiques.

BACKGROUND: EGFR tyrosine kinase inhibitors and crizotinib are nowadays the optimal treatment for metastatic lung cancer with activation of EGFR mutations and ALK rearrangement. In addition, several targeted agents are in development for lung cancer with other oncodrivers. In France, since 2011, six oncodrivers are routinely tested in patients with stage IV. The aim of this study was to assess whether systematic detection of oncodrivers and matched targeted therapy improve overall survival in patients with advanced lung adenocarcinoma. METHODS: This study included all consecutive patients treated in our department for advanced lung adenocarcinoma from January 2012 to December 2013. We studied the impact in survival according to the presence of the driver and the targeted therapy. RESULTS: Among the 261 patients included, oncodrivers alterations were found in 43.5% of patients: EML4-ALK fusion genes (2.1%), EGFR (10.3%), KRAS (27.7%), BRAF (2.5%), HER2 (0.8%), and PI3KCA (0.8%) mutations. Twenty-nine percent of patients (n=32) with oncodrivers received matched targeted therapy. Patient treated by targeted agent appropriate to an oncogenic driver had a median survival of 21.1 months (95% CI: 14.7-27.5). The patients (n=79) who did not receive targeted therapy had a median survival of 6.6 months (95% CI: 4.3-8.9). The patients (n=150) without identified driver had a median survival of 9.7 months (95% CI: 6.7-11.7); P<0.001. CONCLUSION: An actionable oncodriver was routinely detected in nearly half of patients with advanced lung adenocarcinoma. This systematic detection may influence treatment outcomes, notably with matched targeted therapy.

Impact of Continuing First-Line EGFR Tyrosine Kinase Inhibitor Therapy Beyond RECIST Disease Progression in Patients with Advanced EGFR-Mutated Non-Small-Cell Lung Cancer (NSCLC): Retrospective GFPC 04-13 Study.

UNLABELLED: Retrospective studies suggested a benefit of first-line tyrosine kinase inhibitor (TKI) treatment continuation after response evaluation in solid tumors (RECIST) progression in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients. The aim of this multicenter observational retrospective study was to assess the frequency of this practice and its impact on overall survival (OS). The analysis included advanced EGFR-mutated NSCLC patients treated with first-line TKI who experienced RECIST progression between June 2010 and July 2012. Among the 123 patients included (67 ± 12.7 years, women: 69 %, non smokers: 68 %, PS 0-1: 87 %), 40.6 % continued TKI therapy after RECIST progression. There was no difference between the patients who did and did not continue TKI therapy with respect to progression-free survival (PFS1: 10.5 versus 9.5 months, p = 0.4). Overall survival (OS) showed a non-significant trend in favor of continuing TKI therapy (33.0 vs. 21.2 months, p = 0.054). Progressions were significantly less symptomatic in the TKI continuation group than in the discontinuation group (18 % vs. 37 %, p < 0.01). Univariate analysis showed a higher risk of death among patients with PS >1 (HR 4.33, 95 %CI: 2.21-8.47, p = 0.001), >1 one metastatic site (HR 1.96, 95 %CI: 1.06-3.61, p = 0.02), brain metastasis (HR 1.75, 95 %CI: 1.08-2.84, p = 0.02) at diagnosis, and a trend towards a higher risk of death in cases of TKI discontinuation after progression (HR 1.62, 95 %CI: 0.98-2.67, p = 0.056 ). In multivariate analysis only PS >1 (HR 6.27, 95 %CI: 2.97-13.25, p = 0.00001) and >1 metastatic site (HR 2.54, 95 %CI: 1.24-5.21, p = 0.02) at diagnosis remained significant. This study suggests that under certain circumstances, first-line TKI treatment continuation after RECIST progression is an acceptable option in EGFR-mutated NSCLC patients. CLINICAL TRIAL INFORMATION: NCT02293733.

[Treatment of malignant central airways obstruction by rigid bronchoscopy]. / Traitement par bronchoscopie rigide de l'obstruction maligne des voies aériennes centrales.

INTRODUCTION: Endobronchial resection is now the standard treatment for tracheobronchial narrowing due to malignancy. The clinical and functional respiratory improvement has been evaluated previously but only in heterogeneous population. METHODS: Between February 2009 and February 2011, we conducted a prospective single centre study at the University Hospital of Lille. Twenty-five patients with malignant tracheobronchial stenosis received a clinical and functional respiratory evaluation before and after a rigid bronchoscopy procedure to reduce the obstruction followed where appropriate by placement of an endobronchial stent. RESULTS: Thirteen patients (52%) had primary lung cancer and in 12 the tumor had another origin. Nineteen patients (76%) received a stent after bronchial unblocking. Clinically, all patients felt an improvement in their dyspnea estimated by the Borg score with a median improvement of -2 points [-1; -4] following the procedure (P<0.001). In 96% the dyspnea visual analogic scale improved by 40 mm [27; 67] (P<0.0001). The FEV1 increased significantly after unblocking by 9% [-3.5; 28.5] (P<0.05). The Rint decreased significantly by -0.19 kPa/L per second [-0.06; -0.023] (P=0.001). Correlations between scales of dyspnea and spirometric values were not significant (P>0.05). The survival rate at 1 year was 29%. CONCLUSION: Interventional bronchoscopy decreases dyspnea. It modestly improves respiratory function and decreases the Rint. However, lung function and dyspnea scales are not correlated. No spirometry factor can predict clinical dyspnea response but an elevated Borg dyspnea scale might be a good indicator.

NF-κB-dependent DNA damage-signaling differentially regulates DNA double-strand break repair mechanisms in immature and mature human hematopoietic cells.

Hematopoietic stem and progenitor cells (HSPC), that is, the cell population giving rise not only to all mature hematopoietic lineages but also the presumed target for leukemic transformation, can transmit (adverse) genetic events, such as are acquired from chemotherapy or ionizing radiation. Data on the repair of DNA double-strand-breaks (DSB) and its accuracy in HSPC are scarce, in part contradictory, and mostly obtained in murine models. We explored the activity, quality and molecular components of DSB repair in human HSPC as compared with mature peripheral blood lymphocytes (PBL). To consider chemotherapy/radiation-induced compensatory proliferation, we established cycling HSPC cultures. Comparison of pathway-specific repair activities using reporter systems revealed that HSPC were severely compromised in non-homologous end joining and homologous recombination but not microhomology-mediated end joining. We observed a more pronounced radiation-induced accumulation of nuclear 53BP1 in HSPC relative to PBL, despite evidence for comparable DSB formation from cytogenetic analysis and γH2AX signal quantification, supporting differential pathway usage. Functional screening excluded a major influence of phosphatidylinositol-3-OH-kinase (ATM/ATR/DNA-PK)- and p53-signaling as well as chromatin remodeling. We identified diminished NF-κB signaling as the molecular component underlying the observed differences between HSPC and PBL, limiting the expression of DSB repair genes and bearing the risk of an inaccurate repair.

[Brachytherapy training: a survey of French radiation oncology residents]. / État des lieux de la formation des internes français d'oncologie radiothérapie en curiethérapie.

PURPOSE: The goal of this study was to evaluate the interest of the members of the French society of young radiation oncologists (SFjRO) for brachytherapy as well as their theoretical and practical level in this radiation technique. MATERIALS AND METHODS: An anonymous survey was conducted regarding practical and theoretical teaching of brachytherapy before the French national courses on brachytherapy. RESULTS: Among the 106 residents attending this teaching course, 99 (93%) answered the survey. Most of them were interested in brachytherapy but 82% considered they had not received sufficient teaching. Relevant indications of brachytherapy were known by 76% of the residents for gynaecological malignancies and 70% for prostate. Seventy-one percent of the residents have seen at least one gynecological brachytherapy but only 12% knew how to deal with this technique. Fifty-six percent have seen vaginal high dose rate brachytherapy and 21% had acquired the technique. For prostate brachytherapy, 65% had seen and done an implant and only 4% had acquired the technique. Fifty percent have performed at least one brachytherapy treatment during their residency. Residents expressed a strong wish for more courses about dosimetry (82%), technique (75%) and treatment planning (90%). CONCLUSION: Our study shows the interest of French residents for brachytherapy but suggests that practical teaching courses and an evaluation of the existing theoretical courses are warranted.

Bisphosphonate therapy for unresectable symptomatic benign bone tumors: a long-term prospective study of tolerance and efficacy.

OBJECTIVES: To evaluate the long-term tolerance of bisphosphonates proposed as an alternative therapeutic option for symptomatic unresectable benign bone tumors and to evaluate the long-term efficacy of this treatment. METHODS: From March 2007 to March 2011, patients with unresectable symptomatic benign bone tumors were consecutively included in this institutional review board-approved study and treated with bisphosphonates. Prospectively long-term follow-up is reported. The study endpoints were to describe the long-term tolerance, the clinical evolution of pain for each patient and the radiological success defined as a complete disappearance of inflammation and ossification of the bone lesion. All complications and side effects were recorded. RESULTS: Eight patients (mean age 16 years; range 7-42) with various tumor subtypes were included: aneurysmal bone cysts (N=5), Langerhans cell histiocytosis (N=1), osteoblastoma (N=1), and a giant cell tumor (N=1). Tumors were located in cervical (N=4) or thoracic (N=1) vertebrae, femoral shaft (N=1), acetabulum (N=1) and sacrum (N=1). Mean number of bisphosphonate cycles was 3 (range: 1-6) over a median period of 10 months. The median clinical and imaging follow-up period was 21 months (6 to 63 months). No severe complications due to treatment or lesion recurrence were reported. Pain disappeared within 6 weeks of the first cycle for all but one patient. Ossification of the bone lesion was observed for all patients but one, complete for two and partial for the five others. CONCLUSIONS: Bisphosphonates appear to be an effective option without adverse effects for the non-operative management of symptomatic benign bone tumors.

[Diagnostic performance of EBUS-TBNA in patients with mediastinal lymphadenopathy and extrathoracic malignancy]. / Performance diagnostique de l'EBUS-PTBA chez des patients aux antécédents néoplasiques extrapulmonaires adressés pour adénopathies médiastinales.

INTRODUCTION: There is limited data about the diagnostic performance of EBUS-TBNA in patients with mediastinal lymphadenopathy and extrathoracic malignancy. METHODS: From January 2007 to July 2011, EBUS-TBNA was performed in 68 patients with a history of extrathoracic malignancy (current or past) and suspected mediastinal lymph node metastases. RESULTS: Thirty-one patients had a final diagnosis of cancer. In nineteen patients, the same histology was identified in the mediastinal nodes as in their prior extrathoracic cancer (colorectal cancer, esophageal cancer and lymphoma). In 12, the diagnosis was not "as expected" (ten lung cancers, one colorectal cancer, one unidentified cancer). Among 37 patients without diagnosis, biopsies in 27 showed normal lymphoid material, two had non-specific inflammation and eight had no contributory results. It was noted that procedures were reported to have been more difficult in these patients. CONCLUSIONS: Diagnostic performance of EBUS-TBNA in the context of extrathoracic malignancy is very variable depending on the origin of the cancer. Nevertheless, a diagnosis is concluded in almost 50% of the cases. These results underline the necessity to select carefully the indications of EBUS-TBNA in extrathoracic cancer.

A dose-escalating phase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted solid tumours.

BACKGROUND: Preclinical findings suggest that imatinib mesylate (IM) and metronomic cyclophosphamide (MC) combination provides synergistic antiangiogenic activity on both pericytes and endothelial cells. METHODS: We have designed a 3+3 dose-escalating phase I trial with a fixed dose of MC (50 mg two times daily) plus IM (400 mg per day; 300 and 400 mg two times daily). Enrolled patients had IM- and sutininib-refractory advanced gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) and mucosal melanoma (n=2). Dose-limiting toxicities were monitored for the first 6 weeks. Progression-free survival (PFS) and response assessment are based on RECIST 1.0 guidelines. Pharmacokinetics of IM were measured before and after exposure to MC. RESULTS: No dose-limiting toxicity was observed. Fourteen patients of the expanded cohort received 400 mg two times daily of IM with MC. Apart from a case of possibly related acute leukaemia occurring after 4 years of treatment, we did not see unexpected toxicity. No drug-drug pharmacokinetic interaction was observed. There was no objective response. We have observed long-lasting stable disease in chordoma patients (median PFS=10.2 months; range, 4.2-18+) and short-term stable disease in heavily GIST pretreated patients (median PFS=2.3 months; range, 2.1-6.6). CONCLUSION: This combination is feasible and may warrant further exploration in refractory GIST or chordoma patients.

Sorafenib in patients with progressive malignant solitary fibrous tumors: a subgroup analysis from a phase II study of the French Sarcoma Group (GSF/GETO).

Malignant solitary fibrous tumors are rare soft-tissue sarcomas. They are considered as low-grade malignancies, but may display metastatic potential in 20% of the cases. In case of metastatic or locally advanced, unresectable disease, standard treatments, like anthracycline-based regimens, are poorly effective. Previous studies suggested that antiangiogenic drugs, such as sorafenib, could be efficient to treat vascular sarcomas and solitary fibrous tumors. Five patients with progressive SFT were included in this phase 2 study, and treated with sorafenib at a dose of 800 mg daily. Two patients out of the five achieved a 9 months disease control with sorafenib, while their disease had progressed within the month preceding their inclusion. Consequently, our data suggest a potential efficacy of sorafenib in SFT, Further investigation is needed to confirm these data.