Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial.

BACKGROUND: The standard of care for the treatment of locally advanced rectal cancer (LARC) results in an excellent local disease control but the metastasis rates remain high. PRODIGE 23 demonstrated improved disease-free survival (DFS) and metastasis-free survival (MFS) with total neoadjuvant therapy versus standard of care in this population. Long-term analysis of overall survival (OS) is reported here. PATIENTS AND METHODS: The study design, participants, and primary endpoint DFS have been reported for this multicenter, randomized, open-label, phase III trial investigating the neoadjuvant chemotherapy with mFOLFIRINOX (6 cycles) followed by chemoradiotherapy, surgery, and adjuvant chemotherapy (6 cycles), versus chemoradiotherapy, surgery, and adjuvant chemotherapy (12 cycles) in patients with locally advanced rectal adenocarcinoma under peritoneal reflection on magnetic resonance imaging, and staged cT3/T4. Key secondary endpoints included OS, MFS, and local and metastatic recurrence rate. RESULTS: With a median follow-up of 82.2 months, the 7-year DFS was 67.6% [95% confidence interval (CI) 60.7% to 73.9%] and 62.5% (95% CI 55.6% to 68.6%) [restricted mean survival time (RMST) difference 5.73 months, 95% CI 0.05-11.41 months, P = 0.048] in the neoadjuvant chemotherapy and the standard-of-care groups, respectively. The 7-year MFS was 79.2% (95% CI 73.0% to 84.4%) in the neoadjuvant chemotherapy group and 72.3% (95% CI 65.8% to 77.8%) in the standard-of-care group (RMST difference 6.1 months, 95% CI 0.93-11.37 months, P = 0.021). The 7-year OS was 81.9% (95% CI 75.8% to 86.6%) in the neoadjuvant chemotherapy group and 76.1% (95% CI 69.7% to 81.2%) in the standard-of-care group (RMST difference 4.37 months, 95% CI 0.35-8.38 months, P = 0.033). The safety profile remained unchanged since the previous analysis. CONCLUSIONS: Neoadjuvant chemotherapy with mFOLFIRINOX followed by chemoradiotherapy improved OS, confirmed long-term DFS and MFS benefits in LARC patients, and should be considered as one of the best options of care for these patients.

High-dose chemotherapy with autologous stem cell transplants in adult primary non-seminoma mediastinal germ-cell tumors. A report from the Cellular Therapy and Immunobiology working party of the EBMT.

BACKGROUND: Primary mediastinal germ-cell tumors (PMGCTs) account for 1%-3% of all germ-cell tumors (GCTs). Non-seminoma have a poorer prognosis compared to their gonadal counterpart and, according to the International Germ Cell Cancer Collaborative Group, they are considered 'poor risk' disease. Medical treatment is the same, with overall survival (OS) being ∼40%, declining to 10%-15% at 3 years in case of lung and non-visceral metastases. Patients failing first-line chemotherapy have a dismal prognosis, with only 5%-10% of cases being cured in the salvage setting. High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been successfully used to treat patients with relapsed or refractory gonadal GCTs. PATIENTS AND METHODS: This retrospective study aimed to investigate the value of HDC with ASCT in the whole population and define primary mediastinal non seminoma germ cell tumor (PMNSGCT) patient subgroups, who were registered in the European Society for Blood and Marrow Transplantation database from January 2000 to January 2018. Sixty-nine adult male patients with PMNSGCT were included. HDC consisted mainly of carboplatin/etoposide doublet, and most patients received HDC as part of a multiple sequential HDC program. RESULTS: OS was 43.3% at 2 years, and 34.7% at 5 and 10 years for the entire cohort. Analysis of outcomes showed that patients undergoing HDC as upfront therapy had a better progression-free survival (PFS) and OS compared to those treated in subsequent relapses (5-year PFS 51.8% versus 26.8% and 5-year OS 51.3% versus 25.9%). Better remission status before transplantation was predictive of the benefit of HDC. Three treatment-related deaths were recorded. CONCLUSIONS: To our knowledge, this is the most extensive retrospective study of HDC in PMNSGCTs patients and the first to thoroughly investigate potential predictors of benefit from this treatment. HDC with ASCT may well represent a therapeutic option in patients with PMNSGCTs after the first relapse or even as a front-line program.

[Last year of residency for radiation oncologists in France: Overview and perspectives]. / Phase de consolidation (docteur junior) en oncologie­radiothérapie en France : état des lieux et perspectives.

PURPOSE: The last year of the radiotherapy oncology internship in France has become a phase of empowerment, called "junior doctor", allowing interns to validate acts previously reserved only for senior doctors. This study focused on the responsibilities given to the first promotion of junior doctors in France and their feelings on this new status. MATERIAL AND METHODS: A cross-sectional survey was carried out by the French associations of interns and young doctors in oncology, Aerio and SFjRO. A questionnaire was sent to the class referents of each city for transmission to the junior doctors of the year 2021-2022 from September 1st to November 30th, 2022. The questions concerned training, the modalities of this year and the feelings. Responses were analyzed anonymously using R. 4.3.1 software. RESULTS: For radiation oncology, 33 responses were obtained from 21 cities. For most junior doctors, three to four localizations (51%) were performed with an average of five new patients per week. The contours were reviewed either systematically (51%) or only at the beginning (32%). Dosimetry was reported as never countersigned in 19%; 80% of junior doctors described having been the only radiation oncologist during multidisciplinary staff meetings. The two main areas of improvement were theoretical training (45%) and legal frameworks/contracts (42%). CONCLUSION: These results relating to the first class of junior doctors showed an overall agreement with the recommendations of the Cnec. Feedback from interns was positive. The supervision of brachytherapy and dosimetry activities, the presence alone in multidisciplinary panel remained points of vigilance.

Spatial reorganization of low-molecular-weight proteins during cold cataract opacification.

Freeze-fracture electron microscopy of calf lens nuclear cytoplasm undergoing a cold cataract opacification shows the formation of domains within the bulk cytoplasm. The size distribution of these domains (from a few tens of nanometers to a few micrometers) is compatible with previous size evaluations obtained from light scattering experiments for the 'large scattering elements' responsible for cold cataract opacification. In addition, these domains appear to be devoid of crystallins of higher molecular weight and enriched in low-molecular-weight species.

Molecular basis of eye lens transparency. Osmotic pressure and X-ray analysis of alpha-crystallin solutions.

Short range, liquid-like order of the crystallin proteins accounts for eye lens transparency. The relationship between structural and thermodynamic properties of eye lens was further investigated using osmotic pressure and small-angle X-ray scattering measurements of calf lens alpha-crystallins. The consistency of both data sets confirms that the macroscopic thermodynamic properties are determined by the structural properties accessible to X-ray scattering. In addition, the experimental data were correctly accounted for using a model developed in liquid-state physics: the rescaled mean spherical approximation combined with a Verwey-Overbeek potential. This model provides as best fit parameters the excluded volume, the charge and the diameter of an "equivalent" particle that compare well with the corresponding values found in the literature for alpha-crystallins. As a result, transparency may now be expressed as a function of a few structural parameters, the role of which is discussed. The approach presented here may be extended to studies of the thermodynamic-structural relationships of other protein solutions.

Calf lens alpha-crystallin quaternary structure. A three-layer tetrahedral model.

Calf lens alpha-crystallins are polydisperse globular particles made of a large number of two types of subunits, A and B, both of molecular weight congruent to 20,000. alpha-Crystallin populations consisting on average of 40 subunits or more were subjected to various changes in pH, ionic strength, temperature and urea concentration. Modifications in quaternary structure induced by variation of these physicochemical parameters were followed by means of X-ray and quasi-elastic light-scattering and quantified in terms of weight average molecular weight (M), radius of gyration (Rg) and hydrodynamic radius (Rh). High-pressure liquid chromatography was used as a control of polydispersity. Increasing the pH, decreasing the ionic strength and incubating at temperatures from 20 degrees C to 45 degrees C all resulted in the formation of particles of decreasing M, Rg and Rh values. These effects are cumulative. All monomodal alpha-crystallin populations encountered in this study, which covers a wide range of sizes and molecular weights, may be accounted for by a three-layer model with partial filling up of the layers. Applying basic principles of symmetry and postulating specific contacts between protein subunits to construct this three-layer model leads to tetrahedral symmetry, with 12, 24 and 24 sites in the first, second and third layers, respectively. Variations in probabilities of site occupancy account for both the observed quaternary structure modifications and the intrinsic polydispersity of alpha-crystallins

Short-range order of crystallin proteins accounts for eye lens transparency.

In its normal state, the eye lens is transparent despite the presence in the cell cytoplasm of high concentrations of proteins, the crystallins, which, a priori, could be expected to scatter an important part of the incident light. Early on, an explanation was sought in the spatial correlations between individual scatterers. Trokel first proposed that the "high concentration of proteins in the lens must be accompanied by a degree of local order approaching a paracrystalline state"; Benedek subsequently suggested that a dense, noncrystalline packing of the proteins would sufficiently reduce the scattered intensity. However, in spite of an improved understanding of the molecular structure of crystallins, their spatial order remained unknown. We present here a small-angle X-ray scattering study of the problem, performed with calf lens cytoplasm both in intact lenses and in cytoplasmic extracts where the crystallin concentration was varied from 3 to 510 mg ml-1. All our experimental data are consistent with short-range spatial order, as in dense liquids or glasses, and this provides a simple explanation for lens transparency. In addition, we detected no conformational change or reorganization of the crystallin proteins throughout the investigated concentration range.

Neutron scattering by calf lens cytoplasm. A comparison between two models of cataract.

Small angle neutron scattering (SANS) was used to compare two models of cataracts: the cold cataract induced in the lens nucleus cytoplasm by lowering the temperature and the opacification induced by calcium in the lens cortex cytoplasm. In both cases opacified cytoplasms display additional scattering at low angles as compared to their clear controls. An analysis of this additional scattering provides quantitative information concerning the size distribution, the number and contrast of the scatterers responsible for lens opacification. The scatterers of cold cataract and of calcium--induced opacification not only have, as shown elsewhere, a different composition but are also found to display completely different sizes (in the thousand A range for cold-cataract, in the hundred A range for calcium--induced opacification). These results illustrate the diversity of scatterer types which are able to cause comparable lens opacities.

Identification of the scattering elements responsible for lens opacification in cold cataracts.

Using both quasi-elastic light scattering spectroscopy and angular dissymmetry in the intensity of the scattered light, we examined the onset of turbidity for intact calf lenses and for isolated nuclear cytoplasm. In the case of the nuclear cytoplasm these measurements demonstrate the presence of two kinds of scatterers: small units of approximately 100-A radius and larger elements whose size is distributed around 1,500 A. As the temperature is decreased towards the cold cataract temperature, the intensity of light scattered by the small units stays almost constant while the intensity scattered by the large elements increase very strongly. The opacification of the lens cytoplasm produced by decreasing the temperature results principally from an increase in the concentration of the large scattering elements. For the intact nucleus the situation is qualitatively similar, but the mean size of the large scattering elements shows a more substantial increase than in the isolated cytoplasm as temperature is lowered towards the cold cataract temperature.

Calcium decreases transparency of homogenate from lens cortex and has no effect on nucleus.

We studied the effects of calcium on transparency in homogenates of cortical and nuclear cells from calf lenses. Calcium was mixed into samples of homogenate to final concentrations between 0 and 50 mM and the transparency of the calcium-treated homogenates was measured using laser transmittance. In the presence of 10 mM calcium, the transmittance of cortical homogenate decreased 50% while the nuclear homogenate lost less than 4% transmittance after 24 h at 37 degrees C. To better understand the contribution of cytoplasm and membranes to opacity, the nuclear and cortical homogenates were centrifuged to separate membranes from the cytoplasm. When 10 mM calcium was added to cortical homogenate which was then centrifuged, the transmittance of the membrane fraction decreased nearly 60%, while the fraction without membrane decreased only 10%. The strong effect of calcium on the membrane fraction was accompanied by an increase in specific gravity of membranes from 1.23 to 1.32. Ten- and 20 mM calcium had no effect on transparency of membranes or cytoplasm separated from nuclear homogenate, and 50 mM calcium produced only a slight opacity. The results indicate that an effect on membrane-protein interactions may be important in the loss of transparency produced by calcium in cells of lens cortex.

Effect of calcium on the calf lens cytoplasm.

Opacification was induced in calf lens cytoplasmic extracts by addition of calcium. The sample turbidity was shown to increase with calcium molarity, incubation time and temperature and to decrease with the protein cytoplasmic concentration. Although this turbidity was enhanced when membrane fragments were left over in the cytoplasmic extracts, it did show up in the absence of any detectable vesicular fragment. Scattering techniques (X-ray and light) showed that the calcium-induced opacification is linked to enhanced light scattering, which results from the formation of additional scatterers, a few tens of nm in diameter. Additional structures were indeed visualized by freeze-fracture electron microscopy (FFEM): they appear as molecular clusters with diameters ranging from 20 to 90 nm, made of densely packed particles, with heterogeneous sizes. The turbidity expected from these clusters, as well as the expected variation of turbidity with cytoplasmic concentration, was calculated to be in agreement with the measurements. When compared with cold cataract, these results illustrate that similar opacities may result from completely different biophysical mechanisms.