The relationship between the structure and the properties of a drug or material is a key concept of chemistry. Knowledge of the three-dimensional structure is considered to be of such importance that ...almost every report of a new chemical compound is accompanied by an X-ray crystal structure - at least since the 1970s when diffraction equipment became widely available. Crystallographic software of that time was restricted to very limited computing power, and therefore drastic simplifications had to be made. It is these simplifications that make the determination of the correct structure, especially when it comes to hydrogen atoms, virtually impossible. We have devised a robust and fast system where modern chemical structure models replace the old assumptions, leading to correct structures from the model refinement against standard in-house diffraction data using no more than widely available software and desktop computing power. We call this system
NoSpherA2
(Non-Spherical Atoms in Olex2). We explain the theoretical background of this technique and demonstrate the far-reaching effects that the improved structure quality that is now routinely available can have on the interpretation of chemical problems exemplified by five selected examples.
NoSpherA2 brings quantum crystallography to routine structure determination and to the analysis of chemical properties for any class of materials.
New software, OLEX2, has been developed for the determination, visualization and analysis of molecular crystal structures. The software has a portable mouse‐driven workflow‐oriented and fully ...comprehensive graphical user interface for structure solution, refinement and report generation, as well as novel tools for structure analysis. OLEX2 seamlessly links all aspects of the structure solution, refinement and publication process and presents them in a single workflow‐driven package, with the ultimate goal of producing an application which will be useful to both chemists and crystallographers.
Large anatomical variations can be observed during the treatment course intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC), leading to potential dose variations. Adaptive ...radiotherapy (ART) uses one or several replanning sessions to correct these variations and thus optimize the delivered dose distribution to the daily anatomy of the patient. This review, which is focused on ART in the HNC, aims to identify the various strategies of ART and to estimate the dosimetric and clinical benefits of these strategies.
We performed an electronic search of articles published in PubMed/MEDLINE and Science Direct from January 2005 to December 2016. Among a total of 134 articles assessed for eligibility, 29 articles were ultimately retained for the review. Eighteen studies evaluated dosimetric variations without ART, and 11 studies reported the benefits of ART.
Eight in silico studies tested a number of replanning sessions, ranging from 1 to 6, aiming primarily to reduce the dose to the parotid glands. The optimal timing for replanning appears to be early during the first two weeks of treatment. Compared to standard IMRT, ART decreases the mean dose to the parotid gland from 0.6 to 6 Gy and the maximum dose to the spinal cord from 0.1 to 4 Gy while improving target coverage and homogeneity in most studies. Only five studies reported the clinical results of ART, and three of those studies included a non-randomized comparison with standard IMRT. These studies suggest a benefit of ART in regard to decreasing xerostomia, increasing quality of life, and increasing local control. Patients with the largest early anatomical and dose variations are the best candidates for ART.
ART may decrease toxicity and improve local control for locally advanced HNC. However, randomized trials are necessary to demonstrate the benefit of ART before using the technique in routine practice.
Concomitant chemotherapy (CT)–radiotherapy (RT) is a standard of care in locally advanced nasopharyngeal carcinoma (NPC) and a role for induction CT is not established.
Patients with locally advanced ...NPC, WHO type 2 or 3, were randomized to induction TPF plus concomitant cisplatin-RT or concomitant cisplatin-RT alone. The TPF regimen consisted of three cycles of Docetaxel 75mg/m2 day 1; cisplatin 75mg/m2 day 1; 5FU 750mg/m2/day days 1–5. RT consisted of 70Gy in 7weeks plus concomitant cisplatin 40mg/m2 weekly.
A total of 83 patients were included in the study. Demographics and tumour characteristics were well balanced between both arms. Most of the patients (95%) in the TPF arm received three cycles of induction CT. The rate of grade 3–4 toxicity and the compliance (NCI-CTCAE v3) during cisplatin-RT were not different between both arms. With a median follow-up of 43.1months, the 3-year PFS rate was 73.9% in the TPF arm versus 57.2% in the reference arm hazard ratio (HR)=0.44; 95% confidence interval (CI): 0.20–0.97, P=0.042. Similarly the 3years overall survival rate was 86.3% in the TPF arm versus 68.9% in the reference arm (HR=0.40; 95% CI: 0.15–1.04, P=0.05).
In conclusion, several important aspects can be emphasized: the compliance to induction TPF was good and TPF did not compromise the tolerance of the concomitant RT-cisplatin phase. The improved PFS and overall survival rates needs to be confirmed by further trials.
This retrospective report assessed the impact of rabbit antithymocyte globulins (ATG), incorporated within a standard myeloablative conditioning regimen prior to allogeneic stem cell transplantation ...(allo-SCT) using human leukocyte antigen-matched unrelated donors (HLA-MUD), on the incidence of acute and chronic graft-vs-host disease (GVHD). In this series of leukemia patients, 120 patients (70%) did not receive ATG ('no-ATG' group), whereas 51 patients received ATG ('ATG' group). With a median follow-up of 30.3 months, the cumulative incidence of grade 3-4 acute GVHD was 36% in the no-ATG group and 20% in the ATG group (P = 0.11). The cumulative incidence of extensive chronic GVHD was significantly lower in the ATG group as compared to the no-ATG group (4 vs 32%, respectively; P = 0.0017). In multivariate analysis, the absence of use of ATG was the strongest parameter associated with an increased risk of extensive chronic GVHD (relative risk) = 7.14, 95% CI: 1.7-33.3, P = 0.008). At 2 years, the probability of nonrelapse mortality, relapse, overall and leukemia-free survivals was not significantly different between the no-ATG and ATG groups. We conclude that the addition of ATG to GVHD prophylaxis resulted in decreased incidence of extensive chronic GVHD without an increase in relapse or nonrelapse mortality, and without compromising survival after myeloablative allo-SCT from HLA-MUD.
Intensive care unit (ICU) admission is associated with high mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Whether mortality has decreased recently is unknown. The 497 ...adult allogeneic HSCT recipients admitted to three ICUs between 1997 and 2011 were evaluated retrospectively. Two hundred and nine patients admitted between 1997 and 2003 were compared with the 288 patients admitted from 2004 to 2011. Factors associated with 90-day mortality were identified. The recent cohort was characterized by older age, lower conditioning intensity, and greater use of peripheral blood or unrelated-donor graft. In the recent cohort, ICU was used more often for patients in hematological remission (67% vs 44%; P<0.0001) and without GVHD (73% vs 48%; P<0.0001) or invasive fungal infection (85% vs 73%; P=0.0003) despite a stable admission rate (21.7%). These changes were associated with significantly better 90-day survival (49% vs 31%). Independent predictors of hospital mortality were GVHD, mechanical ventilation (MV) and renal replacement therapy (RRT). Among patients who required MV or RRT, survival was 29% and 18%, respectively, but dropped to 18% and 6% in those with GVHD. The use of ICU admission has changed and translated into improved survival, but advanced life support in patients with GVHD usually provides no benefits.
Secondary acute lymphoblastic leukemia (s-ALL) comprises up to 10% of ALL patients. However, data regarding s-ALL outcomes is limited. To answer what is the role of allogeneic hematopoietic cell ...transplantation (HCT) in s-ALL, a matched-pair analysis in a 1:2 ratio was conducted to compare outcomes between s-ALL and de novo ALL (dn-ALL) patients reported between 2000-2021 to the European Society for Blood and Marrow Transplantation registry. Among 9720 ALL patients, 351 (3.6%) were s-ALL, of which 80 were in first complete remission (CR1) with a known precedent primary diagnosis 58.8% solid tumor (ST), 41.2% hematological diseases (HD). The estimated 2-year relapse incidence (RI) was 19.1% (95%CI: 11-28.9), leukemia-free survival (LFS) 52.1% (95%CI: 39.6-63.2), non-relapse mortality (NRM) 28.8% (95%CI: 18.4-40), GvHD-free, relapse-free survival (GRFS) 39.4% (95%CI: 27.8-50.7), and overall survival (OS) 60.8% (95%CI: 47.9-71.4), and did not differ between ST and HD patients. In a matched-pair analysis, there was no difference in RI, GRFS, NRM, LFS, or OS between s-ALL and dn-ALL except for a higher incidence of chronic GvHD (51.9% vs. 31.4%) in s-ALL. To conclude, patients with s-ALL who received HCT in CR1 have comparable outcomes to patients with dn-ALL.
To evaluate potential synergistic effect of pembrolizumab with radiotherapy (RT) compared with a standard-of-care (SOC) cetuximab–RT in patients with locally advanced-squamous cell carcinoma of head ...and neck (LA-SCCHN).
Patients with nonoperated stage III-IV SCC of oral cavity, oropharynx, hypopharynx, and larynx and unfit for receiving high-dose cisplatin were enrolled. Patients received once-daily RT up to 69.96 Gy in 33 fractions with weekly cetuximab (cetuximab–RT arm) or 200 mg Q3W pembrolizumab during RT (pembrolizumab–RT arm). The primary endpoint was locoregional control (LRC) rate 15 months after RT. To detect a difference between arms of 60%-80% in 15-month LRC, inclusion of 66 patients per arm was required to achieve a power of at least 0.85 at two-sided significance level of 0.20.
Between May 2016 and October 2017, 133 patients were randomized to cetuximab–RT (n = 66) and pembrolizumab–RT (n = 67). Two patients (one in each arm) were not included in the analysis (a consent withdrawal and a progression before treatment start). The median age was 65 years (interquartile range 60-70 years), 92% were smokers, 60% were oropharynx (46% of oropharynx with p16+) and 75% were stage IV. Median follow-up was 25 months in both arms. The 15-month LRC rate was 59% with cetuximab–RT and 60% with pembrolizumab–RT odds ratio 1.05, 95% confidence interval (CI) 0.43-2.59; P = 0.91. There was no significant difference between arms for progression-free survival (hazard ratio 0.85, 95% CI 0.55-1.32; P = 0.47) and for overall survival (hazard ratio 0.83, 95% CI 0.49-1.40; P = 0.49). Toxicity was lower in the pembrolizumab–RT arm than in the cetuximab–RT arm: 74% versus 92% patients with at least one grade ≥3 adverse events (P = 0.006), mainly due to mucositis, radiodermatitis, and rash.
Compared with the SOC cetuximab–RT, pembrolizumab concomitant with RT did not improve the tumor control and survival but appeared less toxic in unfit patients with LA-SCCHN.
•This is the first randomized trial testing pembrolizumab–RT versus cetuximab–RT in patients with LA-SCCHN.•No difference of LRC at 15 months between concurrent pembrolizumab–RT and cetuximab–RT.•No difference in overall survival or progression-free survival between the two arms at 2-year follow-up.•Significantly more grade ≥3 adverse events with cetuximab–RT, essentially due to skin and mucosal reactions.
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