PURPOSE Cisplatin plus fluorouracil (PF) induction chemotherapy has been compared with taxane (docetaxel or paclitaxel), cisplatin, and fluorouracil (Tax-PF) in randomized trials in locoregionally ...advanced head and neck cancers (LAHNCs). The aim of this meta-analysis was to study the efficacy and toxicity of Tax-PF and PF and identify differences in outcomes in subsets of patients. METHODS Five randomized trials representing 1,772 patients were identified. Updated individual patient data (IPD) were retrieved for all trials. The log-rank test, stratified by trial, was used for comparison. Interaction or trend tests were used to study the interaction between covariates and treatment. Results Median follow-up was 4.9 years. The hazard ratio (HR) of death was 0.79 (95% CI, 0.70 to 0.89; P < .001; absolute benefit at 5 years: 7.4%) in favor of Tax-PF. Heterogeneity was significant (P = .08, I(2) = 51%) and related to one trial. There was no more heterogeneity after exclusion of this trial (P = .99, I(2) = 0%), and HR of death was 0.72 (95% CI, 0.63 to 0.83) in favor of Tax-PF. There was no interaction between treatment effect and the following patient covariates: age, sex, performance status, tumor stage, or site. Tax-PF was associated with significant reductions of progression, locoregional failure, and distant failure compared with PF, with HRs of 0.78 (95% CI, 0.69 to 0.87; P < .001), 0.79 (95% CI, 0.66 to 0.94; P = .007), and 0.63 (95% CI, 0.45 to 0.89; P = .009) respectively. CONCLUSION This IPD meta-analysis shows the superiority of Tax-PF over PF as induction chemotherapy. Its precise role in the management of LAHNC remains to be determined.
To report the impact of radiotherapy quality on outcome in a large international phase III trial evaluating radiotherapy with concurrent cisplatin plus tirapazamine for advanced head and neck cancer.
...The protocol required interventional review of radiotherapy plans by the Quality Assurance Review Center (QARC). All plans and radiotherapy documentation underwent post-treatment review by the Trial Management Committee (TMC) for protocol compliance. Secondary review of noncompliant plans for predicted impact on tumor control was performed. Factors associated with poor protocol compliance were studied, and outcome data were analyzed in relation to protocol compliance and radiotherapy quality.
At TMC review, 25.4% of the patients had noncompliant plans but none in which QARC-recommended changes had been made. At secondary review, 47% of noncompliant plans (12% overall) had deficiencies with a predicted major adverse impact on tumor control. Major deficiencies were unrelated to tumor subsite or to T or N stage (if N+), but were highly correlated with number of patients enrolled at the treatment center (< five patients, 29.8%; > or = 20 patients, 5.4%; P < .001). In patients who received at least 60 Gy, those with major deficiencies in their treatment plans (n = 87) had a markedly inferior outcome compared with those whose treatment was initially protocol compliant (n = 502): -2 years overall survival, 50% v 70%; hazard ratio (HR), 1.99; P < .001; and 2 years freedom from locoregional failure, 54% v 78%; HR, 2.37; P < .001, respectively.
These results demonstrate the critical importance of radiotherapy quality on outcome of chemoradiotherapy in head and neck cancer. Centers treating only a few patients are the major source of quality problems.
Therapy‐related acute myeloid leukemia (t‐AML) arises as a late complication following antecedent solid tumors or hematologic diseases and their associated treatments. There are limited data ...regarding risk factors and outcomes following allogeneic hematopoietic cell transplantation (HCT) for t‐AML following a prior solid tumor, and furthermore, the impact of myeloablative (MAC) vs reduced‐intensity conditioning (RIC) on survival is unknown. The acute leukemia working party (ALWP) of the European society for blood and bone marrow transplantation (EBMT) performed a large registry study that included 535 patients with t‐AML and prior solid tumor who underwent first MAC or RIC allogeneic HCT from 2000‐2016. The primary endpoints of the study were OS and LFS. Patients receiving RIC regimens had an increase in relapse incidence (hazard ratio HR, 1.52; 95% confidence interval CI 1.02‐2.26; P = 0.04), lower LFS (HR, 1.52; 95% CI 1.12‐2.05, P = 0.007), and OS (HR, 1.51; CI 1.09‐2.09; P = 0.012). There were no differences in NRM and GRFS. Importantly, LFS and OS were superior in patients receiving ablative regimens due to a decrease in relapse. As NRM continues to decline in the current era, it is conceivable that outcomes of HCT for t‐AML with prior solid tumor may be improved by careful patient selection for myeloablative regimens.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The structural characterization of modular proteins containing long intrinsically disordered regions intercalated with folded domains is complicated by their conformational diversity and flexibility ...and requires the integration of multiple experimental approaches. Nipah virus (NiV) phosphoprotein, an essential component of the viral RNA transcription/replication machine and a component of the viral arsenal that hijacks cellular components and counteracts host immune responses, is a prototypical model for such modular proteins. Curiously, the phosphoprotein of NiV is significantly longer than the corresponding protein of other paramyxoviruses. Here, we combine multiple biophysical methods, including x-ray crystallography, NMR spectroscopy, and small angle x-ray scattering, to characterize the structure of this protein and provide an atomistic representation of the full-length protein in the form of a conformational ensemble. We show that full-length NiV phosphoprotein is tetrameric, and we solve the crystal structure of its tetramerization domain. Using NMR spectroscopy and small angle x-ray scattering, we show that the long N-terminal intrinsically disordered region and the linker connecting the tetramerization domain to the C-terminal X domain exchange between multiple conformations while containing short regions of residual secondary structure. Some of these transient helices are known to interact with partners, whereas others represent putative binding sites for yet unidentified proteins. Finally, using NMR spectroscopy and isothermal titration calorimetry, we map a region of the phosphoprotein, comprising residues between 110 and 140 and common to the V and W proteins, that binds with weak affinity to STAT1 and confirm the involvement of key amino acids of the viral protein in this interaction. This provides new, to our knowledge, insights into how the phosphoprotein and the nonstructural V and W proteins of NiV perform their multiple functions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid ...neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18-74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The insulin-like growth factor 1 (IGF1) signaling pathway is implicated in the development of cancer. High levels of circulating IGF1 and certain genetic polymorphisms of IGF1 and IGFBP3 are ...associated with an increased risk of several common cancers. The IGF1 receptor (IGF1R) has been shown to be expressed in a wide range of tumors, and IGF1R signaling is crucial for tumor transformation and the survival of malignant cells. Several monoclonal antibodies and small-molecule inhibitors have been tested in preclinical studies and early-phase clinical studies. IGF1R signaling interferes with numerous growth factors and receptors such as VEGF and EGFR. In the experimental system, IGF1R signaling has been found to correlate with resistance to therapies based on the inhibition of EGFR and HER2. This Review highlights the most relevant studies in this exciting area of research, focusing in particular on the role of IGF1R in resistance to other receptor-targeted therapies for cancer.
Summary
The role of autologous stem cell transplantation (ASCT) in patients with marginal zone lymphoma (MZL) is debatable. This study investigated the outcome and prognostic factors affecting the ...outcome of patients undergoing ASCT for MZL. Eligible patients had non‐transformed nodal, extra‐nodal (MALT) or splenic MZL (SMZL), aged ≥18 years, who underwent a first ASCT between1994 and 2013 and were reported to the European Society for Blood and Marrow Transplantation, Fondazione Italiana Linfomi or Gruppo Italiano Trapianto Di Midollo Osseo registries. The study included 199 patients, 111 MALT lymphoma, 55 nodal MZL (NMZL) and 33 SMZL. Median age at transplantation was 56 years. The median number of prior therapies was 2 (range 1–8), including rituximab in 71%. 95% had chemosensitive disease. 89% received a chemotherapy‐based high‐dose regimen. There were no significant differences in patient and transplant characteristics between the 3 histological subtypes except for a lower percentage of patients previously treated with rituximab in the MALT sub‐group and more transplants performed in recent years in the other sub‐groups. After a median follow‐up of 5 years, 5‐year cumulative incidence of relapse/progression and non‐relapse mortality were 38% and 9%, respectively. Five‐year event‐free survival (EFS) and overall survival (OS) were 53% and 73%, respectively. Five‐year cumulative incidence of second malignancies was 6%. Multivariate analysis revealed age ≥65 years was associated with a shorter EFS and OS. In addition, patients with SMZL had a shorter OS than those with MALT. ASCT may provide clinical benefit in MZL patients who have failed multiple lines of chemoimmunotherapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Antithymocyte globulin (ATG) is commonly used for graft-vs.-host disease (GVHD) prophylaxis in unrelated donor allogeneic transplantation (Allo-HSCT). However, its use is still controversial in ...matched sibling donor (MSD) Allo-HSCT, notably after reduced intensity conditioning (RIC). ATG dose may influence the outcome, explaining in part the discordant conclusions in MSD Allo-HSCT. We, therefore, analyzed the impact of ATG doses in patients with acute myeloid leukemia in first complete remission undergoing RIC Allo-HSCT from a MSD. We analyzed 234 patients from the EBMT registry and compared outcome according to given ATG dose (high dose: ≥ 6 mg/kg, n = 39 or low dose: < 6 mg/kg, n = 195). No difference was found in the cumulative incidence of acute (grade 2-4: high dose vs. low dose: 21% vs. 13%, p = 0.334; adjusted hazard ratio (HR): 1.20, p = 0.712) and chronic GVHD (extensive: high dose vs. low dose: 19% vs. 18%, p = 0.897; adjusted HR: 1.01, p = 0.980). In contrast, high dose of ATG significantly increased the incidence of relapse (52% vs. 26%, p = 0.011; adjusted HR: 1.31, p = 0.001) leading to impaired outcome (HR progression-free survival (PFS): 1.23, p = 0.002; HR overall survival (OS): 1.17, p = 0.029; HR GVHD and relapse-free survival (GRFS): 1.20, p = 0.005). We conclude that an ATG dose <6 mg/kg is sufficient for GVHD prophylaxis, while higher doses impair disease control and outcome.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Promising results in a randomized phase II trial with the hypoxic cytotoxin tirapazamine (TPZ) combined with cisplatin (CIS) and radiation led to this phase III trial.
Patients with previously ...untreated stage III or IV (excluding T1-2N1 and M1) squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were randomly assigned to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either CIS (100 mg/m(2)) on day 1 of weeks 1, 4, and 7 or CIS (75 mg/m(2)) plus TPZ (290 mg/m(2)/d) on day 1 of weeks 1, 4, and 7 and TPZ alone (160 mg/m(2)/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS). The primary end point was overall survival (OS). The planned sample size was 850, estimated to result in 334 deaths, which would provide 90% power to detect a difference in 2-year survival rates of 60% v 70% for CIS versus TPZ/CIS, respectively (hazard ratio = 0.69).
Eight hundred sixty-one patients were accrued from 89 sites in 16 countries. In an intent-to-treat analysis, the 2-year OS rates were 65.7% for CIS and 66.2% for TPZ/CIS (TPZ/CIS--CIS: 95% CI, -5.9% to 6.9%). There were no significant differences in failure-free survival, time to locoregional failure, or quality of life as measured by Functional Assessment of Cancer Therapy-Head and Neck.
We found no evidence that the addition of TPZ to chemoradiotherapy, in patients with advanced head and neck cancer not selected for the presence of hypoxia, improves OS.
•Proton therapy has the potential to reduce the severity of toxicities for head and neck cancers.•The optimization of beam delivery and treatment planning can decrease uncertainties.•Patient ...preparation may be different from that for IMRT.•Robustness is necessary for improving model-based approaches and randomized trials.
The quality of radiation therapy has been shown to significantly influence the outcomes for head and neck squamous cell carcinoma (HNSCC) patients. The results of dosimetric studies suggest that intensity-modulated proton therapy (IMPT) could be of added value for HNSCC by being more effective than intensity-modulated (photon) radiation therapy (IMRT) for reducing side effects of radiation therapy. However, the physical properties of protons make IMPT more sensitive than photons to planning uncertainties. This could potentially have a negative effect on the quality of IMPT planning and delivery. For this review, the three French proton therapy centers collaborated to evaluate the differences between IMRT and IMPT. The review explored the effects of these uncertainties and their management for developing a robust and optimized IMPT treatment delivery plan to achieve clinical outcomes that are superior to those for IMRT. We also provide practical suggestions for the management of HNSCC carcinoma with IMPT. Because metallic dental implants can increase range uncertainties (3–10%), patient preparation for IMPT may require more systematic removal of in-field alien material than is done for IMRT. Multi-energy CT may be an alternative to calculate more accurately the dose distribution. The practical aspects that we describe are essential to guarantee optimal quality in radiation therapy in both model-based and randomized clinical trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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