The Evolving Role of Taxanes in Combination With Cetuximab for the Treatment of Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck : Evidence, Advantages, and Future Directions

The addition of cetuximab to platinum-based chemotherapy (cisplatin or carboplatin plus 5-fluorouracil [5-FU]), followed by maintenance cetuximab until disease progression (EXTREME), resulted in the first regimen to yield significantly improved survival outcomes in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in over 30 years. Currently, the EXTREME regimen is a guideline-recommended treatment in the first-line R/M setting, and, therefore, it is used as a control arm in all new first-line, phase 3 immunotherapy trials. More recently, new checkpoint inhibitor approaches have emerged and are changing the treatment landscape for PD-L1\u2013positive patients with R/M SCCHN. Additionally, alternative chemotherapy backbones in R/M SCCHN are continually investigated. Replacing 5-FU with a taxane in the EXTREME regimen seeks to take advantage of the potential immunogenic and proapoptotic synergy between cetuximab and docetaxel or paclitaxel. These cetuximab-, platinum-, and taxane-based treatments have demonstrated promising survival results and cytoreductive properties in single-arm studies. Thus, these combination treatments may be of importance to patients with high tumor burden and dangerous site involvements (e.g., causing bleeding, suffocation, dysphagia, or ulceration), in whom symptom relief is a key treatment goal. TPExtreme is the first large, randomized trial comparing a cetuximab, platinum, and taxane combination regimen with EXTREME. Currently, the substitution of 5-FU with a taxane is a feasible and clinically beneficial option for patients with contraindications to 5-FU. The TPEx regimen appears to be a new option in first-line R/M SCCHN, with a shorter time on CT and significantly lower toxicity than the EXTREME regimen. For patients with R/M disease in whom further cisplatin- or carboplatin-based treatment is unsuitable, or whose disease has already progressed on first-line R/M therapy, treatment options such as cetuximab plus a taxane, which capitalize on the combinative ability of the 2 agents, can be considered. Notably, it is as of yet unknown what second-line treatments may be suitable to follow a checkpoint inhibitor-based first-line therapy

Nivolumab versus investigator's choice in patients with recurrent or metastatic squamous cell carcinoma of the head and neck : efficacy and safety in CheckMate 141 by age

Objectives: Many patients with squamous cell carcinoma of the head and neck (SCCHN) are 6565 years old; comorbidities and other age-related factors may affect their ability to tolerate traditional chemotherapy. Nivolumab is the only immunotherapy to significantly improve overall survival (OS) versus investigator's choice (IC) of single-agent chemotherapy at primary analysis in a phase 3 trial (CheckMate 141) in patients with recurrent/metastatic SCCHN post-platinum therapy. In this post hoc analysis, we report efficacy and safety by age. Patients and methods: Eligible patients were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks (n = 240) or IC (methotrexate, docetaxel, or cetuximab n = 121). The primary endpoint of the trial was OS. For this analysis, outcomes were analyzed by age < 65 and 6565 years. The data cut-off date was September 2017 (minimum follow-up 24.2 months). Results: At baseline, 68 patients (28.3%) receiving nivolumab and 45 patients (37.2%) receiving IC were 6565 years. Baseline characteristics were generally similar across age groups. OS and tumor response benefits with nivolumab versus IC were maintained regardless of age. The 30-month OS rates of 11.2% (<65 years) and 13.0% ( 6565 years) with nivolumab were more than tripled versus corresponding IC rates of 1.4% and 3.3%, respectively. The nivolumab arm had a lower rate of treatment-related adverse events versus IC regardless of age, consistent with the overall patient population. Conclusion: In CheckMate 141, nivolumab resulted in a higher survival versus IC in patients <65 and 6565 years, with a manageable safety profile in both age groups. ClinicalTrials.gov: NCT02105636

Gauging low-dose X-ray phase-contrast imaging at a single and large propagation distance

The interactions of a beam of hard and spatio-temporally coherent X-rays with a soft-matter sample primarily induce a transverse distribution of exit phase variations δϕ (retardations or advancements in pieces of the wave front exiting the object compared to the incoming wave front) whose free-space propagation over a distance z gives rise to intensity contrast gz. For single-distance image detection and |δϕ| ≪ 1 all-order-in-z phase-intensity contrast transfer is linear in δϕ. Here we show that ideal coherence implies a decay of the (shot-)noise-to-signal ratio in gz and of the associated phase noise as z−1/2 and z−1, respectively. Limits on X-ray dose thus favor large values of z. We discuss how a phase-scaling symmetry, exact in the limit δϕ → 0 and dynamically unbroken up to |δϕ| ∼ 1, suggests a filtering of gz in Fourier space, preserving non-iterative quasi-linear phase retrieval for phase variations up to order unity if induced by multi-scale objects inducing phase variations δϕ of a broad spatial frequency spectrum. Such an approach continues to be applicable under an assumed phase-attenuation duality. Using synchrotron radiation, ex and in vivo microtomography on frog embryos exemplifies improved resolution compared to a conventional single-distance phase-retrieval algorithm

Theory and Applications of X-ray Standing Waves in Real Crystals

Theoretical aspects of x-ray standing wave method for investigation of the real structure of crystals are considered in this review paper. Starting from the general approach of the secondary radiation yield from deformed crystals this theory is applied to different concreat cases. Various models of deformed crystals like: bicrystal model, multilayer model, crystals with extended deformation field are considered in detailes. Peculiarities of x-ray standing wave behavior in different scattering geometries (Bragg, Laue) are analysed in detailes. New possibilities to solve the phase problem with x-ray standing wave method are discussed in the review. General theoretical approaches are illustrated with a big number of experimental results.Comment: 101 pages, 43 figures, 3 table

Whispering to the Deaf: Communication by a Frog without External Vocal Sac or Tympanum in Noisy Environments

Atelopus franciscus is a diurnal bufonid frog that lives in South-American tropical rain forests. As in many other frogs, males produce calls to defend their territories and attract females. However, this species is a so-called “earless” frog lacking an external tympanum and is thus anatomically deaf. Moreover, A. franciscus has no external vocal sac and lives in a sound constraining environment along river banks where it competes with other calling frogs. Despite these constraints, male A. franciscus reply acoustically to the calls of conspecifics in the field. To resolve this apparent paradox, we studied the vocal apparatus and middle-ear, analysed signal content of the calls, examined sound and signal content propagation in its natural habitat, and performed playback experiments. We show that A. franciscus males can produce only low intensity calls that propagate a short distance (<8 m) as a result of the lack of an external vocal sac. The species-specific coding of the signal is based on the pulse duration, providing a simple coding that is efficient as it allows discrimination from calls of sympatric frogs. Moreover, the signal is redundant and consequently adapted to noisy environments. As such a coding system can be efficient only at short-range, territory holders established themselves at short distances from each other. Finally, we show that the middle-ear of A. franciscus does not present any particular adaptations to compensate for the lack of an external tympanum, suggesting the existence of extra-tympanic pathways for sound propagation

Mixed contrast transfer and transport of intensity approach for phase retrieval in the Fresnel region

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