Tumor-agnostic plasma assay for circulating tumor DNA detects minimal residual disease and predicts outcome in locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Forty to fifty percent of patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) relapse despite multimodal treatment. Circulating tumor DNA (ctDNA) has the potential to detect minimal residual disease (MRD) after curative-intent therapy and to identify earlier which patients will progress. We developed a tumor-agnostic plasma ctDNA assay to detect MRD in unselected LA SCCHN with the aim of predicting progression-free survival (PFS) and overall survival without the need for tumor sequencing. PATIENTS AND METHODS: A 26-gene next-generation sequencing panel was constructed that included the most frequently mutated genes in SCCHN and two HPV-16 genes. MRD was assessed in each patient through an in-house informatic workflow informed by somatic mutations identified in the corresponding pre-treatment plasma sample. The presence of MRD was defined as the detection of ctDNA in one plasma sample collected within 1-12 weeks of the end of curative treatment. The primary endpoint was the PFS rate at 2 years. At least 32 patients were planned for inclusion with the hypothesis that PFS at 2 years was >80% in MRD-negative patients and <30% in MRD-positive patients (α = 0.05, ß = 0.9). RESULTS: We sequenced DNA from 116 plasma samples derived from 53 LA SCCHN patients who underwent curative-intent treatment. ctDNA was detected in 41/53 (77%) patients in the pre-treatment samples. Out of these 41 patients, 17 (41%) were MRD positive after treatment. The 2-year PFS rate was 23.53% (9.9% to 55.4%) and 86.6% (73.4% to 100%) in MRD-positive and MRD-negative patients, respectively (P < 0.05). Median survival was 28.37 months (14.30 months-not estimable) for MRD-positive patients and was not reached for the MRD-negative cohort (P = 0.011). CONCLUSIONS: Our ctDNA assay detects MRD in LA SCCHN and predicts disease progression and survival without the need for tumor sequencing, making this approach easily applicable in daily practice.

Dose mimicking based strategies for online adaptive proton therapy of head and neck cancer.

Objective.To compare a not adapted (NA) robust planning strategy with three fully automated online adaptive proton therapy (OAPT) workflows based on the same optimization method: dose mimicking (DM). The added clinical value and limitations of the OAPT methods are investigated for head and neck cancer (HNC) patients.Approach.The three OAPT strategies aimed at compensating for inter-fractional anatomical changes by mimiking different dose distributions on corrected cone beam CT images (corrCBCTs). Order by complexity, the OAPTs were: (1) online adaptive dose restoration (OADR) where the approved clinical dose on the planning-CT (pCT) was mimicked, (2) online adaptation using DM of the deformed clinical dose from the pCT to corrCBCTs (OADEF), and (3) online adaptation applying DM to a predicted dose on corrCBCTs (OAML). Adaptation was only applied in fractions where the target coverage criteria were not met (D98% < 95% of the prescribed dose). For 10 HNC patients, the accumulated dose distributions over the 35 fractions were calculated for NA, OADR, OADEF, and OAML.Main results.Higher target coverage was observed for all OAPT strategies compared to no adaptation. OADEF and OAML outperformed both NA and OADR and were comparable in terms of target coverage to initial clinical plans. However, only OAML provided comparable NTCP values to those from the clinical dose without statistically significant differences. When the NA initial plan was evaluated on corrCBCTs, 51% of fractions needed adaptation. The adaptation rate decreased significantly to 25% when the last adapted plan with OADR was selected for delivery, to 16% with OADEF, and to 21% with OAML. The reduction was even greater when the best plan among previously generated adapted plans (instead of the last one) was selected.Significance. The implemented OAPT strategies provided superior target coverage compared to no adaptation, higher OAR sparing, and fewer required adaptations.

Radiation therapy-induced left vocal cord paralysis following lung stereotactic body radiation therapy: A case report and review of the literature.

We report the case of a 50-year old women with an oncological history of metastatic breast carcinoma who underwent lung stereotactic body radiation therapy (SBRT) of 60Gy in 8 fractions for a left upper lobe metastatic lesion. Seven months later, she complains about hoarseness and weakness of voice. Tumoral relapse and other frequent etiologies were excluded. The diagnosis of radiation induced left recurrent laryngeal nerve paralysis causing left vocal cord paralysis (VCP) was made. The symptomatology did not improve till the disease progression and death of the patient 29 months after SBRT. VCP after lung SBRT is a rare adverse event that has not yet been well described in the medical literature.

Lysine 182 of endothelin B receptor modulates agonist selectivity and antagonist affinity: evidence for the overlap of peptide and non-peptide ligand binding sites.

The potent vasoactive peptide hormone endothelin (ET) binds to receptors which belong to the G-protein coupled receptor family. The availability of non-peptide antagonists for ET receptors allows investigation of the relationship among the binding sites for peptide and non-peptide ligands. In this study, a lysine residue, conserved within transmembrane domain 3 (TM3) of the ETA and ETB receptor subtypes, is implicated in agonist and antagonist binding by its analogous position within TM3 to a binding site aspartate residue conserved within bioactive amine receptors. Replacement of this lysine within hETB by arginine, alanine, methionine, aspartate, or glutamate results in hETB variants with unaltered affinities for agonist peptide ET-1 but which have affinities for peptide agonists ET-2, ET-3, sarafotoxin 6C, and TRL 1736 which are between 1-3 orders of magnitude lower than their corresponding wild-type hETB values. Significantly, the affinities of non-peptide antagonists, (+/-)-SB 209670 and its analogs as well as Ro 46-2005, are abrogated. The results suggest that an interaction of K182 of hETB with the indan 2-carboxyl of (+/-)-SB 209670 may contribute to the high-affinity binding of the diarylindan antagonists. The results indicate that TM3 of hETB is a region of overlap among the binding sites of non-peptide antagonists and the affected peptide agonists.

Comparative study of tibial (single) and tibiofemoral (double) osteotomy for osteoarthrosis and rheumatoid arthritis.

Osteotomies on 101 knees in 79 patients were assessed either prospectively or retrospectively. High tibial osteotomy was performed in 54 knees (27 with rheumatoid arthritis (RA) and 27 with osteoarthrosis (OA)) and double (tibiofemoral) osteotomy in 47 knees (25 RA and 22 OA), and were assessed prospectively in 46 and retrospectively in 55. Using a subjective assessment, 65% showed some improvement--70% of the single and 60% of the double osteotomies. Of the four groups (OA single or double, RA single or double), OA knees having a single osteotomy improved most frequently (74%), and OA knees having a double osteotomy least frequently (50%). Significant improvements in pain score and angular deformity were recorded. The mean range of movement of the operated knee was significantly reduced, and was particularly evident in those knees having a double osteotomy. We conclude that double osteotomies tend to have a higher incidence of complications, including impaired movement, and are not more efficient in relieving pain than single osteotomies in either OA or RA.