During posttreatment surveillance of head and neck cancer patients, imaging is insufficiently accurate for the early detection of relapsing disease. Free circulating tumor DNA (ctDNA) may serve as a ...novel biomarker for monitoring tumor burden during posttreatment surveillance of these patients. In this exploratory study, we investigated whether low level ctDNA in plasma of head and neck cancer patients can be detected using Droplet Digital PCR (ddPCR).
TP53 mutations were determined in surgically resected primary tumor samples from six patients with high stage (II-IV), moderate to poorly differentiated head and neck squamous cell carcinoma (HNSCC). Subsequently, mutation specific ddPCR assays were designed. Pretreatment plasma samples from these patients were examined on the presence of ctDNA by ddPCR using the mutation-specific assays. The ddPCR results were evaluated alongside clinicopathological data.
In all cases, plasma samples were found positive for targeted TP53 mutations in varying degrees (absolute quantification of 2.2-422 mutational copies/ml plasma). Mutations were detected in wild-type TP53 background templates of 7667-156,667 copies/ml plasma, yielding fractional abundances of down to 0.01%.
Our results show that detection of tumor specific TP53 mutations in low level ctDNA from HNSCC patients using ddPCR is technically feasible and provide ground for future research on ctDNA quantification for the use of diagnostic biomarkers in the posttreatment surveillance of HNSCC patients.
Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, ...mediated by the muscle fusogens Myomaker (MYMK) and Myomixer (MYMX). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity. Homozygosity of this human variant resulted in a spectrum of abnormalities that mimicked the clinical presentation of Carey-Fineman-Ziter syndrome (CFZS), caused by hypomorphic MYMK variants. Myoblasts generated from patient-derived induced pluripotent stem cells displayed defective fusion, and mice bearing the human MYMX variant died perinatally due to muscle abnormalities. In vitro assays showed that the human MYMX variant conferred minimal cell-cell fusogenicity, which could be restored with CRISPR/Cas9-mediated base editing, thus providing therapeutic potential for this disorder. Our findings identify MYMX as a recessive, monogenic human disease gene involved in CFZS, and provide new insights into the contribution of myoblast fusion to neuromuscular diseases.
Background
Image‐guided surgery could help obtain clear (≥5.0 mm) resection margins. This feasibility study investigated ultrasound‐guided resection accuracy of buccal mucosa squamous cell carcinoma ...(BMSCC).
Methods
MRI and ultrasound measurements of tumor thickness were compared to histology in 13 BMSCC‐patients. Ultrasound measured margins (at five locations) on the specimen were compared to the corresponding histological margins.
Results
Accuracy of in‐ and ex‐vivo ultrasound (mean deviation from histology: 1.6 mm) for measuring tumor thickness was comparable to MRI (mean deviation from histology: 2.6 mm). The sensitivity to detect clear margins using ex‐vivo ultrasound was low (48%). If an ex‐vivo ultrasound cutoff of ≥7.5 mm would be used, the sensitivity would increase to 86%.
Conclusions
Ultrasound‐guided resection of BMSCC's is feasible. In‐ and ex‐vivo ultrasound measure tumor thickness in BMSCC accurately. We recommend ≥7.5 mm resection margins on ex‐vivo ultrasound to obtain histological clear margins. Additional research is required to establish the effect of 7.5 mm ultrasound cutoff.
Background
To investigate if depth of invasion (DOI) can predict occult nodal disease in patients with cT1‐2N0 (7th TNM) oral squamous cell carcinoma (OSCC) staged by sentinel lymph node biopsy ...(SLNB).
Methods
In 199 OSCC patients, DOI measurements and SLNB were performed.
Results
Metastases were found in 64 of 199 patients (32%). Of these 64 patients, the mean DOI was 6.6 mm compared to 4.7 mm in patients without metastases (P = .003). The ROC‐curve showed an area under the curve of 0.65 with a most optimal cutoff point of 3.4 mm DOI (sensitivity 83% and specificity 47%). Regional metastases were found in 15% of patients with DOI ≤ 3.4 mm.
Conclusion
DOI seems to be a poor predictor for regional metastasis in patients with cT1‐2N0 OSCC. Therefore, staging of the neck using SLNB in patients with early stage oral cancer should also be performed in tumors with limited DOI and probably in T3 (8th TNM) OSCC ≤4 cm diameter.
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•PSMA PET/CT indicated a previously unnoticed paired nasopharyngeal macroscopic salivary gland.•Presence of paired mucous glands was confirmed in 100 consecutive patients and cadaver ...histology.•In 723 patients, the radiotherapy dose to this area was associated with xerostomia and dysphagia.•We propose to name these newly identified macroscopic glands the “tubarial glands”.•Sparing these glands in radiotherapy provides an opportunity to improve quality of life.
The presence of previously unnoticed bilateral macroscopic salivary gland locations in the human nasopharynx was suspected after visualization by positron emission tomography/computed tomography with prostate-specific membrane antigen ligands (PSMA PET/CT). We aimed to elucidate the characteristics of this unknown entity and its potential clinical implications for radiotherapy.
The presence and configuration of the PSMA-positive area was evaluated in a retrospective cohort of consecutively scanned patients with prostate or urethral gland cancer (n = 100). Morphological and histological characteristics were assessed in a human cadaver study (n = 2). The effect of radiotherapy (RT) on salivation and swallowing was retrospectively investigated using prospectively collected clinical data from a cohort of head-neck cancer patients (n = 723). With multivariable logistic regression analysis, the association between radiotherapy (RT) dose and xerostomia or dysphagia was evaluated.
All 100 patients demonstrated a demarcated bilateral PSMA-positive area (average length 4 cm). Histology and 3D reconstruction confirmed the presence of PSMA-expressing, predominantly mucous glands with multiple draining ducts, predominantly near the torus tubarius. In the head-neck cancer patients, the mean RT dose to the gland area was significantly associated with physician-rated post-treatment xerostomia and dysphagia ≥ grade 2 at 12 months (0.019/gy, 95%CI 0.005–0.033, p = .007; 0.016/gy, 95%CI 0.001–0.031, p = .036). Follow-up at 24 months had similar results.
The human body contains a pair of previously overlooked and clinically relevant macroscopic salivary gland locations, for which we propose the name tubarial glands. Sparing these glands in patients receiving RT may provide an opportunity to improve their quality of life.
Purpose
Sentinel lymph node (SLN) biopsy has proven to reliably stage the clinically negative neck in early-stage oral squamous cell carcinoma (OSCC).
99m
TcTc-tilmanocept may be of benefit in OSCC ...with complex lymphatic drainage patterns and close spatial relation to SLNs.
Methods
A prospective within-patient evaluation study was designed to compare
99m
TcTc-tilmanocept with
99m
TcTc-nanocolloid for SLN detection. A total of 20 patients with early-stage OSCC were included, who underwent lymphoscintigraphy with both tracers. Both lymphoscintigraphic images of each patient were evaluated for SLN detection and radiotracer distribution at 2–4 h post-injection.
Results
The injection site’s remaining radioactivity was significantly lower for
99m
TcTc-tilmanocept (29.9%), compared with
99m
TcTc-nanocolloid (60.9%;
p
< 0.001). Radioactive uptake in SLNs was significantly lower for
99m
TcTc-tilmanocept (1.95%) compared with
99m
TcTc-nanocolloid (3.16%;
p
= 0.010). No significant difference was seen in SLN to injection site ratio in radioactivity between
99m
TcTc-tilmanocept (0.066) and
99m
TcTc-nanocolloid (0.054;
p
= 0.232). A median of 3.0 and 2.5 SLNs were identified with
99m
TcTc-tilmanocept and
99m
TcTc-nanocolloid, respectively (
p
= 0.297). Radioactive uptake in higher echelon nodes was not significantly different between
99m
TcTc-tilmanocept (0.57%) and
99m
TcTc-nanocolloid (0.86%) (
p
= 0.052). A median of 2.0 and 2.5 higher echelon nodes was identified with
99m
TcTc-tilmanocept and
99m
TcTc-nanocolloid, respectively (
p
= 0.083).
Conclusion
99m
TcTc-tilmanocept had a higher injection site clearance, but at the same time a lower uptake in the SLN, resulting in an SLN to injection site ratio, which was not significantly different from
99m
TcTc-nanocolloid. The relatively low-radioactive uptake in SLNs of
99m
TcTc-tilmanocept may limit intraoperative detection of SLNs, but can be overcome by a higher injection dose.
Summary Oral squamous-cell carcinomas arise in mucosal linings of the oral cavity and frequently metastasise to regional lymph nodes in the neck. The presence of nodal metastases is a determinant of ...prognosis and clinical management. The neck is staged by palpation and imaging, but accuracy of these techniques to detect small metastases is low. In general, 30–40% of patients will have occult nodal disease and will develop clinically detectable lymph-node metastases when the neck is left untreated. The choice at present is either elective treatment or careful observation followed by treatment of the neck in patients who develop manifest metastases. These unsatisfying therapeutic options have been the subject of debate for decades. Recent developments in staging of the neck, including expression profiling and sentinel lymph-node biopsy, will allow more personalised management of the neck.
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