Factors affecting lymph node yield and density in neck dissection.

BACKGROUND: Studies suggest that neck dissections with a minimum of 16-18 yielded nodes are associated with better overall survival compared to neck dissections with lower yields. AIMS: We aimed to identify factors affecting the lymph node yield and density in patients with oral cavity cancer undergoing elective neck dissection levels 1-3. MATERIALS AND METHODS: Using prospectively registered data, we conducted a population-based cohort study on all patients surgically treated for oral cavity cancer including levels 1-3 neck dissection at our institution from 2018 to 2022. Uni and multivariate analyses were performed to identify factors associated with lymph node yields. RESULTS: In total, 221 patients were included. The mean lymph nodes yield and density were 19 (95%CI 18-20) and 0.12 (95%CI 0.09-0.16), respectively. In multivariate analysis, increasing body weight (p = .034) was positively and previous radiotherapy (p = .006) were negatively correlated with the number of yielded lymph nodes. Lymph node density was positively correlated with body weight (p = .011) and body mass index (p = .032) in univariate analysis. CONCLUSIONS AND SIGNIFICANCE: Increasing body weight was positively and previous radiotherapy was negatively correlated to lymph node yield. These factors should be taken into consideration when interpreting the lymph node yield as an indicator of neck dissection quality.

A Novel and Reliable Pixel Response Correction Method (DAC-Shifting) for Spectral Photon-Counting CT Imaging.

Spectral photon-counting cone-beam computed tomography (CT) imaging is challenged by individual pixel response behaviours, which lead to noisy projection images and subsequent image artefacts like rings. Existing methods to correct for this either use calibration measurements, like signal-to-thickness calibration (STC), or perform a post-processing ring artefact correction of sinogram data or scan reconstructions without taking the pixel response explicitly into account. Here, we present a novel post-processing method (digital-to-analogue converter (DAC)-shifting) which explicitly measures the current pixel response using flat-field images and subsequently corrects the projection data. The DAC-shifting method was evaluated using a repeat series of the spectral photon-counting imaging (Medipix3) of a phantom with different density inserts and iodine K-edge imaging. The method was also compared against polymethyl methacrylate (PMMA)-based STC. The DAC-shifting method was shown to be effective in correcting individual pixel responses and was robust against detector instability; it led to a 47.4% average reduction in CT-number variation in homogeneous materials, with a range of 40.7-55.6%. On the contrary, the STC correction showed varying results; a 13.7% average reduction in CT-number variation, ranging from a 43.7% increase to a 45.5% reduction. In K-edge imaging, DAC-shifting provides a sharper attenuation peak and more uniform CT values, which are expected to benefit iodine concentration quantifications.

Pathology and resection margins following mastectomy prior to immediate breast reconstruction.

Risk of local recurrence (LR) (and even distant disease-free survival) after mastectomy is associated with margin status. Furthermore, the vast majority of LR are located at the anterior (superficial) margin. Margins in mastectomy are considered anatomical borders and not true resection margins; such a conception may erroneously lead to underestimation of the risk of LR after mastectomy. If dissection is accurate along the fascia, only skin, subcutaneous tissue and minimal residual breast gland tissue (rBGT) are expected to remain in the patient. However, the subcutaneous fascia is an inconsistent anatomical structure that may be absent in almost half of patients. Studies and routine clinical practice suggest that resection may frequently, though often focally, be within the breast glandular tissue leaving various amounts of rBGT. Such areas may be nidus for subsequent de novo or recurrent premalignant or malignant disease. There is no consensus on handling of close/positive margins and intervention is extrapolated from studies on breast conserving surgery with subsequent radiotherapy. Handling of a close/positive margin is complicated by poor correlation between the ex vivo findings on the specimen and the attempt to relocate the area of concern in a patient with reconstructed breasts. In this clinical practice review, we strongly advocate for reporting of the lesion-to-margin distance in mastectomies to collect further evidence on the association between LR and margin status.

Separating distant recurrences from second primaries in head and neck squamous cell carcinomas - A DAHANCA group analysis on paired tumor samples.

BACKGROUND: In head and neck squamous cell carcinomas (HNSCC), there is no clinically available method to separate distant metastases (DMs) from SCC secondary primary tumors. The study aimed to assess the genetic relationship in paired tumor samples. METHODS: Patients with pairs of solid biopsies from the primary HNSCC and suspected DMs were identified (2007-2017). Targeted next-generation sequencing of 22 genes was applied, including TP53, supplemented with human papillomavirus (HPV) genotyping. RESULTS: Of 55 pairs obtained, 33 were successfully analyzed. Distant biopsies included lung, liver, and bone. A genetic match was found in 23/33 (70%) patients, primarily with identical TP53 mutations or HPV genotypes. In 10/33 patients (30%), the genetic relationship was absent, all with lung involvement. In patients with no lung involvement, 8/8 had a match. CONCLUSIONS: One-third of patients with DMs in HNSCC lack a genetic relationship with the primary tumors. The risk of misclassification is most prominent for patients with lung involvement.

Increased lesion detectability in patients with locally advanced breast cancer-A pilot study using dynamic whole-body [18F]FDG PET/CT.

BACKGROUND: Accurate diagnosis of axillary lymph node (ALN) metastases is essential for prognosis and treatment planning in breast cancer. Evaluation of ALN is done by ultrasound, which is limited by inter-operator variability, and by sentinel lymph node biopsy and/or ALN dissection, none of which are without risks and/or long-term complications. It is known that conventional 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) has limited sensitivity for ALN metastases. However, a recently developed dynamic whole-body (D-WB) [18F]FDG PET/CT scanning protocol, allowing for imaging of tissue [18F]FDG metabolic rate (MRFDG), has been shown to have the potential to increase lesion detectability. The study purpose was to examine detectability of malignant lesions in D-WB [18F]FDG PET/CT compared to conventional [18F]FDG PET/CT. RESULTS: This study prospectively included ten women with locally advanced breast cancer who were referred for an [18F]FDG PET/CT as part of their diagnostic work-up. They all underwent D-WB [18F]FDG PET/CT, consisting of a 6 min single bed dynamic scan over the chest region started at the time of tracer injection, a 64 min dynamic WB PET scan consisting of 16 continuous bed motion passes, and finally a contrast-enhanced CT scan, with generation of MRFDG parametric images. Lesion visibility was assessed by tumor-to-background and contrast-to-noise ratios using volumes of interest isocontouring tumors with a set limit of 50% of SUVmax and background volumes placed in the vicinity of tumors. Lesion visibility was best in the MRFDG images, with target-to-background values 2.28 (95% CI: 2.04-2.54) times higher than target-to-background values in SUV images, and contrast-to-noise values 1.23 (95% CI: 1.12-1.35) times higher than contrast-to-noise values in SUV images. Furthermore, five imaging experts visually assessed the images and three additional suspicious lesions were found in the MRFDG images compared to SUV images; one suspicious ALN, one suspicious parasternal lymph node, and one suspicious lesion located in the pelvic bone. CONCLUSIONS: D-WB [18F]FDG PET/CT with MRFDG images show potential for improved lesion detectability compared to conventional SUV images in locally advanced breast cancer. Further validation in larger cohorts is needed. CLINICAL TRIAL REGISTRATION: The trial is registered in clinicaltrials.gov, NCT05110443, https://www. CLINICALTRIALS: gov/study/NCT05110443?term=NCT05110443&rank=1 .

Dynamic whole-body [18F]FES PET/CT increases lesion visibility in patients with metastatic breast cancer.

BACKGROUND: Correct classification of estrogen receptor (ER) status is essential for prognosis and treatment planning in patients with breast cancer (BC). Therefore, it is recommended to sample tumor tissue from an accessible metastasis. However, ER expression can show intra- and intertumoral heterogeneity. 16α-[18F]fluoroestradiol ([18F]FES) Positron Emission Tomography/Computed Tomography (PET/CT) allows noninvasive whole-body (WB) identification of ER distribution and is usually performed as a single static image 60 min after radiotracer injection. Using dynamic whole-body (D-WB) PET imaging, we examine [18F]FES kinetics and explore whether Patlak parametric images ( K i ) are quantitative and improve lesion visibility. RESULTS: This prospective study included eight patients with metastatic ER-positive BC scanned using a D-WB PET acquisition protocol. The kinetics of [18F]FES were best characterized by the irreversible two-tissue compartment model in tumor lesions and in the majority of organ tissues. K i values from Patlak parametric images correlated with K i values from the full kinetic analysis, r2 = 0.77, and with the semiquantitative mean standardized uptake value (SUVmean), r2 = 0.91. Furthermore, parametric K i images had the highest target-to-background ratio (TBR) in 162/164 metastatic lesions and the highest contrast-to-noise ratio (CNR) in 99/164 lesions compared to conventional SUV images. TBR was 2.45 (95% confidence interval (CI): 2.25-2.68) and CNR 1.17 (95% CI: 1.08-1.26) times higher in K i images compared to SUV images. These quantitative differences were seen as reduced background activity in the K i images. CONCLUSION: [18F]FES uptake is best described by an irreversible two-tissue compartment model. D-WB [18F]FES PET/CT scans can be used for direct reconstruction of parametric K i images, with superior lesion visibility and K i values comparable to K i values found from full kinetic analyses. This may aid correct ER classification and treatment decisions. Trial registration ClinicalTrials.gov: NCT04150731, https://clinicaltrials.gov/study/NCT04150731.

Antibodies toward Na+,HCO3--cotransporter NBCn1/SLC4A7 block net acid extrusion and cause pH-dependent growth inhibition and apoptosis in breast cancer.

BACKGROUND: Na+,HCO3--cotransporter NBCn1/Slc4a7 accelerates murine breast carcinogenesis. Lack of specific pharmacological tools previously restricted therapeutic targeting of NBCn1 and identification of NBCn1-dependent functions in human breast cancer. METHODS: We develop extracellularly-targeted anti-NBCn1 antibodies, screen for functional activity on cells, and evaluate (a) mechanisms of intracellular pH regulation in human primary breast carcinomas, (b) proliferation, cell death, and tumor growth consequences of NBCn1 in triple-negative breast cancer, and (c) association of NBCn1-mediated Na+,HCO3--cotransport with human breast cancer metastasis. RESULTS: We identify high-affinity (KD ≈ 0.14 nM) anti-NBCn1 antibodies that block human NBCn1-mediated Na+,HCO3--cotransport in cells, without cross-reactivity towards human NBCe1 or murine NBCn1. These anti-NBCn1 antibodies abolish Na+,HCO3--cotransport activity in freshly isolated primary organoids from human breast carcinomas and lower net acid extrusion effectively in primary breast cancer tissue from patients with macrometastases in axillary lymph nodes. Inhibitory anti-NBCn1 antibodies decelerate tumor growth in vivo by ~50% in a patient-derived xenograft model of triple-negative breast cancer and pH-dependently reduce colony formation, cause G2/M-phase cell cycle accumulation, and increase apoptosis of metastatic triple-negative breast cancer cells in vitro. CONCLUSIONS: Inhibitory anti-NBCn1 antibodies block net acid extrusion in human breast cancer tissue, particularly from patients with disseminated disease, and pH-dependently limit triple-negative breast cancer growth.

Tumor volume and cancer stem cell expression as prognostic markers for high-dose loco-regional failure in head and neck squamous cell carcinoma - A DAHANCA 19 study.

BACKGROUND AND PURPOSE: Reliable and accessible biomarkers for patients with Head and Neck Squamous Cell Carcinoma (HNSCC) are warranted for biologically driven radiotherapy (RT). This study aimed to investigate the prognostic value of putative cancer stem cell (CSC) markers, hypoxia, and tumor volume using loco-regional high-dose failure (HDF) as endpoint. MATERIALS AND METHODS: Tumor tissue was retrieved from patients treated with primary chemo-(C-)RT and nimorazole for HNSCC in the Danish Head and Neck Cancer Study Group (DAHANCA) 19 study. Tumor volume, hypoxic classification, and expression of CSC markers CD44, SLC3A2, and MET were analyzed. For patients with eligible data on all parameters (n = 340), the risk of HDF following primary chemo-(C-)RT were analyzed by these biomarkers as a whole and stratified for p16-positive oropharynx (p16 + OPSCC) vs p16-negative (p16-) tumors (oral cavity, p16- oropharynx, hypopharynx and larynx). RESULTS: Higher risk of HDF was seen for patients with larger primary and nodal volume (>25 cm3, Hazard Ratio (HR): 3.00 [95 % CI: 1.73-5.18]), high SLC3A2 (HR: 2.99 [1.28-6.99]), CD44 (>30 % positive, HR: 2.29 [1.05-5.00]), and p16- tumors (HR: 2.53 [1.05-6.11]). p16- tumors had a higher CSC marker expression than p16 + OPSCC. The factors associated with the highest risk of HDF were larger volume (HR: 3.29 [1.79-6.04]) for p16- tumors (n = 178) and high SLC3A2 (HR: 6.19 [1.58-24.23]) for p16 + OPSCC (n = 162). CONCLUSION: Tumor volume, p16, and CSC markers are potential biomarkers for HDF for patients with HNSCC treated with (C-)RT. Lower expression of CSC in p16 + OPSCC may contribute to better tumor control.