Adult stem cells are often touted as therapeutic agents in the regenerative medicine field, however data detailing both the engraftment and functional capabilities of solid tissue derived human adult ...epithelial stem cells is scarce. Here we show the isolation of adult human salivary gland (SG) stem/progenitor cells and demonstrate at the single cell level in vitro self‐renewal and differentiation into multilineage organoids. We also show in vivo functionality, long‐term engraftment, and functional restoration in a xenotransplantation model. Indeed, transplanted human salisphere‐derived cells restored saliva production and greatly improved the regenerative potential of irradiated SGs. Further selection for c‐Kit expression enriched for cells with enhanced regenerative potencies. Interestingly, interaction of transplanted cells with the recipient SG may also be involved in functional recovery. Thus, we show for the first time that salispheres cultured from human SGs contain stem/progenitor cells capable of self‐renewal and differentiation and rescue of saliva production. Our study underpins the therapeutic promise of salisphere cell therapy for the treatment of xerostomia. Stem Cells 2016;34:640–652
Human salivary gland stem cells cultured as salispheres are able to self‐renew and differentiate from single cells into salivary gland organoids. When xeno‐transplanted into an animal model of radiation‐induced hyposalivation, human salivary gland stem cells rescue saliva production.
Abstract
Inadequate surgical margins occur frequently in oral squamous cell carcinoma surgery. Fluorescence molecular imaging (FMI) has been explored for intraoperative margin assessment, but data ...are limited to phase-I studies. In this single-arm phase-II study (NCT03134846), our primary endpoints were to determine the sensitivity, specificity and positive predictive value of cetuximab-800CW for tumor-positive margins detection. Secondary endpoints were safety, close margin detection rate and intrinsic cetuximab-800CW fluorescence. In 65 patients with 66 tumors, cetuximab-800CW was well-tolerated. Fluorescent spots identified in the surgical margin with signal-to-background ratios (SBR) of ≥2 identify tumor-positive margins with 100% sensitivity, 85.9% specificity, 58.3% positive predictive value, and 100% negative predictive value. An SBR of ≥1.5 identifies close margins with 70.3% sensitivity, 76.1% specificity, 60.5% positive predictive value, and 83.1% negative predictive value. Performing frozen section analysis aimed at the fluorescent spots with an SBR of ≥1.5 enables safe, intraoperative adjustment of surgical margins.
Understanding cancer heterogeneity, its temporal evolution over time, and the outcomes of guided treatment depend on accurate data collection in a context of routine clinical care. We have developed ...a hospital-based data-biobank for oncology, entitled OncoLifeS (Oncological Life Study: Living well as a cancer survivor), that links routine clinical data with preserved biological specimens and quality of life assessments. The aim of this study is to describe the organization and development of a data-biobank for cancer research.
We have enrolled 3704 patients aged ≥ 18 years diagnosed with cancer, of which 45 with hereditary breast-ovarian cancer (70% participation rate) as of October 24th, 2019. The average age is 63.6 ± 14.2 years and 1892 (51.1%) are female. The following data are collected: clinical and treatment details, comorbidities, lifestyle, radiological and pathological findings, and long-term outcomes. We also collect and store various biomaterials of patients as well as information from quality of life assessments.
Embedding a data-biobank in clinical care can ensure the collection of high-quality data. Moreover, the inclusion of longitudinal quality of life data allows us to incorporate patients' perspectives and inclusion of imaging data provides an opportunity for analyzing raw imaging data using artificial intelligence (AI) methods, thus adding new dimensions to the collected data.
MRI is the optimal method for sensitive detection of tumour tissue and pre-operative staging in oral cancer. When jawbone resections are necessary, the current standard of care for oral tumour ...surgery in our hospital is 3D virtual planning from CT data. 3D printed jawbone cutting guides are designed from the CT data. The tumour margins are difficult to visualise on CT, whereas they are clearly visible on MRI scans. The aim of this study was to change the conventional CT-based workflow by developing a method for 3D MRI-based lower jaw models. The MRI-based visualisation of the tumour aids in planning bone resection margins.
A workflow for MRI-based 3D surgical planning with bone cutting guides was developed using a four-step approach. Key MRI parameters were defined (phase 1), followed by an application of selected Black Bone MRI sequences on healthy volunteers (phase 2). Three Black Bone MRI sequences were chosen for phase 3: standard, fat saturated, and an out of phase sequence. These protocols were validated by applying them on patients (n = 10) and comparison to corresponding CT data. The mean deviation values between the MRI- and the CT-based models were 0.63, 0.59 and 0.80 mm for the three evaluated Black Bone MRI sequences. Phase 4 entailed examination of the clinical value during surgery, using excellently fitting printed bone cutting guides designed from MRI-based lower jaw models, in two patients with oral cancer. The mean deviation of the resection planes was 2.3 mm, 3.8 mm for the fibula segments, and the mean axis deviation was the fibula segments of 1.9°.
This study offers a method for 3D virtual resection planning and surgery using cutting guides based solely on MRI imaging. Therefore, no additional CT data are required for 3D virtual planning in oral cancer surgery.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Sentinel lymph node biopsy (SLNB) has been introduced as a diagnostic staging modality for detection of occult metastases in patients with early stage oral cancer. Comparisons regarding ...accuracy to the routinely used elective neck dissection (END) are lacking in literature. Methods: A retrospective, multicenter cohort study included 390 patients staged by END and 488 by SLNB. Results: The overall sensitivity (84% vs. 81%, p = 0.612) and negative predictive value (NPV) (93%, p = 1.000) were comparable between END and SLNB patients. The END cohort contained more pT2 tumours (51%) compared to the SLNB cohort (23%) (p < 0.001). No differences were found for sensitivity and NPV between SLNB and END divided by pT stage. In floor-of-mouth (FOM) tumours, SLNB had a lower sensitivity (63% vs. 92%, p = 0.006) and NPV (90% vs. 97%, p = 0.057) compared to END. Higher disease-specific survival (DSS) rates were found for pT1 SLNB patients compared to pT1 END patients (96% vs. 90%, p = 0.048). Conclusion: In the absence of randomized clinical trials, this study provides the highest available evidence that, in oral cancer, SLNB is as accurate as END in detecting occult lymph node metastases, except for floor-of-mouth tumours.
In most oral cancer patients, surgical treatment includes resection of the primary tumor combined with excision of lymph nodes (LNs), either for staging or for treatment. All LNs harvested during ...surgery require tissue processing and subsequent microscopic histopathologic assessment to determine the nodal stage. In this study, we investigated the use of the fluorescent tracer cetuximab-800CW to discriminate between tumor-positive and tumor-negative LNs before histopathologic examination. Here, we report a retrospective ad hoc analysis of a clinical trial designed to evaluate the resection margin in patients with oral squamous cell carcinoma (NCT02415881).
Two days before surgery, patients were intravenously administered 75 mg of cetuximab followed by 15 mg of cetuximab-800CW, an epidermal growth factor receptor-targeting fluorescent tracer. Fluorescence images of excised, formalin-fixed LNs were obtained and correlated with histopathologic assessment.
Fluorescence molecular imaging of 514 LNs (61 pathologically positive nodes) could detect tumor-positive LNs ex vivo with 100% sensitivity and 86.8% specificity (area under the curve, 0.98). In this cohort, the number of LNs that required microscopic assessment was decreased by 77.4%, without missing any metastases. Additionally, in 7.5% of the LNs false-positive on fluorescence imaging, we identified metastases missed by standard histopathologic analysis.
Our findings suggest that epidermal growth factor receptor-targeted fluorescence molecular imaging can aid in the detection of LN metastases in the ex vivo setting in oral cancer patients. This image-guided concept can improve the efficacy of postoperative LN examination and identify additional metastases, thus safeguarding appropriate postoperative therapy and potentially improving prognosis.
Accumulation of geriatric deficits, leading to an increased frailty state, makes patients susceptible for decline in health-related quality of life (HRQOL) after treatment for head and neck cancer ...(HNC).
To assess the association of single and accumulated geriatric deficits with HRQOL decline in patients after treatment for HNC.
Between October 2014 and May 2016, patients at a tertiary referral center were included in the Oncological Life Study (OncoLifeS), a prospective data biobank, and followed up for 2 years. A consecutive series of 369 patients with HNC underwent geriatric assessment at baseline; a cohort of 283 patients remained eligible for analysis, and after 2 years, 189 patients remained in the study. Analysis was performed between March and November 2020.
Geriatric assessment included scoring of the Adult Comorbidity Evaluation 27, polypharmacy, Malnutrition Universal Screening Tool, Activities of Daily Living, Instrumental Activities of Daily Living (IADL), Timed Up & Go, Mini-Mental State Examination, 15-item Geriatric Depression Scale, marital status, and living situation.
The primary outcome measure was the Global Health Status/Quality of Life (GHS/QOL) scale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Differences between patients were evaluated using linear mixed models at 3 months after treatment (main effects, β 95% CI) and declining course per year during follow-up (interaction × time, β 95% CI), adjusted for baseline GHS/QOL scores, and age, sex, stage, and treatment modality.
Among the 283 patients eligible for analysis, the mean (SD) age was 68.3 (10.9) years, and 193 (68.2%) were male. Severe comorbidity (β = -7.00 -12.43 to 1.56), risk of malnutrition (β = -6.18 -11.55 to -0.81), and IADL restrictions (β = -10.48 -16.39 to -4.57) were associated with increased GHS/QOL decline at 3 months after treatment. Severe comorbidity (β = -4.90 -9.70 to -0.10), IADL restrictions (β = -5.36 -10.50 to -0.22), restricted mobility (β = -6.78 -12.81 to -0.75), signs of depression (β = -7.08 -13.10 to -1.06), and living with assistance or in a nursing home (β = -8.74 -15.75 to -1.73) were associated with further GHS/QOL decline during follow-up. Accumulation of domains with geriatric deficits was a major significant factor for GHS/QOL decline at 3 months after treatment (per deficient domain β = -3.17 -5.04 to -1.30) and deterioration during follow-up (per domain per year β = -2.74 -4.28 to -1.20).
In this prospective cohort study, geriatric deficits were significantly associated with HRQOL decline after treatment for HNC. Therefore, geriatric assessment may aid decision-making, indicate interventions, and reduce loss of HRQOL.
trialregister.nl Identifier: NL7839.
•Sarcopenia is relevant for head and neck cancer patients treated with radiotherapy.•Sarcopenia is an independent adverse prognostic factor for survival outcomes.•For oropharyngeal cancer, survival ...is more defined by p16 status than by sarcopenia.•Sarcopenia is associated with late radiation-induced toxicities.
Sarcopenia is emerging as an adverse prognostic factor for survival and complication risk in cancer patients. This study aims to determine the impact of sarcopenia on survival and late toxicity in a large cohort of head and neck squamous cell carcinoma (HNSCC) patients treated with definitive (chemo)radiotherapy ((C)RT).
HNSCC patients treated with definitive (C)RT from January 2007 to June 2016 were included. Sarcopenia was assessed from radiation planning computed tomography (CT) scans using skeletal muscles at level C3. The impact of sarcopenia on overall survival (OS) and disease-free survival (DFS) was evaluated using the Kaplan–Meier method. Multivariable association models were developed to assess the impact of sarcopenia on late toxicity.
The study population was composed of 750 HNSCC patients. Cut-off values for sarcopenia were set at SMI < 42.4 cm2/m2 (men) and <30.6 cm2/m2 (women) corresponding lowest gender specific quartile. Sarcopenic patients had significantly poorer survival rates, especially those with lower performance status and locally advanced disease. In oropharyngeal cancer patients, survival was more determined by p16 status than by sarcopenia. In multivariable analysis, sarcopenia was associated with worse OS (HR 0.72, p = 0.012) and DFS (HR 0.67, p = 0.001). In multivariable association models, sarcopenia was associated with physician-rated xerostomia six months after treatment (OR 1.65, p = 0.027) and physician-rated dysphagia six and twelve months after treatment (OR 2.02, p = 0.012 and 2.51, p = 0.003, respectively).
Sarcopenia in HNSCC patients receiving definitive (C)RT is an independent prognostic factor for worse survival outcomes and is associated with physician-rated toxicity.
Background
Little is known about immediate implant placement in head and neck cancer patients. We studied implant survival and functional outcomes of overdentures fabricated on implants placed ...immediately after removal of the lower dentition during ablative surgery or preceding primary radiotherapy (RT).
Methods
Inclusion criteria were primary head and neck cancer, dentate lower jaw, and indication for removal of remaining teeth. Two implants to support a mandibular overdenture were placed immediately after extraction of the dentition during ablative surgery, or prior to starting primary radiotherapy. Standardized questionnaires and clinical assessments were conducted (median follow-up 18.5 months, IQR 13.3).
Results
Fifty-eight implants were placed in 29 patients. Four implants were lost (implant survival rate 93.1%). In 9 patients, no functional overdenture could be made. All patients were satisfied with their dentures.
Conclusions
Combining dental implant placement with removal of remaining teeth preceding head neck oncology treatment results in a favorable treatment outcome.
Salivary duct carcinoma (SDC) is a subtype of salivary gland cancer with a dismal prognosis and a need for better prognostication and novel treatments. The aim of this national cohort study was to ...investigate clinical outcome, prognostic factors, androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2) expression. SDC patients diagnosed between 1990 and 2014 were identified by the Nationwide Network and Registry of Histo‐ and Cytopathology in the Netherlands (PALGA). Subsequently, medical records were evaluated and pathological diagnoses reviewed. Data were analyzed for overall survival (OS), disease‐free survival (DFS), distant metastasis‐free survival (DMFS) and prognostic factors. AR was evaluated by immunohistochemistry (IHC), HER2 by IHC and fluorescent in‐situ hybridization. A total of 177 patients were included. The median age was 65 years, 75% were male. At diagnosis, 68% presented with lymph node metastases and 6% with distant metastases. Median OS, DFS and DMFS were 51, 23 and 26 months, respectively. In patients presenting without distant metastases, the absolute number of positive lymph nodes was associated with poor OS and DMFS in a multivariable analysis. AR and HER2 were positive in 161/168 (96%) and 44/153 (29%) tumors, respectively, and were not prognostic factors. SDC has a dismal prognosis with primary lymph node involvement in the majority of patients. The absolute number of lymph node metastases was found to be the only prognostic factor for DMFS and OS. AR expression and—to a lesser extent—HER2 expression hold promise for systemic treatment in the metastatic and eventually adjuvant setting.
What's new?
Salivary duct carcinoma (SDC) is a rare and often fatal malignancy. Little is known about associations between its pathological features and clinical outcome. In this study, clinicopathological factors were analyzed for 177 patients diagnosed with SDC in The Netherlands between 1990 and 2014. The data show that median overall survival (OS) and distant metastasis‐free survival (DMFS) were 51 and 26 months, respectively. At diagnosis, 68% of patients presented with lymph node metastases. Lymph node positivity was associated with poor OS and poor DMFS. The absolute number of metastatic lymph nodes was the only significant prognostic factor for survival in a multivariate analysis. Androgen receptor and human epidermal growth factor 2 (HER2) were positive in 96% and 29%, respectively and were not a prognostic factor.
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