Impact of tumor subsite on survival outcomes in oral squamous cell carcinoma: A retrospective cohort study from 2000 to 2019.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is responsible for high morbidity and mortality worldwide. Although the oral cavity encompasses different anatomical subsites, it is unclear whether subsite localization of carcinoma influences outcome. METHODS: This retrospective cohort study examined overall survival (OS), recurrence-free survival (RFS) and local recurrence-free survival (L-RFS) at different subsites by Kaplan-Meier survival curves. Cox proportional hazards regression analysis was performed to investigate the impact of subsite on overall death, locoregional recurrence, and local recurrence. RESULTS: The cohort included 1702 patients treated with curative intent for OSCC according to standardized national guidelines. The 5-year OS was superior in oral tongue to retromolar trigone as well as in both oral tongue and floor-of-mouth (FOM) compared to tumors involving multiple locations. The 3-year RFS in oral tongue and FOM was superior to tumors involving multiple locations, and in FOM compared to retromolar trigone. The 3-year L-RFS in oral tongue and FOM was higher than gingiva, retromolar trigone and tumors involving multiple locations. Adjusting for relevant covariables using oral tongue as reference, tumors involving multiple locations was the only category presenting higher risk for locoregional recurrence, while risk of local recurrence was higher in gingiva, retromolar trigone, hard palate and to tumors involving multiple locations. The study found no difference in risk of death between subsites. CONCLUSION: The study found differences in survival outcomes between subsites. After adjusting for covariables, subsite mainly had significant impact on local recurrence, with no distinct pattern of influence on overall death or locoregional recurrence.

A systematic review on clinical adaptive radiotherapy for head and neck cancer.

INTRODUCTION: Head and neck cancer (HNC) patients' anatomy may undergo significant changes during radiotherapy (RT). This potentially affects dose distribution and compromises conformity between planned and delivered dose. Adaptive radiotherapy (ART) is a promising technique to overcome this problem but requires a significant workload. This systematic review aims to estimate the clinical and dosimetric benefits of ART using prospective data. MATERIAL AND METHODS: A search on PubMed and Web of Science according to the PRISMA guidelines was made on Feb 6, 2023. Search string used was: 'adaptive radiotherapy head neck cancer'. English language filter was applied. All studies were screened for inclusion on title and abstract, and the full text was read and discussed in the research group in case of uncertainty. Inclusion criteria were a prospective ART strategy for HNC investigating clinical or dosimetric outcomes. RESULTS: A total of 1251 articles were identified of which 15 met inclusion criteria. All included studies were published between 2010 and 2023 with a substantial diversity in design, endpoints, and nomenclature. The number of patients treated with ART was small with a median of 20 patients per study (range 4 to 86), undergoing 1-2 replannings. Mean dose to the parotid glands was reduced by 0.4-7.1 Gy. Maximum dose to the spinal cord was reduced by 0.5-4.6 Gy. Only five studies reported clinical outcome and disease control was excellent. Data on toxicity were ambiguous with some studies indicating reduced acute toxicity and xerostomia, while others found reduced quality of life in patients treated with ART. CONCLUSION: The literature on clinical ART in HNC is limited. ART is associated with small reductions in doses to organs at risk, but the influence on toxicity and disease control is uncertain. There is a clear need for larger, prospective trials with a well-defined control group.

A comparison of loco-regional relapse pattern in HPV positive vs negative oropharyngeal cancers following radiotherapy; relation to pretreatment FDG-PET and radiotherapy target volumes.

BACKGROUND: Previous studies have shown that a large proportion of relapses in head-and neck squamous cell carcinoma (HNSCC) following radiotherapy (RT) occur in the pretreatment FDG-PET avid volume (GTV-PET). The aim of the current work was to see if this was valid also in an oropharynx squamous cell carcinoma (OPSCC) only population, and to compare the loco-regional relapse pattern between HPV positive and HPV negative patients. MATERIAL AND METHODS: Among 633 OPSCC patients treated between 2009 and 2017, 46 patients with known HPV (p16) status and isolated loco-regional relapse were included. Oncologists contoured relapse volumes (RV) on relapse scans (PET/CT, CT or MR), which were thereafter deformed to match the anatomy of the planning CTs. The point of origin (center of volume) of the deformed RVs were determined and analyzed in relation to the RT target volumes (GTV-PET, GTV and CTVs). The relapse pattern was compared between HPV positive and HPV negative patients using Fischer's exact test. RESULTS: Sixty RVs were contoured in the 46 patients. 55% (95% CI 44-67%) of relapses originated in GTV-PET, while the other RT volumes harbored 12% (5-20%) (GTV), 18% (9-28%) (high risk CTV) and 5% (0-11%) (low risk CTV) of relapses. Six relapses were found outside the RT target volumes. No significant difference in relapse pattern between HPV positive and HPV negative patients was found (p = .95). CONCLUSION: There were no signs of difference in loco-regional relapse pattern between HPV positive and HPV negative patients. In agreement with previous findings, GTV-PET was the most frequent RT target volume of relapse.

Pretreatment Neutrophil-to-Lymphocyte Ratio as a Prognostic Marker for the Outcome of HPV-Positive and HPV-Negative Oropharyngeal Squamous Cell Carcinoma.

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased in the past decades due to carcinogenic HPV infection. As this patient group suffers from considerable mortality and treatment morbidity it is important to improve prognostic strategies in OPSCC. Inflammation plays a key role in cancer and the neutrophil-to-lymphocyte ratio (NLR) in blood has been suggested as a prognostic factor for OPSCC. This study aimed to investigate the prognostic impact of NLR on overall survival (OS) and recurrence-free survival (RFS) in a retrospective cohort of 1370 patients. Included patients had pretreatment neutrophil and lymphocyte counts available, as well as a known HPV status. Patients were treated with curative intent according to Danish national guidelines. We stratified patients in groups by NLR < 2, NLR 2−4, or NLR > 4 and analyzed the influence of the NLR tertile on OS and RFS. Kaplan−Meier curves illustrated survival probability in OS and RFS in the general cohort and were stratified by HPV status. We found that an increasing NLR was associated with inferior OS (HR = 1.5 for NLR > 4) and RFS (HR = 1.6 for NLR 2−4; HR = 1.8 for NLR > 4) in multivariable analysis. The Kaplan−Meier curves displayed inferior OS and RFS with an increasing NLR for both HPV+ and HPV− patients. In conclusion, we showed that an increasing NLR is prognostic for a worse outcome of OPSCC independently of HPV status. There are possible uses of NLR in prognostication and treatment de-escalation although further studies are warranted to determine the clinical utility.

Efficacy of nivolumab as second line treatment for recurrent or metastatic head and neck squamous cell carcinoma: a national DAHANCA cohort study.

INTRODUCTION: The aim of this study was to investigate phase IV efficacy, of the PD-1 inhibitor nivolumab among an unselected and unbiased national cohort of recurrent/metastatic Head and Neck Squamous Cell Carcinoma (rmHNSCC) patients. MATERIAL AND METHODS: Inclusion criteria included histologically confirmed rmHNSCC and nivolumab as a second-line palliative treatment. Data were collected from patient files at the five Danish head and neck cancer centers and from the DAHANCA database. The iRECIST criteria were used for treatment evaluation.Endpoints were response rate (RR), overall survival (OS), and progression-free survival (PFS), calculated from the start of treatment to the date of event/censoring by the KM-method. Descriptive statistics were used to describe patients and treatment. Analyses were two-sided, with p < .05 considered significant. RESULTS: A total of 146 patients were identified in the period 2017-2020. They had a RR of 14%, median OS of 10.2 months [95% CI: 8.2-12.2] and median PFS of 3.1 months [95% CI: 2.3-4.2]. Patient age (≥ 70 years) or comorbidity did not significantly affect outcome. WHO performance status (PS) =1 was associated with an increased risk of death (HR: 2.1 [95% CI: 1.2-4.0], p = .02) and progression (HR: 1.9 [95% CI: 1.2-3.2], p = .01). Concomitant glucocorticoid-treatment during immunotherapy (≥ 50% of treatment time) appeared important for risk of death (HR: 6.4 [95% CI: 2.3-17.8], p < .001) and risk of progression (HR: 4.8 [95% CI: 1.8-12.5], p = .001). PD-L1 expression ≥ 20% was associated with a lowered risk of progression (HR: 0.5 [95% CI: 0.3-0.7], p = .001), but not lowered risk of death. CONCLUSION: In this unselected national cohort, outcome of second-line treatment reflects data from the registration studies. Furthermore, the results suggest that immunotherapy should be used with great care in treatment of rmHNSCC in patients with poor performance.

Early non-cancer mortality risk prediction after curative-intent radiotherapy or chemoradiotherapy for head and neck squamous cell carcinoma.

BACKGROUND: In patients with head and neck squamous cell carcinoma (HNSCC), curative-intent radiotherapy (RT) and chemoradiotherapy (CRT) are associated with substantial acute morbidity and 5-10% of patients die within 180 days of treatment initiation. Most of these early deaths occur without HNSCC recurrence or progression and may therefore be preventable to some extent. We developed a prediction tool to estimate the risk of non-HNSCC mortality occurring within the first 180 days followingRT/CRT initiation. METHODS: Patients with HNSCC treated with RT/CRT, including postoperative RT/CRT, at Rigshospitalet or Herlev Hospitals between 2010-2017 were identified in the Danish Head and Neck Cancer Group (DAHANCA) database. Predictor variables included age, stage, performance status, tumor subsite including p16 status, comorbidity, postoperative status, smoking and pre-treatment albumin levels. The 180-day non-HNSCCmortality risk was estimated by combining cause-specific Cox regression models. RESULTS: We included 2209 patients. The 180-day non-HNSCCmortality rate was 4.4% and almostone third (31.6%) of non-HNSCCdeathswere caused by pneumonia.After internal model validation, the area under the receiver operating curve was 0.74 (95% CI: 0.66-0.81) and calibration was good for risk predictions ranging from 0% to 20%. CONCLUSION: We developed a prediction tool to estimate the 180-day non-HNSCC mortality risk. This tool can be used to select high-risk patients for supportive interventions aiming to improve survival rates, and is availablefor interactive use at https://emriskpred.shinyapps.io/EMNED_App/.

FDG-PET/CT identified distant metastases and synchronous cancer in squamous cell carcinoma of the head and neck: the impact of smoking and P16-s.

PURPOSE: Whole-body FDG-PET-CT is widely used at diagnosis of squamous cell carcinoma of the head and neck (SCCHN) but may identify suspicious lesions outside the neck that require investigation. This study evaluated the impact of smoking and P16-status on the incidence of malignant disease outside the head and neck region in newly diagnosed patients with SCCHN. METHODS: All PET-positive foci outside the head-neck area were registered in 1069 patients planned for postoperative or curative intent radiotherapy with whole-body FDG-PET/CT from 2006 to 2012. All patient files were retrospectively investigated and clinical parameters, tobacco use, HPV (P16)-status and subsequent malignant disease registered. RESULTS: Malignancy outside the neck was diagnosed in 9% of smokers, 2% of never-smokers, and 5% of patients with P16-positive oropharyngeal squamous cell carcinoma (OPSCC). Clinically suspicious PET-positive foci outside the head-neck were malignant in 55% of smokers, 34% of never-smokers, and in 38% of P16-pos OPSCC. All but two patients with cancer occurring outside the head and neck region were smokers. CONCLUSION: Malignancy outside the neck at diagnosis was more frequent in smokers compared to non-smokers or P16-pos OPSCC. A high proportion of clinically suspicious PET-positive foci were non-malignant.

3D image-guided treatment planning for Ruthenium-106 brachytherapy of choroidal melanomas.

BACKGROUND: Current standard treatment procedures for Ruthenium-106 (Ru-106) brachytherapy for choroidal melanomas do not use 3D image-guided treatment planning. We evaluated the potential impact of introducing 3D treatment planning and quantified the theoretical clinical benefits in terms of tumour control probability (TCP) and normal tissue complication probability (NTCP). MATERIALS AND METHODS: Treatment plans for thirty-two patients were optimized using 3D image-guided treatment planning and compared to the original 2D clinical plans. Optimization of plans was done in an image-based treatment planning system by optimizing the plaque position and treatment time such that the entire tumour received the prescribed dose of 100 Gy. TCP and NTCP for 2D clinical plans and optimized 3D image-guided plans were estimated from published outcome prediction models and compared within patients using Wilcoxon signed-rank test. RESULTS: The median minimum tumour dose (D99% ) for 2D clinical plans was 93 Gy (range: 23-158 Gy), corresponding to 5-year TCP of 75% (IQR 61-86%), while median tumour D99% for optimized 3D image-guided plans was 115 Gy (range 103-141 Gy), corresponding to TCP of 82% (IQR 80-84%). This was a statistically significant increase in estimated TCP (median increase in TCP 8% (IQR: -5-23, p = 0.006). While the dose to normal tissue increased somewhat, there was no significant change in NTCP. CONCLUSION: 3D treatment planning theoretically allows for improved tumour dose delivery for Ru-106 brachytherapy of choroidal melanomas, resulting in a significant increase in expected tumour control compared to traditional approaches using 2D calculations. The deliverability of optimized plans, and potential increased risk of late complications, will have to be confirmed in future clinical studies.

Feasibility of Multiparametric Positron Emission Tomography/Magnetic Resonance Imaging as a One-Stop Shop for Radiation Therapy Planning for Patients with Head and Neck Cancer.

PURPOSE: Multiparametric positron emission tomography (PET)/magnetic resonance imaging (MRI) as a one-stop shop for radiation therapy (RT) planning has great potential but is technically challenging. We studied the feasibility of performing multiparametric PET/MRI of patients with head and neck cancer (HNC) in RT treatment position. As a step toward planning RT based solely on PET/MRI, a deep learning approach was employed to generate synthetic computed tomography (sCT) from MRI. This was subsequently evaluated for dose calculation and PET attenuation correction (AC). METHODS AND MATERIALS: Eleven patients, including 3 pilot patients referred for RT of HNC, underwent PET/MRI in treatment position after a routine fluorodeoxyglucose-PET/CT planning scan. The PET/MRI scan protocol included multiparametric imaging. A convolutional neural network was trained in a leave-one-out process to predict sCT from the Dixon MRI. The clinical CT-based dose plans were recalculated on sCT, and the plans were compared in terms of relative differences in mean, maximum, near-maximum, and near-minimum absorbed doses for different volumes of interest. Comparisons between PET with sCT-based AC and PET with CT-based AC were assessed based on the relative differences in mean and maximum standardized uptake values (SUVmean and SUVmax) from the PET-positive volumes. RESULTS: All 11 patients underwent PET/MRI in RT treatment position. Apart from the 3 pilots, full multiparametric imaging was completed in 45 minutes for 7 out of 8 patients. One patient terminated the examination after 30 minutes. With the exception of 1 patient with an inserted tracheostomy tube, all dosimetric parameters of the sCT-based dose plans were within ±1% of the CT-based dose plans. For PET, the mean difference was 0.4 ± 1.2% for SUVmean and -0.5 ± 1.0% for SUVmax. CONCLUSIONS: Performing multiparametric PET/MRI of patients with HNC in RT treatment position was clinically feasible. The sCT generation resulted in AC of PET and dose calculations sufficiently accurate for clinical use. These results are an important step toward using multiparametric PET/MRI as a one-stop shop for personalized RT planning.

Tumour control probability after Ruthenium-106 brachytherapy for choroidal melanomas.

Purpose: Ruthenium-106 (Ru-106) brachytherapy is a common eye-preserving treatment for choroidal melanomas. However, a dose-response model describing the relationship between the actual delivered tumour dose and tumour control has, to the best of our knowledge, not previously been quantified for Ru-106 brachytherapy; we aimed to rectify this.Material and methods: We considered consecutive patients with primary choroidal melanomas, treated with Ru-106 brachytherapy (2005-2014). Dosimetric plans were retrospectively recreated using 3D image-guided planning software. Pre-treatment fundus photographies were used to contour the tumour; post-treatment photographies to determine the accurate plaque position. Patient and tumour characteristics, treatment details, dose volume histograms, and clinical outcomes were extracted. Median follow-up was 5.0 years. The relationship between tumour dose and risk of local recurrence was examined using multivariate Cox regression modelling, with minimum physical tumour dose (D99%) as primary dose metric.Results: We included 227 patients with median tumour height and largest base dimension of 4 mm (range 1-12, IQR 3-6) and 11 mm (range 4-23, IQR 9-13). The estimated 3 year local control was 82% (95% CI 77-88). Median D99% was 105 Gy (range 6-783, IQR 65-138); this was the most significant factor associated with recurrence (p < .0001), although tumour height, combined TTT and Ru-106 brachytherapy, and sex were also significant. The hazard ratio (HR) for a 10 Gy increase in D99% was 0.87 (95% CI 0.82-0.93). Using biological effective dose in the model resulted in no substantial difference in dose dependence estimates. Robustness cheques with D1-99% showed D99% to be the most significant dose metric for local recurrence.Conclusion: The minimum tumour dose correlated strongly with risk of tumour recurrence, with 100 Gy needed to ensure at least 84% local control at 3 years.

Predicting Visual Acuity Deterioration and Radiation-Induced Toxicities after Brachytherapy for Choroidal Melanomas.

Ruthenium-106 (Ru-106) brachytherapy is an established modality for eye-preserving treatment of choroidal melanoma. To achieve optimal treatment outcomes, there should be a balance between tumour control and the risk of healthy tissue toxicity. In this retrospective study, we examined normal tissue complication probability (NTCP) for visual acuity deterioration and late complications to aid the understanding of dose-dependence after Ru-106 treatments. We considered consecutive patients diagnosed with choroidal melanoma and primarily treated at a single institution from 2005-2014. Treatment plans were retrospectively recreated using dedicated software and image guidance to contour the tumour and determine the actual plaque position. Dose distributions were extracted from each plan for all relevant anatomical structures. We considered visual acuity deterioration and late complications (maculopathy, optic neuropathy, ocular hypertension, vascular obliteration, cataract and retinal detachment). Lasso statistics were used to select the most important variables for each analysis. Outcomes were related to dose and clinical characteristics using multivariate Cox regressions analysis. In total, 227 patients were considered and 226 of those were eligible for analysis. Median potential follow-up time was 5.0 years (95% CI: 4.5-6.0). Visual acuity deterioration was related to optic disc-tumour distance and dose metrics from the retina and the macula, with retina V10Gy showing the strongest correlation. Macula V10Gy was the only dose metric impacting risk of maculopathy, while optic disc-tumour distance also proved important. Optic disc V50Gy had the largest impact on optic neuropathy along with optic disc-tumour distance. Optic disc V20Gy was the only variable associated with vascular obliteration. Lens D2% had the largest impact on the risk of cataract along with older age and the largest base dimension. We found no variables associated with the risk of ocular hypertension and retinal detachment. Visual acuity deterioration and most late complications demonstrated dependence on dose delivered to healthy structures in the eye after Ru-106 brachytherapy for choroidal melanomas.

An Extended Hypofractionated Palliative Radiotherapy Regimen for Head and Neck Carcinomas.

BACKGROUND: Palliative radiotherapy to patients with head and neck cancer is often necessary, but there is a substantial variation in the treatment regimens reported in the literature, and consensus on the most appropriate schedules does not exist. In order to minimize acute toxicity while at the same time trying to achieve prolonged tumor control, a long hypofractionated regimen has been used routinely in Denmark. In the current retrospective study, we investigated the outcome in patients intended for palliative radiotherapy with this regimen. MATERIALS AND METHODS: Patients with newly diagnosed head and neck cancer treated with palliative radiotherapy of 52-56 Gy in 13-14 fractions twice weekly from 2009 to 2014 were included. Patients were excluded if they had previously received radiotherapy. Data on disease location, stage, patient performance status (PS), treatment response, acute skin and mucosal toxicity, and late fibrosis were collected prospectively and supplemented with information from medical records. RESULTS: 77 patients were included in the study. Fifty-eight patients (75%) completed the intended treatment. Loco-regional tumor response (complete or partial) was evaluated 2 months posttreatment and observed in 45% of the entire population corresponding to 71% of patients alive. PS had a significant influence on survival (p = 0.007) and on not completing the intended treatment. Grade III or IV acute mucositis were observed in 25%, and grade III or IV acute dermatitis observed in 15%. CONCLUSION: Palliative hypofractionated radiotherapy with 52-56 Gy in 13-14 fractions shows good tumor response and tolerability in a vulnerable patient population. However, it may not be suited for patients in poor PS.

Electrochemotherapy of mucosal head and neck tumors: a systematic review.

BACKGROUND: Electrochemotherapy, the combination of electroporation and chemotherapy, is mainly used in the palliative setting for treatment of cutaneous and subcutaneous metastases; however, new applications are continuously being explored. Patients with head and neck cancer are primarily treated with surgery and/or radio-chemotherapy. In the setting of local recurrence with no further curative treatment options available, electrochemotherapy could be of value. We therefore performed a systematic search of the present literature. MATERIALS AND METHODS: Eligible studies presented data from patients with head and neck cancer treated across the mucosal surface with electrochemotherapy. The search resulted in 11 studies with a total of 72 patients. RESULTS: Overall complete response was reported as good, especially in primary small tumors. Side effects were minor in primary tumors whereas large, recurrent tumors displayed more frequent side effects and some serious adverse events. Design and structure of the studies differed considerably, making general comparisons difficult. CONCLUSION: Few studies concerning electrochemotherapy on mucosal head and neck tumors are available and they are not easily comparable. Overall response to treatment is good; nonetheless, further systematic studies are warranted.

Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study.

BACKGROUND: Human papillomavirus-related (HPV+) oropharyngeal cancer is a rapidly emerging disease with generally good prognosis. Many prognostic algorithms for oropharyngeal cancer incorporate HPV status as a stratification factor, rather than recognising the uniqueness of HPV+ disease. The International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S) aimed to develop a TNM classification specific to HPV+ oropharyngeal cancer. METHODS: The ICON-S study included patients with non-metastatic oropharyngeal cancer from seven cancer centres located across Europe and North America; one centre comprised the training cohort and six formed the validation cohorts. We ascertained patients' HPV status with p16 staining or in-situ hybridisation. We compared overall survival at 5 years between training and validation cohorts according to 7th edition TNM classifications and HPV status. We used recursive partitioning analysis (RPA) and adjusted hazard ratio (AHR) modelling methods to derive new staging classifications for HPV+ oropharyngeal cancer. Recent hypotheses concerning the effect of lower neck lymph nodes and number of lymph nodes were also investigated in an exploratory training cohort to assess relevance within the ICON-S classification. FINDINGS: Of 1907 patients with HPV+ oropharyngeal cancer, 661 (35%) were recruited at the training centre and 1246 (65%) were enrolled at the validation centres. 5-year overall survival was similar for 7th edition TNM stage I, II, III, and IVA (respectively; 88% [95% CI 74-100]; 82% [71-95]; 84% [79-89]; and 81% [79-83]; global p=0·25) but was lower for stage IVB (60% [53-68]; p<0·0001). 5-year overall survival did not differ among N0 (80% [95% CI 73-87]), N1-N2a (87% [83-90]), and N2b (83% [80-86]) subsets, but was significantly lower for those with N3 disease (59% [51-69]; p<0·0001). Stage classifications derived by RPA and AHR models were ranked according to survival performance, and AHR-New was ranked first, followed by AHR-Orig, RPA, and 7th edition TNM. AHR-New was selected as the proposed ICON-S stage classification. Because 5-year overall survival was similar for patients classed as T4a and T4b, T4 is no longer subdivided in the re-termed ICON-S T categories. Since 5-year overall survival was similar among N1, N2a, and N2b, we re-termed the 7th edition N categories as follows: ICON-S N0, no lymph nodes; ICON-S N1, ipsilateral lymph nodes; ICON-S N2, bilateral or contralateral lymph nodes; and ICON-S N3, lymph nodes larger than 6 cm. This resembles the N classification of nasopharyngeal carcinoma but without a lower neck lymph node variable. The proposed ICON-S classification is stage I (T1-T2N0-N1), stage II (T1-T2N2 or T3N0-N2), and stage III (T4 or N3). Metastatic disease (M1) is classified as ICON-S stage IV. In an exploratory training cohort (n=702), lower lymph node neck involvement had a significant effect on survival in ICON-S stage III but had no effect in ICON-S stage I and II and was not significant as an independent factor. Overall survival was similar for patients with fewer than five lymph nodes and those with five or more lymph nodes, within all ICON-S stages. INTERPRETATION: Our proposed ICON-S staging system for HPV+ oropharyngeal cancer is suitable for the 8th edition of the Union for International Cancer Control/American Joint Committee on Cancer TNM classification. Future work is needed to ascertain whether T and N categories should be further refined and whether non-anatomical factors might augment the full classification. FUNDING: None.

Elective Nodal Irradiation and Patterns of Failure in Head and Neck Cancer After Primary Radiation Therapy.

PURPOSE: The delineation of elective clinical target volumes in head and neck cancer (HNC) is important; however, the extent of lymph node levels necessary to include is debated. A comprehensive analysis of recurrence patterns in a large cohort of patients with HNC was performed, with an emphasis on recurrence in the retropharyngeal region and level IB. METHODS AND MATERIALS: From 2005 to 2012, 942 patients with oropharyngeal, hypopharyngeal, laryngeal or oral cavity carcinomas were curatively treated with primary radiation therapy. The median follow-up period was 34 months, and 77% of the patients underwent intensity modulated radiation therapy. The retropharyngeal region was only routinely included in cases of involvement of the posterior pharynx wall and level IB only in cases of involvement of the oral cavity. In patients with regional recurrence, the anatomic site of the recurrence was assessed from the surgical descriptions or computed tomography scans and compared with the original radiation treatment plan (available from 2007 onward). The p16 status was available for 282 oropharynx carcinoma cases, with 65% p16-positive. RESULTS: Of the 942 patients, 376 (40%) developed recurrences: 228 (24.2%) local, 123 (13.1%) regional, and 109 (11.6%) distant. In 700 patients with available treatment plans, retropharyngeal and level IB recurrence was observed in 2 and 7 patients, respectively. Eight patients (1.1%) had recurrence in a lymph node level not included in their primary treatment plan. For oropharynx carcinoma, the locoregional control rate (90% vs 70%) but not distant control rate (92% vs 87%), was significantly better in the p16-positive than in the p16-negative patients. Although fewer recurrences developed in the p16-positive group, patients with recurrence of p16-positive tumors were more likely to develop recurrence in distant sites. CONCLUSIONS: Retropharyngeal or level IB recurrence after primary HNC radiation therapy is rare. Thus, inclusion of these regions in the elective treatment volumes should be limited to patients with involvement of the posterior pharyngeal wall or oral cavity.

Electroporation-based DNA delivery technology: methods for gene electrotransfer to skin.

DNA delivery to for example skin and muscle can easily be performed with electroporation. The method is efficient, feasible, and inexpensive and the future possibilities are numerous. Here we present our protocol for gene transfection to mouse skin using naked plasmid DNA and electric pulses.

What you always needed to know about electroporation based DNA vaccines.

Vaccinations are increasingly used to fight infectious disease, and DNA vaccines offer considerable advantages, including broader possibilities for vaccination and lack of need for cold storage. It has been amply demonstrated, that electroporation augments uptake of DNA in both skin and muscle, and it is foreseen that future DNA vaccination may to a large extent be coupled with and dependent upon electroporation based delivery. Understanding the basic science of electroporation and exploiting knowledge obtained on optimization of DNA electrotransfer to muscle and skin, may greatly augment efforts on vaccine development. The purpose of this review is to give a succinct but comprehensive overview of electroporation as a delivery modality including electrotransfer to skin and muscle. As well, this review will speculate and discuss future uses for this powerful electrotransfer technology.

Efficacy of transgene expression in porcine skin as a function of electrode choice.

Gene electrotransfer is a non-viral technique using electroporation for gene transfection. The method is widely used in the preclinical setting and results from the first clinical study in tumours have been published. However, the preclinical studies, which form the basis for the clinical trials, have mainly been performed in rodents and the body of evidence on electrode choice and optimal pulsing conditions is limited. We therefore tested plate and needle electrodes in vivo in porcine skin, which resembles human skin in structure. The luciferase (pCMV-Luc) gene was injected intradermally and subsequently electroporated. Simultaneously, studies with gene electrotransfer to porcine skin using plasmids coding for green fluorescent protein (GFP) and betagalactosidase were performed. Interestingly, we found needle electrodes to be more efficient than plate electrodes (p<0.001) and electric field calculations showed that penetration of the stratum corneum led to much more homogenous field distribution at the DNA injection site. Furthermore, we have optimised the electric pulse regimens for both plate and needle electrodes using a range of high voltage and low voltage pulse combinations. In conclusion, our data support that needle electrodes should be used in human clinical studies of gene electrotransfer to skin for improved expression.