Choice of surgery in intestinal-type adenocarcinoma of the sinonasal tract: a long-term comparative study.

PURPOSE: Intestinal-type adenocarcinoma (ITAC) is a rare sinonasal malignancy. Curative treatment requires multidisciplinary approach, with surgical options consist of the endonasal endoscopic approach (EEA) and external surgery (EXTS). Here, we provide the post-operative and survival results from a single-center long-term follow-up. METHODS: We report long-term follow-up of 92 ITAC cases treated between 1998 and 2018, treated with EEA (n = 40) or EXTS (n = 52). Survival estimates, post-operative complications and duration of hospitalization were compared between surgical modalities. RESULTS: Baseline characteristics were similar. A higher number of T4b tumors (16%), and subsequently more tumoral invasion (39%), was present in patients undergoing EXTS compared to EEA (3% and 18%, respectively). No difference in Barnes histology subtypes was noticed. Patients undergoing EEA had a shorter post-operative hospitalization stay versus EXTS (4 versus 7 days). Use of EEA was associated to improved disease-specific survival (DSS; 11.4 versus 4.4 years; HREEA = 0.53), especially for patients with T3-4a tumors (11.4 versus 3.0 years; HREEA = 0.41). Patients with T3-4 stage, tumoral invasion, positive surgical margins, mucinous or mixed histology, and prolonged post-operative hospital stay showed poor local relapse-free, disease-free, overall, and DSS. CONCLUSIONS: Long-term follow-up in locally advanced ITAC demonstrates that resection by EEA is correlated with improved DSS compared to EXTS, especially for T3-4 tumors. No significant differences between both treatment modalities was observed regarding per- and post-operative complications, although hospitalization in patients undergoing EEA was shorter than for patients treated with EXTS. These results confirm that EEA should remain the preferred surgical procedure in operable cases of sinonasal ITAC.

Direct co-registration of [18F]FDG uptake and histopathology in surgically excised malignancies of the head and neck: a feasibility study.

PURPOSE: Recent technical advancements in PET imaging have improved sensitivity and spatial resolution. Consequently, clinical nuclear medicine will be confronted with PET images on a previously unfamiliar resolution. To better understand [18F]FDG distribution at submillimetric scale, a direct correlation of radionuclide-imaging and histopathology is required. METHODS: A total of five patients diagnosed with a malignancy of the head and neck were injected with a clinical activity of [18F]FDG before undergoing surgical resection. The resected specimen was imaged using a preclinical high-resolution PET/CT, followed by slicing of the specimen. Multiple slices were rescanned using a micro-PET/CT device, and one of the slices was snap-frozen for frozen sections. Frozen sections were placed on an autoradiographic film, followed by haematoxylin and eosin staining to prepare them for histopathological assessment. The results from both autoradiography and histopathology were co-registered using an iterative co-registration algorithm, and regions of interest were identified to study radiotracer uptake. RESULTS: The co-registration between the autoradiographs and their corresponding histopathology was successful in all specimens. The use of this novel methodology allowed direct comparison of autoradiography and histopathology and enabled the visualisation of uncharted heterogeneity in [18F]FDG uptake in both benign and malignant tissue. CONCLUSION: We here describe a novel methodology enabling the direct co-registration of [18F]FDG autoradiography with the gold standard of histopathology in human malignant tissue. The future use of the current methodology could further increase our understanding of the distribution of radionuclides in surgically excised malignancies and hence, improve the integration of pathology and molecular imaging in a multiscale perspective. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05068687.

Importance of choice of materials and methods in PD-L1 and TIL assessment in oropharyngeal squamous cell carcinoma.

AIMS: A great deal of research is being conducted into PD-L1 immunohistochemistry (IHC) and tumour-infiltrating lymphocytes (TILs) as predictive or prognostic biomarkers for immunotherapy, although several practical issues exist concerning their assessment. The aim of this research was therefore to assess the importance of choice of materials and methods in PD-L1 and TILs scoring in oropharyngeal squamous cell carcinoma (OSCC). METHODS AND RESULTS: IHC for PD-L1 (SP142 and 22C3 clone) and TILs subtyping was performed on formalin-fixed paraffin-embedded tissue slides (biopsy, resection and/or lymph nodes specimens) of 99 patients with OSCC. A comparative analysis of PD-L1 and TILs scoring was made between different types of tissue specimens, between different PD-L1 clones, between TILs and different subsets of TILs and between the quantitative and semiquantitative assessments. PD-L1 scoring resulted in fair to moderate agreement for 22C3 and SP142 between various tissue specimens, with higher agreement at higher cut-off values, and in moderate agreement for 22C3 versus SP142. Evaluation by four independent observers proved substantial inter-rater agreement for both clones with high consistency in their ratings. Moderate agreement was observed for TILs and TILs subsets for the comparison between biopsy and resection. Lastly, strong correlations were found between quantitative and semiquantitative assessment for all PD-L1 and TILs scores. CONCLUSIONS: Our results highlight the challenges associated with the evaluation of PD-L1 and TILs in OSCC. Further research is warranted to evaluate the use of these biomarkers in order to allow implementation of PD-L1 and TILs infiltrate as biomarkers in daily clinical practice.

Late mucosal ulcers in dose-escalated adaptive dose-painting treatments for head-and-neck cancer.

BACKGROUND: To identify predictive factors for the development of late grade 4 mucosal ulcers in adaptive dose-escalated treatments for head-and-neck cancer. MATERIAL AND METHODS: Patient data of four dose-escalated three-phase adaptive dose-painting by numbers (DPBN) clinical trials were analyzed in this study. Correlations between the development of late grade 4 ulcers and factors related with the treatment, disease characteristics and the patient were investigated. Dosimetrical thresholds were searched among the highest doses received by 1.75 cm3 (D1.75cc) of the primary gross tumor volume (GTVT) and the corresponding normalized isoeffective dose (NID21.75cc, with a reference dose of 2Gy/fraction and α/ß of 3 Gy). RESULTS: From 39 studied patients, nine developed late grade 4 mucosal ulcers. The continuation to either smoke or drink alcohol after therapy was the factor that showed a strong (eight out of nine patients) association with the occurrence of grade 4 ulcers. Six of the patients who continued to smoke or/and drink had D1.75cc and NID21.75cc above 84 Gy and 95.5 Gy, respectively. Seven of the patients with grade 4 had the dose levels above these thresholds, but even if the D1.75cc threshold was significant in the prediction of late grade 4 ulcers, it could not be considered as the only contributing factor. CONCLUSIONS: The search for patterns provided strong reasons to apply a dosimetrical threshold for the peak-dose volume of 1.75 cm3 as a preventive measure for late grade 4 mucosal ulcers. Also, patients that continue to smoke or drink alcohol after therapy have increased risk to develop late mucosal ulcers.

CD70 Expression and Its Correlation with Clinicopathological Variables in Squamous Cell Carcinoma of the Head and Neck.

OBJECTIVE: Over the last decade, efforts have been made to get a better understanding of the tumor microenvironment and the role of the immune system in it. New insights into the CD27/CD70 signaling pathway point towards a role in tumor immunology, making CD70 an attractive target for immunotherapy. Here, we evaluate CD70 expression in squamous cell carcinoma of the head and neck (SCCHN). METHODS: CD70 immunohistochemistry was retrospectively performed on 95 tumor samples. Tumoral CD70 expression was scored and correlated with clinicopathological variables and overall survival (OS). RESULTS: CD70 expression in tumor cells was observed in 66 samples (69%) and was strongly associated with tumor differentiation grade (p < 0.001). CD70 expression was also observed in tumor-associated fibroblasts and endothelial cells. Additionally, the density of tumor-infiltrating lymphocytes correlated with OS (p = 0.042). CONCLUSION: This study describes the tumoral expression of CD70 in SCCHN. Results highlight the role of CD70 in tumor biology and identify CD70 as a novel therapeutic target. Further research is warranted.

Secondary Voice Restoration After Laryngotracheal Separation (LTS) for Dysphagia with Intractable Aspiration.

Intractable aspiration is a serious, often life-threatening condition due to its potential impact on pulmonary function. Aspiration requires therapeutic measures, starting with conservative management but often necessitating surgical treatment. The basic surgical principle is to separate the alimentary and respiratory tracts through a variety of procedures which, unfortunately, nearly all result in the loss of phonation, with the exception of total laryngectomy (TL) which includes the placement of an indwelling voice prosthesis. In this study, we present a modified laryngotracheal separation (LTS) technique that, we believe, offers multiple advantages compared to standard TL. After reviewing the medical records of 35 patients with intractable aspiration who have undergone LTS, we describe the surgical technique and present the postoperative result. In a second surgical procedure about two months following LTS, we aimed to achieve voice restoration by placement of an indwelling voice prosthesis. Intractable aspiration was successfully treated in all patients. Placement of an indwelling voice prosthesis during a second operation was successful in 15 patients, representing the largest reported cohort thus far. LTS is a reliable surgical technique to treat intractable aspiration, with restoration of oral intake, thereby improving the general condition and quality of life of these unfortunate patients. Furthermore, voice restoration can be achieved in selected patients, by placement of a voice prosthesis.

Concordance, Correlation, and Clinical Impact of Standardized PD-L1 and TIL Scoring in SCCHN.

BACKGROUND: The clinical significance of tumor-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression has been thoroughly researched in squamous cell carcinoma of the head and neck (SCCHN). To address the impact of intra- and intertumoral heterogeneity in these biomarkers, we explored the concordance of PD-L1 combined positive score (CPS) and stromal TILs in different paired tissue sample types, while evaluating their internal relationship and prognostic impact. METHODS: A total of 165 tissue blocks from 80 SCCHN patients were reviewed for TILs and PD-L1 CPS. Concordance between paired tissue samples was evaluated, and their association with several clinicopathological variables, overall survival (OS), and disease-free survival (DFS) was determined. RESULTS: Biopsies and paired resection material were severely discordant in 39% and 34% of samples for CPS and TIL count, respectively, of which CPS was underscored in 27% of biopsies. In paired primary tumor-metastatic lesions, the disagreement was lower for CPS (19%) but not for TIL count (44%). PD-L1 CPS was correlated with prolonged OS when calculated from tissue acquirement, while extended OS and DFS were observed for high TIL density. CONCLUSION: Intertumoral and, especially, intratumoral heterogeneity were confounding factors when determining PD-L1 CPS and TIL count on paired tissue samples, indicating the increasing necessity of assessing both biomarkers on representative tissue material. Although TILs hold valuable prognostic information in SCCHN, the robustness of PD-L1 as a biomarker in SCCHN remains ambiguous.

Modern treatment for nasopharyngeal carcinoma: current status and prospects.

PURPOSE OF REVIEW: In this article, we focus on the role of Epstein-Barr virus in the management of nasopharyngeal cancer, intensity-modulated radiotherapy, adjuvant and neoadjuvant chemotherapy, and targeted therapy. RECENT FINDINGS: Epstein-Barr virus DNA clearance has recently been studied for prediction of tumor response and survival. Patients with a short t1/2 of plasma Epstein-Barr virus DNA clearance had significantly higher responses and survival than those with long t1/2. Intensity-modulated radiotherapy, delivering higher doses to the tumor, results in improved local control and overall survival at lower treatment-induced toxicity. Recent reports show that re-planning during the course of radiotherapy could influence outcome and toxicity. The use of newer platinum compounds and combinations with taxanes in adjuvant and neoadjuvant setting have been investigated in phase II trials. They demonstrate acceptable toxicity profiles and promising treatment outcomes. However, antiepidermal growth factor receptor and antivascular endothelial growth factor receptor agents do not show important responses in metastatic disease and when combined with radiotherapy, toxicity is of concern. SUMMARY: Epstein-Barr virus DNA has a potential as a risk stratification marker. Intensity-modulated radiotherapy is standard treatment and adaptive radiotherapy with re-planning has to be considered. Uncertainties on adjuvant/neoadjuvant chemotherapy should be addressed in well designed randomized trials. Currently, the role of targeted agents is not well defined.

Verrucous hyperplasia and verrucous carcinoma in head and neck: use and benefit of methotrexate.

Background and aim: Verrucous hyperplasia (VH) and verrucous carcinoma (VC) of the head and neck are two (pre)malignant entities that are slowly progressive with low tendency to metastasize. However, they can reduce the patient's Quality of Life (QoL) and may even transform into squamous cell carcinoma (SCC). As they are typically approached by surgical resection, some patients do not qualify for surgery. Methotrexate may be a systemic alternative but the response is mostly not durable. This case report tries to illustrate the potential role of methotrexate in VH/VC of the head and neck.Method: We describe four cases of patients with VH or VC of the head and neck who received methotrexate (40-60 mg/m2) in a weekly or two-weekly interval.Results: Two patients received methotrexate in a neoadjuvant setting. The first patient achieved a macroscopical complete response after 16 cycles and remained in remission after surgery. The second patient suffered from residual disease after 26 cycles and refused radical surgery.Two other patients refused surgery at the time of diagnosis and were proposed methotrexate as a salvage treatment. The first patient had an ongoing response on methotrexate after >60 cycles. The second patient achieved macroscopical complete remission after 28 cycles of methotrexate but suffered relapse by developing an oropharyngeal SCC in the same region.Conclusion: When surgery is not desirable in VH and/or VC, patients can be treated with methotrexate which has a reasonable effect and seems to be well tolerated. Nevertheless, surgery should be the preferred strategy to achieve complete remission.

Tumour infiltrating lymphocytes in oropharyngeal carcinoma: prognostic value and evaluation of a standardised method.

Tumour infiltrating lymphocytes (TILs) have been described as a biomarker for the host immune response against the tumour with prognostic properties. The International Immuno-Oncology Biomarkers Working Group (IBWG) proposed a standardised method for quantifying TILs in solid tumours to improve consistent and reproducible scoring. In this study, the methodology was tested in a retrospective population of oropharyngeal squamous cell carcinoma (OPSCC). TIL quantification was performed on 92 OPSCC samples (2004-2013) by four independent observers as described by the IBWG. Interobserver variability was assessed and results were correlated with clinicopathological variables and survival. TIL evaluation turned out to be challenging in OPSCC due to heterogeneity of TILs distribution, presence of pre-existing lymphoid tissue, surface ulceration or erosion and insufficient amount of intertumoural stroma in biopsies. Nonetheless, interobserver variability proved to be good to excellent. High stromal TILs (TILstr) and intratumoural TILs (TILtum) were both correlated to favourable overall survival and multivariate analysis showed TILstr to be the sole independent prognostic factor in OPSCC. The IBWG-proposed TIL quantification method is feasible and reproducible in OPSCC and provides valuable prognostic information regarding clinicopathological characteristics and overall survival. The use of this standardised methodology may facilitate implementation of TILs scoring as a prognostic biomarker in OPSCC.

An open-label, nonrandomized, phase Ib feasibility study of cusatuzumab in patients with nasopharyngeal carcinoma.

CD70 is expressed in up to 80% of nasopharyngeal carcinoma (NPC) cases. Cusatuzumab is a humanized anti-CD70 monoclonal antibody, with dual action mechanisms: induction of cytotoxicity against CD70+ tumor cells and reduction in CD70-CD27 signaling mediated immune evasion. The aim of this study was to assess the safety, pharmacokinetic profile, immunogenicity, pharmacodynamic profile, and preliminary activity of cusatuzumab in advanced NPC. Eleven patients were enrolled: one patient was assigned to arm A (adjuvant cusatuzumab monotherapy after curative chemoradiation), nine patients to arm B (cusatuzumab monotherapy; noncurative setting), and one patient to arm C (cusatuzumab + chemotherapy; noncurative setting); irrespective of tumoral CD70 expression. Both patients in arms A and C completed the study. All patients in arm B discontinued at an early stage. Five patients experienced grade greater than or equal to 3 nondrug related treatment-emergent adverse events, most commonly fatigue and pneumonia (18%). An infusion-related reaction was observed in two of 11 patients. Laboratory results showed no trend over time. Seven patients were eligible for response evaluation. No objective response to cusatuzumab was observed with stable disease being the best response. The current study indicates that the safety profile of cusatuzumab (with or without concurrent chemotherapy) is manageable in patients with advanced NPC, which is consistent with known safety profile. Limited activity of cusatuzumab in advanced NPC was observed. Combination therapies of cusatuzumab and other types of therapy should be explored for the improvement of activity in NPC and other CD70-expressing malignancies.

High-Resolution 18F-FDG PET/CT for Assessing Three-Dimensional Intraoperative Margins Status in Malignancies of the Head and Neck, a Proof-of-Concept.

The surgical treatment of head and neck malignancies relies on the complete removal of tumoral tissue, while inadequate margins necessitate the use of adjuvant therapy. However, most positive margins are identified postoperatively as deep margins, and intraoperative identification of the deep positive margins could help achieve adequate surgical margins and decrease adjuvant therapies. To improve deep-margin identification, we investigated whether the use of high-resolution preclinical PET and CT could increase certainty about the surgical margins in three dimensions. Patients with a malignancy of the head and neck planned for surgical resection were administered a clinical activity of 4MBq/kg 18F-FDG approximately one hour prior to surgical initiation. Subsequently, the resected specimen was scanned with a micro-PET-CT imaging device, followed by histopathological assessment. Eight patients were included in the study and intraoperative PET/CT-imaging of 11 tumoral specimens and lymph nodes of three patients was performed. As a result of the increased resolution, differentiation between inflamed and dysplastic tissue versus malignant tissue was complicated in malignancies with increased peritumoral inflammation. The current technique allowed the three-dimensional delineation of 18F-FDG using submillimetric PET/CT imaging. While further optimization and patient stratification is required, clinical implementation could enable deep margin assessment in head and neck resection specimens.

Epidermal growth factor receptor and K-RAS status in two cohorts of squamous cell carcinomas.

BACKGROUND: With the availability of effective anti-EGFR therapies for various solid malignancies, such as non-cell small lung cancer, colorectal cancer and squamous cell carcinoma of the head and neck, the knowledge of EGFR and K-RAS status becomes clinically important. The aim of this study was to analyse EGFR expression, EGFR gene copy number and EGFR and K-RAS mutations in two cohorts of squamous cell carcinomas, specifically anal canal and tonsil carcinomas. METHODS: Formalin fixed, paraffin-embedded tissues from anal and tonsil carcinoma were used. EGFR protein expression and EGFR gene copy number were analysed by means of immunohistochemistry and fluorescence in situ hybridisation. The somatic status of the EGFR gene was investigated by PCR using primers specific for exons 18 through 21. For the K-RAS gene, PCR was performed using exon 2 specific primers. RESULTS: EGFR immunoreactivity was present in 36/43 (83.7%) of anal canal and in 20/24 (83.3%) of tonsil squamous cell carcinomas. EGFR amplification was absent in anal canal tumours (0/23), but could be identified in 4 of 24 tonsil tumours.From 38 anal canal specimens, 26 specimens were successfully analysed for exon 18, 30 for exon 19, 34 for exon 20 and 30 for exon 21. No EGFR mutations were found in the investigated samples. Thirty samples were sequenced for K-RAS exon 2 and no mutation was identified. From 24 tonsil specimens, 22 were successfully analysed for exon 18 and all 24 specimens for exon 19, 20 and 21. No EGFR mutations were found. Twenty-two samples were sequenced for K-RAS exon 2 and one mutation c.53C > A was identified. CONCLUSION: EGFR mutations were absent from squamous cell carcinoma of the anus and tonsils, but EGFR protein expression was detected in the majority of the cases. EGFR amplification was seen in tonsil but not in anal canal carcinomas. In our investigated panel, only one mutation in the K-RAS gene of a tonsil squamous cell carcinoma was identified. This indicates that EGFR and K-RAS mutation analysis is not useful as a screening test for sensitivity to anti-EGFR therapy in anal canal and tonsil squamous cell carcinoma.

Improved survival in patients with head and neck cancer treated in higher volume centres: A population-based study in Belgium.

OBJECTIVES: The study investigated the association between hospital volume and observed survival of patients with a head and neck squamous cell carcinoma (HNSCC). METHODS: Overall, 9245 patients diagnosed with HNSCC between 2009 and 2014, were identified in the population-based Belgian Cancer Registry. This database was coupled with other databases providing information on diagnostic and therapeutic procedures, vital status, and comorbidities. The overall and relative survival probabilities were estimated using the Kaplan-Meier and the Ederer II methods, respectively. The relation between hospital volume and observed survival since diagnosis was then assessed using Cox proportional hazard models adjusted for potential confounders. RESULTS: The care for patients with HNSCC in Belgium was dispersed over more than 99 centres with half of the centres treating four or less patients with HNSCC per year. Survival probabilities were significantly better for patients treated in higher volume centres (>20 patients/year): the median survival of patients treated in these centres was 1.1 year longer (5.1 versus 4.0 years) than in lower volume centres. This association was confirmed in analyses taking the case-mix between hospitals into account: the hazard to die of any cause decreased on average with 0.4% per increase of one additionally treated patient. Beyond 20 assigned patients per year, there was no further decrease in the hazard to die. CONCLUSIONS: Statistically significant and clinically relevant improved survival probabilities were obtained in patients treated in higher volume centres (>20 patients/year) compared with their peers treated in lower volume centres. This supports the recommendation to concentrate the care for patients with HNSCC in reference centres.

Very late xerostomia, dysphagia, and neck fibrosis after head and neck radiotherapy.

BACKGROUND: Acute and late toxicity after intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC) impacts on patient quality of life; yet, very late toxicity data remain scarce. This study assessed dysphagia, xerostomia, and neck fibrosis 3-8 years after IMRT. METHODS: A retrospective analysis using generalized estimated equations was performed on 60 patients with HNC treated with fractionated IMRT between 2000 and 2015 who had a follow-up ≥8 years. Toxicity was scored using LENT-SOMA scales. RESULTS: A trend towards a nonlinear global time effect (P = .05) was noted for dysphagia with a decrease during the 5 years post-treatment and an increase thereafter. A significant decrease in xerostomia (P = .001) and an increase in neck fibrosis (P = .04) was observed until 8 years. CONCLUSIONS: Dysphagia, xerostomia, and neck fibrosis do not appear stable over time and remain highly prevalent in the very late follow-up. Our findings support the need for prospective trials investigating very late toxicity in patients with HNC.

Quality of life of patients with a colonic interposition postoesophagectomy.

OBJECTIVES: After oesophagectomy, stomach grafts are most frequently used to restore intestinal continuity. Less frequently, a colonic graft is used. There is quite a large body of literature addressing the functional outcome after gastric pull-up, but little is known about the functional results of colonic interposition (CI). The aim of this study was to assess the short-term outcomes and the long-term quality of life and function of the CI postoesophagectomy. METHODS: Between 2002 and 2016, we retrospectively collected data on 80 patients with CI from personal health records at the Ghent University hospital. We prospectively compared the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-OG25 and Swallowing Quality of Life (SWAL-QOL) questionnaire scores to the healthy reference group and the gastric tube (GT) group. RESULTS: The 30-day mortality rate was 5%. Anastomotic leakage occurred in 37.5% and stenosis in 20% of the patients. The median overall survival of all patients was 33.9 months (95% confidence interval 8.3-59.4). The mean general health score of the CI patients was less than the healthy reference group but comparable to the GT group (CI = 62.1 vs healthy reference group = 71.2 vs GT = 60). Fifty percent of the patients reported their health as good and 15% as very good. The mean functional results with a CI were better than with a GT. Compared to GT patients, CI patients had less dyspnoea, reflux and dysphagia, but they reported more food selection, diarrhoea and weight loss. CONCLUSIONS: Despite the high complication rate, the severity of the disease and the demanding operation, patients perceived themselves as being in good health and reported very good long-term functionality after CI. CLINICAL TRIAL REGISTRATION NUMBER: B670201630635.

Prognostic value of 99mTc-HYNIC annexin-V imaging in squamous cell carcinoma of the head and neck.

PURPOSE: The purpose of the study was to report on the prognostic value of (99m)Tc-hydrazinonicotinamide (HYNIC) Annexin-V single-photon emission computed tomography (SPECT) imaging in patients suffering from primary squamous cell carcinoma of the head and neck. METHODS: Twenty-nine patients diagnosed with a primary untreated head and neck squamous cell carcinoma were included in this study. In all patients, (99m)Tc-HYNIC Annexin-V scintigraphy SPECT was performed before treatment instigation. Tumour-to-background ratios (T/N) of the primary tumour, derived from reconstructed images, as well as clinical variables were obtained in all patients and related to patient outcome. Median follow-up was 22.6 months (range 4.1-55.8 months). RESULTS: On univariate as well as multivariate analysis, only the (99m)Tc-HYNIC Annexin-V T/N ratio dichotomized using the group median as cutoff value (T/N ratio of 2) was predictive of recurrence-free survival (respectively, p = 0.0000 and 0.000). On univariate analysis, only lymph node status dichotomized according to N0 vs N1-N2-N3 disease and the (99m)Tc-HYNIC Annexin-V T/N ratio dichotomized using the group median as cutoff value (T/N ratio of 2) were predictive of overall survival (p = 0.0051 and 0.0000). When both factors were included in the multivariate model, both N status and the (99m)Tc-HYNIC Annexin-V T/N ratio showed an independent association with overall survival (p = 0.001 for lymph node status and 0.000 for dichotomized (99m)Tc-HYNIC Annexin-V T/N ratio). CONCLUSION: (99m)Tc-HYNIC Annexin-V T/N ratios derived from SPECT provides independent prognostic information on disease-free survival and overall survival.

Prognostic value of CD25 expression on lymphocytes and tumor cells in squamous-cell carcinoma of the head and neck.

CD4(+) CD25(+) T-cells play a central role in initiating and maintaining anticancer immune response. On the other hand, CD25(+) is also expressed on tumor cells, the meaning of which is currently unclear. Therefore, this study was designed to determine the prognostic value of the presence of CD4(+) CD25(+) T-cells in squamous-cell carcinoma of the head and neck (SCCHN) and of CD25 on SCCHN tumor cells. Thirty-five (35) patients diagnosed with a primary untreated SCCHN were included in this study. Instantly snap-frozen resection or biopsy specimens were analyzed by immunohistochemistry. Histologic results obtained were related to overall, disease-free survival. On univariate analysis, both lymph-node status and the number of CD25(+) lymphocytes were associated with disease-free survival (p=0.039 and 0.04). On multivariate analysis, only the number of CD25(+) lymphocytes showed an association with disease-free survival (p=0.036), whereas both factors showed an independent association with overall survival (p=0.007 and 0.003). Contrarywise, the CD25 expression on SCCHN tumor cells was not associated with disease-free survival nor with overall survival. The presence of a high number of SCCHN-infiltrating CD4(+) CD25(+) lymphocytes is associated with a good prognosis in SCCHN patients. Contrarywise, the CD25 expression on SCCHN tumor cells is not associated with a prognosis in SCCHN patients, and its role and meaning remains to be elucidated.

Upfront vs. no upfront neck dissection in primary head and neck cancer radio(chemo)therapy: Tumor control and late toxicity.

PURPOSE/OBJECTIVE: The benefit of upfront neck dissection (ND) in locally advanced head and neck squamous cell carcinoma (HNSCC) treated with primary (chemo-) radiotherapy (R(C)T) is debated. Therefore, we retrospectively compared disease control and toxicity between patients who were treated with and without upfront ND followed by R(C)T. MATERIAL/METHODS: Two-hundred sixty-four consecutive patients with HNSCC without distant metastases at diagnosis and with lymph node stage N2-N3 were included in 2 centers. Patients were all treated between January 2002 and December 2012, and received definitive R(C)T in center 1 and upfront ND followed by R(C)T in center 2. Clinical data and outcome were assessed retrospectively. Toxicity was scored using the LENT-SOMA scale at 6, 12, 18 and 24months following the end of treatment. RESULTS: We included 150 patients in the group without ND (center 1) and 114 patients in the group with upfront ND (center 2). Mean follow up was 5.68years in the group without ND and 5.83years in the group with upfront ND. Local, regional and distant control after 2years were 91.07% and 85.96% (p=0.09), 89.22% and 83.27% (p=0.12) and 76.74% and 75.13% (p=0.92) in the group with and without upfront ND, respectively. We did not find a significant difference between both groups regarding edema and atrophy at 6, 12, 18 and 24months. We found a trend at all time-points toward worse outcome in the ND group at all time-points (p=0.06). A significantly higher proportion of moderate to severe fibrosis (grade ≥2) was present in the ND group (p=0.01) at all time points. CONCLUSION: There was no significant difference in local, regional or distant control and disease-free survival between both patient populations. Fibrosis, specifically fibrosis grade ≥2 is more prominent following upfront ND and R(C)T when compared to R(C)T alone.

Prognostic markers in oropharyngeal squamous cell carcinoma: focus on CD70 and tumour infiltrating lymphocytes.

We evaluated the expression of CD70 as biomarker for prognosis in patients with oropharyngeal squamous cell carcinoma (OSCC). We also examined the prognostic value of tumour infiltrating lymphocytes (TILs) in our study cohort. Formalin fixed, paraffin embedded tissue originating from the oropharynx of 78 patients was immunohistochemically stained for CD70, CD3, CD8 and FoxP3. Expression of CD70, CD3, CD8, FoxP3 and HPV status was correlated with clinicopathological characteristics. Overall survival (OS) was determined by a log-rank (Mantel-Cox) test whereas the Cox proportional hazard model was used for multivariate analysis. CD70 expression demonstrated no influence on OS. Tumours heavily infiltrated by TILs were linked with better outcome, for the total number of TILs as well as for the CD3+ and CD8+ T cell count. A Cox proportional hazard model proved that solely CD8+ infiltrating T cells exhibit a positive effect on OS (HR=0.30, 95% confidence interval 0.13-0.72). Our results demonstrate that CD8+ TILs constitute an independent prognosticator in patients diagnosed with OSCC. Further validation of the prognostic value of CD8+ TILs in OSCC is warranted and could provide us with a better insight into the immunological status of these malignancies.