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BACKGROUND: Chemotherapy-induced toxicities frequently occur in non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. Low skeletal muscle mass (SMM) has been associated with a higher incidence of toxicities for several types of cancers and cytostatics. The aim of this study was to evaluate the association between skeletal muscle measures and chemotherapy-induced toxicity in a large cohort of NSCLC patients. METHODS: A multicentre prospective follow-up study (PGxLUNG, NTR number NL5373610015) in NSCLC patients was conducted. Included were patients diagnosed with NSCLC (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy of whom pretreatment imaging was available. Skeletal muscle area (SMA) segmentation was performed on abdominal imaging at the level of the third lumbar vertebra (L3). SMA at the level of L3 was corrected for squared height (m2 ) to yield the lumbar skeletal muscle mass index (LSMI). Skeletal muscle density (SMD) was calculated as the mean Hounsfield Unit (HU) of the segmented SMA. SMM and SMD were categorized as low, intermediate, and high, based on LSMI and mean HU tertiles, respectively. Chemotherapy-induced toxicity was scored using CTCAE v4.03 and categorized into haematological (anaemia, leukocytopenia, neutropenia, and thrombocytopenia), non-haematological (nephrotoxicity, neurotoxicity, and esophagitis), and dose-limiting toxicity (DLT) (treatment switch, delay, de-escalation, discontinuation, or hospitalization). The relationship between SMM, SMD, and toxicities was assessed with logistic regression modelling taking into account potential confounders like gender and body mass index (BMI). RESULTS: In total, 297 patients (male n = 167, median age 64 years) were included. Haematological toxicity grade 3/4 was experienced in 36.6% (n = 108) of the patients, 24.6% (n = 73) experienced any non-haematological toxicity grade ≥2, and 55.6% (n = 165) any DLT. Multivariate logistic regression analysis showed that low SMM (ORadj 2.41, 95% CI 1.31-4.45, P = 0.005) and age at diagnosis >65 years (ORadj 1.76, 95% CI 1.07-2.90, P = 0.025) were statistically significantly associated with overall haematological toxicity grade 3/4. No statistically significant associations were found between low SMM or low SMD and non-haematological toxicities. Low SMM (ORadj 2.23, 95% CI 1.23-4.04, P = 0.008) and high SMD (ORadj 0.41, 95% CI 0.23-0.74, P = 0.003) were statistically significantly associated with a higher respectively lower risk of DLT. CONCLUSIONS: Non-small cell lung cancer patients with pretreatment low SMM are at significant higher risk for haematological toxicities grade 3/4 and DLT. NSCLC patients with high SMD are at significant lower risk for DLT. Further studies should be aimed to investigate whether platinum dosing based on skeletal muscle measurements and/or improvement of pretreatment SMM/SMD could reduce the risk of toxicity without compromising efficacy.

Levels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant ctDNA molecules based on somatic variants, extremely sensitive sequencing methods are required. Here, we describe a new technique, CyclomicsSeq, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule. Consensus calling of the DNA copies increased the base-calling accuracy ~60×, enabling accurate detection of TP53 mutations at frequencies down to 0.02%. We demonstrate that a TP53-specific CyclomicsSeq assay can be successfully used to monitor tumor burden during treatment for head-and-neck cancer patients. CyclomicsSeq can be applied to any genomic locus and offers an accurate diagnostic liquid biopsy approach that can be implemented in clinical workflows.

Neutrophil-to-lymphocyte ratio (NLR) in peripheral blood samples has been associated with prognosis in several cancers, including head and neck cancer; but in oropharyngeal carcinomas its prognostic value, especially in relation to human papillomavirus (HPV) infection, has been little studied. This meta-analysis including studies on the prognostic value of NLR in oropharyngeal carcinoma shows that an elevated pretreatment NLR is associated with a worse prognosis in oropharyngeal cancer, regardless of the type of treatment performed, but this prognostic value appears to be specific to HPV-positive oropharyngeal carcinomas. NLR could be used as an affordable prognostic marker in this type of cancers.

BACKGROUND: Chemotherapy-induced toxicities frequently occur in non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. Low skeletal muscle mass (SMM) has been associated with a higher incidence of toxicities for several types of cancers and cytostatics. The aim of this study was to evaluate the association between skeletal muscle measures and chemotherapy-induced toxicity in a large cohort of NSCLC patients. METHODS: A multicentre prospective follow-up study (PGxLUNG, NTR number NL5373610015) in NSCLC patients was conducted. Included were patients diagnosed with NSCLC (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy of whom pretreatment imaging was available. Skeletal muscle area (SMA) segmentation was performed on abdominal imaging at the level of the third lumbar vertebra (L3). SMA at the level of L3 was corrected for squared height (m2 ) to yield the lumbar skeletal muscle mass index (LSMI). Skeletal muscle density (SMD) was calculated as the mean Hounsfield Unit (HU) of the segmented SMA. SMM and SMD were categorized as low, intermediate, and high, based on LSMI and mean HU tertiles, respectively. Chemotherapy-induced toxicity was scored using CTCAE v4.03 and categorized into haematological (anaemia, leukocytopenia, neutropenia, and thrombocytopenia), non-haematological (nephrotoxicity, neurotoxicity, and esophagitis), and dose-limiting toxicity (DLT) (treatment switch, delay, de-escalation, discontinuation, or hospitalization). The relationship between SMM, SMD, and toxicities was assessed with logistic regression modelling taking into account potential confounders like gender and body mass index (BMI). RESULTS: In total, 297 patients (male n = 167, median age 64 years) were included. Haematological toxicity grade 3/4 was experienced in 36.6% (n = 108) of the patients, 24.6% (n = 73) experienced any non-haematological toxicity grade ≥2, and 55.6% (n = 165) any DLT. Multivariate logistic regression analysis showed that low SMM (ORadj 2.41, 95% CI 1.31-4.45, P = 0.005) and age at diagnosis >65 years (ORadj 1.76, 95% CI 1.07-2.90, P = 0.025) were statistically significantly associated with overall haematological toxicity grade 3/4. No statistically significant associations were found between low SMM or low SMD and non-haematological toxicities. Low SMM (ORadj 2.23, 95% CI 1.23-4.04, P = 0.008) and high SMD (ORadj 0.41, 95% CI 0.23-0.74, P = 0.003) were statistically significantly associated with a higher respectively lower risk of DLT. CONCLUSIONS: Non-small cell lung cancer patients with pretreatment low SMM are at significant higher risk for haematological toxicities grade 3/4 and DLT. NSCLC patients with high SMD are at significant lower risk for DLT. Further studies should be aimed to investigate whether platinum dosing based on skeletal muscle measurements and/or improvement of pretreatment SMM/SMD could reduce the risk of toxicity without compromising efficacy.

Contains fulltext : 251419.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Tumor hypoxia results in worse local control and patient survival. We performed a digital, single-cell-based analysis to compare two biomarkers for hypoxia (hypoxia-inducible factor 1-alpha [HIF-1alpha] and pimonidazole [PIMO]) and their effect on outcome in laryngeal cancer patients treated with accelerated radiotherapy with or without carbogen breathing and nicotinamide (AR versus ARCON). MATERIALS AND METHODS: Immunohistochemical staining was performed for HIF-1alpha and PIMO in consecutive sections of 44 laryngeal cancer patients randomized between AR and ARCON. HIF-1alpha expression and PIMO-binding were correlated using digital image analysis in QuPath. High-density areas for each biomarker were automatically annotated and staining overlap was analyzed. Kaplan-Meier survival analyses for local control, regional control and disease-free survival were performed to predict a response benefit of ARCON over AR alone for each biomarker. RESULTS: 106 Tissue fragments of 44 patients were analyzed. A weak, significant positive correlation was observed between HIF-1alpha and PIMO positivity on fragment level, but not on patient level. A moderate strength correlation (r = 0.705, p < 0.001) was observed between the number of high-density staining areas for both biomarkers. Staining overlap was poor. HIF-1alpha expression, PIMO-binding or a combination could not predict a response benefit of ARCON over AR. CONCLUSION: Digital image analysis to compare positive cell fractions and staining overlap between two hypoxia biomarkers using open-source software is feasible. Our results highlight that there are distinct differences between HIF-1alpha and PIMO as hypoxia biomarkers and therefore suggest co-existence of different forms of hypoxia within a single tumor.

Background Recurrences remain an important problem in laryngeal squamous cell carcinoma. Little has been described about histological characteristics of the primary laryngeal tumor that may be associated with recurrences. Identifying risk factors for recurrences might help in adapting treatment or follow-up. Using real-life population-based data, we aimed to identify histological features of the primary tumor associated with recurrences and overall survival. Material and methods Demographic, clinical and treatment information on all first primary invasive laryngeal tumors diagnosed in 2010–2014 (N = 3705) were extracted from the population-based nationwide Netherlands cancer registry (NCR) and linked to PALGA, the nationwide Dutch pathology registry, to obtain data on histological factors and recurrences. For a random 1502 patients histological information i.e., keratinization, perineural invasion (PNI+), vascular invasion (VI+), growth pattern, degree of differentiation, extracapsular spread (ECS+), cartilage- and bone invasion and extralaryngeal extension, was manually extracted from narrative pathology reports and analyzed for locoregional recurrence and overall survival using cox regression analysis. Results In total, 299 patients developed a locoregional recurrence and 555 patients died. Keratinization (HR = 0.96 (95%CI: 0.68–1.34) p = 0.79), two or three adverse characteristics (PNI+, VI+, non-cohesive growth) (HR = 1.38 (95% CI: 0.63–3.01) p = 0.42), and ECS+ (HR = 1.38 (95% CI: 0.48–4.02) p = 0.55) were not associated to recurrence. For death, also no significant association was found. Conclusion In this population-based real-life dataset on laryngeal carcinoma in the Netherlands, histological factors were not associated with locoregional recurrences or overall survival, but future studies should investigate the role of these features in treatment decisions.

Introduction Patients with head and neck cancer (HNC) are usually confronted with functional changes due to the malignancy itself or its treatment. These factors typically affect important structures involved in speech, breathing, chewing, swallowing, and saliva production. Consequently, the intake of food will be limited, which further contributes to loss of body weight and muscle mass, anorexia, malnutrition, fatigue, and anemia. This multifactorial condition can ultimately lead to cancer cachexia syndrome. This study aims to examine the treatment of cachexia in HNC patients. Methods We systematically searched OvidMedline, PubMed, Scopus, and Web of Science for articles examining the treatment of cachexia in HNC. Results A total of nine studies were found, and these suggested interventions including nutritional, pharmacologic, therapeutic exercise, and multimodal approaches. The nutritional intervention includes essential components such as dietary counseling, oral nutritional supplements, and medical nutritional support. Individualized nutritional interventions include oral, enteral (feeding tubes i.e., percutaneous endoscopic gastrostomy [PEG], nasogastric tube [NGT]) and parenteral nutrition. The pharmacologic interventions aim at increasing the appetite and weight of cachectic patients. Therapeutic exercise and increased physical activity can help to enhance the synthesis of muscle protein, reducing inflammation and the catabolic effects of cachexia syndrome. Conclusion Owing to the multifactorial nature of this syndrome, it is expected that the management approach should be multi-interventional. Early implementation of these interventions may help to improve survival and quality of health and life of cachectic HNC patients.

This study was supported by grants from the Plan Nacional de I+D+I 2013–2016 (ISCIII (PI19/00560 to J.P.R.), CIBERONC (CB16/12/00390 to J.P.R.), Ayudas a Grupos PCTI Principado de Asturias (IDI/2021/000079 to J.P.R.), and the FEDER Funding Program from the European Union., Rodrigo J.P., Sánchez-Canteli M., Triantafyllou A., de Bree R., Mäkitie A.A., Franchi A., Hellquist H., Saba N.F., Stenman G., Takes R.P., Valero C., Zidar N., Ferlito A.

Background: Inevitably, the emergence of COVID-19 has impacted non-COVID care. Because timely diagnosis and treatment are essential, especially for patients with head and neck cancer (HNC) with fast-growing tumours in a functionally and aesthetically important area, we wished to quantify the impact of the COVID-19 pandemic on HNC care in the Netherlands. Material and Methods: This population-based study covered all, in total 8468, newly diagnosed primary HNC cases in the Netherlands in 2018, 2019 and 2020. We compared incidence, patient and tumour characteristics, primary treatment characteristics, and time-to-treatment in the first COVID-19 year 2020 with corresponding periods in 2018 and 2019 (i.e. pre-COVID). Results: The incidence of HNC was nearly 25% less during the first wave (n = 433) than in 2019 (n = 595) and 2018 (n = 598). In April and May 2020, the incidence of oral cavity and laryngeal carcinomas was significantly lower than in pre-COVID years. There were no shifts in tumour stage or alterations in initial treatment modalities. Regardless of the first treatment modality and specific period, the median number of days between first visit to a HNC centre and start of treatment was significantly shorter during the COVID-19 year (26–28 days) than pre-COVID (31–32 days, p < 0.001). Conclusion: The incidence of HNC during the Netherlands’ first COVID-19 wave was significantly lower than expected. The expected increase in incidence during the remainder of 2020 was not observed. Despite the overloaded healthcare system, the standard treatment for HNC patients could be delivered within a shorter time interval.

Wai Tong Ng,1,2 Barton But,2 Horace CW Choi,3 Remco de Bree,4 Anne WM Lee,1,2 Victor HF Lee,1,2 Fernando López,5,6 Antti A Mäkitie,7– 9 Juan P Rodrigo,5,6 Nabil F Saba,10 Raymond KY Tsang,11 Alfio Ferlito12 1Clinical Oncology Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, People’s Republic of China; 2Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; 3Department of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; 4Department of Head and Neck Surgical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands; 5Department of Otolaryngology, Hospital Universitario Central de Asturias (HUCA), Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, 33011, Spain; 6Spanish Biomedical Research Network Centre in Oncology, CIBERONC, Madrid, 28029, Spain; 7Department of Otorhinolaryngology - Head and Neck Surgery, HUS Helsinki University Hospital and University of Helsinki, Helsinki, Finland; 8Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 9Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; 10Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA; 11Division of Otorhinolaryngology, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People’s Republic of China; 12Coordinator of the International Head and Neck Scientific Group, Padua, ItalyCorrespondence: Barton ButDepartment of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People’s Republic of ChinaTel +852 2255 4352Fax +852 2872 6426Email bbut@hku.hkIntroduction: Nasopharyngeal carcinoma (NPC) is endemic to Eastern and South-Eastern Asia, and, in 2020, 77% of global cases were diagnosed in these regions. Apart from its distinct epidemiology, the natural behavior, treatment, and prognosis are different from other head and neck cancers. With the growing trend of artificial intelligence (AI), especially deep learning (DL), in head and neck cancer care, we sought to explore the unique clinical application and implementation direction of AI in the management of NPC.Methods: The search protocol was performed to collect publications using AI, machine learning (ML) and DL in NPC management from PubMed, Scopus and Embase. The articles were filtered using inclusion and exclusion criteria, and the quality of the papers was assessed. Data were extracted from the finalized articles.Results: A total of 78 articles were reviewed after removing duplicates and papers that did not meet the inclusion and exclusion criteria. After quality assessment, 60 papers were included in the current study. There were four main types of applications, which were auto-contouring, diagnosis, prognosis, and miscellaneous applications (especially on radiotherapy planning). The different forms of convolutional neural networks (CNNs) accounted for the majority of DL algorithms used, while the artificial neural network (ANN) was the most frequent ML model implemented.Conclusion: There is an overall positive impact identified from AI implementation in the management of NPC. With improving AI algorithms, we envisage AI will be available as a routine application in a clinical setting soon.Keywords: machine learning, neural network, deep learning, prognosis, diagnosis, auto contouring

Andrés Coca-Pelaz,1 Justin A Bishop,2 Nina Zidar,3 Abbas Agaimy,4 Eloisa Maria Mello Santiago Gebrim,5,6 Vanni Mondin,7 Oded Cohen,8 Primož Strojan,9 Alessandra Rinaldo,10 Ashok R Shaha,11 Remco de Bree,12 Marc Hamoir,13 Antti A Mäkitie,14 Luiz P Kowalski,15 Nabil F Saba,16 Alfio Ferlito17 1Department of Otolaryngology, Hospital Universitario Central de Asturias-University of Oviedo, Instituto de Investigación Sanitaria del Principado de Asturias, IUOPA, CIBERONC, Oviedo (Asturias), Spain; 2Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 3Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; 4Institute of Pathology, Friedrich Alexander University Erlangen-Nürnberg, University Hospital, Erlangen, Germany; 5Otorhinolaryngology Department, National Institute of Rehabilitation, Mexico City, Mexico; 6Radiology Department, Hospital das Clínicas, University of São Paulo, São Paulo, Brazil; 7ENT Clinic, Policlinico Città di Udine, Udine, Italy; 8ARM - Center for Otolaryngology - Head and Neck Surgery and Oncology, Assuta Medical Center, Tel Aviv, Affiliated with Ben Gurion University, Beer Sheva, Israel; 9Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia; 10University of Udine School of Medicine, Udine, Italy; 11Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 12Department of Head and Neck Surgical Oncology, University Medical Center Utrecht, Utrecht, The NetherlAnds; 13Department of Head and Neck Surgery, UC Louvain, St Luc University Hospital and King Albert II Cancer Institute, Brussels, Belgium; 14Department of Otorhinolaryngology, Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; 15Head and Neck Surgery and Otorhinolaryngology Department, A C Camargo Cancer Center and Department of Head and Neck Surgery, University of São Paulo Medical School, São Paulo, Brazil; 16Department of Hematology and Medical Oncology, The Winship Cancer Institute of Emory University, Atlanta, GA, USA; 17International Head and Neck Scientific Group, Padua, ItalyCorrespondence: Andrés Coca-Pelaz, Department of Otolaryngology, Hospital Universitario Central de Asturias-University of Oviedo, Instituto de Investigación Sanitaria del Principado de Asturias, IUOPA, CIBERONC, Avenida de Roma s/n, Oviedo (Asturias), 33011, Spain, Email acocapelaz@yahoo.esIntroduction: Lymph node metastasis (LNM) from primary tumors of the central nervous system (CNS) is an infrequent condition, and classically it was thought that CNS tumors could not spread via the lymphatic route. Recent discoveries about this route of dissemination make its knowledge necessary for surgeons and pathologists to avoid delays in diagnosis and unnecessary treatments. The aim of this paper is to review the literature and to discuss the relevant pathogenetic mechanism and the cytologic features along with recommendations for surgical treatment of these cervical LNM.Materials and Methods: Using PRISMA guidelines, we conducted a systematic review of the literature published from 1944 to 2021, updating the comprehensive review published in 2010 by our group.Results: Our review includes data of 143 articles obtaining 174 patients with LNM from a primary CNS tumor. The mean age of the patients was 31.9 years (range, 0.1– 87) and there were 61 females (35.1%) and 103 males (59.2%), and in 10 cases (5.7%) the gender was not specified. The more frequent sites of distant metastasis were bones (23%), lungs (11.5%) and non-cervical lymph nodes (11%).Conclusion: Cervical LNM from CNS tumors is infrequent. Pathologic diagnosis can be obtained by fine-needle aspiration cytology in most cases, giving surgeons the option to plan the appropriate surgical treatment. Given the poor prognosis of these cases, the most conservative possible cervical dissection is usually the treatment of choice.Keywords: brain tumors, central nervous system, extraneural metastasis, extracranial metastasis, cervical lymph node metastasis

Introduction: Nasopharyngeal carcinoma (NPC) is endemic to Eastern and South-Eastern Asia, and, in 2020, 77% of global cases were diagnosed in these regions. Apart from its distinct epidemiology, the natural behavior, treatment, and prognosis are different from other head and neck cancers. With the growing trend of artificial intelligence (AI), especially deep learning (DL), in head and neck cancer care, we sought to explore the unique clinical application and implementation direction of AI in the management of NPC. Methods: The search protocol was performed to collect publications using AI, machine learning (ML) and DL in NPC management from PubMed, Scopus and Embase. The articles were filtered using inclusion and exclusion criteria, and the quality of the papers was assessed. Data were extracted from the finalized articles. Results: A total of 78 articles were reviewed after removing duplicates and papers that did not meet the inclusion and exclusion criteria. After quality assessment, 60 papers were included in the current study. There were four main types of applications, which were auto-contouring, diagnosis, prognosis, and miscellaneous applications (especially on radiotherapy planning). The different forms of convolutional neural networks (CNNs) accounted for the majority of DL algorithms used, while the artificial neural network (ANN) was the most frequent ML model implemented. Conclusion: There is an overall positive impact identified from AI implementation in the management of NPC. With improving AI algorithms, we envisage AI will be available as a routine application in a clinical setting soon.

Additional file 1: Supplementary Table 1. Generalizability sample of pathology data extracted from pathology reports compared to initial cohort. A). Basic clinical characteristics of patients for each year of the sample used in this paper (n = 1502). These are the 3656 patients of which 44% of each year pathology data were extracted and CIS were removed. B). Basic clinical characteristics of the total dataset of patients for each year (n = 3380). These are the 3656 patients with reliable linkage between NKR-PALGA minus 276 CIS patients leaving 3380 patients in total. Supplementary Table 2. Histological characteristics, locoregional recurrences and death of patients treated with tumor-positive lymph nodes (n = 205). Supplementary Table 3. Histological characteristics, locoregional recurrences and death of T3/T4 N0/N+ patients treated with TLE or TLE with RT (n = 98). Supplementary Figure 1. Separate multivariable analysis of extracapsular spread, keratinization and PNI+/VI+/Growth pattern. Each separate histological characteristic was corrected for age, gender, sublocalisation and stage/treatment for locoregional recurrence and death of patients with positive lymph nodes (n = 205). Supplementary Figure 2. Univariable analysis of histological characteristics of the primary tumor for locoregional recurrence and death of T3/T4 N0/N+ patients treated with TLE or TLE with RT (n = 98). * p

The diagnosis is the art of determining the nature of a disease, and an accurate diagnosis is the true cornerstone on which rational treatment should be built. Within the workflow in the management of head and neck tumours, there are different types of diagnosis. The purpose of this work is to point out the differences and the aims of the different types of diagnoses and to highlight their importance in the management of patients with head and neck tumours. Qualitative diagnosis is performed by a pathologist and is essential in determining the management and can provide guidance on prognosis. The evolution of immunohistochemistry and molecular biology techniques has made it possible to obtain more precise diagnoses and to identify prognostic markers and precision factors. Quantitative diagnosis is made by the radiologist and consists of identifying a mass lesion and the estimation of the tumour volume and extent using imaging techniques, such as CT, MRI, and PET. The distinction between the two types of diagnosis is clear, as the methodology is different. The accurate establishment of both diagnoses plays an essential role in treatment planning. Getting the right diagnosis is a key aspect of health care, and it provides an explanation of a patient's health problem and informs subsequent decision. Deep learning and radiomics approaches hold promise for improving diagnosis.

Electrochemotherapy (ECT) is a local ablative treatment that is based on the reversible electroporation and intracellular accumulation of hydrophilic drug molecules, which greatly increases their cytotoxicity. In mucosal head and neck cancer (HNC), experience with ECT is limited due to the poor accessibility of tumors. In order to review the experience with ECT in mucosal HNC, we undertook a systematic review of the literature. In 22 articles, published between 1998 and 2020, 16 studies with 164 patients were described. Curative and palliative intent treatment were given to 36 (22%) and 128 patients (78%), respectively. The majority of tumors were squamous cell carcinomas (79.3%) and located in the oral cavity (62.8%). In the curative intent group, complete response after one ECT treatment was achieved in 80.5% of the patients, and in the palliative intent group, the objective (complete and partial) response rate was 73.1% (31.2% and 41.9%). No serious adverse events were reported during or soon after ECT and late effects were rare (19 events in 17 patients). The quality-of-life assessments did not show a significant deterioration at 12 months post-ECT. Provided these preliminary data are confirmed in randomized controlled trials, ECT may be an interesting treatment option in selected patients with HNC not amenable to standard local treatment. Nasl. z nasl. zaslona. Opis vira z dne 3. 5. 2021. Bibliografija na koncu prispevka. Abstract.

Background The prognostic importance of intraparotid lymph node metastasis (P+) in patients with primary parotid gland carcinoma is unclear. Methods Nineteen retrospective and noncomparative cohort studies, published between 1992 and 2020, met the inclusion criteria and included 2202 patients for this systematic review. Results The pooled prevalence of the P in adult patients in the unselected studies was 24.10% (95% confidence interval = 17.95-30.25). The number of P+ lymph nodes per patient was counted in only three studies and ranged from 1 to 11. The 5-year recurrence-free survival rate based on Kaplan-Meier analysis varied from 83% to 88% in P- patients compared to 36% to 54% in P+ patients. The average hazard ratio for tumor recurrence in patients with P+ compared to P- was 2.67 +/- 0.58. Conclusions P+ is an independent negative prognostic factor in primary parotid gland cancer and should be included into the treatment planning.

Background: Larynx cancer is a common site for tumors of the upper aerodigestive tract. In cases with a clinically negative neck, the indications for an elective neck treatment are still debated. The objective is to define the prevalence of occult metastasis based on the subsite of the primary tumor, T classification and neck node levels involved. Methods: All studies included provided the rate of occult metastases in cN0 larynx squamous cell carcinoma patients. The main outcome was the incidence of occult metastasis. The pooled incidence was calculated with random effects analysis. Results: 36 studies with 3803 patients fulfilled the criteria. The incidence of lymph node metastases for supraglottic and glottic tumors was 19.9% (95% CI 16.4-23.4) and 8.0% (95% CI 2.7-13.3), respectively. The incidence of occult metastasis for level I, level IV and level V was 2.4% (95% CI 0-6.1%), 2.0% (95% CI 0.9-3.1) and 0.4% (95% CI 0-1.0%), respectively. For all tumors, the incidence for sublevel IIB was 0.5% (95% CI 0-1.3). Conclusions: The incidence of occult lymph node metastasis is higher in supraglottic and T3-4 tumors. Level I and V and sublevel IIB should not be routinely included in the elective neck treatment of cN0 laryngeal cancer and, in addition, level IV should not be routinely included in cases of supraglottic tumors.

BackgroundThe optimal evidence-based prophylactic antibiotic regimen for surgical site infections following major head and neck surgery remains a matter of debate.MethodsMedline, Cochrane, and Embase were searched for the current best evidence. Retrieved manuscripts were screened according to the PRISMA guidelines. Included studies dealt with patients over 18 years of age that underwent clean-contaminated head and neck surgery (P) and compared the effect of an intervention, perioperative administration of different antibiotic regimens for a variable duration (I), with control groups receiving placebo, another antibiotic regimen, or the same antibiotic for a different postoperative duration (C), on surgical site infection rate as primary outcome (O) (PICO model). A systematic review was performed, and a selected group of trials investigating a similar research question was subjected to a random-effects model meta-analysis.ResultsThirty-nine studies were included in the systematic review. Compared with placebo, cefazolin, ampicillin-sulbactam, and amoxicillin-clavulanate were the most efficient agents. Benzylpenicillin and clindamycin were clearly less effective. Fifteen studies compared short- to long-term prophylaxis; treatment for more than 48 h did not further reduce wound infections. Meta-analysis of five clinical trials including 4336 patients, where clindamycin was compared with ampicillin-sulbactam, implied an increased infection rate for clindamycin-treated patients (OR=2.73, 95% CI 1.50-4.97, p=0.001).ConclusionIn clean-contaminated head and neck surgery, cefazolin, amoxicillin-clavulanate, and ampicillin-sulbactam for 24-48 h after surgery were associated with the highest prevention rate of surgical site infection.

Differences in cancer gene copy number alterations between Epstein-Barr virus-positive and Epstein-Barr virus-negative nasopharyngeal carcinoma Marc Lucas Ooft MD, PhD1 | Jolique van Ipenburg MD2 | Rob J. M. van de Loo1 | Rick de Jong1 | Cathy B. Moelans PhD1 | Remco de Bree MD, PhD3 | Martine J. de Herdt Ir4 | Senada Koljenović MD, PhD2 | R. Baatenburg de Jong MD, PhD5 | J. Hardillo MD, PhD5 | Stefan Martin Willems MD, PhD1 1Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands 2Department of Pathology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands 3Department of Head and Neck Surgical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands 4Department of Otorhinolaryngology - Head and Neck Surgery, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands 5Department of Otorhinolaryngology - Head and Neck Surgery, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands Correspondence Stefan Willems, Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands Email: s.m.willems-4@umcutrecht.nl Head & Neck. 2018;40:1986-1998 DOI: 10.1002/hed.25195 In the above-mentioned article, author name “R. Baatenburg de Jong” should be updated to “Robert J. Baatenburg de Jong.” We apologize for the error.

Patients diagnosed with head and neck squamous cell carcinoma (HNSCC) are currently treated with surgery and/or radio- and chemotherapy. Despite these therapeutic interventions, 40% of patients relapse, urging the need for more effective therapies. In photodynamic therapy (PDT), a light-activated photosensitizer produces reactive oxygen species that ultimately lead to cell death. Targeted PDT, using a photosensitizer conjugated to tumor-targeting molecules, has been explored as a more selective cancer therapy. Organoids are self-organizing three-dimensional structures that can be grown from both normal and tumor patient-material and have recently shown translational potential. Here, we explore the potential of a recently described HNSCC&ndash, organoid model to evaluate Epidermal Growth Factor Receptor (EGFR)-targeted PDT, through either antibody- or nanobody-photosensitizer conjugates. We find that EGFR expression levels differ between organoids derived from different donors, and recapitulate EGFR expression levels of patient material. EGFR expression levels were found to correlate with the response to EGFR-targeted PDT. Importantly, organoids grown from surrounding normal tissues showed lower EGFR expression levels than their tumor counterparts, and were not affected by the treatment. In general, nanobody-targeted PDT was more effective than antibody-targeted PDT. Taken together, patient-derived HNSCC organoids are a useful 3D model for testing in vitro targeted PDT.

Introduction: Management of clinically negative neck (cN0) in patients with parotid gland cancer is controversial. Treatment options can include observation, elective neck dissection or elective radiotherapy. Areas covered: We addressed the treatment options for cN0 patients with parotid gland cancer. A literature review was undertaken to determine the optimal management of this group of patients. Expert opinion: Patients with parotid carcinoma and clinically negative neck have various options for their management. The analysis of tumor stage, histology and grade is essential to better define patients at risk for occult lymph node metastasis. These patients can be managed by surgery, radiotherapy or their combination, depending on the presence of risk factors, the moment at which such risk factors are detected, patient-related clinical conditions, medical provider expertise and institutional facilities. info:eu-repo/semantics/publishedVersion

Previous studies have described that tumor organoids can capture the diversity of defined human carcinoma types. Here, we describe conditions for long-term culture of human mucosal organoids. Using this protocol, a panel of 31 head and neck squamous cell carcinoma (HNSCC)–derived organoid lines was established. This panel recapitulates genetic and molecular characteristics previously described for HNSCC. Organoids retain their tumorigenic potential upon xenotransplantation. We observe differential responses to a panel of drugs including cisplatin, carboplatin, cetuximab, and radiotherapy in vitro. Additionally, drug screens reveal selective sensitivity to targeted drugs that are not normally used in the treatment of patients with HNSCC. These observations may inspire a personalized approach to the management of HNSCC and expand the repertoire of HNSCC drugs.Significance:This work describes the culture of organoids derived from HNSCC and corresponding normal epithelium. These tumoroids recapitulate the disease genetically, histologically, and functionally. In vitro drug screening of tumoroids reveals responses to therapies both currently used in the treatment of HNSCC and those not (yet) used in clinical practice.See related commentary by Hill and D'Andrea, p. 828.This article is highlighted in the In This Issue feature, p. 813

The pattern of clinical behaviour and response to treatment of recurrent and/or metastatic head and neck squamous cell carcinoma is heterogeneous. Treatment strategies that can be employed vary from potentially curative salvage surgery and re-irradiation to palliative systemic therapies and best supportive care. The advent of new therapeutic options, in terms of more sophisticated surgical approaches and techniques, highly conformal and precise radiation techniques and immunotherapy may offer improved control of disease and longer survival. Moreover, the epidemiological changes during the last decades, including the increase of human papilloma virus-related oropharyngeal primary tumors, are also reflected in the recurrent and metastatic setting. In this complex context the identification of predictive and prognostic factors is urgently needed to tailor treatment, to increase its efficacy, and to avoid unnecessary toxicities. A better knowledge of prognosis may also help the patients and caregivers in decision making on the optimal choice of care. The purpose of our review is to highlight the current evidence and shortcomings in this field.

The parapharyngeal space is a complex anatomical area. Primary parapharyngeal tumors are rare tumors and 80% of them are benign. A variety of tumor types can develop in this location; most common are salivary gland neoplasm and neurogenic tumors. The management of these tumors has improved greatly owing to the developments in imaging techniques, surgery, and radiotherapy. Most tumors can be removed with a low rate of complications and recurrence. The transcervical approach is the most frequently used. In some cases, minimally invasive approaches may be used alone or in combination with a limited transcervical route, allowing large tumors to be removed by reducing morbidity of expanded approaches. An adequate knowledge of the anatomy and a careful surgical plan is essential to tailor management according to the patient and the tumor. The purpose of the present review was to update current aspects of knowledge related to this more challenging area of tumor occurrence.

Purpose To assess the standardized implementation and reporting of surveillance [18F]fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan of the neck in locoregionally advanced head-and-neck squamous cell carcinoma (LAHNSCC) after concurrent chemoradiotherapy (CCRT). Patients and Methods We performed a prospective multicenter study of FDG-PET/CT scanning 12 weeks after CCRT in newly diagnosed patients with LAHNSCC (stage IVa/b) that used standardized reconstruction and Hopkins reporting criteria. The reference standard was histology or > 12 months of clinical follow-up. The primary outcome measure was the negative predictive value (NPV) of FDG-PET/CT scans and other supporting diagnostic test characteristics, including time dependency with increasing follow-up time. Results Of 152 patients, 125 had adequate primary tumor control after CCRT and entered follow-up (median, 20.4 months). Twenty-three (18.4%) had residual neck disease. Overall, NPV was 92.1% (95% CI, 86.9% to 95.3%; null hypothesis: NPV = 85%; P = .012) with sensitivity of 65.2% (95% CI, 44.9% to 81.2%), specificity of 91.2% (95% CI, 84.1% to 95.3%), positive predictive value of 62.5% (95% CI, 45.5% to 76.9%), and accuracy of 86.4% (95% CI, 79.3% to 91.3%). Sensitivity was time dependent and high for residual disease manifesting up to 9 months after imaging but lower (59.7%) for disease detected up to 12 months after imaging. Standardized reporting criteria reduced the number of equivocal reports (95% CI for the difference, 2.6% to 15.0%; P = .003). Test characteristics were not improved with the addition of lymph node CT morphology criteria. Conclusion FDG-PET/CT surveillance using Hopkins criteria 12 weeks after CCRT is reliable in LAHNSCC except for late manifesting residual disease, which may require an additional surveillance scan at 1 year after CCRT to be detected.

BACKGROUND: Intraoperative analysis of lymph nodes during a sentinel lymph node biopsy (SLNB) procedure could result in one-step surgery for early oral squamous cell carcinoma (OSCC) with an occult nodal metastasis. One-step nucleic acid amplification rapidly detects cytokeratin 19 (CK19) RNA with high accuracy. Sensitivity and specificity of CK19 expression in OSCC was evaluated. METHODS: Immunohistochemical CK19 expression was done in 207 patients with OSCC with 65 cases of paired nodal metastases. RESULTS: CK19 was expressed in 65% of all OSCC and even less in early OSCC (56%), with poor correlation between primary tumor and (occult) nodal metastasis. Furthermore, ectopic glandular tissue in close proximity of lymph nodes showed strong CK19 expression. CONCLUSION: CK19 lacks both sensitivity and specificity as a biomarker for nodal metastasis in OSCC, which questions the suitability for CK19-based one-step nucleic acid amplification in SLNB procedures. Therefore, future studies should focus on other biomarkers, because the concept of fast intraoperative diagnostics during SLNB remains attractive.

A 28-year-old woman, originally from the Philippines, presented with a painful, fluctuating swelling of the neck, preceded by peeking fever. CT-imaging showed a multiloculated abscess. A chest X-ray did not show any abnormalities. Incision and drainage were performed. Both PCR and culture revealed an infection with Mycobacterium tuberculosis and the diagnosis of cervical tuberculous lymphadenitis was made.

When resecting head and neck tumours, the aim is mostly to strive for en bloc resection with sufficiently large tumour-free margins. If this is not possible, as is frequently the case with transoral laser microsurgery and endonasal endoscopic surgery, multiblock resection can be carried out by cutting through the tumour. With this approach, it is also essential that the final resection margins are tumour-negative. In such cases, surgeon and pathologist together should pay extra attention to tissue orientation and outer resection margins.

Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) have a better survival than with HPV-negative oropharyngeal SCC. An (18) F-fluorodeoxyglucose positron emission tomography-CT ((18) F-FDG-PET-CT) may also provide prognostic information. We evaluated glycolytic characteristics in HPV-negative and HPV-positive oropharyngeal SCC. METHODS: Forty-four patients underwent pretreatment (18) F-FDG-PET-CT. Standardized uptake values (SUVs) and metabolic active tumor volumes (MATVs) were determined for primary tumors. HPV status was determined with p16 immunostaining, followed by high-risk HPV DNA detection on the positive cases. RESULTS: Twenty-seven patients were HPV-positive (61.4%). Median MATV was 2.8 mL (range = 1.6-5.1 mL) for HPV-positive and 6.0 mL (range = 4.4-18.7 mL) for HPV-negative tumors (p

Neck dissection is an important treatment for metastases from upper aerodigestive carcinoma; an event that markedly reduces survival. Since its inception, the philosophy of the procedure has undergone significant change from one of radicalism to the current conservative approach. Furthermore, nonsurgical modalities have been introduced, and, in many situations, have supplanted neck surgery. The refinements of imaging the neck based on the concept of neck level involvement has encouraged new philosophies to evolve that seem to benefit patient outcomes particularly as this relates to diminished morbidity. The purpose of this review was to highlight the new paradigms for surgical removal of neck metastases using an evidence-based approach. United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) (P30CA008748) United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) (P30 CA008748)

Background Sentinel node biopsy (SNB) in head and neck cancer is recently introduced as the staging technique of oral squamous cell carcinoma. We report the results of SNB in patients diagnosed with a T1-T2 oral squamous cell carcinoma and clinically negative (N0) neck in a single center. Methods A retrospective analysis of 90 previously untreated patients who underwent SNB between 2007 and 2012 was performed. The SNB procedure consisted of preoperatively performed lymphoscintigraphy, intraoperative detection using blue dye, and gamma probe guidance and histopathologic examination including step-serial sectioning (SSS) and immunohistochemical (IHC) staining. A positive SNB was followed by neck dissection, whereas regular follow-up with ultrasound-guided fine-needle aspiration cytology (FNAC) was done in case of a negative SNB. Results The lymphoscintigraphic identification rate was 98% (88 of 90 patients) and the surgical detection rate was 99% (87 of 88 patients). The upstaging rate was 30%. Sensitivity of SNB was 93% and the negative predictive value was 97%. The median follow-up was 18 months (range, 2-62 months). Overall survival (OS) and disease-free survival (DFS) for SNB negative were 100% and 84% and for SNB positive patients 73% and 88%, respectively. Conclusion SNB is a reliable diagnostic staging technique for the clinically negative neck in patients with early-stage (T1-T2, cN0) oral squamous cell carcinoma.

BackgroundLocal and/or regional recurrence and metachronous primary tumor arising in a previously irradiated area are rather frequent events in patients with head and neck squamous cell carcinoma (HNSCC). Re-treatment is associated with an increased risk of serious toxicity and impaired quality of life (QOL) with an uncertain survival advantage. MethodsWe analyzed the literature on the efficacy and toxicity of photon/electron-based external beam reirradiation for previously irradiated patients with HNSCC of non-nasopharyngeal origin. Studies were grouped according to the radiotherapy technique used for reirradiation. Patient selection criteria, target volume identification method, tumor dose, fractionation schedule, systemic therapy administration, and toxicities were reviewed. ResultsIn addition to disease-related factors, current comorbidities and preexisting organ dysfunction must be considered when selecting patients for reirradiation. As morbidity from re-treatment may be considerable and differ depending on which mode of re-treatment is used, it is important to give patients information on potential morbidity outcomes so that an informed choice can be made within a shared decision-making context. With improved dose distribution and adequate imaging support, including positron emission tomography-CT, modern radiotherapy techniques may improve local control and reduce toxicity of reirradiation. A reirradiation dose of 60 Gy and a volume encompassing the gross tumor with up to a 5-mm margin are recommended. Concomitant administration of systemic therapeutics and reirradiation is likely to be of similar benefit as observed in large randomized studies of upfront therapy. ConclusionReirradiation, administered either with or without concurrent systemic therapy, is feasible and tolerable in properly selected patients with recurrent or a new primary tumor in a previously irradiated area of the head and neck, offering a meaningful survival (in the range of 10% to 30% at 2 years). Whenever feasible, salvage surgery is the method of choice for curative intent; patients at high-risk for local recurrence should be advised that postoperative reirradiation is expected to increase locoregional control at the expense of higher toxicity and without survival advantage compared to salvage surgery without reirradiation. (c) 2014 Wiley Periodicals, Inc. Head Neck37: 134-150, 2015

Diffusion-weighted MRI (DW-MRI) has potential to predict chemoradiotherapy (CRT) response in head and neck squamous cell carcinoma (HNSCC) and is generally performed using echo-planar imaging (EPI). However, EPI-DWI is susceptible to geometric distortions. Half-fourier acquisition single-shot turbo spin-echo (HASTE)-DWI may be an alternative. This prospective pilot study evaluates the potential predictive value of EPI- and HASTE-DWI and 18F-fluorodeoxyglucose PET-CT (18F-FDG-PET-CT) early during CRT for locoregional outcome in HNSCC.Eight patients with advanced HNSCC (7 primary tumors and 25 nodal metastases) scheduled for CRT, underwent DW-MRI (using both EPI- and HASTE-DWI) and 18F-FDG-PET(-CT) pretreatment, early during treatment and three months after treatment. Median follow-up time was 38 months.No local recurrences were detected during follow-up. Median Apparent Diffusion Coefficient (ADC)EPI-values in primary tumors increased from 77×10(-5) mm(2)/s pretreatment, to 113×10(-5) mm(2)/s during treatment (P=0.02), whereas ADCHASTE did not increase (74 and 74 mm(2)/s, respectively). Two regional recurrences were diagnosed. During treatment, ADCEPI tended to be higher for patients with regional control [(117.3±12.1)×10(-5) mm(2)/s] than for patients with a recurrence [(98.0±4.2)×10(-5) mm(2)/s]. This difference was not seen with ADCHASTE. No correlations between ΔADCEPI and ΔSUV (Standardized Uptake Value) were found in the primary tumor or nodal metastases.HASTE-DWI seems to be inadequate in early CRT response prediction, compared to EPI-DWI which has potential to predict locoregional outcome. EPI-DWI and 18F-FDG-PET-CT potentially provide independent information in the early response to treatment, since no correlations were found between ΔADCEPI and ΔSUV.

Neck dissection is an important treatment for metastases from upper aerodigestive carcinoma; an event that markedly reduces survival. Since its inception, the philosophy of the procedure has undergone significant change from one of radicalism to the current conservative approach. Furthermore, nonsurgical modalities have been introduced, and, in many situations, have supplanted neck surgery. The refinements of imaging the neck based on the concept of neck level involvement has encouraged new philosophies to evolve that seem to benefit patient outcomes particularly as this relates to diminished morbidity. The purpose of this review was to highlight the new paradigms for surgical removal of neck metastases using an evidence-based approach.

Retropharyngeal lymph node (RPLN) metastasis of primary head and neck cancer often receives less consideration than lymph node metastasis in the neck. With improvements in imaging techniques and reports of surgical pathology, there is an improved understanding of the risk and subsequently the need for treatment of RPLNs. The rates of RPLN metastasis from carcinomas of the nasopharynx, oropharynx, hypopharynx, postcricoid region, maxillary sinus, and cervical esophagus are sufficiently high to warrant routine treatment, either electively or therapeutically, of this region. Through improved diagnostic techniques and heightened awareness of RPLN metastasis, patients at risk of having these metastases can be treated more effectively.

WOS: 000271089200030, PubMed ID: 19795174, Involvement of the cervical lymph nodes is the most important prognostic factor for patients with oral/oropharyngeal squamous cell carcinoma (OSCC), and the decision of whether to electively treat patients with clinically negative necks remains a controversial topic. Sentinel node biopsy (SNB) provides a minimally invasive method for determining the disease status of the cervical node basin, without the need for a formal neck dissection. This technique potentially improves the accuracy of histologic nodal staging and avoids overtreating three-quarters of this patient population, minimizing associated morbidity. The technique has been validated for patients with OSCC, and larger-scale studies are in progress to determine its exact role in the management of this patient population. This document is designed to outline the current best practice guidelines for the provision of SNB in patients with early-stage OSCC, and to provide a framework for the currently evolving recommendations for its use. Preparation of this guideline was carried out by a multidisciplinary surgical/nuclear medicine/pathology expert panel under the joint auspices of the European Association of Nuclear Medicine (EANM) Oncology Committee and the Sentinel European Node Trial (SENT) Committee.

Purpose. Examination of the potential of electroporation therapy (EPT) in a patient with metastatic soft tissue sarcoma. Patient. A 24-year-old male who underwent extensive resection and postoperative radiotherapy for a malignant peripheral nerve sheath tumor in the right infratemporal fossa with intracranial extension and invasion of the maxillary sinus and mandible had a recurrence in the scar of his craniotomy for which he was initially treated with doxorubicin. After discontinuation of doxorubicin he developed a metastatic mass at the same site for which he was treated with electroporation therapy. Method. The subcutaneous metastasis was infiltrated with bleomycin and electroporated. Results. Gradually the tumor became increasingly necrotic and demarcated from surrounding tissue. After 10 weeks no tumor was seen anymore. The wound healed secondarily. Discussion. Intralesional bleomycin followed by EPT is potentially effective, well tolerated, and easy to perform in well accessible soft tissue sarcoma sites.

Purpose: In previous studies, we have shown the potential of radioimmunotherapy (RIT) with 186Re-labeled chimeric monoclonal antibody (MAb) U36 for treatment of head and neck cancer. A limitation of this anti-CD44v6 MAb, however, appeared to be its immunogenicity, resulting in human antichimeric antibodies in 40% of the patients. Aiming for a less immunogenic anti-CD44v6 MAb, the humanized MAb BIWA 4 (bivatuzumab) was introduced. In the present Phase I RIT study, we determined the safety, maximum tolerated dose (MTD), pharmacokinetics, immunogenicity, and therapeutic potential of 186Re-labeled BIWA 4 in patients with squamous cell carcinoma of the head and neck. Experimental Design: Twenty patients with inoperable recurrent and/or metastatic head and neck squamous cell carcinoma received a single dose of 186Re-labeled BIWA 4 in radiation dose-escalation steps of 20, 30, 40, 50, and 60 mCi/m2. Three patients received a second dose at least 3 months after the initial dose. After each administration, whole-body images as well as planar and tomographic images of the head and neck region were obtained, and the pharmacokinetics and the development of human antihuman antibody responses were determined. Radiation absorbed doses were calculated for whole body, red marrow, organs, and tumor. Results: First and second administrations were all well tolerated, and targeting of tumor lesions proved to be excellent. The only significant manifestations of toxicity were dose-limiting myelotoxicity consisting of thrombo- and leukocytopenia and, to a lesser extent, oral mucositis (grade 2). Grade 4 myelotoxicity was seen in two patients treated with 60 mCi/m2. The MTD was established at 50 mCi/m2, at which level dose-limiting myelotoxicity was seen in one of six patients. Stable disease, varying between 6 and 21 weeks, was observed in three of six patients treated at the MTD level. The median tumor dose, recalculated to MTD level, was 12.4 Gy. The absorbed dose in red marrow was 1. 82 ± 0.11 cGy/mCi for males and 2.35 ± 0.10 for females. Two patients experienced a human antihuman antibody response. Pharmacokinetics showed consistency across patients and within the three patients receiving 186Re-BIWA 4 on two occasions. Conclusions: This study shows that 186Re-labeled BIWA 4 can safely be administered, also in a repeated way. The MTD was established at 50 mCi/m2. In comparison with the previously described anti-CD44v6 MAb U36, the humanized MAb BIWA 4 seems to be less immunogenic. The fact that antitumor effects were seen in incurable patients with bulky disease justifies the evaluation of RIT with 186Relabeled BIWA 4 in an adjuvant setting.

Purpose: In previous studies, we have shown the potential of radioimmunotherapy (RIT) with 186Re-labeled chimeric monoclonal antibody (MAb) U36 for treatment of head and neck cancer. A limitation of this anti-CD44v6 MAb, however, appeared to be its immunogenicity, resulting in human antichimeric antibodies in 40% of the patients. Aiming for a less immunogenic anti-CD44v6 MAb, the humanized MAb BIWA 4 (bivatuzumab) was introduced. In the present Phase I RIT study, we determined the safety, maximum tolerated dose (MTD), pharmacokinetics, immunogenicity, and therapeutic potential of 186Re-labeled BIWA 4 in patients with squamous cell carcinoma of the head and neck. Experimental Design: Twenty patients with inoperable recurrent and/or metastatic head and neck squamous cell carcinoma received a single dose of 186Re-labeled BIWA 4 in radiation dose-escalation steps of 20, 30, 40, 50, and 60 mCi/m2. Three patients received a second dose at least 3 months after the initial dose. After each administration, whole-body images as well as planar and tomographic images of the head and neck region were obtained, and the pharmacokinetics and the development of human antihuman antibody responses were determined. Radiation absorbed doses were calculated for whole body, red marrow, organs, and tumor. Results: First and second administrations were all well tolerated, and targeting of tumor lesions proved to be excellent. The only significant manifestations of toxicity were dose-limiting myelotoxicity consisting of thrombo- and leukocytopenia and, to a lesser extent, oral mucositis (grade 2). Grade 4 myelotoxicity was seen in two patients treated with 60 mCi/m2. The MTD was established at 50 mCi/m2, at which level dose-limiting myelotoxicity was seen in one of six patients. Stable disease, varying between 6 and 21 weeks, was observed in three of six patients treated at the MTD level. The median tumor dose, recalculated to MTD level, was 12.4 Gy. The absorbed dose in red marrow was 1. 82 ± 0.11 cGy/mCi for males and 2.35 ± 0.10 for females. Two patients experienced a human antihuman antibody response. Pharmacokinetics showed consistency across patients and within the three patients receiving 186Re-BIWA 4 on two occasions. Conclusions: This study shows that 186Re-labeled BIWA 4 can safely be administered, also in a repeated way. The MTD was established at 50 mCi/m2. In comparison with the previously described anti-CD44v6 MAb U36, the humanized MAb BIWA 4 seems to be less immunogenic. The fact that antitumor effects were seen in incurable patients with bulky disease justifies the evaluation of RIT with 186Relabeled BIWA 4 in an adjuvant setting.