The Light-Dosimeter: A new device to help advance research on the non-visual responses to light.

This article describes the development of a device to investigate the non-visual responses to light: The Light-Dosimeter (lido). Its multidisciplinary team followed a user-centred approach throughout the project, that is, their design decisions focused on researchers' and participants' needs. Together with custom-made mountings and the software Lido Studio, the lidos provide researchers with a holistic solution to record participants' light exposure in the near-corneal plane in laboratory settings and under real-world conditions. Validation measurements with commercial equipment were deemed satisfying, as was the combining with data from other devices. The handling of the lidos and mountings and the use of the software Lido Studio during the trial period by various researchers and participants were successful. Despite some limitations, the lidos can help advance research on the non-visual responses to light over the coming years.

Association between malformation type, location and functional deficits in lymphatic malformations of the head and neck in children.

PURPOSE: Lymphatic malformations (LM) are congenital malformations of the lymphatic system, mainly located in the head and neck area. They can be staged based on location according to de Serres and based on different morbidity items using the Cologne Disease Score (CDS), a clinical staging system. In many cases, functional impairment greatly affects the life of patients suffering from lymphatic malformations. The present study aims to analyze a cohort of pediatric patients with LM. METHODS: A retrospective analysis of 144 pediatric patients with head and neck LM was performed. Location, type of malformation (microcystic, macrocystic, mixed), scoring according to two different scoring systems and therapy were analyzed. Kruskal-Wallis test was used to analyze the difference in CDS between the patient groups and Dunn's test was used for post-hoc pairwise comparison. RESULTS: The average age at presentation was 6.1 years. The most common sites were neck (47%), cheek/parotid gland (26%), tongue (17%) and orbit (8%). Macrocystic malformations dominated the lateral neck, while microcystic malformations were predominantly localized in the tongue and floor of mouth. Macrocystic malformations (mean CDS 9.44) were associated with significantly better CDS than microcystic (mean CDS 7.11) and mixed (mean CDS 5.71) malformations (p < 0.001). LM in stage V according to de Serres had the lowest values (mean CDS: 4.26). The most common therapeutic procedures were conventional surgical (partial) resection, laser therapy and sclerotherapy with OK-432. CONCLUSIONS: There is an association between malformation type, location according to de Serres and CDS in children with LM of the head and neck. Patients with microcystic and mixed malformations in stage V had lowest CDS levels.

Efficacy of sirolimus in children with lymphatic malformations of the head and neck.

PURPOSE: Children with extensive lymphatic malformations of the head and neck often suffer from functional impairment and aesthetic deformity which significantly affect the quality of life and may be life-threatening. Treatment with sirolimus has the potential to improve symptoms and downsize lymphatic malformations. This systematic review summarizes the current information about sirolimus treatment of lymphatic malformations of the head and neck in children, its efficacy and side effects. METHODS: A systematic search of the literature regarding studies on sirolimus treatment of children with lymphatic malformations of the head and neck was performed in PubMed, Embase, and Google Scholar up to July 2021 with the search terms "lymphatic malformation", "lymphangioma", "cystic hygroma", "low-flow malformation", "sirolimus", "rapamycin", "mTOR inhibitor" and "children". RESULTS: In all, 28 studies including 105 children from newborn to 17 years treated with sirolimus for lymphatic malformations of the head and neck were analyzed. The most frequent initial dose was 0.8 mg/m2 per dose, twice daily at 12-h interval. The target blood level differed between studies, 10-15 ng/mL and 5-15 ng/mL were most often used. More than 91% of the children responded to sirolimus treatment which lasts from 6 months to 4 years. Typical side effects were hyperlipidemia, neutropenia and infections. METHODS: Sirolimus could be an effective treatment for children with large complicated lymphatic malformations of the head and neck. As not all patients will benefit from treatment, the decision to treat sirolimus should be made by a multidisciplinary team.

Screening for distress, related problems and perceived need for psycho-oncological support in head and neck squamous cell carcinoma (HNSCC) patients: a retrospective cohort study.

BACKGROUND: In different cancer entities, several studies have shown the adverse effects of cancer on mental health, psychological well-being and the increased risk of high emotional distress in cancer patients. This study aims to analyze psychosocial distress levels and their relationship between sociodemographic parameters and selected items on the Distress Thermometer (DT) Problem List in head and neck squamous cell carcinoma (HNSCC) patients. PATIENTS AND METHODS: We assessed a total of 120 HNSCC patients using the Distress Thermometer (DT) Problem List. Distress scores (DTS) of 90 patients were available. A DTS of ≥ 5 on the visual analogue scale represents clinically relevant distress. Data analysis consisted of descriptive statistics, comparison of mean values for different DTS subcategories and correlation between DTS scores and parameters of tumor classification, sociodemographic variables and selected problems. RESULTS: Distress was present in 57.7% of the sample, with a total of 52 patients with a DTS  ≥ 5. The mean DTS was 4.7 (SD 2.4). Patients with newly diagnosed HNSCC had significantly higher DTS. Distress levels were significantly associated with sadness, general worries, anxiety, nervousness, sleeping disorders, mouth sores and fever. Out of the total sample, 6 patients and out of these 6 individuals, 5 patients with a DTS ≥ 5 requested referrals to psycho-oncological service. CONCLUSION: High distress levels were common in HNSCC patients but only few patients desired psycho-oncological care. Addressing patients' supportive care needs in routine clinical practice is essential to meet unmet needs of HNSCC patients and thus improve cancer care.

Depression, anxiety, fatigue, and quality of life in a large sample of patients suffering from head and neck cancer in comparison with the general population.

BACKGROUND: Treatment of head and neck cancer (HNC) often leads to visible and severe functional impairments. In addition, patients often suffer from a variety of psychosocial problems, significantly associated with a decreased quality of life. We aimed to compare depression, anxiety, fatigue and quality of life (QoL) between HNC patients and a large sample of the general population in Germany and to examine the impact of sociodemographic, behavioral and clinical factors on these symptoms. METHODS: We assessed data of HNC patients during the aftercare consultation at the Leipzig University Medical Center with a patient reported outcome (PRO) tool named "OncoFunction". Depression, anxiety, fatigue and QoL were assessed using validated outcome measures including the PHQ-9, the GAD-2, and the EORTC QLQ-C30 questionnaire. RESULTS: A total of 817 HNC patients were included in our study and compared to a sample of 5018 individuals of the general German population. HNC patients showed significantly higher levels of impairment in all dimensions assessed. Examination of association between depression, anxiety, fatigue and QoL and clinical as well as sociodemographic variables showed significant relationships between occupational status, ECOG-state, body mass index and time since diagnosis. CONCLUSIONS: HNC patients suffer significantly from psychological distress. The used questionnaires are suitable for the use in daily routine practice and can be helpful to increase the detection of depression, anxiety and fatigue and therefore can improve HNC aftercare.

Demonstration of Muon-Beam Transverse Phase-Space Compression.

We demonstrate efficient transverse compression of a 12.5 MeV/c muon beam stopped in a helium gas target featuring a vertical density gradient and crossed electric and magnetic fields. The muon stop distribution extending vertically over 14 mm was reduced to a 0.25 mm size (rms) within 3.5 µs. The simulation including cross sections for low-energy µ^{+}-He elastic and charge exchange (µ^{+}↔ muonium) collisions describes the measurements well. By combining the transverse compression stage with a previously demonstrated longitudinal compression stage, we can improve the phase space density of a µ^{+} beam by a factor of 10^{10} with 10^{-3} efficiency.

[Organ preservation in advanced laryngeal/hypopharyngeal carcinoma: lessons from the DeLOS-II trial]. / Organerhalt beim fortgeschrittenen Larynx­/Hypopharynxkarzinom: Erfahrungen aus der DELOS-II-Studie.

Patients with locoregionally advanced laryngeal and hypopharyngeal squamous cell carcinomas (LHSCC) comprise two broad groups: those who are candidates for functional larynx preservation (LP) with avoidance of ablative surgery and those who are not. Currently, treatment depends on the patient's needs and wishes, the experience and recommendation of the surgeon, the philosophy of the institution, etc. The milestone VA trial established non-surgical LP in advanced LHSCC in the 1990s using induction chemotherapy (IC) with PF (cisplatin, P, plus 5­fluorouracil, F) followed by irradiation (IC + RT) as an appropriate alternative treatment to total laryngectomy (TL). Even though the findings of the VA trial were verified by the EORTC 24891 trial, a debate persists regarding the best protocol for balancing survival and laryngectomy-free survival (LFS) with acceptable late toxicity and good functional outcome. In advanced LHSCC without surgical options for larynx preservation, only IC + RT or primary concurrent platin-based chemoradiotherapy (CRT) are accepted treatment options aiming to preserve a functional larynx. In the US, cisplatin-based CRT is exclusively recommended as the best curative protocol. With regards to long-term survival with functional organ preservation and persistently high failure rates, there is current discussion on the necessity of improving patient selection based on the current literature and the recently published data of the DeLOS-II trial.

Induction chemotherapy (IC) followed by radiotherapy (RT) versus cetuximab plus IC and RT in advanced laryngeal/hypopharyngeal cancer resectable only by total laryngectomy-final results of the larynx organ preservation trial DeLOS-II.

Background: The German multicenter randomized phase II larynx organ preservation (LOP) trial DeLOS-II was carried out to prove the hypothesis that cetuximab (E) added to induction chemotherapy (IC) and radiotherapy improves laryngectomy-free survival (LFS; survival with preserved larynx) in locally advanced laryngeal/hypopharyngeal cancer (LHSCC). Patients and methods: Treatment-naïve patients with stage III/IV LHSCC amenable to total laryngectomy (TL) were randomized to three cycles IC with TPF [docetaxel (T) and cisplatin (P) 75 mg/m2/day 1, 5-FU (F) 750 mg/m2/day days 1-5] followed by radiotherapy (69.6 Gy) without (A) or with (B) standard dose cetuximab for 16 weeks throughout IC and radiotherapy (TPFE). Response to first IC-cycle (IC-1) with ≥30% endoscopically estimated tumor surface shrinkage (ETSS) was used to define early responders; early salvage TL was recommended to non-responders. The primary objective was 24 months LFS above 35% in arm B. Results: Of 180 patients randomized (July 2007 to September 2012), 173 fulfilled eligibility criteria (A/B: larynx 44/42, hypopharynx 41/46). Because of 4 therapy-related deaths among the first 64 randomized patients, 5-FU was omitted from IC in the subsequent 112 patients reducing further fatal toxicities. Thus, IC was TPF in 61 patients and TP in 112 patients, respectively. The primary objective (24 months LFS above 35%) was equally met by arms A (40/85, 47.1%) as well as B (41/88, 46.6%). One hundred and twenty-three early responders completed IC+RT; their overall response rates (TPF/TP) were 94.7%/87.2% in A versus 80%/86.0% in B. The 24 months overall survival (OS) rates were 68.2% and 69.3%. Conclusions: Despite being accompanied by an elevated frequency in adverse events, the IC with TPF/TP plus cetuximab was feasible but showed no superiority to IC with TPF/TP regarding LFS and OS at 24 months. Both early response and 24 months LFS compare very well to previous LOP trials and recommend effective treatment selection and stratification by ETSS. Clinical trial information: NCT00508664.

Spatial hole burning in thin-disk lasers and twisted-mode operation.

Spatial hole burning prevents single-frequency operation of thin-disk lasers when the thin disk is used as a folding mirror. We present an evaluation of the saturation effects in the disk for disks acting as end mirrors and as folding mirrors, explaining one of the main obstacles toward single-frequency operation. It is shown that a twisted-mode scheme based on a multi-order quarter-wave plate combined with a polarizer provides an almost complete suppression of spatial hole burning and creates an additional wavelength selectivity that enforces efficient single-frequency operation.

Highlights from the Second International Symposium on HPV infection in head and neck cancer.

The Second International Symposium on HPV Infection in Head and Neck Cancer was held on 3rd-4th November 2016 in Leipzig, Germany. The meeting brought together researchers and clinicians to share the latest knowledge on HPV infection in head and neck cancer and to join active and constructive scientific discussions. This report summarizes the major themes discussed during the symposium.

[Preclinical models to establish innovative therapy strategies : Ex­vivo assessment of head and neck tumor chemo- and immune responses]. / Präklinische Modelle zur Etablierung innovativer Therapiestrategien : Ex­vivo­Testung der Chemo­ und Immunresponse von Kopf­Hals­Tumoren.

The pharmacological treatment of head and neck squamous cell carcinoma (HNSCC) is currently experiencing an expansion of the spectrum of targeting therapies. It can be expected that use of immune modulators, e.g., checkpoint-inhibitors, and their combination with chemotherapy will lead to a plethora of therapeutic options in the near future, from which the best one for the individual patient can be selected. HNSCCs are heterogeneous in their biology, and responses to chemotherapy are nonuniform and often only observable in subgroups. It would be valuable to know the chance of success of a particular treatment in advance. Evidence-based selection of the best individual treatment is difficult, since predictive biomarkers which are assessable prior to the treatment decision and reliably indicate the suitability of particular therapeutics are lacking. Pretherapeutic predictive ex-vivo chemoresponse testing of HNSCC biopsy specimens could enable identification of responders and allow a more suitable therapy regimen to be chosen for potential non-responders, without exposing them to likely ineffective therapy attempts. However, early ex-vivo assays failed regarding reliable prediction of therapeutic success, even with tolerable doses of pharmaceuticals and, in particular, their combinations. Predictive testing was hence deemed improper for the clinic. Improved methodology has now led to a reappraisal of predictive testing and its additional use in analysis of antitumor immune responses ex vivo. Here we describe recent advances and new results from ex-vivo chemoresponse testing of HNSCC and highlight their ability to facilitate establishment of innovative therapy strategies.

[HPV-associated head and neck cancer : mutational signature and genomic aberrations]. / HPV-assoziierte Kopf­Hals­Karzinome : Mutationssignaturen und genomische Aberrationen.

A significantly increasing proportion of oropharyngeal head and neck carcinomas (OSCC) in North America and Europe are associated with human papillomavirus (HPV) infections. HPV-related OSCC is regarded as a distinct tumor type with regard to its cellular, biologic, and clinical characteristics. Patients with HPV-related OSCC have significantly better local control, but higher rates of regional lymph node and distant metastases as compared to patients with HPV-negative OSCC. Classical molecular genetic investigations demonstrated specific chromosomal aberration signatures in HPV-related OSCC, and recent developments in next generation sequencing (NGS) technology have rendered possible the sequencing of entire genomes, and thus detection of specific mutations, in just a few days. Initial data from The Cancer Genome Atlas (TCGA) project obtained by using genome-wide high throughput methods have confirmed that HPV-related OSCC contain fewer, albeit more specific mutations than HPV-negative tumors. Additionally, these data revealed the presence of specific-potentially therapeutically targetable-activating driver mutations in subgroups of HPV-positive OSCC, some of which have a prognostic impact. Specific targeted NGS technologies provide new possibilities for identification of diagnostic, prognostic, and predictive biomarkers and the development of personalized cancer treatment. Patients with HPV-positive tumors are likely to profit from these developments in the future, since the genetic alterations are relatively homogenous and frequently lead to signal pathway activation. There is an urgent need for network research activities to carry out the necessary basic research in prospective cohort studies.

[Gene expression analyses and their possible clinical benefit in head and neck cancer]. / Genexpressionsanalysen und ihrmöglicher klinischer Nutzen inder Betrachtung der Kopf-Hals-Karzinome

Systems biology approaches for mutational (exome analysis and targeted sequencing) and gene expression analysis (transcriptome-wide gene expression profiling) represent a new and growing scientific field in head and neck oncology. In addition to medical biological expertise, bioinformatic assistance is increasingly required. For squamous cell head and neck cancer (HNSCC), the recent molecular genetic single-gene and signal pathway observations represent basic research. Important aspects of this have now been significantly enhanced by systems biology approaches, which have grown into relevant areas of translational clinical research. It is now known that HPV16 is associated with genetic alterations at various locations, but also that it functionally affects genes not altered in their base sequence at the level of methylation. In transcriptome analyses, various consortia found matching clusters of gene expression and HPV16 association with the spectrum of somatic mutations. The differential methylation of gene promoters discovered in HPV16-driven HNSCC proved predictive for survival­even in HNSCC patients without HPV detection. The authors present an overview of some translationally relevant findings and venture an outlook on possible future clinical developments.

Impact of indication-shift of primary and adjuvant chemo radiation in advanced laryngeal and hypopharyngeal squamous cell carcinoma.

Based on level I evidence, postoperative platinum-based radiochemotherapy (PORCT) is the recommended standard of care in defined risk situations after resection of squamous cell carcinomas of the larynx and hypopharynx (LHSCC). The value of the addition of chemotherapy to adjuvant radiation in intermediate and high risk situations other than extracapsular spread or R1-/R2 resection is still debated. From 1993 to 2009, 555 patients (median follow-up: 24.4 months) with advanced LHSCC (UICC stages III-IVB) were treated in a curative intent. Patient data were continuously documented in the county of Leipzig cancer registry and were retrospectively analyzed as mono institutional survey. PORCT was introduced into the standard procedures in 2004, but also applied before in selected cases. Based on this paradigm shift, the patient population was divided into two comparative groups treated before and after 2004. 361 patients were treated before 2004. 43.8 % received primary surgery (OP) + postoperative radiotherapy (PORT) and 20.2 % OP + PORCT. 194 patients were treated after 2004: 21.1 % received OP + PORT and 35.6 % OP + PORCT. Regarding the PORCT groups, 20.6 % received cisplatin plus 5FU before 2004 which shifted to 59.4 % after 2004. The 3-year tumor-specific-survival rate of the whole cohort was improved from 47 to 60 % (p = 0.006). The subgroup treated with OP + PORT or PORCT improved from 56.1 to 68.5 % (p = 0.028). Localization proved to be a significant and independent factor. Only patients with advanced laryngeal cancer had significant improved survival (p < 0.01), while the improvement for hypopharyngeal cancer patients was not significant (p < 0.2). After 2004, there was a slight increase (+10.2 %) of primary radiochemotherapy (pRCT) due to stronger selection if R0 > 5 mm-resectability is unlikely. Standardised use of PORCT and pRCT considering clear indications showed to be significantly involved in improved survival in advanced LHSCC.

Slice cultures from head and neck squamous cell carcinoma: a novel test system for drug susceptibility and mechanisms of resistance.

BACKGROUND: Human head and neck squamous cell carcinoma (HNSCC) fundamentally vary in their susceptibility to different cytotoxic drugs and treatment modalities. There is at present no clinically accepted test system to predict the most effective therapy for an individual patient. METHODS: Therefore, we established tumour-derived slice cultures which can be kept in vitro for at least 6 days. Upon treatment with cisplatin, docetaxel and cetuximab, slices were fixed and paraffin sections were cut for histopathological analysis. RESULTS: Apoptotic fragmentation, activation of caspase 3, and cell loss were observed in treated tumour slices. Counts of nuclei per field in untreated compared with treated slices deriving from the same tumour allowed estimation of the anti-neoplastic activity of individual drugs on an individual tumour. CONCLUSION: HNSCC-derived slice cultures survive well in vitro and may serve not only to improve personalised therapies but also to detect mechanisms of tumour resistance by harvesting surviving tumour cells after treatment.

Individual and combined effects of mycotoxins from typical indoor moulds.

The mycotoxins patulin, gliotoxin and sterigmatocystin can be produced by common indoor moulds and enter the human body via inhalation of mycotoxin containing spores and particulates. There are various studies about the individual effects of these mycotoxins, but a lack of knowledge about their effects in mixtures. The aim of this study was to evaluate combined effects on the singe celled organism Tetrahymena pyriformis. Using the MIXTOX model (EU project NOMIRACLE) synergistic or antagonistic effects with dose level deviation or dose ratio dependent deviation were analyzed. The most toxic compound gliotoxin (EC50 0.37 µM) and patulin (EC50 9.3 µM) as shown by the MIXTOX model acted synergistic, caused by similar mode of actions. Within the combination with sterigmatocystin (maximum inhibition of 45% at 12.5 µM) antagonistic effects were observed with switch to synergism if the toxicity of the mixture is mainly caused by sterigmatocystin. In the end the MIXTOX model was applicable for the prediction of combined effects of toxic compounds.

[Multimodal laryngeal preservation: current data-based opinion]. / Multimodaler Larynxerhalt: Wege zur besseren Patientenselektion.

This article presents the current data and discussion on multimodal laryngeal preservation strategies in advanced laryngeal/hypopharyngeal carcinoma. Principally a distinction is made between simultaneous and induction chemoradiation protocols. In terms of late toxicity and related functional limitations, induction protocols are far superior to simultaneous platinum-based chemoradiation. Currently, the individual response to the first cycle of (short) induction chemotherapy appears to be the most reliable clinical marker for making treatment decisions, and this is under clinical investigation. No standard multimodal therapeutic alternative to laryngectomy exists; therefore, at this time multimodal strategies should only be carried out within the framework of clinical trials.

[Translational research in head and neck cancer. Biological characteristics and general aspects]. / Translationale Forschung bei Kopf-Hals-Tumoren. Biologische Besonderheiten und generelle Problematik.

Translational research in head and neck oncology is subject to the same laws as all other solid tumors. It is based on the one hand on a solid framework of well prepared clinical studies and / or workflows according to consensus criteria with comparable documentation of clinical outcomes, while on the other on methodolgically solid and reproducible laboratory research within an effeciently interacting network. Translationally applicable single molecular markers from basic research [with the exception of p16(INK4a) as a surrogate marker for human papillomavirus (HPV)] have not found their way into clinical routine in head and neck squamous cell carcinoma (HNSCC). "Correlated gene sets" and "metagenes", including genetic profiling (omics) within clinically characterized patient groups, play an increasing role in the translational research of HNSCC. Although methodological problems currently hinder clinical oncological research, increasing focus on translational research can be observed.

[Translational approaches in cancer stem cell research]. / Translationsansätze in der Tumorstammzellforschung.

There has been a growing body of evidence in recent years to indicate that the presence of cancer stem cells may be responsible for tumour development and early recurrence after conventional therapy strategies such as surgery, radiation, or chemotherapy. Although this concept of a small subpopulation of cancer cells with stem cell properties is not new as such and was already discussed by Virchow decades ago, the identification of cells of this kind in human malignancies was first successful in 1997 in acute myeloid leukemia. The recent identification of cancer stem cells and the detection of their fundamental signalling pathways (e.g. Hedgehog, Notch) may offer new therapeutic options in the future and become part of a therapeutic concept. In this article, we introduce the cancer stem cell model, provide an overview of current cancer stem cell markers in different human malignancies as well as head and neck squamous cell carcinoma, and discuss studies on the first targeted therapies against cancer stem cells and their signalling pathways.

[Pharmacological characterization of head and neck cancer in ex-vivo tests]. / Pharmakologische Charakterisierung von Kopf-Hals-Tumoren in Ex-vivo-Tests.

Precise knowledge about the chance of success of a given pharmacologic therapy of head and neck squamous cell carcinoma (HNSCC) before starting therapy would be very desirable to guide the selection of the most suitable or the most efficient combination out of the ever-growing spectrum of available pharmaceuticals. This selection has hitherto been made at best on the basis of the availability of guideline-conformant and approved combinations according to results of published clinical studies and approved general effectiveness in HNSCC. However, the inhomogeneous biology of HNSCC depending on localization, varying metastatic behavior, TNM and UICC stage in the context of the patient's general condition and risk status according to lifestyle and occupational exposure make it impossible to accurately predict the success of pharmacological therapy regimens for the individual HNSCC based on today's clinical and pathohistological diagnostics. A solution may lie in the testing of biopsy specimens ex vivo before starting therapy. The present review describes recent advances in ex-vivo tests and discusses the requirements for their inclusion in the decision-making process.