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Our aim was to evaluate possible short and long-term benefits of 3-dimensional (3-D) compared to 2-dimensional (2-D) laparoscopy for benign hysterectomy. Primary outcomes were long-term quality of life and postoperative pain. Secondary outcomes were operative time, surgical complications, time to return to work and length of hospitalization. A randomized controlled trial conducted at two Danish university hospitals. In each arm, 190 patients were needed for an alpha of 3.3 % and a power of 90 %. For various reasons, however, the study was prematurely terminated after including 97 patients. Patients were randomized to either 2-D (n = 48) or 3-D (n = 49) laparoscopy. A laparoscopic hysterectomy was performed. Quality of life was assessed by the Short Form Health Survey 36 (SF-36) questionnaire at the time of inclusion and 6 weeks postoperatively. Postoperative pain was assessed using a Numeric Rating Scale (NRS) and by monitoring the amount of analgesic consumption. Out of the 97 randomized patients, 77 patients completed both SF-36 questionnaires. No significant differences in mental (p = 0.5) and physical status (p = 0.9) were found. The 2-D group had significantly higher pain-score registered in the post anesthesia care unit (PACU) (p = 0.004) and higher consumption of oral morphine equivalent dose (MEqD) (p = 0.003) than the 3-D group. This regardless a higher rate of minilaparotomies in the 2D (n = 7) than in the 3D (n = 1) group (p < 0.03). The 2-D group had also higher rate of Clavien-Dindo 2 (CD2) (n = 2) and Clavien-Dindo 3 (CD3) complications (n = 3) (p = 0.03) than 3-D (n = 0). The other secondary outcome parameters did not vary between groups. The results are severely hampered by the premature termination of the study, as less than 25 percent of the patients were recruited. Thus, no firm conclusions can be drawn regarding the quality of life and many of the secondary outcomes, as the lack of difference may be attributed to a type 2 error. However, the significant differences in postoperative pain and in complication rates suggest a greater advantage of 3-D laparoscopy than originally expected. Despite the methodological problems, the current data deserve attention in a sparsely investigated field, emphasizing the urgent need for further studies. [ABSTRACT FROM AUTHOR]

The article focuses on correlation and prognostic impact of human papilloma virus and p16-expression in advanced hypopharynx and larynx cancer treated with definitive radiotherapy. Topics include the human papilloma virus (HPV) is a well-established aetiological factor in oropharynx cancer (OPC), the global variation in the incidence of HPV plus OPC is considerable, and the countries with high age standardized incidence rates of the disease are located in Northern America and Europe.

Abstract Background and purpose Evaluate the prognostic and predictive impact of HPV-associated p16-expression and assess the combined prognostic impact of p16 and smoking on altered fractionated radiotherapy (AFRT) for oropharyngeal cancer (OPC) within the frames of the update of the Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH). Materials and methods Patients with OPC, known tumor p16-status and smoking history were identified from the MARCH update, resulting in a dataset of 815 patients from four randomized trials (RTOG9003, DAHANCA6&7, RTOG0129, ARTSCAN). Analysis was performed using a Cox model stratified by trial and adjusted on gender, age, T-stage, N-stage, type of radiotherapy fractionation, p16, smoking. Primary endpoint was progression-free survival (PFS). Results In total, 465 patients (57%) had p16-positive tumors and 350 (43%) p16-negative. Compared to p16-negative, p16-positive patients had significantly better PFS (HR = 0.42 [95% CI: 0.34–0.51], 28.9% absolute increase at 10 years) and OS (HR = 0.40 [0.32–0.49], 32.1% absolute increase at 10 years). No interaction between p16-status and fractionation schedule was detected. Smoking negatively impacted outcome; in the p16-positive subgroup, never smokers had significantly better PFS than former/current smokers (HR = 0.49 [0.33–0.75], 24.2% survival benefit at 10 years). Conclusions No predictive impact of p16-status on response to AFRT could be detected but the strong prognostic impact of p16-status was confirmed and especially p16-positive never smoking patients have superior outcome after RT. [ABSTRACT FROM AUTHOR]

The prognosis after primary (chemo-)radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC) is affected by Human Papillomavirus (HPV) status, with a better prognosis in HPV-positive OPSCC. HPV-status is routinely assessed by p16 immunohistochemistry (IHC), but additional HPV DNA testing is debated. Also, there are numerous HPV genotypes, which prognostic role may need clarification. The purpose of this study was: (1) to test a custom-made targeted HPV next generation sequencing (NGS) panel in OPSCC, (2) to determine correlation with p16 IHC, and (3) to assess the impact of HPV DNA testing on outcome in the prospectively randomized clinical trial DAHANCA 19. We included 271 patients with OPSCC treated with primary (chemo-)radiotherapy in the DAHANCA 19 trial. Of these, 199 (73%) were p16-positive. HPV-status was determined by targeted HPV next generation sequencing (NGS), using a custom-made HPV genotyping panel. HPV was detected in 194 tumor samples. p16 IHC and NGS HPV status were concordant in 265 (98%) of 271 patients, whereas we did not detect HPV DNA in 5 p16-positive tumors. HPV16 accounted for 169 of 194 HPV-positive cases (87%). HPV genotypes 18, 31, 33, 35, and 59 were also detected. Loco-regional failure and overall survival were similar whether patients were separated by p16 IHC, or HPV DNA status (p < 0.0001 for all) and did not depend on HPV genotype (p = 0.9 and p = 0.7). In the present study, HPV DNA testing or typing in a Danish OPSCC cohort did not add additional information to p16 IHC, the most widely used and accepted prognostic indicator. [ABSTRACT FROM AUTHOR]

The socioeconomic differences in survival are pronounced for patients diagnosed with head and neck cancer; disease stage at diagnosis is suggested to be a main driver of this association. This nationwide, population-based study investigates socioeconomic differences in the pre-diagnostic interval and disease stage at diagnosis. Information on patient-reported symptoms, symptom onset and disease-specific factors was obtained from the nationwide population-based Danish Head and Neck Cancer Group (DAHANCA) database for patients diagnosed with head and neck squamous cell carcinoma between 2008 and 2019 in Denmark. Socioeconomic position (SEP) was measured by individual-level education, income and cohabitation status obtained from administrative registers. Socioeconomic differences in the interval from symptom onset to diagnosis were investigated in general linear models with 95% confidence intervals (CIs); overall and by subsite, symptom and comorbidity score. Consultation patterns prior to diagnosis were examined using methods for change-point detection. Associations with advanced-stage disease were estimated in logistic regression models. Patients with low, medium and high SEP had a similar interval from patient-reported symptom onset to diagnosis of 10 weeks. Although this interval varied according to primary symptom and anatomical subsite, no apparent socioeconomic differences were observed within these subgroups. Aligned with the patient-reported symptom onset, a distinct increase in consultation rates was observed at 9 weeks (95% CI [7.3; 10.7]) for patients with low SEP and 7 weeks (95% CI [4.8; 9.2]) for patients with high SEP, with overlapping CIs. Patients with low compared to high SEP had increased odds for advanced-stage glottic and oral cavity squamous cell carcinoma. For the remaining subsites the association varied according to SEP-indicator and TNM-edition. The interval from symptom onset to diagnosis and consultation patterns were similar across SEP groups. Still, socioeconomic differences in stage at diagnosis were observed for some – but not all – subsites. [ABSTRACT FROM AUTHOR]

Phosphorylation and glycosylation are important protein modifications in the mammalian brain acting as drivers of neural development, neurotransmission signalling and neurite elongation as well as synaptic morphology. Despite their important functional roles in the brain, only a few studies have elucidated them in neurodegenerative diseases such as Alzheimer's disease. Here, we comprehensively review Alzheimer's pathology in relation to protein phosphorylation and glycosylation on synaptic plasticity from neuroproteomics data. Moreover, we highlight several mass spectrometry-based sample processing technologies including an in-house developed TiO 2 -SIMAC-TiO 2 -based enrichment protocol to isolate and enrich phosphorylated and glycosylated peptides enabling to elucidate hopefully new early disease biomarkers. [ABSTRACT FROM AUTHOR]

Background and purpose HPV is found in head and neck cancer from all sites with a higher prevalence in oropharynx cancer (OPC) compared to non-OPC. HPV/p16-status has a significant impact on radiotherapy (RT) outcome in advanced OPC, but less is known about the influence in non-OPC. We analyzed HPV-associated p16-expression in a cohort of patients with stage III–IV pharynx and larynx cancer treated with primary, curatively intended (chemo-)RT, aiming to test the hypothesis that the impact of HPV/p16 also extends to tumors of non-oropharyngeal origin. Material and methods 1294 patients enrolled in previously conducted DAHANCA-trials between 1992 and 2012 were identified. Tumors were evaluated by p16-immunohistochemistry and classified as positive in case of staining in >70% of tumors cells. Results Thirty-eight percent (490/1294) of the tumors were p16-positive with a significantly higher frequency in OPC (425/815) than in non-OPC (65/479), p < .0001. In OPC p16-positivity significantly improved loco-regional control (LRC) (adjusted HR [95% CI]: 0.43 [0.32–0.57]), event-free survival (EFS) (HR 0.44 [0.35–0.56]), and overall survival (OS) (HR: 0.38 [0.29–0.49]), respectively, compared with p16-negativity. In non-OPC no prognostic impact of p16-status was found for either endpoint: LRC (HR: 1.13 [0.75–1.70]), EFS (HR: 1.06 [0.76–1.47]), and OS (HR: 0.82 [0.59–1.16]). Conclusions The independent influence of HPV-associated p16-expression in advanced OPC treated with primary RT was confirmed. However, RT-outcome in the group of non-OPC did not differ by tumor p16-status, indicating that the prognostic impact may be restricted to OPC only. [ABSTRACT FROM AUTHOR]

Abstract: Aim: EGFR and HPV-associated p16 are among the most investigated biomarkers in head and neck cancer. The aim was to investigate the correlation and interaction between these two markers and to evaluate their potential prognostic significance when combined. Materials and methods: 336 Oropharyngeal carcinomas treated with primary radiotherapy (66–68Gy, 2fx/day, 10–12Gy/week) and with known EGFR/p16-status estimated semiquantitatively by immunohistochemistry were included in the study. Data were evaluated by EGFR-expression (high/low) and p16-status (positive/negative) consequently dividing tumours into four groups by combination of the biomarkers. Patient/tumour characteristics and complete 5-year follow-up were available. Results: Low EGFR-expression was significantly more common in p16-positive tumours compared to p16-negative, p <0.0001. p16 positivity showed a strong prognostic impact (p <0.0001, HR=0.22 [0.13–0.38]), whereas EGFR was a weak prognostic marker when local control was used as endpoint (p =0.03, HR=0.53 [0.29–0.94]). Combination of EGFR/p16 did not add significant information to p16 alone and by multivariable analysis only p16 showed significant prognostic information for all evaluated endpoints. Conclusions: Both EGFR and p16 bear prognostic information in oropharyngeal cancer, although p16 is, by far, the strongest prognostic factor. The markers seem to be correlated and this might have influence when evaluating the effect of EGFR inhibition in oropharyngeal tumours. [Copyright &y& Elsevier]

Background. Patients with head and neck squamous cell carcinoma (HNSCC) and a low level of hemoglobin often have a poor response to radiation that may be related to hypoxia-induced radioresistance. We have previously published the importance of hemoglobin level and the effect of transfusion by the results from the randomized DAHANCA 5 trial, including 414 patients in the analysis. Aim of the current analysis was to gain additional power by adding patients from the continued subrandomization in the DAHANCA 7 trial, now including a total of almost 1200 patients. Material and methods. Patients were randomized to treatment in the DAHANCA 5 and 7 study (nimorazole vs. placebo and five fx/week vs. six fx/week), and in addition, patients with 'low' pre-irradiation hemoglobin values (females <13 g/dl; males <14.5 g/dl) were subrandomized to plus or minus transfusion. Transfusion was given with packed red blood cells with the aim to achieve a hemoglobin level in the 'high' value range. Results. A total of 1166 patients were included, 701 patients had high hemoglobin levels and 465 had low hemoglobin levels. Among the low hemoglobin patients, 235 were randomized to receive transfusion. Patient characteristics and treatment arms were well balanced. In the majority of patients, transfusion resulted in increased hemoglobin levels although this decreased slightly throughout treatment as in the non-transfused patients. Overall, the patients with low hemoglobin level had a significant reduced probability of locoregional control, disease-specific and overall survival. In the low hemoglobin group, transfusion did not improve the outcome in locoregional control, disease-specific or overall survival. In multivariate analyses, HPV/p16 status, T and N classification were significant factors for all outcome measures, whereas there was no significant influence of transfusion or hemoglobin level on endpoints. Conclusion. Transfusion prior to and during radiation treatment did not improve the outcome in patients with HNSCC and low hemoglobin values, but may have a negative impact on survival. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Tumour HPV-positivity is a favourable prognostic factor in the radiotherapy of HNSCC, but the optimal radiotherapy regimen for HPV-positive HNSCC is not yet defined. Reducing overall treatment time is known to improve outcome in the radiotherapy of HNSCC as was also demonstrated in the randomised DAHANCA 6&7 trial. We aimed to assess the influence of tumour HPV-status, expressed by p16, on the response to accelerated fractionated radiotherapy in HNSCC through evaluation of the DAHANCA 6&7 trial. Materials and methods: Immunohistochemical detection of HPV-associated p16-expression was performed on FFPE-pre-treatment tumour-tissues from 794 patients enrolled in the DAHANCA 6&7 trial. The influence of tumour p16-status on loco-regional tumour control and survival as a function of fractionation schedule (5Fx/week vs 6Fx/week) was evaluated 5years after the completion of radiotherapy. Results: The significant and independent prognostic value of tumour p16-positivity in HNSCC radiotherapy was confirmed, with adjusted hazard ratios (HR) of 0.58 [0.43–0.78], 0.47 [0.33–0.67] and 0.54 [0.42–0.68] for loco-regional control, disease-specific and overall survival, respectively. Accelerated radiotherapy significantly improved loco-regional tumour control compared to conventional radiotherapy, adjusted HR: 0.73 [0.59–0.92] and the benefit of the 6Fx/week regimen was observed both in p16-positive (HR: 0.56 [0.33–0.96]) as well as in p16-negative tumours (HR: 0.77 [0.60–0.99]). Disease-specific survival was also significantly improved with accelerated radiotherapy in the group of p16-positive tumours (adjusted HR: 0.43 [0.22–0.82]). Conclusion: Accelerated radiotherapy significantly improves outcome in HNSCC compared to conventional fractionation. The observed benefit is independent of tumour p16-status and the use of a moderately accelerated radiotherapy regimen seems advantageous also for HPV/p16-positive HNSCC. [Copyright &y& Elsevier]

Abstract: The profound influence of Human papillomavirus (HPV) on the epidemiological pattern and clinical course of head and neck cancer (HNSCC) has led to a change in the traditional understanding of this disease entity. Separate therapeutic strategies based on tumour HPV status are under consideration and in this light provision of knowledge concerning the influence of tumour HPV on the radiation response in HNSCC appears highly relevant. This review provides a summary of the current understanding of the role of HPV in head and neck cancer with specific focus on the viral impact on radiotherapy outcome of HNSCC. [Copyright &y& Elsevier]

Abstract: Background: HPV/p16-positive head and neck cancers (HNSCC) show superior response to radiotherapy, compared with virus-negative tumours. Tumour hypoxia induces radioresistance and the randomised DAHANCA 5 trial found that the hypoxic cell radiosensitiser nimorazole significantly improved the outcome in HNSCC. Using p16-status as a retrospective stratification parameter, we aimed to assess the influence of p16-expression on the response to nimorazole in HNSCC. Materials and methods: Pre-treatment tumour blocks were available from 331 of the 414 patients in the DAHANCA 5 trial and evaluated by immunohistochemistry for p16-expression. The influence of p16-expression on outcome was analysed as a function of treatment group (nimorazole/placebo) 5years after radiotherapy. Results: Overall, patients treated with nimorazole had significantly better loco-regional control than did those given placebo: hazard ratio (HR) 0.70 [95% CI 0.52–0.93]. Positive expression of p16 also significantly improved outcome after radiotherapy (0.41 [0.28–0.61]). In the subgroup of patients with p16-negative tumours, loco-regional failure was more frequent in the placebo group than in the nimorazole group (0.69 [0.50–0.95]). However, in the p16-positive group, patients treated with nimorazole had a loco-regional control rate similar to patients given placebo (0.93 [0.45–1.91]). Conclusions: HPV/p16-expression significantly improved outcome after radiotherapy in HNSCC. Hypoxic modification improved outcome in HPV/p16-negative tumours but was of no significant benefit in HPV/p16-positive tumours, suggesting that hypoxic radioresistance may not be clinically relevant in these tumours. [Copyright &y& Elsevier]

A unique case of fetal goiter accompanied by bilateral ovarian cysts in a mother treated with methimazole for Graves'disease is reported. The abnormal findings were detected by ultrasound at 31 weeks of gestation. Umbilical fetal blood sampling revealed elevated serum TSH, normal concentrations of free T 4 , normal FSH and LH and high concentrations of E 2 . A series of weekly amniocenteses and intra-amniotic injections of levothyroxine was initiated, along with a reduction of the mother's methimazole dosage. The level of TSH in amniotic fluid was initially high, but was considerably reduced by each injection and followed by a gradual reduction of fetal goiter as well as the left ovarian cyst. The right cyst ruptured spontaneously. At 36 weeks + 4 days, the patient underwent elective caesarean section and gave birth to a female, weighing 2,880 g with 1- and 5-min Apgar scores of 10. The thyroid gland appeared normal in size, and cord blood TSH and free T 4 were both within normal limits. At ultrasound control 6 days later, the right ovarian cyst was not visible, while the left cyst was still present. Thus, our report supports previous findings that fetal goiter can be treated successfully with intra-amniotic injection of levothyroxine.More importantly, it shows that fetal hypothyroidism with elevated levels of TSH can be accompanied by ovarian cysts,suggesting interference between thyreotropic and gonadotropic hormones. [ABSTRACT FROM AUTHOR]

The benefits of laparoscopic hysterectomy are well documented and include less postoperative pain, shorter hospital stay and faster recovery. The objective of this study was to assess the feasibility of laparoscopic hysterectomy as an outpatient procedure. A total of 26 women regarded eligible for an accelerated approach were included. The mean duration of the operation was 40 min (range 23-60 min), with a blood loss of 50 mL (range 10-200 mL). Twenty-three left the hospital the same day (88%). One woman required overnight hospitalization because of a port hematoma, while two stayed for reasons unrelated to the surgery. Three other women were referred with minor problems to an urgent clinic appointment within the first month. Overall, the women were satisfied with the procedure, with a mean rating of 9 of 10 possible points. Thus, outpatient laparoscopic hysterectomy appeared to be safe and well accepted by selected patients. [ABSTRACT FROM AUTHOR]

Radiotherapy treatment planning hinges on a critical factor: the prescribed dose. Surprisingly, no consistent, standardised global approach to interpreting this prescription exists. This study aimed to examine and illustrate the variations in prescribed doses for the same treatment across North European and North American centres. The study analysed consecutively treated oropharynx cancer patients from six globally recognised radiotherapy departments. The criteria for inclusion encompassed curative IMRT or VMAT radiotherapy administered in 2017 or later. These centres were divided into three North American and three North European centres. Dose-volume histogram (DVH) data were extracted from the local treatment planning system for the Gross Tumour Volume (GTV), the high-dose Clinical Target Volume (CTV), and Planning Target Volume (PTV) for each patient. The DVH was sampled in 1 cGy dose bins across the 0 to 100 Gy range. All DVHs were scaled to a standard prescription of 70 Gy delivered in 35 fractions to facilitate straightforward comparisons across centres. No biological corrections were applied. For the three target volumes (GTV, CTV, PTV), we extracted and compared metrics such as D95% (Dose to 95% of the volume), D98%, D99%, V95% (Volume receiving 95% of the prescription dose), V105%, and V107%. We visually compared these metrics and conducted statistical testing using the Mann-Whitney U-test. Our study encompassed 1,375 patients treated across six centres, revealing a spectrum of 38 different dose prescriptions, ranging from 55 Gy in 20 to 70 Gy in 35 fractions. When normalised to 70 Gy, the median mean CTV dose exhibited a 4% difference, ranging from 70.12 Gy to 72.93 Gy across centres. Notably, the three European centres showed a high consistency, deviating by only 0.4%, while the three North American centres showed a slight variation within 2%. Figure 1 presents the mean CTV dose and the D98% boxplots. The interquartile range (IQR) for the mean CTV dose from 0.17 Gy to 1.22 Gy, with European centres showing the smallest IQR. [Display omitted] Examining the near-minimum CTV doses (D98% of CTV), we observed a range from 68.65 Gy to 70.96 Gy, with an IQR from 0.30 Gy to 1.15 Gy. A scatter plot of CTV mean dose against CTV D98% revealed distinct clusters for each of the six centres (Figure 2). Notably, the European centres cluster more densely compared to the North American centres. [Display omitted] The variation in prescribed doses for the same treatment regimen poses a significant challenge. Clinical interpretation of 70 Gy varies widely between centres and is influenced by each centre's individual experience, which, in turn, impacts the interpretation of published results. European centres primarily adhere to the ICRU dose prescription, targeting the median CTV dose. Conversely, North American centres tend to prescribe based on the minimum dose to the CTV or, in some cases, the PTV, as outlined in various RTOG protocols. Our study underscores that prescribing a dose of 70 Gy in 35 fractions for standard oropharynx cancer patients results in substantial variations in mean and near-minimum CTV doses. These dose prescription discrepancies significantly impact the interpretation of clinical trial outcomes comparison. Furthermore, this significant dosimetric variability has important implications for dose de-escalation strategies for HPV+ oropharynx cancer treatment. [ABSTRACT FROM AUTHOR]

Diverse post-translational modifications (PTMs) regulate protein function and interaction to fine-tune biological processes. Reversible phosphorylation, cysteines (Cys) modifications, and N-linked glycosylation are all essentially involved in cellular signaling pathways, such as those initiated by the action of pro-inflammatory cytokines, which can induce pancreatic β-cell death and diabetes. Here we have developed a novel strategy for the simultaneous and comprehensive characterization of the proteome and three PTMs including reversibly modified Cysteines (rmCys), phosphorylation, and sialylated N-linked glycosylation from low amount of sample material. This strategy, termed TiCPG, is based on a combination of chemical labeling and titanium dioxide (TiO 2) chromatography. We applied the TiCPG strategy to study the proteome and the three PTMs changes in β-cells subject to pro-inflammatory cytokines stimulation. It enabled quantitative analysis of 8346 rmCys sites, 10,321 phosphosites and 962 sialylated N-glycosites from 5496 proteins. Significant regulation was found on 100 proteins at the expression level, while 3020 PTM peptide isoforms from 1468 proteins were significantly regulated. The three PTMs were involved in cytokine mediated β-cell apoptosis, such as the NFκB and the inducible NO synthase signaling pathways. Overall, the TiCPG strategy is a cheap, straightforward, and powerful tool for studies targeting the three PTMs described above. The present study presents a fast and easy method for quantitative assessment of the proteome and three PTMs from minimal amount of sample material. This simple method provides comprehensive and significant knowledge on biological systems and cellular signaling with relatively low analysis time, suitable for younger researchers and researchers that do not have direct access to LC-MSMS in their laboratories. From sub-milligram amount of material, we were able to map known cellular signaling events of proinflammatory cytokine effect on beta-cells and to discover novel PTMs involved in several known signaling pathways. [Display omitted] • Presentation of a simple method to assess the proteome and three PTMs from low amount of biological material. • The TiCPG method is used to study changes in the three PTMs in INS-1E beta cells upon proinflammatory cytokine stimulation. • Using TiCPG to study the interplay between phosphorylation and reversibly modified cysteines in a biological system. [ABSTRACT FROM AUTHOR]

Objectives: To demonstrate the correlation between p16 overexpression and HPV in oropharyngeal carcinoma and to evaluate the prognostic impact of p16 status in a prospectively analyzed cohort of Danish oropharyngeal cancer patients. Materials and Methods: 32 tunsillar carcinomas were arranged in a Tissue Micro Array and evaluated by IHC for p16 overexpression. HPV-16 DNA detection was done by in situ hybridization. Between 1986 and 1999 The Danish Head and Neck Cancer group conducted the DAHANCA 5&7 randomized trials. In the present study 335 pre-treatment oropharyngeal tumour blocks from patients enrolled in these trials were evaluated by IHC for p16 status. Results: 20 of 32 (62.5%) tonsillar carcinomas were HPV-16 positive and 19 of these were p16 positive (sensitivity: 0.95). 12 turnouts were H PV-16 negative and 10 of these were p16 negative (specificity: 0.83). The two markers matched in 29 of 32 (90%) of the tumours. In total 135 of 335 (40%) oropharyngeal tumours were p16 positive. In univariate analysis, loco-regional turnout control was significantly improved for p16 positive tumours with 5-year actuarial values of 67% versus 36%, p < 0.0001. A similar beneficial outcome for p16 positive tumours was observed for cancer specific survival (69% versus 35%, p < 0.0001) and overall survival (54% versus 18%, p < 0.0001). In multivariate analysis p16 overexpression remained a very strong independent prognostic factor for loco-regional tumour control [OR: 0.35 (95% C.I. 0.24-0.51)], cancer specific death [OR: 0.28 (0.18-0.42)] and overall death [OR: 0.33 (0.24 0.46)] respectively. p16 was an even stronger prognostic factor related to these outcomes than T-stage and Nodal-status. Conclusions: p16 overexpression proved to be the strongest independent prognostic factor related to survival and loco-regional tumour control in our study and so we conclude that HPV infection is significantly correlated to improved prognosis and response to radiotherapy in oropharyngeal cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of the present study was to evaluate learning curves and short-term outcomes following laparoscopic surgery for early endometrial cancer in women of different body mass index (BMI) classes.Material and Methods: Data from 227 women planned for laparoscopic surgery for presumed stage I endometrial cancer were collected retrospectively from a Danish gynecologic oncology unit. Surgery included laparoscopic hysterectomy and bilateral salpingo-oophorectomy with or without pelvic lymphadenectomy (PLA).Results: Median length of operations was 60 min (range, 30-197) and 120 min (range, 60-230), depending on whether PLA was included. The median pelvic lymph node yield was 18 (range, 7-42). For staging with PLA there was a learning curve when measured as operative time as well as lymph node yield, and a level of proficiency was not reached after 40 operations. The women had a perioperative complication rate of 4.5% and a median hospital stay of one night. Postoperative complication rate was 12%, comprising vaginal cuff hematoma (3.1%), vaginal cuff rupture (0.9%), trocar hernia (1.3%), ureter lesion (0.4%), bowel lesion (0.4%), reoperation (0.9%) and other complications (4.5%). All peri- and postoperative outcomes were independent of BMI classes.Conclusions: Our data suggest that laparoscopic surgery for early endometrial cancer is feasible and safe. With increasing surgeon's experience there is a significant decrease in operative time and increase in the number of lymph nodes harvested. In experienced hands, either operative time, complications or length of stay are not affected by increasing BMI, even when women are morbidly obese. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To validate the predictive impact of a hypoxia gene expression classifier in identifying patients with head and neck squamous cell carcinoma (HNSCC) having benefit from hypoxic modification of radiotherapy. Patients and methods: Gene expressions were quantified from formalin-fixed, paraffin-embedded tumour biopsies of 323 HNSCC patients randomized for placebo or nimorazole in conjunction with radiotherapy in the DAHANCA 5 study. Tumours were classified as either “more” or “less” hypoxic with a classifier constituting of 15 hypoxia responsive genes. The predictive impact was evaluated by analysing the response to nimorazole vs. placebo in terms of loco-regional tumour control (LRC) and disease-specific survival (DSS) in the two classified groups. Results: Hundred and fourteen patients (35%) were classified as having “more” hypoxic tumours. These patients had a significant benefit of hypoxic modification with nimorazole compared with placebo in terms of LRC (5-year actuarial values 49% vs. 18%; p =0.001) and DSS (48% vs. 30%; p =0.04). “Less” hypoxic tumours had no significant effect of hypoxic modification (LRC: 50% vs. 44%; p =0.39, DSS: 57% vs. 51%; p =0.49) and generally an outcome, which was similar to “more” hypoxic tumours treated with nimorazole. In contrast to HPV-negative tumours, HPV-positive tumours had a substantially better outcome in response to radiotherapy, which was irrespective of hypoxic modification. Conclusions: A predictive 15-gene hypoxia classifier could identify patients associated with improved outcome after combining radiotherapy with hypoxic modification and underlines the relevance of such therapy. The impact of the classifier was limited to HPV-negative tumours. [Copyright &y& Elsevier]

In head and neck cancer, distant metastases may be present at diagnosis (M1) or occur after treatment (DM). It is unknown whether M1 and DM follow the same clinical development and share prognosis, as population-based studies regarding outcomes are scarce. Therefore, we investigated the incidence, location of metastases and overall survival of patients with M1 and DM. Patients diagnosed with squamous cell carcinoma of the pharynx and larynx in Denmark 2008–2017 were identified in the Danish Head and Neck Cancer Group (DAHANCA) database. We identified 7300 patients, of whom 197 (3%) had M1 and 498 (8%) developed DM during follow-up. The 5-year cumulative incidence of DM was 8%. 1- and 2-year overall survival for DM (27% and 13%) vs. M1 (28% and 9%) were equally poor. There was no significant difference in location of metastases for M1 and DM and the most frequently involved organs were lungs, bone, lymph nodes and liver, in descending order. In oropharyngeal squamous cell carcinomas, the location of metastases did not differ by p16-status. For p16-positive patients, 21% of DM occurred later than three years of follow-up compared to 7% of p16-negative patients. Incidence, location of metastases and prognosis of primary metastatic (M1) or post-treatment metastatic (DM) disease in pharyngeal and laryngeal squamous cell carcinoma are similar in this register-based study [ABSTRACT FROM AUTHOR]

To identify markers in the CSF of multiple sclerosis (MS) subtypes, we used a two-step proteomic approach: (i) Discovery proteomics compared 169 pooled CSF from MS subtypes and inflammatory/degenerative CNS diseases (NMO spectrum and Alzheimer disease) and healthy controls. (ii) Next, 299 proteins selected by comprehensive statistics were quantified in 170 individual CSF samples. (iii) Genes of the identified proteins were also screened among transcripts in 73 MS brain lesions compared to 25 control brains. F-test based feature selection resulted in 8 proteins differentiating the MS subtypes, and secondary progressive (SP)MS was the most different also from controls. Genes of 7 out these 8 proteins were present in MS brain lesions: GOLM was significantly differentially expressed in active, chronic active, inactive and remyelinating lesions, FRZB in active and chronic active lesions, and SELENBP1 in inactive lesions. Volcano maps of normalized proteins in the different disease groups also indicated the highest amount of altered proteins in SPMS. Apolipoprotein C-I, apolipoprotein A-II, augurin, receptor-type tyrosine-protein phosphatase gamma, and trypsin-1 were upregulated in the CSF of MS subtypes compared to controls. This CSF profile and associated brain lesion spectrum highlight non-inflammatory mechanisms in differentiating CNS diseases and MS subtypes and the uniqueness of SPMS. [ABSTRACT FROM AUTHOR]

Background: Oropharyngeal squamous cell carcinomas (OPSCC) are rising rapidly in incidence due to Human Papillomavirus (HPV) and/or tobacco smoking. Prognosis is better for patients with HPV-positive disease, but may also be influenced by tobacco smoking and other factors. There is a need to individualize treatment to minimize morbidity and improve prognosis. Patient-derived xenografts (PDX) is an emerging pre-clinical research model that may more accurately reflect the human disease, and is an attractive platform to study disease biology and develop treatments and biomarkers. In this study we describe the establishment of PDX models, compare PDX tumors to the human original, and assess the suitability of this model for radiotherapy research and biomarker development. Material and methods: Tumor biopsies from 34 patients with previously untreated OPSCC were implanted in immunodeficient mice, giving rise to 12 squamous cell carcinoma PDX models (7 HPV+, 5 HPV-). Primary and PDX tumors were characterized extensively, examining histology, immunohistochemistry, cancer gene sequencing and gene expression analysis. Radiosensitivity was assessed in vivo in a growth delay assay. Results: Established PDX models maintained histological and immunohistochemical characteristics as well as HPV-status of the primary tumor. Important cancer driver gene mutations, e.g., in TP53, PIK3CA and others, were preserved. Gene expression related to cancer stem cell markers and gene expression subtype were preserved, while gene expression related to hypoxia and immune response differed. Radiosensitivity studies showed high concordance with clinical observations. Conclusion: PDX from OPSCC preserves important molecular characteristics of the human primary tumor. Radiosensitivity were in accordance with clinically observed treatment response. The PDX model is a clinically relevant surrogate model of head and neck cancer. Perspectives include increased understanding of disease biology, which could lead to development of novel treatments and biomarkers. [ABSTRACT FROM AUTHOR]

Purpose To evaluate if correction of low hemoglobin (Hb) levels by means of darbepoetin alfa improves the outcomes of radiotherapy in patients with squamous cell carcinoma of the head and neck (HNSCC). Patients and methods Patients eligible for primary radiotherapy and who had Hb values below 14.0 g/dl were randomized to receive accelerated fractionated radiotherapy with or without darbepoetin alfa. Patients also received the hypoxic radiosensitizer nimorazole. Darbepoetin alfa was given weekly during radiotherapy or until the Hb value exceeded 15.5 g/dl. Results Following a planned interim analysis which showed inferiority of the experimental treatment the trial was stopped after inclusion of 522 patients (of a planned intake of 600). Of these, 513 were eligible for analysis (254 patients treated with darbepoetin alfa and 259 patients in the control group). Overall, the patients were distributed according to the stratification parameters (gender, T and N staging, tumor site). Treatment with darbepoetin alfa increased the Hb level to the planned value in 81% of the patients. The compliance was good without excess serious adverse events. The results showed a poorer outcome with a 5-year cumulative loco-regional failure rate of 47% vs. 34%, Hazard Ratio (HR): 1.53 [1.16–2.02], for the darbepoetin alfa vs. control arm, respectively. This was also seen for the endpoints of event-free survival (HR: 1.36 [1.09–1.69]), disease-specific death (HR: 1.43 [1.08–1.90]), and overall survival (HR: 1.30 [1.02–1.64]). There was no enhanced risk of cardio-vascular events observed in the experimental arm or any significant differences in acute or late radiation related morbidity. All univariate analyses were confirmed in a multivariate setting. Conclusion Correction of the Hb level with darbepoetin alfa during radiotherapy of patients with HNSCC resulted in a significantly poorer tumor control and survival. [ABSTRACT FROM AUTHOR]

Background: Hysterectomy is one of the most common surgical procedures for women of reproductive age. Laparoscopy was introduced in the 1990es and is today one of the recommended routes of surgery. A recent observational study showed that operative time for hysterectomy was significantly lower for 3-dimensional compared to conventional laparoscopy. Complication rates were similar for the two groups. No other observational studies or randomized clinical trials have compared 3-dimensional to conventional laparoscopy in patients undergoing total hysterectomy for benign disease. The objective of the study is to determine if 3D laparoscopy gives better quality of life, less postoperative pain, less per- and postoperative complications, shorter operative time, or a shorter stay in hospital and a faster return to work or normal life, compared to conventional laparoscopy for benign hysterectomy.Methods/design: The design is a randomised multicentre clinical trial. Participants will be 400 women referred for laparoscopic hysterectomy for benign indications. Patients will be randomized to 3-dimensional or conventional laparoscopic hysterectomy. Operative procedures will follow the same principles and the same standard whether the surgeon's vision is 3-dimensional or conventional laparoscopy. Primary outcomes will be the impact of surgery on quality of life, assessed by the SF 36 questionnaire, and postoperative pain, assessed by a Visual Analogue scale for pain measurement. With a standard deviation of 12 points on SF 36 questionnaire, a risk of type I error of 3.3% and a risk of type II error of 10% a sample size of 190 patients in each arm of the trial is needed. Secondarily, we will investigate operative time, time to return to work, length of hospital stay, and - and postoperative complications.Discussion: This trial will be the first randomized clinical trial investigating the potential clinical benefits and harms of 3-dimensional compared to conventional laparoscopy. The results may provide more evidence regarding the future place of 3-dimensional laparoscopy in the range of endoscopic approaches for benign hysterectomy.Trial Registration: This study is registered at ClinicalTrial.gov: NCT02610985 November 16th 2015. November 2015. The regional Ethical committee approved it on the 12. November 2015, approval number: SJ-498. Data handling was approved by the Danish Data Protection Agency: REG-109-2015 on the 13. November 2015. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Hypoxia is a cause of resistance to radiotherapy, especially in patients with head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to evaluate 18F-fluoroazomycin arabinoside (FAZA) positron emission tomography (PET)/computed tomography (CT) hypoxia imaging as a prognostic factor in HNSCC patients receiving radiotherapy. Material and methods: Forty patients with HNSCC treated with radiotherapy (66–76Gy) were included. Static FAZA PET/CT imaging 2h post injection was conducted prior to irradiation. The hypoxic volume (HV) was delineated using a tumor-to-muscle value ⩾1.4. In 13 patients, a repetitive FAZA PET/CT scan was conducted during the radiotherapy treatment. Results: A hypoxic volume could be identified in 25 (63%) of the 40 tumors. FAZA PET HV varied considerably with a range from 0.0 to 30.9 (median: 0.3) cm3. The Tmax/Mmed ranged from 1.1 to 2.9 (median: 1.5). The distribution of hypoxia among the Human Papillomavirus (HPV) positive (12/16) and negative (13/24) tumors was not significant different. In the FAZA PET/CT scans performed during radiotherapy, hypoxia could be detected in six of the 13 patients. For these six patients the location of HV remained stable in location during radiotherapy treatment, though the size of the HV decreased. In 30 patients a positive correlation was detected between maximum FAZA uptake in the primary tumor and the lymph node. During a median follow up of 19months a significant difference in disease free survival rate with 93% for patients with non hypoxic tumors and 60% for patients with hypoxic tumors could be detected. Conclusion: This study emphasizes the role of FAZA PET/CT imaging as a suitable assay with prognostic potential for detection of hypoxia in HNSCC. [Copyright &y& Elsevier]