Safe Stop IPI-NIVO trial: early discontinuation of nivolumab upon achieving a complete or partial response in patients with irresectable stage III or metastatic melanoma treated with first-line ipilimumab-nivolumab - study protocol.

BACKGROUND: Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy. METHODS: The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life. DISCUSSION: From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05652673, registration date: 08-12-2022.

Trends and Variation in the Use of Radiotherapy in Non-metastatic Rectal Cancer: a 14-year Nationwide Overview from the Netherlands.

AIMS: This study describes nationwide primary radiotherapy utilisation trends for non-metastasised rectal cancer in the Netherlands between 2008 and 2021. In 2014, both colorectal cancer screening and a new guideline specifying prognostic risk groups for neoadjuvant treatment were implemented. MATERIALS AND METHODS: Patients with non-metastasised rectal cancer in 2008-2021 (n = 37 510) were selected from the Netherlands Cancer Registry and classified into prognostic risk groups. Treatment was studied over time and age. Multilevel logistic regression analyses were carried out to identify factors associated with (i) radiotherapy versus chemoradiotherapy use for intermediate rectal cancer and (ii) chemoradiotherapy without versus with surgery for locally advanced rectal cancer. RESULTS: For early rectal cancer, the use of neoadjuvant radiotherapy decreased (15% to 5% between 2008 and 2021), whereas the use of endoscopic resections increased (8% in 2015, 17% in 2021). In intermediate-risk rectal cancer, neoadjuvant chemoradiotherapy (43% until 2011, 25% in 2015) shifted to radiotherapy (42% in 2008, 50% in 2015), the latter being most often applied in older patients. In locally advanced rectal cancer, the use of chemoradiotherapy without surgery increased (2-4% in 2008-2013, 17% in 2019-2021). Both neoadjuvant treatment in intermediate disease and omission of surgery following chemoradiotherapy in locally advanced disease varied with increasing age (odds ratio>75vs<50: 2.17, 95% confidence interval 1.54-3.06) and treatment region (Southwest and Northwest odds ratio 0.63, 95% confidence interval 0.42-0.93 and odds ratio 0.65, 95% confidence interval 0.44-0.95, respectively, compared with the North). CONCLUSION: Treatment patterns in non-metastasised rectal cancer significantly changed over time. Effects of both the national screening programme and the new treatment guideline were apparent, as well as a paradigm shift towards organ preservation (watch-and-wait). Observed regional variations may indicate adoption differences regarding new treatment strategies.

Seasonal variation of anti-PD-1 outcome in melanoma-Results from a Dutch patient cohort.

Despite the improved survival rates of patients with advanced stage melanoma since the introduction of ICIs, many patients do not have (long-term) benefit from these treatments. There is evidence that the exposome, an accumulation of host-extrinsic factors including environmental influences, could impact ICI response. Recently, a survival benefit was observed in patients with BRAF wild-type melanoma living in Denmark who initiated immunotherapy in summer as compared to winter. As the Netherlands lies in close geographical proximity to Denmark and has comparable seasonal differences, a Dutch validation cohort was established using data from our nationwide melanoma registry. In this study, we did not observe a similar seasonal difference in overall survival and are therefore unable to confirm the Danish findings. Validation of either the Dutch or Danish findings in (combined) patient cohorts from other countries would be necessary to determine whether this host-extrinsic factor influences the response to ICI-treatment.

Oral health-related quality of life in patients with oligodontia: A FACE-Q assessment.

OBJECTIVES: The present study aimed to investigate the impact of oligodontia on appearance and on the functional and psychosocial aspects of oral health-related quality of life (OHrQoL) in patients aged 8-29 years. METHODS: 62 patients with oligodontia that were registered at Radboud University Medical Center, Nijmegen, The Netherlands were included. A control group included 127 patients that were referred for a first orthodontic consultation. Participants completed the FACE-Q Dental questionnaire. Regression analyses were performed to explore relationships between OHrQoL and patient-identified gender, age, the number of congenitally missing teeth, active orthodontic treatment, and previous orthodontic treatment. RESULTS: The only clear significant difference between the oligodontia and control groups was that patients with oligodontia scored lower in the domain, 'eating and drinking' (p < 0.001). It was found that, in oligodontia, the greater the number of agenetic teeth, the more difficulties eating and drinking. In fact, the Rasch score was reduced by 1.00 (95% CI: 0.23-1.77; p = 0.012) for each extra agenetic tooth. Older children scored significantly lower than younger ones on five out of nine scales: appearance of the face, smile, and jaws; social function; and psychological function. Females scored significantly lower than males on four scales: appearance of the face, appearance distress, social function, and psychological function. CONCLUSION: These findings suggested that, when treating patients with oligodontia, the number of agenetic teeth, age, and gender should be taken into account. These factors could have negative effects on their self-assessment of appearance, their facial function, and their quality of life. CLINICAL SIGNIFICANCE: The increased difficulty with eating and drinking associated with more agenetic teeth highlighted the importance of functional (re)habilitation.

Health-state utilities in long-term advanced melanoma survivors comparable with the general population.

BACKGROUND: Checkpoint inhibitors have been shown to substantially improve the survival of patients with advanced melanoma. With this growing group of survivors treated with immunotherapies, assessing their health-state utilities is essential and can be used for the calculation of quality-adjusted life years and for cost-effectiveness analyses. Therefore, we evaluated the health-state utilities in long-term advanced melanoma survivors. METHODS: Health-state utilities were evaluated in a cohort of advanced melanoma survivors 24-36 months (N = 37) and 36-plus months (N = 47) post-ipilimumab monotherapy. In addition, the health-state utilities of the 24-36 months survivor group were assessed longitudinally, and utilities of the combined survival groups (N = 84) were compared with a matched control population (N = 168). The EQ-5D was used to generate health-state utility values, and quality-of-life questionnaires were used to establish correlations and influencing factors of utility scores. RESULTS: Health-state utility scores were similar between the 24-36 months'- and the 36-plus months' survival group (0.81 vs 0.86; p = .22). In survivors, lower utility scores were associated with symptoms of depression (ß = - .82, p = .022) and fatigue burden (ß = - .29, p = .007). Utility scores did not significantly change after 24-36 months of survival, and the utilities of survivors were comparable to the matched control population (0.84 vs 0.87; p = .07). DISCUSSION: Our results show that long-term advanced melanoma survivors treated with ipilimumab monotherapy experience relatively stable and high health-state utility scores.

Incisal Interference Correction after Severe Extrusive Luxation Trauma during Orthodontic Treatment.

This case report presents the treatment of a 12-year-old boy who suffered serious dental trauma, accompanied with buccal alveolar socket wall fractures, during orthodontic treatment. The maxillary right lateral incisor and canine were severely extruded and laterally luxated to the palatal side, resulting in an anterior crossbite and creating an incisal interference that prevented the jaws from closing in normal occlusion. During emergency treatment, the dentist attempted manual repositioning, but both severely extruded teeth were found to be immobile. One day after trauma, orthodontic repositioning was started using full fixed appliances with light 0.012″ nickel-titanium round wires, and this occlusal interference was corrected within 3 weeks. In the various internationally recognized treatment guidelines, the options for orthodontic repositioning for dental luxation trauma are only marginally described. Internationally accepted dental treatment guidelines may include immediate orthodontic repositioning after trauma as a treatment option in the management of dental extrusive and lateral luxation trauma.

Determinants influencing cholesteatoma recurrence in daily practice: a retrospective analysis.

BACKGROUND: Cholesteatoma is a benign but destructive epithelial lesion in the middle ear and/or mastoid. It is hard to translate data from previous research to daily clinical practice. In this study, factors influencing recurrence rates in daily clinical practice were identified. METHOD: The study included 67 patients who were treated for a cholesteatoma with combined approach tympanoplasty. The average follow-up time was 35 months. RESULTS: The recurrence rate was 23.3 per cent in adults and 45.5 per cent in children. Predictors of recurrence were younger age and a low tegmen. A cholesteatoma in a child and the simultaneous presence of a low tegmen led to recurrence in 82.8 per cent of the patients. CONCLUSION: Patients - especially children - with a low tegmen have an increased risk of recurrence. It is recommended that ENT surgeons be aware of recurrence in children, particularly in the case of a low tegmen.

Trends in survival and costs in metastatic melanoma in the era of novel targeted and immunotherapeutic drugs.

BACKGROUND: The objective of this study was to evaluate trends in survival and health care costs in metastatic melanoma in the era of targeted and immunotherapeutic drugs. MATERIALS AND METHODS: Data on survival and health care resource use were retrieved from the Dutch Melanoma Treatment Registry. The Kaplan-Meier method was used to estimate overall survival. Health care costs and budget impact were computed by applying unit costs to individual patient resource use. All outcomes were stratified by year of diagnosis. RESULTS: Baseline characteristics were balanced across cohort years. The percentage of patients receiving systemic treatment increased from 73% in 2013 to 90% in 2018. Patients received on average 1.85 [standard deviation (SD): 1.14] lines of treatment and 41% of patients received at least two lines of treatment. Median survival increased from 11.8 months in 2013 [95% confidence interval (CI): 10.7-13.7 months] to 21.1 months in 2018 (95% CI: 18.2 months-not reached). Total mean costs were €100 330 (SD: €103 699); systemic treatments accounted for 84% of the total costs. Costs for patients who received systemic treatment [€118 905 (SD: €104 166)] remained reasonably stable over the years even after the introduction of additional (combination of) novel drugs. From mid-2013 to 2018, the total budget impact for all patients was €452.79 million. CONCLUSION: Our study shows a gain in survival in the era of novel targeted and immunotherapeutic drugs. These novel drugs came, however, along with substantial health care costs. Further insights into the cost-effectiveness of the novel drugs are crucial for ensuring value for money in the treatment of patients with metastatic melanoma.

Survival of sentinel node biopsy versus observation in intermediate-thickness melanoma: A Dutch population-based study.

BACKGROUND: The Multicenter Selective Lymphadenectomy Trial (MSLT-1) comparing survival after a sentinel lymph node biopsy (SLNB) versus nodal observation in melanoma patients did not show a significant benefit favoring SLNB. However, in subgroup analyses melanoma-specific survival among patients with nodal metastases seemed better. AIM: To evaluate the association of performing a SLNB with overall survival in intermediate thickness melanoma patients in a Dutch population-based daily clinical setting. METHODS: Survival, excess mortality adjusted for age, gender, Breslow-thickness, ulceration, histological subtype, location, co-morbidity and socioeconomic status were calculated in a population of 1,989 patients diagnosed with malignant cutaneous melanoma (1.2-3.5 mm) on the trunk or limb between 2000-2016 in ten hospitals in the South East area, The Netherlands. RESULTS: A SLNB was performed in 51% of the patients (n = 1008). Ten-year overall survival after SLNB was 75% (95%CI, 71%-78%) compared to 61% (95%CI 57%-64%) following observation. After adjustment for risk factors, a lower risk on death (HR = 0.80, 95%CI 0.66-0.96) was found after SLNB compared to observation only. CONCLUSIONS: SLNB in patients with intermediate-thickness melanoma on trunk or limb resulted in a 14% absolute and significant 10-year survival difference compared to those without SLNB.

Development of a prognostic risk model for clear cell renal cell carcinoma by systematic evaluation of DNA methylation markers.

BACKGROUND: Current risk models for renal cell carcinoma (RCC) based on clinicopathological factors are sub-optimal in accurately identifying high-risk patients. Here, we perform a head-to-head comparison of previously published DNA methylation markers and propose a potential prognostic model for clear cell RCC (ccRCC). PATIENTS AND METHODS: Promoter methylation of PCDH8, BNC1, SCUBE3, GREM1, LAD1, NEFH, RASSF1A, GATA5, SFRP1, CDO1, and NEURL was determined by nested methylation-specific PCR. To identify clinically relevant methylated regions, The Cancer Genome Atlas (TCGA) was used to guide primer design. Formalin-fixed paraffin-embedded (FFPE) tissue samples from 336 non-metastatic ccRCC patients from the prospective Netherlands Cohort Study (NLCS) were used to develop a Cox proportional hazards model using stepwise backward elimination and bootstrapping to correct for optimism. For validation purposes, FFPE ccRCC tissue of 64 patients from the University Hospitals Leuven and a series of 232 cases from The Cancer Genome Atlas (TCGA) were used. RESULTS: Methylation of GREM1, GATA5, LAD1, NEFH, NEURL, and SFRP1 was associated with poor ccRCC-specific survival, independent of age, sex, tumor size, TNM stage or tumor grade. Moreover, the association between GREM1, NEFH, and NEURL methylation and outcome was shown to be dependent on the genomic region. A prognostic biomarker model containing GREM1, GATA5, LAD1, NEFH and NEURL methylation in combination with clinicopathological characteristics, performed better compared to the model with clinicopathological characteristics only (clinical model), in both the NLCS and the validation population with a c-statistic of 0.71 versus 0.65 and a c-statistic of 0.95 versus 0.86 consecutively. However, the biomarker model had limited added prognostic value in the TCGA series with a c-statistic of 0.76 versus 0.75 for the clinical model. CONCLUSION: In this study we performed a head-to-head comparison of potential prognostic methylation markers for ccRCC using a novel approach to guide primers design which utilizes the optimal location for measuring DNA methylation. Using this approach, we identified five methylation markers that potentially show prognostic value in addition to currently known clinicopathological factors.

Early discontinuation of PD-1 blockade upon achieving a complete or partial response in patients with advanced melanoma: the multicentre prospective Safe Stop trial.

BACKGROUND: The introduction of programmed cell death protein 1 (PD-1) blockers (i.e. nivolumab and pembrolizumab) has significantly improved the prognosis of patients with advanced melanoma. However, the long treatment duration (i.e. two years or longer) has a high impact on patients and healthcare systems in terms of (severe) toxicity, health-related quality of life (HRQoL), resource use, and healthcare costs. While durable tumour responses have been observed and PD-1 blockade is discontinued on an individual basis, no consensus has been reached on the optimal treatment duration. The objective of the Safe Stop trial is to evaluate whether early discontinuation of first-line PD-1 blockade is safe in patients with advanced and metastatic melanoma who achieve a radiological response. METHODS: The Safe Stop trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 200 patients with advanced and metastatic cutaneous melanoma and a confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumours (RECIST) v1.1 will be included to early discontinue first-line monotherapy with nivolumab or pembrolizumab. The primary objective is the rate of ongoing responses at 24 months after discontinuation of PD-1 blockade. Secondary objectives include best overall and duration of response, need and outcome of rechallenge with PD-1 blockade, and changes in (serious) adverse events and HRQoL. The impact of treatment discontinuation on healthcare resource use, productivity losses, and hours of informal care will also be assessed. Results will be compared to those from patients with CR or PR who completed 24 months of treatment with PD-1 blockade and had an ongoing response at treatment discontinuation. It is hypothesised that it is safe to early stop first-line nivolumab or pembrolizumab at confirmed tumour response while improving HRQoL and reducing costs. DISCUSSION: From a patient, healthcare, and economic perspective, shorter treatment duration is preferred and overtreatment should be prevented. If early discontinuation of first-line PD-1 blockade appears to be safe, early discontinuation of PD-1 blockade may be implemented as the standard of care in a selected group of patients. TRIAL REGISTRATION: The Safe Stop trial has been registered in the Netherlands Trial Register (NTR), Trial NL7293 (old NTR ID: 7502), https://www.trialregister.nl/trial/7293 . Date of registration September 30, 2018.

Shedding light on light exposure in elderly with intellectual disabilities.

BACKGROUND: Light exposure affects mood and sleep regulation. Sleep problems and mood complaints are common in elderly with intellectual disabilities (ID) living in care facilities. Insufficient light exposure is hypothesised to contribute to the high prevalence of these problems. The current study is the first to describe the personal light exposure pattern during the waking day in elderly with ID. METHODS: The study sample consists of 82 elderly with ID (aged 62.3 ± 9.4 years) living in 16 residential homes of three care organisations in the Netherlands. Personal light exposure was measured continuously for 7-10 days using a HOBO data logger light sensor, measuring illuminance at chest height. Participants wore a wrist-worn accelerometer (Actiwatch or Geneactiv) to indicate the bedtimes to determine the waking day. RESULTS: The variation in illuminance is small during the waking day. Elderly with ID spend most of their waking day (mean duration = 14:32:43 h) in dim light (1-500 lux) environment and spend a median of 32 min in light > 1000 lux. Within participants, the threshold associated with better sleep (>50 min of light > 1000 lux) was reached for 34% of the days, and the threshold associated with less depressive symptoms (>30 min of light > 1000 lux) was reached in 46% of the days. Exposure > 1000 lux was lower during weekends than during weekdays. CONCLUSION: Elderly with ID spend most of their waking day in low light levels and did not meet the proposed values associated with better sleep and mood. Given the importance of adequate light exposure for regulation of sleep and mood, and the prevalence of sleep and mood problems in elderly with ID, the current study suggests that the lit environment for this already frail population should be given more attention.

Survival outcomes of patients with advanced melanoma from 2013 to 2017: Results of a nationwide population-based registry.

BACKGROUND: The treatment landscape has completely changed for advanced melanoma. We report survival outcomes and the differential impact of prognostic factors over time in daily clinical practice. METHODS: From a Dutch nationwide population-based registry, patients with advanced melanoma diagnosed from 2013 to 2017 were analysed (n = 3616). Because the proportional hazards assumption was violated, a multivariable Cox model restricted to the first 6 months and a multivariable landmark Cox model from 6 to 48 months were used to assess overall survival (OS) of cases without missing values. The 2017 cohort was excluded from this analysis because of the short follow-up time. RESULTS: Median OS of the 2013 and 2016 cohort was 11.7 months (95% confidence interval [CI]: 10.4-13.5) and 17.7 months (95% CI: 14.9-19.8), respectively. Compared with the 2013 cohort, the 2016 cohort had superior survival in the Cox model from 0 to 6 months (hazard ratio [HR] = 0.55 [95% CI: 0.43-0.72]) and in the Cox model from 6 to 48 months (HR = 0.68 [95% CI: 0.57-0.83]). Elevated lactate dehydrogenase levels, distant metastases in ≥3 organ sites, brain and liver metastasis and Eastern Cooperative Oncology Group performance score of ≥1 had stronger association with inferior survival from 0 to 6 months than from 6 to 48 months. BRAF-mutated melanoma had superior survival in the first 6 months (HR = 0.50 [95% CI: 0.42-0.59]). CONCLUSION(S): Prognosis for advanced melanoma in the Netherlands has improved from 2013 to 2016. Prognostic importance of most evaluated factors was higher in the first 6 months after diagnosis. BRAF-mutated melanoma was only associated with superior survival in the first 6 months.

Impaired Geriatric 8 Score is Associated with Worse Survival after Radiotherapy in Older Patients with Cancer.

AIMS: To investigate whether the Geriatric 8 (G8) score and the Timed Get Up and Go Test (TGUGT), together with clinical and demographic patient characteristics, are associated with survival and late toxicity after (chemo)radiation therapy, administered with curative intent in older patients with cancer. MATERIALS AND METHODS: Four hundred and two patients aged ≥65 years (median age 72 years, range 65-96 years), diagnosed with either breast, non-small cell lung, prostate, head and neck, rectal or oesophageal cancer, and referred for curative (chemo)radiation therapy, took part in a multicentre prospective cohort study in eight radiotherapy centres in the Netherlands. The G8 and TGUGT scores were assessed before starting treatment. Other potential predictors and late toxicity were also recorded. Survival status and date of death, if applicable, were ascertained at the Dutch national death registry. RESULTS: After 2.5 years, the overall survival was 83%. Survival was 87% for patients with high G8 scores and 55% for patients with low G8 scores (Log-rank P value < 0.0001). Survival was 77% for patients with good TGUGT results and 50% for patients with poor TGUGT results (Log-rank P value < 0.001). In multivariable analysis, in addition to age and type of primary tumour, the association of the G8 score with overall survival remained, with a hazard ratio of 2.1 (95% confidence interval 1.2-3.8) for low versus high scores. CONCLUSIONS: G8 was associated with overall survival in older patients with cancer irradiated with curative intent. This association was independent of the predictive value of age and primary tumour.

Health-related quality of life of long-term advanced melanoma survivors treated with anti-CTLA-4 immune checkpoint inhibition compared to matched controls.

BACKGROUND: Checkpoint inhibitors have changed overall survival for patients with advanced melanoma. However, there is a lack of data on health-related quality of life (HRQoL) of long-term advanced melanoma survivors, years after treatment. Therefore, we evaluated HRQoL in long-term advanced melanoma survivors and compared the study outcomes with matched controls without cancer. MATERIAL AND METHODS: Ipilimumab-treated advanced melanoma survivors without evidence of disease and without subsequent systemic therapy for a minimum of two years following last administration of ipilimumab were eligible for this study. The European Organization for Research and Treatment of Cancer quality of life questionnaire Core 30 (EORTC QLQ-C30), the Multidimensional Fatigue Inventory (MFI), the Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-Melanoma questionnaire (FACT-M) were administered. Controls were individually matched for age, gender, and educational status. Outcomes of survivors and controls were compared using generalized estimating equations, and differences were interpreted as clinically relevant according to published guidelines. RESULTS: A total of 89 survivors and 265 controls were analyzed in this study. After a median follow-up of 39 (range, 17-121) months, survivors scored significantly lower on physical (83.7 vs. 89.8, difference (diff) = -5.80, p=.005), role (83.5 vs. 90, diff = -5.97, p=.02), cognitive (83.7 vs. 91.9, diff = -8.05, p=.001), and social functioning (86.5 vs. 95.1, diff = -8.49, p= <.001) and had a higher symptom burden of fatigue (23.0 vs. 15.5, diff = 7.48, p=.004), dyspnea (13.3 vs. 6.7, diff = 6.47 p=.02), diarrhea (7.9 vs. 4.0, diff = 3.78, p=.04), and financial impact (10.5 vs. 2.5, diff = 8.07, p=.001) than matched controls. Group differences were indicated as clinically relevant. DISCUSSION: Compared to matched controls, long-term advanced melanoma survivors had overall worse functioning scores, more physical symptoms, and financial difficulties. These data may contribute to the development of appropriate survivorship care.

The Influence of Different Alimentary and Biliopancreatic Limb Lengths in Gastric Bypass Patients.

PURPOSE: The aim of this study was to compare the effect of two different limb lengths after RYGB on weight loss, postoperative gastro-intestinal complications, and vitamin deficiencies. MATERIALS AND METHODS: A retrospective analyses of 100 patients after RYGB with 2 different limb lengths were done. Group A (50 patients) had a biliopancreatic limb (BPL) of 75 cm and an alimentary limb (AL) of 150 cm. Group B (50 patients) had a BPL of 150 cm and an AL of 75 cm. The effect on weight loss, body mass index, excess weight loss (EWL), total weight loss (TWL), and postoperative complications was analyzed up to 2 years postoperatively. RESULTS: Patients with a longer BPL achieved significantly more %EWL compared to a shorter BPL 2 years postoperatively (82.8 ± 31.2 versus 93.8 ± 15.1; p = 0.038). A significant difference was also seen in %TWL after 1 year (30.3 ± 10.1 versus 37.4 ± 6.9; p < 0.01) and 2 years (31.6 ± 7.5 versus 35.6 ± 8.6; p = 0.022), both in favor of group B. However, patients with a longer BPL (group B) showed significant more diarrhea and steatorrhea compared to group A (p < 0.01). CONCLUSION: BPL of 150 cm is associated with more %EWL and %TWL 2 years after RYGB. However, it is accompanied by an increase of diarrhea and steatorrhea to disadvantage off group B. Future studies need to focus on further tailoring BPL and AL lengths to achieve the best possible outcomes for patients with morbid obesity.

Immunotherapy as sensitizer for local radiotherapy.

The purpose of this report was to systematically review the radiation enhancement factor (REF) effects of immunotherapy on radiotherapy (RT) to the local tumor in comparison with other traditional radiation sensitizers such as cisplatin. PubMed and Medline databases were searched until February 2019. Reports with abscopal effect in the results were excluded. Graphs of the selected papers were digitized using Plot Digitizer (Sourceforge.net) in order to calculate the tumor growth delay (TGD) caused by immunotherapy. To enable comparison between different studies,the TGD were used to define the REF between RT versus the RT/immunotherapy combination. Thirty-two preclinical papers, and nine clinical series were selected. Different mouse models were exposed to RT doses ranging from 1 to 10 fractions of 1.8 to 20 Gray (Gy) per fraction. Endpoints were heterogeneous, ranging from regression to complete local response. No randomized clinical studies were identified. The median preclinical REF effect of different immunotherapy was varying from 1.7 to 9.1. There was no relationship observed either with subclasses of immunotherapy orRT doses. In the clinical studies, RT doses ranged from 1 to 37 fractions of 1.8 to 24 Gy per fraction. Most clinical trials used ipilimumab and interleukin-2. Local control rate in the clinical series ranged from 66% to 100%. A strong REF of immunotherapy (1.7 to 9.1) was observed, this being higher than traditionally sensitizers such as cisplatin (1.1). This result implies that for the same RT dose, a higher local control was achieved with a combination of immunotherapy and RT in preclinical settings. This study therefore supports the use of combined RT and immunotherapy to improve local tumor control in clinical settings without exacerbation of toxicities.

Referral Patterns and Outcome of Patients With Synchronous Brain Metastases From Non-small Cell Lung Cancer Treated With Gamma Knife Radiosurgery in a Third-Line Treatment Centre in The Netherlands - A Retrospective Analysis.

AIMS: Little understanding exists of referral patterns for patients with brain metastasis from non-small cell lung cancer (NSCLC) towards treatment with Gamma Knife radiosurgery (GKRS). Therefore, we explored current clinical daily practice and prognosis. MATERIAL AND METHODS: In total, 1129 patients with synchronously diagnosed brain metastasis from NSCLC diagnosed between 2008 and 2014 were selected from the population-based Netherlands Cancer Registry; 242 patients were treated with GKRS. RESULTS: Patients receiving GKRS were younger (62 years versus 64 years) and had lower tumour burden: the presence of T2 was higher and T4 was lower (43% versus 33%; P = 0.0158, 19% versus 28%; P = 0.0044, respectively). They more frequently had cN0 (32% versus 19%; P ≤ 0.0001), less frequently had N3 disease (18% versus 29%; P = 0.0004) and there were fewer metastatic sites. In multivariable logistic regression analysis, only age ≤60 years (odds ratio 1.4; 95% confidence interval 1.0-2.0) and patients with N0 stage, compared with those with N2, N3 and NX (odds ratio 0.6 [0.4-0.9], 0.3 [0.2-0.6], 0.3 [0.1-0.6], respectively), were more likely to receive GKRS. Gender, T-stage, histology, number of comorbidities, country of birth as proxy for ethnicity and socioeconomic status were not associated. The median survival was 9.6 months after GKRS versus 4.0 months in the noGKRS group (Log-rank: P ≤ 0.0001). Multivariably, GKRS, female, lower T-/N-stage, <2 comorbidities, adenocarcinoma and higher socioeconomic status were associated with a significantly reduced hazard of death. For the patients with at least one follow-up magnetic resonance image (80%), local intracranial tumour control was achieved in 93% at the last follow-up. CONCLUSION: Patients presenting with synchronic brain metastasis from NSCLC who are referred to a third-line treatment centre for GKRS are younger and have a lower tumour load. Due to a high level of local control, GKRS is able to provide a significant window of opportunity for additional treatment of the primary tumour.

A comparison of international clinical practice guidelines on adult chronic rhinosinusitis shows considerable variability of recommendations for diagnosis and treatment.

OBJECTIVES: To compare international clinical practice guidelines on adult chronic rhinosinusitis (CRS). DESIGN: Extensive literature search in Embase, PubMed and the internet (Google, websites of well-known guideline organizations) on November 21st 2018. MAIN OUTCOME MEASURES: Guidelines' quality was measured by the AGREE II instrument. A summary and comparison of recommendations on diagnosis and treatment with harmonized levels of evidence (LoE) and grade of recommendations (GoR) is given. RESULTS: We selected ten guidelines on CRS. Five guidelines were of sufficient to high quality according to AGREE II, the remaining guidelines predominantly did not meet AGREE II criteria. We harmonized all guideline recommendations so we could compare them, although three guidelines did not provide a LoE. Five guidelines provided recommendations on diagnosis, all of them recommended performing nasal endoscopy, CT scan and allergy testing (with varying GoRs). All ten guidelines provided recommendations on therapy, one treatment, i.e., the use of intranasal steroids, was recommended by all guidelines (with varying GoRs). Recommendations for surgical treatment of CRS were provided by five guidelines. CONCLUSION: We performed an extensive search and included ten (inter)national guidelines on CRS for adults. According to AGREE II, five were of good or sufficient quality. Overall, there was much variation between guidelines in recommended diagnostic test or treatment, direction of evidence and GoR. We found consensus for nasal endoscopy, CT scan, allergy testing and intranasal steroids. We argue for standardization of guideline development, to increase their quality and improve comparability.