Prognostic relevance of high expression of kynurenine pathway markers in glioblastoma.

Glioblastoma (GBM) continues to exhibit a discouraging survival rate despite extensive research into new treatments. One factor contributing to its poor prognosis is the tumor's immunosuppressive microenvironment, in which the kynurenine pathway (KP) plays a significant role. This study aimed to explore how KP impacts the survival of newly diagnosed GBM patients. We examined tissue samples from 108 GBM patients to assess the expression levels of key KP markers-tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenase (IDO1/2), and the aryl hydrocarbon receptor (AhR). Using immunohistochemistry and QuPath software, three tumor cores were analyzed per patient to evaluate KP marker expression. Kaplan-Meier survival analysis and stepwise multivariate Cox regression were used to determine the effect of these markers on patient survival. Results showed that patients with high expression of TDO2, IDO1/2, and AhR had significantly shorter survival times. This finding held true even when controlling for other known prognostic variables, with a hazard ratio of 3.393 for IDO1, 2.775 for IDO2, 1.891 for TDO2, and 1.902 for AhR. We suggest that KP markers could serve as useful tools for patient stratification, potentially guiding future immunomodulating trials and personalized treatment approaches for GBM patients.

Impact of clinical target volume margin reduction in glioblastoma patients treated with concurrent chemoradiation.

Background: Glioblastoma (GBM) is widely treated using large radiotherapy margins, resulting in substantial irradiation of the surrounding cerebral structures. In this context, the question arises whether these margins could be safely reduced. In 2018, clinical target volume (CTV) expansion was reduced in our institution from 20 to 15 mm around the gross target volume (GTV) (ie, the contrast-enhancing tumor/cavity). We sought to retrospectively analyze the impact of this reduction. Methods: All adult patients with GBM treated between January 2015 and December 2020 with concurrent chemoradiation (60Gy/2Gy or 59.4Gy/1.8Gy) were analyzed. Patients treated using a 20 (CTV20, n = 57) or 15 mm (CTV15, n = 56) CTV margin were compared for target volumes, dose parameters to the surrounding organs, pattern of recurrence, and survival outcome. Results: Mean GTV was similar in both groups (ie, CTV20: 39.7cm3; CTV15: 37.8cm3; P = .71). Mean CTV and PTV were reduced from 238.9cm3 to 176.7cm3 (P = .001) and from 292.6cm3 to 217.0cm3 (P < .001), for CTV20 and CTV15, respectively. As a result, average brain mean dose (Dmean) was reduced from 25.2Gy to 21.0Gy (P = .002). Significantly lower values were also observed for left hippocampus Dmean, brainstem D0.03cc, cochleas Dmean, and pituitary Dmean. Pattern of recurrence was similar, as well as patient outcome, ie, median progression-free survival was 8.0 and 7.0 months (P = .80), and median overall survival was 11.0 and 14.0 months (P = .61) for CTV20 and CTV15, respectively. Conclusions: In GBM patients treated with chemoradiation, reducing the CTV margin from 20 to 15 mm appears to be safe and offers the potential for less treatment toxicity.

A multicentric randomized controlled phase III trial of adaptive and 18F-FDG-PET-guided dose-redistribution in locally advanced head and neck squamous cell carcinoma (ARTFORCE).

BACKGROUND AND PURPOSE: This multicenter randomized phase III trial evaluated whether locoregional control of patients with LAHNSCC could be improved by fluorodeoxyglucose-positron emission tomography (FDG-PET)-guided dose-escalation while minimizing the risk of increasing toxicity using a dose-redistribution and scheduled adaptation strategy. MATERIALS AND METHODS: Patients with T3-4-N0-3-M0 LAHNSCC were randomly assigned (1:1) to either receive a dose distribution ranging from 64-84 Gy/35 fractions with adaptation at the 10thfraction (rRT) or conventional 70 Gy/35 fractions (cRT). Both arms received concurrent three-cycle 100 mg/m2cisplatin. Primary endpoints were 2-year locoregional control (LRC) and toxicity. Primary analysis was based on the intention-to-treat principle. RESULTS: Due to slow accrual, the study was prematurely closed (at 84 %) after randomizing 221 eligible patients between 2012 and 2019 to receive rRT (N = 109) or cRT (N = 112). The 2-year LRC estimate difference of 81 % (95 %CI 74-89 %) vs. 74 % (66-83 %) in the rRT and cRT arm, respectively, was not found statistically significant (HR 0.75, 95 %CI 0.43-1.31,P=.31). Toxicity prevalence and incidence rates were similar between trial arms, with exception for a significant increased grade ≥ 3 pharyngolaryngeal stenoses incidence rate in the rRT arm (0 versus 4 %,P=.05). In post-hoc subgroup analyses, rRT improved LRC for patients with N0-1 disease (HR 0.21, 95 %CI 0.05-0.93) and oropharyngeal cancer (0.31, 0.10-0.95), regardless of HPV. CONCLUSION: Adaptive and dose redistributed radiotherapy enabled dose-escalation with similar toxicity rates compared to conventional radiotherapy. While FDG-PET-guided dose-escalation did overall not lead to significant tumor control or survival improvements, post-hoc results showed improved locoregional control for patients with N0-1 disease or oropharyngeal cancer treated with rRT.

Efficacy of pembrolizumab and biomarker analysis in patients with WGS-based intermediate to high tumor mutational load: results from the Drug Rediscovery Protocol.

PURPOSE: To evaluate efficacy of pembrolizumab across multiple cancer types harboring different levels of Whole-Genome Sequencing (WGS)-based tumor mutational load (TML; total of non-synonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234). PATIENTS AND METHODS: Patients with solid, treatment-refractory, microsatellite-stable tumors were enrolled in cohort A: breast cancer TML 140-290, cohort B: tumor-agnostic cohort TML 140-290, and cohort C: tumor-agnostic cohort TML >290. Patients received pembrolizumab 200 mg every three weeks. Primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥16 weeks). Pre-treatment tumor biopsies were obtained for WGS and RNA-sequencing. RESULTS: Seventy-two evaluable patients with 26 different histotypes were enrolled. CB rate was 13% in cohort A (3/24 with partial response (PR)), 21% in cohort B (3/24 with SD, 2/24 with PR), and 42% in cohort C (4/24 with SD, 6/24 with PR). In cohort C, neoantigen burden estimates and expression of inflammation and innate immune biomarkers were significantly associated with CB. Similar associations were not identified in cohort A and B. In cohort A, CB was significantly associated with mutations in the chromatin remodeling gene PBRM1, while in cohort B, CB was significantly associated with expression of MICA/MICB and butyrophilins. CB and clonal TML were not significantly associated. CONCLUSION: While in cohort A pembrolizumab lacked activity, cohort B and cohort C met the study's primary endpoint. Further research is warranted to refine selection of patients with tumors harboring lower TMLs and may benefit from a focus on innate immunity.

Exploring long-term responses to immune checkpoint inhibitors in recurrent and metastatic head and neck squamous cell carcinoma.

OBJECTIVES: Immune checkpoint inhibitors (ICI) have introduced a new era in the treatment of recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Optimal duration for ICI therapy is still unclear and the long-term outcomes and toxicity in patients responding to these therapies warrant further exploration. This study attempts to identify the clinical and biological determinants of a durable response and evaluate outcomes following ICI treatment discontinuation. MATERIALS AND METHODS: A retrospective review of 181 patients treated with ICI for R/M HNSCC was conducted. Long-term responders were defined as patients who sustained disease control at least two years after initiating ICI therapy. We compared clinical and biological characteristics associated with these long-term responders against the broader treatment population. RESULTS: 10 % of R/M HNSCC patients treated with ICIs demonstrated a durable long-term response. Only three relapses (16 %) occurred after discontinuing ICI treatment in this subset, with a median follow-up of 52 months. Upon retreatment with ICI, two attained a documented response. Extended ICI response was observed even with < 2 years of treatment. 74 % of long-term responders experienced immune-related adverse events (irAEs), 37 % of which severe irAEs. Hypothyroidism was the most frequently reported irAEs. The predictive potential of systemic inflammation indices for clinical response appears to be limited. CONCLUSIONS: ICI present an optimistic avenue for HNSCC patients, offering substantial long-term responses. The study suggests that a two-year treatment could be optimal and irAEs, although common, are typically mild.

Efficacy and Safety of Panitumumab in Patients With RAF/RAS-Wild-Type Glioblastoma: Results From the Drug Rediscovery Protocol.

BACKGROUND: The prognosis of malignant primary high-grade brain tumors, predominantly glioblastomas, is poor despite intensive multimodality treatment options. In more than 50% of patients with glioblastomas, potentially targetable mutations are present, including rearrangements, altered splicing, and/or focal amplifications of epidermal growth factor receptor (EGFR) by signaling through the RAF/RAS pathway. We studied whether treatment with the clinically available anti-EGFR monoclonal antibody panitumumab provides clinical benefit for patients with RAF/RAS-wild-type (wt) glioblastomas in the Drug Rediscovery Protocol (DRUP). METHODS: Patients with progression of treatment refractory RAF/RASwt glioblastoma were included for treatment with panitumumab in DRUP when measurable according to RANO criteria. The primary endpoints of this study are clinical benefit (CB: defined as confirmed objective response [OR] or stable disease [SD] ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 in 8 patients had CB in stage 1. RESULTS: Between 03-2018 and 02-2022, 24 evaluable patients were treated. CB was observed in 5 patients (21%), including 2 patients with partial response (8.3%) and 3 patients with SD ≥ 16 weeks (12.5%). After median follow-up of 15 months, median progression-free survival and overall survival were 1.7 months (95% CI 1.6-2.1 months) and 4.5 months (95% CI 2.9-8.6 months), respectively. No unexpected toxicities were observed. CONCLUSIONS: Panitumumab treatment provides limited CB in patients with recurrent RAF/RASwt glioblastoma precluding further development of this therapeutic strategy.

Patient-derived glioblastoma organoids reflect tumor heterogeneity and treatment sensitivity.

Background: Treatment resistance and tumor relapse are the primary causes of mortality in glioblastoma (GBM), with intratumoral heterogeneity playing a significant role. Patient-derived cancer organoids have emerged as a promising model capable of recapitulating tumor heterogeneity. Our objective was to develop patient-derived GBM organoids (PGO) to investigate treatment response and resistance. Methods: GBM samples were used to generate PGOs and analyzed using whole-exome sequencing (WES) and single-cell karyotype sequencing. PGOs were subjected to temozolomide (TMZ) to assess viability. Bulk RNA sequencing was performed before and after TMZ. Results: WES analysis on individual PGOs cultured for 3 time points (1-3 months) showed a high inter-organoid correlation and retention of genetic variants (range 92.3%-97.7%). Most variants were retained in the PGO compared to the tumor (range 58%-90%) and exhibited similar copy number variations. Single-cell karyotype sequencing demonstrated preservation of genetic heterogeneity. Single-cell multiplex immunofluorescence showed maintenance of cellular states. TMZ treatment of PGOs showed a differential response, which largely corresponded with MGMT promoter methylation. Differentially expressed genes before and after TMZ revealed an upregulation of the JNK kinase pathway. Notably, the combination treatment of a JNK kinase inhibitor and TMZ demonstrated a synergistic effect. Conclusions: Overall, these findings demonstrate the robustness of PGOs in retaining the genetic and phenotypic heterogeneity in culture and the application of measuring clinically relevant drug responses. These data show that PGOs have the potential to be further developed into avatars for personalized adaptive treatment selection and actionable drug target discovery and as a platform to study GBM biology.

Multi-Domain Screening: Identification of Patient's Risk Profile Prior to Head-and-Neck Cancer Treatment.

BACKGROUND: Head-and-neck cancer (HNC) can give rise to oropharyngeal dysphagia (OD), malnutrition, sarcopenia, and frailty. Early identification of these phenomena in newly diagnosed HNC patients is important to reduce the risk of complications and to improve treatment outcomes. The aim of this study was (1) to determine the prevalence of the risk of OD, malnutrition, sarcopenia, and frailty; and (2) to investigate the relation between these phenomena and patients' age, performance status, and cancer group staging. METHODS: Patients (N = 128) underwent multi-domain screening consisting of the Eating Assessment Tool-10 for OD, Short Nutritional Assessment Questionnaire and BMI for malnutrition, Short Physical Performance Battery and Hand Grip Strength for sarcopenia, and Distress Thermometer and Maastricht Frailty Screening Tool for frailty. RESULTS: 26.2%, 31.0%, 73.0%, and 46.4% of the patients were at risk for OD, malnutrition, sarcopenia, or frailty, respectively. Patients with an advanced cancer stage had a significantly higher risk of OD and high levels of distress prior to cancer treatment. CONCLUSIONS: This study identified the risk profile of newly diagnosed HNC patients using a standardized 'quick and easy' multi-domain screening prior to cancer treatment.

Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours.

BACKGROUND: In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile. PATIENTS AND METHODS: Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses. RESULTS: Twenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB. CONCLUSION: Durvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings. TRIAL REGISTRATION: Clinical trial registration: NCT02925234. First registration date: 05/10/2016.

Transcriptome analysis reveals tumor microenvironment changes in glioblastoma.

A better understanding of transcriptional evolution of IDH-wild-type glioblastoma may be crucial for treatment optimization. Here, we perform RNA sequencing (RNA-seq) (n = 322 test, n = 245 validation) on paired primary-recurrent glioblastoma resections of patients treated with the current standard of care. Transcriptional subtypes form an interconnected continuum in a two-dimensional space. Recurrent tumors show preferential mesenchymal progression. Over time, hallmark glioblastoma genes are not significantly altered. Instead, tumor purity decreases over time and is accompanied by co-increases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macrophages. A decrease is observed in endothelial marker genes. These composition changes are confirmed by single-cell RNA-seq and immunohistochemistry. An extracellular matrix-associated gene set increases at recurrence and bulk, single-cell RNA, and immunohistochemistry indicate it is expressed mainly by pericytes. This signature is associated with significantly worse survival at recurrence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells.

The predictive and prognostic value of weight loss and body composition prior to and during immune checkpoint inhibition in recurrent or metastatic head and neck cancer patients.

BACKGROUND: Response rates of immune checkpoint inhibitor (ICI) therapy for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are low. PATIENTS AND METHODS: This retrospective multicentre cohort study evaluates the predictive and prognostic value of weight loss and changes in body composition prior and during therapy. Patient, tumor, and treatment characteristics of 98 patients were retrieved, including neutrophil and platelet-lymphocyte-ratio (NLR and PLR). Programmed death-ligand 1 (PD-L1) expression was determined on residual material. Cachexia was defined according to Fearon et al. (2011). Skeletal muscle (SM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were evaluated on computed tomography scans at the third lumbar vertebrae level. Univariable and multivariable regression analyses were performed for 6 months progression free survival (PFS6m) and overall survival (OS). RESULTS: Significant early weight loss (>2%) during the first 6 weeks of therapy was shown in 34 patients (35%). This patient subgroup had a significantly higher NLR and PLR at baseline. NLR and PLR were inversely correlated with SM and VAT index. Independent predictors of PFS6m were lower World Health Organization performance status (HR 0.16 [0.04-0.54] p = 0.003), higher baseline SAT index (HR 1.045 [1.02-1.08] p = 0.003), and weight loss <2% (HR 0.85 [0.74-0.98] p = 0.03). Baseline cachexia in combination with >2% early weight loss remained a predictor of OS, independent of PD-L1 expression (HR 2.09 [1.11-3.92] p = 0.02, HR 2.18 [1.13-4.21] p = 0.02). CONCLUSION: We conclude that the combination of cachexia at baseline and weight loss during ICI therapy is associated with worse OS in R/M HNSCC patients, independent of PD-L1 expression.

Oropharyngeal dysphagia and cachexia: Intertwined in head and neck cancer.

BACKGROUND: This study aims to investigate the relationship between cancer cachexia and oropharyngeal dysphagia (OD) in patients with head and neck cancer (HNC) prior to chemoradiotherapy or bioradiotherapy (CRT/BRT). METHODS: A prospective cohort study with patients with HNC undergoing CRT/BRT (2018-2021) was conducted. Body composition and skeletal muscle function were evaluated using bioelectrical impedance analysis, handgrip strength, and the short physical performance battery (SPPB). The M. D. Anderson Dysphagia Inventory (MDADI), Eating Assessment Tool (EAT)-10 questionnaire, and patient characteristics were collected. A standardized videofluoroscopic swallowing study was offered to patients. RESULTS: Sixty-six patients were included. Twenty-six patients scored EAT-10 ≥ 3 and seventeen were cachectic. ACE-27 score >1, cachexia, abnormal SPPB-derived repeated chair-stand test, lower MDADI scores, and higher overall stage grouping showed potential predictive value (p ≤ 0.10) for EAT-10 ≥ 3. Using multivariable regression analysis, only cachexia remained a significant predictor of EAT-10 ≥ 3 (HR 9.000 [95%CI 2.483-32.619], p = 0.001). CONCLUSION: Cachexia independently predicted the presence of patient-reported OD.

Neurocognition in adults with intracranial tumors: does location really matter?

OBJECTIVE: As preservation of cognitive functioning increasingly becomes important in the light of ameliorated survival after intracranial tumor treatments, identification of eloquent brain areas would enable optimization of these treatments. METHODS: This cohort study enrolled adult intracranial tumor patients who received neuropsychological assessments pre-irradiation, estimating processing speed, verbal fluency and memory. Anatomical magnetic resonance imaging scans were used for multivariate voxel-wise lesion-symptom predictions of the test scores (corrected for age, gender, educational level, histological subtype, surgery, and tumor volume). Potential effects of histological and molecular subtype and corresponding WHO grades on the risk of cognitive impairment were investigated using Chi square tests. P-values were adjusted for multiple comparisons (p < .001 and p < .05 for voxel- and cluster-level, resp.). RESULTS: A cohort of 179 intracranial tumor patients was included [aged 19-85 years, median age (SD) = 58.46 (14.62), 50% females]. In this cohort, test-specific impairment was detected in 20-30% of patients. Higher WHO grade was associated with lower processing speed, cognitive flexibility and delayed memory in gliomas, while no acute surgery-effects were found. No grading, nor surgery effects were found in meningiomas. The voxel-wise analyses showed that tumor locations in left temporal areas and right temporo-parietal areas were related to verbal memory and processing speed, respectively. INTERPRETATION: Patients with intracranial tumors affecting the left temporal areas and right temporo-parietal areas might specifically be vulnerable for lower verbal memory and processing speed. These specific patients at-risk might benefit from early-stage interventions. Furthermore, based on future validation studies, imaging-informed surgical and radiotherapy planning could further be improved.

Study protocol of the GLOW study: maximising treatment options for recurrent glioblastoma patients by whole genome sequencing-based diagnostics-a prospective multicenter cohort study.

BACKGROUND: Glioblastoma (GBM), the most common glial primary brain tumour, is without exception lethal. Every year approximately 600 patients are diagnosed with this heterogeneous disease in The Netherlands. Despite neurosurgery, chemo -and radiation therapy, these tumours inevitably recur. Currently, there is no gold standard at time of recurrence and treatment options are limited. Unfortunately, the results of dedicated trials with new drugs have been very disappointing. The goal of the project is to obtain the evidence for changing standard of care (SOC) procedures to include whole genome sequencing (WGS) and consequently adapt care guidelines for this specific patient group with very poor prognosis by offering optimal and timely benefit from novel therapies, even in the absence of traditional registration trials for this small volume cancer indication. METHODS: The GLOW study is a prospective diagnostic cohort study executed through collaboration of the Hartwig Medical Foundation (Hartwig, a non-profit organisation) and twelve Dutch centers that perform neurosurgery and/or treat GBM patients. A total of 200 patients with a first recurrence of a glioblastoma will be included. Dual primary endpoint is the percentage of patients who receive targeted therapy based on the WGS report and overall survival. Secondary endpoints include WGS report success rate and number of targeted treatments available based on WGS reports and number of patients starting a treatment in presence of an actionable variant. At recurrence, study participants will undergo SOC neurosurgical resection. Tumour material will then, together with a blood sample, be sent to Hartwig where it will be analysed by WGS. A diagnostic report with therapy guidance, including potential matching off-label drugs and available clinical trials will then be sent back to the treating physician for discussing of the results in molecular tumour boards and targeted treatment decision making. DISCUSSION: The GLOW study aims to provide the scientific evidence for changing the SOC diagnostics for patients with a recurrent glioblastoma by investigating complete genome diagnostics to maximize treatment options for this patient group. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05186064.

Correlation of reduced temporal muscle thickness and systemic muscle loss in newly diagnosed glioblastoma patients.

PURPOSE: Reduced temporal muscle thickness (TMT) has recently been postulated as a prognostic imaging marker and an objective tool to assess patients frailty in glioblastoma. Our aim is to investigate the correlation of TMT and systemic muscle loss to confirm that TMT is an adequate surrogate marker of sarcopenia in newly diagnosed glioblastoma patients. METHODS: TMT was assessed on preoperative MR-images and skeletal muscle area (SMA) was assessed at the third lumbar vertebra on preoperative abdominal CT-scans. Previous published TMT sex-specific cut-off values were used to classify patients as 'patient at risk of sarcopenia' or 'patient with normal muscle status'. Correlation between TMT and SMA was assessed using Spearman's rank correlation coefficient. RESULTS: Sixteen percent of the 245 included patients were identified as at risk of sarcopenia. The mean SMA of glioblastoma patients at risk of sarcopenia (124.3 cm2, SD 30.8 cm2) was significantly lower than the mean SMA of patients with normal muscle status (146.3 cm2, SD 31.1 cm2, P < .001). We found a moderate association between TMT and SMA in the patients with normal muscle status (Spearman's rho 0.521, P < .001), and a strong association in the patients at risk of sarcopenia (Spearman's rho 0.678, P < .001). CONCLUSION: Our results confirm the use of TMT as a surrogate marker of total body skeletal muscle mass in glioblastoma, especially in frail patients at risk of sarcopenia. TMT can be used to identify patients with muscle loss early in the disease process, which enables the implementation of adequate intervention strategies.

Detection and localization of early- and late-stage cancers using platelet RNA.

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening.

Disease outcome and associated factors after definitive platinum based chemoradiotherapy for advanced stage HPV-negative head and neck cancer.

BACKGROUND: Definitive concomitant cisplatin-based chemoradiotherapy (CRT) is the current gold standard for most patients with advanced stage head and neck squamous cell carcinoma (HNSCC) of the pharynx and larynx. Since previous meta-analysis on CRT outcomes in HNSCC have been reported, advances have been made in radiotherapy techniques and clinical management, while HPV-status has been identified as a strong confounding prognostic factor in oropharyngeal cancer. Here, we present real-world outcome data from a large multicenter cohort of HPV-negative advanced stage HNSCC treated with CRT using contemporary IMRT-based techniques. METHOD: Retrospective data were collected from a multicenter cohort of 513 patients treated with definitive concurrent platinum-based CRT with curative intent between January 2009 and August 2017. Only patients with HPV-negative advanced stage (III-IV) HNSCC were included. A prognostic model for outcome was developed based on clinical parameters and compared to TNM. RESULTS: Nearly half of the 513 patients (49%) had an oropharyngeal tumor, often locally advanced (73.3% T3-T4b) and with involvement of the regional lymph nodes (84%). Most patients (84%) received cisplatin as single agent. In total 66% received the planned number of cycles and 75% reached a cumulative cisplatin dose of ≥200 mg/m2. Locoregional control was achieved in 324 (63%) patients during follow-up, and no association with tumor sites was observed (p = 0.48). Overall survival at 5 year follow-up was 47%, with a better survival for laryngeal cancer (p = 0.02) compared to other sites. A model with clinical variables (gender, high pre-treatment weight loss, N2c/N3-stage and <200 mg/m2 dose of cisplatin) provided a noticeably stronger association with overall survival than TNM-staging (C- index 0.68 vs 0.55). Simultaneous Integrated Boosting (SIB) significantly outperformed Sequential Boosting (SEQ) to reduce the development of distant metastasis (SEQ vs SIB: OR 1.91 (1.11-3.26; p = 0.02). CONCLUSION: Despite advances in clinical management, more than a third of patients with HPV-negative HNSCC do not complete CRT treatment protocols due to cisplatin toxicity. A model that consists of clinical variables and treatment parameters including cisplatin dose provided the strongest association with overall survival. Since cisplatin toxicity is a major obstacle in completing definitive CRT, the development of alternative and less toxic radiosensitizers is therefore warranted to improve treatment results. The association of RT-boost technique with distant metastasis is an important finding and requires further study.

Unacceptable pain in oncology: The patients' perspective on reasons for absence of pain interventions.

OBJECTIVE: Around 40% of oncology patients receive inadequate pain treatment. A previous study reported pain interventions for only 70% of patients who reported unacceptable pain at the self-service registration desk. The aim of this study is to gain insight in reasons for the absence of pain intervention among oncology patients who reported unacceptable pain. METHODS: In this mixed methods study, 20 patients visiting the oncology outpatient clinic were selected via patient record assessment and interviewed about their perceived reasons for absence of pain intervention. RESULTS: The reasons mentioned by the patients for absence of pain intervention included reluctance of the patient to discuss pain, no treatment preferred by the patient, focus of the physician on treatment of the disease, pain treatment difficult or impossible, and the perception that pain is an inevitable consequence of the cancer treatment. Almost 50% of the patients considered the physician responsible for the absence of pain intervention. CONCLUSION: In conclusion, a variety of reasons for absence of pain intervention are reported by patients, including patient-related and health professional-related reasons. Improvements can be made by promoting regular discussion of pain during hospital visits and empowerment of patients.

The Use of 18F-FET-PET-MRI in Neuro-Oncology: The Best of Both Worlds-A Narrative Review.

Gliomas are the most frequent primary tumors of the brain. They can be divided into grade II-IV astrocytomas and grade II-III oligodendrogliomas, based on their histomolecular profile. The prognosis and treatment is highly dependent on grade and well-identified prognostic and/or predictive molecular markers. Multi-parametric MRI, including diffusion weighted imaging, perfusion, and MR spectroscopy, showed increasing value in the non-invasive characterization of specific molecular subsets of gliomas. Radiolabeled amino-acid analogues, such as 18F-FET, have also been proven valuable in glioma imaging. These tracers not only contribute in the diagnostic process by detecting areas of dedifferentiation in diffuse gliomas, but this technique is also valuable in the follow-up of gliomas, as it can differentiate pseudo-progression from real tumor progression. Since multi-parametric MRI and 18F-FET PET are complementary imaging techniques, there may be a synergistic role for PET-MRI imaging in the neuro-oncological imaging of primary brain tumors. This could be of value for both primary staging, as well as during treatment and follow-up.

Temporal muscle thickness as an independent prognostic imaging marker in newly diagnosed glioblastoma patients: A validation study.

Background: Previous studies have recognized temporal muscle thickness (TMT) as a prognostic marker in glioblastoma, but clinical implementation is hampered due to studies' heterogeneity and lack of established cutoff values. The aim of this study was to assess the validity of recent proposed sex-specific TMT cutoff values in a real-world population of genotyped primary glioblastoma patients. Methods: We measured TMT in preoperative MR images of 328 patients. Sex-specific TMT cutoff values were used to divide patients into "at risk of sarcopenia" or "normal muscle status". Kaplan-Meier analyses and stepwise multivariate Cox-Regression analyses were used to assess the association with overall survival (OS) and progression-free survival (PFS). The association with occurrence of complications and discontinuation of glioblastoma treatment was investigated using odds ratios (OR). Results: Patients at risk of sarcopenia had a significantly higher risk of progression and death than patients with normal muscle status, which remained significant in the multivariate analyses (OS HR = 1.437; 95%CI: 1.046-1.973; P = .025 and PFS HR = 1.453; 95%CI: 1.037-2.036; P = .030). Patients at risk of sarcopenia also had a significantly higher risk of early discontinuation of treatment (OR = 2.45; 95%CI: 1.011-5.952; P = .042) and a significantly lower chance of receiving second-line treatment (OR = 0.23; 95%CI: 0.09-0.60; P = .001). There was no association with the occurrence of complications. Conclusions: Our study confirms external validity of the use of proposed sex-specific TMT cutoff values as an independent prognostic marker in newly diagnosed glioblastoma patients. This simple, noninvasive marker could improve patient counseling and aid in treatment decision processes or trial stratification.