Tumor microenvironmental changes induced by the sulfamate carbonic anhydrase IX inhibitor S4 in a laryngeal tumor model

BACKGROUND AND PURPOSE: Carbonic anhydrase IX (CAIX) plays a pivotal role in pH homeostasis, which is essential for tumor cell survival. We examined the effect of the CAIX inhibitor 4-(3'(3",5"-dimethylphenyl)-ureido)phenyl sulfamate (S4) on the tumor microenvironment in a laryngeal tumor model by analyzing proliferation, apoptosis, necrosis, hypoxia, metabolism and CAIX ectodomain shedding. METHODS: SCCNij202 tumor bearing-mice were treated with S4 for 1, 3 or 5 days. CAIX ectodomain shedding was measured in the serum after therapy. Effects on tumor cell proliferation, apoptosis, necrosis, hypoxia (pimonidazole) and CAIX were investigated with quantitative immunohistochemistry. Metabolic transporters and enzymes were quantified with qPCR. RESULTS: CAIX ectodomain shedding decreased after treatment with S4 (p<0.01). S4 therapy did neither influence tumor cell proliferation nor the amount of apoptosis and necrosis. Hypoxia (pimonidazole) and CAIX expression were also not affected by S4. CHOP and MMP9 mRNA as a reference of intracellular pH did not change upon treatment with S4. Compensatory mechanisms of pH homeostasis at the mRNA level were not observed. CONCLUSION: As the clinical and biological meaning of the decrease in CAIX ectodomain shedding after S4 therapy is not clear, studies are required to elucidate whether the CAIX ectodomain has a paracrine or autocrine signaling function in cancer biology. S4 did not influence the amount of proliferation, apoptosis, necrosis and hypoxia. Therefore, it is unlikely that S4 can be used as single agent to influence tumor cell kill and proliferation, and to target primary tumor growth

Prevalence and clinical and psychological correlates of high fear of cancer recurrence in patients newly diagnosed with head and neck cancer

Funding information: Dutch Cancer Society (KWF- Alpe d'Huzes); Medical Faculty Ljubljana, Department of Family Medicine; Slovenian Research Agency (Young Researcher Program).Background: Patients with head and neck cancer (HNC) are vulnerable to fear of cancer recurrence (FCR) and psychiatric morbidity. We investigated the prevalence of high FCR and demographic, clinical, psychological, and psychiatric factors associated with high FCR prior to the start of the treatment. Methods: In a cross-sectional substudy of the large ongoing prospective NET-QUBIC study questionnaires and psychiatric interviews of 216 patients newly diagnosed with HNC were analyzed. Results: High FCR was observed in 52.8% of patients and among those 21.1% also had a lifetime history of selected anxiety or major depressive disorder. FCR was not related to any clinical characteristics; however, younger age, higher anxiety symptoms, introversion, greater needs for support regarding sexuality, and being an exsmoker were significantly associated with higher FCR. Conclusion: Factors associated with high FCR provide us with a better conceptual understanding of FCR in patients newly diagnosed with HNC.Publisher PDFPeer reviewe

Can FDG PET predict radiation treatment outcome in head and neck cancer? Results of a prospective study

Contains fulltext : 96692.pdf (publisher's version ) (Closed access)PURPOSE: In head and neck cancer (HNC) various treatment strategies have been developed to improve outcome, but selecting patients for these intensified treatments remains difficult. Therefore, identification of novel pretreatment assays to predict outcome is of interest. In HNC there are indications that pretreatment tumour (18)F-fluorodeoxyglucose (FDG) uptake may be an independent prognostic factor. The aim of this study was to assess the prognostic value of FDG uptake and CT-based and FDG PET-based primary tumour volume measurements in patients with HNC treated with (chemo)radiotherapy. METHODS: A total of 77 patients with stage II-IV HNC who were eligible for definitive (chemo)radiotherapy underwent coregistered pretreatment CT and FDG PET. The gross tumour volume of the primary tumour was determined on the CT (GTV(CT)) and FDG PET scans. Five PET segmentation methods were applied: interpreting FDG PET visually (PET(VIS)), applying an isocontour at a standardized uptake value (SUV) of 2.5 (PET(2.5)), using fixed thresholds of 40% and 50% (PET(40%), PET(50%)) of the maximum intratumoral FDG activity (SUV(MAX)) and applying an adaptive threshold based on the signal-to-background (PET(SBR)). Mean FDG uptake for each PET-based volume was recorded (SUV(mean)). Subsequently, to determine the metabolic volume, the integrated SUV was calculated as the product of PET-based volume and SUV(mean). All these variables were analysed as potential predictors of local control (LC), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS). RESULTS: In oral cavity/oropharynx tumours PET(VIS) was the only volume-based method able to predict LC. Both PET(VIS) and GTV(CT) were able to predict DMFS, DFS and OS in these subsites. Integrated SUVs were associated with LC, DMFS, DFS and OS, while SUV(mean) and SUV(MAX) were not. In hypopharyngeal/laryngeal tumours none of the variables was associated with outcome. CONCLUSION: There is no role yet for pretreatment FDG PET as a predictor of (chemo)radiotherapy outcome in HNC in daily routine. However, this potential application needs further exploration, focusing both on FDG PET-based primary tumour volume, integrated SUV and SUV(MAX) of the primary tumour

Hemoglobin level predicts outcome for vulvar cancer patients independent of GLUT-1 and CA-IX expression in tumor tissue

Intratumoral hypoxia has been associated with poor prognosis in several solid tumors. The aim of this study was to determine whether the hypoxia-associated markers glucose transporter (GLUT)-1 and carbonic anhydrase (CA)-IX expression and preoperative hemoglobin (Hb) levels correlate with presence of inguinofemoral or distant metastases, and disease-free survival (DSS) in vulvar squamous cell carcinoma (SCC) patients. Vulvar SCC (n = 103) were reviewed for histopathological characteristics by an expert gynecopathologist and stained for GLUT-1 and CA-IX. Clinical data and preoperative Hb levels were obtained from medical records. No significant correlations were observed between GLUT-1 or CA-IX expression patterns and preoperative Hb levels, presence of inguinofemoral or distant metastases and DSS. However, anemic patients (Hb < 11.2 g/dL) had significantly more inguinofemoral metastases and lower Hb level was an independent prognostic factor for a worse DSS (p < 0.001). The number of comorbidic conditions was inversely correlated with preoperative Hb level. Preoperative Hb levels are associated with poor DSS for vulvar SCC patients, whereas tumor hypoxia reflected by GLUT-1 and CA-IX expression does not have a predictive value. Because preoperative Hb levels inversely correlated with the number of comorbidic conditions and not with GLUT-1 or CA-IX expression, it is most likely that preoperative Hb levels represent overall physical condition

Treatment of T3 laryngeal cancer in the Netherlands : A national survey

Background: Treatment strategies for T3 laryngeal carcinoma include radiotherapy (RT) with or without chemotherapy (CT) and sometimes surgery. We conducted a national survey to determine how T3 laryngeal carcinoma is currently being managed in the Netherlands.  Methods: A questionnaire on general treatment policy, also inquiring details on RT and CT, was sent to all 13 radiotherapy departments accredited for treatment of head and neck cancer (HNC) in the Netherlands.  Results: Twelve centers completed the questionnaire. All centers reported using RT with or without CT. Upfront laryngectomy is rarely performed. At 9/12 centers, CT is added to RT in cases with large tumors in T3N0 disease. Three centers use a volume criterion (3-6 cc); 6 centers don't specify "large" with such criteria. CT consists of cisplatin 3-weekly (7 centers) or weekly (2 centers), unless contra-indicated or age; 6 centers use an age limit of 70 years. RT is given concomitantly with CT 5×/week except at the 2 centers where cisplatin weekly is combined with 6 fractions/week. In case of RT only, treatment is accelerated. Lymph node levels II-IV are treated electively. In T3N+ disease, 11/12 centers treat non-bulky T3N1 with RT only. Volume criteria for combined CT-RT are the same as above. Two centers perform an upfront neck dissection in case of (resectable) N3 disease; 10 centers treat T3N2-3 cancer with primary CT-RT, 2 centers don't use the N-stage criterion. Total RT dose is 68-70 Gy, the elective dose varies between 46 and 57.75 Gy. Eight centers use a simultaneous integrated boost technique. Conclusions: Treatment of T3 laryngeal cancer in the Netherlands is generally comparable, with CT-RT for voluminous T3N0 and most T3N+ tumors, but there are some differences between the centers in the use of chemotherapy and the dose-fractionation schemes. Therefore, the aim of the National Platform RT HNC is further standardization of RT dose, fractionation and delivery techniques

Comparison of Patients With Head and Neck Cancer in Randomized Clinical Trials and Clinical Practice:A Systematic Review

Importance: When patient populations in randomized clinical trials deviate too much from the general population, it undermines the relevance for daily practice. Objective: To investigate if patients with head and neck cancer in randomized clinical trials are representative of the clinically treated population. Evidence Review: A systematic literature search was performed for randomized clinical trials on head and neck cancer evaluating an intervention to improve outcome with total sample size of 100 patients or greater and published between 2009 and 2019. Outcome measures were age, performance status, and recruitment rate. National cancer registries provided reference data. Databases that were searched included MEDLINE and Epub Ahead of Print; Embase; Cochrane Central Register of Controlled Trials; and ClinicalTrials.gov. Abstracts of search results were retrieved to assess selection criteria by 2 reviewers independently. After the selection procedure was completed by both reviewers, the results were compared and reviewed once more to reach consensus. Full articles were downloaded to retrieve general study information and outcome data. Findings: A total of 16 927 publications were identified, resulting in 87 compliant randomized clinical trials with a total of 34 241 patients. Half of the trials included all major head and neck sites, and one-third were exclusively for nasopharynx cancers. The experimental intervention was systemic treatment in 47 (54%) studies, radiotherapy in 23 (26%), and other in 17 (20%). Median sample size was 332, and median duration of accrual was 4.6 years. Median accrual per center per year for head and neck and nasopharynx trials was 5.4 and 39.7 patients, respectively. Median age of patients in head and neck trials was 57 years, which was 7 years younger than in cancer registries. More than 70% of patients had a World Health Organization performance score of 0 to 1 or a Karnofsky performance status of 90 to 100. Conclusions and Relevance: In this systematic review, patients in head and neck randomized clinical trials had a very good performance status, and half of them were younger than 57 years, while half of the clinical population was older than 64 years. In more than 50% of the head and neck trials, the yearly accrual per center was less than 6 patients, suggesting overly restrictive recruitment. Critical appraisal of trial population characteristics is recommended before results are implemented in clinical guidelines and general practice

Acute toxicity profile of craniospinal irradiation with intensity-modulated radiation therapy in children with medulloblastoma : A prospective analysis

Background: To report on the acute toxicity in children with medulloblastoma undergoing intensity-modulated radiation therapy (IMRT) with daily intrafractionally modulated junctions. Methods: Newly diagnosed patients, aged 3-21, with standard-risk (SR) or high-risk (HR) medulloblastoma were eligible. A dose of 23.4 or 36.0Gy in daily fractions of 1.8Gy was prescribed to the craniospinal axis, followed by a boost to the primary tumor bed (54 or 55.8Gy) and metastases (39.6-55.8Gy), when indicated. Weekly, an intravenous bolus of vincristine was combined for patients with SR medulloblastoma and patients participating in the COG-ACNS-0332 study. Common toxicity criteria (CTC, version 2.0) focusing on skin, alopecia, voice changes, conjunctivitis, anorexia, dysphagia, gastro-intestinal symptoms, headache, fatigue and hematological changes were scored weekly during radiotherapy. Results: From 2010 to 2014, data from 15 consecutive patients (SR, n=7; HR, n=8) were collected. Within 72h from onset of treatment, vomiting (66%) and headache (46%) occurred. During week 3 of treatment, a peak incidence in constipation (33%) and abdominal pain/cramping (40%) was observed, but only in the subgroup of patients (n=9) receiving vincristine (constipation: 56 vs 0%, P=.04; pain/cramping: 67 vs 0%, P=.03). At week 6, 73% of the patients developed faint erythema of the cranial skin with dry desquamation (40%) or moist desquamation confined to the skin folds of the auricle (33%). No reaction of the skin overlying the spinal target volume was observed. Conclusions: Headache at onset and gastro-intestinal toxicity, especially in patients receiving weekly vincristine, were the major complaints of patients with medulloblastoma undergoing craniospinal irradiation with IMRT