HIFs, angiogenesis, and metabolism:elusive enemies in breast cancer

Hypoxia-inducible factors (HIFs) and the HIF-dependent cancer hallmarks angiogenesis and metabolic rewiring are well-established drivers of breast cancer aggressiveness, therapy resistance, and poor prognosis. Targeting of HIF and its downstream targets in angiogenesis and metabolism has been unsuccessful so far in the breast cancer clinical setting, with major unresolved challenges residing in target selection, development of robust biomarkers for response prediction, and understanding and harnessing of escape mechanisms. This Review discusses the pathophysiological role of HIFs, angiogenesis, and metabolism in breast cancer and the challenges of targeting these features in patients with breast cancer. Rational therapeutic combinations, especially with immunotherapy and endocrine therapy, seem most promising in the clinical exploitation of the intricate interplay of HIFs, angiogenesis, and metabolism in breast cancer cells and the tumor microenvironment

Hubungan Komunikasi Interpersonal Dengan Tingkat Kecemasan Pasien Sebelum Tindakan Pencabutan Gigi Di Rsgm Fk Unsrat

HUBUNGAN KOMUNIKASI INTERPERSONAL DENGAN TINGKAT KECEMASAN PASIEN SEBELUM TINDAKAN PENCABUTAN GIGI DI RSGM FK UNSRAT Rooroh Fenesia Mariska1), Hendri Opod2), Bernat S.P. Hutagalung1) 1) Program Studi Pendidikan Dokter Gigi Fakultas Kedokteran UNSRAT Manado, 95115 2)Fakultas Kedokteran UNSRAT Manado, 95115 1)Program Studi Pendidikan Dokter Gigi Fakultas Kedokteran UNSRAT Manado, 95115 ABSTRACT In dental care, interpersonal communication is essential for fostering a good relationship operator-patient. The good interpersonal communication can control the patient\u27s anxiety during treatment. Tooth extraction is an action in dentistry that can cause anxiety. Anxiety generated during tooth extraction action can be caused by several factors , among: the patient fears by the tools for tooth extractions and the fear of pain that will be feel. The purpose of this research is to determine the relationship between interpersonal communication operator-patient with patient\u27s anxiety before tooth extraction at RSGM FK UNSRAT. This research is a analytic descriptive research using cross sectional study with sample using a total sampling and held on Department of Oral Surgery RSGM FK UNSRAT in June-July 2016. The research is done by assessing the interpersonal operator-patient using questionnaires and measured the anxiety level of patients before tooth extraction using Hamilton Anxiety Rating Scale (HARS). Analysis of bivariate data were analyze using Chi-square test in SPSS application. The results of data analysis using alternative test Kolmogorov-Smirnov by demonstrating the value p = 0,00 (0,00<0,05) which states that there is a significant relationship between interpersonal communication operator-patient with the patient\u27s anxiety before tooth extraction at RSGM FK UNSRAT. Keywords: Interpersonal Communication, Anxiety, Tooth Extraction ABSTRAK Dalam pelayanan kesehatan gigi, komunikasi interpersonal berperan penting untuk membina hubungan yang baik antara operator-pasien. Komunikasi interpersonal yang baik dapat mengontrol kecemasan pasien pada saat perawatan. Pencabutan gigi merupakan tindakan dalam kedokteran gigi yang dapat menimbulkan kecemasan. Kecemasan yang ditimbulkan pada saat tindakan pencabutan gigi dapat disebabkan oleh beberapa faktor antara lain: ketakutan pasien akan alat-alat pencabutan gigi dan ketakutan terhadap nyeri yang akan dirasakan pada saat pencabutan. Tujuan penelitian ini adalah untuk mengetahui hubungan antara komunikasi interpersonal operator-pasien dengan tingkat kecemasan pasien sebelum tindakan pencabutan gigi di RSGM FK UNSRAT. Penelitian ini merupakan penelitian deskriptif analitik yang menggunakan cross sectional study dengan pengambilan sampel menggunakan total sampling dan dilakukan di departemen Bedah Mulut RSGM FK UNSRAT pada bulan Juni-Juli 2016. Penelitian ini dilakukan dengan menilai komunikasi interpersonal operator-pasien menggunakan kuesioner dan mengukur tingkat kecemasan pasien sebelum tindakan pencabutan gigi menggunakan HARS (Hamilton Anxiety Rating Scale). Analisis data bivariat dianalisis dengan menggunakan uji alternatif Kolmogorov-Smirnov dalam program SPSS. Hasil analisis data menggunakan uji alternatif Kolmogorov-smirnov dengan menunjukkan nilai p = 0,00 (0,00 < 0,05) yang menyatakan bahwa terdapat hubungan yang signifikan antara komunikasi interpersonal operator-pasien dengan tingkat kecemasan pasien sebelum tindakan pencabutan gigi di RSGM FK UNSRAT

Pyruvate Dehydrogenase Kinase Inhibition by Dichloroacetate in Melanoma Cells Unveils Metabolic Vulnerabilities

Melanoma is characterized by high glucose uptake, partially mediated through elevated pyruvate dehydrogenase kinase (PDK), making PDK a potential treatment target in melanoma. We aimed to reduce glucose uptake in melanoma cell lines through PDK inhibitors dichloroacetate (DCA) and AZD7545 and through PDK knockdown, to inhibit cell growth and potentially unveil metabolic co-vulnerabilities resulting from PDK inhibition. MeWo cells were most sensitive to DCA, while SK-MEL-2 was the least sensitive, with IC50 values ranging from 13.3 to 27.0 mM. DCA strongly reduced PDH phosphorylation and increased the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio up to 6-fold. Knockdown of single PDK isoforms had similar effects on PDH phosphorylation and OCR:ECAR ratio as DCA but did not influence sensitivity to DCA. Growth inhibition by DCA was synergistic with the glutaminase inhibitor CB-839 (2-to 5-fold sensitization) and with diclofenac, known to inhibit monocarboxylate transporters (MCTs) (3-to 8-fold sensitization). CB-839 did not affect the OCR:ECAR response to DCA, whereas diclofenac strongly inhibited ECAR and further increased the OCR:ECAR ratio. We conclude that in melanoma cell lines, DCA reduces proliferation through reprogramming of cellular metabolism and synergizes with other metabolically targeted drugs

The immune tumour microenvironment of neuroendocrine tumours and its implications for immune checkpoint inhibitors

Immunotherapy in the form of immune checkpoint inhibitors (ICIs) has transformed the treatment landscape in numerous types of advanced cancer. However, the majority of patients do not benefit from this treatment modality. Although data are scarce, in general, patients with low-grade neuroendocrine tumours (NETs) do not benefit from treatment with ICIs in contrast to patients with neuroendocrine carcinoma, in which a small subgroup of patients may benefit. Low- and intermediate-grade NETs predominantly lack factors associated with response to ICIs treatment, like immune cell infiltration and have an immunosuppressive tumour metabolism and microenvironment. In addition, because of its potential influence on the response to ICIs, major interest has been shown in the tryptophan-degrading enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). These enzymes work along the kynurenine pathway that deplete tryptophan in the tumour microenvironment. IDO and TDO are especially of interest in NETs since some tumours produce serotonin but the majority do not, which potentially deplete the precursor tryptophan. In this review we summarize the current knowledge on the immune tumour microenvironment of neuroendocrine tumours and implications for treatment with immune checkpoint inhibitors. We also discuss (targetable) factors in the NET tumour microenvironment that potentially modulate the anti-cancer immune response

Clinically feasible semi-automatic workflows for measuring metabolically active tumour volume in metastatic melanoma

PURPOSE: Metabolically active tumour volume (MATV) is a potential quantitative positron emission tomography (PET) imaging biomarker in melanoma. Accumulating data indicate that low MATV may predict increased chance of response to immunotherapy and overall survival. However, metastatic melanoma can present with numerous (small) tumour lesions, making manual tumour segmentation time-consuming. The aim of this study was to evaluate multiple semi-automatic segmentation workflows to determine reliability and reproducibility of MATV measurements in patients with metastatic melanoma. METHODS: An existing cohort of 64 adult patients with histologically proven metastatic melanoma was used in this study. 18F-FDG PET/CT diagnostic baseline images were acquired using a European Association of Nuclear Medicine (EANM) Research Limited-accredited Siemens Biograph mCT PET/CT system (Siemens Healthineers, Knoxville, USA). PET data were analysed using manual, gradient-based segmentation and five different semi-automatic methods: three direct PET image-derived delineations (41MAX, A50P and SUV40) and two based on a majority-vote approach (MV2 and MV3), without and with (suffix '+') manual lesion addition. Correlation between the different segmentation methods and their respective associations with overall survival was assessed. RESULTS: Correlation between the MATVs derived by the manual segmentation and semi-automated tumour segmentations ranged from R2 = 0.41 for A50P to R2 = 0.85 for SUV40+ and MV2+, respectively. Manual MATV segmentation did not differ significantly from the semi-automatic methods SUV40 (∆MATV mean ± SD 0.08 ± 0.60 mL, P = 0.303), SUV40+ (∆MATV - 0.10 ± 0.51 mL, P = 0.126), MV2+ (∆MATV - 0.09 ± 0.62 mL, P = 0.252) and MV3+ (∆MATV - 0.03 ± 0.55 mL, P = 0.615). Log-rank tests showed statistically significant overall survival differences between above and below median MATV patients for all segmentation methods with areas under the ROC curves of 0.806 for manual segmentation and between 0.756 [41MAX] and 0.807 [MV3+] for semi-automatic segmentations. CONCLUSIONS: Simple and fast semi-automated FDG PET segmentation workflows yield accurate and reproducible MATV measurements that correlate well with manual segmentation in metastatic melanoma. The most readily applicable and user-friendly SUV40 method allows feasible MATV measurement in prospective multicentre studies required for validation of this potential PET imaging biomarker for clinical use

Modified protocol of omalizumab treatment to prevent carboplatin-induced drug hypersensitivity reactions:a case study

Carboplatin administration can usually be safely continued via a so-called desensitisation protocol when hypersensitivity reactions arise. Severe break-through reactions that occur early during desensitisation are likely to be IgE-mediated; in that case, addition of omalizumab premedication should be strongly considered

Preoperative inhibition in patients with irresectable locally advanced stage III melanoma

Aim: Neoadjuvant treatment of locally advanced disease with BRAF inhibitors is expected to increase the likelihood of a R0 resection. We present six patients with stage III unresectable melanoma, neoadjuvantly treated with BRAF inhibitors. Methods: Patients with unresectable, BRAF-mutated, stage III melanoma, were treated with BRAF inhibitors between 2012 and 2015. Unresectability was determined based on clinical and/or radiological findings. At maximal response, resection was performed. The specimen was reviewed to determine the degree of response. Results: In five of six patients a radical resection was achieved. Postoperative complications were unremarkable. In five of six resected specimens, vital tumor tissue was found. Conclusion: Neoadjuvant BRAF inhibitor treatment of locally advanced melanoma is feasible and has the potential to facilitate an R0 resection

End-of-life care for patients with advanced ovarian cancer in the Netherlands:A retrospective registry-based analysis

OBJECTIVE: Patients with advanced ovarian cancer have a poor prognosis and can experience debilitating symptoms in the last phase of life. Several analyses, mainly performed in the United States (US), show high rates of chemotherapy administration and hospital visits near the end-of-life in this patient category. No large European studies are available, while the organisation of palliative care differs between the US and Europe. We aimed to analyse the intensity of inpatient care near the end-of-life in the Netherlands and perform a cross-study comparison with previous reports. METHODS: All patients with ovarian cancer that died in 2016 and 2017 were identified from the Vektis database, a data warehouse including all insurance declarations in the Netherlands. For the last 6 months of life the following parameters of aggressive care were extracted: administration of chemotherapy, emergency room (ER) visits, surgical procedures, hospital and intensive care unit (ICU) admissions. The intensity of inpatient care was compared to previously reported European and US data. RESULTS: Data on medical care use was available for 1775 patients. During the last 6 months of life, half of the ovarian cancer patients were admitted to hospital. Chemotherapy administration near the end-of-life was infrequent: 12% in the last month of life. Surgery and ICU admissions in the final 6 months of life were rare (<10%). Our cohort showed the lowest percentages of all five indicators of aggressive care reported thus far. CONCLUSION: Aggressive medical care use in the final 6 months of life in this Dutch cohort of ovarian cancer patients was lower than in other previously reported cohorts