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

Rational use of ¹⁸F-FDG PET/CT in patients with advanced cutaneous melanoma:A systematic review

18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is increasingly used in patients with advanced melanoma. Immune checkpoint inhibitors and BRAF/MEK-targeted therapy have transformed the therapeutic landscape of metastatic melanoma. Consequently, a need for markers predicting (early) response to treatment and for monitoring treatment (toxicity) has arisen. This systematic review appraises the current literature evidence for rational use of 18F-FDG PET/CT scans in staging, clinical decision-making, treatment monitoring and follow-up in advanced melanoma. 18F-FDG PET/CT has high overall accuracy for detection of distant metastases and is, combined with cerebral MRI, the preferred imaging strategy for staging metastatic melanoma. In contrast, strong evidence supporting the standard use of 18F-FDG PET/CT for predicting and monitoring therapy response and toxicity is currently lacking. Essential for determining the position of 18F-FDG PET/CT during treatment course in advanced melanoma are well-designed studies with standardized scanning protocols, incorporation of clinical parameters and comparison with contrast-enhanced CT alone

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

Clinical benefit of systemic therapies for recurrent ovarian cancer-ESMO-MCBS scores

BACKGROUND: Licensed systemic treatment options for platinum-sensitive recurrent ovarian cancer are platinum-based chemotherapy and maintenance treatment with bevacizumab and poly (ADP-ribose) polymerase inhibitors. For platinum-resistant disease, several non-platinum options are available. We aimed to assess the clinical benefit of these treatments according to the European Society of Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS). MATERIALS AND METHODS: A PubMed search was carried out including all studies evaluating systemic treatment of recurrent epithelial ovarian cancer, from 1990 onwards. Randomised trials with an adequate comparator and design showing a statistically significant benefit of the study arm were independently scored by two blinded observers using the ESMO-MCBS. RESULTS: A total of 1127 papers were identified, out of which 61 reported results of randomised trials of sufficient quality. Nineteen trials showed statistically significant results and the studied treatments were graded according to ESMO-MCBS. Only three treatments showed substantial benefit (score of 4 on a scale of 1-5) according to the ESMO-MCBS: platinum-based chemotherapy with paclitaxel in the platinum-sensitive setting and the addition of bevacizumab to chemotherapy in the platinum-resistant setting. The WEE1 inhibitor adavosertib (not licensed) also scores a 4, based on a recent small phase II study. Assessment of quality-of-life data and toxicity using the ESMO-MCBS showed to be complex, which should be taken into account in using this score for clinical decision making. CONCLUSION: Only a few licensed systemic therapies for recurrent ovarian cancer show substantial clinical benefit based on ESMO-MCBS scores. Trials demonstrating overall survival benefit are sparse

F-18-FDG PET/CT Scans Can Identify Sub-Groups of NSCLC Patients with High Glucose Uptake in the Majority of Their Tumor Lesions

Background: Reprogrammed glucose metabolism is a hallmark of cancer making it an attractive therapeutic target, especially in cancers with high glucose uptake such as non-small cell lung cancer (NSCLC). Tools to select patients with high glucose uptake in the majority of tumor lesions are essential in the development of anti-cancer drugs targeting glucose metabolism. Type 2 diabetes mellitus (T2DM) patients may have tumors highly dependent on glucose uptake. Surprisingly, this has not been systematically studied. Therefore, we aimed to determine which patient and tumor characteristics, including concurrent T2DM, are related to high glucose uptake in the majority of tumor lesions in NSCLC patients as measured by 2-deoxy-2-[fluorine-18]fluoro-D-glucose (F-18-FDG) positron emission tomography (PET)/computed tomography (CT) scans. Methods: Routine primary diagnostic F-18-FDG PET/CT scans of consecutive NSCLC patients were included. Mean standardized uptake value (SUVmean) of F-18-FDG was determined for all evaluable tumor lesions and corrected for serum glucose levels according to the European Association of Nuclear Medicine Research Ltd guidelines. Patient characteristics potentially determining degree of tumor lesion glucose uptake in the majority of tumor lesions per patient were investigated. Results: The cohort consisted of 102 patients, 28 with T2DM and 74 without T2DM. The median SUVmean per patient ranged from 0.8 to 35.2 (median 4.2). T2DM patients had higher median glucose uptake in individual tumor lesions and per patient compared to non-diabetic NSCLC patients (SUVmean 4.3 vs 2.8, P = 1 mL per patient (odds ratio 0.8, 95% confidence interval 0.7-0.9). Conclusions: F-18-FDG PET/CT scans can identify sub-groups of NSCLC patients with high glucose uptake in the majority of their tumor lesions. T2DM patients had higher tumor lesion glucose uptake than non-diabetic patients. However, this was not independent of other factors such as the histological subtype and number of tumor lesions per patient

Type 2 Diabetes Mellitus and Clinicopathological Tumor Characteristics in Women Diagnosed with Breast Cancer:A Systematic Review and Meta-Analysis

SIMPLE SUMMARY: Female breast cancer continues to be the leading cause of cancer deaths worldwide, and type 2 diabetes mellitus (T2DM) is one of the contributors to the poor prognosis of breast cancer. This raises the issue that T2DM might be associated with aggressive clinicopathological characteristics, which indicate pivotal prognostic values. This study aimed to clarify the differences in breast cancer characteristics at diagnosis between patients with and without pre-existing T2DM. Our meta-analyses showed an increased risk of being diagnosed with a late-stage tumor, large tumor size, and invasive lymph nodes in patients with T2DM. No significant results were observed for grade, estrogen/progesterone receptor, and human epidermal growth factor receptor. These findings indicate an association between T2DM and advanced breast cancer at diagnosis, and suggest that the more active role of breast cancer screening should be further explored for women with T2DM. ABSTRACT: Poor prognosis caused by type 2 diabetes mellitus (T2DM) in women with breast cancer is conferred, while the association between T2DM and breast tumor aggressiveness is still a matter of debate. This study aimed to clarify the differences in breast cancer characteristics, including stage, size, lymph node status, grade, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (Her2), between patients with and without pre-existing T2DM. PubMed, Embase, and Web of Science were searched for studies from 1 January 2010 to 2 July 2021. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were pooled by using a random effects model. T2DM was significantly associated with tumor stages III/IV versus cancers in situ and stages I/II (pooled ORs (pOR), 95% CI: 1.19; 1.04–1.36, p = 0.012), tumor size >20 versus ≤20 mm (pOR, 95% CI: 1.18; 1.04–1.35, p = 0.013), and lymph node invasion versus no involvement (pOR, 95% CI: 1.26; 1.05–1.51, p = 0.013). These findings suggest that women with T2DM are at a higher risk of late-stage tumors, large tumor sizes, and invasive lymph nodes at breast cancer diagnosis