Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity.

Cross-presentation of antigens from dead tumor cells by type 1 conventional dendritic cells (cDC1s) is thought to underlie priming of anti-cancer CD8+ T cells. cDC1 express high levels of DNGR-1 (a.k.a. CLEC9A), a receptor that binds to F-actin exposed by dead cell debris and promotes cross-presentation of associated antigens. Here, we show that secreted gelsolin (sGSN), an extracellular protein, decreases DNGR-1 binding to F-actin and cross-presentation of dead cell-associated antigens by cDC1s. Mice deficient in sGsn display increased DNGR-1-dependent resistance to transplantable tumors, especially ones expressing neoantigens associated with the actin cytoskeleton, and exhibit greater responsiveness to cancer immunotherapy. In human cancers, lower levels of intratumoral sGSN transcripts, as well as presence of mutations in proteins associated with the actin cytoskeleton, are associated with signatures of anti-cancer immunity and increased patient survival. Our results reveal a natural barrier to cross-presentation of cancer antigens that dampens anti-tumor CD8+ T cell responses.

Identification of Areas for Improvement in the Management of Bone Metastases in Patients with Neuroendocrine Neoplasms.

BACKGROUND: There is no global consensus on the optimal management of bone metastases (BMs) in neuroendocrine neoplasms (NENs). OBJECTIVES: To review current management and outcomes of patients with BMs in NENs, in order to identify areas for improvement. METHODS: A retrospective study of all patients with NENs, except Grade 3 lung NENs (April 2002 to March 2018) was conducted. Baseline characteristics, nature of BMs, treatment received and overall survival (OS) were evaluated. Statistical analyses were performed using SPSS version 23.0/STATA v12. RESULTS: Of 1,212 patients, 85 (7%) had BMs; median age 58 years. The majority had a gastro-entero-pancreatic primary (49%, n = 42) followed by lung (25%, n = 21), unknown primary (20%, n = 17), and "others" (6%, n = 5). Two-thirds (n = 57) had G1-2 neuroendocrine tumours, and 41% (n = 35) had functional tumours. Overall, 28% (n = 24) presented with synchronous BMs at first NEN diagnosis, and 55% (n = 47) developed BMs at the same time as other distant metastases. For the subpopulation of patients in whom BMs developed metachronously to other distant metastases (45%, n = 38), median time to development of BMs was 14.0 months. BMs were "widespread" in 61% (n = 52). Although only 22% (n = 19) reported symptoms at initial diagnosis of BMs, most (78%) developed symptoms at some time during the follow-up period (pain/hypercalcaemia 64%, skeletal-related events 20%). BMs were mainly managed with analgesia (44%, n = 37). Radiotherapy and bisphosphonates were used in 34% (n = 29) and 22% (n = 19) respectively. Surgery was rarely performed (2%, n = 2). Median OS from identification of BMs was 31.0, and 18.9 months from development of BMs-related symptoms. CONCLUSIONS: In this cohort study, most patients with BMs developed symptoms. The utility of radiotherapy and/or bisphosphonates should be prospectively and systematically explored further for its potential impact on patients' quality of life and survival outcomes.

Vitamin D regulates microbiome-dependent cancer immunity.

A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis, which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.

The Mental Health Burden of Patients with Colorectal Cancer Receiving Care during the COVID-19 Pandemic: Results of the PICO-SM Study.

The COVID-19 pandemic has resulted in unprecedented changes to the lives of patients with cancer. To evaluate the impact of the COVID-19 pandemic on the mental health and well-being of patients with colorectal cancer, we conducted a prospective longitudinal questionnaire study at a UK tertiary cancer centre. In total, 216 participants were included: mean age 65 years, 57% (n = 122) male, 92% (n = 198) of white ethnicity. Amongst participants who completed the screening psychometric questionnaire, 24% (n = 48/203) reported anxiety (GAD-7 ≥ 5), 15% (n = 31/204) depressive symptoms (PHQ-9 ≥ 10), 3% (n = 5/190) probable post-traumatic stress disorder (PC-PTSD-5 ≥ 4), and 31% (n = 66/213) poor well-being (WHO-5 < 50). In the subgroup (n = 95/216, 44%) who consented to and completed a follow-up survey 6 months later, there was a significant increase in the number of participants at risk of depression (4% vs. 13%, p = 0.021). Self-reported concern about the COVID-19 pandemic impacting one's mental health is associated with increased likelihood of anxiety, depression, and poor well-being, in respective multivariate analyses. In conclusion, screening for the mental health impact of the COVID-19 pandemic is essential to ensure timely action from all key stakeholders and to avoid potentially longer-term detrimental consequences.

Loss of secreted gelsolin enhances response to anticancer therapies.

Type 1 conventional dendritic cells (cDC1) play a critical role in priming anticancer cytotoxic CD8+ T cells. DNGR-1 (a.k.a. CLEC9A) is a cDC1 receptor that binds to F-actin exposed on necrotic cancer and normal cells. DNGR-1 signaling enhances cross-presentation of dead-cell associated antigens, including tumor antigens. We have recently shown that secreted gelsolin (sGSN), a plasma protein, competes with DNGR-1 for binding to dead cell-exposed F-actin and dampens anticancer immunity. Here, we investigated the effects of loss of sGSN on various anticancer therapies that are thought to induce cell death and provoke an immune response to cancer. We compared WT (wildtype) with Rag1-/- , Batf3-/- , Clec9agfp/gfp , sGsn-/- or sGsn-/- Clec9agfp/gfp mice implanted with transplantable tumor cell lines, including MCA-205 fibrosarcoma, 5555 BrafV600E melanoma and B16-F10 LifeAct (LA)-ovalbumin (OVA)-mCherry melanoma. Tumor-bearing mice were treated with (1) doxorubicin (intratumoral) chemotherapy for MCA-205, (2) BRAF-inhibitor PLX4720 (oral gavage) targeted therapy for 5555 BrafV600E, and (3) X-ray radiotherapy for B16 LA-OVA-mCherry. We confirmed that efficient tumor control following each therapy requires an immunocompetent host as efficacy was markedly reduced in Rag1-/- compared with WT mice. Notably, across all the therapeutic modalities, loss of sGSN significantly enhanced tumor control compared with treated WT controls. This was an on-target effect as mice deficient in both sGSN and DNGR-1 behaved no differently from WT mice following therapy. In sum, we find that mice deficient in sGsn display enhanced DNGR-1-dependent responsiveness to chemotherapy, targeted therapy and radiotherapy. Our findings are consistent with the notion some cancer therapies induce immunogenic cell death (ICD), which mobilizes anticancer T cells. Our results point to cDC1 and DNGR-1 as decoders of ICD and to sGSN as a negative regulator of such decoding, highlighting sGSN as a possible target in cancer treatment. Further prospective studies are warranted to identify patients who may benefit most from inhibition of sGSN function.

Modification to Systemic Anticancer Therapy at the Start of the COVID-19 Pandemic and its Overall Impact on Survival Outcomes in Patients with Colorectal Cancer.

BACKGROUND: Since the beginning of the COVID-19 pandemic, multiple changes to the provision of cancer care has been introduced to maximize patient safety and protect staff. We aimed to identify factors influencing clinicians' decision on treatment modification during the initial phase of the pandemic, and to assess its impact on outcomes in patients with colorectal cancer. PATIENTS AND METHODS: Electronic records of patients seen in a large United Kingdom tertiary cancer center was reviewed. The frequency and type of changes to systemic anticancer therapy , as well as the factors predicting clinicians' decision were assessed. RESULTS: A total of 418 patients; mean age 63 ± 12 years and 57% male were included. More than half of the patients had modification to their treatment; with treatment delay (21%) or cancellation (10%), being the most common. Majority of patients on neoadjuvant treatment (97%) proceeded with treatment, with some form of treatment modification in 20%. Half of patients on adjuvant treatment had their treatment plan modified. Overall, a change in treatment was more likely in older patients (OR 1.028 [95% CI 1.010-1.047]; P = .002), and in patients who had already received higher number of cycles of systemic anticancer therapy (OR 1.040 [95% CI 1.016-1.065]; P = .001). A change in treatment was less likely further out of the first national lockdown (OR 0.837 [95% CI 0.758-0.925]; P < .001). Patients on third-line treatment were most likely to have alterations to their treatment plan (69%, n=33/48). CONCLUSION: During the first wave of COVID-19 in the United Kingdom, clinicians adapted clinical practice in accordance to local and national guidance, especially amongst older patients and those on third-line treatment. Further real-world data are needed to document the important impact of changes to treatment on outcomes in patients with cancer.

Knowns and unknowns of bone metastases in patients with neuroendocrine neoplasms: A systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to develop an evidence-based summary of current knowledge of bone metastases (BMs) in neuroendocrine neoplasms (NENs), inform diagnosis and treatment and standardise management between institutions. METHODS: PubMed, Medline, EMBASE and meeting proceedings were searched for eligible studies reporting data on patients with BMs and NENs of any grade of differentiation and site; poorly-differentiated large/small cell lung cancer were excluded. Data were extracted and analysed using STATA v.12. Meta-analysis of proportions for calculation of estimated pooled prevalence of BM and calculation of weighted pooled frequency and weighted pooled mean for other variables of interest was performed . RESULTS: A total of 149 studies met the eligibility criteria. Pooled prevalence of BMs was 18.4% (95% CI 15.4-21.5). BMs were mainly metachronous with initial diagnosis of NEN (61.2%) and predominantly osteoblastic; around 61% were multifocal, with a predisposition in axial skeleton. PET/CT seemed to provide (together with MRI) the highest sensitivity and specificity for BM detection. Almost half of patients (46.4%) reported BM-related symptoms: pain (66%) and skeletal-related events (SREs, fracture/spinal cord compression) (26.2%; weightedweighted mean time-to-SRE 9.9 months). Management of BMs was multimodal [bisphosphonates and bone-modifying agents (45.2%), external beam radiotherapy (34.9%), surgery (14.8%)] and supported by little evidence. Overall survival (OS) from the time of diagnosis of BMs was long [weighted mean 50.9 months (95% CI 40.0-61.9)]. Patients with BMs had shorter OS [48.8 months (95% CI 37.9-59.6)] compared to patients without BMs [87.4 months (95% CI 74.9-100.0); p = 0.001]. Poor performance status and BM-related symptoms were also associated with worse OS. CONCLUSIONS: BMs in patients with NENs remain underdiagnosed and undertreated. Recommendations for management of BMs derived from current knowledge are provided. Prospective studies to inform management are required.

Possible significance of differences in proportions of cytotoxic T cells and B-lineage cells in the tumour-infiltrating lymphocytes of typical and atypical medullary carcinomas of the breast.

Medullary carcinoma (MC) of the breast is a high grade carcinoma that has a relatively favourable prognosis compared to atypical medullary carcinoma (AMC) and other more common breast carcinomas. In a retrospective study in Brunei Darussalam of all available biopsy samples, we compared the nature of the tumour-infiltrating lymphocytes (TILs) in MC and AMC in relation to recorded tumour characteristics. CD4, CD8, CD20, CD25, CD45RO, and CD56 and common tumour biomarkers were detected immunohistochemically. The 11 cases of MC had no nodal metastases and survived without relapse, suggesting good tumour control. In contrast, 7 cases of nodal metastases and 1 relapse were observed in 12 AMCs. Although not statistically significant, there was a tendency for a greater proportion of AMCs to express the Her2/neu oncogene. Higher proportions of CD45RO+ and CD8+ cells, and lower levels of CD20+ cells, were characteristic of TILs in MC compared to AMC. The ratio of CTL to B-lineage cells in TILs in both tumours considered together was inversely related to the expression of HER2/neu and the presence of nodal metastases. The findings suggest that CTLs, rather than antibodies, may give better tumour control in MC relative to AMC. We propose that a comparison of the cellular, molecular and immunological characteristics of MC and AMC, as a paired model system, in a multi-centre investigation with a much larger number of samples will be valuable for better understanding mechanisms of tumour immunity.

Highlights in lung cancer in 2019.

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Adjuvant and neoadjuvant therapies in melanoma.

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Prognostic importance of lymph node yield after curative resection of gastroenteropancreatic neuroendocrine tumours.

BACKGROUND: The prognostic significance of lymph nodes (LNs) metastases and the optimum number of LN yield in gastroenteropancreatic neuroendocrine tumours (GEP NETs) undergoing curative resection is still debatable. Many studies have demonstrated that cure rate for patients with GEP NETs can be improved by the resection of the primary tumour and regional lymphadenectomy. AIM: To evaluate the effect of lymph node (LN) status and yield on relapse-free survival (RFS) and overall survival (OS) in patients with resected GEP NETs. METHODS: Data on patients who underwent curative resection for GEP NETs between January 2002 and March 2017 were analysed retrospectively. Grade 3 tumours (Ki67 > 20%) were excluded. Univariate Cox proportional hazard models were computed for RFS and OS and assessed alongside cut-point analysis to distinguish a suitable binary categorisation of total LNs retrieved associated with RFS. RESULTS: A total of 217 patients were included in the study. The median age was 59 years (21-97 years) and 51% (n = 111) were male. Primary tumour sites were small bowel (42%), pancreas (25%), appendix (18%), rectum (7%), colon (3%), gastric (2%), others (2%). Median follow up times for all patients were 41 mo (95%CI: 36-51) and 71 mo (95%CI: 63-76) for RFS and OS respectively; 50 relapses and 35 deaths were reported. LNs were retrieved in 151 patients. Eight or more LNs were harvested in 106 patients and LN positivity reported in 114 patients. Three or more positive LNs were detected in 62 cases. The result of univariate analysis suggested perineural invasion (P = 0.0023), LN positivity (P = 0.033), LN retrieval of ≥ 8 (P = 0.047) and localisation (P = 0.0049) have a statistically significant association with shorter RFS, but there was no effect of LN ratio on RFS: P = 0.1 or OS: P = 0.75. Tumour necrosis (P = 0.021) and perineural invasion (P = 0.016) were the only two variables significantly associated with worse OS. In the final multivariable analysis, localisation (pancreas HR = 27.33, P = 0.006, small bowel HR = 32.44, P = 0.005), and retrieval of ≥ 8 LNs (HR = 2.7, P = 0.036) were independent prognostic factors for worse RFS. CONCLUSION: An outcome-oriented approach to cut-point analysis can suggest a minimum number of adequate LNs to be harvested in patients with GEP NETs undergoing curative surgery. Removal of ≥ 8 LNs is associated with increased risk of relapse, which could be due to high rates of LN positivity at the time of surgery. Given that localisation had a significant association with RFS, a prospective multicentre study is warranted with a clear direction on recommended surgical practice and follow-up guidance for GEP NETs.

Unusual skull base metastasis from neuroendocrine tumor: a case report.

BACKGROUND: With increasing treatment options available, neuroendocrine tumor has become a chronic disease and may present later on with atypical manifestation of disease spread once resistant to treatment. CASE PRESENTATION: A 74-year-old white British woman undergoing treatment for metastatic well-differentiated neuroendocrine tumor for the past 9 years presented with a brief history of mild frontal headache, and progressive left ptosis and ocular palsy. She had no visual loss, and had neither speech nor motor deficit. At the outset, it was crucial to exclude acute or missed stroke. An urgent magnetic resonance imaging of her head revealed an unusual skull base metastasis extending into the cavernous sinus, with no peritumoral edema. Following discussion at a specialist neuro-oncology meeting and a neuroendocrine tumor multidisciplinary team meeting, she proceeded to have conventional fractionated radiotherapy followed by subsequent palliative chemotherapy. CONCLUSIONS: Intracranial metastasis is rare in patients with neuroendocrine tumor, particularly in those with well-differentiated histology; skull base metastasis is even more uncommon. Management of intracranial metastasis from a rare tumor should always be discussed in a specialist multidisciplinary meeting. Surgery or radiotherapy, including stereotactic radiosurgery, should be considered in skull base metastases. Hormonal abnormalities may occur following radiotherapy to skull base metastases and should be monitored closely in the first few months post treatment.

Contemporary outcomes from the use of regular imaging to detect relapse in high-risk cutaneous melanoma.

BACKGROUND: Agreement on the utility of imaging follow-up in patients with high-risk melanoma is lacking. A UK consensus statement recommends a surveillance schedule of CT or positron-emission tomography-CT and MRI brain (every 6 months for 3 years, then annually in years 4 and 5) as well as clinical examination for high-risk resected Stages II and III cutaneous melanoma. Our aim was to assess patterns of relapse and whether imaging surveillance could be of clinical benefit. PATIENTS AND METHODS: A retrospective study of patients enrolled between July 2013 and June 2015 from three UK tertiary cancer centres followed-up according to this protocol was undertaken. We evaluated time-to-recurrence (TTR), recurrence-free survival (RFS), method of detection and characteristics of recurrence, treatment received and overall survival (OS). RESULTS: A total of 173 patients were included. Most (79%) had treated Stages IIIB and IIIC disease. With a median follow-up of 23.3 months, 82 patients (47%) had relapsed. Median TTR was 10.1 months and median RFS was 21.2 months. The majority of recurrences (66%) were asymptomatic and detected by scheduled surveillance scan. Fifty-six (68%) patients recurred with Stage IV disease, with a median OS of 25.3 months; 26 (31.7%) patients had a locoregional recurrence, median OS not reached (P=0.016). Patients who underwent surgery at recurrence for either Stage III (27%) or IV (18%) disease did not reach their median OS. The median OS for the 33 patients (40%) who received systemic therapy was 12.9 months. CONCLUSION: Imaging appears to reliably detect subclinical disease and identify patients suitable for surgery, conferring favourable outcomes. The short median TTR provides rationale to intensify imaging schedule in the first year of surveillance. The poor OS of patients treated with systemic therapy probably reflects the relatively inferior treatment options during this time and requires further evaluation in the current era.

Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma.

UNLABELLED: Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from ∼9 to over 25 months, but nevertheless most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end, we developed protocols to facilitate individualized treatment decisions for patients with advanced melanoma, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor DNA (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesis-driven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF-mutant tumors, which were then validated in patient-derived xenografts (PDX). We also developed circulating tumor cell-derived xenografts (CDX) as an alternative to PDXs when tumors were inaccessible or difficult to biopsy. Thus, we describe a powerful technology platform for precision medicine in patients with melanoma. SIGNIFICANCE: Although recent developments have revolutionized melanoma care, most patients still die of their disease. To improve melanoma outcomes further, we developed a powerful precision medicine platform to monitor patient responses and to identify and validate hypothesis-driven therapies for patients who do not respond, or who develop resistance to current treatments.

Long-term outcomes after hospitalization with spontaneous bacterial peritonitis.

OBJECTIVE: To assess the determinants of long-term outcome in patients with spontaneous bacterial peritonitis (SBP). METHODS: This study was conducted retrospectively. Kaplan-Meier (KM) and Cox proportional hazards survival analyses were performed. RESULTS: Altogether, 93 patients with SBP were identified, with their mean age of 57.9 ± 12.9 years, Child-Pugh score 10.4 ± 1.9 and model for end-stage liver disease (MELD) score 20.2 ± 6.8. The etiology of chronic liver disease (CLD) was alcohol-related liver disease (ARLD) (n = 58) and viral hepatitis/non-alcoholic steatohepatitis (n = 28). SBP was the index presentation of cirrhosis in 26 (28.0%) patients. Overall mortality was 80.6%; among them 81.3% were liver-related, and 33 (35.5%) died during index hospitalization. In total, 70.0% of patients who survived index hospitalization died during follow-up, with a median survival of 12.5 months. Estimated survival at 3 months, 1 year and 5 years was 54.8%, 34.4% and 15.2%, respectively. Non-ARLD etiology for CLD was an independent predictor of overall mortality (HR 3.484, 95% CI 1.802-6.757, P < 0.001) and mortality in those surviving hospitalization (HR 2.319, 95% CI 1.210-4.444, P = 0.011). Hepatorenal syndrome did not predict outcomes. Two (3.3%) patients surviving hospitalization underwent liver transplantation (LT). CONCLUSIONS: One-year survival after hospitalization with SBP remains poor (34.4%) with unacceptably low LT rates. Non-ARLD etiology for CLD is an independent predictor of both overall mortality and mortality after discharge. In view of the projected increase in non-alcoholic steatohepatitis-related CLD, screening strategies for timely CLD diagnosis are warranted.

Older men with unexplained hepatitis.

A 59-year-old Caucasian man presented with painless jaundice for 6 weeks. He drank 70 units of alcohol per week. Examination revealed jaundice, spider angiomata and a 3 cm firm hepatomegaly. Initial bloods: bilirubin 152 µmol/L, alanine aminotransferase 1484 IU/L, alkaline phosphatase 130 IU/L, γ-glutamyl-transpeptidase 1224 IU/L and International Normalised Ratio 1.1. A standard liver screen was normal, and an abdominal ultrasound/CT scan suggested cirrhosis, confirmed by liver biopsy on day 5. Hepatitis E virus (HEV) serology on day 6 indicated acute infection. He developed severe hepatic decompensation characterised by worsening jaundice, ascites and variceal bleeding. On day 33 ribavirin 600 mg was initiated though discontinued after 2 weeks on receipt of a negative HEV RNA. At the last follow-up he had recovered, and remains abstinent from alcohol. We describe a case of autochthonously (locally) acquired HEV infection with life-threatening hepatic decompensation in the presence of undiagnosed alcohol-related cirrhosis.