The SARS-CoV-2 Pandemic and Cancer Trials Ireland: Impact, Resolution and Legacy.

BACKGROUND: Cancer Trials Ireland (CTI) is the national cooperative group in Ireland. The SARS-CoV-2 pandemic led to significant ongoing disruptive change in healthcare from March 2020 to the present day. Its impact and legacy on a national clinical trials organisation was assessed. METHODS: A review was conducted of prospectively acquired communications, team logs and time sheets, trial activation, closure and accrual, for the period 2019 to September 2021. An online survey of the impact of the pandemic on clinical investigators and of clinical trials units was performed. A National Cancer Retreat was organised on 21 May 2021 to identify and address pandemic related disruption and develop adaptive strategies. RESULTS: In the weeks after the pandemic was declared, remote working was initiated by all central office staff. Nationally, clinical trial accrual fell by 54% compared to the same period in 2019, radiotherapy trial accrual by 90%, and translational studies by 36%. Staff reassignment of research nurse staff occurred in 60% of units, trial monitoring was reduced in 42%, and trial initiations fell by 67%. Extreme fluctuations in monitoring hours were noted paralleling lockdown measures. Significant impact on all clinical trials units was noted including staff reassignments, reduced access to diagnostic imaging and reduced institutional supports. Remote clinic visits and remote monitoring was widely adopted. The National Cancer Retreat identified flexibility in trial conduct, staff recruitment and retention, the need for harmonisation of processes, and research staff support in the context of remote working as priorities. CONCLUSION: The pandemic has had a significant ongoing negative impact on cancer clinical trial activity in Ireland. Adaptive strategies including trial flexibility, expanded telehealth and remote monitoring, harmonisation of processes and staff support have been identified as priorities to ameliorate this impact, and develop a more sustainable clinical trial ecosystem.

hsa_circ_0001275 Is One of a Number of circRNAs Dysregulated in Enzalutamide Resistant Prostate Cancer and Confers Enzalutamide Resistance In Vitro.

BACKGROUND: Enzalutamide is part of the treatment regimen for metastatic castration-resistant prostate cancer (MCRPC). However, both intrinsic and acquired resistance to the drug remain substantial clinical quandaries. circRNAs, a novel type of non-coding RNA, have been identified in a number of cancers including prostate cancer and have been associated with cancer development and progression. circRNAs have shown great potential as clinically useful blood-based 'liquid biopsies' and as therapeutic targets in prostate cancer. The aim of this study was to examine the role of circRNA transcripts in enzalutamide-resistant prostate cancer cells and assess their utility as biomarkers. METHODS: An isogenic cell line model of enzalutamide resistance was subjected to circRNA microarray profiling. Several differentially expressed circRNAs, along with their putative parental genes were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). circRNAs of interest were stably overexpressed in the control cell line and drug sensitivity was assessed using an ELISA-based proliferation assay. The candidate circRNA, hsa_circ_0001275, was measured in patient plasma samples using RT-droplet digital PCR (RT-ddPCR). RESULTS: hsa_circ_0001275 and its parental gene, PLCL2, were significantly up-regulated in strongly resistant clones vs. control (p < 0.05). Overexpression of hsa_circ_0001275 in the control cell line resulted in increased resistance to enzalutamide (p < 0.05). While RT-ddPCR analysis of hsa_circ_0001275 expression in plasma samples of 44 clinical trial participants showed a trend that mirrored the stages of disease activity (as defined by PSA level), the association did not reach statistical significance. CONCLUSIONS: Our data suggest that increased levels of hsa_circ_0001275 contribute to enzalutamide resistance. hsa_circ_0001275 plasma expression showed a trend that mirrors the PSA level at specific disease time points, indicating that circRNAs mirror disease recurrence and burden and may be associated with enzalutamide resistance.

Treatment completion, treatment compliance and outcomes of old and very old patients treated by dose adapted stereotactic ablative radiotherapy (SABR) for T1-T3N0M0 non-small cell lung cancer.

AIM: This is a retrospective single-institution review of the treatment completion and clinical outcomes of patients aged 75 and older, treated with stereotactic ablative body radiotherapy (SABR) for T1-T3 N0 M0 non-small cell lung cancer (NSCLC). METHODS: From April 2008 to September 2015, 200 patients, aged 75-93, received respiratory-managed, intensity-modulated-based SABR. Dose fractionation was risk-adapted and delivered in 2-3 weekly treatments. Treatment completion, local control, overall survival and treatment-related toxicities were evaluated. RESULTS: All patients completed the prescribed SABR course. However, 29 patients required interruption of at least one fraction of SABR and optimization of pain control before continuation of the fraction. Median follow-up was 20.9 months. The median OS was 31.6 months with 1-,3-year survival rates of 80.7%, and 44.4% respectively. Local control at 1- and 3- years were 97.6%, 83.5% respectively. Treatment was well-tolerated. However, there were two (1%) G5 (fatal) toxicities: one acute sudden dyspnoea of unknown cause and one late SABR-related haemoptysis. No statistically significant differences in outcomes/toxicities were observed between old (75-84 years old) and very old patients (>85 years old). CONCLUSIONS: Old and very old patients can successfully complete SABR for NSCLC, with good local control, survival and acceptable toxicity. Old patients might require increased supportive care for successful treatment delivery.

Prognostic role of neutrophil-to-lymphocyte ratio in advanced pancreatic ductal adenocarcinoma: impact of baseline fluctuation and changes during chemotherapy.

AIMS AND BACKGROUND: Inflammation has been implicated in carcinogenesis and progression of pancreatic cancer. The neutrophil-to-lymphocyte ratio is an index of systemic inflammation. We examined the prognostic role of the neutrophil-to-lymphocyte ratio at baseline and the significance of intrapersonal variability of the ratio before and during chemotherapy. METHODS AND STUDY DESIGN: Advanced pancreatic adenocarcinoma patients who had received chemotherapy were included. Baseline clinical and biochemical parameters, including the neutrophil-to-lymphocyte ratio, were extracted and analyzed. The neutrophil-to-lymphocyte ratio threshold was determined via recursive partitioning and assessed at diagnosis, prior to chemotherapy and during treatment. Overall survival was estimated via the Kaplan-Meier method and compared between groups with the logrank test. RESULTS: Between 2005 and 2011, 85 patients with locally advanced (n = 38) and metastatic disease were identified: 68% with a neutrophil-to-lymphocyte ratio >3 had shorter median overall survival than patients with a neutrophil-to-lymphocyte ratio <3 (3.4 vs 9.4 months, P = 0.001). Pretreatment, 35% of repeat neutrophil-to-lymphocyte ratios crossed the threshold of 3. A persistently elevated neutrophil-to-lymphocyte ratio >3 suggested a worse overall survival than in patients with a decreasing, increasing or persistently low neutrophil-to-lymphocyte ratio (1.9 vs 8.2, 12.3 and 11.7 months, respectively, P <0.001). Twenty-three percent of patients had a >50% decrease in neutrophil-to-lymphocyte ratio following 4 weeks of chemotherapy, with a trend towards improvement in overall survival (12.5 vs 5.0 mo, P = 0.068). CONCLUSIONS: The baseline neutrophil-to-lymphocyte ratio is a validated marker for a poor prognosis. Multiple assessments of the pre-treatment neutrophil-to-lymphocyte ratio might be required. Reduction in the neutrophil-to-lymphocyte ratio during chemotherapy may be associated with improved survival.

Identification of distinct phenotypes of locally advanced pancreatic adenocarcinoma.

BACKGROUND: A significant number of pancreatic ductal adenocarcinoma present as locally advanced disease. Optimal treatment remains controversial. We sought to analyze the clinical course of locally advanced pancreatic adenocarcinoma (LAPC) in order to identify potential distinct clinical phenotypes. METHODS: Patients (pts) diagnosed with LAPC who survived >2 months were identified from institutional databases. Clinical details were collected. Sequential re-staging scans were reviewed. Progression-free survival (PFS), time from progression to death (TTD), and overall survival (OS) were estimated with Kaplan-Meier method and compared with log-rank test. RESULTS: Between 2005 and 2011, 40 pts were identified. Median age was 66 yrs (range, 43-74) and 60 % (n=24) were male. All pts received chemotherapy. Median OS was 11.3 months. Twenty patients (50 %) had local progression only (LP) and 16 (40 %) had metastatic progression (MP) at first documentation of progression, while four patients (10 %) had stable disease. PFS was 4.0 vs 5.6 months (hazard ratio (HR) 0.97; 95 % CI 0.49-1.93, p=0.94) for LP and MP, respectively. Three of the patients with LP (15 %) eventually developed metastatic disease after a median of 4.2 months (3.7-9.6). For MP patients, five had concurrent local progression. Sites of disease were lung (eight), peritoneum (five), liver (three), and bone (one). TTD for LP and MP was 5.6 vs 1.4 months (HR 0.62; 95 % CI 0.28-1.39, p=0.24) and OS was 13.2 vs 8.0 months (HR 0.59; 95 % CI 0.28-1.25, p=0.017), respectively. CONCLUSIONS: We identified two subgroups of LAPC with distinctive behavior, one local dominant progression with low predilection for metastases and another with rapid metastatic development and worse survival. Early recognition of these phenotypes might allow a more tailored treatment approach to improve outcome.

Sustained response of adenocarcinoma of the urinary bladder to FOLFOX plus bevacizumab.

BACKGROUND: A 44-year-old patient presented with intermittent macroscopic hematuria on a background of chronic left-sided hydronephrosis and intestinal metaplasia of the bladder. Cystoscopic examination revealed a mass at the dome of the urinary bladder, which was resected. Histopathologic analysis of the specimen confirmed the presence of muscle-invasive adenocarcinoma. Radical cystectomy with curative intent was planned, but review of systems and subsequent CT demonstrated pleural effusion with positive cytology, confirming metastatic disease. Owing to the histologic similarity between this patient's tumor and colorectal cancer, palliative FOLFOX6 (folinic acid, 5-fluorouracil and oxaliplatin) chemotherapy plus bevacizumab was administered. After 3 months of treatment the patient showed a good response, which was sustained for more than 10 months after diagnosis. However, his disease subsequently relapsed, and the patient died shortly thereafter. INVESTIGATION: Physical examination, cystoscopy, transurethral resection of bladder tissue, CT, histopathologic, cytopathologic and immunohistochemical analysis. DIAGNOSIS: Metastatic adenocarcinoma of the urinary bladder. MANAGEMENT: 12 cycles of infused and bolus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX6) plus bevacizumab.

A Case of Metastatic Renal Cell Cancer Presenting as Jaundice.

Renal cell carcinoma is the second most common urological malignancy and it runs a highly variable clinical course. We describe a case of metastatic renal cell carcinoma in a 50-year-old lady with metastasis to the ampulla of Vater, clinically masquerading as cholelithiasis and biliary colic. The clinical, radiographic and endoscopic findings are presented. Ampullary metastases are rare, and prompt recognition and intervention are necessary before patient's performance status is compromised.