Challenges and solutions to system-wide use of precision oncology as the standard of care paradigm.

The personalised oncology paradigm remains challenging to deliver despite technological advances in genomics-based identification of actionable variants combined with the increasing focus of drug development on these specific targets. To ensure we continue to build concerted momentum to improve outcomes across all cancer types, financial, technological and operational barriers need to be addressed. For example, complete integration and certification of the 'molecular tumour board' into 'standard of care' ensures a unified clinical decision pathway that both counteracts fragmentation and is the cornerstone of evidence-based delivery inside and outside of a research setting. Generally, integrated delivery has been restricted to specific (common) cancer types either within major cancer centres or small regional networks. Here, we focus on solutions in real-world integration of genomics, pathology, surgery, oncological treatments, data from clinical source systems and analysis of whole-body imaging as digital data that can facilitate cost-effectiveness analysis, clinical trial recruitment, and outcome assessment. This urgent imperative for cancer also extends across the early diagnosis and adjuvant treatment interventions, individualised cancer vaccines, immune cell therapies, personalised synthetic lethal therapeutics and cancer screening and prevention. Oncology care systems worldwide require proactive step-changes in solutions that include inter-operative digital working that can solve patient centred challenges to ensure inclusive, quality, sustainable, fair and cost-effective adoption and efficient delivery. Here we highlight workforce, technical, clinical, regulatory and economic challenges that prevent the implementation of precision oncology at scale, and offer a systematic roadmap of integrated solutions for standard of care based on minimal essential digital tools. These include unified decision support tools, quality control, data flows within an ethical and legal data framework, training and certification, monitoring and feedback. Bridging the technical, operational, regulatory and economic gaps demands the joint actions from public and industry stakeholders across national and global boundaries.

Efficacy of early PET-CT directed switch to carboplatin and paclitaxel based definitive chemoradiotherapy in patients with oesophageal cancer who have a poor early response to induction cisplatin and capecitabine in the UK: a multi-centre randomised controlled phase II trial.

Background: The utility of early metabolic response assessment to guide selection of the systemic component of definitive chemoradiotherapy (dCRT) for oesophageal cancer is uncertain. Methods: In this multi-centre, randomised, open-label, phase II substudy of the radiotherapy dose-escalation SCOPE2 trial we evaluated the role of 18F-Fluorodeoxyglucose positron emission tomography (PET) at day 14 of cycle 1 of three-weekly induction cis/cap (cisplatin (60 mg/m2)/capecitabine (625 mg/m2 days 1-21)) in patients with oesophageal squamous cell carcinoma (OSCC) or adenocarcinoma (OAC). Non-responders, who had a less than 35% reduction in maximum standardised uptake value (SUVmax) from pre-treatment baseline, were randomly assigned to continue cis/cap or switch to car/pac (carboplatin AUC 5/paclitaxel 175 mg/m2) for a further induction cycle, then concurrently with radiotherapy over 25 fractions. Responders continued cis/cap for the duration of treatment. All patients (including responders) were randomised to standard (50Gy) or high (60Gy) dose radiation as part of the main study. Primary endpoint for the substudy was treatment failure-free survival (TFFS) at week 24. The trial was registered with International Standard Randomized Controlled Trial Number 97125464 and ClinicalTrials.govNCT02741856. Findings: This substudy was closed on 1st August 2021 by the Independent Data Monitoring Committee on the grounds of futility and possible harm. To this point from 22nd November 2016, 103 patients from 16 UK centres had participated in the PET-CT substudy; 63 (61.2%; 52/83 OSCC, 11/20 OAC) of whom were non-responders. Of these, 31 were randomised to car/pac and 32 to remain on cis/cap. All patients were followed up until at least 24 weeks, at which point in OSCC both TFFS (25/27 (92.6%) vs 17/25 (68%); p = 0.028) and overall survival (42.5 vs. 20.4 months, adjusted HR 0.36; p = 0.018) favoured cis/cap over car/pac. There was a trend towards worse survival in OSCC + OAC cis/cap responders (33.6 months; 95%CI 23.1-nr) vs. non-responders (42.5 (95%CI 27.0-nr) months; HR = 1.43; 95%CI 0.67-3.08; p = 0.35). Interpretation: In OSCC, early metabolic response assessment is not prognostic for TFFS or overall survival and should not be used to personalise systemic therapy in patients receiving dCRT. Funding: Cancer Research UK.

The impact of baseline 18F-FDG PET-CT on the management and outcome of patients with gastric cancer: a systematic review.

OBJECTIVE: CT and staging laparoscopy are routinely used to stage patients with gastric cancer, however the role of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with CT (PET-CT) is uncertain. This systematic review synthesised the evidence regarding the impact of baseline PET-CT staging on treatment decisions and patient outcomes. METHODS: Systematic database searches were performed without date restriction. Studies reporting data in patients with gastric adenocarcinoma who underwent radiological staging were included. One reviewer screened titles and abstracts for suitability and two reviewers extracted data from included articles. Primary outcome was the reported change in management after PET-CT. Secondary outcomes were the rates of recurrence and overall survival between patients staged with and without PET-CT. Risk of bias was assessed using the ROBINS-I tool. PROSPERO registration (CRD42022304314). RESULTS: Data from 11 studies recruiting 2101 patients between 2012 and 2021 were included. PET-CT was performed in 1422 patients. Change of management varied between 3% and 29% of cases. No studies compared recurrence or survival rates between patients staged with or without PET-CT. Adenocarcinoma of intestinal subtype tended to be more FDG-avid compared to diffuse or signet-ring subtypes. No randomised data existed, and studies were considered low quality with high risk of bias. CONCLUSION: Evidence for the additional value of PET-CT in the gastric cancer staging pathway is limited. All studies reported a positive impact by preventing those with undetected metastatic disease on CT undergoing futile surgery. Future national guidelines should consider routine staging PET-CT in gastric cancer. ADVANCES IN KNOWLEDGE: Studies indicated that FDG PET-CT added benefit in gastric cancer staging by detecting more distant metastases, but these studies were generally of low quality and at high risk of bias. Intestinal subtype of gastric adenocarcinoma tended to be more FDG-avid and therefore more distant metastases were subsequently detected.

Outcomes from a mechanistic biomarker multi-arm and randomised study of liposomal MTP-PE (Mifamurtide) in metastatic and/or recurrent osteosarcoma (EuroSarc-Memos trial).

The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS.

Image enhancement of whole-body oncology [18F]-FDG PET scans using deep neural networks to reduce noise.

PURPOSE: To enhance the image quality of oncology [18F]-FDG PET scans acquired in shorter times and reconstructed by faster algorithms using deep neural networks. METHODS: List-mode data from 277 [18F]-FDG PET/CT scans, from six centres using GE Discovery PET/CT scanners, were split into ¾-, ½- and »-duration scans. Full-duration datasets were reconstructed using the convergent block sequential regularised expectation maximisation (BSREM) algorithm. Short-duration datasets were reconstructed with the faster OSEM algorithm. The 277 examinations were divided into training (n = 237), validation (n = 15) and testing (n = 25) sets. Three deep learning enhancement (DLE) models were trained to map full and partial-duration OSEM images into their target full-duration BSREM images. In addition to standardised uptake value (SUV) evaluations in lesions, liver and lungs, two experienced radiologists scored the quality of testing set images and BSREM in a blinded clinical reading (175 series). RESULTS: OSEM reconstructions demonstrated up to 22% difference in lesion SUVmax, for different scan durations, compared to full-duration BSREM. Application of the DLE models reduced this difference significantly for full-, ¾- and ½-duration scans, while simultaneously reducing the noise in the liver. The clinical reading showed that the standard DLE model with full- or ¾-duration scans provided an image quality substantially comparable to full-duration scans with BSREM reconstruction, yet in a shorter reconstruction time. CONCLUSION: Deep learning-based image enhancement models may allow a reduction in scan time (or injected activity) by up to 50%, and can decrease reconstruction time to a third, while maintaining image quality.

A DNA-damage immune response assay combined with PET biomarkers predicts response to neo-adjuvant chemotherapy and survival in oesophageal adenocarcinoma.

18F-fluorodeoxyglucose PET-CT may guide treatment decisions in patients with oesophageal adenocarcinoma (OAC). This study evaluated the added value of maximum standardised uptake value (SUVmax) to a novel DNA-damage immune response (DDIR) assay to improve pathological response prediction. The diagnostic accuracy of PET response and the prognostic significance of PET metrics for recurrence-free survival (RFS) and overall survival (OS) were assessed. This was a retrospective, single-centre study of OAC patients treated with neo-adjuvant chemotherapy from 2003 to 2014. SUVmax was recorded from baseline and repeat PET-CT after completion of pre-operative chemotherapy. Logistic regression models tested the additional predictive value of PET metrics combined with the DDIR assay for pathological response. Cox regression models tested the prognostic significance of PET metrics for RFS and OS. In total, 113 patients were included; 25 (22.1%) were DDIR positive and 88 (77.9%) were DDIR negative. 69 (61.1%) were PET responders (SUVmax reduction of 35%) and 44 (38.9%) were PET non-responders. After adding PET metrics to DDIR status, post-chemotherapy SUVmax (hazard ratio (HR) 0.75, p = 0.02), SUVmax change (HR 1.04, p = 0.003) and an optimum SUVmax reduction of 46.5% (HR 4.36, p = 0.021) showed additional value for predicting pathological response. The optimised SUVmax threshold was independently significant for RFS (HR 0.47, 95% CI 0.26-0.85, p = 0.012) and OS (HR 0.51, 95% CI 0.26-0.99, p = 0.047). This study demonstrated the additional value of PET metrics, when combined with a novel DDIR assay, to predict pathological response in OAC patients treated with neo-adjuvant chemotherapy. Furthermore, an optimised SUVmax reduction threshold for pathological response was calculated and was independently significant for RFS and OS.

Response rate and diagnostic accuracy of early PET-CT during neo-adjuvant therapies in oesophageal adenocarcinoma: A systematic review and meta-analysis.

PURPOSE: Only 25% of oesophageal adenocarcinoma (OAC) patients have a pathological response to neo-adjuvant therapy (NAT) before oesophagectomy. Early response assessment using PET imaging may help guide management of these patients. We performed a systematic review and meta-analysis to synthesise the evidence detailing response rate and diagnostic accuracy of early PET-CT assessment. METHODS: We systematically searched several databases including MEDLINE and Embase. Studies with mixed cohorts of histology, tumour location and a repeat PET-CT assessment after more than one cycle of NAT were excluded. Reference standard was pathological response defined by Becker or Mandard classifications. Primary outcome was metabolic response rate after one cycle of NAT defined by a reduction in maximum standardised uptake value (SUVmax) of 35%. Secondary outcome was diagnostic accuracy of treatment response prediction, defined as the sensitivity and specificity of early PET-CT using this threshold. Quality of evidence was also assessed. Random-effects meta-analysis pooled response rates and diagnostic accuracy. This study was registered with PROSPERO (CRD42019147034). RESULTS: Overall, 1341 articles were screened, and 6 studies were eligible for analysis. These studies reported data for 518 patients (aged 27-78 years; 452 [87.3%] were men) between 2005 and 2020. Pooled sensitivity of early metabolic response to predict pathological response was 77.2% (95% CI 53.2%-100%). Significant heterogeneity existed between studies (I2  = 80.6% (95% CI 38.9%-93.8%), P = .006). Pooled specificity was 75.0% (95% CI 68.2%-82.5%), however, no significant heterogeneity between studies existed (I2  = 0.0% (95% CI 0.0%-67.4%), P = .73). CONCLUSION: High-quality evidence is lacking, and few studies met the inclusion criteria of this systematic review. The sensitivity of PET using a SUVmax reduction threshold of 35% was suboptimal and varied widely. However, specificity was consistent across studies with a pooled value of 75.0%, suggesting early PET assessment is a better predictor of treatment resistance than of pathological response. Further research is required to define optimal PET-guided treatment decisions in OAC.

Pulmonary artery enlargement on routine staging 18F-fluodeoxyglucose positron emission tomography/CT for lung and oesophageal cancer.

OBJECTIVE: Pulmonary hypertension (PH) is an underdiagnosed condition associated with poor survival and increased post-operative mortality in lung cancer. CT-based parameters of pulmonary artery enlargement are strong predictors of PH. We used these parameters to investigate pulmonary artery enlargement in lung and oesophageal cancer. METHODS: Consecutive patients with lung cancer (n = 100) or oesophageal cancer (n = 100) undergoing staging 18F-fluodeoxyglucose PET/CT were retrospectively identified. The transverse diameter of the main pulmonary artery (mPA) and ascending aorta, and the pulmonary artery-to-ascending aorta (PA:A) ratio were obtained. Abnormal values were defined following the Framingham Heart Study cohort. RESULTS: Lung cancer patients had a significantly increased mPA diameter compared to the oesophageal cancer patients (males: 27.29 ± 0.39 vs. 25.88 ± 0.24 mm, females: 26.10 ± 0.28 vs. 24.45 ± 0.18 mm). Similarly, a significantly increased proportion of these patients had an abnormal mPA diameter (males: 35.1% vs 12.5%, females: 32.6% vs 10.7%). Lung cancer patients also had a significantly higher PA:A ratio (males: 0.83 ± 0.01 vs. 0.79 ± 0.008, females: 0.85 ± 0.01 vs. 0.79 ± 0.009), with a larger proportion having an abnormal PA:A ratio (males: 24.6% vs 11.1%, females: 27.9% vs 14.3%). CONCLUSION: Simple measurements of mPA diameter and PA:A ratio reveal that lung cancer patients exhibit increased rates of pulmonary artery enlargement compared to oesophageal cancer patients. ADVANCES IN KNOWLEDGE: This study demonstrates there is an increased prevalence of pulmonary enlargement in lung cancer, easily detected on routine staging scans, holding implications for further work-up and risk stratification.

Data-Driven Respiratory Gating Outperforms Device-Based Gating for Clinical 18F-FDG PET/CT.

A data-driven method for respiratory gating in PET has recently been commercially developed. We sought to compare the performance of the algorithm with an external, device-based system for oncologic 18F-FDG PET/CT imaging. Methods: In total, 144 whole-body 18F-FDG PET/CT examinations were acquired, with a respiratory gating waveform recorded by an external, device-based respiratory gating system. In each examination, 2 of the bed positions covering the liver and lung bases were acquired with a duration of 6 min. Quiescent-period gating retaining approximately 50% of coincidences was then able to produce images with an effective duration of 3 min for these 2 bed positions, matching the other bed positions. For each examination, 4 reconstructions were performed and compared: data-driven gating (DDG) (we use the term DDG-retro to distinguish that we did not use the real-time R-threshold-based application of DDG that is available within the manufacturer's product), external device-based gating (real-time position management (RPM)-gated), no gating but using only the first 3 min of data (ungated-matched), and no gating retaining all coincidences (ungated-full). Lesions in the images were quantified and image quality scored by a radiologist who was masked to the method of data processing. Results: Compared with the other reconstruction options, DDG-retro increased the SUVmax and decreased the threshold-defined lesion volume. Compared with RPM-gated, DDG-retro gave an average increase in SUVmax of 0.66 ± 0.1 g/mL (n = 87, P < 0.0005). Although the results from the masked image evaluation were most commonly equivalent, DDG-retro was preferred over RPM-gated in 13% of examinations, whereas the opposite occurred in just 2% of examinations. This was a significant preference for DDG-retro (P = 0.008, n = 121). Liver lesions were identified in 23 examinations. Considering this subset of data, DDG-retro was ranked superior to ungated-full in 6 of 23 (26%) cases. Gated reconstruction using the external device failed in 16% of examinations, whereas DDG-retro always provided a clinically acceptable image. Conclusion: In this clinical evaluation, DDG-retro provided performance superior to that of the external device-based system. For most examinations the performance was equivalent, but DDG-retro had superior performance in 13% of examinations, leading to a significant preference overall.

Effect of 18F-Fluciclovine Positron Emission Tomography on the Management of Patients With Recurrence of Prostate Cancer: Results From the FALCON Trial.

PURPOSE: Early and accurate localization of lesions in patients with biochemical recurrence (BCR) of prostate cancer may guide salvage therapy decisions. The present study, 18F-Fluciclovine PET/CT in biochemicAL reCurrence Of Prostate caNcer (FALCON; NCT02578940), aimed to evaluate the effect of 18F-fluciclovine on management of men with BCR of prostate cancer. METHODS AND MATERIALS: Men with a first episode of BCR after curative-intent primary therapy were enrolled at 6 UK sites. Patients underwent 18F-fluciclovine positron emission tomography/computed tomography (PET/CT) according to standardized procedures. Clinicians documented management plans before and after scanning, recording changes to treatment modality as major and changes within a modality as other. The primary outcome measure was record of a revised management plan postscan. Secondary endpoints were evaluation of optimal prostate specific antigen (PSA) threshold for detection, salvage treatment outcome assessment based on 18F-fluciclovine-involvement, and safety. RESULTS: 18F-Fluciclovine was well tolerated in the 104 scanned patients (median PSA = 0.79 ng/mL). Lesions were detected in 58 out of 104 (56%) patients. Detection was broadly proportional to PSA level; ≤1 ng/mL, 1 out of 3 of scans were positive, and 93% scans were positive at PSA >2.0 ng/mL. Sixty-six (64%) patients had a postscan management change (80% after a positive result). Major changes (43 out of 66; 65%) were salvage or systemic therapy to watchful waiting (16 out of 66; 24%); salvage therapy to systemic therapy (16 out of 66; 24%); and alternative changes to treatment modality (11 out of 66, 17%). The remaining 23 out of 66 (35%) management changes were modifications of the prescan plan: most (22 out of 66; 33%) were adjustments to planned brachytherapy/radiation therapy to include a 18F-fluciclovine-guided boost. Where 18F-fluciclovine guided salvage therapy, the PSA response rate was higher than when 18F-fluciclovine was not involved (15 out of 17 [88%] vs 28 out of 39 [72%]). CONCLUSIONS: 18F-Fluciclovine PET/CT located recurrence in the majority of men with BCR, frequently resulting in major management plan changes. Incorporating 18F-fluciclovine PET/CT into treatment planning may optimize targeting of recurrence sites and avoid futile salvage therapy.

Outcomes with advanced versus basic life support in blunt trauma.

INTRODUCTION: The role of advanced life support (ALS) versus basic life support (BLS) in blunt trauma is controversial. Previous studies have shown no mortality benefit with ALS for penetrating trauma but the blunt population has mostly remained unaddressed. METHODS: A retrospective cohort study was conducted at a Level 1 trauma center comparing outcomes in blunt trauma patients managed by ALS versus BLS from July 1, 2014 to December 31, 2014. Both Injury Severity Score (ISS) and select Abbreviated Injury Score (AIS) were used to determine differences in mortality, length of stay (LOS) and complications based on mode of transportation, prehospital time, and number of prehospital interventions. RESULTS: 698 total patients were identified. Mortality and complications were grossly higher in ALS patients (p = 0.01 and < 0.001, respectively). When accounting for ISS and AIS there was no difference in mortality (p=<0.001-0.003). Prehospital interventions did not increase prehospital time (p = 0.7) but did correlate with increased mortality (p < 0.001). CONCLUSION: There is no mortality advantage for blunt trauma patients managed by ALS versus BLS.

The ERG1a potassium channel increases basal intracellular calcium concentration and calpain activity in skeletal muscle cells.

BACKGROUND: Skeletal muscle atrophy is the net loss of muscle mass that results from an imbalance in protein synthesis and protein degradation. It occurs in response to several stimuli including disease, injury, starvation, and normal aging. Currently, there is no truly effective pharmacological therapy for atrophy; therefore, exploration of the mechanisms contributing to atrophy is essential because it will eventually lead to discovery of an effective therapeutic target. The ether-a-go-go related gene (ERG1A) K+ channel has been shown to contribute to atrophy by upregulating ubiquitin proteasome proteolysis in cachectic and unweighted mice and has also been implicated in calcium modulation in cancer cells. METHODS: We transduced C2C12 myotubes with either a human ERG1A encoded adenovirus or an appropriate control virus. We used fura-2 calcium indicator to measure intracellular calcium concentration and Calpain-Glo assay kits (ProMega) to measure calpain activity. Quantitative PCR was used to monitor gene expression and immunoblot evaluated protein abundances in cell lysates. Data were analyzed using either a Student's t test or two-way ANOVAs and SAS software as indicated. RESULTS: Expression of human ERG1A in C2C12 myotubes increased basal intracellular calcium concentration 51.7% (p < 0.0001; n = 177). Further, it increased the combined activity of the calcium-activated cysteine proteases, calpain 1 and 2, by 31.9% (p < 0.08; n = 24); these are known to contribute to degradation of myofilaments. The increased calcium levels are likely a contributor to the increased calpain activity; however, the change in calpain activity may also be attributable to increased calpain protein abundance and/or a decrease in levels of the native calpain inhibitor, calpastatin. To explore the enhanced calpain activity further, we evaluated expression of calpain and calpastatin genes and observed no significant differences. There was no change in calpain 1 protein abundance; however, calpain 2 protein abundance decreased 40.7% (p < 0.05; n = 6). These changes do not contribute to an increase in calpain activity; however, we detected a 31.7% decrease (p < 0.05; n = 6) in calpastatin which could contribute to enhanced calpain activity. CONCLUSIONS: Human ERG1A expression increases both intracellular calcium concentration and combined calpain 1 and 2 activity. The increased calpain activity is likely a result of the increased calcium levels and decreased calpastatin abundance.

Pilomatricoma on 18F-fluorodeoxyglucose positron emission tomography-computed tomography: Peripheral mimic of an aggressive soft-tissue malignancy.

Pilomatricoma, also known as calcifying epithelioma of Malherbe, is a rare skin tumor originating from the hair follicle matrix. We report a case of pilomatricoma in a 50-year-old woman, presenting as a rapidly growing pretibial mass. Malignant pilomatricoma is associated with potentially fatal metastases and are clinically and histologically indistinguishable from benign pilomatricoma. Thus, an 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) scan was requested for staging, revealing marked FDG uptake restricted to the primary lesion and no evidence of separate disease. The purpose of this report is to demonstrate the importance of PET/CT in the staging of this FDG-avid tumor; the malignancy of which is often first revealed by metastases. Our case also demonstrates that pilomatricoma should be included in the differential diagnosis of a rapidly growing peripheral soft-tissue mass; conventionally, the domain of sarcoma.

18F-Choline PET/CT Detected Skull Base Paraganglioma.

We present a case of a right skull base paraganglioma detected using F-choline PET/CT in a 63-year-old man. The F-choline PET/CT scan was performed to assess a known prostate cancer. In addition, the scan demonstrated a mildly choline-avid (SUVmax, 3.8) tumor within the carotid sheath of the right skull base, extending through the jugular foramen to the cerebellomedullary and cerebellopontine angles. F-choline may provide a superior alternative to FDG in imaging paragangliomas of the skull base because, unlike FDG, there is no significant F-choline uptake in the adjacent brain.

Temporal validation of metabolic nodal response of esophageal cancer to neoadjuvant chemotherapy as an independent predictor of unresectable disease, survival, and recurrence.

OBJECTIVES: We recently described metabolic nodal stage (mN) and response (mNR) of cancer of the esophagus and gastro-esophageal junction (GEJ) to neoadjuvant chemotherapy (NAC) using 18F-FDG PET-CT as new markers of disease progression, recurrence, and death. We aimed to validate our findings. METHODS: Our validation cohort comprised all patients consecutive to our discovery cohort, staged before and after NAC using PET-CT from 2014 to 2017. Multivariate binary logistic and Cox regression were performed. RESULTS: Fifty-one of the 200 patients had FDG-avid nodes after NAC (25.5%; i.e., lack of complete mNR), and were more likely to progress during NAC to incurable disease on PET-CT or at surgery: odds ratio 3.84 (1.46-10.1; p = 0.006). In 176 patients undergoing successful resection, patients without complete mNR had a worse prognosis: disease-free survival hazard ratio 2.46 (1.34-4.50); p = 0.004. These associations were independent of primary tumor metabolic, pathological response, and stage. In a hybrid pathological/metabolic nodal stage, avid nodal metastases conferred a worse prognosis than non-avid metastases. Lack of complete mNR predicted recurrence or death at 1 and 2 years: positive predictive values 44.4% (31.7-57.8) and 74.1% (56.6-86.3) respectively. CONCLUSIONS: This study provides temporal validation for mNR as a new and independent predictive and prognostic marker of esophageal and GEJ cancer treated with NAC and surgery, although external validation is required to assess generalizability. mNR may provide surrogate information regarding the phenotype of metastatic cancer clones beyond the mere presence of nodal metastases, and might be used to better inform patients, risk stratify, and personalize management, including adjuvant therapy. KEY POINTS: • We previously described metabolic nodal response (mNR) of esophageal cancer to neoadjuvant chemotherapy using 18 F-FDG PET-CT as a predictor of unresectable disease, early recurrence, and death. • We report the first validation of these findings. In an immediately consecutive cohort, we found consistent proportions of patients with and without mNR, and associations with abandoned resection, early recurrence, and death. • This supports mNR as a new and actionable biomarker in esophageal cancer. Although external validation is required, mNR may provide surrogate information about the chemosensitivity of metastatic subclones, and the means to predict treatment success, guide personalized therapy, and follow-up.

UK guidelines on 18F-fluciclovine PET/CT in prostate cancer imaging.

The purpose of these guidelines is to assist specialists in Nuclear Medicine and Radionuclide Radiology in recommending, performing, interpreting and reporting F-fluciclovine PET/computed tomography. It should be recognised that adherence to the guidance in this document will not assure an accurate diagnosis or a successful outcome. These guidelines will assist individual departments in the formulation of their own local protocols. The guidelines apply to studies on adults. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources and the needs of the patient in order to deliver effective and safe medical care.

Buparlisib with thoracic radiotherapy and its effect on tumour hypoxia: A phase I study in patients with advanced non-small cell lung carcinoma.

BACKGROUND: Pre-clinically, phosphoinositide 3-kinase (PI3K) inhibition radiosensitises tumours by increasing intrinsic radiosensitivity and by reducing tumour hypoxia. We assessed whether buparlisib, a class 1 PI3K inhibitor, can be safely combined with radiotherapy in patients with non-small cell lung carcinoma (NSCLC) and investigated its effect on tumour hypoxia. METHODS: This was a 3 + 3 dose escalation and dose expansion phase I trial in patients with advanced NSCLC. Buparlisib dose levels were 50 mg, 80 mg and 100 mg once daily orally for 2 weeks, with palliative thoracic radiotherapy (20 Gy in 5 fractions) delivered during week 2. Tumour hypoxic volume (HV) was measured using 18F-fluoromisonidazole positron-emission tomography-computed tomography at baseline and following 1 week of buparlisib. RESULTS: Twenty-one patients were recruited with 9 patients evaluable for maximum tolerated dose (MTD) analysis. No dose-limiting toxicity was reported; therefore, 100 mg was declared the MTD, and 10 patients received this dose in the expansion phase. Ninety-four percent of treatment-related adverse events were ≤grade 2 with fatigue (67%), nausea (24%) and decreased appetite (19%) most common per patient. One serious adverse event (grade 3 hypoalbuminaemia) was possibly related to buparlisib. No unexpected radiotherapy toxicity was reported. Ten (67%) of 15 patients evaluable for imaging analysis were responders with 20% median reduction in HV at the MTD. CONCLUSION: This is the first clinical trial to combine a PI3K inhibitor with radiotherapy in NSCLC and investigate the effects of PI3K inhibition on tumour hypoxia. This combination was well tolerated and PI3K inhibition reduced hypoxia, warranting investigation into whether this novel class of radiosensitisers can improve radiotherapy outcomes.

Routinely staging gastric cancer with 18F-FDG PET-CT detects additional metastases and predicts early recurrence and death after surgery.

OBJECTIVES: Fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) is typically considered to have minimal yield in gastric cancer, and so is not consistently recommended by international guidelines. However, its yield is considerable in esophageal and junctional cancer, identifying unsuspected metastases and risk-stratifying patients using metabolic nodal stage (mN). We aimed to determine the contemporary utility of routine 18F-FDG PET-CT in gastric cancer. METHODS: We routinely stage patients with non-junctional gastric cancer with PET-CT, provided initial CT does not demonstrate unequivocal metastases. We performed a retrospective study of all such patients staged in our institution from January 2007 to July 2016. Our primary endpoint was detection of incurable disease. Our secondary endpoint was disease-free survival following gastrectomy. Decision theory, economic, and predictive models were generated. RESULTS: The primary tumor was FDG-avid in 225/279 patients (80.6%). Seventy-two (25.8%) had FDG-avid nodes (resectable by D2 lymphadenectomy). This was not influenced by the Lauren classification. Unsuspected metastases were identified in 20 patients (7.2%). In 13 (4.7%), these would not have been otherwise identified. Decision theory and economic modeling supported routine PET-CT. Patients with FDG-avid nodes were more likely to have incurable disease (51.4% versus 15.5%; p < 0.001), and a worse prognosis if not: multivariate hazard ratio 2.19 (1.23-3.91; p = 0.008). Prognosis worsened with mN stage. CONCLUSIONS: PET-CT appears useful when used routinely for non-junctional gastric cancer, and should be considered in international recommendations. Any extra costs appear small and offset by avoiding futile investigations and radical treatment. mN stage identifies patients at risk of early recurrence and death. KEY POINTS: • PET-CT is typically not considered useful when staging gastric cancer. We describe a retrospective study of 279 patients routinely staged with PET-CT in the absence of metastases on CT. • The primary tumor was avid in 80% of patients. Twenty-five percent had resectable avid nodes. PET-CT identified previously unsuspected metastases in 7% of patients, which would likely not have been identified by conventional staging without PET-CT in 5%. These patients were much more likely to have avid nodes. • Beyond avoiding futile investigations and radical treatment in this 5%, we found patients with FDG-avid nodes (metabolic nodal stage, mN) to have a worse disease-free survival after gastrectomy.

Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer.

Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect.

Retrospective audit of 957 consecutive 18F-FDG PET-CT scans compared to CT and MRI in 493 patients with different histological subtypes of bone and soft tissue sarcoma.

BACKGROUND: The use of 18F-FDG PET-CT (PET-CT) is widespread in many cancer types compared to sarcoma. We report a large retrospective audit of PET-CT in bone and soft tissue sarcoma with varied grade in a single multi-disciplinary centre. We also sought to answer three questions. Firstly, the correlation between sarcoma sub-type and grade with 18FDG SUVmax, secondly, the practical uses of PET-CT in the clinical setting of staging (during initial diagnosis), restaging (new baseline prior to definitive intervention) and treatment response. Finally, we also attempted to evaluate the potential additional benefit of PET-CT over concurrent conventional CT and MRI. METHODS: A total of 957 consecutive PET-CT scans were performed in a single supra-regional centre in 493 sarcoma patients (excluding GIST) between 2007 and 2014. We compared, PET-CT SUVmax values in relation to histology and FNCCC grading. We compared PET-CT findings relative to concurrent conventional imaging (MRI and CT) in staging, restaging and treatment responses. RESULTS: High-grade (II/III) bone and soft tissue sarcoma correlated with high SUVmax, especially undifferentiated pleomorphic sarcoma, leiomyosarcoma, translocation induced sarcomas (Ewing, synovial, alveolar rhabdomyosarcoma), de-differentiated liposarcoma and osteosarcoma. Lower SUVmax values were observed in sarcomas of low histological grade (grade I), and in rare subtypes of intermediate grade soft tissue sarcoma (e.g. alveolar soft part sarcoma and solitary fibrous tumour). SUVmax variation was noted in malignant peripheral nerve sheath tumours, compared to the histologically benign plexiform neurofibroma, whereas PET-CT could clearly differentiate low from high-grade chondrosarcoma. We identified added utility of PET-CT in addition to MRI and CT in high-grade sarcoma of bone and soft tissues. An estimated 21% overall potential benefit was observed for PET-CT over CT/MRI, and in particular, in 'upstaging' of high-grade disease (from M0 to M1) where an additional 12% of cases were deemed M1 following PET-CT. CONCLUSIONS: PET-CT in high-grade bone and soft tissue sarcoma can add significant benefit to routine CT/MRI staging. Further prospective and multi-centre evaluation of PET-CT is warranted to determine the actual predictive value and cost-effectiveness of PET-CT in directing clinical management of clinically complex and heterogeneous high-grade sarcomas.