Publications by authors named "David Cunningham"

531 Publications

Adjuvant therapy following neoadjuvant chemotherapy and surgery for oesophageal adenocarcinoma in patients with clear resection margins.

Acta Oncol 2021 Feb 15:1-9. Epub 2021 Feb 15.

Department of Upper Gastrointestinal and General Surgery, St Thomas' Hospital, London, UK.

Background: The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy (NAC) and surgery is contentious. In UK practice, surgical resection margin status is often used to classify patients into receiving adjuvant treatment. This study aimed to assess any survival benefit of adjuvant therapy in patients with clear resection margins.

Methods: This was a retrospective collaborative cohort study combining two prospectively collected UK institutional databases of patients with oesophageal adenocarcinoma. Multivariable Cox regression and propensity matched analyses were used to compare overall and recurrence-free survival according to the adjuvant treatment.

Results: Of 374 patients with clear resection margins, 221 patients (59%) had no adjuvant treatment, 137 patients (37%) had adjuvant chemotherapy and 16 patients (4%) had adjuvant chemoradiotherapy. For patients who had received NAC (290, 76%), when adjuvant chemotherapy was compared to no adjuvant treatment, hazard ratios (HRs) favoured adjuvant chemotherapy but did not reach independent significance (overall survival [OS] HR 0.65 95% confidence interval [CI] 0.40-1.06;  .0.087). Responders to NAC (Mandard 1-3) were seemingly more likely to demonstrate a survival benefit from adjuvant chemotherapy (HR 0.42 95% CI 0.15-1.11;  .1.081).

Conclusions: Although no independent survival benefit was observed, the point estimates favoured adjuvant treatment, predominantly in patients with chemo-responsive tumours.
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http://dx.doi.org/10.1080/0284186X.2021.1885057DOI Listing
February 2021

Phase III Study to Evaluate Efficacy and Safety of Andecaliximab With mFOLFOX6 as First-Line Treatment in Patients With Advanced Gastric or GEJ Adenocarcinoma (GAMMA-1).

J Clin Oncol 2021 Feb 12:JCO2002755. Epub 2021 Feb 12.

The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9, an extracellular enzyme involved in matrix remodeling, tumor growth, and metastases. A phase I and Ib study of modified oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6) with ADX revealed encouraging antitumor activity in patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Materials And Methods: This phase III, randomized, double-blinded, placebo (PBO)-controlled multicenter study investigated the efficacy and safety of mFOLFOX6 with and without ADX in patients with untreated human epidermal growth factor receptor 2-negative gastric or GEJ adenocarcinoma. Random assignment was 1:1 to mFOLFOX6 + ADX or mFOLFOX6 + PBO. ADX/PBO 800 mg was infused on days 1 and 15 of each 28-day cycle. Protocol therapy was given until disease progression or intolerance. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), objective response rate (RECIST 1.1), and safety.

Results: Between September 2015 and May 2017, 432 patients were randomly assigned, 218 to ADX and 214 to PBO. The median OS was 12.5 versus 11.8 months in the ADX and PBO groups, respectively. The median PFS was 7.5 versus 7.1 months in the ADX and PBO groups, respectively. The objective response rate was 51% in the ADX group and 41% in the PBO group. Among the subgroup analyses, patients of age ≥ 65 years had an improved OS and PFS with ADX versus PBO; the values and CIs were not adjusted for multiplicity. There were no meaningful differences in the safety profile of the ADX versus PBO groups.

Conclusion: The addition of ADX to mFOLFOX6 did not improve OS in unselected patients with untreated human epidermal growth factor receptor 2-negative gastric or GEJ adenocarcinoma.
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http://dx.doi.org/10.1200/JCO.20.02755DOI Listing
February 2021

Clinical Performance of Abbreviated Liver MRI for the Follow-Up of Patients With Colorectal Liver Metastases.

AJR Am J Roentgenol 2021 Mar 27;216(3):669-676. Epub 2021 Jan 27.

Department of Diagnostic Imaging, Royal Marsden NHS Foundation Trust, Downs Rd, Sutton, Surrey SM2 5PT, UK.

The objective of our study was to compare an abbreviated liver MRI protocol with a standard liver MRI protocol for the posttreatment follow-up of colorectal metastases in assessing disease presence, segmental involvement, and response to chemotherapy and for surgical planning. This retrospective single-center study reviewed consecutive chemotherapy-naïve patients with colorectal liver metastases (April 1, 2011-August 31, 2017) who underwent gadoxetate disodium-enhanced MRI on a 1.5-T unit before and 8-12 weeks after chemotherapy. Two radiologists blinded to outcomes independently reviewed images obtained using standard MRI sequences at baseline and after treatment. The standard MRI sequences were the following: axial T1-weighted, axial T2-weighted, axial DWI (b values = 0-750 s/mm), axial multiphase contrast-enhanced T1-weighted, and axial and coronal hepatobiliary phase (HBP) T1-weighted sequences. The standard sequences obtained at baseline and the abbreviated protocol sequences (i.e., HBP gadoxetate disodium-enhanced T1-weighted and DWI sequences) obtained after treatment were reviewed. For each image set, reviewers assessed disease presence and segmental involvement; in addition, for images obtained after therapy, treatment response according to RECIST 1.1 was recorded. One hundred thirteen patients (73 men and 40 women; mean age, 61.6 years) were evaluated. The total number of metastases showed high agreement between the standard protocol and abbreviated protocol (intraclass correlation coefficient = 0.97). There was good agreement between the protocols for segmental involvement (weighted κ = 0.73-0.85), and the weighted kappa was 0.82 for all segments. Discrepancies in segmental involvement did not alter potential surgical planning. Categorization of RECIST 1.1 treatment response using the abbreviated protocol versus the standard protocol showed excellent agreement (weighted κ = 0.92). An abbreviated liver MRI protocol (i.e., HBP gadoxetate disodium-enhanced T1-weighted and DWI sequences) allows assessment after chemotherapy similar to a standard liver MRI protocol. Use of the abbreviated protocol can reduce imaging time without sacrificing diagnostic performance for the follow-up of colorectal liver metastases.
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http://dx.doi.org/10.2214/AJR.20.22854DOI Listing
March 2021

The Mutational Concordance of Fixed Formalin Paraffin Embedded and Fresh Frozen Gastro-Oesophageal Tumours Using Whole Exome Sequencing.

J Clin Med 2021 Jan 9;10(2). Epub 2021 Jan 9.

The Royal Marsden Hospital NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK.

1.

Background: The application of massively parallel sequencing has led to the identification of aberrant druggable pathways and somatic mutations within therapeutically relevant genes in gastro-oesophageal cancer. Given the widespread use of formalin-fixed paraffin-embedded (FFPE) samples in the study of this disease, it would be beneficial, especially for the purposes of biomarker evaluation, to assess the concordance between comprehensive exome-wide sequencing data from archival FFPE samples originating from a prospective clinical study and those derived from fresh-frozen material. 2.

Methods: We analysed whole-exome sequencing data to define the mutational concordance of 16 matched fresh-frozen and FFPE gastro-oesophageal tumours ( = 32) from a prospective clinical study. We assessed DNA integrity prior to sequencing and then identified coding mutations in genes that have previously been implicated in other cancers. In addition, we calculated the mutant-allele heterogeneity (MATH) for these samples. 3.

Results: Although there was increased degradation of DNA in FFPE samples compared with frozen samples, sequencing data from only two FFPE samples failed to reach an adequate mapping quality threshold. Using a filtering threshold of mutant read counts of at least ten and a minimum of 5% variant allele frequency (VAF) we found that there was a high median mutational concordance of 97% (range 80.1-98.68%) between fresh-frozen and FFPE gastro-oesophageal tumour-derived exomes. However, the majority of FFPE tumours had higher mutant-allele heterogeneity (MATH) scores when compared with corresponding frozen tumours ( < 0.001), suggesting that FFPE-based exome sequencing is likely to over-represent tumour heterogeneity in FFPE samples compared to fresh-frozen samples. Furthermore, we identified coding mutations in 120 cancer-related genes, including those associated with chromatin remodelling and Wnt/β-catenin and Receptor Tyrosine Kinase signalling. 4.

Conclusions: These data suggest that comprehensive genomic data can be generated from exome sequencing of selected DNA samples extracted from archival FFPE gastro-oesophageal tumour tissues within the context of prospective clinical trials.
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http://dx.doi.org/10.3390/jcm10020215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826535PMC
January 2021

The β-encapsulation cage of rearrangement hotspot (Rhs) effectors is required for type VI secretion.

Proc Natl Acad Sci U S A 2020 Dec 15. Epub 2020 Dec 15.

Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106-9625;

Bacteria deploy rearrangement hotspot (Rhs) proteins as toxic effectors against both prokaryotic and eukaryotic target cells. Rhs proteins are characterized by YD-peptide repeats, which fold into a large β-cage structure that encapsulates the C-terminal toxin domain. Here, we show that Rhs effectors are essential for type VI secretion system (T6SS) activity in (ECL). ECL mutants do not kill target bacteria and are defective for T6SS-dependent export of hemolysin-coregulated protein (Hcp). The RhsA and RhsB effectors of ECL both contain Pro-Ala-Ala-Arg (PAAR) repeat domains, which bind the β-spike of trimeric valine-glycine repeat protein G (VgrG) and are important for T6SS activity in other bacteria. Truncated RhsA that retains the PAAR domain is capable of forming higher-order, thermostable complexes with VgrG, yet these assemblies fail to restore secretion activity to ∆ ∆ mutants. Full T6SS-1 activity requires Rhs that contains N-terminal transmembrane helices, the PAAR domain, and an intact β-cage. Although ∆ ∆ mutants do not kill target bacteria, time-lapse microscopy reveals that they assemble and fire T6SS contractile sheaths at ∼6% of the frequency of cells. Therefore, Rhs proteins are not strictly required for T6SS assembly, although they greatly increase secretion efficiency. We propose that PAAR and the β-cage provide distinct structures that promote secretion. PAAR is clearly sufficient to stabilize trimeric VgrG, but efficient assembly of T6SS-1 also depends on an intact β-cage. Together, these domains enforce a quality control checkpoint to ensure that VgrG is loaded with toxic cargo before assembling the secretion apparatus.
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http://dx.doi.org/10.1073/pnas.1919350117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7777165PMC
December 2020

Reply to "On the issue of measuring interhemispheric inhibition in unilateral stroke".

Clin Neurophysiol 2021 Feb 29;132(2):690-691. Epub 2020 Oct 29.

Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Physical Medicine and Rehabilitation, Neurological Institute, Cleveland Clinic, OH, USA. Electronic address:

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http://dx.doi.org/10.1016/j.clinph.2020.10.004DOI Listing
February 2021

Practice-based small group learning (PBSGL) with mixed groups of general practitioners and secondary care doctors: a qualitative study.

Educ Prim Care 2020 Nov 29:1-6. Epub 2020 Nov 29.

GP Education, NHS Education for Scotland , Glasgow, UK.

General practitioners (GPs) and secondary care doctors share a common background of learning together whilst at medical school but their learning paths diverge after specialist qualification. Reconnect is an initiative in NHS Grampian in Scotland which offered a variety of shared activities, including learning, to both groups of medical practitioners. One learning activity was of Practice-Based Small Group Learning (PBSGL) which has proved popular with primary care clinicians. Groups drawn from both health care sectors were started and met over a five month pilot period. A qualitative research method was chosen to identify the perceptions and experiences of participants. They were interviewed in one-to-one telephone interviews. Interviews were audio-recorded, transcribed and analysed using grounded theory methods. Two PBSGL groups were formed with a total of 13 members. One group met twice in the pilot period and the other group met only once. Nine participants were interviewed and four main themes emerged from analysis of the data. Reasons for participation were often related to a desire to improve working relationships between the two sectors and to increase understanding. Practitioners learned about how working conditions and team working affected the working lives of the other sector. Participants found the logistics of arranging further meetings challenging and considered they had a lack of shared learning time together. Considerations to the future of the project were positive but this contrasted with the few meetings that had taken place.
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http://dx.doi.org/10.1080/14739879.2020.1850213DOI Listing
November 2020

EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers.

Gut 2020 Nov 16. Epub 2020 Nov 16.

Department of Medicine, Royal Marsden Hospital NHS Trust, London, UK

Objective: Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785).

Design: CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients.

Results: amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from -amplified aGEA.

Conclusion: CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials.
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http://dx.doi.org/10.1136/gutjnl-2020-322658DOI Listing
November 2020

Lymphomatoid papulosis mimicking relapsed angioimmunoblastic T-cell lymphoma on histology: the importance of clinicopathological correlation.

Histopathology 2021 Feb 8;78(3):470-473. Epub 2020 Dec 8.

Gastrointestinal and Lymphoma Unit, The Royal Marsden Hospital, London, UK.

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http://dx.doi.org/10.1111/his.14287DOI Listing
February 2021

Intratumoral Transcriptome Heterogeneity Is Associated With Patient Prognosis and Sidedness in Patients With Colorectal Cancer Treated With Anti-EGFR Therapy From the CO.20 Trial.

JCO Precis Oncol 2020 29;4. Epub 2020 Sep 29.

Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom.

Purpose: Metastatic colorectal cancers (mCRCs) assigned to the transit-amplifying (TA) CRCAssigner subtype are more sensitive to anti-epidermal growth factor receptor (EGFR) therapy. We evaluated the association between the intratumoral presence of TA signature (TA-high/TA-low, dubbed as TA-ness classification) and outcomes in CRCs treated with anti-EGFR therapy.

Patients And Methods: The TA-ness classes were defined in a discovery cohort (n = 84) and independently validated in a clinical trial (CO.20; cetuximab monotherapy arm; n = 121) and other samples using an established NanoString-based gene expression assay. Progression-free survival (PFS), overall survival (OS), and disease control rate (DCR) according to TA-ness classification were assessed by univariate and multivariate analyses.

Results: The TA-ness was measured in 772 samples from 712 patients. Patients (treated with anti-EGFR therapy) with TA-high tumors had significantly longer PFS (discovery hazard ratio [HR], 0.40; 95% CI, 0.25 to 0.64; < .001; validation HR, 0.65; 95% CI, 0.45 to 0.93; = .018), longer OS (discovery HR, 0.48; 95% CI, 0.29 to 0.78; = .003; validation HR, 0.67; 95% CI, 0.46 to 0.98; = .04), and higher DCR (discovery odds ratio [OR]; 14.8; 95% CI, 4.30 to 59.54; < .001; validation OR, 4.35; 95% CI, 2.00 to 9.09; < .001). TA-ness classification and its association with anti-EGFR therapy outcomes were further confirmed using publicly available data (n = 80) from metastatic samples (PFS < .001) and patient-derived xenografts ( = .042). In an exploratory analysis of 55 patients with wild-type and left-sided tumors, TA-high class was significantly associated with longer PFS and trend toward higher response rate (PFS HR, 0.53; 95% CI, 0.28 to 1.00; = .049; OR, 5.88; 95% CI, 0.71 to 4.55; = .09; response rate 33% in TA-high and 7.7% in TA-low).

Conclusion: TA-ness classification is associated with prognosis in patients with mCRC treated with anti-EGFR therapy and may further help understanding the value of sidedness in patients with wild-type tumors.
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http://dx.doi.org/10.1200/PO.20.00050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529528PMC
September 2020

Diagnostic Accuracy and Safety of Coaxial System in Oncology Patients Treated in a Specialist Cancer Center With Prospective Validation Within Clinical Trial Data.

Front Oncol 2020 4;10:1634. Epub 2020 Sep 4.

Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden Hospital, London, United Kingdom.

Background: Image-guided tissue biopsies are critically important in the diagnosis and management of cancer patients. High-yield samples are also vital for biomarker and resistance mechanism discovery through molecular/genomic analyses.

Patients And Methods: All consecutive patients who underwent plugged image-guided biopsy at Royal Marsden from June 2013 until September 2016 were included in the analysis. In the next step, a second cohort of patients prospectively treated within two clinical trials (PROSPECT-C and PROSPECT-R) were assessed for the DNA yield from biopsies assessed for complex genomic analysis.

Results: A total of 522 plugged core biopsies were performed in 457 patients [men, 52%; median age, 63 years (range, 17-93)]. Histological diagnosis was achieved in 501 of 522 (96%) performed biopsies. Age, gender, modality, metastatic site, and seniority of the interventionist were not found to be significant factors associated with odds of failure on a logistic regression. Seventeen (3.3%) were admitted due to biopsy-related complications; nine, three, two, one, one, and one were admitted for grade I/II pain control, sepsis, vasovagal syncope, thrombosis, hematuria, and deranged liver functions, respectively; two patients with right upper quadrant pain after liver biopsy were found to have radiologically confirmed subcapsular hematoma requiring conservative treatment. One patient (0.2%) developed grade III hemorrhage following biopsy of a gastric gastrointestinal stromal tumor (GIST). Overall molecular analysis was successful in 89% (197/222 biopsies). Prospective validation in 62 biopsies gave success rates of 92.06 and 79.03% for DNA extraction of >1 μm and tmour content of >20%, respectively.

Conclusion: The probability of diagnostic success for complex molecular analysis is increased with plugged large coaxial needle biopsy technique, which also minimizes complications and reduces hospital stay. High-yield DNA acquisition allows genomic molecular characterization for personalized medicine.
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http://dx.doi.org/10.3389/fonc.2020.01634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500492PMC
September 2020

Immune landscape, evolution, hypoxia-mediated viral mimicry pathways and therapeutic potential in molecular subtypes of pancreatic neuroendocrine tumours.

Gut 2020 Sep 3. Epub 2020 Sep 3.

Division of Molecular Pathology, Institute of Cancer Research, London, UK

Objective: A comprehensive analysis of the immune landscape of pancreatic neuroendocrine tumours (PanNETs) was performed according to clinicopathological parameters and previously defined molecular subtypes to identify potential therapeutic vulnerabilities in this disease.

Design: Differential expression analysis of 600 immune-related genes was performed on 207 PanNET samples, comprising a training cohort (n=72) and two validation cohorts (n=135) from multiple transcriptome profiling platforms. Different immune-related and subtype-related phenotypes, cell types and pathways were investigated using different in silico methods and were further validated using spatial multiplex immunofluorescence.

Results: The study identified an immune signature of 132 genes segregating PanNETs (n=207) according to four previously defined molecular subtypes: metastasis-like primary (MLP)-1 and MLP-2, insulinoma-like and intermediate. The MLP-1 subtype (26%-31% samples across three cohorts) was strongly associated with elevated levels of immune-related genes, poor prognosis and a cascade of tumour evolutionary events: larger hypoxic and necroptotic tumours leading to increased damage-associated molecular patterns (viral mimicry), stimulator of interferon gene pathway, T cell-inflamed genes, immune checkpoint targets, and T cell-mediated and M1 macrophage-mediated immune escape mechanisms. Multiplex spatial profiling validated significantly increased macrophages in the MLP-1 subtype.

Conclusion: This study provides novel data on the immune microenvironment of PanNETs and identifies MLP-1 subtype as an immune-high phenotype featuring a broad and robust activation of immune-related genes. This study, with further refinement, paves the way for future precision immunotherapy studies in PanNETs to potentially select a subset of MLP-1 patients who may be more likely to respond.
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http://dx.doi.org/10.1136/gutjnl-2020-321016DOI Listing
September 2020

Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma.

Blood 2021 Feb;137(5):637-645

Mayo Clinic, Rochester, MN.

Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, showed promising activity in relapsed or refractory (R/R) follicular lymphoma (FL) in a phase 1 study. We conducted a phase 2 trial to further evaluate its efficacy and safety in patients with R/R FL and to explore biomarkers of response. Patients with R/R FL and at least 2 prior lines of therapy, each containing a CD20 antibody or an alkylating agent, were treated with nivolumab 3 mg/kg every 2 weeks. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Biomarker analyses included gene expression profiling and multiplex immunofluorescence studies of pretreatment tumor samples. A total of 92 patients were treated. After a minimum follow-up of 12 months, ORR was 4% (4 of 92 patients). Median progression-free survival (PFS) was 2.2 months (95% confidence interval [CI], 1.9-3.6 months). Median duration of response was 11 months (95% CI, 8-14 months). Exploratory analyses suggested that responders had significantly higher proportion of CD3+ T cells in the tumor microenvironment than nonresponders, but no significant differences in PD-1 or programmed death-ligand 1 expression were observed. High expression of a set of tumor-associated macrophage genes was associated with reduced PFS (hazard ratio, 3.28; 95% CI, 1.76-6.11; P = .001). The safety profile was consistent with previous reports of nivolumab. In conclusion, nivolumab monotherapy was associated with very limited activity in patients with R/R FL. Better understanding of the immune biology of this disease may facilitate the development of effective checkpoint-based strategies. This trial was registered at www.clinicaltrials.gov as #NCT02038946.
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http://dx.doi.org/10.1182/blood.2019004753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869188PMC
February 2021

Impact of sex and age on chemotherapy efficacy, toxicity and survival in localised oesophagogastric cancer: A pooled analysis of 3265 individual patient data from four large randomised trials (OE02, OE05, MAGIC and ST03).

Eur J Cancer 2020 09 31;137:45-56. Epub 2020 Jul 31.

Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, SM2 5PT, United Kingdom. Electronic address:

Background: There is a lack of large-scale randomised data evaluating the impact of sex and age in patients undergoing chemotherapy followed by potentially curative surgery for oesophagogastric cancer.

Patients And Methods: Individual patient data from four prospective randomised controlled trials were pooled using a two-stage meta-analysis. For survival analysis, hazard ratios (HRs) were calculated for patients aged <70 and ≥ 70 years, as well as between males and females. Mandard tumour regression grade (TRG) and, ≥grade III toxicities were compared using logistic regression models to calculate odds ratios. All analyses were adjusted for the type of chemotherapy received.

Results: 3265 patients were included for survival analysis (2668 [82%] male, 597 [18%] female; 2627 (80%) <70 years, 638 (20%) ≥70 years). A significant improvement in overall survival (OS) (HR: 0.78; p < 0.001) and disease-specific survival (DSS) (HR: 0.78; p < 0.001) was observed in females compared with males. No significant differences in OS (HR: 1.11; p = 0.045) or DSS (HR: 1.01; p = 0.821) were observed in older patients compared with younger patients. For patients who underwent resection, older patients (15% vs 10%; p = 0.03) and female patients (14% vs 10%, p = 0.10) were more likely to achieve favourable Mandard TRG scores. Females experienced significantly more ≥grade III nausea (10% vs 5%; p≤0.001), vomiting (10% vs 4%; p≤0.001) and diarrhoea (9% vs 4%; p≤0.001) than males.

Conclusions: In this large pooled analysis using prospective randomised trial data, females had significantly improved survival while experiencing more gastrointestinal toxicities. Older patients achieved comparable survival to younger patients and thus, dependent on fitness, should be offered the same treatment paradigm.
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http://dx.doi.org/10.1016/j.ejca.2020.06.005DOI Listing
September 2020

Stratifying chronic stroke patients based on the influence of contralesional motor cortices: An inter-hemispheric inhibition study.

Clin Neurophysiol 2020 Oct 3;131(10):2516-2525. Epub 2020 Jul 3.

Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Physical Medicine and Rehabilitation, Neurological Institute, Cleveland Clinic, OH, USA. Electronic address:

Objective: A recent "bimodal-balance recovery" model suggests that contralesional influence varies based on the amount of ipsilesional reserve: inhibitory when there is a large reserve, but supportive when there is a low reserve. Here, we investigated the relationships between contralesional influence (inter-hemispheric inhibition, IHI) and ipsilesional reserve (corticospinal damage/impairment), and also defined a criterion separating subgroups based on the relationships.

Methods: Twenty-four patients underwent assessment of IHI using Transcranial Magnetic Stimulation (ipsilateral silent period method), motor impairment using Upper Extremity Fugl-Meyer (UEFM), and corticospinal damage using Diffusion Tensor Imaging and active motor threshold. Assessments of UEFM and IHI were repeated after 5-week rehabilitation (n = 21).

Results: Relationship between IHI and baseline UEFM was quadratic with criterion at UEFM 43 (95%conference interval: 40-46). Patients less impaired than UEFM = 43 showed stronger IHI with more impairment, whereas patients more impaired than UEFM = 43 showed lower IHI with more impairment. Of those made clinically-meaningful functional gains in rehabilitation (n = 14), more-impaired patients showed further IHI reduction.

Conclusions: A criterion impairment-level can be derived to stratify patient-subgroups based on the bimodal influence of contralesional cortex. Contralesional influence also evolves differently across subgroups following rehabilitation.

Significance: The criterion may be used to stratify patients to design targeted, precision treatments.
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http://dx.doi.org/10.1016/j.clinph.2020.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487004PMC
October 2020

Comparison of a coaxial versus non-coaxial liver biopsy technique in an oncological setting: diagnostic yield, complications and seeding risk.

Eur Radiol 2020 Dec 14;30(12):6702-6708. Epub 2020 Jul 14.

Department of Radiology, The Royal Marsden NHS Foundation Trust, Downs Rd, Sutton, London, SW2 5PT, UK.

Objectives: Percutaneous liver biopsy (PLB) poses specific challenges in oncological patients such as bleeding and tumour seeding. This study's aim was to compare a coaxial (C-PLB) and non-coaxial (NC-PLB) biopsy technique in terms of diagnostic yield, safety and seeding risk of image-guided PLB techniques in an oncological setting.

Methods: Local research committee approval was obtained for this single-site retrospective study. Patients who underwent a PLB between November 2011 and December 2017 were consecutively included. Medical records were reviewed to determine diagnostic yield and complications. Follow-up imaging was re-reviewed for seeding, defined as visible tumour deposits along the PLB track. Mann-Whitney U and chi-squared tests were performed to investigate differences between biopsy techniques in sample number, complications and seeding rate.

Results: In total, 741 patients (62 ± 13 years, 378 women) underwent 932 PLB (C-PLB 72.9% (679/932); NC-PLB 27.1% (253/932)). More tissue cores (p < 0.001) were obtained with C-PLB (median 4 cores; range 1-12) compared with NC-PLB (2 cores; range 1-4) and diagnostic yield was similar for both techniques (C-PLB 92.6% (629/679); NC-PLB 92.5% (234/253); p = 0.940). Complication rate (9.3%; 87/932) using C-PLB (8.2% (56/679)) was lower compared with NC-PLB (12.3% (31/253); p = 0.024). Major complications were uncommon (C-PLB 2.7% (18/679); NC-PLB 2.8% (7/253)); bleeding developed in 1.2% (11/932; C-PLB 1.2% (8/679); NC-PLB 1.2% (3/253)). Seeding was a rare event, occurring significantly less in C-PLB cases (C-PLB 1.3% (7/544); NC-PLB 3.1% (6/197); p = 0.021).

Conclusions: C-PLB allows for high diagnostic tissue yield with a lower complication and seeding rate than a NC-PLB and should be the preferred method in an oncological setting.

Key Points: • A coaxial percutaneous liver biopsy achieves a significant higher number of cores and fewer complications than a non-coaxial biopsy technique. • The risk of tumour seeding is very low and is significantly lower using the coaxial biopsy technique. • In this study, a larger number of cores (median = 4) could be safely acquired using the coaxial technique, providing sufficient material for advanced molecular analysis.
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http://dx.doi.org/10.1007/s00330-020-07038-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599171PMC
December 2020

FDG-PET/CT after two cycles of R-CHOP in DLBCL predicts complete remission but has limited value in identifying patients with poor outcome - final result of a UK National Cancer Research Institute prospective study.

Br J Haematol 2021 Feb 4;192(3):504-513. Epub 2020 Jul 4.

King's College London and Guy's and St Thomas' PET Centre, School of Biomedical Engineering and Imaging Sciences, King's College London, King's Health Partners, London, UK.

The UK National Cancer Research Institute initiated a prospective study (UKCRN-ID 1760) to assess the prognostic value of early fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in diffuse large B-cell lymphoma (DLBCL). In total, 189 patients with DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) had baseline and post-cycle-2 PET (PET2) within a quality assurance framework. Treatment decisions were based on CT; PET2 was archived for central blinded reporting after treatment completion. The association of PET2 response with end-of-treatment CT, progression-free (PFS) and overall survival (OS) was explored. The end-of-treatment complete response rate on CT was 83·9%, 75·0%, 70·5%, 40·4% and 36·4% for Deauville score (DS) 1 (n = 34), 2 (n = 39), 3 (n = 46), 4 (n = 56) and 5 (n = 14) (P < 0·001); and 64·1% and 50·0% for the maximum standardised uptake value (∆SUV ) of ≥66% (n = 168) and <66% (n = 21), respectively (P = 0·25). After a median 5·4 years of follow-up, the 5-year PFS was 69·4%, 72·8%, 76·7%, 71·2% and 47·6% by DS 1-5 (P = 0·01); and 72·6% and 57·1% by ∆SUV of ≥66% and <66% (P = 0·03), respectively. The association with DS remained in multivariable analyses, and was consistent for OS. Early complete metabolic response (DS 1-3) at interim PET/CT after two cycles of R-CHOP in DLBCL was associated with a higher end-of-treatment complete and overall response rate; however, only DS-5 patients had inferior PFS and OS.
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http://dx.doi.org/10.1111/bjh.16875DOI Listing
February 2021

Histological intratumoral heterogeneity in pretreatment esophageal cancer biopsies predicts survival benefit from neoadjuvant chemotherapy: results from the UK MRC OE02 trial.

Dis Esophagus 2020 Aug;33(8)

Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center + Maastricht, The Netherlands.

Despite the use of multimodal treatment, survival of esophageal cancer (EC) patients remains poor. One proposed explanation for the relatively poor response to cytotoxic chemotherapy is intratumor heterogeneity. The aim was to establish a statistical model to objectively measure intratumor heterogeneity of the proportion of tumor (IHPoT) and to use this newly developed method to measure IHPoT in the pretreatment biopsies from from EC patients recruited to the OE02 trial. A statistical mixed effect model (MEM) was established for estimating IHPoT based on variation in hematoxylin/eosin (HE) stained pretreatment biopsy pieces from the same individual in 218 OE02 trial patients (103 treated by chemotherapy and surgery (chemo+surgery); 115 patients treated by surgery alone). The relationship between IHPoT, prognosis, chemotherapy survival benefit, and clinicopathological variables was assessed. About 97 (44.5%) and 121 (55.5%) ECs showed high and low IHPoT, respectively. There was no significant difference in IHPoT between surgery (median [range], 0.1637 [0-3.17]) and chemo+surgery (median [range], 0.1692 [0-2.69]) patients (P = 0.43). Chemo+surgery patients with low IHPoT had a significantly longer survival than surgery patients (HR = 1.81, 95% CI: 1.20-2.75, P = 0.005). There was no survival difference between chemo+surgery and surgery patients with high IHPoT (HR = 1.15, 95% CI: 0.72-1.81, P = 0.566). This is the first study suggesting that IHPoT measured in the pretreatment biopsy can predict chemotherapy survival benefit in EC patients. IHPoT may represent a clinically useful biomarker for patient treatment stratification. Future studies should determine if pathologists can reliably estimate IHPoT.
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http://dx.doi.org/10.1093/dote/doaa058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397482PMC
August 2020

International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct.

J Clin Oncol 2020 08 12;38(22):2510-2518. Epub 2020 Jun 12.

Royal Marsden Hospital, London, United Kingdom.

Purpose: To compare cisplatin plus fluorouracil (FU) versus carboplatin plus paclitaxel in chemotherapy-naïve advanced anal cancer to establish the optimal regimen.

Patients And Methods: Patients who had not received systemic therapy for advanced anal cancer were randomly assigned 1:1 to intravenous cisplatin 60 mg/m (day 1) plus FU 1,000 mg/m (days 1-4) every 21 days or carboplatin (area under the curve, 5; day 1) plus paclitaxel 80 mg/m (days 1, 8, and 15) every 28 days for 24 weeks, until disease progression, intolerable toxicity, or withdrawal of consent. Primary end point was objective response rate (ORR). Primary and secondary end points were assessed in a hierarchic model to compare the regimens and pick the winner.

Results: We conducted an international multicenter randomized phase II study in 60 centers between December 2013 and November 2017. Median follow-up was 28.6 months. A total of 91 patients were randomly assigned: 46 to cisplatin plus FU and 45 to carboplatin plus paclitaxel. ORR was 57% (95% CI, 39.4% to 73.7%) for cisplatin plus FU versus 59% (95% CI, 42.1% to 74.4%) for carboplatin plus paclitaxel. More serious adverse events were noted in the cisplatin plus FU arm (62%) compared with the carboplatin plus paclitaxel arm (36%; = .016). Median progression-free survival was 5.7 months (95% CI, 3.3 to 9.0 months) for cisplatin plus FU compared with 8.1 months (95% CI, 6.6 to 8.8 months) for carboplatin plus paclitaxel. Median overall survival was 12.3 months for cisplatin plus FU (95% CI, 9.2 to 17.7 months) compared with 20 months (95% CI, 12.7 months to not reached) for carboplatin plus paclitaxel (hazard ratio, 2.00; 95% CI, 1.15 to 3.47; = .014).

Conclusion: This is the first international randomized trial to our knowledge conducted in chemotherapy-naïve advanced anal cancer. Although there was no difference in ORR, the association with clinically relevant reduced toxicity and a trend toward longer survival suggest that carboplatin plus paclitaxel should be considered as a new standard of care.
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http://dx.doi.org/10.1200/JCO.19.03266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406334PMC
August 2020

Quantification of cranberry proanthocyanidins by normal-phase high-performance liquid chromatography using relative response factors.

Phytochem Anal 2020 Nov 29;31(6):874-883. Epub 2020 May 29.

Methods and Application of Food Composition Laboratory, USDA, ARS, Beltsville Human Nutrition Research Center, Beltsville, MD, USA.

Introduction: American cranberries (Vaccinium macrocarpon) contain primarily A-type proanthocyanidins (PACs), which have been shown to prevent urinary tract infection. Currently, the accurate quantification of cranberry PACs is still lacking.

Objective: A normal-phase high-performance liquid chromatography (NP-HPLC) method using relative response factors was developed and validated to quantify cranberry PAC oligomers and polymers.

Materials And Methods: PAC oligomers with degree of polymerisation (DP) 3-9 and total polymers were isolated from the cranberry juice concentrate. Characterisation of the isolated PAC oligomers was performed by ultra-performance liquid chromatography-high resolution mass spectrometry. The relative response factors of oligomers from DP 2-9 and total polymers were determined against procyanidin A2. Method validation was conducted to assess limit of detection, limit of quantification, the linearity and working range, precision and accuracy. In addition, quantifications of PACs by NP-HPLC using relative response factors and two other commonly used methods were conducted in three cranberry food products.

Results: Cranberries PACs oligomers contained both A-type and B-type linkage, with epicatechin and epigallocatechin as basic units. Method validation results suggested this method is reliable and reproducible. Quantifications of PACs by NP-HPLC using relative response factors yielded higher values than that by the other two methods.

Conclusion: A NP-HPLC method using the relative response factors was developed and validated. This method provides a more accurate approach in determining cranberry PACs. It can be used to quantify individual oligomers from DP 2-9, total polymers and total PACs in cranberries and cranberry products.
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http://dx.doi.org/10.1002/pca.2952DOI Listing
November 2020

Landmark survival analysis and impact of anatomic site of origin in prospective clinical trials of biliary tract cancer.

J Hepatol 2020 Nov 21;73(5):1109-1117. Epub 2020 May 21.

Division of Cancer Sciences, The University of Manchester and The Christie NHS Foundation Trust, Manchester M20 4BX, UK.

Background & Aims: Whether all patients with advanced biliary tract cancer (aBTC) should be included in prospective trials, irrespective of the anatomic site of origin, is debated. Herein, we aimed to assess the survival impact of anatomic site of origin in prospective clinical trials of aBTC using landmark survival analysis.

Methods: Patients enrolled into prospective first-line aBTC clinical trials (Jan 97-Dec 15) were included. Overall survival (OS) was analysed using Cox proportional hazard regression; landmark survival (LS) and 95% CIs were calculated.

Results: Overall, 1,333 patients were included: median age 63 years (range 23-85); 46% male; 84% ECOG-PS0/1; 25% with locally advanced disease, 72% with metastatic, 3% not reported (NR). Patients were treated with mono-chemotherapy (23%), cisplatin/gemcitabine (36%), other combinations (39%), or NR (2%). Median OS was 10.2 months (95% CI 9.6-10.9). All sites (treatment-adjusted) had decreased risk of death vs. gallbladder cancer (GBC) (p <0.001). This reduced risk vs. GBC was maintained in those receiving cisplatin/gemcitabine for extrahepatic cholangiocarcinoma (p<0.001) and intrahepatic cholangiocarcinoma (IHC, p<0.001), but not in cholangiocarcinoma-not specified (CCA-NS, p = 0.82) or ampullary carcinoma (p = 0.96). One-year OS rates amongst patients who survived beyond 1, 2, 3 and 4 years post-trial registration were 37%, 45%, 61%, and 63%, respectively. For patients who survived 1 year, those receiving combination therapy vs. mono (p = 0.008) (acknowledging potential selection bias) and those with IHC and CCA-NS vs. GBC had better LS (both p <0.05). Metastatic disease was associated with shorter LS than locally advanced disease (p = 0.002). ECOG-PS and gender were not associated with LS (p >0.05, p = 0.08 respectively).

Conclusions: GBC is associated with worse OS than other BTC sites and should be considered as a stratification factor in clinical trials. LS rates enable adjusted prognostication for aBTC survivors.

Lay Summary: Patients with gallbladder cancer have worse overall survival compared to those with biliary tract cancers of different primary origin. Thus, gallbladder cancer should be considered as a stratification factor in future clinical trials. Landmark survival rates enable adjusted prognosis prediction for patients with advanced biliary tract cancer who survive for some time.
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http://dx.doi.org/10.1016/j.jhep.2020.05.014DOI Listing
November 2020

Prognostic indices in diffuse large B-cell lymphoma in the rituximab era: an analysis of the UK National Cancer Research Institute R-CHOP 14 versus 21 phase 3 trial.

Br J Haematol 2020 May 20. Epub 2020 May 20.

University College London, London, UK.

We compared the International Prognostic Index (IPI), Revised (R)-IPI and age-adjusted (aa)-IPI as prognostic indices for patients with diffuse large B-cell lymphoma (DLBCL) in the UK National Cancer Research Institute (NCRI) R-CHOP 14 versus 21 trial (N = 1080). The R-IPI and aa-IPI showed no marked improvement compared to the IPI for overall and progression-free survival, in terms of model fit or discrimination. Similar results were observed in exploratory analyses incorporating the Grupo Español de Linfomas/Transplante de Médula Ósea (GELTAMO)-IPI, where baseline β2-microglobulin data were available (N = 655). Although our findings support current use of the IPI, a novel prognostic tool to better delineate a high-risk DLBCL group in the rituximab era is needed.
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http://dx.doi.org/10.1111/bjh.16691DOI Listing
May 2020

Imaging and clinical correlates with regorafenib in metastatic colorectal cancer.

Cancer Treat Rev 2020 Jun 4;86:102020. Epub 2020 Apr 4.

Institut Jules Bordet, 121 Boulevard de Waterloo, 1000 Brussels, Belgium. Electronic address:

In colorectal cancer (CRC), imaging is important in determining tumor stage, selecting treatment strategies, and in assessing response to therapy. However, some challenges remain with established imaging techniques, such as computed tomography, and with some commonly used response criteria, such as Response Evaluation Criteria in Solid Tumors, which measures change in size of several target lesions instead of change in tumor morphology or metabolic function. In addition, these assessments are not typically conducted until after 8 weeks of treatment, meaning that potential non-responders are often not identified in a timely manner. Regorafenib, an oral tyrosine kinase inhibitor indicated for the treatment of metastatic CRC, blocks the activity of several protein kinases involved in angiogenesis, oncogenesis, metastasis, and tumor immunity. Timely differentiation of regorafenib responders from non-responders using appropriate imaging techniques that recognize not only changes in tumor size but also changes in tumor density or vasculature, may reduce unnecessary drug-related toxicity in patients who are unlikely to respond to treatment. This review discusses the latest developments in computed tomography, magnetic resonance imaging, and positron emission tomography tumor imaging modalities, and how these aid in identifying patients with metastatic CRC who are responders or non-responders to regorafenib treatment.
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http://dx.doi.org/10.1016/j.ctrv.2020.102020DOI Listing
June 2020

Transition from open and laparoscopic to robotic pancreaticoduodenectomy in a UK tertiary referral hepatobiliary and pancreatic centre - Early experience of robotic pancreaticoduodenectomy.

HPB (Oxford) 2020 Nov 1;22(11):1637-1644. Epub 2020 Apr 1.

HPB Surgical Unit, Dept. of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0HS, UK; Surgery and Oncology, The Royal Marsden Hospital, 203 Fulham Road, London, SW3 6JJ, UK. Electronic address:

Background: Pancreaticoduodenectomy is performed using an open technique (OPD) as the gold standard. An increase in those performed laparoscopically (LPD) and robotically (RPD) are now reported. We compared the short-term outcomes of RPD cases with LPD and OPD.

Methods: A retrospective review of a prospectively collected database was undertaken of our first consecutive RPD, our first LPD and consecutive OPD cases. Those requiring venous and/or arterial resection were excluded.

Results: RPD (n = 25) had longer median operating times (461 (IQR 358-564) mins) than LPD (n = 41) (330 (IQR 262.5-397.5) mins) and OPD (n = 37) (330 (IQR 257-403) mins, p < 0.0001). Estimated blood loss and transfusion requirement was less after RPD and LPD compared to OPD (p = 0.012 and p < 0.0001 respectively). No RPD cases required conversion to open operation compared to 24.4% of LPD. Morbidity was comparable with a Clavien Dindo score ≥3 in 20.00%, 24.39% and 18.92% for RPD, LPD and OPD respectively (p = 0.83). Post-operative pancreatic fistula rates were seen in 16.00%, 29.27% and 21.62% of our RPD, LPD and OPD cohorts respectively (p = 0.81). 90-day mortality was seen in 0.97% of the total cohort. Length of hospital stay (LOS) was shorter for RPD compared to both LPD (p = 0.030) and OPD (p = 0.002).

Conclusion: RPD is safe to perform with comparable outcomes to LPD and OPD. Further evidence is provided that a randomised controlled trial for PD techniques is required.
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http://dx.doi.org/10.1016/j.hpb.2020.03.008DOI Listing
November 2020

International prognostic indices in diffuse large B-cell lymphoma: a comparison of IPI, R-IPI, and NCCN-IPI.

Blood 2020 06;135(23):2041-2048

Department of Hematology and Oncology, University Hospital Muenster, Muenster, Germany.

Great heterogeneity in survival exists for patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL). Three scoring systems incorporating simple clinical parameters (age, lactate dehydrogenase, number/sites of involvement, stage, performance status) are widely used: the International Prognostic Index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI). We evaluated 2124 DLBCL patients treated from 1998 to 2009 with frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; or variant) across 7 multicenter randomized clinical trials to determine which scoring system best discriminates overall survival (OS). Median age was 63 years, and 56% of patients were male. Five-year OS estimates ranged from 54% to 88%, from 61% to 93%, and from 49% to 92% using the IPI, R-IPI, and NCCN-IPI, respectively. The NCCN-IPI had the greatest absolute difference in OS estimates between the highest- and lowest-risk groups and best discriminated OS (concordance index = 0.632 vs 0.626 [IPI] vs 0.590 [R-IPI]). For each given IPI risk category, NCCN-IPI risk categories were significantly associated with OS (P ≤ .01); the reverse was not true, and the IPI did not provide additional significant prognostic information within all NCCN-IPI risk categories. Collectively, the NCCN-IPI outperformed the IPI and R-IPI. Patients with low-risk NCCN-IPI had favorable survival outcomes with little room for further improvement. In the rituximab era, none of the clinical risk scores identified a patient subgroup with long-term survival clearly <50%. Integrating molecular features of the tumor and microenvironment into the NCCN-IPI or IPI might better characterize a high-risk group for which novel treatment approaches are most needed.
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http://dx.doi.org/10.1182/blood.2019002729DOI Listing
June 2020

Inactivation of Promotes Resistance to EGFR Inhibition in -Wild-Type Colorectal Cancer.

Mol Cancer Res 2020 06 25;18(6):835-846. Epub 2020 Feb 25.

Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.

Through the use of an unbiased, genome-scale CRISPR modifier screen, we identified NF1 suppression as a mechanism of resistance to EGFR inhibition in -wild-type colorectal cancer cells. Reduced NF1 expression permitted sustained signaling through the MAPK pathway to promote cell proliferation in the presence of EGFR inhibition. Targeting of MEK in combination with EGFR inhibition leads to synergistic antiproliferative activity. Human -wild-type colorectal cancer cell lines with mutations displayed reduced mRNA or protein expression and were resistant to EGFR blockade by gefitinib or cetuximab. Cooccurring loss-of-function mutations in were associated with resistance to dual EGFR/MEK inhibition but cotreatment with a PI3K inhibitor further suppressed proliferation. Loss of NF1 may be a useful biomarker to identify patients that are less likely to benefit from single-agent anti-EGFR therapy in colorectal cancer and may direct potential combination strategies. IMPLICATIONS: This study suggests that further clinical validation of status as predictor of response to anti-EGFR targeting antibodies in patients with colorectal cancer with -wild-type tumors is warranted.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-1201DOI Listing
June 2020

Rationale and design of the POLEM trial: avelumab plus fluoropyrimidine-based chemotherapy as adjuvant treatment for stage III mismatch repair deficient or POLE exonuclease domain mutant colon cancer: a phase III randomised study.

ESMO Open 2020 02;5(1)

Royal Surrey NHS Foundation Trust, Guildford, UK

Background: 10%-15% of early-stage colon cancers harbour either deficient mismatch repair (dMMR), microsatellite instability high (MSI-H) or exonuclease domain mutations, and are characterised by high tumour mutational burden and increased lymphocytic infiltrate. Metastatic dMMR colon cancers are highly sensitive to immune checkpoint inhibition, and recent data show -mutant tumours are similarly responsive. We are conducting a phase III randomised trial to determine if the addition of the anti-PD-L1 antibody avelumab following adjuvant chemotherapy improves disease-free survival (DFS) in patients with stage III dMMR/MSI-H or mutant colon cancer and is a cost-effective approach for the UK National Health Service (NHS).

Methods: We are recruiting patients with completely resected, stage III colon cancer confirmed to have dMMR/MSI-H, locally or exonuclease domain mutation on central testing. Eligible patients are randomised in a 1:1 ratio to standard fluoropyrimidine-based chemotherapy (capecitabine, oxaliplatin for 12 weeks or capecitabine for 24 weeks) or chemotherapy, followed by avelumab (10 mg/kg, 2 weekly for 24 weeks). Stratification is by chemotherapy received and MMR/MSI-H status. The primary endpoint is DFS. Secondary endpoints include overall survival, toxicity, quality of life and health resource use. The 3-year DFS rate in the control arm is expected to be ~75%. Avelumab is expected to improve the 3-year DFS rate by 12% (ie, 87%). Target accrual is 402 patients, which provides 80% power to detect an HR of 0.48 for DFS at a two-sided alpha of 0.05. This national, multicentre phase III trial is sponsored by the Royal Marsden NHS Foundation Trust and it is anticipated that approximately 40 centres in the UK will participate. This study opened to recruitment in August 2018.

Trial Registration Number: NCT03827044.
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http://dx.doi.org/10.1136/esmoopen-2019-000638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046393PMC
February 2020