The association of clinical and patient factors with chemotherapy-induced peripheral neuropathy (CIPN) in colorectal cancer: secondary analysis of the SCOT trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of oxaliplatin. CIPN can impair long-term quality of life and limit the dose of chemotherapy. We investigated the association of CIPN over time with age, sex, body mass index, baseline neuropathy, and chemotherapy regimen in people treated with adjuvant oxaliplatin-containing chemotherapy for colorectal cancer. PATIENTS AND METHODS: We carried out secondary analysis of data from the SCOT randomised controlled trial. SCOT compared 3 months to 6 months of oxaliplatin-containing adjuvant chemotherapy in 6088 people with colorectal cancer recruited between March 2008 and November 2013. Two different chemotherapy regimens were used: capecitabine with oxaliplatin (CAPOX) or fluorouracil with oxaliplatin (FOLFOX). CIPN was recorded with the Functional Assessment of Cancer Therapy/Gynaecologic Oncology Group-Neurotoxicity 4 tool in 2871 participants from baseline (randomisation) for up to 8 years. Longitudinal trends in CIPN [averages with 95% confidence intervals (CIs)] were plotted stratified by the investigated factors. Analysis of covariance (ANCOVA) was used to analyse the association of factors with CIPN adjusting for the SCOT randomisation arm and oxaliplatin dose. P < 0.01 was adopted as cut-off for statistical significance to account for multiple testing. RESULTS: Patients receiving CAPOX had lower CIPN scores than those receiving FOLFOX. Chemotherapy regimen was associated with CIPN from 6 months (P < 0.001) to 2 years (P = 0.001). The adjusted ANCOVA coefficient for CAPOX at 6 months was -1.6 (95% CIs -2.2 to -0.9) and at 2 years it was -1.6 (95% CIs -2.5 to -0.7). People with baseline neuropathy scores ≥1 experienced higher CIPN than people with baseline neuropathy scores of 0 (P < 0.01 for all timepoints apart from 18 months). Age, sex, and body mass index did not link with CIPN. CONCLUSIONS: A neuropathy assessment before treatment with oxaliplatin can help identify people with an increased risk of CIPN. More research is needed to understand the CIPN-inducing effect of different chemotherapy regimens.

Uptake and incorporation of Al, Cr, V, Zn and Mo in hematite: Competition, synergies and influence on structural properties.

This study investigated multiple (di-, tri- and tetra-)incorporation of selected minor and trace elements (Al3+, Cr3+, V3-5+, Zn2+, Mo6+ and As5+) into hematite. The purpose was to improve understanding of how hematite may control trace element mobility in the environment, and how physical and chemical properties of hematite are impacted by multi-element incorporation at x/Fe molar ratios of up to 10%. Simultaneous structural incorporation of Al±Cr±V±Zn into hematite was achieved, with both synergistic and antagonistic effects occurring between certain element combinations. Cr+Al had synergistic effects on their co-incorporation, while V negatively affected Al incorporation, and both V and Zn negatively affected Cr incorporation. In contrast, Mo was minimally associated with hematite, and As prevented hematite formation completely. X-ray diffraction indicated contraction and expansion of the hematite unit-cell upon substitution was related to the ionic radius of the substituting element in single-element samples, while V predominantly controlled the direction of deviation in multi-element samples. X-ray absorption near-edge structure spectroscopy indicated V was present as a mixture of V3+-V5+, with a higher average V oxidation state associated with multi-element samples. Results provide new insights into trace element geochemistry within hematite, and highlight the importance of multi-element studies to better understand natural and anthropogenic systems.

CXD101 and nivolumab in patients with metastatic microsatellite-stable colorectal cancer (CAROSELL): a multicentre, open-label, single-arm, phase II trial.

BACKGROUND: Patients with microsatellite stable (MSS) colorectal carcinoma (CRC) do not respond to immune checkpoint inhibitors. Preclinical models suggested synergistic anti-tumour activity combining CXD101 and anti-programmed cell death protein 1 treatment; therefore, we assessed the clinical combination of CXD101 and nivolumab in heavily pre-treated patients with MSS metastatic CRC (mCRC). PATIENTS AND METHODS: This single-arm, open-label study enrolled patients aged 18 years or older with biopsy-confirmed MSS CRC; at least two lines of systemic anticancer therapies (including oxaliplatin and irinotecan); at least one measurable lesion; Eastern Cooperative Oncology Group performance status of 0, 1 or 2; predicted life expectancy above 3 months; and adequate organ and bone marrow function. Nine patients were enrolled in a safety run-in study to define a tolerable combination schedule of CXD101 and nivolumab, followed by 46 patients in the efficacy assessment phase. Patients in the efficacy assessment cohort were treated orally with 20 mg CXD101 twice daily for 5 consecutive days every 3 weeks, and intravenously with 240 mg nivolumab every 2 weeks. The primary endpoint was immune disease control rate (iDCR). RESULTS: Between 2018 and 2020, 55 patients were treated with CXD101 and nivolumab. The combination therapy was well tolerated with the most frequent grade 3 or 4 adverse events being neutropenia (18%) and anaemia (7%). Immune-related adverse reactions commonly ascribed to checkpoint inhibitors were surprisingly rare although we did see single cases of pneumonitis, hypothyroidism and hypopituitarism. There were no treatment-related deaths. Of 46 patients assessable for efficacy, 4 (9%) achieved partial response and 18 (39%) achieved stable disease, translating to an immune disease control rate of 48%. The median overall survival (OS) was 7.0 months (95% confidence interval 5.13-10.22 months). CONCLUSIONS: The primary endpoint was met in this phase II study, which showed that the combination of CXD101 and nivolumab, at full individual doses in the treatment of advanced or metastatic MSS CRC, was both well tolerated and efficacious.

A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202).

BACKGROUND: Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC. PATIENTS AND METHODS: Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% [95% confidence interval (CI) 7.6% to 22.5%], with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class. CONCLUSIONS: Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.

First-line trifluridine/tipiracil + bevacizumab in patients with unresectable metastatic colorectal cancer: final survival analysis in the TASCO1 study.

BACKGROUND: Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results. METHODS: TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m2 orally twice daily on days 1-5 and 8-12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m2 orally twice daily on days 1-14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS. RESULTS: At 1 September 2020, median OS was 22.3 months (95% CI: 18.0-23.7) with TT-B and 17.7 months (95% CI: 12.6-19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55-1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings. CONCLUSIONS: TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy. CLINICAL TRIAL INFORMATION: NCT02743221 (clinicaltrials.gov).

Clinico-pathological predictors of clinical complete response in rectal cancer.

PURPOSE: Prediction of clinical complete response in rectal cancer before neoadjuvant chemo-radiotherapy treatment enables treatment selection. Patients predicted to have complete response could have chemo-radiotherapy, and others could have additional doublet chemotherapy at this stage of their treatment to improve their overall outcome. This work investigates the role of clinical variables in predicting clinical complete response. METHOD: Using the UK-based OnCoRe database (2008 to 2019), we performed a propensity-score matched study of 322 patients who received neoadjuvant chemoradiotherapy. We collected pre-treatment clinic-pathological, inflammatory and radiotherapy-related characteristics. We determined the odds for the occurrence of cCR using conditional logistic regression models. We derived the post-model Area under the Curve (AUC) as an indicator of discrimination performance and stated a priori that an AUC of 0.75 or greater was required for potential clinical utility. RESULTS: Pre-treatment tumour diameter, mrT-stage, haemoglobin, alkaline phosphate and total radiotherapy depths were associated with cCR on univariable and multivariable analysis. Additionally, neutrophil to lymphocyte ratio (NLR), neutrophil-monocyte to lymphocyte ratio (NMLR), lymphocyte count and albumin were all significantly associated with cCR on multivariable analysis. A nomogram using the above parameters was developed with a resulting ROC AUC of 0.75. CONCLUSION: We identified routine clinic-pathological, inflammatory and radiotherapy-related variables which are independently associated with cCR. A nomogram was developed to predict cCR. The performance characteristics from this model were on the prior clinical utility threshold. Additional research is required to develop more associated variables to better select patients with rectal cancer undergoing chemoradiotherapy who may benefit from pursuing a W&W strategy.

Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study.

BACKGROUND: In preclinical studies trifluridine/tipiracil (FTD/TPI) plus oxaliplatin (Industriestrasse, Holzkirchen, Germany) sensitised microsatellite stable (MSS) metastatic colorectal cancer (mCRC) to anti-programmed cell death protein-1; the addition of oxaliplatin or bevacizumab (F Hoffmann- la ROCHE AG, Kaiseraugst, Switzerland) enhanced the antitumour effects of FTD/TPI. This study aimed to investigate the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab (Uxbridge business Park, Uxbridge, United Kingdom) in patients with mCRC who had progressed after at least one prior line of treatment. PATIENTS AND METHODS: In 14-day cycles, patients received FTD/TPI 35 mg/m2 (twice daily, days 1-5) plus oxaliplatin 85 mg/m2 (day 1), and, on day 1, either bevacizumab 5 mg/kg (cohort A) or nivolumab 3 mg/kg (cohort B). Patients in Cohort B had confirmed MSS status. RESULTS: In total, 54 patients were enrolled: 37 in cohort A and 17 in cohort B. Recruitment in cohort B was stopped early due to the low response rate (RR) observed at interim analyses of efficacy. The most common adverse events (AEs) in cohort A were neutropenia/decreased neutrophils (75.7%), nausea (59.5%), vomiting (40.5%), diarrhoea (37.8%), peripheral sensory neuropathy (37.8%), fatigue (35.1%) and decreased appetite (35.1%). In cohort B, the most common AEs were neutropenia/decreased neutrophils (70.6%), diarrhoea (58.8%), nausea (47.1%), vomiting (47.1%), fatigue (47.1%), asthenia (41.2%), paraesthesia (41.2%), thrombocytopenia/decreased platelets (35.3%) and decreased appetite (35.3%). Confirmed objective RR was 17.1% in cohort A and 7.1% in cohort B; the corresponding values for median progression-free survival in the two cohorts were 6.3 and 6.0 months. CONCLUSION: FTD/TPI plus oxaliplatin and bevacizumab or nivolumab had an acceptable safety profile and demonstrated antitumour activity in previously treated patients with mCRC.

Trifluridine/tipiracil plus bevacizumab in patients with untreated metastatic colorectal cancer ineligible for intensive therapy: the randomized TASCO1 study.

BACKGROUND: We designed an open-label, noncomparative phase II study to assess the safety and efficacy of first-line treatment with trifluridine/tipiracil plus bevacizumab (TT-B) and capecitabine plus bevacizumab (C-B) in untreated patients with unresectable metastatic colorectal cancer (mCRC) who were not candidates for combination with cytotoxic chemotherapies. PATIENTS AND METHODS: From 29 April 2016 to 29 March 2017, 153 patients were randomly assigned (1:1) to either TT-B (N = 77) or C-B (N = 76). The primary end point was progression-free survival (PFS). The primary PFS analysis was performed after 100 events (radiological progression or death) were observed. Secondary end points included overall survival (OS), quality of life (QoL; QLQ-C30 and QLQ-CR29 questionnaires), and safety. RESULTS: Median (range) duration of treatment was 7.8 (6.0-9.7) months and 6.2 (4.1-9.1) months in the TT-B and C-B groups, respectively. Median (range) PFS was 9.2 (7.6-11.6) and 7.8 (5.5-10.1) months, respectively. Median (range) OS was 18 (15.2 to NA) and 16.2 (12.5 to NA) months, respectively. QoL questionnaires showed no relevant changes over time for either treatment. Therapies were well tolerated. Patients receiving TT-B had more grade ≥3 neutropenia (47% versus 5% with C-B). Patients receiving C-B had more grade ≥3 hand-foot syndrome (12% versus 0% with TT-B) and grade ≥3 diarrhea (8% versus 1% with TT-B), consistent with the known safety profiles of these agents. CONCLUSION: TT-B treatment showed promising clinical activity in untreated patients with unresectable mCRC ineligible for intensive therapy, with an acceptable safety profile and no clinically relevant changes in QoL. CLINICAL TRIAL INFORMATION: NCT02743221 (ClinicalTrials.gov).

Beyond neurotransmission: acetylcholine in immunity and inflammation.

Acetylcholine (ACh) is best known as a neurotransmitter and was the first such molecule identified. ACh signalling in the neuronal cholinergic system has long been known to regulate numerous biological processes (reviewed by Beckmann and Lips). In actuality, ACh is a ubiquitous signalling molecule that is produced by numerous non-neuronal cell types and even by some single-celled organisms. Within multicellular organisms, a non-neuronal cholinergic system that includes the immune system functions in parallel with the neuronal cholinergic system. Several immune cell types both respond to ACh signals and can directly produce ACh. Recent work from our laboratory has demonstrated that the capacity to produce ACh is an intrinsic property of T cells responding to viral infection, and that this ability to produce ACh is dependent upon IL-21 signalling to the T cells. Furthermore, during infection this immune-derived ACh is necessary for the T cells to migrate into infected tissues. In this review, we will discuss the various sources of ACh that are relevant during immune responses and describe how ACh acts on immune cells to influence their functions. We will also address the clinical implications of this fascinating aspect of immunity, focusing on ACh's role in the migration of T cells during infection and cancer.

Novel phase I trial design to evaluate the addition of cediranib or selumetinib to preoperative chemoradiotherapy for locally advanced rectal cancer: the DREAMtherapy trial.

BACKGROUND: The DREAMtherapy (Dual REctal Angiogenesis MEK inhibition radiotherapy) trial is a novel intertwined design whereby two tyrosine kinase inhibitors (cediranib and selumetinib) were independently evaluated with rectal chemoradiotherapy (CRT) in an efficient manner to limit the extended follow-up period often required for radiotherapy studies. PATIENTS AND METHODS: Cediranib or selumetinib was commenced 10 days before and then continued with RT (45 Gy/25#/5 wks) and capecitabine (825 mg/m2 twice a day (BID)). When three patients in the cediranib 15-mg once daily (OD) cohort were in the surveillance period, recruitment to the selumetinib cohort commenced. This alternating schedule was followed throughout. Three cediranib (15, 20 and 30 mg OD) and two selumetinib cohorts (50 and 75 mg BID) were planned. Circulating and imaging biomarkers of inflammation/angiogenesis were evaluated. RESULTS: In case of cediranib, dose-limiting diarrhoea, fatigue and skin reactions were seen in the 30-mg OD cohort, and therefore, 20 mg OD was defined as the maximum tolerated dose. Forty-one percent patients achieved a clinical or pathological complete response (7/17), and 53% (9/17) had an excellent clinical or pathological response (ECPR). Significantly lower level of pre-treatment plasma tumour necrosis factor alpha (TNFα) was found in patients who had an ECPR. In case of selumetinib, the 50-mg BID cohort was poorly tolerated (fatigue and diarrhoea); a reduced dose cohort of 75-mg OD was opened which was also poorly tolerated, and further recruitment was abandoned. Of the 12 patients treated, two attained an ECPR (17%). CONCLUSIONS: This novel intertwined trial design is an effective way to independently investigate multiple agents with radiotherapy. The combination of cediranib with CRT was well tolerated with encouraging efficacy. TNFα emerged as a potential predictive biomarker of response and warrants further evaluation.

A model of gross primary productivity based on satellite data suggests formerly afforested peatlands undergoing restoration regain full photosynthesis capacity after five to ten years.

Peatlands are an important terrestrial carbon store, but disturbance has resulted in the degradation of many peatland ecosystems and caused them to act as a net carbon source. Restoration work is being undertaken but monitoring the success of these schemes can be difficult and costly using traditional field-based methods. A landscape-scale alternative is to use satellite data to assess the condition of peatlands and to estimate gaseous carbon fluxes. In this study we used Moderate Resolution Imaging Spectroradiometer (MODIS) products to model Gross Primary Productivity (GPP) over peatland sites at various stages of restoration. We found that the MOD17A2H GPP product overestimates GPP modelled from data collected by eddy covariance towers situated at two ex-forestry sites undergoing restoration towards blanket bog at the Forsinard Flows RSPB reserve, Scotland, UK (one full year of data), and a near-natural Atlantic blanket bog site in Glencar, Ireland (ten-year data series). We calibrated a Temperature and Greenness (TG) model for the Forsinard sites and found it to be more accurate than the MODIS GPP product at local scale. We also found that inclusion of a wetness factor using the Normalised Difference Water Index (NDWI) improved inter-annual accuracy of the model. This TGWa (annual Temperature, Greenness and Wetness) model was then applied to six control sites comprising near-natural bog across the reserve, and to six sites on which restoration began between 1998 and 2006. GPP from 2005 to 2016 was estimated for each site using the model. The resulting modelled trends are positive at all six restored sites, increasing by approximately 5.5 g C/m2/yr every year since restoration began in the Forsinard Flows reserve. The results suggest that peatland sites undergoing restoration at Forsinard Flows reach the carbon assimilation potential of near-natural bog sites between 5 and 10 years after restoration was begun.

Biomarker concordance between primary colorectal cancer and its metastases.

BACKGROUND: The use of biomarkers to target anti-EGFR treatments for metastatic colorectal cancer (CRC) is well-established, requiring molecular analysis of primary or metastatic biopsies. We aim to review concordance between primary CRC and its metastatic sites. METHODS: A systematic review and meta-analysis of all published studies (1991-2018) reporting on biomarker concordance between primary CRC and its metastatic site(s) was undertaken according to PRISMA guidelines using several medical databases. Studies without matched samples or using peripheral blood for biomarker analysis were excluded. FINDINGS: 61 studies including 3565 patient samples were included. Median biomarker concordance for KRAS (n = 50) was 93.7% [67-100], NRAS (n = 11) was 100% [90-100], BRAF (n = 22) was 99.4% [80-100], and PIK3CA (n = 17) was 93% [42-100]. Meta-analytic pooled discordance was 8% for KRAS (95% CI = 5-10%), 8% for BRAF (95% CI = 5-10%), 7% for PIK3CA (95% CI = 2-13%), and 28% overall (95% CI = 14-44%). The liver was the most commonly biopsied metastatic site (n = 2276), followed by lung (n = 438), lymph nodes (n = 1123), and peritoneum (n = 132). Median absolute concordance in multiple biomarkers was 81% (5-95%). INTERPRETATION: Metastatic CRC demonstrates high concordance across multiple biomarkers, suggesting that molecular testing of either the primary or liver and lung metastasis is adequate. More research on colorectal peritoneal metastases is required.

Return to emergency department after pediatric urology procedures.

BACKGROUND: Unplanned postoperative return visits to the emergency department (ED) and readmission represent a quality bench outcome and pose a considerable cost burden to health-care systems. OBJECTIVE: The aim of this study is to evaluate ED return visits after pediatric urology procedures in a tertiary care children's hospital, trying to identify potential causes. This may constitute a platform for future improvement areas. MATERIALS AND METHODS: A Quality Board-approved retrospective study was performed identifying all urologic cases completed between October 2012 and September 2015. Baseline demographics, American Society of Anesthesia class, operating surgeon, type of admission, type and duration of surgical procedure, and type of anesthesia given were evaluated. Patients who returned to the ED within 30 days of the surgery date were identified. The ED records were reviewed for time of return, etiology for visit, and management received. Univariate and subsequent multivariate logistic regression statistical analyses were performed to identify variables associated with ED return. Odds ratio (OR) and 95% confidence intervals (95% CIs) were generated to determine the significance of relationships. RESULTS: Total of 4125 cases was identified. Median age was 32.9 months, with 85.1% of them being male. 349 (8.5%) cases returned to the ED within 30 days of the surgery. The majority of the returned patients, 295 (84.5%), managed conservatively with medications or reassurance, whereas 54 (15.5%) required readmission, and of those readmitted, 15 (4.3%) cases needed further surgical interventions, mainly urinary tract drainage procedures. Multivariate logistic regression analysis identified that the age, residence, admission type, inguinoscrotal surgery, and duration of surgical procedure were significantly associated with ED return (Table). The most common reason for the ED visit was UTI in 17.2%, followed by stent and catheter issues in 14.3%, wound-related in 14.3%, and bleeding in 11.7%. DISCUSSION: Pediatric literature show varying rates of ED return ranging from 2.4% to 2.6% after urologic procedures. Our return to ED rate exceeds that found in US studies, which can perhaps be attributed to the differences between the Canadian and US health-care systems. As found with other studies, age, inpatient admission, procedure type, and increased operative time were related to ED returns, possibly because of the difficulty of young children expressing themselves and the presumed complex nature of longer operations that mostly need inpatient admission. The most common reason for ED return in this study as in others was presumptive UTI. A known limitation of this study is its retrospective nature, along with the possible missed visits of patients who presented to outside hospitals. CONCLUSION: We present an account of the status of ED return visits after pediatric urology procedures in our institute. The majority of ED returns can be managed conservatively and are probably preventable.

PATRIOT: A phase I study to assess the tolerability, safety and biological effects of a specific ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) as a single agent and in combination with palliative radiation therapy in patients with solid tumours.

PATRIOT is a phase I study of the ATR inhibitor, AZD6738, as monotherapy, and in combination with palliative radiotherapy. Here, we describe the protocol for this study, which opened in 2014 and is currently recruiting and comprises dose escalation of both drug and radiotherapy, and expansion cohorts.

Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study.

Background: Angiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies. Patients and methods: Eligible patients (Eastern Cooperative Oncology Group performance status 0-1, with histologically/cytologically confirmed metastatic/locally advanced CRC adenocarcinoma unamenable to surgery and/or radiotherapy) were randomized 1 : 1 to receive nintedanib (200 mg twice daily) or placebo (twice daily), until disease progression or undue toxicity. Patients were stratified by previous regorafenib, time from onset of metastatic disease to randomization, and region. Co-primary end points were overall survival (OS) and progression-free survival (PFS) by central review. Secondary end points included objective tumor response and disease control by central review. Results: From October 2014 to January 2016, 768 patients were randomized; 765 were treated (nintedanib n = 384; placebo n = 381). Median follow-up was 13.4 months (interquartile range 11.1-15.7). OS was not improved [median OS 6.4 months with nintedanib versus 6.0 months with placebo; hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.86-1.19; P = 0.8659]. There was a significant but modest increase in PFS with nintedanib versus placebo (median PFS 1.5 versus 1.4 months, respectively; HR 0.58; 95% CI 0.49-0.69; P < 0.0001). There were no complete or partial responses. Adverse events (AEs) occurred in 97% of 384 nintedanib-treated patients and 93% of 381 placebo-treated patients. The most frequent grade ≥3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%). Conclusions: The study failed to meet both co-primary end points. Nintedanib did not improve OS and was associated with a significant but modest increase in PFS versus placebo. Nintedanib was well tolerated. ClinicalTrials.gov number: NCT02149108 (LUME-Colon 1).

Estimating terrestrial gross primary productivity in water limited ecosystems across Africa using the Southampton Carbon Flux (SCARF) model.

The amount of carbon uptake by vegetation is an important component to understand the functioning of ecosystem processes and their response/feedback to climate. Recently, a new diagnostic model called the Southampton Carbon Flux (SCARF) Model driven by remote sensing data was developed to predict terrestrial gross primary productivity (GPP) and successfully applied in temperate regions. The model is based on the concept of quantum yield of plants and improves on the previous diagnostic models by (i) using the fraction of photosynthetic active radiation absorbed by the photosynthetic pigment (FAPARps) and (ii) using direct quantum yield by classifying the vegetation into C3 or C4 classes. In this paper, we calibrated and applied the model to evaluate GPP across various ecosystems in Africa. The performance of the model was evaluated using data from seven eddy covariance flux tower sites. Overall, the modelled GPP values showed good correlation (R>0.59, p<0.0001) with estimated flux tower GPP at most sites (except at a tropical rainforest site, R=0.38, p=0.02) in terms of their seasonality and absolute values. Mean daily GPP across the investigated period varied significantly across sites depending on the vegetation types from a minimum of 0.44gCm-2day-1 at the semi-arid and sub-humid savanna grassland sites to a maximum of 9.86gCm-2day-1 at the woodland and tropical rain forest sites. Generally, strong correlation is observed in savanna woodlands and grasslands where vegetation follows a prescribed seasonal cycle as determined by changes in canopy chlorophyll content and leaf area index. Finally, the mean annual GPP value for Africa predicted by the model was 35.25PgCyr-1. The good performance of the SCARF model in water-limited ecosystems across Africa extends its potential for global application.

Mineralisation of filamentous cyanobacteria in Lake Thetis stromatolites, Western Australia.

Stromatolites are cited as some of the earliest evidence for life on Earth, but problems remain in reconciling the paucity of microfossils in ancient carbonate examples with the abundance of microbes that help construct modern analogues. Here, we trace the mineralisation pathway of filamentous cyanobacteria within stromatolites from Lake Thetis, Western Australia, providing new insights into microfossil preservation in carbonate stromatolites. Lake Thetis cyanobacteria exhibit a spectrum of mineralisation processes that include early precipitation of Mg-silicates, largely controlled by the morphochemical features of the cyanobacteria, followed by aragonite formation that is inferred to be driven by heterotrophic activity. Fossilised cyanobacteria with high-quality morphological preservation are characterised by a significant volume of authigenic Mg-silicates, which have preferentially nucleated in/on extracellular organic material and on cell walls, and now replicate the region once occupied by the cyanobacterial sheath. In such specimens, aragonite is restricted to the outer sheath margin and parts of the cell interior. Cyanobacteria that display more significant degradation appear to possess a higher ratio of aragonite to Mg-silicate. In these specimens, aragonite forms micronodules in the sheath zone and is spatially associated with the inferred remains of heterotrophic bacteria. Aragonite also occurs as an advancing front from the outer margin of the sheath where it is commonly intergrown with Mg-silicates. Where there is no evidence of Mg-silicates within filaments, the fidelity of microfossil preservation is poor. In these cases, individual filaments may no longer be visible under light microscopy, and little organic material remains, but filament traces remain detectable using electron microscopy due to variations in aragonite texture. These data provide further evidence that authigenic silicate minerals play a crucial role in the fossilisation of micro-organisms; in their absence, carbonate crystal growth potentially mediated by heterotrophic microbial decay may largely obliterate morphological evidence for life within stromatolites, although mineralogical traces may still be detectable using electron microscopy.