Southern Ocean phytoplankton dynamics and carbon export: insights from a seasonal cycle approach.

Quantifying the strength and efficiency of the Southern Ocean biological carbon pump (BCP) and its response to predicted changes in the Earth's climate is fundamental to our ability to predict long-term changes in the global carbon cycle and, by extension, the impact of continued anthropogenic perturbation of atmospheric CO2. There is little agreement, however, in climate model projections of the sensitivity of the Southern Ocean BCP to climate change, with a lack of consensus in even the direction of predicted change, highlighting a gap in our understanding of a major planetary carbon flux. In this review, we summarize relevant research that highlights the important role of fine-scale dynamics (both temporal and spatial) that link physical forcing mechanisms to biogeochemical responses that impact the characteristics of the seasonal cycle of phytoplankton and by extension the BCP. This approach highlights the potential for integrating autonomous and remote sensing observations of fine scale dynamics to derive regionally optimized biogeochemical parameterizations for Southern Ocean models. Ongoing development in both the observational and modelling fields will generate new insights into Southern Ocean ecosystem function for improved predictions of the sensitivity of the Southern Ocean BCP to climate change. This article is part of a discussion meeting issue 'Heat and carbon uptake in the Southern Ocean: the state of the art and future priorities'.

Catheter-related thrombosis incidence and risk factors in adult cancer patients with central venous access devices.

BACKGROUND: Central venous access devices (CVAD) are commonly employed in the management of cancer patients. While having several benefits they are associated with significant risks. AIM: To review the incidence and risk factors for catheter-related thrombosis (CRT) in cancer patients with a CVAD. METHODS: We performed a prospective observational cohort study of adult patients with cancer requiring a CVAD between 1 January 2004 and 29 June 2016. The rate of, and risk factors for the development of, symptomatic CRT were evaluated. RESULTS: A total of 4920 central lines was inserted into 3130 patients. The incidence of CRT was 3.6%. CRT developed a median of 12 days following line insertion. Peripherally inserted central catheters (PICC) were associated with the highest rates of CRT (hazards ratio (HR) 22.2, 95% confidence interval (CI) 2.9-170.6). Older age groups developed CRT at lower rates (HR 0.57; 95% CI 0.39-0.84 for age 50-61 years, and HR 0.63; 95% CI 0.45-0.89 for age >61 years) compared to age <50 years. Increased CRT was seen in patients with prior CRT (HR 1.81; 95% CI 1.19-2.77). There was a trend to more CRT events with a Khorana tumour score of 1 compared to those with a score of 0 (HR 1.37, 95% CI 1.00-1.88). Hodgkin lymphoma, germ cell and oesophagus cancers had the highest CRT rates. Side of insertion was not associated with thrombosis risk (HR 0.77; 95% CI 0.57-1.05; P = 0.10). CONCLUSIONS: Age <50 years, PICC lines and prior CRT were associated with highest CRT rate. Cancer subtype and insertion side were not predictive of thrombosis.

Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trial.

BACKGROUND: Alveolar soft-part sarcoma (ASPS) is a rare soft-tissue sarcoma that is unresponsive to chemotherapy. Cediranib, a tyrosine-kinase inhibitor, has shown substantial activity in ASPS in non-randomised studies. The Cediranib in Alveolar Soft Part Sarcoma (CASPS) study was designed to discriminate the effect of cediranib from the intrinsically indolent nature of ASPS. METHODS: In this double-blind, placebo-controlled, randomised, phase 2 trial, we recruited participants from 12 hospitals in the UK (n=7), Spain (n=3), and Australia (n=2). Patients were eligible if they were aged 16 years or older; metastatic ASPS that had progressed in the previous 6 months; had an ECOG performance status of 0-1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function. Participants had to have no anti-cancer treatment within 4 weeks before trial entry, with exception of palliative radiotherapy. Participants were randomly assigned (2:1), with allocation by use of computer-generated random permuted blocks of six, to either cediranib (30 mg orally, once daily) or matching placebo tablets for 24 weeks. Treatment was supplied in number-coded bottles, masking participants and clinicians to assignment. Participants were unblinded at week 24 or sooner if they had progression defined by Response Evaluation Criteria in Solid Tumors (version 1.1); those on placebo crossed over to cediranib and all participants continued on treatment until progression or death. The primary endpoint was percentage change in sum of target marker lesion diameters between baseline and week 24 or progression if sooner, assessed in the evaluable population (all randomly assigned participants who had a scan at week 24 [or sooner if they progressed] with target marker lesions measured). Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01337401; the European Clinical Trials database, number EudraCT2010-021163-33; and the ISRCTN registry, number ISRCTN63733470 recruitment is complete and follow-up is ongoing. FINDINGS: Between July 15, 2011, and July 29, 2016, of 48 participants recruited, all were randomly assigned to cediranib (n=32) or placebo (n=16). 23 (48%) were female and the median age was 31 years (IQR 27-45). Median follow-up was 34·3 months (IQR 23·7-55·6) at the time of data cutoff for these analyses (April 11, 2018). Four participants in the cediranib group were not evaluable for the primary endpoint (one did not start treatment, and three did not have their scan at 24 weeks). Median percentage change in sum of target marker lesion diameters for the evaluable population was -8·3% (IQR -26·5 to 5·9) with cediranib versus 13·4% (IQR 1·1 to 21·3) with placebo (one-sided p=0·0010). The most common grade 3 adverse events on (blinded) cediranib were hypertension (six [19%] of 31) and diarrhoea (two [6%]). 15 serious adverse reactions in 12 patients were reported; 12 of these reactions occurred on open-label cediranib, and the most common symptoms were dehydration (n=2), vomiting (n=2), and proteinuria (n=2). One probable treatment-related death (intracranial haemorrhage) occurred 41 days after starting open-label cediranib in a patient who was assigned to placebo in the masked phase. INTERPRETATION: Given the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors. FUNDING: Cancer Research UK and AstraZeneca.

Atmospheric HCFC-22, HFC-125, and HFC-152a at Cape Point, South Africa.

One hydrochlorofluorocarbon and two hydrofluorocarbons (HCFC-22, HFC-125, and HFC-152a) were measured in air samples at the Cape Point observatory (CPT), South Africa, during 2017. These data represent the first such atmospheric measurements of these compounds from southwestern South Africa (SWSA). Baseline atmospheric growth rates were estimated to be 8.36, 4.10, and 0.71 ppt year-1 for HCFC-22, HFC-125, and HFC-152a, respectively. The CPT measurements were combined with an inverse model to investigate emissions from SWSA. For all three halocarbons, Cape Town was found to be the dominant source within SWSA. These estimates were extrapolated, based on population statistics, to estimate emissions for the whole of South Africa. We estimate South Africa's 2017 emissions to be 3.0 (1.6-4.4), 0.8 (0.5-1.2), and 1.1 (0.6-1.6) Gg year-1 for HCFC-22, HFC-125, and HFC-152a, respectively. For all three halocarbons, South Africa's contribution to global emissions is small (<2.5%), but future monitoring is needed to ensure South Africa's compliance with regulation set out by the Montreal Protocol and its Amendments.

Neoadjuvant chemotherapy or chemoradiotherapy for adenocarcinoma of the esophagus.

BACKGROUND: The optimal treatment strategy for patients with esophageal adenocarcinoma (EAC) remains undetermined. This study compared outcomes in patients undergoing neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) for EAC. METHODS: Patients who underwent nCT or nCRT followed by surgery for EAC were identified from a prospective database (2000-2017) and included. After propensity score matching, the impact of the treatments on postoperative complications, in-hospital mortality, pathological outcomes, and survival rates were compared. RESULTS: Of the 396 eligible patients, 262 patients were analysed following matching with 131 patients in both groups. There were no significant differences between the nCT and nCRT groups for overall complications (59% vs 57%, P = 0.802) or in-hospital mortality (2% vs 0%, P = 0.156). Patients who had nCRT had more R0 resections (93% vs 83%, P = 0.013), and higher pathological complete response rates (15% vs 5%, P < 0.001). No differences in 5-year overall survival rates (nCT vs nCRT; 44% vs 33%, P = 0.645) were found. CONCLUSION: In this study no differences between nCT and nCRT were seen in postoperative complications and in-hospital mortality in patients treated for EAC. Inspite of improved complete resection and pathological response there was no difference in the overall survival between the treatment modalities.

Patterns of care for patients with advanced soft tissue sarcoma: experience from Australian sarcoma services.

BACKGROUND: There is a paucity of data on the current management of patients with advanced soft tissue sarcoma (STS) in the Australian health care setting. This study utilised the Australian sarcoma database to evaluate the patterns of care delivered to patients with advanced STS at Australian sarcoma services. METHODS: Prospectively collected data from six sarcoma centres in Australia were sourced to identify patients diagnosed with advanced STS between 1 January 2010 and 31 December 2012. Descriptive statistics were analysed for patient demographics, clinicopathological characteristics and treatment patterns. Overall survival was estimated using the Kaplan-Meier product limit method. RESULTS: Of 253 patients with advanced STS, four major STS subtypes were identified: undifferentiated pleomorphic sarcoma (23 %), leiomyosarcoma (17 %), liposarcoma (14 %), and synovial sarcoma (8 %); with the rest grouped as "other STS" (38 %). Approximately one-third of patients received palliative systemic therapy with the most common first-line therapy being doxorubicin alone (50 %). A small percentage of patients participated in clinical trials (20 %). Palliative radiotherapy was utilised mostly for treatment of symptomatic distant metastases and one-third of patients underwent metastasectomy, most commonly for pulmonary metastases. The median overall survival (OS) in this series was 18 months and no significant difference in OS was observed across different STS histological subtypes. CONCLUSIONS: This is the first detailed study outlining patterns of care for Australian patients with advanced STS managed at sarcoma services. These data highlight a particular area of weakness in the lack of clinical trials for sarcoma patients and also serve as an important reference point for understanding how practice may change over time as treatment options evolve.

ICECREAM: randomised phase II study of cetuximab alone or in combination with irinotecan in patients with metastatic colorectal cancer with either KRAS, NRAS, BRAF and PI3KCA wild type, or G13D mutated tumours.

BACKGROUND: Patients with metastatic colorectal cancer whose disease has progressed on oxaliplatin- and irinotecan-containing regimens may benefit from EGFR-inhibiting monoclonal antibodies if they do not contain mutations in the KRAS gene (are "wild type"). It is unknown whether these antibodies, such as cetuximab, are more efficacious in refractory metastatic colorectal cancer as monotherapy, or in combination with irinotecan. Lack of mutation in KRAS, BRAF and PIK3CA predicts response to EFGR-inhibitors. The ICECREAM trial examines the question of monotherapy versus combination with chemotherapy in two groups of patients: those with a "quadruple wild type" tumour genotype (no mutations in KRAS, NRAS, PI3KCA or BRAF genes) and those with the specific KRAS mutation in codon G13D, for whom possibly EGFR-inhibitor efficacy may be equivalent. METHODS AND DESIGN: ICECREAM is a randomised, phase II, open-label, controlled trial comparing the efficacy of cetuximab alone or with irinotecan in patients with "quadruple wild type" or G13D-mutated metastatic colorectal cancer, whose disease has progressed on, or who are intolerant of oxaliplatin- and fluoropyrimidine-based chemotherapy. The primary endpoint is the 6-month progression-free survival benefit of the treatment regimen. Secondary endpoints are response rate, overall survival, and quality of life. The tertiary endpoint is prediction of outcome with further biological markers. International collaboration has facilitated recruitment in this prospective trial of treatment in these infrequently found molecular subsets of colorectal cancer. DISCUSSION: This unique trial will yield prospective information on the efficacy of cetuximab and whether this is further enhanced with chemotherapy in two distinct populations of patients with metastatic colorectal cancer: the "quadruple wild type", which may 'superselect' for tumours sensitive to EGFR-inhibition, and the rare KRAS G13D mutated tumours, which are also postulated to be sensitive to the drug. The focus on establishing both positive and negative predictive factors for the response to targeted therapy is an attempt to improve outcomes, reduce toxicity and contain treatment costs. Tissue and blood will yield a resource for molecular studies. Recruitment, particularly of patients with the rare G13D mutation, will demonstrate the ability for international collaboration to run prospective trials in small colorectal cancer molecular subgroups. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12612000901808 , registered 16 August 2012.

Single institution retrospective review of perioperative chemotherapy in adult and adolescent patients with operable osteosarcoma.

AIMS: Perioperative chemotherapy has improved the prognosis for patients with operable osteosarcoma. The literature is conflicting about which regimen is optimal. The aim of this study was to evaluate the survival outcomes of two cohorts of patients with operable osteosarcoma treated with different perioperative chemotherapy regimens. METHODS: This was a retrospective review of patients diagnosed with operable osteosarcoma treated at the Princess Alexandra Hospital from 1986 to 2009. The standard perioperative chemotherapy regimen changed from the modified T10 Rosen protocol to cisplatin/doxorubicin in 1997. Using the Kaplan-Meier method, overall survival (OS) and disease-free survival (DFS) curves were generated for the cisplatin/doxorubicin and the modified T10 Rosen cohorts. RESULTS: Seventy-one patients were identified of whom 63 had potentially curable disease. Of these, 24 received the modified T10 Rosen regimen and 39 received cisplatin/doxorubicin. There was a non-significant trend toward better OS and DFS in the patients who received the modified T10 Rosen protocol. CONCLUSION: The trend toward poorer survival in the cisplatin/doxorubicin cohort, in combination with current evidence, has prompted our institution to change its practice.