Viability and dormancy of the Clematis vitalba aerial seed bank.

Old man's beard (Clematis vitalba L.) is a liana species that has become invasive in many areas of its introduced range. Seeds are produced in abundance and are both physiologically and morphologically dormant upon maturity. To understand the importance of seeds to its invasiveness, changes in viability and dormancy of the aerial seed bank were tracked throughout the after-ripening period and during storage. Seeds collected every second month for 2 years were subjected to germination tests. Other seeds stored in outdoor ambient conditions or in a dry, chilled state were dissected before, during, and after imbibition, as well as during incubation, to measure embryo size. Less than 72% of seeds on the mother plant were viable. Viable seeds remained completely morpho-physiologically dormant throughout autumn, even when treated with nitrate. Physiological dormancy declined in response to seasonal changes, yet morphological dormancy did not change until seeds had been exposed to appropriate germination conditions for several days. Fully dormant autumn seeds decayed at higher rates during incubation than partially or fully after-ripened seeds, which were also more germinable and less dormant. Furthermore, seeds incubated in complete darkness were more likely to decay or remain dormant than those exposed to light. This study demonstrates that fewer than three-quarters of seeds produced are viable and further decay occurs after dispersal, yet total fertility is still very high, with enormous propagule pressure from seeds alone. Viable seeds are protected with two forms of dormancy; morphological dormancy requires additional germination cues in order to break after seasonal changes break physiological dormancy.

Pembrolizumab versus methotrexate, docetaxel, or cetuximab in recurrent or metastatic head and neck squamous cell carcinoma (KEYNOTE-040): Subgroup analysis by pattern of disease recurrence.

BACKGROUND: In the phase 3 KEYNOTE-040 study, pembrolizumab prolonged OS versus chemotherapy in previously treated recurrent or metastatic (R/M) HNSCC. We present a post hoc subgroup analysis by disease recurrence pattern: recurrent-only, recurrent and metastatic (recurrent-metastatic), and metastatic-only HNSCC. MATERIALS AND METHODS: Patients had HNSCC that progressed during or after platinum-containing treatment for R/M disease or had recurrence or progression within 3-6 months of previous platinum-containing definitive therapy for locally advanced disease. Patients were randomly assigned (1:1) to pembrolizumab 200 mg Q3W or investigator's choice of standards of care (SOC): methotrexate, docetaxel, or cetuximab. Outcomes included OS, PFS, ORR, and DOR. The data cutoff was May 15, 2017. RESULTS: There were 125 patients (pembrolizumab, 53; SOC, 72) in the recurrent-only subgroup, 204 in the recurrent-metastatic subgroup (pembrolizumab, 108; SOC, 96), and 166 in the metastatic-only subgroup (pembrolizumab, 86; SOC, 80). The hazard ratio (95% CI) for death for pembrolizumab versus SOC was 0.83 (0.55-1.25) in the recurrent-only, 0.78 (0.58-1.06) in the recurrent-metastatic, and 0.74 (0.52-1.05) in the metastatic-only subgroups. PFS was similar between treatment arms in all subgroups. ORR was 22.6% for pembrolizumab versus 16.7% for SOC in the recurrent-only, 10.2% versus 6.3% in the recurrent-metastatic, and 15.1% versus 8.8% in the metastatic-only subgroups. DOR was numerically longer with pembrolizumab in all subgroups. CONCLUSION: Pembrolizumab provided numerically longer OS and durable responses in all subgroups compared with SOC, suggesting that patients with previously treated R/M HNSCC benefit from pembrolizumab regardless of recurrence pattern.

COVID-19 in cancer patients: update from the joint analysis of the ESMO-CoCARE, BSMO, and PSMO international databases.

BACKGROUND: COVID-19 has significantly affected patients with cancer and revealed unanticipated challenges in securing optimal cancer care across different disciplines. The European Society for Medical Oncology COVID-19 and CAncer REgistry (ESMO-CoCARE) is an international, real-world database, collecting data on the natural history, management, and outcomes of patients with cancer and SARS-CoV-2 infection. METHODS: This is the 2nd CoCARE analysis, jointly with Belgian (Belgian Society of Medical Oncology, BSMO) and Portuguese (Portuguese Society of Medical Oncology, PSMO) registries, with data from January 2020 to December 2021. The aim is to identify significant prognostic factors for COVID-19 hospitalization and mortality (primary outcomes), as well as intensive care unit admission and overall survival (OS) (secondary outcomes). Subgroup analyses by pandemic phase and vaccination status were carried out. RESULTS: The cohort includes 3294 patients (CoCARE: 2049; BSMO: 928, all hospitalized by eligibility criteria; PSMO: 317), diagnosed in four distinct pandemic phases (January to May 2020: 36%; June to September 2020: 9%; October 2020 to February 2021: 41%; March to December 2021: 12%). COVID-19 hospitalization rate was 54% (CoCARE/PSMO), ICU admission 14%, and COVID-19 mortality 22% (all data). At a 6-month median follow-up, 1013 deaths were recorded with 73% 3-month OS rate. No significant change was observed in COVID-19 mortality among hospitalized patients across the four pandemic phases (30%-33%). Hospitalizations and ICU admission decreased significantly (from 78% to 34% and 16% to 10%, respectively). Among 1522 patients with known vaccination status at COVID-19 diagnosis, 70% were non-vaccinated, 24% had incomplete vaccination, and 7% complete vaccination. Complete vaccination had a protective effect on hospitalization (odds ratio = 0.24; 95% confidence interval [0.14-0.38]), ICU admission (odds ratio = 0.29 [0.09-0.94]), and OS (hazard ratio = 0.39 [0.20-0.76]). In multivariable analyses, COVID-19 hospitalization was associated with patient/cancer characteristics, the first pandemic phase, the presence of COVID-19-related symptoms or inflammatory biomarkers, whereas COVID-19 mortality was significantly higher in symptomatic patients, males, older age, ethnicity other than Asian/Caucasian, Eastern Cooperative Oncology Group performance status ≥2, body mass index <25, hematological malignancy, progressive disease versus no evident disease, and advanced cancer stage. CONCLUSIONS: The updated CoCARE analysis, jointly with BSMO and PSMO, highlights factors that significantly affect COVID-19 outcomes, providing actionable clues for further reducing mortality.

Durvalumab with or without tremelimumab versus the EXTREME regimen as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck: KESTREL, a randomized, open-label, phase III study.

BACKGROUND: Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis. The phase III KESTREL study evaluated the efficacy of durvalumab [programmed death-ligand 1 (PD-L1) antibody] with or without tremelimumab [cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody], versus the EXTREME regimen in patients with R/M HNSCC. PATIENTS AND METHODS: Patients with HNSCC who had not received prior systemic treatment for R/M disease were randomized (2 : 1 : 1) to receive durvalumab 1500 mg every 4 weeks (Q4W) plus tremelimumab 75 mg Q4W (up to four doses), durvalumab monotherapy 1500 mg Q4W, or the EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) until disease progression. Durvalumab efficacy, with or without tremelimumab, versus the EXTREME regimen in patients with PD-L1-high tumors and in all randomized patients was assessed. Safety was also assessed. RESULTS: Durvalumab and durvalumab plus tremelimumab were not superior to EXTREME for overall survival (OS) in patients with PD-L1-high expression [median, 10.9 and 11.2 versus 10.9 months, respectively; hazard ratio (HR) = 0.96; 95% confidence interval (CI) 0.69-1.32; P = 0.787 and HR = 1.05; 95% CI 0.80-1.39, respectively]. Durvalumab and durvalumab plus tremelimumab prolonged duration of response versus EXTREME (49.3% and 48.1% versus 9.8% of patients remaining in response at 12 months), correlating with long-term OS for responding patients; however, median progression-free survival was longer with EXTREME (2.8 and 2.8 versus 5.4 months). Exploratory analyses suggested that subsequent immunotherapy use by 24.3% of patients in the EXTREME regimen arm contributed to the similar OS outcomes between arms. Grade 3/4 treatment-related adverse events (TRAEs) for durvalumab, durvalumab plus tremelimumab, and EXTREME were 8.9%, 19.1%, and 53.1%, respectively. CONCLUSIONS: In patients with PD-L1-high expression, OS was comparable between durvalumab and the EXTREME regimen. Durvalumab alone, and with tremelimumab, demonstrated durable responses and reduced TRAEs versus the EXTREME regimen in R/M HNSCC.

COVID-19 in patients with cancer: first report of the ESMO international, registry-based, cohort study (ESMO-CoCARE).

BACKGROUND: ESMO COVID-19 and CAncer REgistry (ESMO-CoCARE) is an international collaborative registry-based, cohort study gathering real-world data from Europe, Asia/Oceania and Africa on the natural history, management and outcomes of patients with cancer infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). PATIENTS AND METHODS: ESMO-CoCARE captures information on patients with solid/haematological malignancies, diagnosed with coronavirus disease 2019 (COVID-19). Data collected since June 2020 include demographics, comorbidities, laboratory measurements, cancer characteristics, COVID-19 clinical features, management and outcome. Parameters influencing COVID-19 severity/recovery were investigated as well as factors associated with overall survival (OS) upon SARS-CoV-2 infection. RESULTS: This analysis includes 1626 patients from 20 countries (87% from 24 European, 7% from 5 North African, 6% from 8 Asian/Oceanian centres), with COVID-19 diagnosis from January 2020 to May 2021. Median age was 64 years, with 52% of female, 57% of cancer stage III/IV and 65% receiving active cancer treatment. Nearly 64% patients required hospitalization due to COVID-19 diagnosis, with 11% receiving intensive care. In multivariable analysis, male sex, older age, Eastern Cooperative Oncology Group (ECOG) performance status ≥2, body mass index (BMI) <25 kg/m2, presence of comorbidities, symptomatic disease, as well as haematological malignancies, active/progressive cancer, neutrophil-to-lymphocyte ratio (NLR) ≥6 and OnCovid Inflammatory Score ≤40 were associated with COVID-19 severity (i.e. severe/moderate disease requiring hospitalization). About 98% of patients with mild COVID-19 recovered, as opposed to 71% with severe/moderate disease. Advanced cancer stage was an additional adverse prognostic factor for recovery. At data cut-off, and with median follow-up of 3 months, the COVID-19-related death rate was 24.5% (297/1212), with 380 deaths recorded in total. Almost all factors associated with COVID-19 severity, except for BMI and NLR, were also predictive of inferior OS, along with smoking and non-Asian ethnicity. CONCLUSIONS: Selected patient and cancer characteristics related to sex, ethnicity, poor fitness, comorbidities, inflammation and active malignancy predict for severe/moderate disease and adverse outcomes from COVID-19 in patients with cancer.

OX40 and 4-1BB delineate distinct immune profiles in sarcoma.

Systemic relapse after radiotherapy and surgery is the major cause of disease-related mortality in sarcoma patients. Combining radiotherapy and immunotherapy is under investigation as a means to improve response rates. However, the immune contexture of sarcoma is understudied. Here, we use a retrospective cohort of sarcoma patients, treated with neoadjuvant radiotherapy, and TCGA data. We explore therapeutic targets of relevance to sarcoma, using genomics and multispectral immunohistochemistry to provide insights into the tumor immune microenvironment across sarcoma subtypes. Differential gene expression between radioresponsive myxoid liposarcoma (MLPS) and more radioresistant undifferentiated pleomorphic sarcoma (UPS) indicated UPS contained higher transcript levels of a number of immunotherapy targets (CD73/NT5E, CD39/ENTPD1, CD25/IL2RA, and 4-1BB/TNFRSF9). We focused on 4-1BB/TNFRSF9 and other costimulatory molecules. In TCGA data, 4-1BB correlated to an inflamed and exhausted phenotype. OX40/TNFRSF4 and 4-1BB/TNFRSF9 were highly expressed in sarcoma subtypes versus other cancers. Despite OX40 and 4-1BB being described as Treg markers, we identified that they delineate distinct tumor immune profiles. This was true for sarcoma and other cancers. While only a limited number of samples could be analyzed, spatial analysis of OX40 expression identified two diverse phenotypes of OX40+ Tregs, one associated with and one independent of tertiary lymphoid structures (TLSs). Patient stratification is of intense interest for immunotherapies. We provide data supporting the viewpoint that a cohort of sarcoma patients, appropriately selected, are promising candidates for immunotherapies. Spatial profiling of OX40+ Tregs, in relation to TLSs, could be an additional metric to improve future patient stratification.

Re-evaluating the Economic Injury Level for Alfalfa Weevil (Coleoptera: Curculionidae) Control in Low Desert Irrigated Alfalfa.

Alfalfa (Medicago sativa L.) dominates cropping systems in the Western United States and is first in terms of acreage planted in Arizona. The alfalfa weevil, Hypera postica (Gylenhall) and/or Hypera brunneipennis (Boheman), respectively, is the most destructive pest in terms of yield loss in low desert-grown alfalfa hay. The current economic threshold of 15-20 larvae per sweep, established in California in 1975, is currently not suitable or adopted by growers in the western U.S. low desert. Here, we conducted 4 yr of field trials to re-evaluate this economic threshold. Supporting observations of agricultural growers and professionals in the region, our results indicate that the economic threshold established in 1975 is too high. Specifically, one to three large larvae often cause a significant decrease in yield justifying weevil control based on current hay prices and costs of insecticide application. These results are discussed in the context of sustainable alfalfa production in the western U.S. low desert.

Molecular characteristics of the first case of haloxyfop-resistant Poa annua.

Haloxyfop is one of two acetyl-coenzyme A carboxylase (ACCase) inhibitors that is recommended for controlling Poa annua. We have characterised a population of P. annua that had developed resistance to haloxyfop. This resistant population was found to be almost 20 times less sensitive to haloxyfop than a susceptible population based on percentage survival of individuals in two dose-response experiments. However, the haloxyfop-resistant population was still susceptible to clethodim. Pre-treatment of resistant individuals with a cytochrome P450 inhibitor, malathion, did not change the sensitivity level of the resistant plants to haloxyfop, suggesting that a non-target site mechanism of resistance involving enhanced metabolism, was not responsible for this resistance in P. annua. Gene sequencing showed that a target site mutation at position 2041, which replaced isoleucine with threonine in the carboxyltransferase (CT) domain of the ACCase enzyme, was associated with resistance to haloxyfop in the resistant population. An evaluation of the 3-D structure of the CT domain suggested that, unlike Asn-2041, which is the most common mutation at this position reported to date, Thr-2041 does not change the conformational structure of the CT domain. This is the first study investigating the molecular mechanism involved with haloxyfop resistance in P. annua.

Time spent outside of target glucose range for young children with type 1 diabetes: a continuous glucose monitor study.

AIM: To assess the associations between demographic and clinical characteristics and sensor glucose metrics in young children with type 1 diabetes, using masked, continuous glucose monitoring data from children aged 2 to < 8 years. RESEARCH DESIGN AND METHODS: The analysis included 143 children across 14 sites in the USA, enrolled in a separate clinical trial. Eligibility criteria were: age 2 to <8 years; type 1 diabetes duration ≥3 months; no continuous glucose monitoring use for past 30 days; and HbA1c concentration 53 to <86 mmol/mol (7.0 to <10.0%). All participants wore masked continuous glucose monitors up to 14 days. RESULTS: On average, participants spent the majority (13 h) of the day in hyperglycaemia (>10.0 mmol/l) and a median of ~1 h/day in hypoglycaemia (<3.9 mmol/l). Participants with minority race/ethnicity and higher parent education levels spent more time in target range, 3.9-10.0 mmol/l, and less time in hyperglycaemia. More time in hypoglycaemia was associated with minority race/ethnicity and younger age at diagnosis. Continuous glucose monitoring metrics were similar in pump and injection users. CONCLUSIONS: Given that both hypo- and hyperglycaemia negatively impact neurocognitive development, strategies to increase time in target glucose range for young children are needed.

High-resolution air-clad imaging fibers.

We present a coherent fiber bundle comprising over 11,000 doped silica cores separated by an air-filled cladding. The fiber is characterized, and its imaging quality is shown to be a substantial improvement over the commercial state of the art, with comparable resolution over an unparalleled spectral range.

Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT).

A European Society for Medical Oncology (ESMO)-sponsored expert meeting was held in Paris on 8 March 2018 which comprised 11 experts from academia, 11 experts from the pharmaceutical industry and 2 clinicians who were representatives of ESMO. The focus of the meeting was exclusively on the intratumoral injection/delivery of immunostimulatory agents with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies. The goal was to provide a reference document, endorsed by the panel members that could provide guidance to clinical investigators, pharmaceutical companies, ethics committees, independent review boards, patient advocates and the regulatory authorities and promote an increase in the number and quality of HIT-IT clinical trials in the future. Particular emphasis was placed not only on the development of precise definitions to facilitate a better understanding between investigators but also on the importance of systematic serial biopsies as a driver for translational research and the need for the recording and reporting of data, to facilitate a better understanding of the key processes involved.

Circulating tumour DNA is a potential biomarker for disease progression and response to targeted therapy in advanced thyroid cancer.

BACKGROUND: Conventional biomarkers in thyroid cancer are not disease specific and fluctuate in advanced disease, making interpretation difficult. Circulating tumour DNA (ctDNA) has been shown to be a useful biomarker in other solid tumours. This is a multimutational study of ctDNA over multiple timepoints, designed to test the hypothesis that ctDNA is a potential biomarker in patients with advanced thyroid cancer. METHODS: Mutational analysis of archival tumour tissue was performed using NGS with a targeted gene panel. Custom TaqMan assays were designed for plasma ctDNA testing using digital droplet polymerase chain reaction. Concentrations of detected ctDNA were correlated with the conventional biomarker concentration and axial imaging status defined by the Response Evaluation Criteria in Solid Tumours criteria. RESULTS: Tumour tissue from 51 patients was obtained, with the following histologies: 32 differentiated (differentiated thyroid cancer [DTC]), 15 medullary (medullary thyroid cancer [MTC]), three poorly differentiated and one anaplastic. NGS analysis detected variants in 42 (82%) of cases. Plasma was assayed for these patients in 190 samples, and ctDNA was detected in 67% of patients. Earlier detection of disease progression was noted in three patients with MTC. In two cases (PTC and ATC), where conventional biomarkers were not detectable, ctDNA was detected before disease progression. Changes in ctDNA concentration occurred earlier than conventional markers in response to disease progression in multiple patients with DTC receiving targeted therapies. CONCLUSION: The majority of patients with advanced thyroid cancer had detectable ctDNA. ctDNA measurement may offer superiority over conventional markers in several scenarios: earlier detection of progression in MTC; as an alternative biomarker when conventional markers are not available; more rapid assessment of the disease status in response to targeted therapies, thereby potentially allowing prompter discontinuation of futile therapies. These early results support the hypothesis that ctDNA may be a clinically useful biomarker in thyroid cancer.

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.

An Investigation of Dosimetric Correlates of Acute Toxicity in Prostate Stereotactic Body Radiotherapy: Dose to Urinary Trigone is Associated with Acute Urinary Toxicity.

AIMS: There are limited data on dosimetric correlates of toxicity in stereotactic body radiotherapy (SBRT) for prostate cancer. We aimed to identify potential relationships between dose and toxicity using conventional dose-volume histograms (DVHs) and dose-surface maps (DSMs). MATERIALS AND METHODS: Urinary bladder trigone and rectum DSMs were produced for a single-institution service evaluation cohort of 50 patients receiving SBRT for localised prostate cancer, together with conventional DVHs for bladder and rectum. Patients had been prospectively recruited to this cohort and treated according to a pre-defined protocol to a dose of 36.25 Gy in five fractions. Radiation Therapy Oncology Group (RTOG) and International Prostate Symptom Score (IPSS) toxicity data were recorded prospectively. Logistic regression was used to identify dosimetric predictors of acute IPSS+10 (rise of 10 points or more above baseline) and grade 2+ RTOG toxicity. RESULTS: On univariate analysis, trigone area receiving 40 Gy and trigone Dmax were associated with IPSS+10 (odds ratio 1.06 [1.02-1.11], P = 0.007 and odds ratio 1.54 [1.06-2.25], P = 0.024, respectively). These two variables were highly correlated. In a multivariate model, including all baseline variables, trigone Dmax remained associated with IPSS+10 (odds ratio 1.91 [1.13-3.22], P = 0.016). These findings were not significant with Holm-Bonferroni correction for multiple testing (corrected P value threshold 0.006). No associations were seen between rectal toxicity and DVH or DSM parameters. CONCLUSIONS: Our study suggests a potential relationship between high doses to the urinary bladder trigone and patient-reported urinary toxicity in prostate SBRT, and is consistent with previous studies in conventionally fractionated radiotherapy, justifying further evaluation in larger cohorts.

Intensity modulated radiotherapy in locally advanced thyroid cancer: Outcomes of a sequential phase I dose-escalation study.

BACKGROUND AND PURPOSE: To determine the safety and tolerability of dose-escalation using modestly accelerated IMRT in high-risk locally advanced thyroid cancer requiring post-operative radiotherapy, and to report preliminary data on efficacy. MATERIALS AND METHODS: A sequential Phase I dose-escalation design was used. Dose level one (DL1) received 58.8 Gy/28F to the post-operative bed and 50 Gy/28F to elective nodes. DL2 received 66.6 Gy/30F to the thyroid bed, 60 Gy/30F to post-operative nodal levels and 54 Gy/30F to elective nodal levels. Acute (NCICTCv.2.0) and late toxicities (RTOG and modified LENTSOM) were recorded. The primary endpoint was the number of patients with ≥Grade 3 (G3) toxicity at 12 months post-treatment. RESULTS: Fifteen patients were recruited to DL1 and twenty-nine to DL2. At 12 months ≥G3 toxicities were 8.3% in both DL1 and DL2. At 60 months, ≥G3 toxicity was reported in 3 (33%) patients in DL1 and 1 (7%) in DL2. One patient in DL2 died at 24 months from radiation-induced toxicity. Time to relapse and overall survival rates were higher in DL2, but this was not statistically significant. Dose-escalation using this accelerated regimen can be safely performed with a toxicity profile similar to reported series using conventional doses.