IMPORTANCE Single-agent immune checkpoint inhibition has not shown activities in advanced refractory colorectal cancer (CRC), other than in those patients who are microsatellite-instability high (MSI-H).OBJECTIVE To evaluate whether combining programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition improved patient survival in metastatic refractory CRC. DESIGN, SETTING, AND PARTICIPANTSA randomized phase 2 study was conducted in 27 cancer centers across Canada between August 2016 and June 2017, and data were analyzed on October 18, 2018. Eligible patients had histologically confirmed adenocarcinoma of the colon or rectum; received all available standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab if appropriate; cetuximab or panitumumab if RAS wild-type tumors; regorafenib if available); were aged 18 years or older; had adequate organ function; had Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease.INTERVENTIONS We randomly assigned patients to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg durvalumab every 28 days, or best supportive care alone (BSC) in a 2:1 ratio. MAIN OUTCOMES AND MEASURESThe primary end point was overall survival (OS) and a 2-sided P<.10 was considered statistically significant. Circulating cell-free DNA from baseline plasma was used to determine microsatellite instability (MSI) and tumor mutation burden (TMB). RESULTSOf 180 patients enrolled (121 men [67.2%] and 59 women [32.8%]; median [range] age, 65 [36-87] years), 179 were treated. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (hazard ratio [HR], 0.72; 90% CI, 0.54-0.97; P = .07). Progression-free survival was 1.8 months and 1.9 months respectively (HR, 1.01; 90% CI, 0.76-1.34). Grade 3 or 4 adverse events were significantly more frequent with immunotherapy (75 [64%] patients in the treatment group had at least 1 grade 3 or higher adverse event vs 12 [20%] in the BSC group). Circulating cell-free DNA analysis was successful in 168 of 169 patients with available samples. In patients who were microsatellite stable (MSS), OS was significantly improved with durvalumab and tremelimumab (HR, 0.66; 90% CI, 0.49-0.89; P = .02). Patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) had the greatest OS benefit (HR, 0.34; 90% CI, 0.18-0.63; P = .004). CONCLUSIONS AND RELEVANCEThis phase 2 study suggests that combined immune checkpoint inhibition with durvalumab plus tremelimumab may be associated with prolonged OS in patients with advanced refractory CRC. Elevated plasma TMB may select patients most likely to benefit from durvalumab and tremelimumab. Further confirmation studies are warranted.

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Soil degradation by salinity and accumulation of trace elements such as cadmium (Cd) in the soils are expected to become one of the most critical issues hindering sustainable production and feeding the increasing population. Biochar (BC) has been known to protect the plants against soil salinity and heavy metal stress. A soil culture study was performed to evaluate the effect of BC on wheat (Triticum aestivum L.) growth, biomass, and reducing Cd and sodium (Na) uptake grown in Cd-contaminated saline soil under ambient conditions. Soil salinity decreased the plant growth, biomass, grain yield, chlorophyll contents, and gas exchange parameters and caused oxidative stress in plants compared with Cd stress alone. Salt stress increased Cd and Na uptake and reduced the potassium (K) and zinc (Zn) uptake by plants. AB-DTPA-extractable Cd and soil electrical conductivity (ECe) increased under salt stress compared to the soil without NaCl stress. Biochar application improved the plant growth and reduced the Cd and Na uptake except in plants treated with higher BC and salt stress (5.0% BC + 50 mM NaCl). Biochar application reduced the oxidative stress in plants and modified the antioxidant enzyme activities, and reduced the bioavailable Cd under salt stress. The positive effects of BC under lower salt stress while the negative effects of BC under higher BC and salt levels indicated that BC doses should be used with great care in higher soil salinity levels simultaneously contaminated with Cd to avoid the negative effects of BC on growth and metal uptake.

Trace elements (TEs) contamination is one of the main abiotic stresses which limit plant growth and deteriorate the food quality by their entry into food chain. In recent, biochar (BC) soil amendment has been widely reported for the reduction of TE(s) uptake and toxicity in plants. This review summarizes the role of BC in enhancing TE(s) tolerance in plants. Under TE(s) stress, BC application increased plant growth, biomass, photosynthetic pigments, grain yield, and quality. The key mechanisms evoked are immobilization of TE(s) in the soil, increase in soil pH, alteration of TE(s) redox state in the soil, and improvement in soil physical and biological properties under TE(s) stress. However, these mechanisms vary with plant species, genotypes, growth conditions, duration of stress imposed, BC type, and preparation methods. This review highlights the potential for improving plant resistance to TE(s) stress by BC application and provides a theoretical basis for application of BC in TE(s) contaminated soils worldwide.