First-line avelumab for patients with PD-L1-positive metastatic or locally advanced urothelial cancer who are unfit for cisplatin.

BACKGROUND: Cisplatin-based chemotherapy is the most recommended treatment for metastatic urothelial cancer (mUC). However, about 50% of patients are considered to be cisplatin ineligible. Anti-programmed cell death protein 1/programmed death-ligand 1 (PD-L1) therapies have, nevertheless, increased the options available to clinicians and are especially valuable for treating these patients. This study therefore tested the activity and safety of avelumab as first-line therapy for mUC. PATIENTS AND METHODS: Patients with mUC who were ineligible for cisplatin-based chemotherapy were screened centrally for PD-L1 expression and only those with a tumour proportion score ≥ 5% were enrolled in the trial. The primary endpoint was 1-year overall survival (OS), and the secondary endpoints were median OS, median progression-free survival, overall response rate, duration of the response, safety and tolerability. All the survival rates were estimated with the Kaplan-Meier product-limit methodology and compared across groups using the log-rank test. RESULTS: A total of 198 patients were screened, with 71 (35.9%) whose PD-L1 expression was ≥5% enrolled in the study. The median age was 75 years, bladder cancer was the primary tumour in 73.2% of cases and 25.3% had liver metastases. The main reasons for the cisplatin ineligibility were a low rate of creatinine clearance (<60 ml/min), present in 70.4% of patients, and an Eastern Cooperative Oncology Group performance status of 2, which affected 31%. The median OS was 10.0 months (95% confidence interval 5.5-14.5 months) and 43% of patients were alive at 1 year. A complete response was achieved in 8.5% of cases, and 15.5% had a partial response. Adverse any-grade and high-grade events occurred in 49.3% and 8.5% of patients, respectively. A grade 3 infusion reaction was the only high-grade treatment-related adverse event. No treatment-related deaths were reported. CONCLUSIONS: This ARIES trial confirmed the activity and safety of avelumab for treating mUC, adding a new therapy option to the armamentarium of checkpoint inhibitors already approved for platinum-ineligible, locally advanced/mUC.

Immune-inflammatory biomarkers as prognostic factors for immunotherapy in pretreated advanced urinary tract cancer patients: an analysis of the Italian SAUL cohort.

BACKGROUND: Reliable and affordable prognostic and predictive biomarkers for urothelial carcinoma treated with immunotherapy may allow patients' outcome stratification and drive therapeutic options. The SAUL trial investigated the safety and efficacy of atezolizumab in a real-world setting on 1004 patients with locally advanced or metastatic urothelial carcinoma who progressed to one to three prior systemic therapies. PATIENTS AND METHODS: Using the SAUL Italian cohort of 267 patients, we investigated the prognostic role of neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) and the best performing one of these in combination with programmed death-ligand 1 (PD-L1) with or without lactate dehydrogenase (LDH). Previously reported cut-offs (NLR >3 and NLR >5; SII >1375) in addition to study-defined ones derived from receiver operating characteristic (ROC) analysis were used. RESULTS: The cut-off values for NLR and SII by the ROC analysis were 3.65 (sensitivity 60.4; specificity 63.0) and 884 (sensitivity 64.4; specificity 67.5), respectively. The median overall survival (OS) was 14.7 months for NLR <3.65 [95% confidence interval (CI) 9.9-not reached (NR)] versus 6.0 months for NLR ≥3.65 (95% CI 3.9-9.4); 14.7 months for SII <884 (95% CI 10.6-NR) versus 6.0 months for SII ≥884 (95% CI 3.7-8.6). The combination of SII, PD-L1, and LDH stratified OS better than SII plus PD-L1 through better identification of patients with intermediate prognosis (77% versus 48%, respectively). Multivariate analyses confirmed significant correlations with OS and progression-free survival for both the SII + PD-L1 + LDH and SII + PD-L1 combinations. CONCLUSION: The combination of immune-inflammatory biomarkers based on SII, PD-L1, with or without LDH is a potentially useful and easy-to-assess prognostic tool deserving validation to identify patients who may benefit from immunotherapy alone or alternative therapies.

Pathogenicity of Phytopythium chamaehyphon: A New Player in Kiwifruit Vine Decline Syndrome of Actinidia chinensis var. deliciosa 'Hayward' in Italy.

Kiwifruit vine decline syndrome (KVDS) is a serious soil-borne disease that degrades the fine roots of both Actinidia chinensis var. deliciosa and var. chinensis. The disease seems to be the result of an interaction between several soil-borne pathogens, mostly oomycetes, and waterlogging. This work investigates the pathogenicity of the oomycete Phytopythium chamaehyphon recently isolated from roots of diseased plants. Pathogenicity was tested in 6-month-old and 1-year-old plants that, after inoculation, were flooded up to three times to induce symptom appearance. Leaf wilting and root rot typical of KVDS was observed in all the plants inoculated with P. chamaehyphon strain KD-15 (PCHA) and in all the positive controls potted in a mix of peat and soils collected in KVDS-affected orchards, while negative controls remained symptomless. Disease development on 6-month-old plants was characterized by unusual degradation of the not-lignified collar, occurring even in absence of flooding. Conversely, on 1-year-old plants, symptoms faithfully reproduced KVDS dynamics observed in orchard. This work confirmed the pathogenicity of P. chamaehyphon and raised new questions about the actual role of waterlogging in KVDS etiology.

Acquired Tolerance in Apricot Plants that Stably Recovered from European Stone Fruit Yellows.

European stone fruit yellows (ESFY) is one of the most destructive phytoplasma diseases of plum, apricot, and peach in Europe. Conventional preventive defense strategies have been ineffective. Because apricot cultivars with innate-constitutive resistance against ESFY are not available, the aim of this more than 20-year-long study was to seek acquired resistance or tolerance. In the first experiment, we surveyed an orchard with seven apricot cultivars for 12 years in an area of northern Italy with a high rate of natural occurrence of ESFY. Of the diseased plants, a few (8.7%) became completely symptomless but retained the phytoplasma, as confirmed by polymerase chain reaction (PCR). In the second experiment, we grafted buds from two stably recovered plants and from two nonrecovered plants onto 'Rubira' peach. Over the next 9 years in an orchard with a high rate of natural infection, 93.0% of the "nonrecovered clones" became diseased but only 1.5% of the plants grafted with the two "recovered clones" developed ESFY symptoms. According to PCR analyses, all of the exposed test plants were ESFY-infected, whether they were derived from recovered or nonrecovered mothers. This could indicate that epigenetic changes occurred in recovered plants due to a graft-transmissible memory. Based on the results attained from the two described experiments, we propose that an acquired tolerance that occurred in stably recovered apricot trees was graft transmitted from two tolerant apricot clones. In contrast, we did not demonstrate a cross-protection process based on protectant avirulent phytoplasma strains that suppress severe strains.

Phloem cytochemical modification and gene expression following the recovery of apple plants from apple proliferation disease.

Recovery of apple trees from apple proliferation was studied by combining ultrastructural, cytochemical, and gene expression analyses to possibly reveal changes linked to recovery-associated resistance. When compared with either healthy or visibly diseased plants, recovered apple trees showed abnormal callose and phloem-protein accumulation in their leaf phloem. Although cytochemical localization detected Ca(2+) ions in the phloem of all the three plant groups, Ca(2+) concentration was remarkably higher in the phloem cytosol of recovered trees. The expression patterns of five genes encoding callose synthase and of four genes encoding phloem proteins were analyzed by quantitative real-time reverse transcription-polymerase chain reaction. In comparison to both healthy and diseased plants, four of the above nine genes were remarkably up-regulated in recovered trees. As in infected apple trees, phytoplasma disappear from the crown during winter, but persist in the roots, and it is suggested that callose synthesis/deposition and phloem-protein plugging of the sieve tubes would form physical barriers preventing the recolonization of the crown during the following spring. Since callose deposition and phloem-protein aggregation are both Ca(2+)-dependent processes, the present results suggest that an inward flux of Ca(2+) across the phloem plasma membrane could act as a signal for activating defense reactions leading to recovery in phytoplasma-infected apple trees.

Evidence for a putative flavonoid translocator similar to mammalian bilitranslocase in grape berries (Vitis vinifera L.) during ripening.

During maturation, Vitis vinifera berries accumulate a large amount of several anthocyanins in the epidermal tissue, whereas their precursors and intermediates are ubiquitously synthesized within the fruit. Up to date, several mechanisms of flavonoid transport at subcellular level have been hypothesized, but it is not possible to identify a general model applicable in every plant tissue and organ. Recently, a putative anthocyanin carrier, homologue to mammalian bilitranslocase (BTL) (TC 2.A.65.1.1), was found in Dianthus caryophyllus petal microsomes. In the present paper, an immunohistochemical and immunochemical analysis, using an antibody raised against a BTL epitope, evidences the expression and function of such a transporter in V. vinifera berries (cv. Merlot). Specific localisations of the putative carrier within berry tissues together with expression changes during different developmental stages are shown. Water stress induces an increase in protein expression in both skin and pulp samples. A bromosulfalein (BSP) uptake activity, inhibitable by the BTL antibody, is detected in berry mesocarp microsomes, with K (m) = 2.39 microM BSP and V (max) = 0.29 micromol BSP min(-1) mg(-1) protein. This BSP uptake is also competitively inhibited by quercetin (K (i) = 4 microM). A putative role for this carrier is discussed in relation to the membrane transport of secondary metabolites.

Recovery in apple trees infected with the apple proliferation phytoplasma: an ultrastructural and biochemical study.

ABSTRACT Localization of hydrogen peroxide (H(2)O(2)) and the roles of peroxidases, malondialdehyde, and reduced glutathione in three apple cultivars were compared in healthy trees, trees infected with apple proliferation phytoplasma (APP), and trees that had recovered from the infection. In recovered apple trees, symptoms of the disease and the pathogen had disappeared from the canopy, but phytoplasmas remained in the roots. H(2)O(2) was detected cytochemically by its reaction with cerium chloride to produce electron-dense deposits of cerium perhydroxides.H(2)O(2) occurred in the plasmalemma of the phloem of leaves of recovered apple trees, but not in healthy or APP-infected leaves. In all cultivars, the peroxidase activity detected in tissue from APP-diseased trees was greater than or equal to that of tissue from recovered trees, which equaled or exceeded that of tissue from healthy trees, at two sampling times (May and September). In contrast, the glutathione content of leaves decreased in the reverse order. More malondialdehyde was observed in leaves from recovered trees than in leaves from healthy or APP-infected trees in three of six cultivar-date combinations; in the other three combinations, the malondialdehyde contents of leaves from healthy, infected, and recovered trees were not significantly different from one another. The results suggest that some components of the oxidant-scavenging system in recovered leaves are not very active, leading to an overproduction of H(2)O(2) and, possibly, to a membrane lipid peroxidation.The production of H(2)O(2) appears to be involved in counteracting pathogen virulence.