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Introduction: Cisplatin, nab-paclitaxel, capecitabine, and gemcitabine (PAXG) regimen activity was assessed in a single institution phase II trial (PACT-19) on pancreatic ductal adenocarcinoma (PDAC). The PACT-31 study explored the external validity of PACT-19 results., Materials and Methods: Patients aged ≥18 and ≤75 years with KPS ≥70, and PDAC diagnosis receiving PAXG in the participating institutions were eligible and categorized as follows: A) PACT-19; B) PACT-31-HSR; C) PACT-31-non-HSR. With a sample of 175 patients, assuming a target 1-year overall survival of 60 % for metastatic and of 80 % for non-metastatic patients, the trial will be considered successful with the 1-year OS falling into the 95 % CI., Results: Data from 68 PACT-19 and 168 PACT-31 patients were retrieved. After 124 events, 1yOS was 52.5 % (95 %CI: 44.6-60.4 %) for metastatic and 80.5 % (95 %CI: 71.9-89.1 %) for non-metastatic patients. Survival overlapped between PACT-19 and PACT-31-HSR (median 17.6 and 17.4 months, p = 0.21) and was significantly shorter in PACT-31-non-HSR (median 11.3 months; p = 0.03). Differences of dose-intensity, use of maintenance therapy, and treatment after progression between PACT-31-HSR and non-HSR were evidenced., Discussion: PACT-19 results have external validity. The outcome difference between HSR and non-HSR centers endorses the need of creating a hub-and-spoke network aimed at sharing the expertise on rare-diseases., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Ectomycorrhizal (ECM) fungi distribute tree-derived carbon (C) via belowground hyphal networks in forest ecosystems. Here, we asked the following: (1) Is C transferred belowground to a neighboring tree retained in fungal structures or transported within the recipient tree? (2) Is the overlap of ectomycorrhizal fungi in mycorrhizal networks related to the amount of belowground C transfer? We used potted sapling pairs of European beech (Fagus sylvatica) and North-American Douglas-fir (Pseudotsuga menziesii) for 13 CO 2 pulse-labeling. We compared 13 C transfer from beech (donor) to either beech or Douglas-fir (recipient) and identified the ECM species. We measured the 13 C enrichment in soil, plant tissues, and ECM fractions of fungal-containing parts and plant transport tissues. In recipients, only fungal-containing tissue of ectomycorrhizas was significantly enriched in 13 C and not the plant tissue. Douglas-fir recipients shared on average one ECM species with donors and had a lower 13 C enrichment than beech recipients, which shared on average three species with donors. Our results support that recently assimilated C transferred belowground is shared among fungi colonizing tree roots but not among trees. In mixed forests with beech and Douglas-fir, the links for C movement might be hampered due to low mycorrhizal overlap with consequences for soil C cycling., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Neuroendocrine differentiation (NED) represents a possible androgen receptor pathway inhibitors (ARPI) resistance mechanism in metastatic castration resistance prostate cancer (mCRPC). As mCRPC with NED has been excluded from clinical trials evaluating ARPI efficacy, this study investigates the prognostic impact of NED in mCRPC patients treated with ARPIs. Methods: We retrospectively analyzed 327 mCRPC patient data treated with Enzalutamide or Abiraterone in the first and second or successive lines of treatment. NED was assessed using prostate biopsy samples through immunohistochemical staining. Results: NED was confirmed in 32/327 (9.8%) mCRPC patients. In the overall population, mCRPC with NED showed worse PFS (4.38 vs. 11.48 months HR 2.505 [1.71-3.68] p < 0.05), disease control rate (DCR), and PSA response. In the first line setting, mCRPC with NED demonstrated worse PFS (8.5 vs. 14.9 months HR 2.13 [1.18-3.88], p < 0.05). Similarly, in the second or successive lines, mCRPC with NED showed worse PFS (4.0 vs. 7.5 months HR 2.43 [1.45-4.05] p < 0.05), DCR, PSA response and OS (12.53 vs. 18.03 months HR 1.86 [1.12-3.10] p < 0.05). The adverse impact of NED on PFS was consistence across all subgroups; we also noted a trend of worse PFS in patients with high vs. low NED. Conclusions: In our study, mCRPC with NED treated with Enzalutamide or Abiraterone showed worse clinical outcomes. NED assessment should be considered to optimize treatment decisions in the mCRPC setting.

To increase the resilience of forests to drought and other hazards, foresters are increasingly planting mixed stands. This requires knowledge about the drought response of tree species in pure and mixed-culture neighborhoods. In addition, drought frequently interacts with continued atmospheric nitrogen (N) deposition. To disentangle these factors for European beech, Norway spruce and Douglas fir, we conducted a replicated 3-factorial sapling growth experiment with three moisture levels, (high, medium, and low), two N levels (high and ambient), and pure and mixed-culture neighborhoods. We measured biomass, stomatal conductance (GS), shoot water potential (at predawn: ΨPD, midday, and turgor loss point: ΨTLP), branch xylem embolism resistance (Ψ50) and minimum epidermal conductance (Gmin). The three species differed most with respect to Gmin (10-fold higher in beech than in the conifers), hydroscape area (larger in beech), and the time elapsed to reach stomatal closure (TΨGS90) and ΨTLP (TTLP; shorter in beech), while Ψ50 and ΨTLP were remarkably similar. Neighborhood (pure vs mixed-culture) influenced biomass production, water status and hydraulic traits, notably GS (higher in Douglas fir, but lower in spruce and beech, in mixtures than pure culture), hydraulic safety margin (smaller for beech in mixtures), and TΨGS90 and TTLP (shorter for spruce in mixture). High N generally increased GS, but no consistent N effects on leaf water status and hydraulic traits were detected, suggesting that neighbor identity had a larger effect on plant water relations than N availability. We conclude that both tree neighborhood and N availability modulate the drought response of beech, spruce, and Douglas fir. Species mixing can alleviate the drought stress of some species, but often by disadvantaging other species. Thus, our study suggests that stabilizing and building resilience of production forests against a drier and warmer climate may depend primarily on the right species choice; species mixing can support the agenda., (© Crown copyright 2024.)

Introduction: Randomised controlled trials (RCTs) are usually considered the highest level of evidence for clinical practice. Patients assigned to control arm in RCTs should always receive the best available treatments to protect participants while also allowing for proper interpretation and applicability of study results. Here we analysed RCTs published in oncology between 2017 and 2021 to describe the frequency of suboptimal control arms., Methods: We identified phase III studies testing active treatments in patients with solid tumours among 11 major oncology journals. Each control arm was analysed, and the standard of care was determined according to international guidelines and scientific evidence at accrual beginning and until accrual completion. We identified studies with suboptimal control arm from the beginning (type 1) and studies with an initially optimal control arm which became outdated during the accrual period (type 2)., Results: This analysis included 387 studies. Forty-three (11.1%) control arms were judged as suboptimal: 24 (6.2%) type 1 and 19 (4.9%) type 2. These rates were higher in industry-sponsored compared to academic trials: 9.3% versus 1.9% for type 1 (p = 0.003); 7.9% versus 0.6% for type 2 (p = 0.001). Rates of suboptimal control arms were higher in studies with positive results: 8.1% versus 4.0% for type 1 (p = 0.09); 7.6% versus 1.7% for type 2 (p = 0.007)., Conclusions: Many trials have suboptimal control arms, even in journals with high-impact factors, leading to suboptimal treatment of control patients and biased evaluation of trial results., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, RDL reports honoraria from Astellas Pharma and Janssen. LM reports honoraria from Gilead and Merck; research grant from AstraZeneca; travel expenses from Janssen. CP reports support for attending meetings and/or travel from Eli Lilly and Takeda; institutional research grant from IQVIA. MLR reports honoraria from Eli Lilly, AstraZeneca and Janssen. AF reports honoraria from Roche, Pfizer, Novartis, Dompè , Astra Zeneca, Seagen, Gilead, Exact Science, Eli Lilly; support for attending meetings and/or travel from Roche, Pfizer, Novartis, Dompè , Astra Zeneca, Seagen, Gilead, Exact Science, Eli Lilly; participation on advisory boards for Roche, Pfizer, Novartis, Astra Zeneca, Seagen, Gilead, Eli Lilly. FP reports honoraria from Bayer, Pierre Fabre, AstraZeneca, Incyte, Ipsen, Clovis, Astellas, Sanofi, Roche, Pfizer; institutional funding for work in clinical trials/contracted research from Roche, Bayer, AstraZeneca, Pfizer, Incyte, Tesaro/GlaxoSmithKline and Merck. MDM reports honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche, Takeda for consultancy or participation to advisory boards institutional research funding from Tesaro/GlaxoSmithKline, institutional funding for work in clinical trials/contracted research from Beigene, Exelixis, MSD, Pfizer and Roche. Other authors declare no relationships or activities that could appear to have influenced the submitted work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Radium 223 (Ra-223) was approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) patients with bone-only disease, following demonstration of significant improvement in overall survival (OS). To date, there are no validated prognostic factors useful in predicting outcome of mCRPC patients treated with Ra-223. Our retrospective study aims to evaluate the prognostic role of treatment discontinuation due to adverse events in mCRPC patients treated with Ra-223, and to identify which factors correlate with the toxicity onset., Methods: We performed a retrospective analysis of all consecutive mCRPC patients treated with Ra-223 from September 2013 to December 2019 at our institute. Patients were divided in 2 groups according to the reason of Ra-223 therapy discontinuation: toxicity versus other causes. Outcome measures were progression-free survival (PFS) and OS., Results: In the overall population (75 patients) median PFS and OS were 5.46 months and 11.15 months respectively. Patients who discontinued treatment due to toxicity had a lower median PFS (3.49 vs 5.89 months, HR: 1.88, 95% CI: 1.14-3.12, p = 0.014) and OS (8.59 vs 14.7 months HR: 3.33, 95% CI: 1.85-6.01, p < 0.001) than patients who discontinued therapy due to other causes. The risk of Ra-223 discontinuation due to toxicity correlates with the number of previous treatments ( p = 0.002), previous chemotherapy treatment ( p = 0.039), baseline LDH ( p = 0.012), Hb ( p = 0.021) and platelet-to-lymphocyte ratio ( p = 0.024)., Conclusions: Discontinuation due to toxicity is associated with worse outcomes in mCRPC patients treated with Ra-223. To reduce the risk of developing toxicities that may compromise treatment efficacy, Ra-223 should be used early in mCRPC patients.

In the last fifteen years a better understanding of the biological processes promoting tumour growth and progression led to an impressive revolution in metastatic renal cell carcinoma (mRCC) treatment landscape. Angiogenesis plays a critical role in the pathogenesis of RCC. These biological evidences led to targeted therapies interfering with vascular endothelial growth factor and mammalian target of rapamycin pathway. Another big step in the RCC therapeutic landscape was recently made because of the understanding of the interplay between angiogenesis and immune cells. Dual immune checkpoint inhibitors (ICIs) and ICIs plus tyrosine kinase inhibitors (TKI) combinations have been approved considering overall survival benefit compared to targeted therapies as first line treatment. We summarize the activity and the biological rationale of ICIs combinations as mRCC first line therapy. Additionally, we review the clinical and biological criteria useful to guide clinicians in the choice of treatment sequencing focusing on ICIs combinations resistance mechanisms., Competing Interests: Declaration of Competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The simultaneous or metachronous occurrence of pancreatic neuroendocrine tumor (panNET) and renal cell carcinoma (RCC) may represent a rare coincidence or a manifestation of von Hippel-Lindau disease (VHL). These two malignancies share both radiological and cytopathological features, making the differential diagnosis very challenging. In this review, we collected all cases of concurrent diagnosis of localized panNET and RCC, with or without VHL, as reported in the literature to date. We aimed to provide an insight into the differential diagnosis between panNET and RCC pancreatic metastasis with a focus on the optimal therapeutic algorithm depending on the diagnosis. We performed literature research in PubMed library databases for articles about coexisting panNET and RCC published from 2001 to 2018. We selected nine articles with a total of 13 patients, including one treated at our institution. Patients' median age was 49 years and eight out of 13 patients were women. VHL was diagnosed in nine cases. Most patients underwent radical nephrectomy for RCC (9/13) and a clear cell renal carcinoma variant was identified in six cases. The diagnosis of panNET was synchronous with RCC detection in nine cases and metachronous in four cases. The diameter of the pancreatic lesion was >2 cm in six cases. In two cases the panNET was misdiagnosed as metastatic RCC by radiological tests. Somatostatin receptor scanning was performed only in our patient (Octreoscan) showing intense uptake in the pancreatic mass. Endoscopic ultrasound fine needle aspiration of the pancreatic lesion was performed in four patients: in two cases the panNET was confused with metastatic RCC by cytological analysis. Most patients underwent pancreatic surgery (10/13) without histological confirmation. Clear cell panNET was recognized in six cases, while mixed neuroendocrine non-neuroendocrine neoplasm was diagnosed in one patient. Immunohistochemistry (IHC) staining showed positivity to typical neuroendocrine markers (chromogranin A and synaptophysin) in all reported tested cases (8/8). Three patients underwent systemic treatment: two patients received sunitinib and one patient interleukin-2 (IL-2). Other neoplasms were observed in seven patients, of whom six were affected by VHL syndrome. When neoplastic lesions are recognized in both the kidney and pancreas, panNET and RCC pancreatic metastasis are often misdiagnosed due to similar radiological and cytopathological features. An accurate differential diagnosis is crucial and IHC plays a central role in distinguishing the two entities. The therapeutic algorithm may change depending on the diagnosis: while pancreatic RCC metastases benefit from resection, in panNETs and VHL the indication for surgery must be carefully evaluated., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In recent years the introduction of immunotherapy has importantly changed the treatment landscape of advanced urothelial carcinoma. Several immune checkpoint inhibitors are now the standard of care as maintenance treatment after disease control with platinum-based first-line chemotherapy (avelumab), in subsequent lines (pembrolizumab) or as upfront therapy in platinum-ineligible patients (atezolizumab or pembrolizumab). Moreover, personalized therapy based on tumor molecular features has been developed. Namely, the increasing knowledge of the pathogenesis and molecular pathways underlying cancer development and progression is leading the introduction of target therapies such as the recently approved fibroblastic growth factor receptor (FGFR) inhibitor erdafitinib or the anti-nectin 4 antibody drug-conjugated enfortumab vedotin. Consequently, clinicians face new challenges, such as the choice of the best therapeutic sequence for each patient. The aim of this review is focusing on the emerging treatment options in metastatic urothelial carcinoma and discussing clinical features for choosing therapeutic sequencing., (Copyright © 2022. Published by Elsevier B.V.)

Background: The prognostic relevance of early immune-related adverse events (irAEs) in patients affected by non-small cell lung cancer (NSCLC) upon immunotherapy is not fully understood., Methods: The Leading to Treatment Discontinuation cohort included 24 patients experiencing severe irAEs after one of two administrations of single anti-PD-1/PD-L1 in any line setting for metastatic NSCLC between November 2015 and June 2019. The control cohort was composed of 526 patients treated with single anti-PD-1/PD-L1 in any line setting with no severe irAE reported. The primary end points were median progression-free survival, overall survival, objective response rate, risk of progression of disease and risk of death. The correlation of clinic pathological features with early severe irAEs represented the secondary end point., Results: Median PFS was 9.3 and 8.4 months, median OS was 12.0 months and 14.2 months at a median follow-up of 18.1 and 22.6 months in the LTD cohort and in the control cohort, respectively. The ORR was 40% (95% CI 17.2-78.8) in the LTD cohort and 32.7% (95% CI 27.8-38.2) in the control cohort. The risk of disease progression was higher in the LTD cohort (HR 2.52 [95% 1.10-5.78], P = .0288)., Conclusions: We found no survival benefit in LTD cohort compared to the control cohort. However, early and severe irAEs might underly an immune anti-tumor activation. We identified a significant association with first-line immune checkpoints inhibitors treatment and good PS. Further studies on risk prediction and management of serious and early irAEs in NSCLC patients are needed., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Advanced stage malignant mesothelioma (asMM) patients have poor prognosis. Several trials investigated the role of programmed cell death protein-1 (PD-1) and its ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) in pre-treated asMM., Methods: A systematic review of the literature of clinical trials testing single-agent anti PD-1/PD-L1 ICIs in pre-treated asMM was performed. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) data were extracted. The predictive role of PD-L1 was assessed., Results: We selected 13 studies including 888 patients. ORR and DCR were 18.1% (95% confidence interval [CI] 13.9-22.8%) and 55.4% (95% CI: 48.1-62.5%), respectively. Median PFS and OS ranged from 2.1 to 5.9 and from 6.7 to 20.9 months, respectively. ORR according to PD-L1 was 27.0% (95% CI: 18.7-36.2%)., Conclusions: Anti-PD-(L)1 ICIs might be considered a treatment option for chemotherapy-resistant asMM, even if reliable predictive factors are still lacking., (Copyright © 2022 Elsevier B.V. All rights reserved.)